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Prodromal Symptoms and the Determination of Coronary Artery Disease in Women

Permanent Link: http://ufdc.ufl.edu/UFE0022646/00001

Material Information

Title: Prodromal Symptoms and the Determination of Coronary Artery Disease in Women An Exploratory Study
Physical Description: 1 online resource (95 p.)
Language: english
Creator: Warrington, William
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: cad, cardiac, mapmiss, predictive, prodromal, symptoms, women
Nursing -- Dissertations, Academic -- UF
Genre: Nursing Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Globally cardiovascular heart disease (CHD) is the number one killer of women and men. The major component of CHD, coronary artery disease (CAD) is a significant health threat. The purpose of this exploratory study was to help healthcare professionals have a better understanding of which prodromal symptoms can be most helpful in identifying women who are at-risk of having CAD and allow healthcare providers to determine which women should undergo cardiovascular diagnostic tests that are highly predictive such as cardiac catheterization. Women ages 40 to 89 years that had not previously had a diagnostic cardiac catheterization and were scheduled for an elective outpatient procedure were asked to participate. A convenience sample of 166 women completed a structured interview using the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey to explore prodromal symptom presence. Women underwent a catheterization procedure to quantify CAD. To address the major hypothesis of the study, analysis of frequency (chi-square test) was used to determine the difference in proportion of variables measured on nominal and ordinal scales between the two groups of subjects diagnosed with CAD or without it. The t-test was utilized to find the difference in mean of the variables measured on interval or ratio scales between the two groups. For simultaneous testing of hypotheses, the Bonferroni method for controlling the overall error rate was used. Logistic regression analysis was used to explore the potential differences in possible predictor variables between those who had CAD from those who did not. Results of the logistic regression analysis indicated that subjects with one or more of the following; tingling of the hand or arms, were diabetic, had a history of thyroid disease or who had experienced menopause onset had higher odds of facing severe CAD.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by William Warrington.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: Jessup, James V.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-08-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022646:00001

Permanent Link: http://ufdc.ufl.edu/UFE0022646/00001

Material Information

Title: Prodromal Symptoms and the Determination of Coronary Artery Disease in Women An Exploratory Study
Physical Description: 1 online resource (95 p.)
Language: english
Creator: Warrington, William
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: cad, cardiac, mapmiss, predictive, prodromal, symptoms, women
Nursing -- Dissertations, Academic -- UF
Genre: Nursing Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Globally cardiovascular heart disease (CHD) is the number one killer of women and men. The major component of CHD, coronary artery disease (CAD) is a significant health threat. The purpose of this exploratory study was to help healthcare professionals have a better understanding of which prodromal symptoms can be most helpful in identifying women who are at-risk of having CAD and allow healthcare providers to determine which women should undergo cardiovascular diagnostic tests that are highly predictive such as cardiac catheterization. Women ages 40 to 89 years that had not previously had a diagnostic cardiac catheterization and were scheduled for an elective outpatient procedure were asked to participate. A convenience sample of 166 women completed a structured interview using the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey to explore prodromal symptom presence. Women underwent a catheterization procedure to quantify CAD. To address the major hypothesis of the study, analysis of frequency (chi-square test) was used to determine the difference in proportion of variables measured on nominal and ordinal scales between the two groups of subjects diagnosed with CAD or without it. The t-test was utilized to find the difference in mean of the variables measured on interval or ratio scales between the two groups. For simultaneous testing of hypotheses, the Bonferroni method for controlling the overall error rate was used. Logistic regression analysis was used to explore the potential differences in possible predictor variables between those who had CAD from those who did not. Results of the logistic regression analysis indicated that subjects with one or more of the following; tingling of the hand or arms, were diabetic, had a history of thyroid disease or who had experienced menopause onset had higher odds of facing severe CAD.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by William Warrington.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: Jessup, James V.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-08-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022646:00001


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71c1b8223797bf2dc95f4a30362949cb1936f77a







PRODROMAL SYMPTOMS AND THE DETERMINATION OF
CORONARY ARTERY DISEASE INT WOMEN: AN EXPLORATORY STUDY





















By

WILLIAM GARRETT WARRINGTON, JR.


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

2008

































O 2008 William Garrett Warrington, Jr.































To my wife Maggie:
"Until now you have not asked for anything in my name. Ask and you will receive, and your j oy
will be complete." John 16:24









ACKNOWLEDGE1VENTS

I am privileged to extend my sincerest appreciation to Dr. James V. Jessup, Jr., my friend

and mentor for his continued support and guidance during my education. I am deeply honored

and grateful to have someone to encourage me to develop, mature and be independent in my own

way. Jim has been there to consult in times of heartrending loss, recovery and celebration.

I thank my supervisory committee, (Dr. Peter Sayeski, Dr. Joyce Stechmiller, and Dr.

Donna Neff). They have been most patient with me through this process. Each has encouraged

me to challenge myself and think more critically.

I would also like to thank my father, William G. Warrington, Sr. for being my example,

and my wife, Margaret Love Warrington for her unconditional love, help and encouragement.












TABLE OF CONTENTS

IM g e


ACKNOWLEDGEMENT S ................. ...............4.......... ......


LI ST OF T ABLE S ................. ...............7.................


FIGURE ................. ...............8.......... ......


AB S TRAC T ......_ ................. ............_........9


CHAPTER


1 INTRODUCTION ................. ...............11.......... ......


2 LITERATURE REVIEW ................. ...............18................


Introduction ................... ........ .................1
Women's Symptoms Quantitative Studies............... ...............20
Women's Symptoms Qualitative Studies............... ...............28
Women's Symptoms Mixed Method Studies............... ...............36
Sum m ary .............. ...............39....
Theoretical Model .............. ...............40....
Model Assumption .............. ...............42....
Conceptual Definitions ................. ...............42.................
Operational Definitions .............. ...............43....

3 METHOD S ................. ...............46.......... .....


Design ................. ...............46.................
Funding ................. ...............46.................
Consent ................ ..... ........ ...............46.......

Subj ects and Recruitment ................. ...............47......... .....
Sample Size Determination ...._.._ ................ ...............47......
V ariables................ ... .....................4
Procedure: Quantification of CAD ................. ...............50......... .....
Statistical Analysis Plan .............. ...............52....


4 FINDINGS ................. ...............58......... ......


Data Collection and Descriptive Statistics .............. ...............58....
Subj ect Demographics .........._.... ........ .._._.......... ._._ .... ..........5
McSweeney Acute and Prodromal Myocardial Infarction Survey .............. ....................59
Medical Variables............... ...............6
Comorbidity Variables .............. ...............61....
Coronary Angiography Variables .............. ...............62....
Data Analysis .............. ...............62....













5 DI SCUS SSION ............. ...... ._ ............... 1...


Summary of the Study ............_...... ............... 1...
Conclusions ............... ...............8 1...

Strengths and Limitations ............. ...... .__ ...............85..

Implications and Recommendations .............. ...............86....
Conclusion............... ...............8


REFERENCES .............. ...............89....


BIOGRAPHICAL SKETCH ............. ...... ...............95...











LIST OF TABLES


Table page

2-1 Thirty-three prodromal symptoms .............. ...............44....

3-1 Inclusion/exclusion criteria data collection .............. ...............55....

3-2 Sample sizes for estimated 50% of sample with CAD .............. ...............55....

3-3 Complete list of dependent variables for hypothesis 1 ................... ...............5

4-1 Recruitment locations of the sample. ......____ ..... .._. .....___.. ..._._..........68

4-2 Demographic characteristics of the sample ........._._.__........ ....___.. ..........6

4-3 Prodromal symptom frequency distribution and relative percentages ........._...... .............69

4-4 Medical variables distribution............... ..............7

4-5 Comorbidity frequency distribution and relative percentages ................. ............... .....70

4-6 Coronary angiography variables distribution ................. ...............70...............

4-7 Example of the contingency table for CAD 20% by history of high cholesterol ...........71

4-8 Relationship between CAD presence and women's prodromal cardiac symptoms ..........72

4-9 Differences in variable means between CAD <20% and > 20% ................. ................. .74

4-10 Relationship between severe CAD and women's prodromal cardiac symptoms ........._....76

4-11 Differences in variable means between CAD < 50% and > 50% ................. ........_.......78

4-12 Optimal logistic regression model for the presence of CAD 20%............... ..................79

4-13 Odds ratio estimates of the presence of CAD 20%. ................. ....__. ................. .79

4-14 Optimal logistic regression model for severe CAD ....._.__._ ............ ........_._......80

4-15 Odds ratio estimates of severe CAD .........__. ........... ............. .80.










LIST OF FIGURES


FiMr IM Le

2-1 Revised theory of unpleasant symptoms ................. ...............45...............

3-1 Example of a MAPMISS type question with calculation formula and score ....................57









Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

PRODROMAL SYMPTOMS AND THE DETERMINATION OF
CORONARY ARTERY DISEASE INT WOMEN: AN EXPLORATORY STUDY

By

William Garrett Warrington, Jr.

August 2008

Chair: James Vernon Jessup, Jr.
Major: Nursing Science

Globally cardiovascular heart disease (CHD) is the number one killer of women and men.

The maj or component of CHD, coronary artery disease (CAD) is a significant health threat. The

purpose of this exploratory study was to help healthcare professionals have a better

understanding of which prodromal symptoms can be most helpful in identifying women who are

at-risk of having CAD and allow healthcare providers to determine which women should

undergo cardiovascular diagnostic tests that are highly predictive such as cardiac catheterization.

Women ages 40 to 89 years that had not previously had a diagnostic cardiac

catheterization and were scheduled for an elective outpatient procedure were asked to participate.

A convenience sample of 166 women completed a structured interview using the McSweeney

Acute and Prodromal Myocardial Infarction Symptom Survey to explore prodromal symptom

presence. Women underwent a catheterization procedure to quantify CAD. To address the maj or

hypothesis of the study, analysis of frequency (chi-square test) was used to determine the

difference in proportion of variables measured on nominal and ordinal scales between the two

groups of subj ects diagnosed with CAD or without it. The t-test was utilized to Eind the

difference in mean of the variables measured on interval or ratio scales between the two groups.









For simultaneous testing of hypotheses, the Bonferroni method for controlling the overall error

rate was used. Logistic regression analysis was used to explore the potential differences in

possible predictor variables between those who had CAD from those who did not.

Results of the logistic regression analysis indicated that subj ects with one or more of the

following; tingling of the hand or arms, were diabetic, had a history of thyroid disease or who

had experienced menopause onset had higher odds of facing severe CAD.









CHAPTER 1
INTTRODUCTION

Cardiovascular heart disease (CHD) in women is a global health and economic problem.

CHD is America's number one killer of women and men (American Heart Association, 2008).

Currently, the American Heart Association (AHA) (2008) estimates that 7.3 million women

living today have a history of myocardial infarction (MI), angina pectoris or both. The AHA

(2008) estimates that 1.2 million Americans will have a new or recurrent MI this year.

More women than men die of CHD every year in the United States (AHA, 2008). Despite

a well-documented recent decline of 17% in cardiovascular mortality in women for the year

2007, CHD remains the leading single cause of death (Mosca et al., 2007). The morbidity

connected with CHD is also substantial. Although an estimated 1.2 million people will

experience a MI, many more will be hospitalized for evaluation and treatment of angina and

chest pain syndromes (AHA, 2008). The AHA (2008) estimates that more than 403 billion

dollars per year are spent on the healthcare of patients suffering from CHD. However, beyond

the need for hospitalization, countless men and women troubled with chest pain syndromes are

unable to perform normal activities of daily living, thereby experiencing a reduced quality of life

(Bourassa et al., 2000). Published data from the Bypass Angioplasty Revascularization

Investigation (BARI) states that approximately 30% of patients never return to work following

coronary artery bypass or percutaneous coronary intervention (Bourassa et al., 2000). This report

validates the pervasive clinical impression that CHD continues to be linked with substantial

patient morbidity regardless of the decline in cardiovascular mortality. The enormity of the

problem can be simplified : CHD affects millions of Americans, with annual costs that are

measured in hundreds of billions of dollars (AHA, 2005b).









Several reports indicate that women who suffer with CHD are not treated as aggressively,

have worse outcomes and have significantly higher mortality rates than men (Gibbons et al.,

1999; Kosuge et al., 2006; McSweeney, Cody, & Crane, 2001; Omran & Al-Hassan, 2006; Shaw

et al., 2008). A survey by the AHA (2005b) found that a mere 13% of women believe the maj or

component of CHD, coronary artery disease (CAD) is a significant health threat. Estimates are

that less than 30% of women have discussed CAD with their primary healthcare provider (Jones,

Edwards, Vallis, Ruggiero, & al, 2003). As the age of the general population rises and as

comorbidities such as diabetes, hyperlipidemia and obesity escalate in the general population,

women are at risk more than ever before (National Institute of Health, 2004). In response to the

mounting dangers of CAD in women, organizations such as the AHA have partnered with public

health officials to launch nationwide campaigns to raise awareness related to the danger of CAD

for women (National Institute of Nursing Research, 2004).

The scientific community has been busy attempting to demystify the unique ways in

which CAD manifests itself within a woman's body. From an anatomical viewpoint, a woman's

and a man's heart have no differences. However, the warning symptoms of CAD in men and

women are very different (DeVon, Ryan, Ochs, & Shapiro, 2008; McSweeney et al., 2001;

Norris, Hegadoren, Patterson, & Pilote, 2008). Men typically present with the classic symptoms

of MI such as shortness of breath, chest pain and pressure radiating to the jaw and down the left

arm (Gibbons et al., 1999). McSweeney and colleagues report that women rarely feel chest ;

sensation at all, and that their symptoms are often more covert or subtle such as fatigue,

indigestion, back pain, shortness of breath or just an unwell feeling (McSweeney et al., 2001;

McSweeney et al., 2003; McSweeney & Crane, 2000; Zuzelo, 2002). These less impressive,

unclear, subtle symptoms often do not lead healthcare professionals to further investigate CAD









in women (Miller, 2002). The absence of considerable chest pain or pressure in women may be

the significant factor that women have more unrecognized MI than men (Miller, 2002).

Primary healthcare providers in the know are only now beginning to educate their peers

to the differences in presentation of CAD between men and women (McSweeney et al., 2001;

McSweeney et al., 2003; McSweeney & Crane, 2000; Miller, 2000). In 2003, McSweeney and

colleagues reported that women who had been diagnosed with a MI, experienced symptoms such

as fatigue or sleep disturbances as much as one month prior to the event, demonstrating the

likelihood that by quickly acting on these early warning symptoms healthcare providers may

thwart a looming MI. This seminal study assessed prodromal (early warning) symptoms that

might be harbingers of MI.

The researchers employed the McSweeney Acute and Prodromal Myocardial Infarction

Symptom Survey (MAPMISS), a survey instrument developed to assess the presence of 37 acute

and 33 prodromal symptoms identified by women in previous studies (Mc Sweeney, O'Sullivan,

Cody, & Crane, 2004). Mc Sweeney defines prodromal symptoms as sensations that are new or

vary in frequency, intensity or duration preceding the MI. Approximately 95% of women

reported having new or variable symptoms up to one month prior to MI. This finding led

Mc Sweeney and colleagues (2003) to surmise that these prodromal cardiac symptoms were

associated with the ensuing MI. The 5 most reported prodromal symptoms were

* Tiredness/ unusual fatigue : 70%
* Sleep disturbance/insomnia : 48%
* Dyspnea/ shortness of breath : 42%
* Gastric reflux/ indigestion : 39%
* Apprehension/anxiety: 35%

In the study, a mere 30% of women complained of chest discomfort of any type prior to MI.

Women expressed the discomfort in ambiguous terms such as an aching, tightness and pressure,









but excluded the adj ective pain. The report has made the case that women must be well-informed

that the manifestation of any new onset symptoms no matter how vague, may be related to CAD

and should seek out medical care to establish the source of the symptoms, particularly in the

presence of known CAD risks such as smoking, hypertension, hyperlipidemia, diabetes, obesity

or a familial history of CHD (Mc Sweeney et al., 2003).

Mc Sweeney and colleagues (McSweeney & Crane, 2000) earlier found that women could

identify an assortment of symptoms that they had experienced prior to their MI but had

disregarded the symptoms or received an incorrect diagnosis when they went for medical

treatment. Compounding and confusing the problem of symptom identification are two factors.

First, women often present with multiple symptoms and are extremely vague in the description

of symptoms to healthcare providers (Miller, 2000). Second, countless women ignore their own

health condition citing family responsibilities as the reason (Zuzelo, 2002).

The internal expression of women's CAD is deceptive to healthcare providers. In CAD,

men and women build up coronary plaque; however, CAD in women often manifests itself in a

more diffuse pattern (Kruk et al., 2007; Sheifer, Arora, Gersh, & Weissman, 2001). Instead of

forming discrete lesions, women' s plaque is more uniform along the entire length of the vessel

lining(Sheifer et al., 2001). These more diffuse disease patterns angiographically present as small

coronary vessels and not as diseased vessels. Women who suffer with angina or a MI are more

apt than men suffering the same circumstances to have only moderate or more evenly spread

blockages in their four maj or coronary arteries (Eagle et al., 2004). Women often do not present

with one severe discrete stenosis in the coronary artery. Meaning that in women, symptoms are

probably caused by blockages in smaller, less flexible and accessible coronary arteries (Kruk et










al., 2007). These differences in plaque formation may well explain some of the dissimilarity in

the approach of treatment between men and women with CAD.

Noninvasive cardiac diagnostic tests such as electrocardiograms (EKG) and exercise or

nuclear stress tests that identify ischemia are not as predictive in women (50%) as in men (90%)

(D'Antono, Dupuis, Fortin, Arsenault, & Burelle, 2006; DeCara, 2003). In Exercise Tolerance

Testing, ST-segment response does not predict future risk for CAD events in women (Fowler-

Brown et al., 2004; Mora et al., 2003). Low exercise capacity, along with low heart rate recovery

after exercise, is the best independent predictor of death from CAD (Fowler-Brown et al., 2004).

Instead of diagnosing CAD, indeterminate or false negative diagnostic tests lead primary

healthcare providers to incomplete or incorrect diagnosis. This fact, combined with a woman's

inclination to assess improperly their risk and interpret their symptoms, will often result in health

tragedies that are preventable (Lockyer, 2005; Ruston & Clayton, 2007).

Another obstacle that women face in the cardiac healthcare arena, is that women are often

prescribed or receive less appropriate CAD drugs such as cholesterol-lowering medications,

devices like pacemakers/defibrillators or angioplasty/intracoronary stents after a diagnosis of

heart disease is established (Enriquez, Pratap, Zbilut, Calvin, & Volgman, 2008; Omran & Al-

Hassan, 2006; Shaw et al., 2008). When compared, men and women with equivalent rates of MI,

women were less apt to receive aggressive drug therapy (Carruthers et al., 2004; Omran & Al-

Hassan, 2006; Shaw et al., 2008). In view of the fact that women' s dominant coronary vessels

are more prone to contain only moderate CAD angiographically, women are frequently sent

home from the hospital with an incorrect diagnosis and with a less aggressive therapeutic

medication regimen subsequent to experiencing CAD symptoms (Carruthers et al., 2004; Eagle

et al., 2004). This aberrancy may elucidate the mysterious inequality among the rate of










angioplasty and bypass surgery performed after a severe stenosis is diagnosed during angiogram

between genders. Eagle and colleagues (2004) evaluated data in records from over 10,000

patients and found that in women and men whom had comparable CAD; women were prescribed

and administered aspirin, and beta-blockers less frequently, common medication therapies which

often avert a future MI.

CAD characteristically affects women postmenopausal beginning in their late 50s, 10

years later than it typically affects men (AHA, 2005a; Kosuge et al., 2006).This possibly

accounts for why women have worse outcomes and have significantly elevated mortality rates

post MI (AHA, 2005b, 2008).The key to improving rapid identification of CAD in women is

through careful cardiac evaluation of women with known cardiac risk factors and by

acknowledging less anticipated symptoms (Arslanian-Engoren et al., 2006; King & McGuire,

2007).

The consequence of healthcare providers not being in tune with the varied symptom

presentation that women may have can not be overstated. Roughly 50% of women will die of

some form of heart disease which is two times more than the number of women who will

succumb to cancer of all types, including breast cancer in the United States (AHA, 2005a, 2008).

While the specific value of prodromal symptoms in predicting an impending MI is unclear, the

emergence of prodromal symptoms, in combination with women's typical CAD risk factors,

might aid healthcare providers in determining if women should be referred for invasive

diagnostic tests with high predictive value such as cardiac catheterization.

In summary, research related to the prodromal symptoms that women frequently

experience with MI is progressing; however, an obvious conclusion is that women's symptoms

vary from what they anticipate. Traditional diagnostic tests such as EKG and exercise stress tests










used to predict CAD in men are not as predictive in women (D'Antono et al., 2006; DeCara,

2003). Furthermore, a bias against women in the treatment of CAD has been suggested for quite

some time, and in fact, research does demonstrate a bias against women receiving aggressive

therapies related to CAD (Carruthers et al., 2004; Eagle et al., 2004; Shaw et al., 2008). To date,

the prodromal cardiac symptoms of women prior to cardiac catheterization and MI have not been

fully investigated. Given the magnitude of this problem, the need for further research is evident.

Mc Sweeney and colleagues (2004) have provided the medical community with a vast

array of clues to solving the mystery of CAD in women, however, the list of 33 prodromal

symptoms are so overwhelming that it becomes difficult for healthcare providers to focus on

which symptoms or groups/clusters of symptoms could possibly predict CAD in women with a

high degree of accuracy. The need to define the relationship that prodromal symptoms

experienced by women have to one another as well as the relationship to CAD must be explored.

A unique opportunity has become available to explore theses relationships within the cardiac

catheterization setting. Thus, the proposed exploratory research question for this study is: Do

women's prodromal cardiac symptoms discriminate for coronary artery disease as evidenced by

cardiac catheterization?

* Aim 1: Examine the potential differences in women' s prodromal cardiac symptoms
between those that have CAD and those that do not by assessing symptom presence prior
to cardiac catheterization and quantifying CAD in the cardiac catheterization laboratory
setting.

o Hypothesis 1: There are differences in women's prodromal cardiac symptoms
between those that have CAD and those that do not.

* Aim 2: Determine a prodromal cardiac symptom or a cluster of prodromal cardiac
symptoms that can be most helpful to healthcare professionals in identifying women who
are at-risk of having CAD.

o Hypothesis 2: A prodromal cardiac symptom or a cluster of prodromal cardiac
symptoms will discriminate between those women who have CAD and those that
do not.









CHAPTER 2
LITERATURE REVIEW

Introduction

Over the past two decades an increasing amount of research involving the experiences of

women concerning CHD has been done. Research studies have focused on the gender differences

of symptom identification, symptom perception, clinical presentation, risk factors and linguistic

expression during the prodromal and acute phases of CAD. The current body of literature has

shed light on the differences of gender presentation highlighting the female perspective and

experiences of CAD. However, a need exists to determine how cardiac prodromal symptoms

differ for women and the clinical implications that this information can provide.

This review of the literature will examine the current knowledge of women' s cardiac

prodromal symptoms. A literature search was used to select research studies reporting cardiac

symptoms and including women, between 2000 and 2008. The research studies included were

identified by a search of the PubMed database for the specified years. The studies included

samples of adult women patients with cardiac disease reported in refereed j ournals. Only j ournal

articles available in English were reviewed. The key terms searched were prodromal symptoms,

cardiac symptoms, symptom presentation, symptom perceptions, gender differences, sex

differences, women's interpretation, women's descriptions and women's symptoms. The

obj ective of this literature review was to explore the available evidence on CHD and CAD

symptoms mn women.

During 1997- 1999 a flurry of studies were published that compared symptoms between

genders and found apparent differences particularly among women (Goldberg et al., 1998;

Hochman et al., 1998; McSweeney, 1998; Meischke, Larsen, & Eisenberg, 1998; Meshack, Goff,

& Chan, 1998; Penque et al., 1998). In 2002, Christine Miller published a comprehensive









integrative literature review and meta-analysis that examined these studies. While each study

investigated a unique population and in different settings, the common theme present in all the

1997-1999 studies was that they investigated the primary (not yet prodromal) symptoms of heart

disease in women. Four quantitative studies reported chest pain to be the most frequently

reported initial symptom followed by order of frequency either shortness of breath or fatigue

(Goldberg et al., 1998; Meischke et al., 1998; Meshack et al., 1998; Penque et al., 1998). Miller

(2002) postulated that while chest pain was the most frequently reported symptom in these

studies most likely it was the most frequently identified symptom. Mc Sweeney (1998) in a

qualitative study interviewed 20 women after they suffered a MI. She found that the symptoms

of breaking into a cold sweat and having a feeling of an unrelenting unusual fatigue were the

most common symptoms in her sample (Mc Sweeney, 1998). Women often experienced this cold

sweat and fatigue or other atypical symptoms such as pain in the back, both arms and the left

breast for 2 to 4 weeks prior to the MI. McSweeney (1998) also reported that only 30% of the

women experienced significant chest pain and that 25% of the women in her analysis never

experienced any chest pain at all.

Included in the review were two studies that investigated predictors of cardiac disease in

women. Jadin and Margolis (1998) reported that the overall best predictor of CHD in women

was age. Vaccarino and colleagues indicated that co-existing comorbidities such as diabetes,

congestive heart failure, and stroke were more prevalent in women with CHD concluding that it

was only logical that later onset of disease processes coupled with comorbidities would

invariably impact the nature and recognition of symptoms (Vaccarino, Parsons, Every, Barron, &

Krumholz, 1999). Miller (2002) suggested that as a result of the aforementioned studies in the

review that there may be underlying physiological, pathophysiological and anatomical reasons









for the varied clinical and symptom presentation of women. She implied that anatomically

women are smaller in stature overall, have smaller hearts and smaller coronary vessels which

contributes to the altered physiological and pathophysiology presentation of disease (Miller,

2002). Miller (2002) also addressed the implications for practice by pointing out that it was not

surprising that women did not fit the current diagnostic model for CHD that was built on

research of men.

There continues to be an expansion of the body of knowledge of symptom experiences of

women with CHD (Miller, 2002). Miller (2002) concluded that the distinctive physiological,

pathophysiological and anatomical differences among men and women had raised the bar for

researchers. It has become essential that researchers be able to find a way to differentiate the

unique symptom experience of women leading to improvements of early recognition and overall

improved health status (Miller, 2002).

Women's Symptoms Quantitative Studies

Previous studies has implicated age as a promising source for the symptom differences

between genders (Jadin & Margolis, 1998; Miller, 2002). Then and colleagues (2001) performed

a systematic retrospective chart review of symptom differences of men (n=105) and women

(n=48) in three acute care hospitals to determine symptom trends in subj ects that had been

diagnosed as suffering a MI. Subj ects were stratified into three age groups 3 5-64, 65-75 old and

>75 years old. Then (2001) found that the age group that reported the highest percentage (n = 6,

40%) of atypical symptoms were women in the group 65-75 years old (n=15).

Atypical symptoms experienced by the sample included indigestion, shortness of breath,

abdominal pain, nausea, vomiting, diarrhea, and feeling ill (Then, Rankin, & Fofonoff, 2001).

Typical symptoms experienced by the subj ects of this study were chest pain, pressure,

discomfort or heaviness (Then et al., 2001). The study results indicated an increasing trend of









atypical symptom presentation for male subj ects > 75 years old that was not the trend for

females. The authors cautioned readers that the small sample of women may limit the

generalizability of the study (Then et al., 2001).

In 2003, DeVon and Zerwic investigated gender differences of symptoms in a descriptive

study of women (n = 50) and men (n =50) hospitalized with unstable angina (UA). Subj ects

were approached for data collection after they had been hospitalized and pain free for 12 hours.

Subj ects were recruited regardless of their previous CHD history.

The subj ects were administered three structure instruments the Unstable Angina

Symptoms Questionnaire, the Canadian Cardiovascular Society Classification of Angina

instrument and the Hospital Anxiety and Depression Scale to assess the severity and location of

the UA symptoms. Results indicated that the majority of the sample was Caucasian, had some

high school education, earned less than $20,000 dollars per year and were married. A history of

MI was present for 40% of the sample with approximately 50% having had a previous bout with

angina. More women than men were diabetic (46% vs. 34%) were hypertensive (80% vs. 56%)

and had high cholesterol (72% vs. 68%). Women of the sample significantly reported more

shortness of breath, difficulty breathing, weakness, nausea and loss of appetite as symptoms than

men. Women also reported statistically significant more pain in the upper back than men (42%

vs. 18%) of a stabbing or knifelike quality (DeVon & Zerwic, 2003). The authors concluded that

men and women often experience comparable symptoms dung UA, women experience more

atypical symptoms.

Kimble and colleagues (2003) reported a descriptive study that assessed the gender

differences of the pain characteristics and physical limitations between men (n = 89) and women

(n = 39) with chronic stable angina (CSA). Subj ects were identified from chart review at









physician offices that had a history of CHD and positive score on the Rose questionnaire as a

screening for angina. Subj ects were excluded if they had experienced a MI, coronary artery

bypass surgery (CABG) or percutaneous coronary intervention (PCI) within six months of the

study. Subj ects were administered the short-form McGill pain questionnaire to assess pain

dimensions and the physical limitation subscale of the Seattle angina questionnaire to assess

physical activity limitation (Kimble et al., 2003).

Results indicated that women were slightly older than men (mean 64.1 years vs. mean

62.8 years), were more often diabetic (3 5.9% vs. 32.6%) and experienced less history of MI,

CABG and PCI. Overall, men reported a greater pain dimension score for the descriptor of heavy

tiring-exhausting sensation and women reported more intensity of tiring-exhausting and aching

sensations and for the descriptor of hot-burning and tender. Women also, reported a greater

physical limitation when angina was involved. Kimble concluded that men and women with

CSA have more similarities than differences in the characteristics of pain with the exception of

women having significantly more hot-burning and tender sensations. The authors believed that

the description of tender was a unique finding to women when describing chest pain and

warranted further exploration (Kimble et al., 2003).

In the report of a descriptive study, Granot and colleagues (2004) assessed gender

differences of perceptions of pain symptoms among men (n =32) and women (n = 29) with UA.

Characteristics of chest pain were described by hospitalized subjects using a semi-structured

questionnaire that evaluated the intensity, duration and location of chest pain. Precipitating

events and factors that relieved pain were also explored.

Results of the study indicated that 58% of the sample had a history of CAD with no

statistical difference between genders. Women reported significantly more intense pain than









men. Women located pain more inn the stomach, jaw and back, whereas men had more chest

pain. More women than men described their pain as pressure (84% vs., 37%). There were no

significant differences between men and women in the events that provoked of factors that

relieved chest pain however, women reported that rest reduced chest pain more often. Both men

and women reported shortness of breath as the most frequent symptom. The authors concluded

that women more often described a portrait of chest pain that was atypical and more intense in

character (Granot, Goldstein-Ferber, & Azzam, 2004).

In a study that evaluated gender differences and similarities of men (n = 1258) and

women (n = 683) presenting with acute coronary syndrome (ACS), Arslanian-Engoren and

colleagues (2006) offered results from the ACS registry at the University of Michigan.

Researches extracted information retrospectively from patient charts diagnosed with ACS

regarding demographics, presentation, symptoms and comorbidities. Data was analyzed using

chi-square for categorical variables and t-test for continuous variables. Logistic regression was

used to create odds ratios for predictor variables (Arslanian-Engoren et al., 2006). Subj ects were

stratified by gender and age (<65 and > 65years).

Results indicated that 72% of those in the study had a confirmed MI and 28% had UA.

Women in the older age group were more likely than men of the same age group to be obese and

have hypertension and less likely to smoke. Rates for MI, positive stress test and angina were

equivalent but men were more likely to have had PCI and CABG surgery. Both men and women

in the older age group were more likely to have a ST- segment elevated myocardial infarction

(STEMI). There was no significant difference in the type of MI between genders. Men were

more likely to present to the hospital with the complaint of chest pain, left arm pain and

diaphoresis. Women presented more often with nausea, vomiting, jaw pain, neck pain and back










pain. Shortness of breath was present as the most reported symptom of all groups. Logistic

regression offered that age was a significant predictor of nausea and diaphoresis and not of chest

pain, shortness of breath or of arm pain. The authors concluded that small but statistically

significant differences are apparent between genders in age, comorbidities and with initial

presentation and location of symptoms to the hospital for ACS (Arslanian-Engoren et al., 2006).

Kosuge and colleagues (2006) investigated differences in the clinical features of men (n =

3 51) and women (n = 106) with STEMI. Subj ects were enrolled upon diagnosis of acute

myocardial infarction (AMI) with non-invasive methods such as EKG demonstrating ST

segment elevation in two leads and an increase of cardiac enzymes. Subj ects were interviewed

and asked to describe the quality, severity and location of their pain. Immediately after admission

93% of the subj ects underwent cardiac catheterization and reperfusion if appropriate.

