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A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance

Abstract

Background Truncating variants in the TTN gene ( TTNtv) are common in patients with dilated cardiomyopathy (DCM) but also occur in the general population. Whether TTNtv are sufficient to cause DCM or require a second hit for DCM manifestation is an important clinical issue. Methods We generated a zebrafish model of an A-band TTNtv identified in 2 human DCM families in which early-onset disease appeared to be precipitated by ventricular volume overload. Cardiac phenotypes were serially assessed from 0 to 12 months using video microscopy, high-frequency echocardiography, and histopathologic analysis. The effects of sustained hemodynamic stress resulting from an anemia-induced hyperdynamic state were also evaluated. Results Homozygous ttna mutants had severe cardiac dysmorphogenesis and premature death, whereas heterozygous mutants ( ttnatv/+) survived into adulthood and spontaneously developed DCM. Six-month-old ttnatv/+ fish had reduced baseline ventricular systolic function and failed to mount a hypercontractile response when challenged by hemodynamic stress. Pulsed wave and tissue Doppler analysis also revealed unsuspected ventricular diastolic dysfunction in ttnatv/+ fish with prolonged isovolumic relaxation and increased diastolic passive stiffness in the absence of myocardial fibrosis. These defects reduced diastolic reserve under stress conditions and resulted in disproportionately greater atrial dilation than observed in wild-type fish. Conclusions Heterozygosity for A-band titin truncation is sufficient to cause DCM in adult zebrafish. Abnormalities of systolic and diastolic reserve in titin-truncated fish reduce stress tolerance and may contribute to a substrate for atrial arrhythmogenesis. These data suggest that hemodynamic stress may be an important modifiable risk factor in human TTNtv-related DCM.

Type Journal
Authors Huttner IG1,2, Wang LW1,2,3, Santiago CF1,2, Horvat C1, Johnson R1, Cheng D4, von Frieling-Salewsky M5, Hillcoat K6, Bemand TJ1, Trivedi G1, Braet F4,7,8, Hesselson D2,9, Alford K6, Hayward CS10,2,3, Seidman JG11,12, Seidman CE12,13, Feneley MP10,2,3, Linke WA5, Fatkin D1,2,3.
Responsible Garvan Author Dr Daniel Hesselson
Publisher Name Circulation. Genomic and Precision Medicine
Published Date 2018-08-11
Published Volume 11
Published Issue 8
Published Pages e002135
Status Always Electronic
DOI 10.1161/CIRCGEN.118.002135
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/30354343