Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model for Phospholamban R14del cardiomyopathy

Abstract

The heterozygous phospholamban (PLN) p.Arg14del (R14del) mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. The PLN R14del mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+ dynamics. Little is known about the physiological processes preceding PLN R14del induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we addressed these issues using a knock-in PLN R14del zebrafish model. Hearts from adult zebrafish with the R14del mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography revealed contractile pulsus alternans before overt structural changes occurred, which correlated at the cellular level with action potential duration (APD) alternans. These functional alterations are preceded by diminished Ca2+ transient amplitudes in embryonic hearts. We found that istaroxime treatment ameliorates the in vivo Ca2+ dysregulation, rescues the cellular APD alternans, while it improves cardiac relaxation. Thus, we present novel insight into the pathophysiology of PLN R14del cardiomyopathy and identify istaroxime as a potential novel drug for its treatment.

RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac Function

“…GO term analysis did not identify overrepresentation of any terms in either gene set (false discovery rate <0.05). However, among the downregulated transcripts, we found three well-characterized myocardial genes including phospholamban ( pln/plna ), 63,64 atrial myosin heavy chain 6 ( myh6 ), 65 and natriuretic peptide precursor a ([ nppa ] 66,67 ; Figure S8B; Table S3). We documented trending downregulation of nppa by reverse-transcription quantitative PCR (RT-qPCR) at 33 hpf (Figure S7C).…”

Istaroxime and Beyond: New Therapeutic Strategies to Specifically Activate SERCA and Treat Heart Failure

“…At the molecular level, they report a first critical difference between istaroxime and PST3093, given that PST3093 does not inhibit the Na 1 /K 1 ATPase pump but only stimulates SERCA2a, thus qualifying PST3093 as a selective activator (Arici et al, 2022). In addition, they revealed that PST3093 acts by weakening the SERCA-PLN interaction, a mechanism that had been previously confirmed, although not in an exclusive manner (Racioppi et al, 2021), also for istaroxime (Ferrandi et al, 2013;Kamel et al, 2021). Importantly, the authors were able to assess the pharmacokinetics of PST3093 in patients with HF, measuring a half-life of approximately 9 hours, substantially longer than that of istaroxime (Arici et al, 2022).…”

Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN:c.40_42delAGA Carriers

“…Previous studies have shown computational evidence and suggestive experimental evidence in other organisms. In Zebrafish, the plna R14del variant causes beat-to-beat variations in cardiac output in the absence of cardiac remodeling, suggesting that the cardiac contractile dysfunction is not caused by but rather causal for cardiac remodeling [36]. Causal relationships between anomalies in the QRS complex, specifically in the Q-R upslope, and increased risk of DCM have been found through the Mendelian randomization approach using genetic variants of ECG signatures [37].…”