Data was evaluated for differences between genders using t-tests and differences in

prevalence were assessed using chi-square tests. Results revealed that women of the sample were

older than men (mean age 72 vs. 62). Women were also more often than men to be diabetics

(36% vs. 26%) and hypertensive (70% vs. 56%). Men most often had a squeezing feeling (35%)

as the quality of their chest pain whereas women had a vague indescribable (45%) quality to the

chest pain. Women reported more jaw, neck, back and arm pain than men. Men more often than

women reported severe (52% vs. 38%) chest pain during a STEMI. Shortness of breath was

equal between the groups, men experienced more sweating and women experienced more nausea

and vomiting. In both men and women the culprit vessel for onset of the STEMI was most often

the left anterior descending artery followed by the right coronary artery. Women with STEMI

had a significantly higher in-hospital mortality rate than men (6 vs. 0). The authors concluded

clinical profiles and presentation are different between genders. Women presenting with STEMI









tend to be older than men, have more comorbidities, more atypical symptoms and higher

mortality then men (Kosuge et al., 2006).

To investigate gender differences in pain symptoms associated with exercise induced

ischemia, D'Antono and colleagues (2006) recruited 38 women and 94 men to participate in a

prospective study of subj ects with both angina symptoms and a positive myocardial perfusion

imaging study. The study excluded subjects with significant and debilitating comorbidities in

order to exclude cofounders. Subj ects were assessed for pain presence, quality, location and

other symptom presence before and immediately after a dual stress test. Instruments used for

assessment included the Dermatome Pain Map, a Symptom checklist, the short-form McGill Pain

Questionnaire, the Chest Pain Quality Scale, The Canadian Cardiovascular Society grading scale

for angina pectoris and the Psychiatric Symptom Index. Medical assessment for ischemia was

performed by a board certified nuclear imaging cardiologist reading the dual stress test a giving a

clinical impression (D'Antono et al., 2006).

Results revealed that there was no significant difference in age between the men and

women and that while not significant women (37%) had less than a high school degree. Less

women than men had diabetes (5% vs. 21%) and hypertension (40% vs. 50%). More women than

men had thyroid dysfunction (18% vs., 4%). Women rated pain as more intense on the McGill

Questionnaire than men including class IV angina (28% vs. 23%) (D'Antono et al., 2006).

Women reported experiencing more hot-burning, stabbing or pressing pain than men. Women

reported more pain in the neck/throat area and men had more right chest/shoulder and middle

right chest pain. The most common symptoms for both genders were shortness of breath and

fatigue. Women complained of more nausea, palpitations, trembling and numbness in the face

and throat. Post hoc analysis comparing symptoms to dual stress test imaging results indicated









that women with more severe imaging ischemia had more atypical symptoms such as a

throbbing, tight chest pain and numbness in the arms explained 48% of the variance. The authors

suggested that small differences in the symptoms associated imaging studies exist. The real

danger is in the way women express the symptoms that they have with ischemia making them

more prone to misdiagnosis and delayed treatment (D'Antono et al., 2006).

Omran and Al-Hassan (2006) using a descriptive comparative study investigated the

gender differences of signs and symptoms of presentation in Jordanian men (n = 57) and women

(n = 26) subjects with MI. Subj ects were enrolled in the study while hospitalized if they had been

diagnosed with an MI and were hemodynamically stable. Data was collected by chart review

and a structured interview that focused on the initial symptom presentation. Pain intensity was

rated using a visual analog scale. As an obj ective indicator of the severity of MI cardiac enzymes

were noted.

Results reflected that the sample mean age was 52 years and women more than men had

less than a high school degree (69% vs. 20%). Women were significantly more hypertensive than

men (31% vs. 14%). Among men and women chest pain was the most common presenting

symptom. Subj ects pain levels reported by the researchers from the visual analog scales were of

moderate levels (mean 7.2, SD =2.8) (Omran & Al-Hassan, 2006). Men and women alike

reported nausea, sweating, fatigue and general weakness as the most common symptoms with

women reporting slightly more general weakness and sweating. Cardiac enzymes were reported

higher in men than women (no data). The authors concluded that small differences in symptom

presentation between men and women experiencing MI exist. These differences are subtle and

may confuse healthcare professionals thus delaying time of treatment for women (Omran & Al-

Hassan, 2006).









Lovlien, Schei and Hole (2006) investigated the gender differences of the interpretation

of patient' s pre-hospitalization AMI symptom experiences. Only first time AMI patients were

considered. AMI was confirmed by chart review of EKG ST segment elevation in two or more

leads. Subj ects were sent by mail a questionnaire two weeks after discharge. The questionnaire

focused on demographics and symptoms prior to hospital admission. The questionnaire was sent

to 777 subjects, 533 responded (149 women and 384 men).

Data was analyzed using chi-square and logistic regression techniques. Results indicated

that women were slightly older than men (mean age 61.2 vs. 58.5). Women had more

hypertension (3 8% vs. 29%) and high cholesterol (26% vs. 15%) than men. Women had less

high school education than men (60% vs. 33%). Anterior (31% vs. 34%) and posterior (40% vs.

3 1%) infarcts were the most common sites of AMI in both men and women (Lovlien, Schei, &

Hole, 2006). Men experienced chest symptoms more often pre-hospitalization. Women were

more likely to report nausea, shortness of breath, palpitations, fainting, scapulae, jaw, throat, and

back pain. Lovlien (2006) concluded that women are more likely to experience an atypical

presentation of symptoms differing from the expectation that they have. The presentation of

atypical symptoms influences the interpretation of the symptoms often delaying care.

King and McGuire (2007) conducted a descriptive correlational study of 30 men and 30

women to assess gender differences of symptom presentation in subj ects with AMI. Subj ects

who were diagnosed with AMI were interviewed after revascularization in the hospital. All

subj ects were interviewed using the Symptom Representation Questionnaire.

Data analysis was performed using chi-square, t-tests and logistic regression techniques.

Results indicated that women were statistically significantly older than men (mean age 69.9 vs.

55.2). The sample was predominately white (88.3%). There were no significant differences









between men and women for diabetes, hypertension or education levels within the sample.

Evaluation of the symptom experience among men and women indicated two significant

differences. Women reported less pain than men in the center of the chest (56.7% vs. 90.0%) and

more right shoulder (53.3% vs. 13.3%) discomfort. Pain descriptors did not differ between the

genders. Associated symptoms of weakness, fatigue, diaphoresis, shortness of breath were the

same for both genders with the exception that women reported less indigestion than men (26.7%

vs. 50%) (King & McGuire, 2007). Approximately 42% of the subj ects in the study reported that

the symptoms that were experienced were not what they expected. The pain was less than

expected in 61.9% for the sample and 3 8. 1% reported the location of the pain was different from

anticipated. King (2007) concluded that there were minimal differences between genders in

symptom presentation. She commented that it was more likely that the difference in expected

symptoms of AMI and experienced symptoms was the factor that was most dangerous to both

genders.

Women's Symptoms Qualitative Studies

Several qualitative studies have explored women's symptom experiences (DeVon et al.,

2008; McSweeney et al., 2001; McSweeney et al., 2003; McSweeney & Crane, 2000; Miller,

2000; Norris et al., 2008; Philpott, Boynton, Feder, & Hemingway, 2001; Ruston & Clayton,

2007; Ryan & Zerwic, 2004; Sj ostrom-Stranda & Fridlund, 2007). Miller (2000) presented data

from a grounded theory study of women with heart disease that provided subj ective symptoms

experienced by 10 women with cardiac disease who ranged in age from 40 to 78 years old.

Women with different medical diagnosis and length of illness were included (five Caucasian,

four African American and one Latina). Diagnosis included MI, congestive heart failure and

angina. Shortness of breath, swelling, fatigue, and weakness were more common in this group

although several reported experiencing mild chest discomfort. Several women prior to cardiac









diagnosis indicated feeling too weak or tired to complete usual daily tasks. This study concluded

that healthcare seeking behavior is prompted by cardiac cues, which include the nature and

severity of embodied symptoms.

In a qualitative study McSweeney and Crane (2000) identified symptoms women

experienced prior to and during an AMI. The nonprobability sample for this descriptive

naturalistic study consisted of 40 women. Using content analysis and constant comparison, the

researchers identified specific symptoms and grouped them according to time of occurrence,

prodromal and acute. Thirty-seven women experienced prodromal symptoms, beginning from a

few weeks to 2 years prior to their AMI and ranging from 0 to 11 symptoms per woman. The

most frequent prodromal symptoms were unusual fatigue (n = 27), discomfort in the shoulder

blade area (n = 21), and chest sensations (n = 20), whereas the most frequent acute symptoms

were chest sensations (n = 26), shortness of breath (n = 22), feeling hot and flushed (n = 21), and

unusual fatigue (n = 18). Only 11 women experienced severe pain during their AMI. Conclusions

of this study offered by the authors are threefold: (a) women identified classic and unique

symptoms of AMI, which challenge the content of current literature; (b) women experienced a

gradual progression of number and severity of AMI symptoms; and (c) women need sufficient

time to recognize the prodromal symptoms of their AMI.

Mc Sweeney and colleagues (2001) presented a study based on interviews of 76 women

who discussed women's symptoms prodromal and acute that were associated with an MI

experienced in the previous year. Sixty-eight out of the 76 women had experienced prodromal

symptoms that included fatigue (70%), dyspnea (53%), and pain in the upper back or shoulder

blade (47%). All 76 women reported acute symptomology to include chest pain/discomfort

(90%), fatigue (59%), dyspnea (59%), and upper back discomfort or shoulder blade pain (42%).










Despite the fact that women had reported several prodromal symptoms, none were given a new

diagnosis of CAD prior to their MI. The authors suggested from their findings that a need for

healthcare practitioners to become more acutely aware of and take a more extensive approach

when assessing women at risk for CAD is evident.

Mc Sweeney and colleagues (2003) reported a study of 515 women from five research

sites, that described the prodromal and AMI symptoms that they experienced. The research team

administered the MAPMISS, to assess women about their symptoms, comorbidities, and

demographic characteristics post MI. The sample was principally white (94%), high school

educated (55%), and older (mean age, 66), with 95% (n=489) reporting prodromal symptoms.

The prodromal symptoms reported were fatigue (71%), problems sleeping (48%), and dyspnea

(42%). Only 30% reported chest discomfort, the distinctive symptom of MI in men. The most

frequent acute symptoms reported were dyspnea (58%), weakness (55%), and fatigue (43%). The

symptom of acute chest pain/discomfort was not reported by 43% of the women. The more

women reported prodromal symptoms experienced the more the rise in acute symptoms were

reported. Prodromal scores on the MAPMISS accounted for 33% of the acute symptoms. The

authors concluded that most women experience prodromal symptoms before an AMI and the

issue remains unclear if prodromal symptoms are able to predict potential CHD events.

Lockyer (2005) conducted a semi-structured interview of 29 women who had been

admitted to and discharged from the coronary care unit. The goal of the study was to examine

each woman' s own interpretation of the presenting symptom had experienced in relation to the

onset of CHD (Lockyer, 2005). Narrative analysis was used analyze the interviews. The mean

age of the 29 women was 69 years.









Results revealed that 3 women in the study had no symptoms until the day of their MI

and that the women identified the initial symptom as what was labeled by the researchers as

acute chest pain. Several women (no number given) reported tingling in the arms, jaw pain, chest

tightness and heaviness as the presenting symptom labeled by the researchers as undifferentiated

chest pain. Most women reported ignoring the symptoms or self medicating to ease the pain for

several months before seeking medical attention. The most common presenting symptom was

breathlessness on exercise for several weeks or months. The maj ority of subj ects with this

complaint only sought medical attention when they were incapacitated Many of the women in

the study believed that breathlessness in its evolving stage to be a normal part of the aging

process (Lockyer, 2005).

Lockyer (2005) stated that many women delayed seeking help out of social obligation to

their family and only accessed healthcare systems after family and friends encouraged them to

see their primary physician. She concluded that women were often unable to distinguish cardiac

symptoms from symptoms of aging being fatigued or being unfit. Lockyer (2005) emphasized

the need for further research to examine early warning signs of cardiac disease to decrease

morbidity and mortality in women.

Albarran and colleagues (2006) performed a qualitative study using a semi-structured

interview of 12 women to explore the cardiac symptom experience prior to MI. Hospitalized

subj ects were chosen based on a rise in cardiac enzymes with or without ST elevation on EKG.

Content analysis was used to code and deconstructt the interviews for emerging themes.

Results revealed that the mean age of the subj ects was 63 years. None had a history of

previous MI. Eight of the 12 women experienced STEMI. The fundamental nature of the

symptom experience for the women emerged as three distinct themes (Albarran, Clarke, &










Crawford, 2007). First, gradual awareness of symptoms was reported from over a few days, up to

several weeks. The most common symptom associated with gradual onset was shortness of

breath without exertion. Other common symptoms were a chest heaviness and frequent

indigestion. Secondly, rationalizing of symptoms was an emerging theme. Women with chronic

comorbidities often attributed the new symptoms to old disease diagnoses. Other women often

blamed the new symptoms as a normal part of the aging process. Finally, women experienced an

unpredictable distribution of pain. Pain was reported as varying, vague and unexpected.

Common locations of pain were the back, neck, upper arms, hands and stomach. Many women

(10/12) experienced nausea and vomiting as the most common symptom for these women with

MI.

The authors concluded that the presentation and location of cardiac symptoms are

untraditional. Women experiencing a MI have difficulty interpreting cardiac symptoms of MI

due to the unanticipated and atypical nature of the symptoms. A danger for women is the

continued reliance by healthcare providers on symptom presentation as the primary clinical

impression for decision making regarding coronary ischemia (Albarran et al., 2007).

In 2007, Ruston and Clayton reported the results of a study that examined the effect of

comorbidities on the interpretation of cardiac symptoms by women (n = 44) experiencing a

cardiac event. Semi-structured interviews were conducted and subj ects were stratified into two

groups, those (n = 20) that presented to the hospital <12 hours of symptom onset and those (n =

24) that presented to the hospital >12 hours after symptom onset. Interviews were conducted

during hospitalization for the cardiac event. Constant comparison method was used to analyze

the interviews. Results for the <12 hour group indicated that 14 of the 20 subj ects had a known

history of CHD. Comorbidities including emphysema, bronchitis, anemia and arthritis were










present for 14 of the 20 subj ects in this group. Only 2 subjects reported experiencing any early

symptoms both complained of fatigue. None of the subj ects reported having symptoms that were

associated with or that they could attribute to their comorbidities. Results for the >12 hour group

indicated that 5 of the 24 subjects had a known history of CHD. Comorbidities of a non-cardiac

nature were present for 22 of the 24 subj ects in this group. The maj ority of subj ects reported

having a least one symptom that could be attributed to a comorbid illness and 20 subj ects

reported experiencing early unusual vague symptoms up to 72 hours prior to hospitalization

(Ruston & Clayton, 2007).

During analysis common threads of symptom cues or mental triggers that the subj ects

used to assess their symptoms became apparent. Women in the <12 hour group were able to

distinguish cardiac symptoms that were new from usual comorbid symptoms by experience of

CHD and further to qualify them as dangerous and requiring attention. Women in the >12 hour

group were unable to distinguish cardiac symptoms that were new from usual comorbid

symptoms due to a lack of experience with CHD. Women in the >12 hour group attributed new

symptoms to an escalation of their comorbid illnesses (Ruston & Clayton, 2007).

Ruston and Clayton (2007) stated that symptom recognition by the <12 hour group was a

process of comparison and differentiation that led women to come to the conclusion that an

emergent cardiac event was taking place prompting them to seek medical attention. Women of

the >12 hour group lacked experience with CHD prompting them to a normalization of the

symptoms into the typical advancement of symptoms of their comorbid illness. The authors

concluded that symptom interpretation is a product of experience and the repertoire of

knowledge that allows women correctly to assess symptoms of CHD from those of chronic

comorbid illness.










Sj ostrom-Stranda and Fridlund (2007) conducted an explorative and descriptive designed

research study to examine the symptoms that women experienced and the reasons for delay in

treatment. An interview guide was constructed by the authors based on literature review and the

experiences of critical care nurses whom worked in the cardiac unit. The interviews focused on

the women' s understanding of their symptoms. Interviews were conducted on women (n = 19)

after hospitalization for a MI and prior to hospital discharge. The interviews lasted

approximately one hour and included open ended questions such as: Describe the symptoms of

your heart attack? At the time how did you interpret these symptoms? The interviews included

several follow-up questions to further elucidate the answers to the initial questions (Sjostrom-

Stranda & Fridlund, 2007).

Data analysis was performed using content analysis. Results indicated that women

described the pain associated with the MI in different ways. Some women described an acute

pain that came on suddenly, was very painful as pressure in the chest. Some women described

left arm and scapula pain over the entire back that was intense and made it difficult to breath

(Sj ostrom-Stranda & Fridlund, 2007). Other women stated that the pain or discomfort in the

throat and shortness of breath would come and go for 10 to 14 days prior to their hospitalization

for the MI.

Most women had trouble interpreting the symptoms as cardiac even though many of them

had strong family histories of CHD or CAD. Many believed that they were too young to

experience a MI. Several had the belief that they had developed a healthy lifestyle and were thus

immune to the risks of CHD (Sj ostrom-Stranda & Fridlund, 2007).

An interesting finding of the study was that while many women did not recognize the

cardiac related symptoms as dangerous, the pain or discomfort caused anxiety. In turn the









anxiety exacerbated the pain and vice versa. The symptoms were often perceived as severe when

they were associated by the women with anxiety. Subsequently, women would consult family

and friends about the anxiety and be referred to the medical center for help (Sj ostrom-Stranda &

Fridlund, 2007).

Sj ostrom-Stranda and Fridlund (2007) concluded that women had difficulty interpreting

the symptoms of MI if they had not experienced one prior. That many women delay seeking

treatment because the do not anticipate the risk that may be in or that they may experience

prodromal or atypical symptoms. In order to overcome the potential catastrophic consequences

associated with MI women need to be made aware of the clinical symptoms that they may

experience.

Devon, Ryan and Ochs (2008) conducted a structured interview study of 256 subjects

(144 men and 112 women) to assess the differences between genders in type, severity, location,

and quality of reported symptoms. Subjects that presented to the emergency department were

categorized into one of 3 acute coronary syndromes (ACS) (unstable angina, non ST-segment

elevated MI and STEMI). Results concluded that women regardless of the category they were

admitted to were significantly more likely to report numbness in the hands/arms, indigestion,

fatigue, palpitations, and nausea. However, both women and men reported similar chest

pain/discomfort episodes. The authors concluded that while a difference in the expression of

atypical symptoms exists, the issue is unclear if the atypical symptoms are clinically significant

(DeVon et al., 2008).

Norris and colleagues (2008) conducted a pilot study that investigated the differences in

gender presentation of prodromal symptoms of ACS. The researchers employed the MAPMISS

to perform a structured interview of 24 women and 52 men. Results suggested that women










reported more prodromal symptoms than men. Premenopausal and perimenopausal women

reported more prodromal symptoms than menopausal women and men. The researchers

concluded that both men and women do report prodromal symptoms, although women report

significantly more and menopausal status plays a role (Norris et al., 2008).

Women's Symptoms Mixed Method Studies

Few mixed method studies have explored women's symptom experiences (Philpott et al.,

2001; Ryan & Zerwic, 2004; Vodopiutz et al., 2002). Philpott and colleagues (2001) reported

results from a mixed method study that examined if language differed in the expression of

symptoms between genders in subj ects with chronic stable angina after angiography. Content

analysis of a free text answer to an open ended question asking what health problems or

symptoms had been responsible for the need of an angiogram was used to obtain how men (n

=104) and women (n = 96) described the symptoms that they had perceived (Philpott et al.,

2001). Subj ects also completed the Rose Angina criteria to assess chest pain. Previous

angiograms were reviewed to quantify CAD status using one or more diseased vessels as the

criteria.

The sample was garnered from the Appropriateness of Coronary Revascularization

(ACRE) study. The sample was stratified into 4 groups male, female, <60, >60 years of age. The

free text answers were then coded into categories that included location of pain, character of

pain, other symptoms and symptom qualities. Results of the free text portion of the study

indicated that women used the words neck, throat and jaw pain in describing a location for chest

pain when compared to men especially if the women had low physical functioning, had CAD or

were not revascularized (Philpott et al., 2001). The researchers reported that for the Rose Angina

criteria there was no significant difference in the intensity of chest pain between men and

women. Women however, reported significantly less chest pain than men (Philpott et al., 2001).









Women were also less likely to have angiographically significant CAD (62% vs. 92%, p<0.01).

Philpott (2001) concluded that there were differences in gender expression present in relation to

chest pain symptoms and that these differences could influence clinical decision making.

Atypical chest pain symptoms may cloud clinical judgment to proceed with invasive procedures

like angiography and create delay in treatment.

In 2002, Vodopiutz and colleagues conducted a coronary-linguistic mixed method study

to assess the gender specific differences in symptoms of hospitalized men (44) and women (48)

reporting chest pain as their main complaint. The researchers administered a 69 item

questionnaire to gather demographic data, cardiac risk factors, chest pain frequency, chest pain

descriptors, information regarding activities or medicines that brought on or relieved chest pain

and additional symptoms present. To assess the linguistic portion of the study subj ects were

interviewed while hospitalized using a recorded semi-structured interview process. The topics of

the open ended questions to discuss their chest pain experiences were predetermined. Interviews

lasted 15 to 50 minutes mimicking a conventional healthcare provider interaction allowing the

opportunity for patients to describe fully their chest pain experience (Vodopiutz et al., 2002).

Subj ects were stratified into cardiac and non-cardiac chest pain categories by chart

review at patient discharge. Coronary disease was diagnosed if subj ects had angiography or upon

autopsy demonstrated a coronary lesion of >60% or had a nuclear or exercise tolerance test that

was positive for ischemia. Patients were considered to have a non-coronary diagnosis if another

disease process was discovered to be the cause during the hospitalization or if angiography or

autopsy revealed there was no evidence of a coronary lesion of >60% or if the subj ect had a

negative nuclear or exercise tolerance test (Vodopiutz et al., 2002).









Statistical analysis was performed only on the cardiac portion. Results indicated that 18

women and 25 men met the cardiac chest pain criteria. Significant difference was found in

symptoms between those that had cardiac chest and those that did not. Cardiac chest pain was

reported to be more retrosternal (93% vs. 71%, p = 0.0078) and in the right arm (23% vs. 6%, p

= 0.0186) and less in the back (28% vs. 51%, p = 0.0241) than non-cardiac chest pain

(Vodopiutz et al., 2002). Women (mean 65.6 years) of the sample were older than the men (mean

59.0 years). Women with cardiac chest pain reported more gradual onset of chest pain that was

relieved by rest.

Subj ect interview narrations were analyzed using interactional analysis. Analysis

discovered that men offered more concise concrete descriptions of cardiac chest pain. Women

were verbose and vague in the description of their cardiac chest pain. Vodopiutz (2002

concluded that while gender differences do exist in the symptoms of chest pain, they are not

specific enough to distinguish cardiac from non-cardiac origin. The stronger evidence of the

study points to gender differences in presentation and description of symptoms to healthcare

providers by women. This factor may explain misdiagnosis and delay of care (Vodopiutz et al.,

2002).

Ryan and Zerwic (2004) using Q methodology, a mixed method, investigated symptoms

that subj ects at high risk for acute myocardial infarction (AMI) and their significant others

understood to be related AMI. After qualitative interviews were conducted of 140 AMI

survivors, a quantitative Q sort instrument was developed by the researchers that comprised 49

statements that described AMI symptoms in lay terms. Women (n = 22) and men (n = 31) with

known CAD or their significant others (n = 10) were subsequently recruited and administered the

instrument.









Results indicated that four factors emerged. Factor 1, traditional symptoms (respondents

=12 men, 3 women, and 4 significant others) encompassed symptoms taught to the lay public by

healthcare professionals and at cardio-pulmonary resuscitation classes. Symptoms focused on

severe sustained pain. Factor 2, (respondents =7 men, 3 women, and 3 significant others) focused

on gastrointestinal symptoms which included chest symptoms that could mimic stomach

problems such as dullness, fullness and heaviness. Factor 3, (respondents = 4 men, 2 women, and

0 significant others) non-specific symptoms identified as an unusual tired feeling, labored

breathing and weakness. Factor 4, (respondents =1 men, 1 women, and 0 significant others) a

variation of traditional symptoms that identified other upper body parts (neck, shoulders, and

arms) as a locus of pain and shortness of breath (Ryan & Zerwic, 2004).

Ryan and Zerwic (2004) concluded that the symptoms that people and their significant

others expect with an AMI are different that they expect. Furthermore, a significant difference

between how genders expect AMI symptoms to be exists.

Summary

The body of research exploring the symptoms and experiences of women with CAD is

ever increasing. Many studies have been able to illustrate that the current framework established

for the diagnosis of CAD in men is an ill fit for women (D'Antono et al., 2006; Granot et al.,

2004; Miller, 2002; Omran & Al-Hassan, 2006). The unique presentation differences between

women and men experiencing CSA, UA and MI make it imperative that new studies elucidate

the unique symptoms in women presenting with cardiac disease. Countless stories of women

whose diagnosis and treatment have been delayed because their symptoms were not immediately

identified as cardiac abound (Arslanian-Engoren et al., 2006; Granot et al., 2004; Kosuge et al.,

2006; Lovlien et al., 2006; Shaw et al., 2008). If researchers and healthcare practitioners

continue to look exclusively for the traditional symptoms of CAD that include mid-sternal chest










pain radiating to the jaw and down the left arm, women will continue to be misled about their

susceptibility to cardiac diseases (Miller, 2002). Healthcare professionals must take their share of

the blame for this state of affairs, in that traditional expectations and warnings regarding CAD

are still targeted predominately to men.

Critical to the improvement of the identification of cardiac problems in women is the

careful screening of women with diabetes and hypertension as well as paying close attention to

atypical symptoms on presentation. Subtle symptoms such as fatigue, shortness of breath, back

pain and transient non-specific chest discomfort should prompt thorough assessments

particularly in women with two or more cardiac risk factors (Miller, 2002). For healthcare

providers ruling out CHD based simply on age, race or gender is no longer appropriate. Each

patient should be individually evaluated based on cardiac risk profile and symptom presentation

(Miller, 2002; Shaw et al., 2008).

Theoretical Model

An exceptional way to investigate this problem is through the use of nursing theory. The

conceptual framework that will guide this exploratory research proposal and was chosen based

on the literature review is the Theory of Unpleasant Symptoms (TUS); a middle ranged nursing

theory introduced by Lenz and colleagues in 1995. The TUS posits a dimensional structure for

unpleasant sensations that reflects intensity, distress, timing and quality of symptoms or

symptom clusters (Lenz, Suppe, Gift, Pugh, & Milligan, 1995). These unpleasant sensations

mimic the intensity, time frame and frequency dimensions assessed on the MAPMISS. The

relational structure of the TUS shows that symptoms arise from correlated physiological,

psychological and situational influencing forces that result in altered functional, cognitive and

physical performance. For the revised version of the TUS the model assumes a feedback loop

from symptom to symptom and a possible catalyst effect of each symptom to another (Lenz,










Pugh, Milligan, Gift, & Suppe, 1997). This feedback loop was a serendipitous finding by

Sj ostrom-Stranda and Fridlund (2007) where pain fed anxiety and vise versa. This portion of the

model will be tested in this research proj ect. The maj or hypothesis that there are differences in

women's prodromal cardiac symptoms between those that have CAD and those that do not will

be explored.

The focus of the revised model of the TUS is to facilitate the understanding of the

multidimensional often influential aspects underlying symptoms and symptom clusters (Parker,

Kimble, Dunbar, & Clark, 2005). Using this framework will allow for the future translation of

research findings into symptom recognition models that can change practice paradigms within

the current healthcare system and optimize patient outcomes (Parker et al., 2005). The structure

of the revised theory framework is shown in Figure 2-1. The revised model of the TUS

emphasizes that symptoms may arise independently of other symptoms but frequently, symptoms

are experienced concurrently (Arslanian-Engoren et al., 2006; D'Antono et al., 2006; Kosuge et

al., 2006). The occurrence of several symptoms simultaneously is liable to have multiplicative

effect as opposed to an additive effect (Lenz et al., 1997; McSweeney & Crane, 2000). Thus,

simultaneously occurring symptoms are more apt to have a catalytic effect on one another.

Prodromal symptoms are those symptoms that are new onset or increase in intensity or

frequency of existing symptoms. Accuracy in describing women's prodromal symptoms is a

critical step in providing a complete picture of women' s typical presentation of coronary artery

disease (McSweeney, personal communication, June 11, 2004). The 33 prodromal symptoms

identified by McSweeney and colleagues (2003) that appear on the MAPMISS are listed in

Table 2-1.









Model Assumption

The revised model of the TUS is based on the following assumption. The gold standard

for the study of symptoms is based on the perception of the individual experiencing the symptom

and his or her self-report.

Conceptual Definitions

In the revised model of the TUS, three forces influence the occurrence, intensity, time

frame and frequency of symptoms they are: physiologic, psychological, and situational forces. In

the revised version of the theory, interactional aspects are acknowledged within each of the three

categories of forces influencing the symptom experience of the subject (Lenz et al., 1997).

Forces will be assessed as comorbidities, medical variables and situational factors on subj ect

demographics that are either categorical or continuous variables. Analysis of these variables will

be tested as outlined in chapter 3 under the statistical data plan.

An accepted theory is that unpleasant symptoms are often a reflection of physiological

distress (Lenz et al., 1997; Parker et al., 2005). Examples of physiological distress include but

are not limited to the existence of pathology, trauma or a decrease in the individual's level of

energy as a result in nutrition and hydration deficiencies (Lenz et al., 1997; Parker et al., 2005).

The psychological forces of the revised TUS model include the individual's state of mind,

their response to illness, and lack of knowledge about experienced symptoms vs. expected

symptoms. Previous research established that states of anxiety and depression contribute to

symptom presence, intensity, timing and frequency (Lenz et al., 1997; Parker et al., 2005).

Correspondingly, individuals with anxiety and who view their illness as extremely stressful

frequently exhibit more severe symptoms than those who perceive less stress (Lenz et al., 1997;

Parker et al., 2005).









Situational forces such as one's social and physical environment affect the reporting and

experience of an individual's symptoms. Job status, home and marital issues, education, support

systems, healthcare access, and everyday life behaviors such as nutrition and exercise (Lenz et

al., 1997; Parker et al., 2005).

Operational Definitions

To explore prodromal symptoms the MAPMISS will be used. The MAPMISS, originally

a telephone administered survey, lists 33 prodromal symptoms that women previously identified

in qualitative studies. The MAPMISS contains descriptors for each symptom. Women rate

prodromal symptoms according to intensity (i.e., mild, severe), frequency (i.e., daily, weekly),

and time frame (i.e., week of, more than 1 month) (Mc Sweeney et al., 2004). The MAPMISS

also contains questions relating to comorbidities, risk factors, medications, and demographics.

Prodromal scores are constructed from the product of intensity and frequency for each symptom,

then the summed scores for each symptom to create an overall prodromal score. In this

exploratory study symptoms are both the dependent variables for hypothesis land the potential

independent variables for hypothesis 2. Variable testing and analysis are explained in chapter 3

under the statistical data plan.










Table 2-1. Thirty-three prodromal symptoms


Pain/ discomfort in the
general chest
Pain/ discomfort centered
high in chest
Pain/ discomfort in left
breast
Pain/ discomfort in
neck/throat
Pain/ discomfort in
jaw/teeth
Pain/ discomfort in back,
between/ under shoulder
blades
Pain/ discomfort at top of
shoulders
Pain/ discomfort in both
arms
Pain/ discomfort in left arm
or shoulder
Pain/ discomfort in right
arm or shoulder
Pain/ discomfort in legs


Very tired/ unusual fatigue

Sleep disturbance

Anxious

Cough

Heart racing

Shortness of breath/
orthopnea

Difficulty breathing at night

Loss of appetite

Frequent indigestion

Arms week / heavy

Arms ache


Hand/Arm tingling

Numbness or burning of
both arms
Numbness or burning of
right arm
Numbness or burning of left
arm
Numbness or burning of
fingers on both hands
Numbness or burning of
fingers right hand

Numbness or burning of
fingers left hand
New onset of vision
problem
Increased intensity of
headaches
Increased frequency of
headaches
Change in thinking or
remembering

































Figure 2-1. Revised theory of unpleasant symptoms

Note: From "Collaborative development of middle-range nursing theories: toward a theory of
unpleasant symptoms," by Lenz, E. R., Suppe, F., Gift, A. G., Pugh, L. C., & Milligan, R.
A.,1995, Advances in Nursing Science, 1 7(3), p.5.Copyright 1995 by Lippincott Williams
and Wilkins. Adapted with permission.









CHAPTER 3
IVETHOD S

Design

The study conducted was an exploratory cross-sectional structured interview survey of a

convenience sample of 166 women undergoing primary event, elective, cardiac catheterization at

multiple (4) cardiac catheterization laboratory sites within the Orlando area. The cardiac

catheterization laboratory sites are the outpatient laboratories of Florida Heart Group, Central

Florida Cardiology and Cardiovascular Centers, LLC (2 sites). The main advantage to

conducting this cross-sectional design was its inherent practicality. This design was relatively

easy to manage and economical (Portney & Watkins, 2000).

Funding

Funding for this project was provided by a Sigma Theta Tau International Small Grant

sponsored by the Alpha Theta Chapter of Sigma Theta Tau International at the University of

Florida, Gainesville, Florida. Research materials and facilities support was provided by the

cardiac catheterization laboratories of Florida Heart Group, Central Florida Cardiology and

Florida Cardiology located in Orlando, Florida.

