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

Medientyp: E-Artikel
Titel: Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy
Beteiligte: 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.
Erschienen: Wiley, 2017
Erschienen in: European Journal of Heart Failure
Sprache: Englisch
DOI: 10.1002/ejhf.673
ISSN: 1388-9842; 1879-0844
Schlagwörter: Cardiology and Cardiovascular Medicine
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Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>Truncating titin mutations (<jats:italic><jats:styled-content style="fixed-case">tTTN</jats:styled-content></jats:italic>) occur in 25% of dilated cardiomyopathy (<jats:styled-content style="fixed-case">DCM</jats:styled-content>) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether <jats:italic><jats:styled-content style="fixed-case">tTTN</jats:styled-content></jats:italic> variants are associated with a clinically distinguishable form of <jats:styled-content style="fixed-case">DCM</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Methods and results</jats:title><jats:p>We compared clinical data on <jats:styled-content style="fixed-case">DCM</jats:styled-content> probands and relatives with a <jats:italic><jats:styled-content style="fixed-case">tTTN</jats:styled-content></jats:italic> mutation (<jats:italic>n</jats:italic> = 45, <jats:italic>n</jats:italic> = 73), <jats:italic><jats:styled-content style="fixed-case">LMNA</jats:styled-content></jats:italic> mutation (<jats:italic>n</jats:italic> = 28, <jats:italic>n</jats:italic> = 29), and probands who tested negative for both genes [idiopathic <jats:styled-content style="fixed-case">DCM</jats:styled-content> (<jats:styled-content style="fixed-case">iDCM</jats:styled-content>); <jats:italic>n</jats:italic> = 60]. Median follow‐up was at least 2.5 years in each group. <jats:italic><jats:styled-content style="fixed-case">TTN</jats:styled-content></jats:italic> subjects presented with <jats:styled-content style="fixed-case">DCM</jats:styled-content> at higher age than <jats:italic><jats:styled-content style="fixed-case">LMNA</jats:styled-content></jats:italic> subjects (probands 47.9 vs. 40.4 years, <jats:italic>P</jats:italic> = 0.004; relatives 59.8 vs. 47.0 years, <jats:italic>P</jats:italic> = 0.01), less often developed <jats:styled-content style="fixed-case">LVEF</jats:styled-content> <35% [probands hazard ratio (<jats:styled-content style="fixed-case">HR</jats:styled-content>) 0.38, <jats:italic>P</jats:italic> = 0.002], had higher age of death (probands 70.4 vs. 59.4 years, <jats:italic>P</jats:italic> < 0.001; relatives 74.1 vs. 58.4 years, <jats:italic>P</jats:italic> = 0.008), and had better composite outcome (malignant ventricular arrhythmia, heart transplantation, or death; probands <jats:styled-content style="fixed-case">HR</jats:styled-content> 0.09, <jats:italic>P</jats:italic> < 0.001; relatives <jats:styled-content style="fixed-case">HR</jats:styled-content> 0.21, <jats:italic>P</jats:italic> = 0.02) than <jats:italic><jats:styled-content style="fixed-case">LMNA</jats:styled-content></jats:italic> subjects and <jats:styled-content style="fixed-case">iDCM</jats:styled-content> subjects (<jats:styled-content style="fixed-case">HR</jats:styled-content> 0.36, <jats:italic>P</jats:italic> = 0.07). An <jats:styled-content style="fixed-case">LVEF</jats:styled-content> increase of at least 10% occurred in 46.9% of <jats:italic><jats:styled-content style="fixed-case">TTN</jats:styled-content></jats:italic> subjects after initiation of standard heart failure treatment, while this only occurred in 6.5% of <jats:italic><jats:styled-content style="fixed-case">LMNA</jats:styled-content></jats:italic> subjects (<jats:italic>P</jats:italic> < 0.001) and 18.5% of <jats:styled-content style="fixed-case">iDCM</jats:styled-content> subjects (<jats:italic>P</jats:italic> = 0.02). This was confirmed in families with co‐segregation, in which the 10% point <jats:styled-content style="fixed-case">LVEF</jats:styled-content> increase occurred in 55.6% of subjects (<jats:italic>P</jats:italic> = 0.003 vs. <jats:italic><jats:styled-content style="fixed-case">LMNA</jats:styled-content></jats:italic>, <jats:italic>P</jats:italic> = 0.079 vs. <jats:styled-content style="fixed-case">iDCM</jats:styled-content>).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>This study shows that <jats:italic><jats:styled-content style="fixed-case">tTTN</jats:styled-content></jats:italic>‐associated <jats:styled-content style="fixed-case">DCM</jats:styled-content> is less severe at presentation and more amenable to standard therapy than <jats:italic><jats:styled-content style="fixed-case">LMNA</jats:styled-content></jats:italic> mutation‐induced <jats:styled-content style="fixed-case">DCM</jats:styled-content> or <jats:styled-content style="fixed-case">iDCM</jats:styled-content>.</jats:p></jats:sec>
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