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New insight into titin cardiomyopathy

Commented by W. Linke


Approximately 15–20% of DCM patients have a truncating variant in the titin gene (TTNtv),1 largely enriched in the titin region located in the sarcomeric A-band.2,3 Furthermore, TTNtv located in constitutive exons (spliced in >90% of transcripts) are strongly associated with DCM, irrespective of their position in TTN.3 As the pathogenicity of these TTNtv becomes increasingly evident, the non-genetic factors determining their penetrance remain largely unknown. Recently, chemotherapy was reported as a potential factor uncovering TTNtv effects.4 Also, peripartum changes can be a factor uncovering the underlying genetic mutation as TTNtv are prevalent in patients with peripartum cardiomyopathy.5 A recent translational study by Verdonschot et al. from Maastricht (NL) identifies unique histological, molecular and functional alterations in patients with a dilated cardiomyopathy (DCM) caused by truncating titin mutations.  Titin DCM patients have increased cardiac fibrosis and obvious metabolic/mitochondrial alterations related to oxidative phosphorylation, with clear overexpression of genes related to electron transport chain complexes. These patients have improved functional recovery and lower cardiac mass as compared to other genetic DCM, but paradoxically increased atrial and ventricular arrhythmias at baseline and long-term follow-up. The latter mainly occurred in those patients with additional cardiac triggers such as chemotherapy, alcohol or cardiac virus presence. Thus, titin truncating mutations result in unique mitochondrial and structural alterations in the heart. These findings may help to develop titin-DCM targeted therapies.


  1. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366(7):619-28, 2012.
  2. Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O'Regan DP, San TR, de Marvao A, Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O'Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 7(270):270ra6, 2015.
  3. Schafer S, de Marvao A, Adami E, Fiedler LR, Ng B, Khin E, Rackham OJ, van Heesch S, Pua CJ, Kui M, Walsh R, Tayal U, Prasad SK, Dawes TJ, Ko NS, Sim D, Chan LL, Chin CW, Mazzarotto F, Barton PJ, Kreuchwig F, de Kleijn DP, Totman T, Biffi C, Tee N, Rueckert D, Schneider V, Faber A, Regitz-Zagrosek V, Seidman JG, Seidman CE, Linke WA, Kovalik JP, O'Regan D, Ware JS, Hubner N, Cook SA. Titin-truncating variants affect heart function in disease cohorts and the general population. Nat Genet 49(1):46-53, 2017.
  4. Linschoten M, Teske AJ, Baas AF, Vink A, Dooijes D, Baars HF, Asselbergs FW. Truncating titin (TTN) variants in chemotherapy-induced cardiomyopathy. J Card Fail 23(6):476-479, 2017.

van Spaendonck-Zwarts KY, Posafalvi A, van den Berg MP, Hilfiker-Kleiner D, Bollen IA, Sliwa K, Alders M, Almomani R, van Langen IM, van der Meer P, Sinke RJ, van der Velden J, Van Veldhuisen DJ, van Tintelen JP, Jongbloed JD. Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy. Eur Heart J 35(32):2165-73, 2014.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.