BACKGROUND-Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases1–3. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction4–7 can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development8. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Sudden cardiac death (SCD) from cardiac arrest is a major international public health problem accounting for an estimated 15–20% of all deaths. Although resuscitation rates are generally improving throughout the world, the majority of individuals who suffer a sudden cardiac arrest will not survive. SCD most often develops in older adults with acquired structural heart disease, but it also rarely occurs in the young, where it is more commonly due to inherited disorders. Coronary heart disease (CHD) is known to be the most common pathology underlying SCD, followed by cardiomyopathies, inherited arrhythmia syndromes, and valvular heart disease. Over the past three decades, declines in SCD rates have not been as steep as for other causes of CHD deaths, and there is a growing fraction of SCDs not due to CHD and/or ventricular arrhythmias, particularly among certain subsets of the population. The growing heterogeneity of the pathologies and mechanisms underlying SCD present major challenges for SCD prevention, which are magnified further by a frequent lack of recognition of the underlying cardiac condition prior to death. Multifaceted preventative approaches, which address risk factors in seemingly low risk and known high-risk populations will be required to decrease the burden of SCD. In this Compendium, we review the wide-ranging spectrum of epidemiology underlying SCD within both the general population and in high-risk subsets with established cardiac disease placing an emphasis on recent global trends, remaining uncertainties, and potential targeted preventive strategies.

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Background-Ghrelin is a novel growth hormone (GH)-releasing peptide that may also induce vasodilation and stimulate feeding through GH-independent mechanisms. We investigated whether ghrelin improves left ventricular (LV) dysfunction and attenuates cardiac cachexia in rats with chronic heart failure (CHF). Methods and Results-Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, rat ghrelin (100 g/kg SC BID) or saline was administered for 3 weeks. Echocardiography and cardiac catheterization were performed. Serum GH and insulin-like growth factor-1 were significantly higher in both CHF and sham rats treated with ghrelin than in those given placebo (PϽ0.05 for both). CHF rats given placebo showed an impaired increase in body weight compared with sham rats given placebo (PϽ0.05). CHF rats treated with ghrelin, however, showed a significantly greater increase in body weight than those given placebo (ϩ10% versus ϩ3%, PϽ0.05). They showed significantly higher cardiac output (315Ϯ49 versus 266Ϯ31 mL · min Ϫ1 · kg Ϫ1 , PϽ0.05) and LV dP/dt max (5738Ϯ908 versus 4363Ϯ973 mm Hg/s, PϽ0.05) than CHF rats given placebo. Ghrelin increased diastolic thickness of the noninfarcted posterior wall, inhibited LV enlargement, and increased LV fractional shortening in CHF rats (from 15Ϯ3% to 19Ϯ3%, PϽ0.05). Conclusions-Chronic subcutaneous administration of ghrelin improved LV dysfunction and attenuated the development of LV remodeling and cardiac cachexia in rats with CHF.

Our results suggest that although pacing and sodium channel block are very effective in abbreviating the QT interval and TDR in LQT3, these therapeutic approaches may also be valuable in reducing the incidence of arrhythmogenesis in LQT2.

Our data suggest that beta-adrenergic stimulation induces TdP by increasing transmural dispersion of repolarization in LQT1 and LQT2 but suppresses TdP by decreasing dispersion in LQT3. The data indicate that beta-blockers are protective in LQT1 and LQT2 but may facilitate TdP in LQT3.

Background-DNA variants appearing to predispose to drug-associated "acquired" long-QT syndrome (aLQTS) have been reported in congenital long-QT disease genes. However, the incidence of these genetic risk factors has not been systematically evaluated in a large set of patients with aLQTS. We have previously identified functionally important DNA variants in genes encoding K ϩ channel ancillary subunits in 11% of an aLQTS cohort. Methods and Results-The coding regions of the genes encoding the pore-forming channel proteins KvLQT1, HERG, and SCN5A were screened in (1) the same aLQTS cohort (nϭ92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (nϭ67) and cross sections of the Middle Tennessee (nϭ71) and US populations (nϭ90). The frequency of three common nonsynonymous coding region polymorphisms was no different between aLQTS and control subjects, as follows: 24% versus 19% for H558R (SCN5A), 3% versus 3% for R34C (SCN5A), and 14% versus 14% for K897T (HERG). Missense mutations (absent in controls) were identified in 5 of 92 patients. KvLQT1 and HERG mutations (one each) reduced K ϩ currents in vitro, consistent with the idea that they augment risk for aLQTS. However, three SCN5A variants did not alter I Na , which argues that they played no role in the aLQTS phenotype. Conclusions-DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in Ϸ10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits. (Circulation. 2002; 105:1943-1948.)