Consent

The primary investigator (PI) sought approval from the dissertation committee and the

Institutional Review Board-0 1 (IRB-0 1) for human subj ects at the University of Florida. The

IRB-01 granted approval to conduct research on expedited project # 398-2007 on September 9,

2007 with an expiration date of September 9, 2008. Subsequently, enrollment and data collection

began. A waver of health information patient protection act (HIPPA) was granted by IRB-01 in

order to more efficiently identify potential subj ects.









Potential participants were then recruited at the outpatient labs after they were prepped

for their cardiac catheterization procedure. A brief explanation of the study was presented to

each potential subj ect and permission to proceed with the consent process was sought.

Participants that agreed then reviewed and signed an informed consent, including consent for

chart review, collection and review of cardiac catheterization digital angiography disks. Once

consent was obtained, subj ects were assigned an identification (ID) number (i.e., 398-2007-201)

to de-identify them. A handwritten table containing the coding system converting patient identity

to ID number was kept in a double locked cabinet (PI access only). This was the only source of

data matching subj ects to ID numbers. The table was destroyed after data collection was

complete and prior to the study closure. Subj ects were not compensated for participation and had

the option to withdraw from the study at any time. No subj ects withdrew from the study. There

were no anticipated health benefits or risks to subj ects; subj ects did not receive any information

concerning cardiovascular status or scores on the MAPMISS. No adverse events were reported.

The PI had no conflict of interest regarding this protocol. A continuing review/ study closure

report was submitted to the IRB-01 on July 14, 2008 with a request to close the study.

Subjects and Recruitment

The convenience sample consisted of 166 women who presented to multiple (4) cardiac

catheterization laboratory sites within the Orlando area (who have not had a prior catheterization

or been diagnosed with CAD). Direct recruitment was performed in the cardiac catheterization

laboratory pre-procedure rooms. Physician referral was used. Inclusion and exclusion criteria are

listed in Table 3-1.

Sample Size Determination

Sample size was determined using a confidence interval method to calculate the required

sample size. Confidence interval method is one of the methods used when calculating n for a









logistic regression analysis (Jaccard, 2001; Menard, 2002). It was assumed that if 50% of

women with prodromal cardiac symptoms were diagnosed with CAD approximately 96 subj ects

would be required if the estimate was to fall within 10% points of the true proportion with 95%

confidence. This estimate of CAD presence was based on reported research that noninvasive

cardiovascular testing that identifies ischemia is not as predictive in women (50%) as in men

(90%) (DeCara, 2003). Additionally, the 50% assumption requires the largest sample size when

using this method for calculation. Originally the sample size was chosen to assume the estimated

proportion of CAD within 5% of the true proportion and that to complete the study 3 84 subj ects

would be required. Since recruiting that number was not possible in the timeline to complete this

dissertation, with permission of the supervisory committee chair, a change was made to assume

the estimated proportion of CAD within 10% and the required sample size was dropped to 96

subjects. Since data was already collected on 166 subjects, that number was used for the

analysis. Table 3-2 shows sample sizes for estimated 50% CAD proportion (P) to be within 10%,

5%, or 2% (d) of the true proportion with 95% confidence (Cohen, 1998; Murphy & Myors,

2004).

Variables

To address hypothesis 1: there are differences in women's prodromal cardiac symptoms

between those that have CAD and those that do not, the independent variables are CAD > 20%

and CAD > 50% stenosis as described later in the chapter. The dependent variables are inclusive

of the 33 prodromal symptoms identified on the MAPMISS, as well as presence of an abnormal

EKG, an abnormal dual stress test, comorbidities, situational forces and demographic data. Table

3-3 shows a complete list of the dependent variables for hypothesis 1.To address hypothesis 2: a

prodromal cardiac symptom or a cluster of prodromal cardiac symptoms will discriminate

between those women who have CAD and those that do not, the potential independent variables









are those same variables listed in Table 3-3. The dependent variables are CAD > 20% and CAD

S50% stenosis as described later in the chapter.

Consented subj ects were asked demographic data about their race, age, height, weight,

marital status, educational level, income, exercise regimen, menopausal status, comorbidities and

smoking history as part of the MAPMISS. Race was determined by self-report, using the Office

of Management and Budget revised race and ethnicity categories (Federal Drug Administration,

2003). Chart review was performed to ascertain information concerning results of

electrocardiograms, dual stress tests and left ventricular ej section fraction percentage.

The MAPMISS, which lists 33 prodromal symptoms previously identified by women in

qualitative studies, was administered via a structured interview technique. Patients were

interviewed in privacy, behind closed doors or pulled curtains without family members or other

staff present when possible. When family members attended the interview, instructions were

given that only the subj ect could respond to the questions and that for the purpose of this proj ect

comments or consultation should be withheld. Assurances of confidentiality regarding the

subject' s responses and anonymity after data collection were offered. The MAPMISS was used

to assess the independent variable prodromal symptoms (McSweeney et al., 2003). Prodromal

symptoms were considered new symptoms or ones that had increased in intensity/frequency (J.

C. McSweeney, personal communication, June 11, 2004). The MAPMISS contained descriptors

for each symptom (i.e., very tired, unusual fatigue). Women rated their symptoms according to

intensity (mild, severe), frequency (daily, weekly), and time frame (week of, more than 1 month).

The MAPMISS, was developed in a series of studies to establish content validity, and contains

questions relating to co-morbidities, risk factors, medications, and demographics (Mc Sweeney et

al., 2004). Prodromal scores were constructed from the product of intensity and frequency for









each symptom, then summed scores for each created an overall prodromal score. The minimum

prodromal score per symptom is 0 and the maximum score is 18. The minimum MAPMISS

prodromal score total is 0 and the maximum score is 594. Figure 3-1 shows an example of a

MAPMISS type question with calculation formula and score. (McSweeney et al., 2004).

To assess presence of the variable of CAD, coronary angiography was performed and

reviewed at the cardiac catheterization laboratory sites according to usual methods (Baim &

Grossman, 2000). Then, de-identified copies of the catheterization images were transferred to

CD-ROM format for offline review and quantitative coronary analysis (QCA) at a single location

to guard against image variability. QCA is a tool that detects and quantifies any coronary artery

lesion. The basic principles of QCA are the automatic detection of the vessel edges in a selected

portion of the artery, then quantitative measurement of the vessel length and diameters along the

selected segment (Sanmartin et al., 2004). These measurements, when applied during coronary

angiography, allow quantification of lesion severity from its shape and length (General Electric,

2003; Sanmartin et al., 2004). The success rate of QCA has been appraised to be greater than or

equal to 93% (Lienard, Sureda, & Finet, 2002).

Procedure: Quantification of CAD

All coronary angiograms were reviewed and analyzed by the PI. All coronary segments

identified visually as abnormal were measured quantitatively. The QCA required minimal user

interaction. Calibration of the QCA software was achieved with user selected portions of the

angiographic catheter using the external diameter of the catheter image for scale (Sharaf et al.,

2001). Conventional calibration of the catheter to a value for external diameter was determined

by the package insert label in either 5 or 6 French units (Sanmartin et al., 2004). Arterial

segments were then analyzed in a single view, which minimized vessel overlap/foreshortening

and maximized the apparent severity of a stenosis (Sanmartin et al., 2004; Sheifer, Arora, Gersh,









& Weissman, 2001). The start and end points of the segment of interest was user determined.

Vessel centerline and contour were determined by the edge detection algorithm. Percent stenosis

was then auto calculated by the software package from minimum lumen diameter (MLD) and a

normal reference vessel diameter (RVD) value obtained as an extrapolation of the proximal and

distal segments surrounding the stenosis. Diameter stenosis (DS) was computed in percent as

RVD MLD/RVD (100) = DS. As contours for both the catheter and arterial segments were

auto quantified by the QCA software, no manual adjustment was attempted (Sanmartin et al.,

2004; Sheifer et al., 2001).

Maj or coronary arteries analyzed were the left anterior descending, left circumflex, and

right coronary arteries. Diagonal, acute, and obtuse marginal branch vessels were considered

maj or and analyzed if they supplied enough myocardium to be potentially suitable for

revascularization (>2 mm lumen diameter) (Sheifer et al., 2001). All women with 1 or more

stenoses of > 20% and up to a 100% stenosis were defined as having CAD. Rationale for

choosing this indicator as CAD is that 20% stenosis is the marker at which aggressive therapy is

initiated in the clinical setting. Often medications such as aspirin, cholesterol lowering agents

and beta-blockers are prescribed with an elevation in noninvasive diagnostic test performance.

Women with stenoses < 20% were considered to have normal coronary arteries (Sharaf et al.,

2001). As a subcategory, women with 1 or more stenoses of> 50% were defined as having

severe CAD. Rationale for choosing this indicator as severe CAD is that 50% stenosis is the

marker at which aggressive treatment is initiated in the clinical setting. Interventions such as

intravascular coronary ultrasound, vessel hemodynamic flow studies, angioplasty and

intracoronary stenting may be recommended as an adjunct to medical therapy.









Statistical Analysis Plan

SAS (Version 9.1.3) was used for all statistical analyses and for writing the scientific

report of the quantitative data. Descriptive statistics were used to obtain the summary measures

for all data including a description of the sample characteristics. Descriptive statistics included

means, ranges, and standard deviations for continuous variables. Categorical variables were

statistically represented in frequency distributions and percentage distributions. A p-value of less

than 0.05 was considered to be statistically significant (Polit, 1996).

To address hypothesis 1, analysis of frequency (chi-square test) was used to determine

the difference in proportion of the variables that were measured on nominal and ordinal scales

between the two groups of subj ects who were diagnosed with CAD or without it. The t-test was

utilized to find the difference in mean of the variables measured on interval or ratio scales

between the two groups. To address hypothesis 2, logistic regression analysis was used to

explore the potential differences in the predictor variables between those who had CAD from

those who did not. In this study, the dependent variable CAD has been coded as zero if CAD <

20 or one if CAD > 20; and zero if CAD < 50 or one if CAD > 50. What distinguishes a logistic

regression model from the linear regression model is that the dependent variable in logistic

regression is binary or dichotomous. The analysis and interpretation of logistic regression,

however, is quite similar to the procedures of multiple regression. The predictor variables in

logistic regression can be categorical or continuous. Logistic Regression techniques have been

widely used for identifying risk factors that are associated with disease in healthcare research.

This method also has popular application in analyzing prospective clinical trials and in

identifying potentially important covariates in exploratory analyses of clinical research data

(Menard 2002).










Logistic regression overcomes many of the restrictive assumptions of regression analysis.

The fundamental assumption in logistic regression analysis is that the natural logarithm of odds

[ln (odds)] is linearly related to the independent variables. No assumptions are made regarding

the distributions of the independent variables. In fact, one of the maj or advantages of using

logistic regression is that the independent variables may be discrete or continuous. However,

since logistic regression uses maximum likelihood procedures, multivariate normal distribution

for the continuous independent variables makes the solution more stable (Hair, Anderson,

Tatham, & Black, 1998). There is no homogeneity of variance assumption, that is, variances

need not be the same within categories. Normally distributed error terms are not assumed. It is

not required that the independent variables be measured on interval or ratio scales. Logistic

regression does not rely on distributional assumptions in the same sense that discriminate

analysis does. Additionally, as with other forms of regression, multicollinearity among the

predictors can lead to biased estimates and inflated standard errors (Menard, 2002).

Estimation of model parameters in logistic regression uses the method of Maximum

Likelihood. This is a technique from probability theory which is widely used in the derivation of

statistical tests. As its name implies, Maximum Likelihood is a method which provides estimates

of the parameters which maximize the likelihood of observing the data set collected. The

Maximum Likelihood method establishes a set of equations involving the estimates of the model

parameters. These equations are then solved simultaneously to obtain the Maximum Likelihood

estimates (Pampel, 2000).

The recommended test for overall fit of a logistic regression model is the Hosmer and

Lemeshow (HL) test, also called the chi-square test. It is considered more robust than the

traditional chi-square test, particularly if continuous covariates are in the model or if the sample









size is small. If the HL goodness-of-fit test statistic is greater than 0.05, the null hypothesis that

states that there is no difference between observed and model-predicted values will not be

rej ected, implying that the model's estimates fit the data at an acceptable level (Garson, 2008).

In addition, there are several measures that provide evidence for goodness-of-fit in logistic

regression. These are: the Akaike Information Criterion (AIC), the Bayesian Information

Criterion (BIC), and the Schwartz Information Criterion (SIC). The lower these measures are the

better model fit (Pampel, 2000).

To obtain an optimal model, the predictor variables were added in a step-type fashion.

There are three step-type logistic regression procedures, forward, backward and stepwise. For

this study, backward procedure was used to determine the optimal model from the maximum

model. In addition, the point and interval estimates of the odd ratios of the predictor variables

were reported. The odds ratio for a given independent variable represents the factor by which

the odds of an event (e.g. CAD > 50) change for a one-unit change in the independent variable

(Hair et al., 1998).










Table 3-1. Inclusion/exclusion criteria data collection
Inclusion criteria Exclusion criteria
Signed consent Inability to verbally communicate (Aphasia, Intubated)
Over age 40, under the age of Emergent catheterization (AMI)
90
Without prior catheterization Pre-medicated with narcotics
Without prior diagnosis of CAD Catheterization for surgical clearance without cardiac
indication (Abnormal EKG or exercise/nuclear stress test)
Elective Catheterization Any other psychiatric/medical condition which in PI' s
opinion would make participation not in subj ect' s best
interest.
English speaking

Table 3-2. Sample sizes for estimated 50% of sample with CAD
P d n
0.50 0.10 96
0.50 0.05 384
0.50 0.02 2401









for hypothesis 1

Increased frequency of headaches
Change in thinking or remembering
History of chest pain
History of congestive heart failure
History of coronary heart disease
History of heart irregularity, heart murmur or
valve disease
History of high blood pressure
History of high cholesterol
History of depression or other emotional problems
History of cancer
History of diabetes/ low blood sugar
History of chronic heart burn, stomach problems
(GERD
History of chronic back pain
History of joint problems (arthritis)
History of osteoporosis (brittle bones)
History of stroke
History of thyroid disease
History of gallbladder disease
History of hysterectomy
History of menopause onset
History of estrogen replacement
Current estrogen replacement use
History of birth control use
History of smoking (at least 100 cigarettes in life)
Current smoker
Exposed to secondhand smoke
Exercise
Employed
Retired
Children living at home
Income of < $30,000
Income of > $30,000
Years of birth control use
Family history of MI
Pack year history of smoking
Years of secondhand smoke exposure
Weight (lbs)
Height (inches)
Exercise times per month
Hours per attempt of exercise


Table 3-3. Complete list of dependent variables
Variables
Abnormal EKG
Abnormal dual stress test
Generalized chest pain
Centered high in chest pain
Left breast pain
Neck/throat pain

Jaw/teeth pain
Back, between/under shoulder blade pain
Top of shoulders pain
Both arms pain
Left arm pain
Right arm pain

Leg pain
Very tired, unusual fatigue
Sleep disturbance
Anxious
Cough
Heart racing
Shortness of breath/ orthopnea
Difficulty breathing during the night
Loss of appetite
Frequent indigestion
Arms weak/heavy
Arms ache
Hands/arms tingling
Numbness or burning of both arms
Numbness or burning of right arm
Numbness or burning of left arm
Numbness or burning of fingers on both hands
Numbness or burning of fingers on right hand
Numbness or burning of fingers on left hand
New onset vision problem
Increased intensity of headaches
Age of subj ect
MAPMISS score
Symptom score
History of chronic lung disease
History of migraine headaches
Age at hysterectomy
Years of estrogen replacement use
Current estrogen replacement use












LOCATION OF PAIN OR DISCOMFORT
Symptom:
Chest Pain/Discomfort/Pressure for Yes, designate Intensity

SNo (0)* Severe (3)1 Medium (2)0 Mild (1)

Time Frame: week of I month of O more than month

Freq: Odaily (6) sev;eraltimes week (5) at least lxperwieek (4)

SAt least 2x per month (3) 1 monthly (2) less than monthly (1)

*= (point value)
Calculation Formula: Intensity x Frequency (minimum score = 0, maximum
score = 18)
Score for this example: 3x5=15


Figure 3-1. Example of a MAPMISS type question with calculation formula and score
(McSweeney et al., 2004)









CHAPTER 4
FINDINGS

The primary purpose of this study was twofold. First, to examine the potential differences

in women's prodromal cardiac symptoms between those that have CAD and those that do not by

assessing symptom presence prior to cardiac catheterization and quantifying CAD in the cardiac

catheterization laboratory setting. The second purpose was to determine a prodromal symptom or

a cluster of prodromal cardiac symptoms that can be most helpful to healthcare professionals in

identifying women who are at-risk of having CAD. Analysis of frequency (chi-square test), two

independent samples t-test, and logistic regression analysis were performed to evaluate the

proposed hypotheses for this research proj ect. SAS (Version 9. 1.3) was used to perform all the

analyses. This statistical software was chosen for its recommendation of being superior for

logistic regression analysis (Menard, 2002).

Data Collection and Descriptive Statistics

Female patients (n=166) were recruited during outpatient cardiac catheterization

laboratory appointments at one of four enrollment sites in Orlando, Florida: Cardiovascular

Centers, LLC. (2 centers)(n=98), Florida Heart Group, PA (n=13), and Central Florida

Cardiology Group, PA (n=55). Patients were excluded from the study if they were younger than

40 years of age or older than 89 years of age, not able to speak English, had a previous

diagnostic cardiac catheterization or were present for surgical clearance. After an introduction of

the study and gathering of informed consent, patients were administered the MAPMISS. The

survey took approximately 20-30 minutes to complete. Upon completion of the survey

questionnaire, patients completed their participation in the study. Medical record review was

conducted for information regarding medications and previously performed non-invasive

diagnostic tests (i.e., electrocardiogram and stress tests). Immediately post survey patients









underwent a diagnostic catheterization. Cardiac catheterization films were reviewed and

analyzed by the primary investigator for the presence of CAD using quantitative QCA. Table 4-1

presents relative percentages of the total sample by recruitment site.

Subject Demographics

The mean age of the sample was 65.86 years with a range of 40 to 87 years of age. The

mean weight of the sample was 77.4 kilograms (kg) with a range of 37.3 to 147.7 kg. The mean

height was 161.2 centimeters (cm) with a range of 130.8 to 177.8 cm. The mean body mass

index (BMI) was 29.7 with a range of 14. 1 to 52.5. Subj ects (75%) reported exercising on

average of 17 times per month for an average of .97 hours per attempt. The most frequent

exercise performed was walking (37%) with 18% engaging in aerobic exercise. Ethnically,

85.54% of participants self-rated as Caucasian, 7.83% rated as African American/Black, 5.42%

rated as Hispanic/non-white, 0.6% rated as Asian and 0.6% rated as Indian. The maj ority of

participants were married (54.22%), 18.67% reported being separated/divorced, 5.42% reported

being single/never married, and 21.69% reported being widowed. Of the total sample, 59.03%

had earned less than a high school diploma, 33.13% had earned a high school diploma, and

7.83% had achieved greater than a high school degree. The maj ority of the subjects were

retired/not working (61.45%), 29.52% were employed full time, 6.63% worked part time and

2.4% were unemployed. Of the participants, 67.47% reported a total household income of

<$30,000. Table 4-2 provides demographic information for the total sample of female patients.

McSweeney Acute and Prodromal Myocardial Infarction Survey

The MAPMISS, which lists 33 prodromal symptoms previously identified by women in

qualitative studies, was administered via a structured interview technique and was used to assess

the variables for prodromal symptoms. The MAPMISS contains descriptors for each symptom.

Women rated prodromal symptoms according to intensity (i.e., mild, severe), frequency (i.e.,










daily, weekly), and time frame (i.e., week of, more than 1 month). The MAPMISS also contains

questions relating to comorbidities, risk factors, medications, and demographics (Mc Sweeney et

al., 2004). Women never added symptoms during the current study, indicating that the tool was

comprehensive. Prodromal scores were constructed from the product of intensity and frequency

for each symptom, and then summed scores for each symptom were calculated to create an

overall prodromal score. Subj ects of this study had a mean MAPMISS score of 79.95 (SD = 53,

Range = 6-307) and the symptom mean score was 8.67 (SD = 4, Range 1-24).

Particular points of interest among the variables contained on the MAPMISS for the total

sample were the symptoms of neck/throat pain, hand/arm tingling and numbness or burning of

the arms. Those subjects that reported experiencing neck/throat pain (25.30%) had a mean age of

64.3, slightly younger than the overall mean age of 65.9 years that was reported for the sample.

The same is true for those that had a complaint of hand/arm tingling (37.35%) to one or both

arms, the mean age of these subj ects was 65.1 years. The MAPMISS did not discriminate

between those with tingling in both hands/arms, the right hand/arm or the left hand/arm. In order

to differentiate this variable from others, subj ects were given the additional descriptors of a

stinging or prickling sensation. The variable of numbness or burning of the arms was split into

three separate variables according to the MAPMISS instructions. To differentiate this variable

numbness was given the additional descriptor of no feeling, and burning was described as being

hot or on fire. Of those subj ects that experienced numbness or burning to the arms 19.27% had

this symptom in both arms (mean age of 59.7), 8.43% had numbness or burning to the right arm

(mean age of 66.8) and 7.22% had numbness or burning to the left arm (mean age of 54.6).

Other variables of interest included on the MAPMISS are described as follows.

Approximately 48% of the women in the study reported having experienced the onset of









menopause. The average age of onset was 50 years of age. The mean age of the 80 women who

experienced menopause onset is currently 69.31 years. Slightly more than 50% of the sample

reported having had a hysterectomy at the mean age of 43.70 years with 37% having had both

ovaries removed. A history of birth control use was reported by 56.02% of the sample with the

mean 7.76 years of use. A history of estrogen replacement therapy was reported by 54.21% of

the sample with mean years of use of 9.70. Current estrogen replacement therapy was reported

by about 15% of the women for a range of 1 to 32 years, with a mean of 18.18 years of use.

There were 13 (7.83%) current smokers enrolled in the study and 79 (44.57%) former smokers

with an average pack year history of 21.6. The vast maj ority of women (80.72%) in the study

reported having been exposed to secondhand smoke for an average of 32.50 years (range 3 to 66

years). Table 4-3 presents the frequency distribution and relative percentages of prodromal

symptom variables of the total sample.

Medical Variables

Patients' medical records were reviewed to obtain the following information. The sample

of women possessed a mean left ventricular ej section fraction of 62%. About 48% of the subj ects

were diagnosed with an abnormal electrocardiogram, while 69% were diagnosed with an

abnormal dual stress test, and 38% had both. Of the entire sample, 63.86% had a history of high

blood pressure and 73.49% met criteria for high cholesterol. In the sample, 24. 10% of patients

were diabetic and 20.48% had a reference of mild to moderate valve disease. Table 4-4 provides

information regarding medical variables for subj ects.

Comorbidity Variables

As part of the MAPMISS administration each subj ect self-reported comorbidity. Sixty-

three percent of subj ects reported that they had some form of chronic j oint problems (arthritis)

while 26.5 1% reported having osteoarthritis. Chronic heart burn was reported by 50.60% of the









subj ects in the study. A history of migraine headaches was reported by 28.92% of the sample.

Approximately 3 8% reported some form of thyroid disease. Both chronic lung disease and

chronic back pain were reported by 59 of the subj ects (3 5.54%). Forty six subj ects (27.71%)

revealed that they had previous to this study, been diagnosed with some form of cancer. Table 4-

5 provides the frequency distribution regarding comorbidity variables for the subj ects.

Coronary Angiography Variables

Post MAPMISS administration, each patient was subj ected to an elective diagnostic

cardiac catheterization by her physician. Selective coronary angiography was performed from the

femoral approach.. Coronary arteries were evaluated by the primary investigator with the use of

QCA which allows both for catheter-based image calibration and for automated vessel

contour detection (General Electric, 2003; Sanmartin et al., 2004). Reference vessel diameter

(RVD) and minimal luminal diameter (MLD) were computed automatically by the QCA

software. Diameter stenosis (DS) was computed in percent as: RVD MLD/RVD (100) = DS

(General Electric, 2003). Only segments with a reference diameter >2.0 mm were evaluated.

Segments with smaller diameter were considered to be absent; DS > 20% was used as a cutoff

value to define the presence of CAD. DS > 50% was used as a cutoff value to define significant

severe CAD stenosis. CAD > 20% DS was present in 61.4% of the subj ects, while 53.6% of the

subj ects demonstrated severe CAD > 50% DS. The left anterior descending artery was the vessel

that most commonly demonstrated stenosis for both > 20% CAD (51.8%) and for severe CAD >

50% (39.1%). Table 4-6 provides information regarding coronary artery variables for subjects.

Data Analysis

*Hypothesis 1: There are differences in women's prodromal cardiac symptoms between
those that have CAD and those that do not.









To address hypothesis 1, analysis of frequency was used to determine the difference in

proportion (or percentage) of the variables measured on nominal or ordinal scales between the

two groups. Analysis of frequency is analogous to testing the relationship between the two

variables that are measured on the nominal or ordinal scales (i.e., presence and absence of high

cholesterol versus presence or absence of CAD). In addition, the two samples t-test was used to

determine the difference in means of the variables measured on the interval and ratio scales

between the two groups. The results indicated that among those with a high cholesterol, higher

percentages of the subj ects had CAD > 20%, or equivalently, it can be stated that the results

indicated that there was a significant relationship between CAD presence and high cholesterol

(Chi-square = 8.43, p = 0.0037). Among those with high cholesterol, 81.37% had CAD> 20%

vs. 60.94% with CAD < 20%. This report of percentages is the conditional probability, which

SAS calls Row Percent; it comes from a contingency table by cross classifying CAD > 20% and

a history of high cholesterol. These percentages will not add to 100% since the Row Percent of

the two different rows are reported. Table 4-7 shows an example of the contingency table of

CAD > 20% by history of high cholesterol. There was a significant relationship between cancer

and CAD in that more women with a history of cancer had CAD (Chi-square = 4. 18, p =

0.0410). A significantly higher percentage of diabetic woman had CAD (30.39% vs. 14.06%,

Chi-square = 5.73, p = 0.0138). The relationship between CAD and subjects who had

experienced menopause was statistically significant (Chi-square = 5.67, p = 0.0173). Among

those who were or had used hormones, 8.82% had CAD > 20% vs. 20.31% with CAD < 20%

(Chi-square = 4.5 1, p = 0.0336). A lower percentage of those who had used birth control had

CAD (47.08% vs. 70.31%, Chi-square = 8.63, p = 0.0030). Among those who had a history of

smoking, 12.50% had CAD > 20% vs. 3.92% with CAD < 20% (Chi-square = 4.31, p = 0.0378).










The relationship between CAD presence and employment was statistically significant (Chi-

square = 15.52, p < 0.0001). The results reflected a lower percent of employment for women

with CAD (24.5 1% vs. 54.61%). A higher percentage of women who were retired had CAD

(72.55% vs. 43.75%, Chi-square = 13.77, p = 0.0002). A lower percentage of women who had

children at home had CAD (11.76% vs. 34.38%, Chi-square = 12.34, p = 0.0004). This study is

viewed as exploratory. The study consists of a large number of variables that can have an effect

on CAD. Both levels of significance are specified. If the tests were performed under the

complete null hypothesis which indicates that the difference in proportion for all the variables

that are listed in table 4-8 between the two groups were zero, then the level of significance

(alpha) must have been adjusted for the overall error. Using the Bonferroni procedure, the new

level of significance was calculated as: 0.05/65 = 0.0007. As shown in Table 4-8, under the

complete null hypothesis, fewer variables were statistically significant given alpha = 0.0007.

Table 4-9 shows the mean difference of symptom variables between two levels of CAD >

20%. Using the t-test, as indicated in Table 4-9, the differences in mean age (p = 0.0001) of the

subj ects, history of migraine headaches (p = 0.023 5), years of birth control use (p = 0.0346), and

years of secondhand smoke exposure (p = 0.0058) between the two CAD levels were statistically

significant, meaning those with CAD > 20% were older, had shorter years of birth control use,

fewer migraine headaches and had longer secondhand smoke exposure. If these t-tests were

performed under the complete null hypothesis, the new level of significance, controlling for the

overall error, would be 0.0031.

Table 4-10 shows the relationship between severe CAD and women's prodromal cardiac

symptoms. As indicated in Table 4-10, the relationship between severe CAD and neck/throat

pain indicates that a lower percentage of women who experienced neck/throat pain had severe










CAD (19.10% vs. 32.47%, Chi-square = 3.90, p = 0.0482) as did those with numbness or

burning of both arms (12.36% vs. 27.27%, Chi-square = 5.90, p = 0.0151). A higher percentage

of women who experienced hand/arm tingling had severe CAD (44.94% vs. 28.57%, Chi-square

= 4.73, p = 0.0297). Among those with a history of high cholesterol 79.78% had severe CAD vs.

66.23% that did not (Chi-square = 3.89, p = 0.0487) A higher percentage of those with a history

of stroke had severe CAD (11.24% vs. 2.60%, Chi-square = 4.59, p = 0.0321). A lower

percentage of those with a history of birth control use had severe CAD (47. 19% vs. 66.23%, Chi-

square = 6.08, p = 0.0137). A higher percentage of those with a history of gallbladder disease

had severe CAD (39.33% vs. 23.3 8%, Chi-square = 4.83, p = 0.0279) as did those with a history

of menopause (58.43% vs. 35.06%, Chi-square = 9.03, p = 0.0027). The relationship between

severe CAD and a history of thyroid disease was statistically significant (Chi-square = 8.75, p =

0.0031). The relationship between severe CAD and those women who were employed, had

children living at home and were retired was also statistically significant. Finally, the association

between CAD>50% and CADI50% and the demographic variables of race, marital status, and

education were statistically nonsignificant. As before, if these tests were performed under the

complete null hypothesis, the new level of significance, controlling for the overall error, would

be 0.0007.

Table 4-11 shows the mean difference of symptom variables between two levels of

severe CAD. Using the t-test, as indicated in Table 4-8, the differences in mean age of the

subj ects (p = 0.0001) and years of secondhand smoke exposure (p = 0.003 1) between the two

severe CAD levels were statistically significant. If these t-tests were performed under the

complete null hypothesis, the new level of significance, controlling for the overall error, would

be 0.0020.










*Hypothesis 2: A prodromal symptom or a cluster of prodromal cardiac symptoms will
discriminate between those women who have CAD and those that do not.

To address Hypothesis 2, backward stepwise logistic regression models, permitting the

use of both continuous and categorical variables, were constructed to determine if differences

existed between those with CAD < 20% (coded as 0) and with CAD > 20% (coded as 1).

Modeling began by including in the model all predictor variables that either had at least a

marginal bivariate association with the outcome variables or for which there is some rationale

that the variable may be a confounder or effect modifier for other variables. In this study the

rationale for inclusion was based on the TUS theoretical model. In particular, the variables that

had a p-value of no more than 0. 10 using the chi-square and t test (Tables 4-8 and 4-9) were

included in the maximum logistic model. To obtain an optimal model, the predictor variables

were deleted in a stepwise fashion. The results of the optimal logistic regression model indicated

that the variables abnormal dual stress tests, age of the subject, history of high cholesterol,

history of diabetes and hand/arm tingling were statistically significant between the two CAD

20% levels (Table 4-12). In the optimal model, the tests for assessing model fit through

explanatory capability was supportive of the model; the likelihood ratio test had a value of 56.50

(p < 0.0001) with 5 degrees of freedom (df) and the score test has a value of 48.57 (p < 0.0001)

with 5 df. In addition the Hosmer-Lemeshow statistic was 30.41, df = 23, p = 0. 1379, which

supported the adequacy of the model, i.e., this measure of goodness of fit suggests that model-

predicted cell proportions are acceptably close to the observed proportions.

Those subj ects with an abnormal dual stress test had 2.58 times higher odds of having

CAD > 20%. Subj ects who complained of the prodromal symptom of hand/arm tingling had

3.1 1 times higher odds of having CAD > 20%. Diabetic subj ects had 4.57 times higher odds of

having CAD > 20%. In addition, high cholesterol and age were significant risk factors for CAD.









Subj ects with high cholesterol had 2.90 times higher odds of having CAD >20% and with every

one year increase in age the odds of them having CAD > 20% increased by 1.12 times (Table 4-

13).

Then backward logistic regression models were constructed to determine if differences

existed between those with CAD < 50% (coded as 0) and with CAD > 50% (coded as 1). The

results of the optimal logistic regression model indicated that the variables hand/arm tingling,

years of secondhand smoke exposure, history of thyroid disease, history of menopause onset, age

of the subj ect, and a history of diabetes were statistically significant between the two severe

CAD levels (Table 4-14). In the optimal model (Table 4-14), the tests for assessing model fit

through explanatory capability was supportive of the model; the likelihood ratio test had a value

of 60.96 (p < 0.0001) with 6 df and the score test has a value of 49.87 (p < 0.0001) with 6 df. In

addition the residual chi-square test was 21.41, df = 20, p = 0.3496, which supported the

adequacy of the model.

