Faculty Bibliography

Syncope and risk of sudden death due to ventricular tachyarrhythmia are the common manifestations of several inherited disorders. Abnormalities of the genetic makeup may directly affect proteins controlling cardiac excitability in a structurally normal heart. Other diseases manifest primarily with ventricular arrhythmias even though the genetic mutations cause structural abnormalities of the myocardium. This is the case of arrhythmogenic right ventricular cardiomyopathy and hypertrophic cardiomyopathy. Groundbreaking discoveries, starting from the 1990s until the beginning of the current decade, have provided fundamental knowledge on the major genes that confer an increased risk of arrhythmias and sudden death. Stems of such knowledge are the availability of genetic diagnosis, genotype-phenotype correlation, and genotype-based risk stratification schemes currently used in the clinical practice. This review provides a concise description of the known genes and key mechanisms involved in the pathogenesis of inherited arrhythmias. In addition, we outline possibilities, limitations, advantages, and potential threats of genetically screening for these genes.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is characterized by stress-triggered syncope and sudden death. Patients with catecholaminergic polymorphic ventricular tachycardia manifest sinoatrial node (SAN) dysfunction, the mechanisms of which remain unexplored. METHODS AND RESULTS: We investigated SAN [Ca(2+)](i) handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation of ryanodine receptor (RyR2(R4496C)) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2(R4496C) mice after isoproterenol injection, analogous to what was observed in catecholaminergic polymorphic ventricular tachycardia patients after exercise. Pacemaker activity was explored by measuring spontaneous [Ca(2+)](i) transients in SAN cells within the intact SAN by confocal microscopy. RyR2(R4496C) SAN presented significantly slower pacemaker activity and impaired chronotropic response under beta-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca(2+)](i) transients and action potentials) in 75% of the cases. Ca(2+) spark frequency was increased by 2-fold in RyR2(R4496C) SAN. Whole-cell patch-clamp experiments performed on isolated RyR2(R4496C) SAN cells showed that L-type Ca(2+) current (I(Ca,L)) density was reduced by approximately 50%, an effect blunted by internal Ca(2+) buffering. Isoproterenol dramatically increased the frequency of Ca(2+) sparks and waves by approximately 5 and approximately 10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca(2+) content was significantly reduced in RyR2(R4496C) SAN cells in the presence of isoproterenol, which may contribute to stopping the "Ca(2+) clock" rhythm generation, originating SAN pauses. CONCLUSION: The increased activity of RyR2(R4496C) in SAN leads to an unanticipated decrease in SAN automaticity by a Ca(2+)-dependent decrease of I(Ca,L) and sarcoplasmic reticulum Ca(2+) depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.

BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) predicts adverse prognosis in patients with stable coronary artery disease (CAD). However, the interaction with conventional risk factors remains uncertain. Our aim was to assess whether the extent of LGE is an independent predictor of adverse cardiac outcome beyond conventional risk factors, including left ventricle ejection fraction (LVEF). METHODS: We enrolled 376 patients (88% males, 64 +/- 11 years) with stable CAD, who underwent LGE assessment and a detailed conventional evaluation (clinical and pharmacological history, risk factors, ECG, Echocardiography). During a follow-up of 38 +/- 21 months, 56 events occurred (32 deaths, 24 hospitalizations for heart failure). RESULTS: LGE and LVEF showed the strongest univariate associations with end-points (HR: 13.61 [95%C.I.: 7.32-25.31] for LGE >/= 45% of LV mass; and 12.34 [6.80-22.38] for LVEF /= 45% and/or LVEF