Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Background— Brugada syndrome is a rare, autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterized by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac Na ⁺ channel SCN5A on chromosome 3p21 cause ≈20% of the cases of Brugada syndrome; most mutations decrease inward Na ⁺ current, some by preventing trafficking of the channels to the surface membrane. We previously used positional cloning to identify a new locus on chromosome 3p24 in a large family with Brugada syndrome and excluded SCN5A as a candidate gene. Methods and Results— We used direct sequencing to identify a mutation (A280V) in a conserved amino acid of the glycerol-3-phosphate dehydrogenase 1–like ( GPD1-L ) gene. The mutation was present in all affected individuals and absent in >500 control subjects. GPD1-L RNA and protein are abundant in the heart. Compared with wild-type GPD1-L, coexpression of A280V GPD1-L with SCN5A in HEK cells reduced inward Na ⁺ currents by ≈50% ( P <0.005). Wild-type GPD1-L localized near the cell surface to a greater extent than A280V GPD1-L. Coexpression of A280V GPD1-L with SCN5A reduced SCN5A cell surface expression by 31±5% ( P =0.01). Conclusions— GPD1-L is a novel gene that may affect trafficking of the cardiac Na ⁺ channel to the cell surface. A GPD1-L mutation decreases SCN5A surface membrane expression, reduces inward Na ⁺ current, and causes Brugada syndrome.

Background— Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO ^· ) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO ^· levels observed in AF may be associated with increased superoxide (O ₂ ^·− ) production. Methods and Results— After a week of AF induced by rapid atrial pacing in pigs, O ₂ ^·− production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase–inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O ₂ ^·− production was increased 2.7-fold ( P <0.01) and 3.0-fold ( P <0.02) in the LA and LAA, respectively. A similar 3.0-fold ( P <0.01) increase in LAA O ₂ ^·− production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O ₂ ^·− , implying that NADPH and xanthine oxidases both contributed to increased O ₂ ^·− production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase ( P =0.04) and xanthine oxidase ( P =0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase. Conclusions— AF increased O ₂ ^·− production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O ₂ ^·− production. This increase in O ₂ ^·− and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.

Background— In the arterial endothelium, laminar flow and cyclical stretch induce expression of NO synthase (NOS). We hypothesized that atrial fibrillation (AF) causes a downregulation of atrial endocardial NOS expression and NO ^· production. Because NO ^· has antithrombotic properties, this may contribute to thromboembolism in AF. Methods and Results— In pigs, AF was produced with rapid atrial pacing at 600 bpm for 1 week, whereas controls had atrial pacing at 100 bpm. All animals had catheter ablation of the AV junction and ventricular pacing at 100 bpm. NO ^· production from freshly isolated tissue was measured by a NO ^· -specific microelectrode. Left atrial basal and stimulated NO ^· production was decreased in AF by 73% and 71% ( P <0.01). Endocardial NOS expression, determined by Western analysis, was also significantly decreased by 46%. Expression of the prothombotic protein plasminogen activator inhibitor 1 (PAI-1) is known to be regulated by NO ^· and was increased in the left atrium by 1.8-fold in AF ( P <0.05). NO ^· concentration was decreased in the left atrial appendage, although NOS expression was not affected. Neither NOS concentration, NO ^· levels, nor PAI-1 expression were altered in the aortas or right atria of animals with AF. Conclusions— AF is associated with a marked decrease in endocardial NOS expression and NO ^· bioavailability and an increase in PAI-1 expression in the left atrium. These data suggest that organized atrial contraction is needed to maintain normal endocardial expression of NOS. It is likely that loss of this antithrombotic enzyme contributes to the thromboembolic phenomena commonly observed in AF.

Background— Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH ₄ ) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction. Methods and Results— In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH ₄ , and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterins, NOS-dependent superoxide production, reduced NO production, and dephosphorylated phospholamban. Feeding hypertensive mice BH ₄ (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH ₄ stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH ₄ treatment. Targeted cardiac overexpression of angiotensin-converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension. Conclusions— Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH ₄ may represent a possible treatment for diastolic dysfunction.