As indicated in Table 4-15, those subjects who experienced the prodromal symptom of

hand/arms tingling had 3.18 times higher odds of having severe CAD. Subj ects who were

diabetics had 3.22 times higher odds of having severe CAD. Women of in this study who had a

history of thyroid disease had 2.76 times higher odds of having severe CAD. To conclude

subjects that had experienced menopause onset had a 2.44 times higher odds of having severe

CAD. Finally, those subj ects who were exposed to secondhand smoke had 1.03 higher odds of

having severe CAD and with every one year increase in age the odds of those exposed to

secondhand smoke having severe CAD increased by 1.10.

















Table 4-2. Demographic characteristics of the sample
Demographic variable Mean SD
Age (years) 65.86 11.26
Weight (kilograms) 77.4 42.21
Height (centimeters) 161.2 2.90

Ethnicity N (166) %
Caucasian 142 85.54
African American/Black 13 7.83
Hispanic/Non-White 9 5.42
Asian 1 0.60
Indian 1 0.60

Marital status
Married 90 54.22
Widowed 36 21.69
Separated/Divorced 31 18.67
Single/Never Married 9 5.42

Education
Less than High School Degree 98 59.03
High School Degree 55 33.13
More than High School Degree 13 7.83

Employment
Retired 102 61.54
Employed Full Time 49 29.42
Employed Part Time 11 6.63
Unemployed 4 2.4

Income
Less than $30K 112 67.47
Equal or More than $30K 54 32.53


Table 4-1. Recruitment locations of the sample
Recruitment site
Cardiovascular Centers, LLC
Central Florida Cardiology, PA
Florida Heart Group, PA


N (166)
98
55
13


59.36
33.13
7.83









Table 4-3. Prodromal symptom frequency distribution and relative percentages
Pain symptom N (166) %
Back, between/under shoulder blades 81 48.79
Centered high in chest 68 40.96
Left arm 49 29.51
Neck/throat 42 25.30
Left breast 41 24.69
Generalized chest 37 22.29
Jaw/teeth 30 19.28
Right arm 27 18.07
Legs 32 16.27
Top of shoulders 18 10.84
Both arms 18 10.84

General symptom N (166) %
Very tired, unusual fatigue 136 81.93
Shortness ofbreath/orthopnea 126 75.90
Heart racing 87 52.41
Change in thinking or remembering 70 42.17
Sleep disturbance 70 42.17
Cough 66 39.76
Numbness or burning of fingers on both hands 64 38.55
Hands/arms tingling 62 37.35
Frequent indigestion 57 34.34
Anxious 39 23.49
Arms weak/heavy 35 21.08
Numbness or burning of both arms 32 19.27
Arms ache 30 18.07
Numbness or burning of fingers on left hand 26 15.66
Increased frequency of headaches 22 13.25
Loss of appetite 20 12.04
Increased intensity of headaches 19 11.44
Numbness or burning of fingers on right hand 16 9.63
Difficulty breathing during the night 16 9.63
New onset of vision problems 15 9.03
Numbness or burning of the right arm 14 8.43
Numbness or burning of the left arm 12 7.22









Table 4-4. Medical variables distribution
Medical variable Mean SD
Ejection fraction 0.62 0.08

N= 166 %
High cholesterol 122 73.49
Abnormal dual stress test 114 68.67
High blood pressure 106 63.86
Abnormal EKG 80 48.19
Both abnormal EKG & dual 63 37.95
Diabetic 40 24.10
Valve disease 34 20.48

Table 4-5. Comorbidity frequency distribution and relative percentages
Comorbidity variable N (166) %
Chronic j oint problem 105 63.25
Chronic heart burn 84 50.60
Thyroid disease 63 37.95
Chronic lung disease 59 35.54
Chronic back pain 59 35.54
Gallbladder disease 53 31.93
Depression 49 29.52
Migraine headaches 48 28.92
Cancer 46 27.71
Osteoporosis 44 26.51
Stroke 12 7.22
History of chest pain 11 6.62
History of CAD 6 3.61
Congestive heart failure 6 3.61

Table 4-6. Coronary angiography variables distribution
CAD > 20 CAD > 50
Coronary angiography variable N (166) % N (166) %
Presence of disease 102 61.4 89 53.6
Left anterior descending 86 51.8 65 39.1
Right coronary artery 61 36.7 43 25.9
Left circumflex 44 26.5 23 13.8
Diagonal 36 21.6 26 15.6
Obtuse marginal 22 13.2 15 13.2
Left main 4 2.4 3 1.8
Septal 2 1.2 0 0.0










Table 4-7. Example of the contingency table for CAD > 20% by history of high cholesterol
CAD >20% History of high cholesterol Total
Frequency percent
Row percent
Column percent 0 1
0 25.00 39.00 64.00
15.06 23.49 38.55
39.06 60.94
56.82 31.97
1 19.00 83.00 102.00
11.45 50.00 61.45
18.63 81.37
43.18 68.03
Total 44.00 122.00 166.00
26.51 73.49 100.00










Table 4-8. Relationship between CAD presence and women's prodromal cardiac symptoms


CAD < 20
(%)
48.44
60.94
20.31
46.88
25.00
32.81
25.63
53.13
9.38
10.94
32.81
18.75
15.63
75.00
45.31
22.58
34.38
57.81
70.31
8.38
15.63
35.94
23.44
17.11
29.69
26.56
9.38
10.94
40.63
9.38
14.06
14.06
14.06
14.06
46.88
14.69
0.00
1.61
53.13

54.69


CAD > 20
(%)
48.04
73.53
23.53
37.83
24.51
20.59
19.61
46.08
11.76
10.78
27.45
14.71
21.57
86.27
40.20
24.51
43.14
49.02
79.41
9.80
9.80
33.33
19.61
18.63
42.16
14.71
7.84
4.70
37.25
9.80
16.67
5.88
9.80
12.75
39.22
7.84
4.90
4.90
47.06

69.61


Chi-
suare
0.01
2.89
0.23
1.50
0.01
3.11
0.42
0.78
0.23
0.01
0.54
0.47
0.89
3.38
0.42
0.08
1.26
1.22
1.78
0.01
1.26
0.12
0.35
0.06
2.61
3.55
0.12
2.14
0.19
0.01
0.20
3.20
0.70
0.06
0.95
0.63
3.23
1.18
0.58

3.79


Variables
Abnormal EKG
Abnormal dual stress test
Generalized chest pain
Centered high in chest pain
Left breast pain
Neck/throat pain
Jaw/teeth pain
Back, between/under shoulder blade pain
Top of shoulders pain
Both arms pain
Left arm pain
Right arm pain
Leg pain
Very tired, unusual fatigue
Sleep disturbance
Anxious
Cough
Heart racing
Shortness of breath/ orthopnea
Difficulty breathing during the night
Loss of appetite
Frequent indigestion
Arms weak/heavy
Arms ache
Hands/arms tingling
Numbness or burning of both arms
Numbness or burning of right arm
Numbness or burning of left arm
Numbness or burning of fingers on both hands
Numbness or burning of fingers on right hand
Numbness or burning of fingers on left hand
New onset vision problem
Increased intensity of headaches
Increased frequency of headaches
Change in thinking or remembering
History of chest pain
History of congestive heart failure
History of coronary heart disease
History of heart irregularity, heart murmur or
valve D
History of high blood pressure


p-value
0.9601
0.0887
0.6279
0.2199
0.9432
0.0778
0.5163
0.3767
0.6798
0.9754
0.4610
0.4933
0.3447
0.0661
0.5159
0.7784
0.2615
0.2696
0.1821
0.9273
0.2621
0.7309
0.5560
0.8145
0.1060
0.0594
0.7296
0.1435
0.6641
0.9274
0.6532
0.0736
0.4016
0.8075
0.3307
0.4263
0.1575
0.4102
0.4467

0.0515













p-value
0.0037
0.0880

0.0410
0.0166
0.9021

0.3601
0.2495
0.4780
0.1058
0.0822
0.0691
0.8446
0.0173
0.9232
0.0336
0.0033
0.4170

0.0378
0.1560
0.7622
0.0001
0.0002
0.0004
0.1936
0.1936


Table 4-8. Continued


CAD < 20
(%)
60.94
37.50

18.75
14.06
50.00

31.25
57.81
23.44
3.13
29.69
23.44
51.56
35.94
54.61
20.31
70.31
51.56

3.92
75.00
73.44
54.69
43.75
34.98
26.56
73.44


CAD > 20
(%)
81.37
25.00

33.33
30.39
50.98

38.54
66.67
28.43
9.80
43.14
37.25
50.00
54.90
53.92
8.82
47.26
45.10

12.50
84.00
75.49
24.51
72.55
11.76
36.27
63.73


Chi-
suare
8.43
2.91

4.18
5.73
0.02

0.84
1.32
0.51
2.61
3.02
3.45
0.04
5.67
0.01
4.51
8.63
0.66

4.31
2.01
0.09
15.52
13.77
12.34
1.59
1.69


Variables
History of high cholesterol
History of depression or other emotional
problems
History of cancer
History of diabetes/ low blood sugar
History of chronic heart burn, stomach problems
(GERD
History of chronic back pain
History of joint problems (arthritis)
History of osteoporosis (brittle bones)
History of stroke
History of thyroid disease
History of gallbladder disease
History of hysterectomy
History of menopause onset
History of estrogen replacement
Current estrogen replacement use
History of birth control use
History of smoking (at least 100 cigarettes in
life)
Current smoker
Exposed to secondhand smoke
Exerci se
Employed
Retired
Children living at home
Income of < $30,000
Income of > $30,000
Note: N= 166
























































64

102

64

102


112.00

82.00

54.00

51.50


Table 4-9. Differences in variable means between CAD <20% and > 20%
Variable CAD N Mean Std dev Minimum Maximum t-test p-value


Age of subj ect


MAPMISS score



Symptom score


History of chronic
lung disease

History of migraine
headaches

Age at
hysterectomy

Years of estrogen
replacement use

Current estrogen
replacement use

Years of birth
control use

Family history of
MI

Pack year history
of smoking

Years of
secondhand smoke
exposure

Weight (lbs)


Height (inches)


< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20

< 20

> 20


59.8440

69.6370

83.8440

77.5100

8.9219

8.5098

0.4063

0.4216

0.6875

0.2353

21.4840

22.5690

6.42970

4.52940

0.31250

0.0000

5.6797

3.4363

0.7969

0.7647

10.617

10.123

21.4060

29.6670

174.840

167.4100

63.4800

63.4750


10.8850

9.7866

56.8430

50.5970

4.2958

4.4226

1.4111

0.4962

1.9262

0.4263

22.1400

24.1120

9.6110

7.8481

2.3763

0.0000

6.9461

6.3790

1.3936

0.51080

15.5320

15.4690

18.1960

18.7240

43.8300

41.1200

3.2594

2.6754


40.00

42.00

8.00

6.00

2.00

1.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00

0.00


87.00

85.00

307.00

250.00

21.00

24.00

11.00

1.00

11.00

1.00

66.00

73.00

32.00

35.00

19.00

0.00

30.00

30.00

11.00

2.00

80.00

60.00

61.00

66.00

310.00

325.00

69.00

70.00


6.01 0.0001


0.75 0.4554


0.59 0.5555


0.08 0.9396


2.29 0.0235


0.29 0.7715


1.39 0.1662


1.33 0.1852


2.13 0.0346


0.21 0.8325


0.20 0.8416



2.80 0.0058



1.10 0.2708


0.01 0.9915










Table 4-9. Continued
Variable CAD N Mean Std dev Minimum Maximum t-test p-value

Exercise times per < 20 64 12.0630 10.4210 0.00 30.00
Month > 20 102 13.2160 10.6090 0.00 30.00

< 20 64 0.7539 0.9210 0.00 4.00 0.69 0.4935
Hours ~ prte t 20 102 0.7132 1.0153 0.00 6.00
of exercise
> 20 102 0.4028 0.3819 0.00 1.00
Note: N= 166









Table 4-10. Relationship between severe CAD and women's prodromal cardiac symptoms
CAD < 50 CAD > 50 Chi-
Variables (%) (%) square p-value
Abnormal EKG 46.75 49.44 0.12 0.7299
Abnormal dual stress test 64.94 71.91 0.93 0.3339
Generalized chest pain 23.38 21.35 0.10 0.7543
Centered high in chest pain 42.86 39.33 0.21 0.6445
Left breast pain 23.38 25.84 0.14 0.7133
Neck/throat pain 32.47 19.10 3.90 0.0482
Jaw/teeth pain 18.18 17.98 0.01 0.9728
Back, between/under shoulder blade pain 51.95 46.07 0.57 0.4497
Top of shoulders pain 12.99 4.82 0.68 0.4087
Both arms pain 10.39 11.24 0.03 0.8612
Left arm pain 31.17 28.09 0.19 0.6645
Right arm pain 22.08 11.24 3.56 0.0591
Leg pain 19.48 19.10 0.01 0.9507
Very tired, unusual fatigue 76.62 86.52 2.72 0.0985
Sleep disturbance 42.86 41.57 0.03 0.8673
Anxious 24.00 22.60 0.01 0.9517
Cough 37.66 41.57 0.26 0.6077
Heart racing 57.14 48.31 1.29 0.2560
Shortness of Breath/ orthopnea 72.73 78.65 0.79 0.3734
Difficulty breathing during the night 9.09 10.11 0.05 0. 8240
Loss of appetite 14.24 10.11 0.68 0.4101
Frequent indigestion 33.77 34.83 0.02 0.8854
Arms weak/heavy 23.38 19.10 0.45 0.5007
Arms ache 19.48 16.85 0.19 0.6610
Hands/arms tingling 28.57 44.94 4.73 0.0297
Numbness or burning of both arms 27.27 12.36 5.90 0.0151
Numbness or burning of right arm 11.69 5.62 1.97 0.1605
Numbness or burning of left arm 9.09 5.62 0.74 0.3889
Numbness or burning of fingers on both hands 42.86 34.83 1.12 0.2894
Numbness or burning of fingers on right hand 11.69 7.87 0.69 0.4052
Numbness or burning of fingers on left hand 12.99 17.98 0.78 0.3776
New onset vision problem 12.99 5.62 2.72 0.0986
Increased intensity of headaches 14.29 8.99 1.14 0.2851
Increased frequency of headaches 12.99 13.48 0.01 0.9251
Change in thinking or remembering 45.45 39.33 0.64 0.4252
History of chest pain 6.49 6.74 0.01 0.9489
History of congestive heart failure 0.00 5.62 4.46 0.0620
History of coronary heart disease 1.33 5.62 2.11 0.1454
History of heart irregularity, heart murmur or 50.65 48.31 0.09 0.7641
valve disease









Table 4-10. Continued
CAD < 50 CAD > 50 Chi-
Variables (%) (%) square p-value
History of high blood pressure 58.44 68.54 1.81 0. 1769
History of high cholesterol 66.23 79.78 3.89 0.0487
History of depression or other emotional 33.77 26.44 1.05 0.3061
problems
History of cancer 25.97 29.21 0.22 0.6419
History of diabetes/ low blood sugar 18.18 29.21 2.75 0.0974
History of chronic heart burn, stomach problems 53.25 48.31 0.40 0.5262
(GERD
History of chronic back pain 28.57 41.57 3.05 0.0809
History of joint problems (arthritis) 61.04 65.17 0.30 0.5821
History of osteoporosis (brittle bones) 22.08 30.34 1.45 0.2292
History of stroke 2.60 11.24 4.59 0.0321
History of thyroid disease 25.97 48.31 8.75 0.0031
History of gallbladder disease 23.38 39.33 4.83 0.0279
History of hysterectomy 53.25 48.31 0.40 0.5262
History of menopause onset 35.06 58.43 9.03 0.0027
History of estrogen replacement 53.25 55.06 0.05 0.8155
Current estrogen replacement use 16.88 10.11 1.64 0.1995
History of birth control use 66.23 47.19 6.08 0.0137
History of smoking (at least 100 cigarettes in 53.25 42.70 1.84 0. 1747
life)
Current smoker 10.39 4.49 2.14 0.1436
Exposed to secondhand smoke 75.32 85.06 2.46 0.1165
Exercise 72.73 76.40 0.29 0.5868
Employed 51.95 22.47 15.54 0.0001
Retired 46.75 74.71 13.09 0.0003
Children living at home 31.17 11.24 10.07 0.0015
Income of < $30,000 27.27 37.08 1.81 0.1787
Income of > $30,000 72.73 62.92 1.81 0.1787










Table 4-11. Differences in variable means between CAD < 50% and > 50%


(166)
77
89

77
89

77
89

77
89

77
89

77
89

77
89

77
89

77
89

77
89

77

89

77
89


Variable


Age of subj ect



MAPMISS score



Symptom score


History of chronic
lung disease


History of migraine
headaches


Aoe at
hysterectomy


Years of estrogen
replacement use


Current estrogen
replacement use


Years of birth
control use


Family history of
MI


Pack year history of
smoking

Years of
secondhand smoke
exposure


CAD50

< 50
> 50

< 50

> 50

< 50

> 50

< 50
> 50

< 50

> 50

< 50
> 50

< 50
> 50

< 50
> 50

< 50

> 50

< 50

> 50

< 50
> 50

< 50

> 50


Mean

60.818
70.225

85.143
75.461

9.039
8.3483

0.4286

0.4045

0.5974
0.2472

22.961
21.449

5.7922

4.8034

0.2597

0.0000

5.2143
3.5112

0.8052
0.7528

11.286
9.4719

21.857
30.483


Std dev

11.2400
9.3271

59.8190
46.2070

4.5550
4.1944

1.3021

0.4936

1.7716
0.4338

22.877
23.784

9.0249

8.2239

2.1667

0.0000

6.8328
6.4662

1.2777
0.5283

15.585
15.366

18.793
18.166


Minimum

40.00
44.00

6.00
12.00

1.00
2.00

0.00

0.00

0.00
0.00

0.00
0.00

0.00

0.00

0.00

0.00

0.00
0.00

0.00
0.00

0.00
0.00

0.00
0.00


Maximum t-test


p-value


87.00
85.00

307.00
189.00

24.00
23.00

11.00

1.00

11.00
1.00

66.00
73.00

32.00

35.00

19.00

0.00

30.00
30.00

11.00
2.00

80.00
60.00

61.00
66.00


5.89 0.0001



1.17 0.2418



1.02 0.3109



0.42 0.6782



1.80 0.0730



0.42 0.6782



0.74 0.4613



1.13 0.2595



1.65 0.1012



0.35 0.7241



0.75 0.4523



3.00 0.0031
































Table 4-12. Optimal logistic regression model for the presence of CAD 20%
Estimate
Maximum Standard Wald
Parameter Likelihood error Chi-Square p-value

Intercept -8.7953 1.6464 28.5372 <.0001
Abnormal Dual Stress 0.9484 0.4445 4.5536 0.0328

Hands/Arms Tingling 1.1351 0.4394 6.6727 0.0098
History of High 1.0649 0.4377 5.9205 0.0150
Cholesterol

History of Diabetes 1.5191 0.5062 9.0075 0.0027

Age 0.1091 0.0215 25.6454 <.0001

Table 4-13. Odds ratio estimates of the presence of CAD 20%
95% Wald
Effect Point estimate confidence limits

Abnormal Dual Stress 2.58 1.08 6.17

Hands/Arms Tingling 3.11 1.32 7.36
History of High Cholesterol 2.90 1.23 6.84

History of Diabetes 4.57 1.69 12.32

Age 1.12 1.07 1.16
Note: N= 166


Table 4-11. Continued


Variable


Weight (lbs)


Height (inches)


Exercise times per
month


Hours per attempt
of exercise

Note: N= 166


CAD50

< 50
> 50
< 50

> 50


(166) Mean Std dev Minimum Maximum


t-test p-value

1.09 0.2786


0.05 0.9570


174.1
166.97

63.464
63.489

11.792
13.618

0.711

0.7444


42.847
41.607

3.5093
2.277

10.202
10.773

0.8623

1.0716


112.00
82.00

51.5
58.00


310.00
325.00

70.00
70.00


< 50
> 50

< 50

> 50


0.00
0.00

0.00

0.00


30.00
30.00

4.00

6.00


1.12 0.2661



0.22 0.8273






























Table 4-15. Odds ratio estimates of severe CAD
95% Wald
Effect Point estimate confidence limits

Hands/Arms Tingling 3.18 1.41 7.18
History of Diabetes 3.22 1.29 8.06
History of Thyroid Disease 2.76 1.24 6.14
History of Menopause Onset 2.44 1.13 5.28

Age 1.10 1.05 1.15
Years of Secondhand Smoke 1.03 1.01 1.05
Exposure


Table 4-14. Optimal logistic regression model for severe CAD
Estimate
Maximum Standard
Parameter Likelihood error

Intercept -8.3010 1.5933
Hands/Arms Tingling 1.1557 0.4159
History of Diabetes 1.1706 0.4676
History of Thyroid Disease 1.0147 0.4079
History of Menopause Onset 0.8907 0.3943

Age 0.0951 0.0215
Years of Secondhand Smoke 0.0260 0.0105
Exposure


Wald
Chi-Square
27.1443
7.7216
6.2660
6.1877
5.1040
19.5499
6.0737


p-value
<.0001
0.0055
0.0123
0.0129
0.0239
<.0001
0.0137









CHAPTER 5
DISCUS SION

The purpose of this exploratory research study was to help healthcare professionals have

a better understanding of which symptoms can be most helpful in identifying women who are at-

risk of having CAD and allow healthcare workers to determine which women should undergo

cardiovascular diagnostic tests that are highly predictive such as cardiac catheterization. The

following chapter provides a discussion of the findings and suggests clinical implications and

future research.

Summary of the Study

This exploratory study was carried out in four outpatient cardiac catheterization

laboratories in Orlando, Florida. Women between the ages of 40 and 89 years that had not

previously had a diagnostic cardiac catheterization performed and were scheduled for an elective

procedure were asked to volunteer for participation. One hundred and sixty six women were

recruited and agreed to the informed consent to undergo a structured interview by the PI

completing the survey and a catheterization by their own cardiologist. The structured interview

survey portion of the study, the MAPMISS, consisted of a comprehensive measure of overall

health symptoms that contained multiple variables in the study. The remainder of the study

consisted of the subj ects undergoing the cardiac catheterization procedure in order to quantify

CAD. Logistic Regression analysis was used to determine how well the symptoms discriminated

for CAD level of the subjects.

Conclusions

Two research hypotheses were explored and are considered. The first hypothesis was to

examine if there were differences in women' s prodromal cardiac symptoms between those that

have CAD and those that do not. Results from this study suggest that women's prodromal










symptoms do not exhibit a significant relationship to the presence of CAD (2 20% stenosis). The

most unanticipated finding was that neither pain symptoms nor general symptoms made the list

of maj or contributors. Surprisingly, only comorbidities have a significant relationship with the

presence of CAD 20%. Comorbidity conditions such as high cholesterol (Chi-square = 8.43,

p = 0.0037), cancer (Chi-square = 4.18, p = 0.0410) and diabetes (Chi-square = 5.73, p = 0.0138)

can possibly help predict the presence of CAD in women. Those women who had experienced

menopause onset (Chi-square = 5.67, p = 0.0173) were also statistically significant for the

presence of CAD. As was expected these results confirm that those women who had a history of

smoking (Chi-square = 4.31, p = 0.0378) were more likely to have CAD 20% (AHA, 2005b,

2008). Not expected however, was that with our knowledge of the suspected dangers of the use

of exogenous estrogens in women, that a lower percentage of those who had used birth control

(Chi-square = 8.63, p = 0.0030) and who were currently using estrogen replacement therapy

(Chi-square = 4.51, p = 0.0336) had CAD (Mosca et al., 2007). Between those women who did

and did not have severe CAD, statistically significant differences were found to include the mean

age of the subj ects, a history of migraine headaches, the number of years of birth control use, and

the years of secondhand smoke exposure. The TUS posits that symptoms are multiplicative and

result in a feedback loop; results from this portion of the study suggest that possibly

physiological, psychological and situational forces create a milieu that fosters CAD.

By way of contrast, results from this study revealed that women' s prodromal symptoms

do exhibit a significant relationship to the presence of severe CAD (> 50% stenosis).

Overall, the finding that the hallmark symptoms for men with CAD were absent from these

results is not surprising. Men typically present with the classic symptoms of MI such as shortness

of breath ,chest pain and pressure radiating to the j aw and down the left arm (Gibbons et al.,










1999; Mosca et al., 2007). McSweeney and colleagues reported that women rarely feel any chest

sensation at all, and that their symptoms are often more covert or subtle (Mc Sweeney et al.,

2001; McSweeney et al., 2003; McSweeney & Crane, 2000). In the current study, a lower

percentage of women who had neck/throat pain had severe CAD (19. 10% vs. 32.47%, Chi-

square = 3.90, p = 0.0482) and a lower percentage of women who had numbness or burning of

arms had severe CAD (12.36% vs. 27.27%, Chi-square = 5.90, p = 0.0151). These particular

inverse significant relationships are interesting. These relationships suggest a possible opposing

or neutralizing effect as to a multiplicative effect as proposed on the TUS. When one closely

scrutinizes the sample demographics it is hard not to notice the education status (54.22% with

less than a high school degree) of the subj ects. Questions may arise as to how the sample

population differentiated numbness and burning from hand/arm tingling (Chi-square = 4.73,

p = 0.0297) that demonstrated a statistically significant relationship, 44.94% of women who had

severe CAD vs. 28.57% that did not. It may be suggested that the symptom of pressure radiating

to the jaw and neck/throat pain as well as pressure radiating down the left arm when compared to

hand/arm tingling or numbness or burning of arms are very similar. In argument against this

suggestion, the MAPMISS specifically questions women regarding pain symptoms in the jaw,

neck/throat, left arm pain, right arm pain and top of shoulder pain. During the structured

interview additional descriptors were used to distinguish between the sensations of pressure,

tingling, numbness and burning. Research on language expression between genders in the way

that angina symptoms are described and reported is scant at best. A few studies suggest that

differences do exist: however, additional research is needed to examine the nature and

consequences of language use (Kimble et al., 2003; Philpott et al., 2008).









The second hypothesis was if the identification of a prodromal symptom or a cluster of

prodromal cardiac symptoms would discriminate between those women who have CAD and

those that do not. Thus, allowing healthcare professionals to identify women who are at-risk of

having CAD. In order to answer this hypothesis, a backward logistic regression model was built,

allowing the use of both continuous and categorical variables to determine if differences existed

between those with and without the presence of CAD (> 20% stenosis). The model revealed that

subj ects who complained of tingling of the hand/arms had 3.11 times higher odds of having the

presence of CAD > 20%. Thus a single symptom emerged. This finding is alluded to in a recent

research study that examined differences in symptoms between men and women when

hospitalized for ACS, non-ST segment myocardial infarction, or STEMI (DeVon et al., 2008).

Unsurprisingly the usual suspect triad of diabetes, high cholesterol and age reappeared as part of

the optimal model. Diabetic subj ects had 4.57 times higher odds of having the presence of CAD

(> 20% stenosis). In addition, high cholesterol (OR = 2.90, 95% CI, 1.23-6.84, p = 0.0150) and

age (OR = 1.12, 95% CI, 1.07-1.16, p = <.0001) were significant risk factors for the presence of

CAD > 20%. Contrary to reported research, in this study, those women with an abnormal dual

stress test had 2.58 times higher odds of having the presence of CAD > 20% (DeCara, 2003).

Then a backward logistic regression model was constructed to determine if differences

existed between those with and without severe CAD (> 50% stenosis). The results of the logistic

regression model indicated once again that subj ects who expressed that they had experienced the

symptom of a tingling of the hand/arms had 3.18 times higher odds of having severe CAD.

Other factors that were included in the model were exposure to secondhand smoke (OR = 1.03,

95% CI, 1.01-1.05, p = 0.0137), a history of thyroid disease (OR = 2.76, 95% CI, 1.24-6. 14, p =

0.0129), history of menopause onset (OR = 2.44, 95% CI, 1.13-5.28, p = 0.0239), the age of the










subj ect (OR = 1.10, 95% CI, 1.05-1.15, p = <.0001) and a history of diabetes (OR = 3.22, 95%

CI, 1.29-8.06, p = 0.0123).

Strengths and Limitations

When evaluating the results of this study, several strengths and limitations should be

considered. The real strength of this study is that to my knowledge this study is the first to

explore the relationship between prodromal symptoms and disease presence of CAD among

women prior to MI. Furthermore, while many studies have examined prodromal symptoms post

MI in a retrospective method, this study has been the first to prospectively explore prodromal

symptoms in the clinical setting using an invasive procedure. Secondly, it should be pointed out

that if this study had to pay for the cardiac catheterization portion of this investigation it would

have cost more than $2,075,000 dollars (166 x $12,500).

In an attempt to enroll an unbiased sample, subj ects were recruited from multiple

locations. However, despite the attempt to limit bias, it should be noted that the women who

participated in this study were already identified by their primary healthcare provider as having

an indication that placed them at-risk for CAD in the first place. Although analysis evaluating the

sample did show similar rates of CAD (61% with CAD> 20% stenosis and 54% with CAD> 50%

stenosis) to published reports (DeCara, 2003; Fowler-Brown et al., 2004; Mora et al., 2003) one

must remember that medicine is a business and motivation for diagnostic evaluation is not

always clear cut.

Physician skill in performing the catheterization as well as the primary investigators

expertise in reading coronary angiography in most instances was a strength; however, from time

to time consultation was necessary. Variation in diagnostic imaging between cardiac

catheterization laboratories is another potential limitation. The manufacturers of the imaging

equipment were different in each laboratory with the exception of the two Cardiovascular









Centers, LLC sites. To combat the possibility that QCA would differ in each laboratory care was

taken to transfer all images to CD-ROM format for offline review and quantifieation at a single

location using the same QCA software package (Sanmartin et al., 2004). Additionally, image

quality is may be degraded if the image intensifier is to far from the radiation source and is also

dependent on patient size. The larger the subj ect the more radiation is needed to visualize the

coronary anatomy.

Another limitation may be the sample size, in the face of significant recruitment

challenges (i.e. labs closing, or cases being moved to inpatient facilities) it may be considered

relatively limited. This limitation may have resulted in reduced significant Eindings regarding the

stated hypothesis. It should also be noted that this study was a cross-sectional design and

therefore, examined cardiac status in a single time point along the continuum of life and may not

accurately reflect the dynamics of cardiovascular disease.

As with all research involving self report measures consideration should be given to the

fact that patients may lack language skills necessary to express themselves fully, be influenced

by their surrounding or how they would like themselves to be perceived. In an attempt to

minimize these factors patients were interviewed in privacy, behind closed doors or pulled

curtains without family members or other staff present when possible. Assurances of

confidentiality regarding their responses and anonymity after data collection were offered.

Implications and Recommendations

The review of the literature relevant to prodromal symptoms in women suggests a vast

difference between what is expected by healthcare providers and what is expressed or

experienced by women. The current study will add to the body of literature in a substantial way.

Given that women report different symptoms than men when faced with MI a reasonable









assumption is to expect that women will have a different presentation in the prodromal phase of

cardiac disease; these hypotheses were in part supported by these results.

Particular to the findings of this study and other research differences in symptom

expression and experience between genders, future research needs next to address the formation

of an assessment tool that will help healthcare workers quickly identify women at-risk for CAD.

Timely diagnosis of CAD is the key to abating the catastrophic consequences that occur as a

result of a MI. Results from this study have revealed the symptom of hand/arm tingling is

possibly more telling of CAD in women while neck/throat pain and numbness or burning of the

arms may have a negative discriminating quality. The prodromal symptoms of hand/arm tingling,

neck/throat pain and numbness or burning of the arms in combination with comorbidities

including diabetes, onset of menopause, exposure to secondhand smoke, age and a history of an

abnormal dual stress test warrant further exploration. The revised model of the TUS conceptual

framework suggests several further research directions. One recommended direction is to explore

how the prodromal symptoms of hand/arm tingling, neck/throat pain and numbness or burning of

the arms are differentiated and influence each other. Another recommended direction is to

examine the functional, cognitive and physical performance deficits that are a result of

prodromal symptoms. The revised model of TUS offers a lifetime of future research

opportunities.

Many women are unaware that they may experience atypical prodromal symptoms that

change in intensity, frequency and have varied times of onset that can warn them of impending

cardiac problems. Furthermore, many healthcare providers are not in tune to the differences in

prodromal symptom presentation that may be present between men and women involving CAD.

Further research is indicated to facilitate early symptom recognition by both patient and provider.










Effective prodromal symptom recognition in women with CAD the maj or component of CHD

can prevent a negative diagnostic experience and improve overall healthcare outcomes.

Conclusion

In summary, CHD in women is a global health and economic problem. Cardiovascular

heart disease is America's number 1 killer of women and men. Women are unaware that the

maj or component of CHD, CAD is a significant health threat and that few women have discussed

CAD with their primary healthcare provider. Healthcare professionals need to have a better

understanding of which symptoms would be most helpful in identifying women who are at-risk

of having CAD and allow them to determine which women should undergo cardiovascular

diagnostic tests that are highly predictive such as cardiac catheterization. The prodromal

symptoms of hand/arm tingling, neck/throat pain and numbness or burning of the arms in

combination with comorbidities including diabetes, onset of menopause, exposure to secondhand

smoke, history of thyroid disease, age and a history of an abnormal dual stress test have emerged

as possible predictors of CAD in women. Given these considerations, this study offers new

information regarding prodromal symptoms and the determination of CAD in women.










