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Background - Truncating variants of the titin gene (TTNtv) are a leading cause of dilated cardiomyopathy (DCM) and have been associated with an increased risk of ventricular arrhythmias. This study evaluated the substrate distribution and the acute and long-term outcomes of patients with TTN-related cardiomyopathy undergoing ventricular tachycardia (VT) ablation. Methods - This multicenter registry included 15 patients with DCM (age 59±11 years, 93% male, ejection fraction 30±12%) and genotypically confirmed TTNtvs who underwent VT ablation between July 2014 and July 2020. Results - All patients presented with sustained monomorphic VT, including electrical storm in 4 of them. A median of 2 VTs per patient were induced during the procedure (cycle-length 318±68 ms) and the predominant morphologies were left bundle branch block with inferior axis (39%) and right bundle branch block with inferior axis (29%). A complete map of the left ventricle (LV) was created in 12 patients and showed voltage abnormalities mainly at the periaortic (92%) and basal septal region (58%). A preprocedural cardiac magnetic resonance imaging was available in 13 patients and in 11 there was evidence of LV delayed gadolinium enhancement, with predominantly midmyocardial distribution. Sequential ablation from both sides of the septum was required in 47% of patients to target septal intramural substrate and epicardial ablation was performed in 20%. At the end of the procedure, the clinical VT was noninducible in all patients, while in 3 cases a non-clinical VT was still inducible. After a follow-up of 26.5±23.0 months, 53% of patients experienced VT recurrence, 20% received transplant or mechanical circulatory support and 7% died. Conclusion - The arrhythmogenic substrate in TTN-related cardiomyopathy involves the basal septal and perivalvular regions. Long-term outcomes of catheter ablation are modest, with high recurrence rate, likely related to an intramural location of VT circuits.

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Misalignment of the internal circadian time with external physical time due to environmental factors or due to genetic variantion in circadian clock genes has been associated with increased incidence of cardiovascular risk factors. Common genetic variation in circadian genes in the United States have been identified predominantly in European ancestry individuals. We therefore examined the association between circadian clock single nucleotide polymorphisms (SNPs) in Clock, Cry1, Cry2, Bmal1 and Per3 genes and cardiovascular risk factors in African Americans and Hispanic/Latinos. We analyzed 17 candidate circadian SNPs in 1,166 subjects who self-identified as African-American or Hispanic/Latino and were enrolled in the UIC Cohort of Patients, Family and Friends. We found significant differences in the minor allele frequencies between African American and Hispanic/Latino subjects. Our analyses also established ethnic-specific SNPs that are associated with cardiovascular risk factors. In Hispanic/Latinos, the rs6850524 in Clock was associated with increased risk for hypertension, meanwhile rs12649507, rs4864546, and rs4864548 reduced the risk, also rs8192440 ( Cry1 ) reduced the risk for type 2 diabetes. In African Americans, the Clock rs1801260 and rs6850524 were negatively associated with the presence of obesity; Bmal1 rs11022775 reduced the risk for dyslipidemia; and the Cry2 rs2292912 increased the risk for dyslipidemia and diabetes. Genetic variations in candidate circadian-clock genes are associated with risk factors for cardiovascular disease in African-Americans and Hispanic/Latinos. Our findings may help to improve cardiovascular risk assessment as well as better understand how circadian misalignment impacts cardiovascular risk in diverse populations.