New Approaches to Heart Failure: From Pharmacogenomics to Drug Development

State of the Art: Pharmacogenomics of Heart Failure

Arthur M. Feldman

Thomas Jefferson University, Philadelphia, USA

Clinical trials have shown that not all heart failure patients respond to pharmacologic therapy. Nor have they demonstrated a correlation between patient phenotype and response to any given drug. Recent studies, reviewed by Dr. Arthur M. Feldman, Thomas Jefferson University, show that an individual’s genotype can predict response to heart failure drugs.

In 1990, the CONSENSUS trial reported that heart failure patients with higher levels of angiotensin II, norepinephrine, or aldosterone had higher mortality than those with lower levels (p<0.001). Analysis of ACE genotypes revealed that patients with the wild type ACE gene (ACE I/I) have normal angiotensin II levels, while patients with a deletion in both alleles (ACE D/D) have far higher levels, and those with a single allele deletion have intermediate levels (Figure 1). The presence or absence of these genes is not associated with incidence of heart failure. However, follow-up of heart failure patients over time has shown that patients with the ACE I/I gene have a longer transplant free survival than those with the ACE I/D or DD gene (p=0.04). In the GRACE trial of low-dose ACE inhibitors, patients with the I/I gene had a much better response and higher event-free survival than those with the D/D gene (p=0.005). This difference in outcomes was not observed in patients receiving high-dose ACE inhibitors.

Two adrenergic receptor gene variants are important with respect to norepinephrine release and response to beta-blockers (Figure 2). The BEST trial studied the beta-blocker bucindolol versus placebo in a population enriched for women and minorities, from whom genetic material was prospectively collected. Overall, there was no survival difference between the two treatment groups, but patients with homozygous Arg 389 receiving bucindolol had better survival than those receiving placebo (HR=0.62, p=0.030).

Increased aldosterone levels are associated with an aldosterone synthase promoter polymorphism at position -344. While the normal genotype is -344 TT, a C shift can occur on one (-344 TC) or both (-344 CC) alleles. No difference in survival was found between these genotypes in a heterogeneous population with heart failure. The GRACE and GRAHF trials found a lower incidence of the C allele in the African-American subset (A-HeFT) than in white Americans. However, the African-American patients with the CC gene had a much worse prognosis than those with the TT gene (p=0.018). Further, patients with the TC or CC gene had no response to treatment with isorsorbide-dinitrate therapy.

Dr. Feldman concluded that pharmacogenetics is the future of therapy for patients with heart failure. This approach will allow prospective individualized targeting of cardiovascular drugs.

Statin Pharmacogenomics in Heart Failure Treatment: Lessons from Coronary Heart Disease Prevention

Kouji Kajinami

Kanazawa Medical University, Uchinada

Evidence from recent studies suggests potential clinical applications for statins in the prevention of coronary artery disease (CAD). The pleiotropism of statins on endothelial function, inflammation, and oxidative stress may also lead to statin therapy for prevention of heart failure. Dr. Kouji Kajinami, Kanazawa Medical University, described pharmacogenomic studies his group conducted to explore genetic factors influencing statin therapy in CAD prevention. The study outcomes were lipid response and cardiovascular event response.

To determine genetic influence on statin pharmacokinetics, atorvastatin response was studied in patients with different CYP3A4A-290G and multidrug resistance-1 (MDR1) C3435T genotypes. After therapy, patients with the CYP3A4A-290G GG variant had significantly higher LDL cholesterol (LDL-C) than those with AA or AG genotypes (p=0.038). This difference appears to be associated with greater CYP3A4 expression in GG homozygotes, resulting in less atorvastatin reaching the liver and decreased LDL-C reduction (Figure 1). Comparison of MDR1 C3435T genotypes showed a significantly greater reduction from baseline in LDL-C (p=0.023) and triglycerides (p=0.0313) in women with TT and CT variants compared to wild-type (CC). This difference was not observed in men. These variants were shown to reduce MDR1 activity (Figure 2).