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BIOGRAPHICAL SKETCH

William Garrett Warrington, Jr. was born in Amsterdam, New York to William and Joyce

Warrington. He has one younger brother, Richard, and younger twin sisters Sandra and Suzanne.

Bill has five sons, William, Marc, Patrick, Adam, and Andrew. After serving in the United States

Army, Bill graduated with honors from California State University, Fullerton in June 1993 with a

Bachelor of Science in Nursing degree. Bill has worked as a registered nurse in acute care

facilities specializing in cardiology for more than 18 years. He recently married Margaret Love

Gilson on June 4th, 2008. Maggie has two daughters, Lindsey and Kara. Bill and his wife,

Maggie, currently live and work in Orlando, while he attends the University of Florida in

Gainesville, pursuing his Ph.D. in nursing science with a minor in physiology. His research

interests lie in cardiovascular nursing and in using symptom models to predict occlusive

coronary artery disease in women focusing on visceral pain responses, alternative therapies,

symptom expression, coronary artery disease progression and women's health issues.





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PRODROMAL SYMPTOMS AND THE DETERMINATION OF CORONARY ARTERY DISEASE IN WOMEN: AN EXPLORATORY STUDY By WILLIAM GARRETT WA RRINGTON, JR. A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2008 1

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2008 William Garrett Warrington, Jr. 2

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To my wife Maggie: Until now you have not asked for anything in my name. Ask and you will receive, and your joy will be complete. John 16:24 3

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ACKNOWLEDGEMENTS I am privileged to extend my sincerest appr eciation to Dr. James V. Jessup, Jr., my friend and mentor for his continued support and guidance during my education. I am deeply honored and grateful to have someone to encourage me to develop, mature and be independent in my own way. Jim has been there to consult in times of heartrending loss, recovery and celebration. I thank my supervisory committee, (Dr. Peter Sayeski, Dr. Joyce Stechmiller, and Dr. Donna Neff). They have been most patient with me through this process. Each has encouraged me to challenge myself and think more critically. I would also like to thank my father, W illiam G. Warrington, Sr. for being my example, and my wife, Margaret Love Warrington for he r unconditional love, help and encouragement. 4

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TABLE OF CONTENTS Page ACKNOWLEDGEMENTS .............................................................................................................4LIST OF TABLES ...........................................................................................................................7FIGURE ........................................................................................................................ ...................8ABSTRACT ...................................................................................................................... ...............9 CHAPTER 1 INTRODUCTION .................................................................................................................. 112 LITERATURE REVIEW .......................................................................................................18Introduction .................................................................................................................. ..........18Womens Symptoms Quan titative Studies .............................................................................20Womens Symptoms Qualitative Studies ...............................................................................28Womens Symptoms Mixe d Method Studies .........................................................................36Summary ....................................................................................................................... .........39Theoretical Model ............................................................................................................. .....40Model Assumption .................................................................................................................42Conceptual Definitions ........................................................................................................ ...42Operational Definitions ....................................................................................................... ...433 METHODS ....................................................................................................................... ......46Design ........................................................................................................................ .............46Funding ....................................................................................................................... ............46Consent ....................................................................................................................... ............46Subjects and Recruitment ...................................................................................................... .47Sample Size Determination ....................................................................................................4 7Variables ..................................................................................................................... ............48Procedure: Quantification of CAD .........................................................................................50Statistical Analysis Plan ..................................................................................................... ....524 FINDINGS ...................................................................................................................... ........58Data Collection and Desc riptive Statistics .............................................................................58Subject Demographics ............................................................................................................59McSweeney Acute and Prodromal M yocardial Infarction Survey ........................................59Medical Variables ...................................................................................................................61Comorbidity Variables ...........................................................................................................61Coronary Angiography Variables ..........................................................................................62Data Analysis .........................................................................................................................62 5

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5 DISCUSSION .................................................................................................................... .....81Summary of the Study ............................................................................................................81Conclusions ............................................................................................................................81Strengths and Limitations ..................................................................................................... ..85Implications and Recommendations ......................................................................................86Conclusion .................................................................................................................... ..........88REFERENCES .................................................................................................................... ..........89BIOGRAPHICAL SKETCH .........................................................................................................95 6

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LIST OF TABLES Table page 2-1 Thirty-three prodr omal symptoms .....................................................................................443-1 Inclusion/exclusion criteria data collection .......................................................................553-2 Sample sizes for estimated 50% of sample with CAD ......................................................553-3 Complete list of dependent variables for hypothesis 1 ......................................................564-1 Recruitment locations of the sample ..................................................................................684-2 Demographic characteristics of the sample .......................................................................684-3 Prodromal symptom frequency dist ribution and relative percentages ...............................694-4 Medical variables distribution ............................................................................................704-5 Comorbidity frequency distri bution and relative percentages ...........................................704-6 Coronary angiography variables distribution .....................................................................704-7 Example of the contingency table for CAD 20% by history of high cholesterol ...........714-8 Relationship between CAD presence and womens prodromal ca rdiac symptoms ..........724-9 Differences in variable mean s between CAD <20% and > 20% .......................................744-10 Relationship between severe CAD and womens prodromal cardiac symptoms ..............764-11 Differences in variable mean s between CAD < 50% and > 50% ......................................784-12 Optimal logistic regression mode l for the presence of CAD 20%.....................................794-13 Odds ratio estimates of the presence of CAD 20%............................................................794-14 Optimal logistic regre ssion model for severe CAD ...........................................................804-15 Odds ratio estimates of severe CAD ..................................................................................80 7

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LIST OF FIGURES Figure page 2-1 Revised theory of unpleasant symptoms............................................................................453-1 Example of a MAPMISS type question with calculation formula and score ....................57 8

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Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy PRODROMAL SYMPTOMS AND THE DETERMINATION OF CORONARY ARTERY DISEASE IN WOMEN: AN EXPLORATORY STUDY By William Garrett Warrington, Jr. August 2008 Chair: James Vernon Jessup, Jr. Major: Nursing Science Globally cardiovascular heart disease (CHD) is the number on e killer of women and men. The major component of CHD, coronary artery di sease (CAD) is a significant health threat. The purpose of this exploratory study was to help healthcare professionals have a better understanding of which prodromal symptoms can be most helpful in identifying women who are at-risk of having CAD and allow healthcare providers to determine which women should undergo cardiovascular dia gnostic tests that are highly predictive such as cardiac catheterization. Women ages 40 to 89 years that had not previously had a diagnostic cardiac catheterization and were scheduled for an elective outpatient procedure were asked to participate. A convenience sample of 166 women completed a structured interview using the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey to explore prodromal symptom presence. Women underwent a catheterization proce dure to quantify CAD. To address the major hypothesis of the study, analysis of frequency (c hi-square test) was used to determine the difference in proportion of variables measured on nominal and ordinal sc ales between the two groups of subjects diagnosed with CAD or without it. The t-test was utilized to find the difference in mean of the variab les measured on interval or ratio scales between the two groups. 9

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For simultaneous testing of hypotheses, the Bonf erroni method for controlling the overall error rate was used. Logistic regression analysis was used to explore the potential differences in possible predictor variable s between those who had C AD from those who did not. Results of the logistic regressi on analysis indicated that subjects with one or more of the following; tingling of the hand or arms, were diabetic, had a history of thyroid disease or who had experienced menopause onset had higher odds of facing severe CAD. 10

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CHAPTER 1 INTRODUCTION Cardiovascular heart disease (CHD) in women is a global health and economic problem. CHD is America's number one killer of women and men (Ameri can Heart Association, 2008). Currently, the American Heart Association (AHA) (2008) esti mates that 7.3 million women living today have a history of myocardial infarction (MI), an gina pectoris or both. The AHA (2008) estimates that 1.2 million Americans will have a new or recurrent MI this year. More women than men die of CHD every year in the United States (AHA, 2008). Despite a well-documented recent decline of 17% in card iovascular mortality in women for the year 2007, CHD remains the leading single cause of death (Mosca et al., 2007). The morbidity connected with CHD is also substantial. Although an estimated 1.2 million people will experience a MI, many more will be hospitalized for evaluation and treatment of angina and chest pain syndromes (AHA, 2008). The AHA (2008) estimates that more than 403 billion dollars per year are spent on the healthcare of patients suffering from CHD. However, beyond the need for hospitalization, coun tless men and women troubled w ith chest pain syndromes are unable to perform normal activities of daily livin g, thereby experiencing a reduced quality of life (Bourassa et al., 2000). Published data from the Bypass Angioplasty Revascularization Investigation (BARI) states that approximately 30% of patients never return to work following coronary artery bypass or percutaneous coronary intervention (Bourassa et al., 2000). This report validates the pervasive clinical impression that CHD continues to be linked with substantial patient morbidity regardless of the decline in cardiovascular mortality. The enormity of the problem can be simplified : CHD affects millions of Americans, with annual costs that are measured in hundreds of billions of dollars (AHA, 2005b). 11

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Several reports indicate that women who suffer with CHD are not trea ted as aggressively, have worse outcomes and have significantly high er mortality rates than men (Gibbons et al., 1999; Kosuge et al., 2006; McSweeney, Cody, & Crane, 2001; Omran & Al-Hassan, 2006; Shaw et al., 2008). A survey by the AHA (2005b) found that a mere 13% of women believe the major component of CHD, coronary artery disease (CAD) is a significant health threat. Estimates are that less than 30% of women have discussed CAD with their prim ary healthcare provider (Jones, Edwards, Vallis, Ruggiero, & al, 2003). As th e age of the general population rises and as comorbidities such as diabetes, hyperlipidemia and obesity escalate in the general population, women are at risk more than ever before (Nationa l Institute of Health, 200 4). In response to the mounting dangers of CAD in women, organizations such as the AHA have partnered with public health officials to launch nationwide campaigns to raise awareness related to the danger of CAD for women (National Institute of Nursing Research, 2004). The scientific community has been busy attempting to demystify the unique ways in which CAD manifests itself within a woman's bo dy. From an anatomical viewpoint, a woman's and a mans heart have no differences. Howeve r, the warning symptoms of CAD in men and women are very different (DeVon, Ryan, Ochs, & Shapiro, 2008; McSweeney et al., 2001; Norris, Hegadoren, Patterson, & Pilote, 2008). Men t ypically present with the classic symptoms of MI such as shortness of breath, chest pain and pressure radiating to the jaw and down the left arm (Gibbons et al., 1999). McSweeney and coll eagues report that women rarely feel chest ; sensation at all, and that their symptoms are often more covert or subtle such as fatigue, indigestion, back pain, shortness of breath or just an unwell feeling (McSweeney et al., 2001; McSweeney et al., 2003; McSweeney & Crane, 2000; Zuzelo, 2002). These less impressive, unclear, subtle symptoms often do not lead health care professionals to further investigate CAD 12

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in women (Miller, 2002). The absen ce of considerable chest pain or pressure in women may be the significant factor that women have more unrecognized MI than men (Miller, 2002). Primary healthcare providers in the know are only now begi nning to educate their peers to the differences in presentation of CAD be tween men and women (McSweeney et al., 2001; McSweeney et al., 2003; McSweeney & Crane, 2000; Miller, 2000). In 2003, McSweeney and colleagues reported that women who had been dia gnosed with a MI, experienced symptoms such as fatigue or sleep disturbances as much as one month prior to the ev ent, demonstrating the likelihood that by quickly acting on these early warning symptoms healthcare providers may thwart a looming MI. This seminal study assessed prodromal (early warning) symptoms that might be harbingers of MI. The researchers employed the McSweeney Ac ute and Prodromal Myocardial Infarction Symptom Survey (MAPMISS), a survey instrument developed to assess th e presence of 37 acute and 33 prodromal symptoms identified by women in previous studies (McSweeney, O'Sullivan, Cody, & Crane, 2004). McSweeney defines prodromal symptoms as sensati ons that are new or vary in frequency, intensity or duration preceding the MI. Approximately 95% of women reported having new or variable symptoms up to one month prior to MI. This finding led McSweeney and colleagues (2003) to surmise that these prodromal cardiac symptoms were associated with the ensuing MI. The 5 most reported prodromal symptoms were Tiredness/ unusual fatigue : 70% Sleep disturbance/insomnia : 48% Dyspnea/ shortness of breath : 42% Gastric reflux/ i ndigestion : 39% Apprehension/anxiety: 35% In the study, a mere 30% of women complained of chest discomfort of any type prior to MI. Women expressed the discomfort in ambiguous te rms such as an aching, tightness and pressure, 13

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but excluded the adjective pain. The report has ma de the case that women must be well-informed that the manifestation of any new onset sympto ms no matter how vague, may be related to CAD and should seek out medical care to establish th e source of the symptoms particularly in the presence of known CAD risks such as smoking, h ypertension, hyperlipidemia, diabetes, obesity or a familial history of CHD (McSweeney et al., 2003). McSweeney and colleagues (McSweeney & Cr ane, 2000) earlier found that women could identify an assortment of symptoms that th ey had experienced prior to their MI but had disregarded the symptoms or received an inco rrect diagnosis when they went for medical treatment. Compounding and confusing the problem of symptom identification are two factors. First, women often present with multiple symptoms and are extremely vague in the description of symptoms to healthcare pr oviders (Miller, 2000). Second, countless women ignore their own health condition citing family respons ibilities as the reason (Zuzelo, 2002). The internal expression of women's CAD is deceptive to healthcare providers. In CAD, men and women build up coronary plaque; however CAD in women often manifests itself in a more diffuse pattern (Kruk et al., 2007; Sheife r, Arora, Gersh, & Weissman, 2001). Instead of forming discrete lesions, womens plaque is more uniform along the entire length of the vessel lining(Sheifer et al., 2001). These more diffuse di sease patterns angiographically present as small coronary vessels and not as diseased vessels. Wo men who suffer with angina or a MI are more apt than men suffering the same circumstances to have only moderate or more evenly spread blockages in their four major co ronary arteries (Eagle et al., 2004). Women often do not present with one severe discrete stenos is in the coronary artery. Mean ing that in women, symptoms are probably caused by blockages in smaller, less flexib le and accessible corona ry arteries (Kruk et 14

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al., 2007). These differences in pl aque formation may well explain some of the dissimilarity in the approach of treatment betw een men and women with CAD. Noninvasive cardiac diagnostic tests such as electrocardiograms (EKG) and exercise or nuclear stress tests that identify ischemia are not as predictive in women (50%) as in men (90%) (D'Antono, Dupuis, Fortin, Arsena ult, & Burelle, 2006; DeCara, 2003). In Exercise Tolerance Testing, ST-segment response does not predict fu ture risk for CAD events in women (FowlerBrown et al., 2004; Mora et al., 2003). Low exercise capacity, along wi th low heart rate recovery after exercise, is the best independent predicto r of death from CAD (Fowler-Brown et al., 2004). Instead of diagnosing CAD, indeterminate or false negative diagnosti c tests lead primary healthcare providers to incomplete or incorrect diagnosis. This fact, combined with a woman's inclination to assess improperly their risk and inte rpret their symptoms, will often result in health tragedies that are preventable (L ockyer, 2005; Ruston & Clayton, 2007). Another obstacle that women face in the cardi ac healthcare arena, is that women are often prescribed or receive less appropriate CAD dr ugs such as cholesterol-lowering medications, devices like pacemakers/defibrillators or angiopla sty/intracoronary stents after a diagnosis of heart disease is established (Enriquez, Prata p, Zbilut, Calvin, & Volgman, 2008; Omran & AlHassan, 2006; Shaw et al., 2008). When compared, men and women with equivalent rates of MI, women were less apt to receive aggressive drug therapy (Carruthers et al., 2004; Omran & AlHassan, 2006; Shaw et al., 2008). In view of the f act that womens dominant coronary vessels are more prone to contain only moderate CAD angiographically, women are frequently sent home from the hospital with an incorrect diagnosis and with a less aggressive therapeutic medication regimen subsequent to experiencing CAD sy mptoms (Carruthers et al., 2004; Eagle et al., 2004). This aberrancy ma y elucidate the mysterious in equality among the rate of 15

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angioplasty and bypass surgery performed after a se vere stenosis is diagnosed during angiogram between genders. Eagle and colleagues (2004) evaluated data in records from over 10,000 patients and found that in women and men whom had comparable CAD; women were prescribed and administered aspirin, and beta-blockers le ss frequently, common medi cation therapies which often avert a future MI. CAD characteristically affects women postmenopausal beginning in their late 50s, 10 years later than it typically affects men ( AHA, 2005a; Kosuge et al., 2006).This possibly accounts for why women have worse outcomes and ha ve significantly elevated mortality rates post MI (AHA, 2005b, 2008).The key to improving ra pid identification of CAD in women is through careful cardiac evaluation of wome n with known cardiac risk factors and by acknowledging less anticipated sy mptoms (Arslanian-Engoren et al., 2006; King & McGuire, 2007). The consequence of healthcare providers not being in tune with the varied symptom presentation that women may have can not be overstated. Roughly 50% of women will die of some form of heart disease which is two tim es more than the numb er of women who will succumb to cancer of all types, including breas t cancer in the United States (AHA, 2005a, 2008). While the specific value of prodr omal symptoms in predicting an impending MI is unclear, the emergence of prodromal symptoms, in combina tion with women's typical CAD risk factors, might aid healthcare providers in determining if women should be referred for invasive diagnostic tests with high predictive va lue such as cardiac catheterization. In summary, research related to the pr odromal symptoms that women frequently experience with MI is progressi ng; however, an obvious conclusi on is that women's symptoms vary from what they anticipate. Traditional diagno stic tests such as EKG a nd exercise stress tests 16

PAGE 17

used to predict CAD in men are not as pred ictive in women (D'Antono et al., 2006; DeCara, 2003). Furthermore, a bias against women in the treatment of CAD has been suggested for quite some time, and in fact, research does demons trate a bias against women receiving aggressive therapies related to CAD (Carruth ers et al., 2004; Eagle et al., 2004; Shaw et al., 2008). To date, the prodromal cardiac symptoms of women prior to cardiac catheter ization and MI have not been fully investigated. Given the magnitude of this probl em, the need for further research is evident. McSweeney and colleagues (2004) have provided the medical community with a vast array of clues to solving the mystery of CAD in women, however, the list of 33 prodromal symptoms are so overwhelming that it becomes difficult for healthcare providers to focus on which symptoms or groups/clusters of symptoms could possibly predict CAD in women with a high degree of accuracy. The need to define the relationship that prodromal symptoms experienced by women have to one another as well as the relationship to CAD must be explored. A unique opportunity has become available to expl ore theses relationships within the cardiac catheterization setting. Thus, the proposed exploratory research question for this study is: Do women's prodromal cardiac symptoms discriminate for coronary artery disease as evidenced by cardiac catheterization? Aim 1 : Examine the potential differences in womens prodromal cardiac symptoms between those that have CAD and those that do not by assessing symptom presence prior to cardiac catheterization and quantifying CAD in the cardiac catheterization laboratory setting. o Hypothesis 1 : There are differences in wome ns prodromal cardiac symptoms between those that have CAD and those that do not. Aim 2 : Determine a prodromal cardiac sympto m or a cluster of prodromal cardiac symptoms that can be most helpful to healthcare professionals in identifying women who are at-risk of having CAD. o Hypothesis 2 : A prodromal cardiac symptom or a cluster of prodromal cardiac symptoms will discriminate between thos e women who have CAD and those that do not. 17

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CHAPTER 2 LITERATURE REVIEW Introduction Over the past two decades an increasing amount of research involvi ng the experiences of women concerning CHD has been done. Research studies have focused on the gender differences of symptom identification, sympto m perception, clinical presentati on, risk factors and linguistic expression during the prodromal and acute phases of CAD. The current body of literature has shed light on the differences of gender presen tation highlighting the female perspective and experiences of CAD. However, a need exists to determine how cardiac prodromal symptoms differ for women and the clinical implicati ons that this information can provide. This review of the literature will examin e the current knowledge of womens cardiac prodromal symptoms. A literature search was used to select re search studies reporting cardiac symptoms and including women, between 2000 a nd 2008. The research studies included were identified by a search of the PubMed database for the specified years. The studies included samples of adult women patients with cardiac diseas e reported in refereed journals. Only journal articles available in English were reviewed. Th e key terms searched were prodromal symptoms, cardiac symptoms, symptom presentation, symp tom perceptions, gender differences, sex differences, womens interpre tation, womens descriptions and women's symptoms. The objective of this literature review was to explore the available evidence on CHD and CAD symptoms in women. During 19971999 a flurry of studies were published that compared symptoms between genders and found apparent differences partic ularly among women (Goldberg et al., 1998; Hochman et al., 1998; McSweeney, 1998; Meischke, Larsen, & Eisenberg, 1998; Meshack, Goff, & Chan, 1998; Penque et al., 1998). In 2002, Ch ristine Miller published a comprehensive 18

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integrative literature review and meta-analysis that examined these studies. While each study investigated a unique population and in different settings, the common theme present in all the 1997-1999 studies was that they inve stigated the primary (not yet prodromal) symptoms of heart disease in women. Four quantitat ive studies reported chest pain to be the most frequently reported initial symptom followed by order of fre quency either shortness of breath or fatigue (Goldberg et al., 1998; Meischke et al., 1998; Meshack et al., 1998; Penque et al., 1998). Miller (2002) postulated that while chest pain was the most frequently reported symptom in these studies most likely it was the most frequently identified symptom. McSweeney (1998) in a qualitative study interviewed 20 women after they suffered a MI. She found that the symptoms of breaking into a cold sweat and having a fee ling of an unrelenting unus ual fatigue were the most common symptoms in her sample (McSween ey, 1998). Women often experienced this cold sweat and fatigue or other atypi cal symptoms such as pain in the back, both arms and the left breast for 2 to 4 weeks prior to the MI. McSweeney (1998) also reported that only 30% of the women experienced significant ch est pain and that 25% of the women in her analysis never experienced any chest pain at all. Included in the review were two studies that investigated predictors of cardiac disease in women. Jadin and Margolis (1998) reported that the overall best predictor of CHD in women was age. Vaccarino and colleagues indicated that co-existing comorbidities such as diabetes, congestive heart failure, and stroke were more prevalent in women with CHD concluding that it was only logical that later ons et of disease processes coupled with comorbidities would invariably impact the nature and recognition of symptoms (Vaccarino, Parsons, Every, Barron, & Krumholz, 1999). Miller (2002) sugg ested that as a result of the aforementioned studies in the review that there may be underlying physiologica l, pathophysiological and anatomical reasons 19

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for the varied clinical and symptom presentati on of women. She implie d that anatomically women are smaller in stature overall, have sma ller hearts and smaller coronary vessels which contributes to the altered physio logical and pathophysiology pres entation of disease (Miller, 2002). Miller (2002) also addresse d the implications for practice by pointing out that it was not surprising that women did not fit the current diagnostic model for CHD that was built on research of men. There continues to be an expansion of th e body of knowledge of symptom experiences of women with CHD (Miller, 2002). Miller (2002) concluded that the distinctive physiological, pathophysiological and anatomical differences among men and women had raised the bar for researchers. It has become essential that resear chers be able to find a way to differentiate the unique symptom experience of women leading to improvements of early r ecognition and overall improved health status (Miller, 2002). Womens Symptoms Quantitative Studies Previous studies has implicated age as a promising source for the symptom differences between genders (Jadin & Margolis, 1998; Miller, 2002). Then and colleagues (2001) performed a systematic retrospective char t review of symptom differenc es of men (n=105) and women (n=48) in three acute care hospi tals to determine symptom trends in subjects that had been diagnosed as suffering a MI. Subjects were st ratified into three age groups 35-64, 65-75 old and >75 years old. Then (2001) found that the age group that reported the highest percentage (n = 6, 40%) of atypical symptoms were women in the group 65-75 years old (n=15). Atypical symptoms experienced by the sample included indigestion, shortness of breath, abdominal pain, nausea, vomiting, diarrhea, a nd feeling ill (Then, Rankin, & Fofonoff, 2001). Typical symptoms experienced by the subjects of this study were chest pain, pressure, discomfort or heaviness (Then et al., 2001). The study results indicated an increasing trend of 20

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atypical symptom presentation for male subject s > 75 years old that was not the trend for females. The authors cautione d readers that the small sample of women may limit the generalizability of the st udy (Then et al., 2001). In 2003, DeVon and Zerwic investigated gender differences of symptoms in a descriptive study of women (n = 50) and men (n =50) hosp italized with unstable angina (UA). Subjects were approached for data collection after they had been hospitalized and pain free for 12 hours. Subjects were recruited regardless of their previous CHD history. The subjects were administered three st ructure instruments the Unstable Angina Symptoms Questionnaire, the Canadian Cardio vascular Society Cla ssification of Angina instrument and the Hospital Anxi ety and Depression Scale to asse ss the severity and location of the UA symptoms. Results indicated that the majo rity of the sample was Caucasian, had some high school education, earned less than $20,000 dollars per year and were married. A history of MI was present for 40% of the sample with a pproximately 50% having had a previous bout with angina. More women than men were diabetic (46% vs. 34%) were hypertensive (80% vs. 56%) and had high cholesterol (72% vs. 68%). Wome n of the sample significantly reported more shortness of breath, difficulty breathing, weakness, nausea and loss of appetite as symptoms than men. Women also reported statis tically significant more pain in the upper back than men (42% vs. 18%) of a stabbing or knifelike quality (DeV on & Zerwic, 2003). The authors concluded that men and women often experience comparable symptoms dung UA, women experience more atypical symptoms. Kimble and colleagues (2003) reported a de scriptive study that assessed the gender differences of the pain characteristics and physic al limitations between men (n = 89) and women (n = 39) with chronic stable angina (CSA). Subjects were identified from chart review at 21

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physician offices that had a history of CHD a nd positive score on the Rose questionnaire as a screening for angina. Subjects we re excluded if they had experi enced a MI, coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) within six months of the study. Subjects were administered the short-form McGill pain questionnaire to assess pain dimensions and the physical limitation subscale of the Seattle angina questionnaire to assess physical activity limitation (Kimble et al., 2003). Results indicated that women were slightly older than men (mean 64.1 years vs. mean 62.8 years), were more often diabetic (35.9% vs. 32.6%) and experienced less history of MI, CABG and PCI. Overall, men reported a greater pa in dimension score for the descriptor of heavy tiring-exhausting sensation and women reported more intensity of tiring-exhausting and aching sensations and for the descriptor of hot-bur ning and tender. Women al so, reported a greater physical limitation when angina was involved. K imble concluded that men and women with CSA have more similarities than differences in th e characteristics of pain with the exception of women having significantly more hot-burning and tender sensations The authors believed that the description of tender was a unique finding to women when describing chest pain and warranted further explora tion (Kimble et al., 2003). In the report of a descriptive study, Granot and colleagues (2004) assessed gender differences of perceptions of pain symptoms among men (n =32) and women (n = 29) with UA. Characteristics of chest pain were described by hospitalized subjects us ing a semi-structured questionnaire that evaluated th e intensity, duration a nd location of chest pain. Precipitating events and factors that relieve d pain were also explored. Results of the study indicated that 58% of the sample had a history of CAD with no statistical difference between genders. Women re ported significantly more intense pain than 22

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men. Women located pain more inn the stomac h, jaw and back, whereas men had more chest pain. More women than men described their pain as pressure (84% vs., 37%). There were no significant differences between me n and women in the events th at provoked of factors that relieved chest pain however, women reported that rest reduced chest pain more often. Both men and women reported shortness of breath as the most frequent symptom. The authors concluded that women more often described a portrait of ch est pain that was atypical and more intense in character (Granot, Goldstei n-Ferber, & Azzam, 2004). In a study that evaluated gender differences and similarities of men (n = 1258) and women (n = 683) presenting with acute corona ry syndrome (ACS), Arslanian-Engoren and colleagues (2006) offered results from the ACS registry at the Univ ersity of Michigan. Researches extracted information retrospectiv ely from patient charts diagnosed with ACS regarding demographics, presenta tion, symptoms and comorbiditie s. Data was analyzed using chi-square for categorical variables and t-test for continuous variables. Logistic regression was used to create odds ratios for predictor variables (Ars lanian-Engoren et al., 2006). Subjects were stratified by gender and age (<65 and 65years). Results indicated that 72% of those in the study had a confirmed MI and 28% had UA. Women in the older age group were more likely than men of the same age group to be obese and have hypertension and less likely to smoke. Rates for MI, positive stress test and angina were equivalent but men were more likely to have had PCI and CABG surgery. Both men and women in the older age group were more likely to have a STsegment elevated myocardial infarction (STEMI). There was no significant difference in the type of MI between genders. Men were more likely to present to the hospital with the complaint of chest pain, left arm pain and diaphoresis. Women presented more often with nausea, vomiting, jaw pain, neck pain and back 23

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pain. Shortness of breath was present as the most reported symptom of all groups. Logistic regression offered that age was a significant pred ictor of nausea and diaphoresis and not of chest pain, shortness of breath or of arm pain. The authors concluded that small but statistically significant differences are apparent between genders in age, comorbidities and with initial presentation and location of symptoms to the hospital for ACS (Arslani an-Engoren et al., 2006). Kosuge and colleagues (2006) investigated differe nces in the clinical features of men (n = 351) and women (n = 106) with STEMI. Subj ects were enrolled upon diagnosis of acute myocardial infarction (AMI) w ith non-invasive methods such as EKG demonstrating ST segment elevation in two leads and an increase of cardiac enzymes. Subjects were interviewed and asked to describe the quality, severity and location of their pain. Immediately after admission 93% of the subjects underwent cardiac catheterizati on and reperfusion if appropriate. Data was evaluated for differences between genders using t-tests and differences in prevalence were assessed using chisquare tests. Results revealed that women of the sample were older than men (mean age 72 vs. 62). Women were also more often than men to be diabetics (36% vs. 26%) and hypertensive (70% vs. 56%). Men most often had a squeezing feeling (35%) as the quality of their chest pain whereas women had a vague indescribable (45%) quality to the chest pain. Women reported more jaw, neck, back and arm pain than men. Men more often than women reported severe (52% vs. 38%) chest pa in during a STEMI. Shortness of breath was equal between the groups, men experienced more sweating and women experienced more nausea and vomiting. In both men and women the culprit ve ssel for onset of the STEMI was most often the left anterior descending artery followed by the right coronary ar tery. Women with STEMI had a significantly higher in-hospi tal mortality rate than men (6 vs. 0). The authors concluded clinical profiles and presentati on are different between genders. Women presenting with STEMI 24

PAGE 25

tend to be older than men, have more comorbidities, more atypical symptoms and higher mortality then men (Kosuge et al., 2006). To investigate gender differences in pain sy mptoms associated with exercise induced ischemia, DAntono and colleagues (2006) recrui ted 38 women and 94 men to participate in a prospective study of subjects with both angina symptoms and a positive myocardial perfusion imaging study. The study excluded subjects with significant and debilita ting comorbidities in order to exclude cofounders. Subjects were assessed for pain presence, quality, location and other symptom presence before and immediately after a dual stress test. Instruments used for assessment included the Dermatome Pain Map, a Sy mptom checklist, the short-form McGill Pain Questionnaire, the Chest Pain Quality Scale, The Canadian Cardiovascular Society grading scale for angina pectoris and the Psychiatric Sympto m Index. Medical assessment for ischemia was performed by a board certified nuclear imaging car diologist reading the dual stress test a giving a clinical impression (D'Antono et al., 2006). Results revealed that there was no signifi cant difference in age between the men and women and that while not signi ficant women (37%) had less th an a high school degree. Less women than men had diabetes (5% vs. 21%) and hypertension (40% vs. 50%). More women than men had thyroid dysfunction (18% vs., 4%). Wome n rated pain as more intense on the McGill Questionnaire than men including class IV a ngina (28% vs. 23%) (D'Antono et al., 2006). Women reported experiencing more hot-burning, stabbing or pressing pa in than men. Women reported more pain in the neck/throat area and men had more right ch est/shoulder and middle right chest pain. The most common symptoms fo r both genders were shortness of breath and fatigue. Women complained of more nausea, pa lpitations, trembling and numbness in the face and throat. Post hoc analysis comparing symptoms to dual stress test imaging results indicated 25

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that women with more severe imaging ischemia had more atypical symptoms such as a throbbing, tight chest pain and numbness in the ar ms explained 48% of the variance. The authors suggested that small differences in the symptoms associated imaging st udies exist. The real danger is in the way women express the symptoms that they have with ischemia making them more prone to misdiagnosis and delaye d treatment (D'Antono et al., 2006). Omran and Al-Hassan (2006) using a descri ptive comparative study investigated the gender differences of signs and symptoms of presentation in Jordanian men (n = 57) and women (n = 26) subjects with MI. Subjects were enrolled in the study while hospitalized if they had been diagnosed with an MI and were hemodynamically stable. Data was collected by chart review and a structured interview that focused on the initial symptom presentation. Pain intensity was rated using a visual analog scale. As an objective indicator of the severity of MI cardiac enzymes were noted. Results reflected that the sample mean ag e was 52 years and women more than men had less than a high school degree (69% vs. 20%). Women were signifi cantly more hypertensive than men (31% vs. 14%). Among men and women ch est pain was the most common presenting symptom. Subjects pain levels re ported by the researchers from the visual analog scales were of moderate levels (mean 7.2, SD =2.8) (Omr an & Al-Hassan, 2006). Men and women alike reported nausea, sweating, fatigue and general weakness as the most common symptoms with women reporting slightly more general weakness and sweating. Cardiac enzymes were reported higher in men than women (no data). The author s concluded that small differences in symptom presentation between men and women experiencing MI exist. These differences are subtle and may confuse healthcare professionals thus delayi ng time of treatment for women (Omran & AlHassan, 2006). 26

