Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy

Abstract

Background

Hypertrophic cardiomyopathy is an inherited primary disorder of the myocardium characterised by clinical heterogeneity. The severity and rate of progression of hypertrophy is an important factor in prognosis, and is likely to be dependent on factors including age, the disease-causing gene mutation, environmental influences and genetic modifiers.

Methods

To study the influence of age on progression of hypertrophy, 62 patients with hypertrophic cardiomyopathy followed up for a minimum of 2 years were studied to determine the changes in left ventricular hypertrophy based on transthoracic M-mode and 2D echocardiography. DNA studies were performed to determine the role of the angiotensin-converting enzyme (ACE) gene deletion polymorphism in modulating progression of left ventricular hypertrophy.

Results

Sixty-two patients were followed-up over a period of 6.0±3.2 years (range 2–16 years). Patient data were analysed in two age groups: group 1 (patients aged ≤30 years at first echocardiogram) had an increase in left ventricular septal wall thickness from 23.8±8.9 to 28.8±8.7 mm (p<0.001), while group 2 (patients aged >30 years) had a smaller but significant increase from 17.8±4.2 to 19.5±6.2 mm (p<0.05). DNA analysis of the ACE gene deletion polymorphism showed those with the deletion/deletion (D/D) genotype had a greater progression of left ventricular hypertrophy compared to those carrying the other ACE genotypes (increase in hypertrophy: 6.2±3.3 vs. 1.7±4.2 mm; p<0.01, D/D vs. I/D genotype; 2.8±5.8 mm; p=ns, D/D vs. I/I genotype). This association was independent of age, body mass and resting blood pressure.

Conclusions

Progression of left ventricular hypertrophy is most evident in the first 3 decades of life, but is also observed in older age groups. Presence of the ACE gene D/D polymorphism may be an important marker to identify those individuals with hypertrophic cardiomyopathy who are likely to have more progressive disease, and therefore at higher risk of adverse clinical outcomes.

Introduction

Hypertrophic cardiomyopathy is a primary disorder of the myocardium characterised by cardiac hypertrophy in the absence of other loading conditions such as hypertension [1], [2]. The clinical course of hypertrophic cardiomyopathy is variable. Some patients remain asymptomatic throughout life while others suffer from intractable cardiac symptoms, heart failure and in the most severe circumstances, premature sudden death. Indeed, hypertrophic cardiomyopathy is the commonest structural cause of sudden cardiac death in people aged less than 35 years, including competitive athletes [3], [4], [5]. Genetic studies over the last 15 years have shown that hypertrophic cardiomyopathy is an autosomal dominant condition caused by defects in at least 11 genes, the majority of which encode sarcomeric proteins (for review, see Ref. [6]).

Despite an escalation in the knowledge of the gene defects which cause hypertrophic cardiomyopathy, genotype–phenotype correlation studies have shown that the primary gene defect alone does not completely explain the vast clinical heterogeneity seen in this condition. Although defects in some genes have been associated with different degrees of disease penetrance, for example, mutations in the β-myosin heavy chain gene show 90% disease penetrance by age 20 years compared to 30% penetrance at the same age with myosin-binding protein-C mutations [7], [8], many families have been described in which affected individuals within the same family (and therefore carrying the same gene defect) have vastly different clinical outcomes [9]. Furthermore, specific mutations previously described as “benign” or “malignant” have been shown to cause a diverse range of severity of disease [10]. Collectively, these data strongly suggest that modifying factors, both genetic and/or environmental, play an important role in explaining the phenotypic diversity seen in hypertrophic cardiomyopathy.

The diagnostic hallmark of hypertrophic cardiomyopathy is the presence of myocardial hypertrophy, with variability seen in the severity, distribution and progression of left ventricular wall thickening [11]. This heterogeneity is seen both between and within families and is seen independent of the underlying gene defect. The renin-angiotensin system is important in myocardial growth and may play a role in modifying the hypertrophic phenotype in this condition [12]. Polymorphisms in a key component of the renin-angiotensin system, the angiotensin-1 converting enzyme (ACE) gene, have been studied extensively in cardiovascular diseases such as myocardial infarction, hypertension and dilated cardiomyopathy [13], [14], [15]. The ACE gene, localised to chromosome 17, has a polymorphic region consisting of an insertion (I) or deletion (D) of a 287-bp fragment called the I/D polymorphism. In hypertrophic cardiomyopathy, deletion homozygotes (D/D) have been associated with higher serum ACE levels, risk of sudden cardiac death, severity of hypertrophy and the incidence of atrial fibrillation [16], [17], [18], [19], [20], [21]. The variability in progression of left ventricular hypertrophy amongst individuals carrying the same gene mutation suggests a potential role for modifying genes and specifically the ACE gene in hypertrophic cardiomyopathy.

The aim of the present study was to characterise the progression of left ventricular hypertrophy in patients with known hypertrophic cardiomyopathy, and to determine the relationship between age and progression of hypertrophy. Furthermore, this study aimed to describe the frequency of the ACE polymorphism alleles with respect to the change in left ventricular hypertrophy.