Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy

S. M. Kamel, C. J. M. Opbergen, C. D. Koopman, A. O. Verkerk, B. J. D. Boukens, B. Jonge, Y. L. Onderwater, E. Alebeek, S. Chocron, C. Polidoro Pontalti, W. J. Weuring, M. A. Vos, T. P. Boer, T. A. B. Veen () and J. Bakkers ()
Additional contact information
S. M. Kamel: University Medical Centre Utrecht
C. J. M. Opbergen: University Medical Center Utrecht
C. D. Koopman: University Medical Centre Utrecht
A. O. Verkerk: University of Amsterdam, Amsterdam University Medical Centers
B. J. D. Boukens: University of Amsterdam, Amsterdam University Medical Centers
B. Jonge: University of Amsterdam, Amsterdam University Medical Centers
Y. L. Onderwater: University Medical Centre Utrecht
E. Alebeek: University Medical Centre Utrecht
S. Chocron: University Medical Centre Utrecht
C. Polidoro Pontalti: University Medical Center Utrecht
W. J. Weuring: University Medical Center Utrecht, Utrecht University
M. A. Vos: University Medical Center Utrecht
T. P. Boer: University Medical Center Utrecht
T. A. B. Veen: University Medical Center Utrecht
J. Bakkers: University Medical Centre Utrecht

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The heterozygous Phospholamban p.Arg14del mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. This mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+ dynamics. Little is known about the physiological processes preceding induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we address these issues using a knock-in Phospholamban p.Arg14del zebrafish model. Hearts from adult zebrafish with this mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography reveals contractile variations before overt structural changes occur, which correlates at the cellular level with action potential duration alternans. These functional alterations are preceded by diminished Ca2+ transient amplitudes in embryonic hearts as well as an increase in diastolic Ca2+ level, slower Ca2+ transient decay and longer Ca2+ transients in cells of adult hearts. We find that istaroxime treatment ameliorates the in vivo Ca2+ dysregulation, rescues the cellular action potential duration alternans, while it improves cardiac relaxation. Thus, we present insight into the pathophysiology of Phospholamban p.Arg14del cardiomyopathy.

Date: 2021
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DOI: 10.1038/s41467-021-27461-8

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