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Influence of β1-adrenergic Receptor Polymorphisms on the Prognosis of Patients with Heart Failure

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Influence of β1-adrenergic Receptor Polymorphisms on the Prognosis of Patients with Heart Failure
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Waliji, Alifia
Johnson, Julie ( Mentor )
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Gainesville, Fla.
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University of Florida
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English

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University of Florida
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University of Florida
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Journal of Undergraduate Research
Volume 4, Issue 5 - January 2003


Influence of Bl-adrenergic Receptor Polymorphisms on the Prognosis

of Patients with Heart Failure

Alifia Waliji


The Pi-adrenergic receptor (p1AR) contains two common coding polymorphisms at codons 49 (Ser49Gly) and

389 (Arg389Gly). In vitro and human data suggest greater sympathetic mediated activity with the Arg389 form
of PiAR. The specific aim of this study is to determine whether 1PAR polymorphisms are associated with a

poorer prognosis among heart failure (HF) patients.

We will recruit 400 patients with HF from Shands at UF HF clinics. The following data will be collected on
each patient: demographics, etiology of HF, ejection fraction (percent of blood ejected from the left
ventricle), hemodynamics, MVO2 (myocardial oxygen demand), New York Heart Association Functional Class,

and medications. A buccal cell sample will be collected for genomic DNA analysis. Polymorphisms will be
identified using a single primer extension method from Orchid Biosciences, Inc. The primary endpoint of the study
will be the composite of all cause mortality, cardiac transplant, or hospitalization for worsening HF. Follow-up will
be conducted at six, twelve, and 18-month intervals.

The goals of this study are to identify genetic variations associated with the poorest prognosis in HF patients
and tailor treatment strategies to alter the course of their disease. My specific role in this study was to assist
in recruiting patients, conducting follow-up interviews, isolating DNA, and genotyping samples.



INTRODUCTION


An estimated 4.8 million Americans have HF. Increasing prevalence, hospitalizations, and deaths have made HF
a major chronic condition in the United States. Cases of HF are increasing for two main reasons: first, people
are living longer and incidence of HF increases with advancing age. Second, more patients survive a
myocardial infarction which means they are living longer. Half of the patients diagnosed with HF will be dead within
5 years. Each year, there are an estimated 400,000 new HF cases. The incidence of HF approaches 10 per
1,000 populations after the age of 65. Seventy-five percent of HF cases have hypertension. About 22% of male
and 46% of female heart attack victims will be disabled with HF within six years. From 1979 to 1999, HF

deaths increased by 145%.1

HF results when the heart loses some of its blood-pumping ability. HF is a symptom of heart disease and HF
is associated with risk factors such as smoking, high cholesterol, hypertension, and diabetes.
Uncontrolled hypertension can increase the risk of HF by 200%. This risk also appears to be related to the severity

of high blood pressure.2 People with diabetes have a two- to eight-fold greater risk of HF then those
without diabetes.1 The presence of coronary disease is among the greatest risk for HF. Muscle damage and
scarring caused by a heart attack greatly increase the risk of HF. Irregular heartbeats can also increase the risk
of HF. Hence, any disorder that causes abnormal swelling or thickening of the heart sets the stage for HF.


F_ UF I �1 ou r ti al of Ul ii d e rg rad Lt ate Resea rc h University of Florida







Heart failure results from dysfunction of the left ventricle and is a syndrome due to a decrease in cardiac output.

As cardiac output falls, renal perfusion diminishes with activation of the sympathetic nervous system, which acts

on peripheral vascular resistance and plasma volume. This is followed by a compensatory increase in the

renin-angiotensin aldosterone system and hence an increase in aldosterone. These increases occur due to a

decrease in blood pressure, which stimulates baroreceptors in the aortic and carotid arteries, which in turn

stimulates the sympathetic nervous system.2 The activation of the sympathetic nervous system has a

deleterious effect on the heart and thus leads to HF.

HF interferes with the kidney's normal function of eliminating excess sodium and water from the body. Therefore,

an excess fluid is retained and causes swelling of the ankles and legs. Fluid can also collect in the lungs, which

results in shortness of breath. The severity of the condition and symptoms depends on how much of the

heart's "pumping" capacity has been lost. The body can compensate for the loss in cardiac function for some

time, but in the long term it has a negative effect. At first, deterioration may only be noticeable by a shortness

of breath and fatigue when stress is put on the heart, for example during exercise. Over time cardiac

function deteriorates to the point where the heart is no longer able to meet the body's metabolic demand, even

while the patient is at rest.

