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Background The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response to medical therapy would elucidate the genetic basis of cardiac function. Objectives This study sought to identify genetic variations associated with response to HF therapy. Methods This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription-deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography. Results Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 × 10−5). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2-deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model. Conclusions A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model.

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death among athletes in the United States [(1)][1]. The electrocardiogram (ECG) can be used for screening athletes to identify HCM [(2–4)][2]; however, its routine use remains controversial due to false positives [(5)][3]. We

Purpose Previous studies have shown that hypertrophic cardiomyopathy (HCM) can also affect the right ventricle (RV), but there are not univoque data about it. The aim of this study is to describe RV dysfunction in patients with HCM using the myocardial performance index (MPI), tricuspid annular plane systolic excursion (TAPSE) and RV fractional area change (RVFAC) and their association with clinical outcome. Methods and Materials Consecutive patients with HCM followed at Stanford Hospital from 1999 to 2012 were included in the study. A total of 324 patients with HCM were included in the study. A group of 99 age and sex matched healthy volunteers were used as controls. Multivariable regression analysis was used to determine independent correlates of RV function. Results Compared to matched controls, patients with HCM had higher RVMPI (0.51±0.18 vs. 0.25±0.06, p 0.4 (HR 3.13 per 0.3, CI 95% 1.63 to 6.0, p Conclusions RV dysfunction based on RVMPI is common in patients with HCM and is more frequently observed among patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on RVMPI was associated with a history of syncope, defibrillator discharge or lower maximal VO2.