Pharmacogenomics of left ventricular hypertrophy reversal

The ultimate goal of antihypertensive treatment is to prevent hypertension-associated cardiovascular events and death. In general, the achieved blood pressure reduction is considered to be the main determinant of any benefit from antihypertensive drugs and a good short-term surrogate for long-term cardiovascular prevention 1. Furthermore, a favourable change in other cardiovascular risk factors or disease markers is accepted as a desirable, additional treatment goal in the management of hypertensive subjects, on the basis of the assumption that such modifications would eventually lead to an improved prognosis. Left ventricular hypertrophy, one of the major manifestations of hypertensive heart disease, holds a prominent place among these intermediate end-points, and its occurrence is a strong and independent herald for cardiovascular morbidity and mortality 2–4. Moreover, left ventricular hypertrophy is the only available marker of preclinical cardiovascular disease 5, for which an association has been unequivocally demonstrated between its treatment-induced regression and a better prognosis over subsequent years, even after accounting for the confounding effect of treatment-induced blood pressure reduction 6–9. In a recent meta-analysis of the available studies, left ventricular hypertrophy regression was associated with a highly significant 59% reduction in the risk of cardiovascular events compared to the persistence or development of left ventricular hypertrophy 10. Thus, despite the lack of definitive confirmation, hypertensive patients with left ventricular hypertrophy might benefit more from therapy that is selected not only to control blood pressure, but also to specifically target left ventricular hypertrophy 11. Left ventricular hypertrophy is a multifactorial condition, and is influenced by a complex interplay of haemodynamic, neurohumoral, and genetic determinants 12,13. Not all of the variation in left ventricular mass among hypertensive individuals can be predicted by measurements of blood pressure, and 24-h blood pressure, which is generally considered to be more representative of an individual's usual blood pressure than the average of a few office measurements, can usually explain no more than 25% of the overall variance of left ventricular mass 14. Correspondingly, its regression is determined by a number of factors, of which only a few have been identified (Table 1). Antihypertensive treatment with most of the available drug classes is able to cause left ventricular hypertrophy reversal 15 but, for a given level of blood pressure reduction, individual responses vary greatly due to a large genotype-dependent variability in left ventricular mass change. With this background, pharmacogenetics is expected to play an essential role in the development of an individualized approach to hypertensive heart disease 16. Knowledge of polymorphic variation in genes that potentially influence pharmacodynamic mechanisms would allow the identification of individuals who are likely to have beneficial or harmful responses to treatment with a particular drug. In this regard, single nucleotide polymorphisms may be regarded as useful tools to explore the influence of genetic factors on treatment-induced left ventricular mass changes in hypertensive patients.Table 1: Factors influencing left ventricular hypertrophy reversal in hypertensive patientsSingle nucleotide polymorphisms, defined as positions in the genome at which two alternative nucleotides occur at an appreciable frequency (> 1%), represent the most common form of polymorphism in the human genome. Until now, only a few studies have examined the effects of individual gene polymorphisms on left ventricular mass change, and the results have not always been concordant. For example, in two studies, the angiotensin-converting enzyme DD genotype was found to predict a significantly greater left ventricular hypertrophy reversal under treatment with angiotensin-converting enzyme inhibitors 17,18, whereas the opposite was found in another study 19. However, the complex molecular mechanisms underlying the hypertrophic process make the list of plausible candidate genes very long, thus rendering the examination of each of the individual polymorphisms impractical. In this issue of the journal, Liljedahl et al. 20 use a novel approach to explore the role of genetic factors in modulating left ventricular hypertrophy reversal. In their study, several single nucleotide polymorphisms were examined through a microarray-based, multiplexed genotyping system, which allows extensive investigation of numerous candidate genes in a single study. Using the database obtained from a trial comparing the effects of the angiotensin II type 1 receptor blocker, irbesartan, and the β-blocker, atenolol, on echocardiographic left ventricular mass, the authors explored a total of 74 single nucleotide polymorphisms in several candidate genes involved in the renin–angiotensin–aldosterone and adrenergic systems, as well as in endothelial function and lipid metabolism. Selected polymorphisms in the angiotensinogen gene (the T allele of the M235T polymorphism) and in the apolipoprotein B gene (the G allele of the G10108A polymorphism) predicted a greater response to irbesartan but not to atenolol. Conversely, a genetic variant of the adrenoreceptor α2A (the G allele of the A1817G polymorphism) was associated with a greater left ventricular mass reduction with atenolol, but not with irbesartan. What is the biological plausibility of these associations? The angiotensinogen genotype might affect drug-induced reversal of left ventricular hypertrophy through different mechanisms, including its effect on plasma angiotensinogen levels 21 and its linkage with other genetic polymorphisms 22 that are able to cause a change in gene expression. The association between left ventricular hypertrophy regression and selected polymorphisms of the apolipoprotein B and adrenoreceptor α2A genes might serve as a stimulus for further studies on the complex molecular events involved in the hypertrophic process. Methodologically, the findings by Liljedahl et al. 20 need to be considered with some caution for a number of reasons, mostly as noted by the authors. First, the rather small sample size (n = 97 hypertensive patients) might have introduced bias. In a previous study 23 using the same database, the angiotensinogen T174M polymorphism, but not the M235T one, was identified as the only significant predictor of left ventricular mass change in a stepwise multiple regression analysis whereas, in the present study, the angiotensinogen M235T genotype prevailed over T174M. This inconsistency, which is partially attributable to the close linkage disequilibrium between the two polymorphisms 23, emphasizes the importance of investigating larger populations before drawing any firm conclusions about the relative importance of selective genetic polymorphisms in influencing left ventricular hypertrophy reversal. Second, left ventricular mass changes were assessed after 3 months of treatment, while ≥ 2 years of effective antihypertensive treatment are needed to obtain maximum left ventricular hypertrophy regression 24. Third, most of the patients in this study had been treated previously, and this may have diluted the relation between genetic polymorphisms and left ventricular mass changes. No doubt, the time is not yet ripe for recommending genetic screening before selecting a particular blood pressure-lowering drug or drug class. However, the approach used by Liljedahl et al. 20 represents a step toward a more comprehensive understanding of the factors underlying an individual's responsiveness to antihypertensive drugs, and their findings are provocative enough to be explored further in larger intervention trials. In this respect, genome-wide association studies will likely represent a formidable tool of investigation 25. Clarification of the role of genetic factors in modulating left ventricular mass reduction in response to a particular drug or drug class may be of the utmost importance in determining optimal drug therapy in the individual patient with hypertensive heart disease.