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Lovlien, Schei and Hole (2006) investigated th e gender differences of the interpretation of patients pre-hospita lization AMI symptom experiences. Only first time AMI patients were considered. AMI was confirmed by chart review of EKG ST segment elevation in two or more leads. Subjects were sent by mail a questionnai re two weeks after discharge. The questionnaire focused on demographics and symptoms prior to hospital admission. The questionnaire was sent to 777 subjects, 533 responded (149 women and 384 men). Data was analyzed using chi-square and logi stic regression technique s. Results indicated that women were slightly older than men (mean age 61.2 vs. 58.5). Women had more hypertension (38% vs. 29%) and high choleste rol (26% vs. 15%) than men. Women had less high school education than men (60% vs. 33%). An terior (31% vs. 34%) a nd posterior (40% vs. 31%) infarcts were the most common sites of AMI in both men and women (Lovlien, Schei, & Hole, 2006). Men experienced chest symptoms more often pre-hospitalization. Women were more likely to report nausea, shortness of breath, palpitations, fainting, sca pulae, jaw, throat, and back pain. Lovlien (2006) concluded that wome n are more likely to experience an atypical presentation of symptoms differing from the e xpectation that they have. The presentation of atypical symptoms influences the interpreta tion of the symptoms often delaying care. King and McGuire (2007) conducted a descri ptive correlational study of 30 men and 30 women to assess gender differences of symptom presentation in subjects with AMI. Subjects who were diagnosed with AMI were interviewed after revascularization in the hospital. All subjects were interviewed using the Sy mptom Representation Questionnaire. Data analysis was performed using chi-square t-tests and logistic regression techniques. Results indicated that women we re statistically significantly older than men (mean age 69.9 vs. 55.2). The sample was predominately white (88. 3%). There were no significant differences 27

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between men and women for diabetes, hypertensi on or education levels within the sample. Evaluation of the symptom experience among men and women indicated two significant differences. Women reported less pain than men in the center of the chest (56.7% vs. 90.0%) and more right shoulder (53.3% vs. 13.3%) discomfort. Pain descript ors did not differ between the genders. Associated symptoms of weakness, fatig ue, diaphoresis, shortness of breath were the same for both genders with the exception that women reported less indigestion than men (26.7% vs. 50%) (King & McGuire, 2007). Approximately 42% of the subjects in the study reported that the symptoms that were experienced were not what they expected. The pain was less than expected in 61.9% for the sample and 38.1% reported the location of the pain was different from anticipated. King (2007) concluded that there were minimal differences between genders in symptom presentation. She commented that it was more likely that the difference in expected symptoms of AMI and experienced symptoms was the factor that was most dangerous to both genders. Womens Symptoms Qualitative Studies Several qualitative studies have explored women's symptom experiences (DeVon et al., 2008; McSweeney et al., 2001; McSweeney et al., 2003; McSweeney & Crane, 2000; Miller, 2000; Norris et al., 2008; Philpott, Boynton, Fe der, & Hemingway, 2001; Ruston & Clayton, 2007; Ryan & Zerwic, 2004; Sjostrom-Stranda & Fridlund, 2007). Miller (2000) presented data from a grounded theory study of women with hear t disease that provided subjective symptoms experienced by 10 women with cardiac disease w ho ranged in age from 40 to 78 years old. Women with different medical diagnosis and length of illness were included (five Caucasian, four African American and one Latina). Diagnos is included MI, congestive heart failure and angina. Shortness of breath, swelling, fatigue, and weakness were more common in this group although several reported experiencing mild chest discomfort. Several women prior to cardiac 28

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diagnosis indicated feeli ng too weak or tired to complete usua l daily tasks. This study concluded that healthcare seeking behavior is prompted by cardiac cues which include the nature and severity of embodied symptoms. In a qualitative study McSweeney and Cr ane (2000) identifie d symptoms women experienced prior to and during an AMI. Th e nonprobability sample for this descriptive naturalistic study consisted of 40 women. Using content analysis and constant comparison, the researchers identified specific symptoms and gr ouped them according to time of occurrence, prodromal and acute. Thirty-seven women experienced prodromal symptoms, beginning from a few weeks to 2 years prior to their AMI and ranging from 0 to 11 symptoms per woman. The most frequent prodromal symptoms were unusual fatigue (n = 27), discom fort in the shoulder blade area (n = 21), and chest sensations (n = 20), whereas the most frequent acute symptoms were chest sensations (n = 26), shortness of breat h (n = 22), feeling hot and flushed (n = 21), and unusual fatigue (n = 18). Only 11 women experienced severe pain during th eir AMI. Conclusions of this study offered by the authors are threef old: (a) women identified classic and unique symptoms of AMI, which challenge the content of current literature; (b) women experienced a gradual progression of number and severity of AMI symptoms; and (c) women need sufficient time to recognize the prodromal symptoms of their AMI. McSweeney and colleagues (2001) presented a study based on interviews of 76 women who discussed womens symptoms prodromal and acute that were associated with an MI experienced in the previous year. Sixty-eight out of the 76 women had experienced prodromal symptoms that included fatigue (70%), dyspnea ( 53%), and pain in the upper back or shoulder blade (47%). All 76 women reported acute symp tomology to include chest pain/discomfort (90%), fatigue (59%), dyspnea (59%), and upper back discomfort or shoulder blade pain (42%). 29

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Despite the fact that women had reported severa l prodromal symptoms, none were given a new diagnosis of CAD prior to their MI. The authors suggested from their findings that a need for healthcare practitioners to become more acutely aware of and take a more extensive approach when assessing women at risk for CAD is evident. McSweeney and colleagues (2003) reported a study of 515 women fr om five research sites, that described the prodromal and AMI symp toms that they experienced. The research team administered the MAPMISS, to assess women about their symptoms, comorbidities, and demographic characteristics post MI. The samp le was principally white (94%), high school educated (55%), and older (mean age, 66), with 95% (n=489) reporting prodromal symptoms. The prodromal symptoms reporte d were fatigue (71%), proble ms sleeping (48%), and dyspnea (42%). Only 30% reported chest discomfort, the distinctive symptom of MI in men. The most frequent acute symptoms reported were dyspnea ( 58%), weakness (55%), and fatigue (43%). The symptom of acute chest pain/discomfort was not reported by 43% of the women. The more women reported prodromal symptoms experienced the more the rise in acute symptoms were reported. Prodromal scores on the MAPMISS acc ounted for 33% of the acute symptoms. The authors concluded that most women experience prodromal symptoms before an AMI and the issue remains unclear if prodr omal symptoms are able to predict potential CHD events. Lockyer (2005) conducted a semi-structure d interview of 29 women who had been admitted to and discharged from the coronary care unit. The goal of the study was to examine each womans own interpretation of the presenti ng symptom had experienced in relation to the onset of CHD (Lockyer, 2005). Narr ative analysis was used analyze the interviews. The mean age of the 29 women was 69 years. 30

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Results revealed that 3 women in the study had no symptoms until the day of their MI and that the women identified the initial sympto m as what was labeled by the researchers as acute chest pain. Several women ( no number given) reported tingli ng in the arms, jaw pain, chest tightness and heaviness as the presenting symptom labeled by the researcher s as undifferentiated chest pain. Most women reported ig noring the symptoms or self medicating to ease the pain for several months before seeking medical atte ntion. The most common presenting symptom was breathlessness on exercise for several weeks or months. The majority of subjects with this complaint only sought medical attention when th ey were incapacitated Many of the women in the study believed that breathlessness in its e volving stage to be a normal part of the aging process (Lockyer, 2005). Lockyer (2005) stated that many women delaye d seeking help out of social obligation to their family and only accessed healthcare systems after family and friends encouraged them to see their primary physician. She co ncluded that women were often unable to distinguish cardiac symptoms from symptoms of aging being fatig ued or being unfit. Lo ckyer (2005) emphasized the need for further research to examine early warning signs of cardiac disease to decrease morbidity and mortality in women. Albarran and colleagues (2006) performed a qualitative study usi ng a semi-structured interview of 12 women to explore the cardiac sy mptom experience prior to MI. Hospitalized subjects were chosen based on a rise in cardiac enzymes with or without ST elevation on EKG. Content analysis was used to code and dec onstruct the interviews for emerging themes. Results revealed that the mean age of the subjects was 63 years. None had a history of previous MI. Eight of the 12 women experien ced STEMI. The fundamental nature of the symptom experience for the women emerged as three distinct themes (Albarran, Clarke, & 31

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Crawford, 2007). First, gradual awareness of symptoms was reported from over a few days, up to several weeks. The most common symptom associated with gradual ons et was shortness of breath without exertion. Other common symptoms were a chest heaviness and frequent indigestion. Secondly, rati onalizing of symptoms was an emer ging theme. Women with chronic comorbidities often attributed the new symptoms to old disease diagnoses. Other women often blamed the new symptoms as a normal part of the aging process. Finally women experienced an unpredictable distributio n of pain. Pain was reported as varying, vague and unexpected. Common locations of pain were the back, n eck, upper arms, hands and stomach. Many women (10/12) experienced nausea and vomiting as the most common symptom for these women with MI. The authors concluded that the presentation and location of cardiac symptoms are untraditional. Women experiencing a MI have di fficulty interpreting cardiac symptoms of MI due to the unanticipated and atypical nature of the symptoms. A danger for women is the continued reliance by healthcare providers on sy mptom presentation as the primary clinical impression for decision making regarding coro nary ischemia (Albarran et al., 2007). In 2007, Ruston and Clayton reported the results of a study that examined the effect of comorbidities on the interpretation of cardiac symptoms by women (n = 44) experiencing a cardiac event. Semi-structured in terviews were conducted and subjects were stratified into two groups, those (n = 20) that pres ented to the hospital <12 hours of symptom onset and those (n = 24) that presented to the hospital >12 hours af ter symptom onset. Interviews were conducted during hospitalization for the cardiac event. C onstant comparison method was used to analyze the interviews. Results for the <12 hour group indicated that 14 of the 20 subjects had a known history of CHD. Comorbidities including emphysema, bronchitis anemia and arthritis were 32

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present for 14 of the 20 subjects in this group. Only 2 subjects reporte d experiencing any early symptoms both complained of fatigue. None of the subjects reported having symptoms that were associated with or that they c ould attribute to their comorbiditi es. Results for the >12 hour group indicated that 5 of the 24 subjects had a known history of CHD. Comorb idities of a non-cardiac nature were present for 22 of the 24 subjects in this group. The majority of subjects reported having a least one symptom that could be attrib uted to a comorbid illness and 20 subjects reported experiencing early unusual vague symp toms up to 72 hours prior to hospitalization (Ruston & Clayton, 2007). During analysis common threads of symptom cu es or mental triggers that the subjects used to assess their symptoms became apparent Women in the <12 hour group were able to distinguish cardiac symptoms that were new fr om usual comorbid symptoms by experience of CHD and further to qualify them as dangerous and requiring a ttention. Women in the >12 hour group were unable to distinguish cardiac symptoms that were new from usual comorbid symptoms due to a lack of experience with CHD. Women in the >12 hour group attributed new symptoms to an escalation of their como rbid illnesses (Ruston & Clayton, 2007). Ruston and Clayton (2007) stated that symptom recognition by the <12 hour group was a process of comparison and differe ntiation that led women to come to the conclusion that an emergent cardiac event was taking place prompting them to seek medical attention. Women of the >12 hour group lacked experience with C HD prompting them to a normalization of the symptoms into the typical advancement of symp toms of their comorbid illness. The authors concluded that symptom interpretation is a pr oduct of experience a nd the repertoire of knowledge that allows women correctly to asse ss symptoms of CHD from those of chronic comorbid illness. 33

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Sjostrom-Stranda and Fridlund (2007) conducted an explorative and descriptive designed research study to examine the symptoms that women experienced and the reasons for delay in treatment. An interview guide was constructed by the authors based on literature review and the experiences of critical care nurses whom worked in the cardiac unit. The interviews focused on the womens understanding of their symptoms. Interviews were conducted on women (n = 19) after hospitalization for a MI and prior to hospita l discharge. The interviews lasted approximately one hour and included open ended que stions such as: Describe the symptoms of your heart attack? At the time how did you interpret these symptoms? The interviews included several follow-up questions to further elucidate the answers to the initial questions (SjostromStranda & Fridlund, 2007). Data analysis was performed using conten t analysis. Results indicated that women described the pain associated with the MI in different ways. Some women described an acute pain that came on suddenly, was very painful as pressure in the chest. Some women described left arm and scapula pain over the entire back that was intense and made it difficult to breath (Sjostrom-Stranda & Fridlund, 2007). Other women st ated that the pain or discomfort in the throat and shortness of breath would come and go for 10 to 14 days prior to their hospitalization for the MI. Most women had trouble interpreting the symp toms as cardiac even though many of them had strong family histories of CHD or CAD. Many believed that they were too young to experience a MI. Several had the belief that they had developed a healthy lifestyle and were thus immune to the risks of CHD (S jostrom-Stranda & Fridlund, 2007). An interesting finding of the study was th at while many women did not recognize the cardiac related symptoms as dange rous, the pain or discomfort caused anxiety. In turn the 34

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anxiety exacerbated the pain and vice versa. The symptoms were often per ceived as severe when they were associated by the women with anxi ety. Subsequently, women would consult family and friends about the anxiety and be referred to the medical cente r for help (Sjostrom-Stranda & Fridlund, 2007). Sjostrom-Stranda and Fridlund (2007) conclu ded that women had di fficulty interpreting the symptoms of MI if they had not experien ced one prior. That many women delay seeking treatment because the do not anticipate the risk that may be in or that they may experience prodromal or atypical sy mptoms. In order to overcome the potential catastrophic consequences associated with MI women need to be made aw are of the clinical symptoms that they may experience. Devon, Ryan and Ochs (2008) conducted a st ructured interview study of 256 subjects (144 men and 112 women) to assess the differences between genders in t ype, severity, location, and quality of reported symptoms Subjects that presented to th e emergency department were categorized into one of 3 acute coronary s yndromes (ACS) (unstable angina, non ST-segment elevated MI and STEMI). Results concluded that women regardless of the category they were admitted to were significantly more likely to report numbness in the hands/arms, indigestion, fatigue, palpitations, and nausea. However, both women and men reported similar chest pain/discomfort episodes. The authors concluded that while a difference in the expression of atypical symptoms exists, the issue is unclear if the atypical symptoms are clinically significant (DeVon et al., 2008). Norris and colleagues (2008) conducted a pilot st udy that investigated the differences in gender presentation of prodromal symptoms of ACS. The researchers employed the MAPMISS to perform a structured interview of 24 wo men and 52 men. Results suggested that women 35

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reported more prodromal symptoms than me n. Premenopausal and perimenopausal women reported more prodromal symptoms than menopausal women and men. The researchers concluded that both men and women do repor t prodromal symptoms, although women report significantly more and menopausal status plays a role (Nor ris et al., 2008). Womens Symptoms Mixed Method Studies Few mixed method studies have explored women's symptom e xperiences (Philpott et al., 2001; Ryan & Zerwic, 2004; Vodopiutz et al., 2002). Philpott and colleagues (2001) reported results from a mixed method study that examined if language differed in the expression of symptoms between genders in subjects with ch ronic stable angina af ter angiography. Content analysis of a free text answer to an open ended question asking what health problems or symptoms had been responsible for the need of an angiogram was used to obtain how men (n =104) and women (n = 96) described the symptoms that they had perceived (Philpott et al., 2001). Subjects also completed the Rose Angina criteria to assess chest pain. Previous angiograms were reviewed to quantify CAD status using one or more diseased vessels as the criteria. The sample was garnered from the Appropr iateness of Coronary Revascularization (ACRE) study. The sample was stratified into 4 groups male, female, 60, >60 years of age. The free text answers were then coded into categorie s that included location of pain, character of pain, other symptoms and symp tom qualities. Results of the free text portion of the study indicated that women used the words neck, throat and jaw pain in describing a location for chest pain when compared to men especially if th e women had low physical functioning, had CAD or were not revascularized (Philpott et al., 2001). Th e researchers reported that for the Rose Angina criteria there was no significant difference in the intensity of chest pain between men and women. Women however, reported significantly less chest pain than men (Philpott et al., 2001). 36

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Women were also less likely to have angiographically signi ficant CAD (62% vs. 92%, p<0.01). Philpott (2001) concluded that ther e were differences in gender e xpression present in relation to chest pain symptoms and that these differences could infl uence clinical decision making. Atypical chest pain symptoms may cloud clinical judgment to proceed with invasive procedures like angiography and create delay in treatment. In 2002, Vodopiutz and colleagues conducted a coronary-linguistic mixed method study to assess the gender specific differences in symp toms of hospitalized men (44) and women (48) reporting chest pain as their main complain t. The researchers administered a 69 item questionnaire to gather demogra phic data, cardiac risk factors, chest pain frequency, chest pain descriptors, information regardi ng activities or medicines that br ought on or relieved chest pain and additional symptoms present. To assess th e linguistic portion of the study subjects were interviewed while hospitalized usi ng a recorded semi-structured inte rview process. The topics of the open ended questions to discuss their chest pa in experiences were predetermined. Interviews lasted 15 to 50 minutes mimicking a conventiona l healthcare provider in teraction allowing the opportunity for patients to describe fully thei r chest pain experience (Vodopiutz et al., 2002). Subjects were stratified into cardiac a nd non-cardiac chest pain categories by chart review at patient discharge. Coronary diseas e was diagnosed if subj ects had angiography or upon autopsy demonstrated a coronary lesion of >60% or had a nuclear or exerci se tolerance test that was positive for ischemia. Patients were considered to have a non-coronary diagnosis if another disease process was discovered to be the cause during the hospitalization or if angiography or autopsy revealed there was no evidence of a coro nary lesion of >60% or if the subject had a negative nuclear or exercise tolera nce test (Vodopiutz et al., 2002). 37

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Statistical analysis was performed only on th e cardiac portion. Resu lts indicated that 18 women and 25 men met the cardi ac chest pain criteria. Signifi cant difference was found in symptoms between those that had cardiac chest and those that did not. Cardiac chest pain was reported to be more retrosternal (93% vs. 71%, p = 0.0078) and in the right arm (23% vs. 6%, p = 0.0186) and less in the back (28% vs. 51% p = 0.0241) than non-cardiac chest pain (Vodopiutz et al., 2002). Women (mean 65.6 years) of the sample were older than the men (mean 59.0 years). Women with cardiac ches t pain reported more gradual onset of chest pain that was relieved by rest. Subject interview narrations were analyzed using interactional analysis. Analysis discovered that men offered more concise concre te descriptions of car diac chest pain. Women were verbose and vague in the description of their cardiac chest pain. Vodopiutz (2002 concluded that while gender differences do exist in the symptoms of chest pain, they are not specific enough to distinguish cardiac from noncardiac origin. The strong er evidence of the study points to gender differences in presentation and description of symptoms to healthcare providers by women. This factor may explain mi sdiagnosis and delay of care (Vodopiutz et al., 2002). Ryan and Zerwic (2004) using Q methodology, a mixed method, investigated symptoms that subjects at high risk for acute myocardial infarction (AMI) and their significant others understood to be related AMI. After qualita tive interviews were conducted of 140 AMI survivors, a quantitative Q sort instrument was developed by the researchers that comprised 49 statements that described AMI symptoms in lay terms. Women (n = 22) and men (n = 31) with known CAD or their significant others (n = 10) we re subsequently recruite d and administered the instrument. 38

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Results indicated that four factors emerged. Factor 1, trad itional symptoms (respondents =12 men, 3 women, and 4 significant others) enco mpassed symptoms taught to the lay public by healthcare professionals and at cardio-pulmonary resuscitation classes. Symptoms focused on severe sustained pain. Factor 2, (respondents =7 men, 3 women, and 3 significant others) focused on gastrointestinal symptoms which included chest symptoms that could mimic stomach problems such as dullness, fullness and heavin ess. Factor 3, (respondents = 4 men, 2 women, and 0 significant others) non-specific symptoms identi fied as an unusual tired feeling, labored breathing and weakness. Factor 4, (respondents =1 men, 1 women, a nd 0 significant others) a variation of traditional symptoms that iden tified other upper body parts (neck, shoulders, and arms) as a locus of pain and shortn ess of breath (Ryan & Zerwic, 2004). Ryan and Zerwic (2004) concluded that the symptoms that people and their significant others expect with an AMI are different that they expect. Furt hermore, a significant difference between how genders expect AM I symptoms to be exists. Summary The body of research explori ng the symptoms and experiences of women with CAD is ever increasing. Many studies have been able to illustra te that the current framework established for the diagnosis of CAD in men is an ill fit for women (D'Antono et al., 2006; Granot et al., 2004; Miller, 2002; Omran & Al-Hassan, 2006). The unique presentation differences between women and men experiencing CSA, UA and MI make it imperative that new studies elucidate the unique symptoms in women presenting with cardiac disease. Countless stories of women whose diagnosis and treatment have been delaye d because their symptoms were not immediately identified as cardiac abound (Ars lanian-Engoren et al., 2006; Granot et al., 2004; Kosuge et al., 2006; Lovlien et al., 2006; Shaw et al., 2008). If researchers and healthcare practitioners continue to look exclusively for the traditional sympto ms of CAD that include mid-sternal chest 39

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pain radiating to the jaw and down the left arm, women will continue to be misled about their susceptibility to cardiac diseases (Miller, 2002). Hea lthcare professionals must take their share of the blame for this state of affair s, in that traditional expectat ions and warnings regarding CAD are still targeted pr edominately to men. Critical to the improvement of the identific ation of cardiac problems in women is the careful screening of women with diabetes and hyp ertension as well as pa ying close attention to atypical symptoms on presentation. Subtle symptoms such as fatigue, shortness of breath, back pain and transient non-specific chest disc omfort should prompt thorough assessments particularly in women with two or more card iac risk factors (Miller 2002). For healthcare providers ruling out CHD based simply on age, race or gender is no longer appropriate. Each patient should be individually evaluated based on cardiac risk profile and symptom presentation (Miller, 2002; Shaw et al., 2008). Theoretical Model An exceptional way to inves tigate this problem is through the use of nursing theory. The conceptual framework that will guide this exploratory research proposal and was chosen based on the literature review is the Theory of U npleasant Symptoms (TUS); a middle ranged nursing theory introduced by Lenz and colleagues in 1995. The TUS posits a dimensional structure for unpleasant sensations that reflec ts intensity, distress, timing and quality of symptoms or symptom clusters (Lenz, Suppe, Gift, Pugh, & Milligan, 1995). These unpleasant sensations mimic the intensity, time frame and frequency dimensions assessed on the MAPMISS. The relational structure of the TUS shows that symptoms arise from correlated physiological, psychological and situational influe ncing forces that result in a ltered functional, cognitive and physical performance. For the revised version of the TUS the model a ssumes a feedback loop from symptom to symptom and a possible catalys t effect of each symptom to another (Lenz, 40

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Pugh, Milligan, Gift, & Suppe, 1997). This f eedback loop was a serendipitous finding by Sjostrom-Stranda and Fridlund (2007) where pain fe d anxiety and vise versa. This portion of the model will be tested in this re search project. The major hypothesi s that there are differences in womens prodromal cardiac symptoms between thos e that have CAD and those that do not will be explored. The focus of the revised model of the TUS is to facilitate the understanding of the multidimensional often influentia l aspects underlying symptoms and symptom clusters (Parker, Kimble, Dunbar, & Clark, 2005). Using this framework will allow for the fu ture translation of research findings into symptom recognition mode ls that can change practice paradigms within the current healthcare sy stem and optimize patient outcomes (Parker et al., 2005). The structure of the revised theory framework is shown in Figure 2-1. The revised model of the TUS emphasizes that symptoms may arise independently of other symptoms but frequently, symptoms are experienced concurrently (A rslanian-Engoren et al., 2006; D' Antono et al., 2006; Kosuge et al., 2006). The occurrence of several symptoms simultaneously is liable to have multiplicative effect as opposed to an additive effect (Len z et al., 1997; McSweeney & Crane, 2000). Thus, simultaneously occurring symptoms are more apt to have a catalytic effect on one another. Prodromal symptoms are those symptoms that are new onset or increase in intensity or frequency of existing symptoms. Accuracy in describing womens prodromal symptoms is a critical step in providing a comp lete picture of womens typical presentation of coronary artery disease (McSweeney, personal communication, June 11, 2004). The 33 prodromal symptoms identified by McSweeney and colleagues (2003) that appear on the MAPMISS are listed in Table 2-1. 41

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Model Assumption The revised model of the TUS is based on the following assumption. The gold standard for the study of symptoms is based on the per ception of the individual experiencing the symptom and his or her self-report. Conceptual Definitions In the revised model of the TUS, three forces influence the occurrence, intensity, time frame and frequency of symptoms they are: physiologic, psychological, and situational forces. In the revised version of the theory, interactional aspects are acknowledged with in each of the three categories of forces influenc ing the symptom experience of the subject (Lenz et al., 1997). Forces will be assessed as comorbidities, medical variables and situatio nal factors on subject demographics that are either cate gorical or continuous va riables. Analysis of these variables will be tested as outlined in chapter 3 under the statistical data plan. An accepted theory is that unpleasant symp toms are often a refl ection of physiological distress (Lenz et al., 1997; Park er et al., 2005). Examples of phys iological distress include but are not limited to the existence of pathology, trau ma or a decrease in th e individuals level of energy as a result in nutrition and hydration deficiencies (Lenz et al ., 1997; Parker et al., 2005). The psychological forces of the revised TUS model include the individual's state of mind, their response to illn ess, and lack of knowle dge about experienced symptoms vs. expected symptoms. Previous research esta blished that states of anxiet y and depression contribute to symptom presence, intensity, timing and freque ncy (Lenz et al., 1997; Parker et al., 2005). Correspondingly, individuals with anxiety and who view their il lness as extremely stressful frequently exhibit more severe symptoms than those who perceive less stress (Lenz et al., 1997; Parker et al., 2005). 42

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Situational forces such as ones social a nd physical environment a ffect the reporting and experience of an individuals symptoms. Job status, home and marital issues, education, support systems, healthcare access, and everyday life behaviors such as nutrition and exercise (Lenz et al., 1997; Parker et al., 2005). Operational Definitions To explore prodromal symptoms the MAPMISS will be used. The MAPMISS, originally a telephone administered survey, lists 33 prodromal symptoms that women previously identified in qualitative studies. The MAPMISS contains descriptors for each symptom. Women rate prodromal symptoms according to intensity (i.e., mild, severe), frequency (i.e., daily, weekly), and time frame (i.e., week of, more than 1 m onth) (McSweeney et al., 2004). The MAPMISS also contains questions relating to comorbiditie s, risk factors, medica tions, and demographics. Prodromal scores are constructed from the product of intensity and frequency for each symptom, then the summed scores for each symptom to create an overall prodromal score. In this exploratory study symptoms are both the depend ent variables for hypothesis 1and the potential independent variables for hypothesis 2. Variable testing and analys is are explained in chapter 3 under the statistical data plan. 43

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Table 2-1. Thirty-three prodromal symptoms Pain/ discomfort in the general chest Very tired/ unusual fatigue Hand/Arm tingling Pain/ discomfort centered high in chest Sleep disturbance Nu mbness or burning of both arms Pain/ discomfort in left breast Anxious Numbness or burning of right arm Pain/ discomfort in neck/throat Cough Numbness or burning of left arm Pain/ discomfort in jaw/teeth Heart racing Numbness or burning of fingers on both hands Pain/ discomfort in back, between/ under shoulder blades Shortness of breath/ orthopnea Numbness or burning of fingers right hand Pain/ discomfort at top of shoulders Difficulty breathing at night Numbness or burning of fingers left hand Pain/ discomfort in both arms Loss of appetite New onset of vision problem Pain/ discomfort in left arm or shoulder Frequent indigestion In creased intensity of headaches Pain/ discomfort in right arm or shoulder Arms week / heavy Increased frequency of headaches Pain/ discomfort in legs Arms ache Change in thinking or remembering 44

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WGW UF CON Unpleasant Symptom 1 DiagnosisofCHD 33 Prodromal Symptoms Psychological Forces Situational Forces Physiological Forces CHDEvent Treatment Misdiagnosis Mistreatment CHDEvent Not Tested Tested Figure 2-1. Revised theory of unpleasant symptoms Note : From Collaborative development of middle-r ange nursing theories: toward a theory of unpleasant symptoms, by Lenz, E. R., Suppe, F., Gift, A. G., Pugh, L. C., & Milligan, R. A.,1995, Advances in Nursing Science, 17(3) p.5.Copyright 1995 by Lippincott Williams and Wilkins. Adapted with permission. 45

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CHAPTER 3 METHODS Design The study conducted was an exploratory cross-se ctional structured interview survey of a convenience sample of 166 women undergoing primary event, electiv e, cardiac catheterization at multiple (4) cardiac catheteriz ation laboratory sites within the Orlando area. The cardiac catheterization laboratory sites are the outpatient laboratories of Florida Heart Group, Central Florida Cardiology and Cardiova scular Centers, LLC (2 site s). The main advantage to conducting this cross-sectional design was its in herent practicality. This design was relatively easy to manage and economical (Portney & Watkins, 2000). Funding Funding for this project was provided by a Sigma Theta Tau International Small Grant sponsored by the Alpha Theta Chapter of Sigma Theta Tau International at the University of Florida, Gainesville, Florida. Research mate rials and facilities support was provided by the cardiac catheterization laboratories of Florida Heart Group, Central Florida Cardiology and Florida Cardiology located in Orlando, Florida. Consent The primary investigator (PI) sought approva l from the dissertation committee and the Institutional Review Board-01 (I RB-01) for human subjects at the University of Florida. The IRB-01 granted approval to c onduct research on expedited pr oject # 398-2007 on September 9, 2007 with an expiration date of September 9, 20 08. Subsequently, enrollment and data collection began. A waver of health information patient protection act (HIPPA) wa s granted by IRB-01 in order to more efficiently identify potential subjects. 46

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Potential participants were then recruited at the outpatient labs after they were prepped for their cardiac catheter ization procedure. A brief explana tion of the study was presented to each potential subject and permission to proceed with the consent process was sought. Participants that agreed then reviewed and si gned an informed consent, including consent for chart review, collection and revi ew of cardiac catheterization di gital angiography disks. Once consent was obtained, subjects were assigned an identification (ID) number (i.e., 398-2007-201) to de-identify them. A handwritten table containi ng the coding system conve rting patient identity to ID number was kept in a double locked cabinet (PI access only). This was the only source of data matching subjects to ID numbers. The table was destroyed afte r data collection was complete and prior to the study cl osure. Subjects were not compen sated for participation and had the option to withdraw from the study at any time. No subjects withdrew from the study. There were no anticipated health benefits or risks to subjects; subjects did not receive any information concerning cardiovascular status or scores on the MAPMISS. No adverse events were reported. The PI had no conflict of interest regarding th is protocol. A continui ng review/ study closure report was submitted to the IRB-01 on July 14, 2008 with a request to close the study. Subjects and Recruitment The convenience sample consisted of 166 women who presented to multiple (4) cardiac catheterization laboratory sites within the Orland o area (who have not had a prior catheterization or been diagnosed with CAD). Di rect recruitment was performed in the cardiac catheterization laboratory pre-procedure rooms. Ph ysician referral was used. Inclus ion and exclusion criteria are listed in Table 3-1. Sample Size Determination Sample size was determined using a confiden ce interval method to calculate the required sample size. Confidence interval method is one of the methods used when calculating n for a 47

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logistic regression analysis (Jaccard, 2001; Menard, 2002). It was assumed that if 50% of women with prodromal cardiac symptoms were diagnosed with CAD approximately 96 subjects would be required if the estimate was to fall wi thin 10% points of the true proportion with 95% confidence. This estimate of CAD presence was based on reported research that noninvasive cardiovascular testing that identifies ischemia is not as predictive in women (50%) as in men (90%) (DeCara, 2003). Additionally the 50% assumption requires the largest sample size when using this method for calculation. Originally the sample size was chosen to assume the estimated proportion of CAD within 5% of the true proporti on and that to complete the study 384 subjects would be required. Since recruiting that number wa s not possible in the timeline to complete this dissertation, with permission of the supervisory committee chair, a change was made to assume the estimated proportion of CAD within 10% an d the required sample size was dropped to 96 subjects. Since data was already collected on 166 subjects, that number was used for the analysis. Table 3-2 shows sample sizes for esti mated 50% CAD proportion (P) to be within 10%, 5%, or 2% (d) of the true proportion with 95% confidence (Cohen, 1998; Murphy & Myors, 2004). Variables To address hypothesis 1: th ere are differences in women s prodromal cardiac symptoms between those that have CAD and those that do not, the independent variables are CAD 20% and CAD 50% stenosis as described la ter in the chapter. The depe ndent variables are inclusive of the 33 prodromal symptoms identified on the MA PMISS, as well as presence of an abnormal EKG, an abnormal dual stress test, comorbidities, situational forces and demographic data. Table 3-3 shows a complete list of th e dependent variables for hypothe sis 1.To address hypothesis 2: a prodromal cardiac symptom or a cluster of prodromal cardiac symptoms will discriminate between those women who have CAD and those that do not, the potential independent variables 48

