A prospective evaluation of the angiotensin‐converting enzyme D/I polymorphism and left ventricular remodeling in the ‘Healing and Early Afterload Reducing Therapy’ Study

Abstract

The D/I (deletion, D, insertion, I) polymorphism of the angiotensin-converting enzyme (ACE) gene has been extensively studied for its association with a number of cardiovascular and other disease states. However, its potential association with differential clinical efficacy of ACE inhibitors (ACE-I) administered to patients who had suffered a myocardial infarction (MI), i.e. the prevention of left ventricular (LV) remodeling, has so far not been specifically studied. The aim of the study was to investigate whether the D/I polymorphism of the ACE gene is associated with the incidence of post-MI LV remodeling in patients drawn from the 'Healing and Early Afterload Reducing Therapy' (HEART) Study. The ACE D/I polymorphism was characterized by the polymerase chain reaction (PCR) in 265 subjects from the 'Healing and Early Afterload Reducing Therapy' Study, a double-blind, placebo-controlled trial with the objective of determining whether early or delayed administration of the ACE-I, ramipril, in patients with acute anterior wall MI would be optimal in reducing LV enlargement. Selected frequencies for the ACE D and I alleles were 0.59 and 0.41 (placebo-high dose group), 0.56 and 0.44 (low dose-low dose group), and, 0.60 and 0.40 (high dose-high dose group), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and outcome regarding LV size or function, nor with the initial blood pressure response after ACE-I administration (adjusted for covariates). Our data provide no evidence for an association of the ACE D/I polymorphism with the risk of LV remodeling post-MI in the presence of ACE-I therapy, and therefore do not suggest that differential clinical efficacy of ACE-inhibitors is related to this genetic marker.

Pharmacogenomics of Renin Angiotensin System Inhibitors in Coronary Artery Disease

“…Zee and colleagues, in a substudy of the Healing and Early Afterload Reducing Therapy Study, evaluated the effects of ramipril (target dose of 10 mg daily) on left ventricular remodeling post-myocardial infarction in 265 patients with ACE genotyping performed. [82] In contrast to the Pinto study, this investigation found no evidence for an association between the ACE DD genotype and risk for remodeling in the setting of ACE inhibitor use. This study followed left ventricular echocardiographic parameters for only 90 days following the acute event and thereby may be limited in extrapolating longterm differences in remodeling among genotypes.…”

Pharmacogenetically Tailored Treatments for Heart Disease

“…However, several inconsistencies are evident in the findings of some hypertension, left ventricular hypertrophy and cardiomyopathy studies, and consequently the extent of the modification effect of this polymorphism remains unclear [46][47][48][49][50]. A meta-analysis assessed the possibility of an association between the ACE I/D polymorphism and the response to ACE inhibitors among 4 previously published pharmacogenetic reports that included a total of 925 patients.…”

Association of polymorphisms of zinc metalloproteinases with clinical response to stem cell therapy

“…However, the data concerning the association of ACE polymorphism and LV remodeling after MI remain controversial. While some studies showed an association of the D allele with greater mortality and increased LV dilatation and hypertrophy [43,44,45,46], others found no or only weak association between them [40,47,48,49].…”