Genomic Response Analysis of Heart Failure Therapy in African Americans

The response to therapy with a fixed dose combination of isosorbide dinitrate and hydralazine
(FDC I/H) is enhanced in African Americans with heart failure and reduced ejection fraction
(HFrEF) when compared to similar white cohorts. Despite the clear survival benefits of
treatment with FDC I/H in the African American Heart Failure Trial (AHeFT), the drug is
prescribed in only 25% of black subjects who would potentially benefit.

In terms of the enhanced response evident in the A-HeFT investigation, race is likely a
marker of differences in genomic background. Genetic variation of the G protein beta sub unit
GNB3 has been studied extensively for its role in hypertension. A polymorphism exists at
position 825 (T/C) which is functionally silent but tightly linked to a splicing variant
resulting in a truncated protein. The GNB3 T haplotype is far more prevalent in blacks and
associated with low renin hypertension. Evaluation of 350 subjects in the genetic sub-study
of AHeFT suggests that the GNB3 TT genotype, found in 50% of African Americans but only
10-15% of whites, was linked to an enhanced therapeutic response to FDC I/H. This
investigation will evaluate the hypothesis that the GNB3 TT genotype is a marker of enhanced
therapeutic response to FDC I/H in African Americans with HFrEF.

The study will enroll a cohort of 500 African Americans with HFrEF, initiate therapy with FDC
I/H and follow them for up to two years. Subjects will be genotyped at entry for the GNB3
polymorphism and response to therapy compared by genotype. Therapeutic response will be
quantified using the composite score, the primary endpoint of AHeFT, which incorporates
mortality, heart failure hospitalizations, and a change in quality of life (QoL) score at six
months.

Aim 2 will do a similar analysis of response to therapy by GNB3 genotype using improvement in
left ventricular end diastolic diameter (LVEDD) or left ventricular ejection fraction (LVEF)
by echocardiogram after six months on therapy as the outcomes measure. Aim 3 will use
admixture analysis to determine first how global ancestry (the % African ancestral DNA for an
individual) impacts on the outcome measures of drug response, and how the global ancestry
acts as a modifier for the effect of GNB3.

Inclusion Criteria:

1. 18 years and older

2. History of heart failure with an LVEF (less than OR equal to) < 0.35 for at least 6
months OR an LVEF < 0.45 with left ventricular internal end diastole (defined by a
diameter of more than 2.9 cm per square meter of body surface area OR more than 6.5 cm
on the basis of echocardiography). ** Echo must be done within 6 months of
enrollment**

3. New York Heart Association (NYHA) Class II-IV

4. Background heart failure therapy that includes angiotensin converting enzyme
inhibitors (ACEi) or angiotensin receptor blockers (ARBs), and beta blockers (BBs) for
at least 3 months (or documentation of intolerance to ACEi/ARBs and BBs)

5. Self-designated race as African American or black (would include subjects whose
country of origin was outside the USA such as Africa, the Caribbean, or Central
America).

Exclusion Criteria:

1. History of intolerance to either nitrates or hydralazine

2. Treatment with the combination of hydralazine and nitrates for the previous 3 months

3. Revascularization or myocardial infarction within last 90 days

4. Received cardiac resynchronization therapy (CRT) AND did not have an assessment of
cardiac function documenting an LVEF < 35% (less than OR equal to 35%) at least 90
days post CRT

5. Presence of clinically significant valvular heart disease, hypertrophic or restrictive
cardiomyopathy, active myocarditis, or uncontrolled hypertension. (Note that
uncontrolled hypertension is defined as blood pressure consistenly greater than 160
mmHg systolic and 95 mmHg diastolic)

6. Women who are currently pregnant, planning on becoming pregnant in the next two years,
or those who do not agree to prevent pregnancy.

7. Subjects who are on continuous home inotropes, a left ventricular assist device, or
who are post cardiac transplant.