Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy

• Published in: European journal of heart failure Vol. 19; no. 4; pp. 512 - 521
• Main Authors: Jansweijer, Joeri A., Nieuwhof, Karin, Russo, Francesco, Hoorntje, Edgar T., Jongbloed, Jan D.H., Lekanne Deprez, Ronald H., Postma, Alex V., Bronk, Marieke, van Rijsingen, Ingrid A.W., de Haij, Simone, Biagini, Elena, van Haelst, Paul L., van Wijngaarden, Jan, van den Berg, Maarten P., Wilde, Arthur A.M., Mannens, Marcel M.A.M., de Boer, Rudolf A., van Spaendonck‐Zwarts, Karin Y., van Tintelen, J. Peter, Pinto, Yigal M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK John Wiley & Sons, Ltd 01.04.2017
• Subjects: Adult; Aged; Arrhythmias, Cardiac; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - mortality; Cardiomyopathy, Dilated - physiopathology; Cardiomyopathy, Dilated - therapy; Case-Control Studies; Connectin - genetics; Diagnosis; Dilated cardiomyopathy; Female; Follow-Up Studies; Gene; Genotype; Heart Failure - genetics; Heart Failure - mortality; Heart Failure - physiopathology; Heart Failure - therapy; Heart Transplantation; Heart-Assist Devices; Humans; Lamin Type A - genetics; Male; Middle Aged; Mortality; Mutation; Phenotype; Prognosis; Proportional Hazards Models; Retrospective Studies; Severity of Illness Index; Stroke Volume; Treatment; Prognosis; Treatment; Diagnosis; Dilated cardiomyopathy; Gene
• ISSN: 1388-9842; 1879-0844; 1879-0844
• DOI: 10.1002/ejhf.673

Aims Truncating titin mutations (tTTN) occur in 25% of dilated cardiomyopathy (DCM) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether tTTN variants are associated with a clinically distinguishable form of DCM. Methods and results We compared clinical data on DCM probands and relatives with a tTTN mutation (n = 45, n = 73), LMNA mutation (n = 28, n = 29), and probands who tested negative for both genes [idiopathic DCM (iDCM); n = 60]. Median follow‐up was at least 2.5 years in each group. TTN subjects presented with DCM at higher age than LMNA subjects (probands 47.9 vs. 40.4 years, P = 0.004; relatives 59.8 vs. 47.0 years, P = 0.01), less often developed LVEF <35% [probands hazard ratio (HR) 0.38, P = 0.002], had higher age of death (probands 70.4 vs. 59.4 years, P < 0.001; relatives 74.1 vs. 58.4 years, P = 0.008), and had better composite outcome (malignant ventricular arrhythmia, heart transplantation, or death; probands HR 0.09, P < 0.001; relatives HR 0.21, P = 0.02) than LMNA subjects and iDCM subjects (HR 0.36, P = 0.07). An LVEF increase of at least 10% occurred in 46.9% of TTN subjects after initiation of standard heart failure treatment, while this only occurred in 6.5% of LMNA subjects (P < 0.001) and 18.5% of iDCM subjects (P = 0.02). This was confirmed in families with co‐segregation, in which the 10% point LVEF increase occurred in 55.6% of subjects (P = 0.003 vs. LMNA, P = 0.079 vs. iDCM). Conclusions This study shows that tTTN‐associated DCM is less severe at presentation and more amenable to standard therapy than LMNA mutation‐induced DCM or iDCM.