Premium
Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy
Author(s) -
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 SpaendonckZwarts Karin Y.,
van Tintelen J. Peter,
Pinto Yigal M.
Publication year - 2017
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1002/ejhf.673
Subject(s) - titin , medicine , dilated cardiomyopathy , cardiomyopathy , cardiology , heart failure , mutation , genetics , gene , sarcomere , myocyte , biology
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 .