EP News: Basic and Translational

Abstract

Patients with dilated cardiomyopathy are at high risk for ventricular arrhythmia and sudden cardiac death. According to the Heart Rhythm Society Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies (Ackerman et al, HeartRhythm 2011;8:1308–1339), none of the >25 known disease-associated genes has been shown to account for ≥5% of this disease. A recent article by Herman et al (N Engl J Med 2012;366:619, PMID 22335739) is likely to change that statement. The authors analyzed TTN (the gene encoding the sarcomere protein titin) in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls. They were able to identify 72 unique mutations that altered full-length titin. The frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (27%) than among subjects with hypertrophic cardiomyopathy (1%) or controls (3%). TTN mutations cosegregated with dilated cardiomyopathy in families with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin. More than half of the patients in the study have an implantable cardioverter-defibrillator. Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers. The authors suggest that truncated titin proteins found in subjects with dilated cardiomyopathy may be integrated into the sarcomere and cause dilated cardiomyopathy by means of a dominant negative mechanism. The authors conclude that TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy.