Genetic polymorphisms and heart failure

Abstract

Heart failure is a complex clinical syndrome. There is evidence for a genetic contribution to the pathophysiology of heart failure. Considering the fundamental role of neurohormonal factors in the pathophysiology and progression of cardiac dysfunction and hypertrophy, variants of genes involved in this system are logical candidate genes in heart failure. In this report, genetic polymorphisms of the major neurohormonal systems in heart failure will be discussed. Studies on polymorphisms of the renin-angiotensin-aldosterone system (RAAS), adrenergic receptor polymorphisms, endothelin (receptor) polymorphisms, and a group of miscellaneous polymorphisms that may be involved in the development or phenotypic expression of heart failure will be reviewed. Research on left ventricular hypertrophy is also included. The majority of genetic association studies focused on the ACE I/D polymorphism.Initial genetic associations have often been difficult to replicate, mainly due to problems in study design and lack of power. Promising results have been obtained with genetic polymorphisms of the RAAS and sympathetic system.Considering the evidence so far, a modifying role for these polymorphisms seems more likely than a role of these variants as susceptibility genes. Besides the need for larger studies to examine the effects of single nucleotide polymorphisms and haplotypes, future studies also need to focus on the complexity of these systems and study Heart failure is a complex clinical syndrome with high morbidity and mortality. 1,2 Impairment of cardiac function activates compensatory neurohormonal mechanisms, which at a later stage may accelerate progression of heart failure. 3 Coronary heart disease and hypertension are major underlying causes of heart failure. Other frequent underlying conditions include valvular heart disease and idiopathic dilated cardiomyopathy. It is difficult to predict who will develop heart failure in response to myocardial injury. Racial differences in occurrence and outcome of heart failure 4,5 and heritability estimates of variability in left ventricular mass of 28% to 65% 6,7 suggest a genetic contribution to the pathophysiology of left ventricular remodeling and heart failure.Many studies have been published on the role of single gene mutations in (familial) cardiomyopathies. 8,9 These Mendelian traits are by nature rare, and although important at an individual level and for the understanding of disease mechanisms, are of limited significance in terms of prediction of heart failure occurrence in the population. 10 Moreover, in patients with identical gene mutations clinical manifestations of cardiomyopathy may differ. This suggests that probably also environmental and/or other genetic factors play a role.In this report, genetic polymorphisms of major neurohormonal systems involved in the pathophysiology of heart failure will be discussed, including the renin-angiotensin-aldosterone system (RAAS), adrenergic receptor polymorphisms, endothelin (receptor) polymorphisms, and a group of miscellaneous...

Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — A population study

“…Genetic polymorphisms have been shown to be important in the pathophysiology and the response to treatment of CHF [22][23][24] and could also explain our results. For example, a new gene in the ACE family, the ACE2 gene, has been identified and shown to map to defined quantitative trait loci on the X chromosome [3,4].…”

KATP channel polymorphism is associated with left ventricular size in hypertensive individuals: a large-scale community-based study

“…Susceptibility or resistance to heart failure, despite apparently similar risk load, is attributable to individual variation in homeostatic reserve (Bleumink et al 2004). Ventricular cardiomyocytes are rich in stress-responsive K ATP channels comprised pore-forming Kir6.2 and SUR2A regulatory subunits encoded by KCNJ11 and ABCC9, respectively (Zingman et al 2002;Yamada et al 2006).…”

Screening of the endothelin1 gene (EDN1) in a cohort of patients with essential left ventricular hypertrophy.

“…In some of these unexplained cases, LVH is familial and the disease segregates with mutations in one of the several genes encoding sarcomeric proteins (Schwartz et al 1995;Marian et al 1995). However, functional variants in other genes encoding proteins involved in cell signal transduction, hormones, growth factors, calcium haemostasis, substrate metabolism, and blood pressure are candidates for the risk of developing cardiac hypertrophy (Bleumink et al 2004). These candidate genes have been implicated in (32) 4 (2) * AA+KK, patients vs. controls, p = 0.0009.…”

“…Left Ventricular Hypertrophy is a complex disease, the consequence of interactions between genetic and environmental risk factors (Bleumink et al 2004). Hypertension, obesity, and other clinicopathological conditions are strong predictors of LVH, but many individuals with this condition do not have these acquired risk factors.…”

“…These sporadic patients could be at a higher risk for LVH due to mutations/polymorphisms in several genes (Annett et al 2004). In recent years, a number of studies have suggested that polymorphisms in the genes encoding components of the renin-angiotensin and endothelin systems, among others, could be involved in the risk of developing hypertrophy (Bleumink et al 2004).…”