The P1AR is the dominant PAR subtype expressed on myocytes and its activation by norepinephrine from

sympathetic nerves and circulating epinephrine results in increased cardiac contractility.3 Cardiac pi AR

activation represents a major mechanism by which the sympathetic nervous system increases contractility. In

HF, activation of pi AR via a therapeutic agonist can serve to increase cardiac output during decompensation.3


Two polymorphisms occur on the b receptors; more specifically on the P1AR at codons 49 (Serine or Glycine) and

389 (Arginine or Glycine), which is located on chromosome number 10q24, and are thought to mediate changes

in heart rate, which is the emphasis of this study.5 The reason for studying the polymorphisms on the P1AR is

to observe whether the presence of one variant Ser49Gly or Arg389Gly influences long-term survival in HF

patients. Background studies of P1AR have shown that Ser49Gly appears to have no racial differences and

whereas Arg389Gly reports racial differences between Caucasians and African Americans. In vitro

mutagenesis studies of codon 389 polymorphism revealed nearly 2-fold greater basal and 3-fold greater

agonist-mediated adenylyl cyclase activities with the Arg389Gly receptor form.5 A missense mutation in the

P1AR gene has been associated with a decreased mortality risk in patients with HF. The Ser49Gly variant might

be associated with altered receptor function, resulting in myocardial protection in patients with HF.4 Determining

the variations on codons 49 and 389 will therefore help identify genetic polymorphisms associated with the

poorest prognosis in HF patients and therefore treatment can be tailored to alter the course of the disease.



MATERIALS AND METHODS


Patient Recruitment


Patients meeting eligibility of a history of HF and an ejection fraction of less than 40% were enrolled

in the study. Patients were recruited with proper informed consent approved for use by the University

of Florida Health Center Institutional Review Board. The following data were collected on every

patient: demographics, etiology of HF, ejection fraction, hemodynamics, MVO2, New York

Heart Association Functional Class, and medications. At the time patients were recruited, they

were asked to give a buccal cell sample for DNA analysis (explained below).







Patient Sample Collection and Storage


Each patient was given a lOmL sample of Scope� mouthwash in a 50mL conical tube. The patient

then rinsed and swished vigorously throughout the mouth for one minute. The contents were then

put back into the conical tube. The DNA was isolated using a protocol determined by the PUREGENE�

Kit. The samples were then stored in -200 C freezers and then aliquoted and sent to Orchid

Biosciences, Inc for genetic analysis using a single primer extension method. The patients' genotype

was then ascertained for the .6AR codon 49 and codon 389 polymorphisms.


Study Endpoints


This study will include three endpoints after which the patients will no longer be followed.

These endpoints include exacerbation, cardiac transplant, or death.


Patient Follow-up


At intervals of six, 12, and 18-months, follow up phone calls/interviews were conducted with patients

to determine if between the times the patient was enrolled in the study to present-day did they have

any trips to the emergency room or hospitalized as a result of their heart problem. Current

medications for the patient were also obtained.



RESULTS



Currently, 236 patients have been enrolled in the study. Table 1 below lists the number of patients

and important variables regarding the study.




Table 1.
A summary of the patients enrolled in the study and the data available on those patients. (n = 236)

Variable Number of Patients n (%)

African
Ethnicity American 39 (16.5%)

Caucasian 184 (77.9%)

Hispanic 5(2.1%)

Other 8 (3.4%)

Gender Female 77 (32.7%)

Male 159 (67.4%)

Mean Age (years)
(Patients range from 19 to 53.3 +/- 3.2
91)

Percent on ACE Inhibitors
67%
(Antihypertensive Drugs)

Percent of Patients who
53.3 +/- 3.2
Have reached an endpoint

Exacerbation 8.1%

Transplant 7.2%





Death

Mean follow-up


5.9%

9 months

5-20 months


DISCUSSION


This study is still under progress and therefore final results are not available. We believe that at the completion

of this study we will identify genetic variations associated with the poorest prognosis in HF patients and

alter treatment strategies to modify the course of their disease.


Range for follow-up


REFERENCES



American Heart Association. 2002 Heart and Stroke Statistical Update-Heart Disease. 19-20.

McCance, KL, Huether SE, Pathophysiology: The Biologic Basis for Disease in Adults and Children. 3rd ed. St.
Louis: MO: Mosby; 1998.

Rathz, D. A., Brown, K. M., Kramer, L. A., Liggett, S. B. Amino Acid 49 Polymorphisms of the Human 31-

Adrenergic Receptor Affect Agonist-Promoted Trafficking. Journal of Cardiovascular Pharmacology. 2002: 39, 155-160.

Magnusson MB, Hjalmarson, A, Andersson, B. A novel polymorphism in the gene for the betal-adrenergic

receptor associated with survival in patients with heart failure. European Heart Journal. 2000;21,1853-1858.

Humma L et al. Effects of bl-Adrenoceptor Genetic Polymorphisms on Resting Hemodynamics in Patients

Undergoing Diagnostic Testing for Ischemia. American Journal of Cardiology. 2001; Nov 1; 88(9): 1034-7.


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