The Etiology of LVH - A Review Of Genetic Predispositions

My research fellowship was focused on assessing putative associations of polymorphisms in candidate genes with cardiovascular disease. Two previously well publicized associations were tested in the Dallas Heart Study (DHS), a stratified random population-sample of 6,101 Dallas County residents aged 18-65, with equivalent numbers of Black and non-Black women and men.1 The first putative association tested was whether two polymorphisms in adrenergic receptors (alpha 2CDel322-325 and ß1Arg389) synergistically increased the risk of heart failure in Blacks as reported by others (adjusted odds ratio, 10.1; 95% CI: 2.11 to 48.53; p=0.004).2 In the DHS, we found that these variant alleles were not associated with self-reported heart failure or traits commonly accepted to be precursors for systolic HF, including left ventricular hypertrophy, increased left ventricular volume, reduced ejection fraction, and left ventricular mass (LVM).3 The second putative association tested was whether polymorphisms in the alpha 2A-adrenergic receptor (DraI restriction fragment length protein) and the alpha 2C-adrenergic receptor (Del 322-325) increased the risk of hypertension in Blacks.4, 5 Again, we were unable to replicate these findings. We found that these variant alleles were not associated with hypertension in Blacks in the DHS, alone or in combination.6 Based on this experience, the present review was undertaken to analyze the genetic influence on a cardiovascular disease and determine whether lack of reproducibility of genetic association studies occurs commonly. Given the breadth of this topic, I have chosen to focus on association studies of putative polymorphisms with the development of the "complex" trait of left ventricular hypertrophy (LVH). LVH can be defined as increased LV mass in relation to body size. The geometric pattern of this increased LV mass in LVH is important.7 In response to pressure overload from conditions like hypertension, there is increased LV wall thickness leading to an increase in LV mass and the ratio of wall thickness to chamber dimension, the combination of which has been termed "concentric hypertrophy".8 When volume overload conditions prevail, there is an increase in the left ventricular chamber volume with resultant chamber dilatation leading to a decrease in the ratio of wall thickness to chamber dimension, a pattern called "eccentric hypertrophy".8 For purposes of this review, the focus will be largely on concentric hypertrophy. Although there are inherited monogenic causes of hypertrophy, ("familial hypertrophy cardiomyopathy"), established by linkage and family studies,9 that body of work will not be evaluated in this review. Rather, the reproducibility of associations in polymorphisms with LVH performed in reported studies will be examined. Evidence looking at the role of polymorphisms in exercise-induced hypertrophy ("physiological" hypertrophy) also will be assessed. The review will conclude with a summary of "lessons learned" from previous work in this area with the intent of providing clues to improve future association studies in this field.