Other studies examined pharmacodynamic targets, including intestinal cholesterol absorption (ABCG8), cholesterol production (CYP7A1), and lipoprotein catabolism (APOE). Patients with the ABCG8 DH/HH genotype had a significantly greater response to atorvastatin than DD homozygotes in LDL-C (p=0.028) and triglyceride (p=0.012) lowering. Patients with wild-type CYP7AA1 had greater cholesterol reduction than those with CYP7AA1 Ht or Hm variants. A study of interactions between CYP7A1 and ABCG8 showed that patients with an ABCG8 variant and CYP7A1 wild-type genotype had the greatest cholesterol lowering. The mechanisms of these effects are shown in Figure 3. APOE variants also have different effects on response to atorvastatin, which are increased when analyzed in combination with CYP7A1 variants (wild-type CYP7A1 plus APOE E3 results in greatest LDL-C reductions).

In these and other studies, the absolute difference in LDL-C reductions across genotypes has been 3-6%. Combined analysis of multiple variants in several genes produced greater absolute differences of 8-10%. Dr. Kajinami concluded that these studies provide data that could lead to similar studies for therapy of heart failure with statins, resulting in more individualized management.

Adenylyl Cyclase as a New Therapeutic Target of Gene Therapy for Heart Failure

Toshiyuki Takahashi

Keio University School of Medicine, Tokyo, Japan

Adenylyl cyclase (AC) is a pivotal mediator of cAMP production in cardiac myocytes. Increased expression of the AC gene increases left ventricular (LV) function and survival and prevents deleterious remodeling in cardiomyopathy. Dr. Takahashi, Keio University School of Medicine, reviewed recent work on AC and described a proposed clinical trial of AC gene therapy in patients with severe congestive heart failure (CHF).

AC function and cAMP generation are reduced in heart failure. AC_V and AC_VI are the major AC isoforms in cardiac myocytes. AC_VI is dysfunctional in patients with heart failure. In the proposed clinical trial, a modified adenovirus vector encoding human AC_VI (Ad.AC_VI) will be transferred by intracoronary infusion during coronary angiography.

Preclinical data from Dr. Takahashi’s laboratory form the basis for the clinical trial. In transgenic mice with cardiac-directed AC_VI expression, catecholamine stimulation increased AC_VI expression in cardiac myocytes, resulting in structurally normal hearts with normal basal heart rate but markedly increased LV function. Expecting that increased cardiac AC_VI expression would increase mortality after myocardial infarction (MI), large MIs were induced in AC_VI mice and their transgene negative siblings. Surprisingly, survival in AC_VI mice was increased (74%) compared to the control mice (41%). The mechanisms contributing to this survival benefit were reduced LV dilation, increased LV contractile reserve, and reduced incidence of AV block.

Next, the laboratory performed intracoronary gene transfer with adenovirus encoding AC_VI in pigs with CHF. Five days after coronary delivery, substantial gene transfer was detected in LV transmural sections. Impaired LV function was induced in another group of pigs, which then received either AC_VI gene transfer or saline. Pigs with AC_VI gene transfer had better LV contractile function, smaller increases in LV end-diastolic diameter, and less impairment of LV function.

The objective of the proposed phase I/II clinical trial is to examine the safety of intracoronary Ad.AC_VI transfer and identify doses for future study. The endpoints are a six minute walk test before and 4 and 12 weeks after treatment, invasive monitoring, and echocardiograms. The protocol calls for coronary artery infusion of the vector after infusion of intracoronary nitroprusside, to increase gene transfer efficiency.

The pig studies show that cardiac gene transfer can be efficiently and safely achieved by intracoronary delivery of adenovirus vector. Heart function can be improved by AC_VI gene transfer. Dr. Takahashi concluded that the rationale, safety, and preclinical data warrant a clinical trial of AC_VI gene transfer in patients with severe CHF.