Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes

Petr G. Vikhorev, Natalia Smoktunowicz, Alex B. Munster, O'Neal Copeland, Sawa Kostin, Cecile Montgiraud, Andrew E. Messer, Mohammad R. Toliat, Amy Li, Cristobal G. Dos Remedios, Sean Lal, Cheavar A. Blair, Kenneth S. Campbell, Maya Guglin, Ralph Knoll, Steven B. Marston

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Dilated cardiomyopathy (DCM) is an important cause of heart failure. Single gene mutations in at least 50 genes have been proposed to account for 25-50% of DCM cases and up to 25% of inherited DCM has been attributed to truncating mutations in the sarcomeric structural protein titin (TTNtv). Whilst the primary molecular mechanism of some DCM-associated mutations in the contractile apparatus has been studied in vitro and in transgenic mice, the contractile defect in human heart muscle has not been studied. In this study we isolated cardiac myofibrils from 3 TTNtv mutants, and 3 with contractile protein mutations (TNNI3 K36Q, TNNC1 G159D and MYH7 E1426K) and measured their contractility and passive stiffness in comparison with donor heart muscle as a control. We found that the three contractile protein mutations but not the TTNtv mutations had faster relaxation kinetics. Passive stiffness was reduced about 38% in all the DCM mutant samples. However, there was no change in maximum force or the titin N2BA/N2B isoform ratio and there was no titin haploinsufficiency. The decrease in myofibril passive stiffness was a common feature in all hearts with DCM-associated mutations and may be causative of DCM.

Original languageEnglish
Article number14829
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Bibliographical note

Funding Information:
This work was supported by grants from the British Heart Foundation (RG/11/20/29266 and PG/17/5/32705). R.K. was supported by the Fondation LeDucq. We thank the patients and staff of St. Vincent’s Hospital Sydney and the University of Kentucky Hospital, Lexington, KY.

Publisher Copyright:
© 2017 The Author(s).

ASJC Scopus subject areas

  • General

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