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are those same variables listed in Table 3-3. The dependent variables are CAD 20% and CAD 50% stenosis as described later in the chapter. Consented subjects were asked demographic da ta about their race, age, height, weight, marital status, educational level, income, exerci se regimen, menopausal status, comorbidities and smoking history as part of the MAPMISS. Race wa s determined by self-report, using the Office of Management and Budget revised race and et hnicity categories (Feder al Drug Administration, 2003). Chart review was performed to ascer tain information concerning results of electrocardiograms, dual stress tests and left ventricular ejection fraction percentage. The MAPMISS, which lists 33 prodromal symp toms previously identified by women in qualitative studies, was administ ered via a structured interview technique. Patients were interviewed in privacy, behind closed doors or pul led curtains without family members or other staff present when possible. When family memb ers attended the interview, instructions were given that only the subject could respond to the qu estions and that for the purpose of this project comments or consultation should be withheld. Assurances of confidentiality regarding the subjects responses and anonymity after data collection were offered. The MAPMISS was used to assess the independent variable prodromal symptoms (McSweeney et al., 2003). Prodromal symptoms were considered new symptoms or ones that had increased in intensity/frequency (J. C. McSweeney, personal communication, June 1 1, 2004). The MAPMISS contained descriptors for each symptom (i.e., very tired, unusual fatigue ) Women rated their symptoms according to intensity (mild, severe), frequency (daily, weekly), and time frame (week of, more than 1 month). The MAPMISS, was developed in a series of studies to establish content validity, and contains questions relating to co-morbidities, risk factors, medications, and demographics (McSweeney et al., 2004). Prodromal scores were constructed from the product of intensity and frequency for 49

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each symptom, then summed scores for each created an overall prodromal score. The minimum prodromal score per symptom is 0 and the maximum score is 18. The minimum MAPMISS prodromal score total is 0 and the maximum sc ore is 594. Figure 3-1 shows an example of a MAPMISS type question with calculation formul a and score. (McSweeney et al., 2004). To assess presence of the variable of C AD, coronary angiography was performed and reviewed at the cardiac cathet erization laboratory sites accord ing to usual methods (Baim & Grossman, 2000). Then, de-identified copies of the catheterization images were transferred to CD-ROM format for offline review and quantitative coronary analys is (QCA) at a single location to guard against image variability. QCA is a tool that detects and quantifies any coronary artery lesion. The basic principles of QC A are the automatic detection of the vessel edges in a selected portion of the artery, then quantitative measurement of the vesse l length and diameters along the selected segment (Sanmartin et al., 2004). Thes e measurements, when applied during coronary angiography, allow quantification of lesion severity from its shape and length (General Electric, 2003; Sanmartin et al., 2004). The success rate of QC A has been appraised to be greater than or equal to 93% (Lienard, Su reda, & Finet, 2002). Procedure: Quantification of CAD All coronary angiograms were reviewed and analyzed by the PI. All coronary segments identified visually as abnormal were measured quantitatively. The QCA required minimal user interaction. Calibration of the QC A software was achieved with user selected portions of the angiographic catheter using the external diameter of the catheter image fo r scale (Sharaf et al., 2001). Conventional calibration of the catheter to a valu e for external diameter was determined by the package insert label in either 5 or 6 Fr ench units (Sanmartin et al., 2004). Arterial segments were then analyzed in a single vi ew, which minimized vessel overlap/foreshortening and maximized the apparent severity of a stenosis (Sanmartin et al., 2004; Sheifer, Arora, Gersh, 50

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& Weissman, 2001). The start and end points of th e segment of interest was user determined. Vessel centerline and contour were determined by the edge detection algorithm. Percent stenosis was then auto calculated by the software pack age from minimum lumen diameter (MLD) and a normal reference vessel diameter (RVD) value obt ained as an extrapolation of the proximal and distal segments surrounding the stenosis. Diameter stenosis (DS) was computed in percent as RVD MLD/RVD (100) = DS. As contours for both the catheter and arterial segments were auto quantified by the QCA software, no manual ad justment was attempted (Sanmartin et al., 2004; Sheifer et al., 2001). Major coronary arteries analy zed were the left anterior de scending, left circumflex, and right coronary arteries. Diagonal, acute, and obtuse marginal branch vessels were considered major and analyzed if they supplied enough myocardium to be potentially suitable for revascularization ( 2 mm lumen diameter) (Sheifer et al ., 2001). All women with 1 or more stenoses of 20% and up to a 100% stenosis were defined as having CAD. Rationale for choosing this indicator as CAD is that 20% stenosis is the marker at which aggressive therapy is initiated in the clinical setting. Often medications such as aspirin, cholesterol lowering agents and beta-blockers are prescribed with an elevation in noninvasive diagnostic test performance. Women with stenoses < 20% were considered to have normal cor onary arteries (Sharaf et al., 2001). As a subcategory, women w ith 1 or more stenoses of 50% were defined as having severe CAD. Rationale for choosing this indicato r as severe CAD is that 50% stenosis is the marker at which aggressive treatment is initiate d in the clinical setting. Interventions such as intravascular coronary u ltrasound, vessel hemodynamic flow studies, angioplasty and intracoronary stenting may be recommende d as an adjunct to medical therapy. 51

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Statistical Analysis Plan SAS (Version 9.1.3) was used for all statistica l analyses and for writing the scientific report of the quantitative data. De scriptive statistics were used to obtain the summary measures for all data including a description of the sample characteristics. Descriptive statistics included means, ranges, and standard deviations for continuous variables. Categorical variables were statistically represented in fre quency distributions and percentage distributions. A p-value of less than 0.05 was considered to be stat istically significant (Polit, 1996). To address hypothesis 1, analysis of frequenc y (chi-square test) was used to determine the difference in proportion of the variables that were measured on nominal and ordinal scales between the two groups of subjects who were diagnosed with CAD or without it. The t-test was utilized to find the difference in mean of the variables measured on interval or ratio scales between the two groups. To address hypothesis 2, logistic regr ession analysis was used to explore the potential differences in the predictor variables be tween those who had CAD from those who did not. In this study, the dependent variable CAD has been coded as zero if CAD < 20 or one if CAD 20; and zero if CAD < 50 or one if CAD 50. What distinguishes a logistic regression model from the linear regression model is that the de pendent variable in logistic regression is binary or dichotomous. The anal ysis and interpretation of logistic regression, however, is quite similar to the procedures of multiple regression. The predictor variables in logistic regression can be categor ical or continuous. Logistic Regression techniques have been widely used for identifying risk factors that are associated with disease in healthcare research. This method also has popular ap plication in analyzi ng prospective clinic al trials and in identifying potentially important covariates in explorat ory analyses of clinical research data (Menard 2002). 52

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Logistic regression overcomes many of the re strictive assumptions of regression analysis. The fundamental assumption in logi stic regression analysis is that the natural logarithm of odds [ln (odds)] is linearly related to the independent variables. No assumptions are made regarding the distributions of the independent variables. In fact, one of the major advantages of using logistic regression is that the independent variables may be discrete or continuous. However, since logistic regression uses maximum likelihood procedures, multivariate normal distribution for the continuous independent variables make s the solution more stable (Hair, Anderson, Tatham, & Black, 1998). There is no homogeneity of variance assumpti on, that is, variances need not be the same within categories. Norma lly distributed error term s are not assumed. It is not required that the independent variables be measured on interv al or ratio scal es. Logistic regression does not rely on dist ributional assumptions in the same sense that discriminate analysis does. Additionally, as with other fo rms of regression, multicollinearity among the predictors can lead to biased estimates a nd inflated standard e rrors (Menard, 2002). Estimation of model parameters in logist ic regression uses th e method of Maximum Likelihood. This is a technique from probability theory which is widely used in the derivation of statistical tests. As its name implies, Maximum Likelihood is a method which provides estimates of the parameters which maximize the likelihood of observing the data set collected. The Maximum Likelihood method establishes a set of e quations involving the estimates of the model parameters. These equations are then solved simultaneously to obtain the Maximum Likelihood estimates (Pampel, 2000). The recommended test for overall fit of a l ogistic regression model is the Hosmer and Lemeshow (HL) test, also called the chi-square test. It is considered more robust than the traditional chi-square test, particularly if continuo us covariates are in the model or if the sample 53

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size is small. If the HL goodnessof-fit test statistic is greater than 0.05, the null hypothesis that states that there is no difference between obs erved and model-predicted values will not be rejected, implying that the model's estimates fit the data at an acceptable level (Garson, 2008). In addition, there are several measures that provide evidence for goodness-of-fit in logistic regression. These are: the Akaike Informa tion Criterion (AIC), the Bayesian Information Criterion (BIC), and the Schwartz Information Criterion (SIC). Th e lower these measures are the better model fit (Pampel, 2000). To obtain an optimal model, the predicto r variables were added in a step-type fashion. There are three step-type logistic regression pr ocedures, forward, backward and stepwise. For this study, backward procedure was used to determine the optimal model from the maximum model. In addition, the point and interval estimates of the odd rati os of the predictor variables were reported. The odds ratio for a given independe nt variable represents the factor by which the odds of an event (e.g. CAD 50) change for a one-unit change in the independent variable (Hair et al., 1998). 54

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Table 3-1. Inclusion/exclusion criteria data collection Inclusion criteria Exclusion criteria Signed consent Inability to verbally comm unicate (Aphasia, Intubated) Over age 40, under the age of 90 Emergent catheterization (AMI) Without prior catheterization Pre-medicated with narcotics Without prior diagnosis of CAD Catheterization for surgical clearance w ithout cardiac indication (Abnormal EKG or ex ercise/nuclear stress test) Elective Catheterization Any other psychiatric/medica l condition which in PIs opinion would make participa tion not in subjects best interest. English speaking Table 3-2. Sample sizes for estimated 50% of sample with CAD P d n 0.50 0.10 96 0.50 0.05 384 0.50 0.02 2401 55

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Table 3-3. Complete list of de pendent variables for hypothesis 1 Variables Abnormal EKG Increased frequency of headaches Abnormal dual stress test Change in thinking or remembering Generalized chest pain History of chest pain Centered high in chest pain Hist ory of congestive heart failure Left breast pain History of coronary heart disease Neck/throat pain History of hear t irregularity, heart murmur or valve disease Jaw/teeth pain History of high blood pressure Back, between/under shoulder blade pa in History of high cholesterol Top of shoulders pain History of de pression or other emotional problems Both arms pain History of cancer Left arm pain History of diabetes/ low blood sugar Right arm pain History of chr onic heart burn, stomach problems (GERD Leg pain History of chronic back pain Very tired, unusual fatigue Histor y of joint problems (arthritis) Sleep disturbance History of osteoporosis (brittle bones) Anxious History of stroke Cough History of thyroid disease Heart racing History of gallbladder disease Shortness of breath/ orthopnea History of hysterectomy Difficulty breathing during the nigh t History of menopause onset Loss of appetite History of estrogen replacement Frequent indigestion Current estrogen replacement use Arms weak/heavy History of birth control use Arms ache History of smoking (at least 100 cigarettes in life) Hands/arms tingling Current smoker Numbness or burning of both arms Exposed to secondhand smoke Numbness or burning of right arm Exercise Numbness or burning of left arm Employed Numbness or burning of finge rs on both hands Retired Numbness or burning of fingers on ri ght hand Children living at home Numbness or burning of fingers on left hand Income of $30,000 New onset vision problem Income of $30,000 Increased intensity of headaches Years of birth control use Age of subject Family history of MI MAPMISS score Pack year history of smoking Symptom score Years of secondhand smoke exposure History of chronic lung disease Weight (lbs) History of migraine head aches Height (inches) Age at hysterectomy Exercise times per month Years of estrogen replacement use Hours per attempt of exercise Current estrogen replacement use 56

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LOCATION OF PAIN OR DISCOMFORT Symptom: Chest Pain/Discomfort/Pressure for Yes, designate Intensity No (0)* Severe (3) Medium (2) Mild (1) Time Frame: week of month of more than month Freq: daily (6) several times a week (5) at least 1x per week (4) At least 2x per month (3) monthly (2) less than monthly (1) *= (point value) CalculationFormula: Intensity x Frequency (minimum score = 0, maximum score = 18) Score for this example: 3x5=15 X X X Figure 3-1. Example of a MAPMISS type question with calculation formula and score (McSweeney et al., 2004) 57

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CHAPTER 4 FINDINGS The primary purpose of this study was twofold. First, to examine the potential differences in womens prodromal cardiac symptoms between those that have CAD and those that do not by assessing symptom presence prior to cardiac cath eterization and quantifying CAD in the cardiac catheterization laboratory setti ng. The second purpose was to determine a prodromal symptom or a cluster of prodromal cardiac symptoms that can be most helpful to healthcare professionals in identifying women who are at-risk of having CAD. Analysis of frequency (chi-square test), two independent samples t-test, and logistic regressi on analysis were performed to evaluate the proposed hypotheses for this research project. SAS (Version 9.1.3) was used to perform all the analyses. This statistical software was chosen for its recommendation of being superior for logistic regression an alysis (Menard, 2002). Data Collection and Descriptive Statistics Female patients (n=166) were recruited during outpatient cardiac catheterization laboratory appointments at one of four enrollment sites in Orlando, Florida: Cardiovascular Centers, LLC. (2 centers)(n=98), Florida Heart Group, PA (n=13), and Central Florida Cardiology Group, PA (n=55). Patien ts were excluded from the study if they were younger than 40 years of age or older than 89 years of age, not able to speak English, had a previous diagnostic cardiac catheterization or were present for surgical clea rance. After an introduction of the study and gathering of inform ed consent, patients were administered the MAPMISS. The survey took approximately 20-30 minutes to complete. Upon completion of the survey questionnaire, patients complete d their participation in the study. Medical record review was conducted for information regarding medicatio ns and previously performed non-invasive diagnostic tests (i.e., electrocar diogram and stress tests). Imme diately post survey patients 58

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underwent a diagnostic catheterization. Cardiac catheterization films were reviewed and analyzed by the primary investigator for the pr esence of CAD using quantitative QCA. Table 4-1 presents relative percentages of the total sample by recruitment site. Subject Demographics The mean age of the sample was 65.86 years with a range of 40 to 87 years of age. The mean weight of the sample was 77.4 kilogram s (kg) with a range of 37.3 to 147.7 kg. The mean height was 161.2 centimeters (cm) with a range of 130.8 to 177.8 cm. The mean body mass index (BMI) was 29.7 with a range of 14.1 to 52.5. Subjects (75%) re ported exercising on average of 17 times per month for an average of .97 hours per attempt. The most frequent exercise performed was walking (37%) with 18 % engaging in aerobic exercise. Ethnically, 85.54% of participants self-rate d as Caucasian, 7.83% rated as African American/Black, 5.42% rated as Hispanic/non-white, 0.6 % rated as Asian and 0.6% rated as Indian. The majority of participants were married (54.22%), 18.67% repo rted being separated/divorced, 5.42% reported being single/never married, and 21.69% reporte d being widowed. Of the total sample, 59.03% had earned less than a high school diploma, 33.1 3% had earned a high school diploma, and 7.83% had achieved greater than a high school de gree. The majority of the subjects were retired/not working (61.45%), 29.52% were em ployed full time, 6.63% worked part time and 2.4% were unemployed. Of the participants, 67.47% reported a total household income of <$30,000. Table 4-2 provides demographic informati on for the total sample of female patients. McSweeney Acute and Prodromal Myocardial Infarction Survey The MAPMISS, which lists 33 prodromal symp toms previously identified by women in qualitative studies, was administer ed via a structured interview t echnique and was used to assess the variables for prodromal symptoms. The MAPM ISS contains descriptors for each symptom. Women rated prodromal symptoms according to intensity (i.e., mild, severe), frequency (i.e., 59

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daily, weekly), and time frame (i.e., week of, more than 1 month). The MAPMISS also contains questions relating to comorbidities, risk factors, medications, and demographics (McSweeney et al., 2004). Women never added symptoms duri ng the current study, indicating that the tool was comprehensive. Prodromal scores were construc ted from the product of intensity and frequency for each symptom, and then summed scores for each symptom were calculated to create an overall prodromal score. Subjects of this study had a mean MAPMISS score of 79.95 (SD = 53, Range = 6-307) and the symptom mean score was 8.67 (SD = 4, Range 1-24). Particular points of interest among the vari ables contained on the MAPMISS for the total sample were the symptoms of neck/throat pa in, hand/arm tingling and numbness or burning of the arms. Those subjects that reported experienci ng neck/throat pain (25.30%) had a mean age of 64.3, slightly younger than the overall mean age of 65.9 years that was reported for the sample. The same is true for those that had a compla int of hand/arm tingling (37.35%) to one or both arms, the mean age of these subjects was 65.1 years. The MAPMISS did not discriminate between those with tingling in both hands/arms, the right hand/arm or the left hand/arm. In order to differentiate this variable from others, subjects were given the addi tional descriptors of a stinging or prickling sensation. The variable of numbness or burning of the arms was split into three separate variables according to the MAPMI SS instructions. To differentiate this variable numbness was given the additional descriptor of no feeling, and burning was described as being hot or on fire. Of those subject s that experienced numbness or burning to the arms 19.27% had this symptom in both arms (mean age of 59.7), 8.43% had numbness or bur ning to the right arm (mean age of 66.8) and 7.22% had numbness or burning to the left arm (mean age of 54.6). Other variables of interest included on the MAPMISS are described as follows. Approximately 48% of the women in the study reported having experi enced the onset of 60

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menopause. The average age of onset was 50 year s of age. The mean age of the 80 women who experienced menopause onset is currently 69.31 year s. Slightly more than 50% of the sample reported having had a hysterectomy at the mean age of 43.70 years with 37% having had both ovaries removed. A history of bi rth control use was reported by 56.02% of the sample with the mean 7.76 years of use. A history of estrogen replacement therapy was reported by 54.21% of the sample with mean years of use of 9.70. Current estrogen replacement therapy was reported by about 15% of the women for a range of 1 to 32 years, with a mean of 18.18 years of use. There were 13 (7.83%) current smokers enrolled in the study and 79 (44.57%) former smokers with an average pack year history of 21.6. Th e vast majority of wo men (80.72%) in the study reported having been exposed to secondhand smoke for an average of 32.50 years (range 3 to 66 years). Table 4-3 presents the frequency distribution and relative percentages of prodromal symptom variables of the total sample. Medical Variables Patients medical records were reviewed to obtain the following information. The sample of women possessed a mean left ventricular ejection fraction of 62%. About 48% of the subjects were diagnosed with an abnormal electrocardi ogram, while 69% were diagnosed with an abnormal dual stress test, and 38% had both. Of th e entire sample, 63.86% had a history of high blood pressure and 73.49% met criteria for high cholesterol. In the sample, 24.10% of patients were diabetic and 20.48% had a reference of mild to moderate valve disease. Table 4-4 provides information regarding medical variables for subjects. Comorbidity Variables As part of the MAPMISS administration each subject self-reporte d comorbidity. Sixtythree percent of subjects reported that they had some form of ch ronic joint problems (arthritis) while 26.51% reported having osteoa rthritis. Chronic heart burn was reported by 50.60% of the 61

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subjects in the study. A history of migraine headaches was repor ted by 28.92% of the sample. Approximately 38% reported some form of thyroid disease. Both chronic lung disease and chronic back pain were reported by 59 of the subjects (35.54%). Forty six subjects (27.71%) revealed that they had previous to this study, be en diagnosed with some form of cancer. Table 45 provides the frequency distri bution regarding comorbidity variables for the subjects. Coronary Angiography Variables Post MAPMISS administration, each patient was subjected to an elective diagnostic cardiac catheterization by her phys ician. Selective cor onary angiography was performed from the femoral approach.. Coronary arteries were evaluate d by the primary investigator with the use of QCA which allows both for catheter-based image calibration and for automated vessel contour detection (General Elec tric, 2003; Sanmartin et al., 20 04). Reference vessel diameter (RVD) and minimal luminal diameter (MLD) were computed automatically by the QCA software. Diameter stenosis (DS) was computed in percent as: RVD MLD/RVD (100) = DS (General Electric, 2003). Only segm ents with a reference diameter 2.0 mm were evaluated. Segments with smaller diameter were considered to be absent; DS 20% was used as a cutoff value to define the presence of CAD. DS 50% was used as a cutoff value to define significant severe CAD stenosis. CAD 20% DS was present in 61.4% of the subjects, while 53.6% of the subjects demonstrated severe CAD 50% DS. The left anterior descending artery was the vessel that most commonly demonstrated stenosis for both 20% CAD (51.8%) and for severe CAD 50% (39.1%). Table 4-6 provides in formation regarding coronary ar tery variables for subjects. Data Analysis Hypothesis 1: There are diffe rences in womens prodromal cardiac symptoms between those that have CAD and those that do not. 62

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To address hypothesis 1, analysis of frequenc y was used to determine the difference in proportion (or percentage) of the variables measur ed on nominal or ordinal scales between the two groups. Analysis of frequency is analogous to testing the relationship between the two variables that are measured on th e nominal or ordinal scales (i.e ., presence and absence of high cholesterol versus presence or absence of CAD). In addition, the two samples t-test was used to determine the difference in means of the variable s measured on the interval and ratio scales between the two groups. The results indicated that among those with a high cholesterol, higher percentages of the subjects had CAD 20%, or equivalently, it can be stated that the results indicated that there was a signi ficant relationship between C AD presence and high cholesterol (Chi-square = 8.43, p = 0.0037). Among those with high cholesterol, 81.37% had CAD 20% vs. 60.94% with CAD < 20%. This report of per centages is the condition al probability, which SAS calls Row Percent; it comes from a contingency table by cross classifying CAD 20% and a history of high cholesterol. These percentage s will not add to 100% since the Row Percent of the two different rows are reported. Table 4-7 sh ows an example of the contingency table of CAD 20% by history of high cholesterol. There was a significant relationship between cancer and CAD in that more women with a histor y of cancer had CAD (Chi-square = 4.18, p = 0.0410). A significantly higher percentage of diabetic woman had CAD (30.39% vs. 14.06%, Chi-square = 5.73, p = 0.0138). The relations hip between CAD and subjects who had experienced menopause was statistically si gnificant (Chi-square = 5.67, p = 0.0173). Among those who were or had used hormones, 8.82% had CAD 20% vs. 20.31% with CAD < 20% (Chi-square = 4.51, p = 0.0336). A lower percentage of those who had used birth control had CAD (47.08% vs. 70.31%, Chi-square = 8.63, p = 0.0030). Among those who had a history of smoking, 12.50% had CAD 20% vs. 3.92% with CAD < 20 % (Chi-square = 4.31, p = 0.0378). 63

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The relationship between CAD presence and empl oyment was statistically significant (Chisquare = 15.52, p < 0.0001). The results reflected a lower percent of employment for women with CAD (24.51% vs. 54.61%). A higher percenta ge of women who were retired had CAD (72.55% vs. 43.75%, Chi-square = 13.77, p = 0.0002). A lower percentage of women who had children at home had CAD (11.76% vs. 34.38%, Chi-square = 12.34, p = 0.0004). This study is viewed as exploratory. The study consists of a larg e number of variables that can have an effect on CAD. Both levels of signi ficance are specified. If the tests were performed under the complete null hypothesis which indi cates that the difference in proportion for all the variables that are listed in table 4-8 between the two groups were zero, then th e level of significance (alpha) must have been adjusted for the overall er ror. Using the Bonferroni procedure, the new level of significance was calculated as: 0.05/65 = 0.0007. As shown in Table 4-8, under the complete null hypothesis, fewer variables were st atistically significant gi ven alpha = 0.0007. Table 4-9 shows the mean difference of symp tom variables between two levels of CAD 20%. Using the t-test, as indicated in Table 4-9, the differences in mean age (p = 0.0001) of the subjects, history of migraine headaches (p = 0.0235), years of birth c ontrol use (p = 0.0346), and years of secondhand smoke exposure (p = 0.0058) be tween the two CAD levels were statistically significant, meaning those with CAD 20% were older, had shorter years of birth control use, fewer migraine headaches and had longer secon dhand smoke exposure. If these t-tests were performed under the complete nul l hypothesis, the new level of si gnificance, controlling for the overall error, would be 0.0031. Table 4-10 shows the relationship between se vere CAD and women s prodromal cardiac symptoms. As indicated in Table 4-10, the relationship between severe CAD and neck/throat pain indicates that a lower percentage of wome n who experienced neck/throat pain had severe 64

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CAD (19.10% vs. 32.47%, Chi-square = 3.90, p = 0.0482) as did those with numbness or burning of both arms (12.36% vs. 27.27%, Chi-sq uare = 5.90, p = 0.0151). A higher percentage of women who experienced hand/arm tingling had severe CAD (44.94% vs. 28.57%, Chi-square = 4.73, p = 0.0297). Among those with a history of high cholesterol 79.78% had severe CAD vs. 66.23% that did not (Chi-square = 3.89, p = 0.0487) A higher percentage of those with a history of stroke had severe CAD (11.24% vs. 2.60%, Chi-square = 4.59, p = 0.0321). A lower percentage of those with a history of birth control use had severe CAD (47.19% vs. 66.23%, Chisquare = 6.08, p = 0.0137). A higher percentage of those with a history of gallbladder disease had severe CAD (39.33% vs. 23.38%, Chi-square = 4.83, p = 0.0279) as did those with a history of menopause (58.43% vs. 35.06%, Chi-square = 9.03, p = 0.0027). The relationship between severe CAD and a history of thyroid disease was statistically significant (Chi-square = 8.75, p = 0.0031). The relationship between severe CAD and those women who were employed, had children living at home and were retired was also statistically significant. Finally, the association between CAD 50% and CAD 50% and the demographic variables of race, marital status, and education were statistically nonsignificant. As be fore, if these tests we re performed under the complete null hypothesis, the new level of signifi cance, controlling for the overall error, would be 0.0007. Table 4-11 shows the mean difference of symptom variables between two levels of severe CAD. Using the t-test, as indicated in Table 4-8, the differences in mean age of the subjects (p = 0.0001) and year s of secondhand smoke exposure (p = 0.0031) between the two severe CAD levels were statis tically significant. If these t-tests were performed under the complete null hypothesis, the new level of signifi cance, controlling for the overall error, would be 0.0020. 65

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Hypothesis 2: A prodromal sy mptom or a cluster of prodr omal cardiac symptoms will discriminate between those women who have CAD and those that do not. To address Hypothesis 2, backward stepwise logistic regression models, permitting the use of both continuous and categoric al variables, were constructe d to determine if differences existed between those with CAD < 20% (coded as 0) and with CAD 20% (coded as 1). Modeling began by including in th e model all predictor variables that either had at least a marginal bivariate association with the outcome variables or for which there is some rationale that the variable may be a confounder or effect modifier for other variables. In this study the rationale for inclusion was based on the TUS theoreti cal model. In particular, the variables that had a p-value of no more than 0.10 using the chi-square and t te st (Tables 4-8 and 4-9) were included in the maximum logistic model. To obt ain an optimal model, the predictor variables were deleted in a stepwise fashion. The results of the optimal logistic regression model indicated that the variables abnormal dual stress tests, ag e of the subject, histor y of high cholesterol, history of diabetes and hand/ar m tingling were statistically significant between the two CAD 20% levels (Table 4-12). In the optimal model, the tests for assessing model fit through explanatory capability was supportive of the mo del; the likelihood ratio test had a value of 56.50 (p < 0.0001) with 5 degrees of freedom (df) a nd the score test has a value of 48.57 (p < 0.0001) with 5 df. In addition the Hosmer-Lemesho w statistic was 30.41, df = 23, p = 0.1379, which supported the adequacy of the m odel, i.e., this measure of go odness of fit suggests that modelpredicted cell proportions are acceptably close to the observed proportions. Those subjects with an abnormal dual stre ss test had 2.58 times higher odds of having CAD 20%. Subjects who complained of the prodromal symptom of hand/arm tingling had 3.11 times higher odds of having CAD 20%. Diabetic subjects had 4.57 times higher odds of having CAD 20%. In addition, high cholesterol and age were significant risk factors for CAD. 66

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Subjects with high cholesterol had 2.90 times higher odds of having CAD 20% and with every one year increase in age the odds of them having CAD 20% increased by 1.12 times (Table 413). Then backward logistic regression models we re constructed to determine if differences existed between those with CAD < 50% (coded as 0) and with CAD 50% (coded as 1). The results of the optimal logistic regression mode l indicated that the va riables hand/arm tingling, years of secondhand smoke exposure, history of t hyroid disease, history of menopause onset, age of the subject, and a history of diabetes were statistically significant between the two severe CAD levels (Table 4-14). In the optimal model (Table 4-14), the tests for assessing model fit through explanatory capability was supportive of the model; the lik elihood ratio test had a value of 60.96 (p < 0.0001) with 6 df and the score test has a value of 49.87 (p < 0.0001) with 6 df. In addition the residual chi-square test was 21.41, df = 20, p = 0.3496, which supported the adequacy of the model. As indicated in Table 4-15, those subjects who experienced the prodromal symptom of hand/arms tingling had 3.18 times higher odds of having severe CAD. Subjects who were diabetics had 3.22 times higher odds of having seve re CAD. Women of in this study who had a history of thyroid disease had 2.76 times higher odds of having severe CAD. To conclude subjects that had experienced menopause onset had a 2.44 times higher odds of having severe CAD. Finally, those subjects who were exposed to secondhand smoke had 1.03 higher odds of having severe CAD and with every one year in crease in age the odds of those exposed to secondhand smoke having severe CAD increased by 1.10. 67

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Table 4-1. Recruitment locations of the sample Recruitment site N (166) % Cardiovascular Centers, LLC 98 59.36 Central Florida Cardiology, PA 55 33.13 Florida Heart Group, PA 13 7.83 Table 4-2. Demographic charac teristics of the sample Demographic variable Mean SD Age (years) 65.86 11.26 Weight (kilograms) 77.4 42.21 Height (centimeters) 161.2 2.90 Ethnicity N (166) % Caucasian 142 85.54 African American/Black 13 7.83 Hispanic/Non-White 9 5.42 Asian 1 0.60 Indian 1 0.60 Marital status Married 90 54.22 Widowed 36 21.69 Separated/Divorced 31 18.67 Single/Never Married 9 5.42 Education Less than High School Degree 98 59.03 High School Degree 55 33.13 More than High School Degree 13 7.83 Employment Retired 102 61.54 Employed Full Time 49 29.42 Employed Part Time 11 6.63 Unemployed 4 2.4 Income Less than $30K 112 67.47 Equal or More than $30K 54 32.53 68

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Table 4-3. Prodromal symp tom frequency distribution and relative percentages Pain symptom N (166) % Back, between/under shoulder blades 81 48.79 Centered high in chest 68 40.96 Left arm 49 29.51 Neck/throat 42 25.30 Left breast 41 24.69 Generalized chest 37 22.29 Jaw/teeth 30 19.28 Right arm 27 18.07 Legs 32 16.27 Top of shoulders 18 10.84 Both arms 18 10.84 General symptom N (166) % Very tired, unusual fatigue 136 81.93 Shortness of breath/orthopnea 126 75.90 Heart racing 87 52.41 Change in thinking or remembering 70 42.17 Sleep disturbance 70 42.17 Cough 66 39.76 Numbness or burning of fi ngers on both hands 64 38.55 Hands/arms tingling 62 37.35 Frequent indigestion 57 34.34 Anxious 39 23.49 Arms weak/heavy 35 21.08 Numbness or burning of both arms 32 19.27 Arms ache 30 18.07 Numbness or burning of fi ngers on left hand 26 15.66 Increased frequency of headaches 22 13.25 Loss of appetite 20 12.04 Increased intensity of headaches 19 11.44 Numbness or burning of fi ngers on right hand 16 9.63 Difficulty breathing during the night 16 9.63 New onset of vision problems 15 9.03 Numbness or burning of the right arm 14 8.43 Numbness or burning of the left arm 12 7.22 69

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Table 4-4. Medical vari ables distribution Medical variable Mean SD Ejection fraction 0.62 0.08 N = 166 % High cholesterol 122 73.49 Abnormal dual stress test 114 68.67 High blood pressure 106 63.86 Abnormal EKG 80 48.19 Both abnormal EKG & dual 63 37.95 Diabetic 40 24.10 Valve disease 34 20.48 Table 4-5. Comorbidity frequency di stribution and relative percentages Comorbidity variable N (166) % Chronic joint problem 105 63.25 Chronic heart burn 84 50.60 Thyroid disease 63 37.95 Chronic lung disease 59 35.54 Chronic back pain 59 35.54 Gallbladder disease 53 31.93 Depression 49 29.52 Migraine headaches 48 28.92 Cancer 46 27.71 Osteoporosis 44 26.51 Stroke 12 7.22 History of chest pain 11 6.62 History of CAD 6 3.61 Congestive heart failure 6 3.61 Table 4-6. Coronary angiogra phy variables distribution Coronary angiography variable CAD 20 CAD 50 N (166) % N (166) % Presence of disease 102 61.4 89 53.6 Left anterior descending 86 51.8 65 39.1 Right coronary artery 61 36.7 43 25.9 Left circumflex 44 26.5 23 13.8 Diagonal 36 21.6 26 15.6 Obtuse marginal 22 13.2 15 13.2 Left main 4 2.4 3 1.8 Septal 2 1.2 0 0.0 70

