Background-Tetralogy of Fallot is the most common form of congenital heart disease in implantable cardioverterdefibrillator (ICD) recipients, yet little is known about the value of ICDs in this patient population. Methods and Results-We conducted a multicenter cohort study in high-risk patients with Tetralogy of Fallot to determine actuarial rates of ICD discharges, identify risk factors, and characterize ICD-related complications. A total of 121 patients (median age 33.3 years; 59.5% male) were enrolled from 11 sites and followed up for a median of 3.7 years. ICDs were implanted for primary prevention in 68 patients (56.2%) and for secondary prevention in 53 (43.8%), defined by clinical sustained ventricular tachyarrhythmia or resuscitated sudden death. Overall, 37 patients (30.6%) received at least 1 appropriate and effective ICD discharge, with a median ventricular tachyarrhythmia rate of 213 bpm. Annual actuarial rates of appropriate ICD shocks were 7.7% and 9.8% in primary and secondary prevention, respectively (Pϭ0.11). A higher left ventricular end-diastolic pressure (hazard ratio 1.3 per mm Hg, Pϭ0.004) and nonsustained ventricular tachycardia (hazard ratio 3.7, Pϭ0.023) independently predicted appropriate ICD shocks in primary prevention. Inappropriate shocks occurred in 5.8% of patients yearly. Additionally, 36 patients (29.8%) experienced complications, of which 6 (5.0%) were acute, 25 (20.7%) were late lead-related, and 7 (5.8%) were late generator-related complications. Nine patients died during follow-up, which corresponds to an actuarial annual mortality rate of 2.2%, which did not differ between the primary and secondary prevention groups. Conclusions-Patients with tetralogy of Fallot and ICDs for primary and secondary prevention experience high rates of appropriate and effective shocks; however, inappropriate shocks and late lead-related complications are common.

Background-Transposition of the great arteries with intra-atrial baffle repair is among the congenital heart defects at highest risk of sudden death. Little is known about mechanisms of sudden death and the role of implantable cardioverter defibrillators. Methods and Results-We conducted a multicenter cohort study in patients with transposition of the great arteries to determine actuarial rates of implantable cardioverter defibrillator shocks, identify risk factors, assess underlying arrhythmias, and characterize complications. Overall, 37 patients (age, 28.0Ϯ7.6 years; 89.2% male) were enrolled from 7 sites. Implantable cardioverter defibrillators were implanted for primary prevention in 23 (62.1%) patients and secondary prevention in 14 patients (37.8%). Annual rates of appropriate shocks were 0.5% and 6.0% in primary and secondary prevention, respectively (Pϭ0.0366). Independent predictors were a secondary prevention indication (hazard ratio, 18.0; Pϭ0.0341) and lack of ␤-blockers (hazard ratio, 16.7; Pϭ0.0301). In patients with appropriate shocks, intracardiac electrograms documented supraventricular tachycardia preceding or coexisting with ventricular tachycardia in 50%. No patient with inducible ventricular tachycardia received an appropriate shock in comparison with 37.5% of noninducible patients (Pϭ0.0429). Inappropriate shocks occurred in 6.6% per year, more so in patients of lesser weight (hazard ratio, 0.91 per kg; Pϭ0.0168). Additionally, 14 patients (37.8%) experienced complications: 5 (13.5%) acute, 1 (2.7%) late generator related, and 12 (32.4%) late lead related. Conclusion-In

Left-sided congenital heart disease (CHD) encompasses a spectrum of malformations that range from bicuspid aortic valve to hypoplastic left heart syndrome. It contributes significantly to infant mortality and has serious implications in adult cardiology. Although left-sided CHD is known to be highly heritable, the underlying genetic determinants are largely unidentified. In this study, we sought to determine the impact of structural genomic variation on left-sided CHD and compared multiplex families (464 individuals with 174 affecteds (37.5%) in 59 multiplex families and 8 trios) to 1,582 well-phenotyped controls. 73 unique inherited or de novo CNVs in 54 individuals were identified in the left-sided CHD cohort. After stringent filtering, our gene inventory reveals 25 new candidates for LS-CHD pathogenesis, such as SMC1A, MFAP4, and CTHRC1, and overlaps with several known syndromic loci. Conservative estimation examining the overlap of the prioritized gene content with CNVs present only in affected individuals in our cohort implies a strong effect for unique CNVs in at least 10% of left-sided CHD cases. Enrichment testing of gene content in all identified CNVs showed a significant association with angiogenesis. In this first family-based CNV study of left-sided CHD, we found that both co-segregating and de novo events associate with disease in a complex fashion at structural genomic level. Often viewed as an anatomically circumscript disease, a subset of left-sided CHD may in fact reflect more general genetic perturbations of angiogenesis and/or vascular biology.

The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-β signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm.