Pharmacogenetics in Chronic Heart Failure: New Developments and Current Challenges

Abstract

The individual patient responses to chronic heart failure (HF) pharmacotherapies are highly variable. This variability cannot be entirely explained by clinical characteristics, and genetic variation may play a role. Therefore the purpose of this review is to 1) summarize the background pharmacogenetic literature for major HF pharmacotherapy classes (i.e. beta-blockers, angiotensin converting enzyme inhibitors, digoxin, and loop diuretics), 2) evaluate recent advances in the HF pharmacogenetic literature in the context of previous findings, and 3) discuss the challenges and conclusions for HF pharmacogenetic data and its clinical application.

Race and Beta‐Blocker Survival Benefit in Patients With Heart Failure: An Investigation of Self‐Reported Race and Proportion of African Genetic Ancestry

“…This study is the first to examine this issue by quantified genetic ancestry, which can potentially offer a more‐granular view of the biological portion of race. Previous studies on the genetic differences in beta‐blocker response have relied on candidate gene approaches, particularly candidate polymorphisms affecting adrenergic activity 29. Adverse genetic polymorphisms in the adrenergic system that are associated with decreased beta‐blocker response are most frequent in blacks.…”

Prognostic impact of carboxylesterase 1 gene variants in patients with congestive heart failure treated with angiotensin-converting enzyme inhibitors

“…Accordingly, research on pharmacogenetic risk stratification of patients treated with ACEIs has primarily focused on the importance of genetic variants affecting ACEI pharmacodynamics, notably the I/D polymorphism of ACE (rs1799752) [8,33,34]. This polymorphism has previously been suggested to influence ACE activity in patients with IHD and hypertension, as well as CV outcomes in patients with CHF [8,[33][34][35].…”

“…Accordingly, research on pharmacogenetic risk stratification of patients treated with ACEIs has primarily focused on the importance of genetic variants affecting ACEI pharmacodynamics, notably the I/D polymorphism of ACE (rs1799752) [8,33,34]. This polymorphism has previously been suggested to influence ACE activity in patients with IHD and hypertension, as well as CV outcomes in patients with CHF [8,[33][34][35]. In addition, a combination of SNPs in the angiotensin II receptor type 1 gene and the bradykinin receptor B1 gene, as well as in the ACE and ABO blood group genes, respectively, have been associated with CV outcomes in patients treated with ACEIs, albeit the clinical value of these ACEI, angiotensin-converting enzyme inhibitor; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; WMI, wall motion score index.…”

“…CES1 gene variations and ACEI treatment Nelveg- Kristensen et al 173 genetic variants, including the ACE I/D polymorphism, remains controversial [8,33,36,37]. To our knowledge, only very few genetic variations of CES1, for example, rs71647871, have been specifically associated with reduced activation of ACEIs in vitro, and just one polymorphism (− 816A > C of CES1A2) has been associated with in-vivo reduction of the antihypertensive effect of an ACEI (imidapril) in Japanese patients with hypertension [17,38].…”

“…Previous pharmacogenetic studies assessing individual variability in the response to ACEIs have primarily focused on genetic variation in ACEI pharmacodynamics, notably the controversial importance of the insertion/deletion (I/D) polymorphism (rs1799752) in the angiotensin-converting enzyme gene (ACE) [8]. However, the variability in response to ACEIs may also be explained, in part, by individual differences in ACEI pharmacokinetics, for example, as evidenced by apparent dose-response relationships between plasma concentrations of the active metabolites of ACEIs and circulating ACE activity and arterial blood pressure reduction, respectively [9,10].…”