PMID: 11910285

Issn Print: 0263-6352

Publication Date: 2002/04/01


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The drive to identify genetic factors influencing left ventricular mass responses to antihypertensive treatment

Robert H. Fagard; Tatiana Kuznetsova

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Left ventricular hypertrophy (LVH) is a major and independent risk factor for cardiovascular morbidity and mortality [1], even among normotensive subjects [2]. In addition, several studies indicate that a reduction of left ventricular mass (LVM) over time is associated with a better outcome in the following years [3,4]. Therefore, it would be of interest to treat hypertensive patients with LVH with drugs that decrease LVM more compared to other drugs. The conclusion from an early meta-analysis, which was mainly based on uncontrolled studies, that converting enzyme inhibitors are superior to other first-line antihypertensive agents in this respect [5], was not confirmed in a later meta-analysis in which the influence of the main drug classes on LVM was analysed with respect for the comparative design of the original studies [6]. More recently, a large prospective randomized clinical trial found that LVM was reduced to a similar extent by the converting enzyme inhibitor, enalapril, and the long-acting dihydropyridine calcium channel blocker, amlodipine [7]. As no drug class appears to be superior with regard to the regression of LVH in general, it would be of interest to find out whether the response of LVM to a particular drug can be predicted in the individual patient. Polymorphisms in genes involved in the renin–angiotensin–aldosterone system (RAAS) might be candidates for such predictions.
In this issue of the journal, Kurland et al. [8] report that particular polymorphisms in the angiotensinogen gene and in the angiotensin II type 1 receptor gene, but not in the angiotensin-converting enzyme (ACE) and aldosterone synthase genes, are associated with a better regression of LVM in response to the angiotensin II type 1 receptor blocker irbesartan in hypertensive patients with LVH. This was not the case for the beta-blocker atenolol. In addition, there were no significant associations between the various genotypes of RAAS and baseline LVM.
Left ventricular mass results from the complex interaction of genetic factors and environmental variables in the context of highly complicated regulatory and feedback circuits. The understanding of the molecular basis of LVH may provide us with new and more specific pharmacological agents, and perhaps the ability to individualize treatment and maximize the reduction in risk of morbidity and mortality from cardiovascular disease.
Since clinical and experimental data indicate the role of local RAAS in myocardial growth [9,10], it has been suggested that polymorphisms of the genes involved in this pathway might play a role in the genetic predisposition to LVH. Cloning of the human genes coding for ACE [11], angiotensinogen [12], angiotensin II type 1 receptor [13] and aldosterone synthase [14] has led to the discovery of several polymorphisms.
To date, the ACE gene has been the most studied polymorphism in relation to LVH. Results of studies are conflicting, but the findings of a recent meta-analysis [15] support the hypothesis that the enhanced ACE activity associated with the D allele may promote LVH if the pathophysiological process causing this disorder remains unopposed by treatment.
There are few studies regarding the association between the angiotensinogen gene variants and the non-familial form of LVH. Some of those studies revealed no association between the T allele of M235T polymorphism and LVM in White hypertensive patients [16–18]. In one Chinese study, a positive association was observed in a small group of hypertensive subjects [19]. On the other hand, some studies demonstrated a synergistic effect of angiotensin I-converting enzyme gene DD genotype and angiotensinogen gene TT genotype on the development of cardiac hypertrophy in patients with cardiovascular diseases [20] and on LVM in endurance athletes [21]. The T174M angiotensinogen gene polymorphism is in complete linkage disequilibrium with the M235T variant [12].

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