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Table 4-7. Example of the contingency table for CAD 20% by history of high cholesterol CAD 20% History of high cholesterol Total Frequency percent Row percent Column percent 0 1 0 25.00 15.06 39.06 56.82 39.00 23.49 60.94 31.97 64.00 38.55 1 19.00 11.45 18.63 43.18 83.00 50.00 81.37 68.03 102.00 61.45 Total 44.00 26.51 122.00 73.49 166.00 100.00 71

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Table 4-8. Relationship between CAD presence and womens prodromal cardiac symptoms Variables CAD < 20 (%) CAD > 20 (%) Chisquare p-value Abnormal EKG 48.44 48.04 0.01 0.9601 Abnormal dual stress test 60.94 73.53 2.89 0.0887 Generalized chest pain 20.31 23.53 0.23 0.6279 Centered high in chest pain 46.88 37.83 1.50 0.2199 Left breast pain 25.00 24.51 0.01 0.9432 Neck/throat pain 32.81 20.59 3.11 0.0778 Jaw/teeth pain 25.63 19.61 0.42 0.5163 Back, between/under shoulder blade pain 53.13 46.08 0.78 0.3767 Top of shoulders pain 9.38 11.76 0.23 0.6798 Both arms pain 10.94 10.78 0.01 0.9754 Left arm pain 32.81 27.45 0.54 0.4610 Right arm pain 18.75 14.71 0.47 0.4933 Leg pain 15.63 21.57 0.89 0.3447 Very tired, unusual fatigue 75.00 86.27 3.38 0.0661 Sleep disturbance 45.31 40.20 0.42 0.5159 Anxious 22.58 24.51 0.08 0.7784 Cough 34.38 43.14 1.26 0.2615 Heart racing 57.81 49.02 1.22 0.2696 Shortness of breath/ orthopnea 70.31 79.41 1.78 0.1821 Difficulty breathing during the night 8.38 9.80 0.01 0.9273 Loss of appetite 15.63 9.80 1.26 0.2621 Frequent indigestion 35.94 33.33 0.12 0.7309 Arms weak/heavy 23.44 19.61 0.35 0.5560 Arms ache 17.11 18.63 0.06 0.8145 Hands/arms tingling 29.69 42.16 2.61 0.1060 Numbness or burning of both arms 26.56 14.71 3.55 0.0594 Numbness or burning of right arm 9.38 7.84 0.12 0.7296 Numbness or burning of left arm 10.94 4.70 2.14 0.1435 Numbness or burning of finge rs on both hands 40.63 37.25 0.19 0.6641 Numbness or burning of finge rs on right hand 9.38 9.80 0.01 0.9274 Numbness or burning of finge rs on left hand 14.06 16.67 0.20 0.6532 New onset vision problem 14.06 5.88 3.20 0.0736 Increased intensity of headaches 14.06 9.80 0.70 0.4016 Increased frequency of headaches 14.06 12.75 0.06 0.8075 Change in thinking or remembering 46.88 39.22 0.95 0.3307 History of chest pain 14.69 7.84 0.63 0.4263 History of congestive heart failure 0.00 4.90 3.23 0.1575 History of coronary heart disease 1.61 4.90 1.18 0.4102 History of heart irregul arity, heart murmur or valve D 53.13 47.06 0.58 0.4467 History of high blood pressure 54.69 69.61 3.79 0.0515 72

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Table 4-8. Continued Variables CAD < 20 (%) CAD > 20 (%) Chisquare p-value History of high cholesterol 60.94 81.37 8.43 0.0037 History of depression or other emotional problems 37.50 25.00 2.91 0.0880 History of cancer 18.75 33.33 4.18 0.0410 History of diabetes/ low blood sugar 14.06 30.39 5.73 0.0166 History of chronic heart burn, stomach problems (GERD 50.00 50.98 0.02 0.9021 History of chronic back pain 31.25 38.54 0.84 0.3601 History of joint problems (arthritis) 57.81 66.67 1.32 0.2495 History of osteoporosis (brittle bones) 23.44 28.43 0.51 0.4780 History of stroke 3.13 9.80 2.61 0.1058 History of thyroid disease 29.69 43.14 3.02 0.0822 History of gallbladder disease 23.44 37.25 3.45 0.0691 History of hysterectomy 51.56 50.00 0.04 0.8446 History of menopause onset 35.94 54.90 5.67 0.0173 History of estrogen replacement 54.61 53.92 0.01 0.9232 Current estrogen replacement use 20.31 8.82 4.51 0.0336 History of birth control use 70.31 47.26 8.63 0.0033 History of smoking (at l east 100 cigarettes in life) 51.56 45.10 0.66 0.4170 Current smoker 3.92 12.50 4.31 0.0378 Exposed to secondhand smoke 75.00 84.00 2.01 0.1560 Exercise 73.44 75.49 0.09 0.7622 Employed 54.69 24.51 15.52 0.0001 Retired 43.75 72.55 13.77 0.0002 Children living at home 34.98 11.76 12.34 0.0004 Income of $30,000 26.56 36.27 1.59 0.1936 Income of $30,000 73.44 63.73 1.69 0.1936 Note : N = 166 73

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Table 4-9. Differences in variable means between CAD <20% and > 20% Variable CAD N Mean Std dev Minimum Maximum t-test p-value Age of subject < 20 64 59.8440 10.8850 40.00 87.00 6.01 0.0001 > 20 102 69.6370 9.7866 42.00 85.00 MAPMISS score < 20 64 83.8440 56.8430 8.00 307.00 0.75 0.4554 > 20 102 77.5100 50.5970 6.00 250.00 Symptom score < 20 64 8.9219 4.2958 2.00 21.00 0.59 0.5555 > 20 102 8.5098 4.4226 1.00 24.00 History of chronic lung disease < 20 64 0.4063 1.4111 0.00 11.00 0.08 0.9396 > 20 102 0.4216 0.4962 0.00 1.00 History of migraine headaches < 20 64 0.6875 1.9262 0.00 11.00 2.29 0.0235 > 20 102 0.2353 0.4263 0.00 1.00 Age at hysterectomy < 20 64 21.4840 22.1400 0.00 66.00 0.29 0.7715 > 20 102 22.5690 24.1120 0.00 73.00 Years of estrogen replacement use < 20 64 6.42970 9.6110 0.00 32.00 1.39 0.1662 > 20 102 4.52940 7.8481 0.00 35.00 Current estrogen replacement use < 20 64 0.31250 2.3763 0.00 19.00 1.33 0.1852 > 20 102 0.0000 0.0000 0.00 0.00 Years of birth control use < 20 64 5.6797 6.9461 0.00 30.00 2.13 0.0346 > 20 102 3.4363 6.3790 0.00 30.00 Family history of MI < 20 64 0.7969 1.3936 0.00 11.00 0.21 0.8325 > 20 102 0.7647 0.51080 0.00 2.00 Pack year history of smoking < 20 64 10.617 15.5320 0.00 80.00 0.20 0.8416 > 20 102 10.123 15.4690 0.00 60.00 Years of secondhand smoke exposure < 20 64 21.4060 18.1960 0.00 61.00 2.80 0.0058 > 20 102 29.6670 18.7240 0.00 66.00 Weight (lbs) < 20 64 174.840 43.8300 112.00 310.00 1.10 0.2708 > 20 102 167.4100 41.1200 82.00 325.00 Height (inches) < 20 64 63.4800 3.2594 54.00 69.00 0.01 0.9915 > 20 102 63.4750 2.6754 51.50 70.00 74

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Table 4-9. Continued Variable CAD N Mean Std dev Minimum Maximum t-test p-value Exercise times per Month < 20 64 12.0630 10.4210 0.00 30.00 0.69 0.4935 > 20 102 13.2160 10.6090 0.00 30.00 Hours per attempt of exercise < 20 64 0.7539 0.9210 0.00 4.00 > 20 102 0.7132 1.0153 0.00 6.00 > 20 102 0.4028 0.3819 0.00 1.00 Note : N = 166 75

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Table 4-10. Relationship between severe C AD and womens prodromal cardiac symptoms Variables CAD < 50 (%) CAD > 50 (%) Chisquare p-value Abnormal EKG 46.75 49.44 0.12 0.7299 Abnormal dual stress test 64.94 71.91 0.93 0.3339 Generalized chest pain 23.38 21.35 0.10 0.7543 Centered high in chest pain 42.86 39.33 0.21 0.6445 Left breast pain 23.38 25.84 0.14 0.7133 Neck/throat pain 32.47 19.10 3.90 0.0482 Jaw/teeth pain 18.18 17.98 0.01 0.9728 Back, between/under shoulder blade pain 51.95 46.07 0.57 0.4497 Top of shoulders pain 12.99 4.82 0.68 0.4087 Both arms pain 10.39 11.24 0.03 0.8612 Left arm pain 31.17 28.09 0.19 0.6645 Right arm pain 22.08 11.24 3.56 0.0591 Leg pain 19.48 19.10 0.01 0.9507 Very tired, unusual fatigue 76.62 86.52 2.72 0.0985 Sleep disturbance 42.86 41.57 0.03 0.8673 Anxious 24.00 22.60 0.01 0.9517 Cough 37.66 41.57 0.26 0.6077 Heart racing 57.14 48.31 1.29 0.2560 Shortness of Breath/ orthopnea 72.73 78.65 0.79 0.3734 Difficulty breathing during the night 9.09 10.11 0.05 0.8240 Loss of appetite 14.24 10.11 0.68 0.4101 Frequent indigestion 33.77 34.83 0.02 0.8854 Arms weak/heavy 23.38 19.10 0.45 0.5007 Arms ache 19.48 16.85 0.19 0.6610 Hands/arms tingling 28.57 44.94 4.73 0.0297 Numbness or burning of both arms 27.27 12.36 5.90 0.0151 Numbness or burning of right arm 11.69 5.62 1.97 0.1605 Numbness or burning of left arm 9.09 5.62 0.74 0.3889 Numbness or burning of finge rs on both hands 42.86 34.83 1.12 0.2894 Numbness or burning of finge rs on right hand 11.69 7.87 0.69 0.4052 Numbness or burning of finge rs on left hand 12.99 17.98 0.78 0.3776 New onset vision problem 12.99 5.62 2.72 0.0986 Increased intensity of headaches 14.29 8.99 1.14 0.2851 Increased frequency of headaches 12.99 13.48 0.01 0.9251 Change in thinking or remembering 45.45 39.33 0.64 0.4252 History of chest pain 6.49 6.74 0.01 0.9489 History of congestive heart failure 0.00 5.62 4.46 0.0620 History of coronary heart disease 1.33 5.62 2.11 0.1454 History of heart irregul arity, heart murmur or valve disease 50.65 48.31 0.09 0.7641 76

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Table 4-10. Continued Variables CAD < 50 (%) CAD > 50 (%) Chisquare p-value History of high blood pressure 58.44 68.54 1.81 0.1769 History of high cholesterol 66.23 79.78 3.89 0.0487 History of depression or other emotional problems 33.77 26.44 1.05 0.3061 History of cancer 25.97 29.21 0.22 0.6419 History of diabetes/ low blood sugar 18.18 29.21 2.75 0.0974 History of chronic heart burn, stomach problems (GERD 53.25 48.31 0.40 0.5262 History of chronic back pain 28.57 41.57 3.05 0.0809 History of joint problems (arthritis) 61.04 65.17 0.30 0.5821 History of osteoporosis (brittle bones) 22.08 30.34 1.45 0.2292 History of stroke 2.60 11.24 4.59 0.0321 History of thyroid disease 25.97 48.31 8.75 0.0031 History of gallbladder disease 23.38 39.33 4.83 0.0279 History of hysterectomy 53.25 48.31 0.40 0.5262 History of menopause onset 35.06 58.43 9.03 0.0027 History of estrogen replacement 53.25 55.06 0.05 0.8155 Current estrogen replacement use 16.88 10.11 1.64 0.1995 History of birth control use 66.23 47.19 6.08 0.0137 History of smoking (at l east 100 cigarettes in life) 53.25 42.70 1.84 0.1747 Current smoker 10.39 4.49 2.14 0.1436 Exposed to secondhand smoke 75.32 85.06 2.46 0.1165 Exercise 72.73 76.40 0.29 0.5868 Employed 51.95 22.47 15.54 0.0001 Retired 46.75 74.71 13.09 0.0003 Children living at home 31.17 11.24 10.07 0.0015 Income of $30,000 27.27 37.08 1.81 0.1787 Income of $30,000 72.73 62.92 1.81 0.1787 77

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Table 4-11. Differences in variable means between CAD < 50% and > 50% Variable CAD50 N (166) Mean Std dev Minimum Maximum t-test p-value Age of subject < 50 77 60.818 11.2400 40.00 87.00 5.89 0.0001 > 50 89 70.225 9.3271 44.00 85.00 MAPMISS score < 50 77 85.143 59.8190 6.00 307.00 1.17 0.2418 > 50 89 75.461 46.2070 12.00 189.00 Symptom score < 50 77 9.039 4.5550 1.00 24.00 1.02 0.3109 > 50 89 8.3483 4.1944 2.00 23.00 History of chronic lung disease < 50 77 0.4286 1.3021 0.00 11.00 0.42 0.6782 > 50 89 0.4045 0.4936 0.00 1.00 History of migraine headaches < 50 77 0.5974 1.7716 0.00 11.00 1.80 0.0730 > 50 89 0.2472 0.4338 0.00 1.00 Age at hysterectomy < 50 77 22.961 22.877 0.00 66.00 0.42 0.6782 > 50 89 21.449 23.784 0.00 73.00 Years of estrogen replacement use < 50 77 5.7922 9.0249 0.00 32.00 0.74 0.4613 > 50 89 4.8034 8.2239 0.00 35.00 Current estrogen replacement use < 50 77 0.2597 2.1667 0.00 19.00 1.13 0.2595 > 50 89 0.0000 0.0000 0.00 0.00 Years of birth control use < 50 77 5.2143 6.8328 0.00 30.00 1.65 0.1012 > 50 89 3.5112 6.4662 0.00 30.00 Family history of MI < 50 77 0.8052 1.2777 0.00 11.00 0.35 0.7241 > 50 89 0.7528 0.5283 0.00 2.00 Pack year history of smoking < 50 77 11.286 15.585 0.00 80.00 0.75 0.4523 > 50 89 9.4719 15.366 0.00 60.00 Years of secondhand smoke exposure < 50 77 21.857 18.793 0.00 61.00 3.00 0.0031 > 50 89 30.483 18.166 0.00 66.00 78

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Table 4-11. Continued Variable CAD50 N (166) Mean Std dev Minimum Maximum t-test p-value Weight (lbs) < 50 77 174.1 42.847 112.00 310.00 1.09 0.2786 > 50 89 166.97 41.607 82.00 325.00 Height (inches) < 50 77 63.464 3.5093 51.5 70.00 0.05 0.9570 > 50 89 63.489 2.277 58.00 70.00 Exercise times per month < 50 77 11.792 10.202 0.00 30.00 1.12 0.2661 > 50 89 13.618 10.773 0.00 30.00 Hours per attempt of exercise < 50 77 0.711 0.8623 0.00 4.00 0.22 0.8273 > 50 89 0.7444 1.0716 0.00 6.00 Note : N = 166 Table 4-12. Optimal logistic regression model for the presence of CAD 20% Parameter Estimate Maximum Likelihood Standard error Wald Chi-Square p-value Intercept -8.7953 1.6464 28.5372 <.0001 Abnormal Dual Stress 0.9484 0.4445 4.5536 0.0328 Hands/Arms Tingling 1.1351 0.4394 6.6727 0.0098 History of High Cholesterol 1.0649 0.4377 5.9205 0.0150 History of Diabetes 1.5191 0.5062 9.0075 0.0027 Age 0.1091 0.0215 25.6454 <.0001 Table 4-13. Odds ratio estimates of the presence of CAD 20% Effect Point estimate 95% Wald confidence limits Abnormal Dual Stress 2.58 1.08 6.17 Hands/Arms Tingling 3.11 1.32 7.36 History of High Cholesterol 2.90 1.23 6.84 History of Diabetes 4.57 1.69 12.32 Age 1.12 1.07 1.16 Note : N = 166 79

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Table 4-14. Optimal logistic re gression model for severe CAD Parameter Estimate Maximum Likelihood Standard error Wald Chi-Square p-value Intercept -8.3010 1.5933 27.1443 <.0001 Hands/Arms Tingling 1.1557 0.4159 7.7216 0.0055 History of Diabetes 1.1706 0.4676 6.2660 0.0123 History of Thyroid Disease 1.0147 0.4079 6.1877 0.0129 History of Menopause Onset 0.8907 0.3943 5.1040 0.0239 Age 0.0951 0.0215 19.5499 <.0001 Years of Secondhand Smoke Exposure 0.0260 0.0105 6.0737 0.0137 Table 4-15. Odds ratio estimates of severe CAD Effect Point estimate 95% Wald confidence limits Hands/Arms Tingling 3.18 1.41 7.18 History of Diabetes 3.22 1.29 8.06 History of Thyroid Disease 2.76 1.24 6.14 History of Menopause Onset 2.44 1.13 5.28 Age 1.10 1.05 1.15 Years of Secondhand Smoke Exposure 1.03 1.01 1.05 80

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CHAPTER 5 DISCUSSION The purpose of this exploratory research study was to help healthcare professionals have a better understanding of which symptoms can be most helpful in identifying women who are atrisk of having CAD and allow healthcare wo rkers to determine which women should undergo cardiovascular diagnostic tests that are highly predictive such as car diac catheterization. The following chapter provides a discussion of the fi ndings and suggests clinic al implications and future research. Summary of the Study This exploratory study was carried out in four outpatient cardiac catheterization laboratories in Orlando, Florida. Women betwee n the ages of 40 and 89 years that had not previously had a diagnostic cardi ac catheterization performed and were scheduled for an elective procedure were asked to volunteer for partic ipation. One hundred and sixty six women were recruited and agreed to the informed consent to undergo a structured interview by the PI completing the survey and a catheterization by thei r own cardiologist. The structured interview survey portion of the study, the MAPMISS, cons isted of a comprehensive measure of overall health symptoms that contained multiple variables in the study. The remainder of the study consisted of the subjects undergoi ng the cardiac catheterization pr ocedure in order to quantify CAD. Logistic Regression analysis was used to determine how well the symptoms discriminated for CAD level of the subjects. Conclusions Two research hypotheses were explored and ar e considered. The first hypothesis was to examine if there were differences in womens prodromal cardiac symptoms between those that have CAD and those that do not. Results from this study suggest th at womens prodromal 81

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symptoms do not exhibit a significant relationship to the presence of CAD ( 20% stenosis). The most unanticipated finding was that neither pain symptoms nor general symptoms made the list of major contributors. Surprisingly, only comorbid ities have a significant relationship with the presence of CAD 20%. Comorbid ity conditions such as high cholesterol (Chi-square = 8.43, p = 0.0037), cancer (Chi-square = 4.18, p = 0.0410) and diabetes (Chi-square = 5.73, p = 0.0138) can possibly help predict the presence of CA D in women. Those women who had experienced menopause onset (Chi-square = 5.67, p = 0.0173) we re also statistically significant for the presence of CAD. As was expected these result s confirm that those women who had a history of smoking (Chi-square = 4.31, p = 0.0378) were mo re likely to have CAD 20% (AHA, 2005b, 2008). Not expected however, was that with our knowledge of the suspected dangers of the use of exogenous estrogens in women, that a lower pe rcentage of those who had used birth control (Chi-square = 8.63, p = 0.0030) and who were curre ntly using estrogen replacement therapy (Chi-square = 4.51, p = 0.0336) had CAD (Mosca et al., 2007). Between those women who did and did not have severe CAD, st atistically significant differences were found to include the mean age of the subjects, a history of migraine headaches, the number of years of birth control use, and the years of secondhand smoke exposure. The TUS posits that symptoms are multiplicative and result in a feedback loop; results from this portion of the study suggest that possibly physiological, psychological and situational fo rces create a milieu that fosters CAD. By way of contrast, results from this study revealed that women s prodromal symptoms do exhibit a significant relationship to the presence of severe CAD ( 50% stenosis). Overall, the finding that the hallmark symptoms for men with CAD were absent from these results is not surprising. Men typically present with the classic symptoms of MI such as shortness of breath ,chest pain and pressu re radiating to the jaw and dow n the left arm (Gibbons et al., 82

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1999; Mosca et al., 2007). McSweeney and colleague s reported that women rarely feel any chest sensation at all, and that thei r symptoms are often more covert or subtle (McSweeney et al., 2001; McSweeney et al., 2003; McSweeney & Cr ane, 2000). In the current study, a lower percentage of women who ha d neck/throat pain had severe CAD (19.10% vs. 32.47%, Chisquare = 3.90, p = 0.0482) and a lower percenta ge of women who had numbness or burning of arms had severe CAD (12.36% vs. 27.27%, Chisquare = 5.90, p = 0.0151). These particular inverse significant relationship s are interesting. Thes e relationships suggest a possible opposing or neutralizing effect as to a multiplicative e ffect as proposed on the TUS. When one closely scrutinizes the sample demographics it is hard not to notice the educat ion status (54.22% with less than a high school degree) of the subjects Questions may arise as to how the sample population differentiated num bness and burning from hand/arm tingling (Chi-square = 4.73, p = 0.0297) that demonstrated a statistically significant relati onship, 44.94% of women who had severe CAD vs. 28.57% that did not. It may be suggested that the symptom of pressure radiating to the jaw and neck/throat pain as well as pressu re radiating down the left arm when compared to hand/arm tingling or numbness or burning of arms are very similar. In argument against this suggestion, the MAPMISS specifically questions wo men regarding pain symptoms in the jaw, neck/throat, left arm pain, right arm pain and top of shoulder pain. During the structured interview additional descriptors were used to di stinguish between the sensations of pressure, tingling, numbness and burning. Res earch on language expression between genders in the way that angina symptoms are descri bed and reported is scant at be st. A few studies suggest that differences do exist: however, additional research is needed to examine the nature and consequences of language use (Kimble et al., 2003; Philp ott et al., 2008). 83

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The second hypothesis was if th e identification of a prodromal symptom or a cluster of prodromal cardiac symptoms would discriminate between those women who have CAD and those that do not. Thus, allowi ng healthcare professionals to id entify women who are at-risk of having CAD. In order to answer this hypothesis, a backward logistic regression model was built, allowing the use of both continuous and categorical variables to determine if differences existed between those with and without the presence of CAD ( 20% stenosis). The model revealed that subjects who complained of tingling of the ha nd/arms had 3.11 times higher odds of having the presence of CAD 20%. Thus a single symptom emerged. Th is finding is allude d to in a recent research study that examined differences in symptoms between men and women when hospitalized for ACS, non-ST segment myocardi al infarction, or STEMI (DeVon et al., 2008). Unsurprisingly the usual suspect triad of diabetes high cholesterol and age reappeared as part of the optimal model. Diabetic subjects had 4.57 times higher odds of having the presence of CAD ( 20% stenosis). In addition, high chol esterol (OR = 2.90, 95% CI, 1.23-6.84, p = 0.0150) and age (OR = 1.12, 95% CI, 1.07-1.16, p = <.0001) were signi ficant risk factors for the presence of CAD 20%. Contrary to reported re search, in this study, those women with an abnormal dual stress test had 2.58 times higher odds of having the presence of CAD 20% (DeCara, 2003). Then a backward logistic regression model wa s constructed to determine if differences existed between those with and without severe CAD ( 50% stenosis). The results of the logistic regression model indicated once ag ain that subjects who expressed that they had experienced the symptom of a tingling of the hand/arms had 3.18 times higher odds of having severe CAD. Other factors that were included in the m odel were exposure to secondhand smoke (OR = 1.03, 95% CI, 1.01-1.05, p = 0.0137), a history of thyr oid disease (OR = 2.76, 95% CI, 1.24-6.14, p = 0.0129), history of menopause onset (OR = 2.44, 95% CI, 1.13-5.28, p = 0.0239), the age of the 84

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subject (OR = 1.10, 95% CI, 1.05-1.15, p = <.0001) a nd a history of diabetes (OR = 3.22, 95% CI, 1.29-8.06, p = 0.0123). Strengths and Limitations When evaluating the results of this study, several strengths and limitations should be considered. The real strength of this study is that to my knowle dge this study is the first to explore the relationship between prodromal symptoms and disease presence of CAD among women prior to MI. Furthermore, while many studies have examined prodromal symptoms post MI in a retrospective method, this study has been the first to prospect ively explore prodromal symptoms in the clinical setting using an inva sive procedure. Secondly, it should be pointed out that if this study had to pay for the cardiac cathete rization portion of this investigation it would have cost more than $2,075,000 dollars (166 x $12,500). In an attempt to enroll an unbiased sample subjects were recruited from multiple locations. However, despite the attempt to limit bias, it should be noted that the women who participated in this study were already identi fied by their primary healthcare provider as having an indication that placed them at-risk for CAD in the first place. Although analysis evaluating the sample did show similar rates of CAD (61% with CAD 20% stenosis and 54% with CAD 50% stenosis) to published reports (DeCara, 2003; Fo wler-Brown et al., 2004; Mora et al., 2003) one must remember that medicine is a business and motivation for diagnos tic evaluation is not always clear cut. Physician skill in performing the catheterization as well as the primary investigators expertise in reading coronary angiography in most instances wa s a strength; however, from time to time consultation was necessary. Variati on in diagnostic imag ing between cardiac catheterization laboratories is another potential limitation. The manufacturers of the imaging equipment were different in each laboratory with the exception of the two Cardiovascular 85

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Centers, LLC sites. To combat the possibility th at QCA would differ in each laboratory care was taken to transfer all images to CD-ROM format for offline review and qua ntification at a single location using the same QCA software package (Sanmartin et al., 2004). Additionally, image quality is may be degraded if the image intensifie r is to far from the radiation source and is also dependent on patient size. The larger the subject the more radiation is needed to visualize the coronary anatomy. Another limitation may be the sample size, in the face of significant recruitment challenges (i.e. labs closing, or cases being moved to inpatient f acilities) it may be considered relatively limited. This limitation may have resulted in reduced significant findings regarding the stated hypothesis. It should also be noted th at this study was a cros s-sectional design and therefore, examined cardiac status in a single time point along th e continuum of life and may not accurately reflect the dynamics of cardiovascular disease. As with all research involvi ng self report measures consider ation should be given to the fact that patients may lack language skills necessary to express themselves fully, be influenced by their surrounding or how they would like themse lves to be perceived. In an attempt to minimize these factors patients were intervie wed in privacy, behind closed doors or pulled curtains without family members or other st aff present when possible. Assurances of confidentiality regarding their responses and anonymity after da ta collection were offered. Implications and Recommendations The review of the literature relevant to prodromal sympto ms in women suggests a vast difference between what is expected by hea lthcare providers and wh at is expressed or experienced by women. The current study will add to the body of literature in a substantial way. Given that women report differe nt symptoms than men when faced with MI a reasonable 86

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assumption is to expect that women will have a different presentation in the prodromal phase of cardiac disease; these hy potheses were in part supported by these results. Particular to the findings of this study and other research differences in symptom expression and experience between genders, future research needs next to address the formation of an assessment tool that will help healthcar e workers quickly identify women at-risk for CAD. Timely diagnosis of CAD is the key to abating the catastrophic consequences that occur as a result of a MI. Results from this study have revealed the symptom of hand/arm tingling is possibly more telling of CAD in women while neck/throat pain and numbness or burning of the arms may have a negative discriminating quality. The prodromal symptoms of hand/arm tingling, neck/throat pain and numbness or burning of the arms in combination with comorbidities including diabetes, onset of menopause, exposure to secondhand smoke, age and a history of an abnormal dual stress test warrant further exploration. The revised model of the TUS conceptual framework suggests several further research dire ctions. One recommended di rection is to explore how the prodromal symptoms of hand/arm tingli ng, neck/throat pain and numbness or burning of the arms are differentiated and influence each other. Another recommended direction is to examine the functional, cognitive and physical performance deficits that are a result of prodromal symptoms. The revised model of TU S offers a lifetime of future research opportunities. Many women are unaware that they may expe rience atypical prodromal symptoms that change in intensity, frequency a nd have varied times of onset that can warn them of impending cardiac problems. Furthermore, many healthcare providers are not in tune to the differences in prodromal symptom presentation that may be present between men and women involving CAD. Further research is indicated to facilitate early symptom recogniti on by both patient and provider. 87

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Effective prodromal symptom recognition in wo men with CAD the major component of CHD can prevent a negative diagnos tic experience and improve ove rall healthcare outcomes. Conclusion In summary, CHD in women is a global he alth and economic problem. Cardiovascular heart disease is America's number 1 killer of women and men. Women are unaware that the major component of CHD, CAD is a significant health threat and that few women have discussed CAD with their primary healthcare provider. Hea lthcare professionals need to have a better understanding of which symptoms would be most helpful in identifying women who are at-risk of having CAD and allow them to determine which women should undergo cardiovascular diagnostic tests that are highly predictive su ch as cardiac cathete rization. The prodromal symptoms of hand/arm tingling, neck/throat pa in and numbness or burning of the arms in combination with comorbidities including diabet es, onset of menopause, exposure to secondhand smoke, history of thyroid disease, age and a history of an abnorma l dual stress test have emerged as possible predictors of CAD in women. Given these considerations, this study offers new information regarding prodromal symptoms and the determination of CAD in women. 88

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REFERENCES Albarran, J. W., Clarke, B. A., & Crawford, J. (2007) 'It was not chest pain really, I can't explain it!' An exploratory study on th e nature of symptoms experienced by women during their myocardial infarction. Journal of Clinical Nursing, 16 (7), 1292-1301. American Heart Association. (2005a). Biostatistical fact sheet. Dallas, TX: American Heart Association. American Heart Association. (2005b). Heart and stroke statistical update. Dallas, TX: American Heart Association. American Heart A ssociation. (2008). Heart and stroke statistical update. Dallas, TX: American Heart Association. Arslanian-Engoren, C., Patel, A., Fang, J., Arms trong, D., Kline-Rogers, E., Duvernoy, C. S., et al. (2006). Symptoms of men and women presenting with acute coronary syndromes. The American Journal of Cardiology, 98 (9), 1177-1181. Baim, D. S., & Grossman, W. (2000). Grossman's catheterization, angiography, and intervention. (6th ed.). Philadelphia: Lippincott, Williams & Wilkins. Bourassa, M. G., Brooks, M. M., Mark, D. B., Trudel, J., Detre, K. M., Pitt, B., et al. (2000). Quality of life after coronary revascularization in the US and Canada. American Journal of Cardiology, 85, 548-553. Carruthers, K. F., Dabbous, O. H., Flather, M. D., Starkey, I., Jacob, A., MacLeod, D., et al. (2004). Contemporary management of acute co ronary syndromes: Does the practice match the evidence? Heart, 90 (9), 1144-1153. Cohen, J. (1998). Statistical power analysis for the behavior sciences (2nd ed.). Hillsdale, NJ: Lawrence Erlbaum Associates. D'Antono, B., Dupuis, G., Fortin, C., Arsenault, A., & Burelle, D. (2006). Angina symptoms in men and women with stable coronary artery disease and evidence of exercise-induced myocardial perfusion defects. American Heart Journal, 151 (4), 813-819. DeCara, J. M. (2003). Noninvasi ve cardiac testing in women. Journal of the American Medical Women's Association., 58 (4), 254-263. DeVon, H. A., Ryan, C. J., Ochs, A. L., & Shap iro, M. (2008). Symptoms across the continuum of acute coronary syndromes: Di fferences between women and men. American Journal of Critical Care, 17 (1), 14-24. DeVon, H. A., & Zerwic, J. J. (2003). The sy mptoms of unstable angina: Do women and men differ? Nursing Research, 52(2), 108-118. 89

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95 BIOGRAPHICAL SKETCH William Garrett Warrington, Jr. was born in Amsterdam, New York to William and Joyce Warrington. He has one younger brother, Richard, and younger twin sisters Sandra and Suzanne. Bill has five sons, William, Marc, Patrick, Adam, and Andrew. After serving in the United States Army, Bill graduated with honors from California St ate University, Fullerton in June 1993 with a Bachelor of Science in Nursing degree. Bill has worked as a registered nurse in acute care facilities specializing in cardiology for more than 18 years. He recently married Margaret Love Gilson on June 4th, 2008. Maggie has two daughters, Lindsey and Kara. Bill and his wife, Maggie, currently live and work in Orlando, while he attends the University of Florida in Gainesville, pursuing his Ph.D. in nursing scie nce with a minor in physiology. His research interests lie in cardiovascula r nursing and in using symptom models to predict occlusive coronary artery disease in wo men focusing on visceral pain re sponses, alternative therapies, symptom expression, coronary artery diseas e progression and wome ns health issues.