A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance
2018 | journal article; research paper
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A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance
Huttner, I. G.; Wang, L. W.; Santiago, C. F.; Horvat, C.; Johnson, R.; Cheng, D. & von Frieling-Salewsky, M. et al. (2018)
Circulation: Genomic and Precision Medicine, 11(8) art. e002135. DOI: https://doi.org/10.1161/CIRCGEN.118.002135
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Details
- Authors
- Huttner, Inken G.; Wang, Louis W.; Santiago, Celine F.; Horvat, Claire; Johnson, Renee; Cheng, Delfine; von Frieling-Salewsky, Marion; Hillcoat, Karen; Bemand, Timothy J.; Trivedi, Gunjan; Braet, Filip; Hesselson, Dan; Alford, Kevin; Hayward, Christopher S.; Seidman, J. G.; Seidman, Christine E.; Feneley, Michael P.; Linke, Wolfgang A. ; Fatkin, Diane
- Abstract
- BackgroundTruncating 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.MethodsWe 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.ResultsHomozygous 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.ConclusionsHeterozygosity 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.
- Issue Date
- 2018
- Journal
- Circulation: Genomic and Precision Medicine
- Project
- SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | A08: Translationale und posttranslationale Kontrolle trunkierter Titinproteine in Kardiomyozyten von Patienten mit dilatativer Kardiomyopathie - Working Group
- RG Linke (Kardiovaskuläre Physiologie)
- Language
- English