Hazel L. White

An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study.

The Glycine389 variant of the beta‐1 adrenergic receptor (β1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant.

Polymorphisms of adrenoceptors are not associated with an increased risk of adverse event in heart failure: a MERIT-HF substudy.

BACKGROUND Enhanced sympathetic activation has a central role in the development of heart failure (HF). We assessed whether the alpha(2C)-adrenoceptor (Del322-325) polymorphism exclusively or in combination with a beta(1)-adrenoceptor (Arg389) polymorphism, each with known independent effects on sympathetic function, were associated with an increased risk of adverse events in HF. METHODS AND RESULTS A total of 526 patients enrolled in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure study were genotyped for both adrenoceptor polymorphisms. The distribution of alpha(2C) genotypes was similar between the event and nonevent groups. However, a reduced prevalence of the Del322-325 allele was found in individuals with ischemic congestive HF (P=.022). Patients possessing both the alpha(2C) Del322-325 and beta(1) Arg389 alleles had no increased risk of events. Adjusting for confounding variables and the beta(1) Arg389Gly polymorphism, the odds ratio of being ins/del + del/del for the alpha(2C) Del322-325 and having an event was 0.89 with 95% CI 0.49-1.63, P=.715. Similarly, adjusting for confounding variables and the alpha(2C) Del322-325 polymorphism the odds ratio of being Arg/Arg or Arg/Gly for the beta(1) Arg389Gly polymorphism and having an event was 1.13 with 95% CI 0.52-2.17, P=.864. CONCLUSIONS The alpha(2C) Del322-325 polymorphism exclusively or in combination with the beta(1)Arg389 allele is not associated with an increased risk of adverse events in HF.

An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT-HF Substudy

To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended‐release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT‐HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1, 60.4%; IM: *1*4, 35.8%; and PM: *4*4, 3.8%). Plasma metoprolol concentrations were 2.1‐/4.6‐fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose–response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT‐HF‐defined titration schedule remains recommended for all patients, regardless of genotype.

‘ACE inhibitors are better than AT1 receptor blockers (ARBs)’ — controversies in heart failure

Ž . Angiotensin-converting enzyme kininase II governs the equilibrium between the renin]angiotensin system and the kallakrein]kinin system. This in turn influences a wide variety of pathophysiological mechanisms including water and salt homeostasis, vascular tone, fibrinolysis, cell growth and inflammation, all of which are implicated in cardiac failure and two of the main underlying pathologies: coronary artery disease and systemic hypertension. ACE inhibitors, by adjusting this balance, play a pivotal role in the natural history of cardiac failure, a phenomenon reflected by the survival benefit observed in the numerous largescale clinical trials of ACE inhibitors. In contrast, similar trials performed with the AT , angiotensin II 1 Ž . receptor blockers ARBs have yielded very disappointing results with a statistically non-significant excess of deaths.

AN INVESTIGATION INTO THE EFFECT OF CYTOCHROME P450 (CYP) 2D6 GENOTYPE ON PHARMACOKINETICS, PHARMACODYNAMICS AND OUTCOMES DURING METOPROLOL CR/XL THERAPY IN A HEART FAILURE COHORT : A MERIT-HF SUB-STUDY

Pharmacogenetic studies of low-dose metoprolol – a selective, s1-adrenergic receptor antagonist metabolised by the highly-polymorphic CYP2D6 enzyme – have demonstrated diverse pharmacokinetic and pharmacodynamic responses. We explored the impact of CYP2D6 genotype in heart failure patients