What is the clinical evidence from this study?

Study design: Other. Population: Arrhythmia and Heart Failure (Preclinical Models). Intervention: GM1869 vs. Vehicle (DMSO), Dantrolene, S36. Primary outcome: RyR2-mediated Ca2+ spark frequency and SERCA2a-mediated Ca2+ uptake kinetics.

November 27, 2023Open Access

A dual-targeted drug inhibits cardiac ryanodine receptor Ca2+leak but activates SERCA2a Ca2+uptake

JWJörg W. WegenerBielefeld University GMGyuzel Yu. MitronovaGerman Centre for Cardiovascular Research LELina ElShareifMedizinische Hochschule Hannover

Key Result

The novel compound GM1869 simultaneously inhibited RyR2-mediated Ca2+ leak and activated SERCA2a-mediated Ca2+ uptake in both murine and human cardiomyocytes.

Structured PICO

Does GM1869 improve intracellular Ca2+ handling by modulating RyR2 and SERCA2a activity in cardiomyocytes?

Population

Preclinical study utilizing murine ventricular cardiomyocytes (wild-type and RyR2 R2474S/+ mice) and human iPSC-derived cardiomyocytes to assess the dual-acting calcium handling properties of GM1869.

Intervention

GM1869 (a 1,4-benzothiazepine derivative)

Comparator

Vehicle control, Dantrolene, S36, and S107

Outcome

RyR2-mediated Ca2+ spark frequency and SERCA2a-mediated decay of Ca2+ transientssurrogate

GM1869 is a novel dual-acting compound that simultaneously inhibits RyR2 Ca2+ leak and activates SERCA2a Ca2+ uptake, representing a potential new lead for treating arrhythmias and heart failure.

Limitations

The exact mode of action of GM1869 on SERCA2a activity remains unclear.
Potential stimulatory actions on β-adrenergic signaling cannot be completely excluded.
In vivo efficacy and safety in larger animal models or humans remain to be established.

Abstract

In the heart, genetic or acquired mishandling of diastolic Ca 2+ by ryanodine receptor type 2 (RyR2) overactivity correlates with risks of arrhythmia and sudden cardiac death. Strategies to avoid these risks include decrease of Ca 2+ release by drugs modulating RyR2 activity or increase in Ca 2+ uptake by drugs modulating SR Ca 2+ ATPase (SERCA2a) activity. Here, we combine these strategies by developing experimental compounds that act simultaneously on both processes. Our screening efforts identified the new 1,4-benzothiazepine derivative GM1869 as a promising compound. Consequently, we comparatively studied the effects of the known RyR2 modulators Dantrolene and S36 together with GM1869 on RyR2 and SERCA2a activity in cardiomyocytes from wild type and arrhythmia-susceptible RyR2 R2474S/+ mice by confocal live-cell imaging. All drugs reduced RyR2-mediated Ca 2+ spark frequency but only GM1869 accelerated SERCA2a-mediated decay of Ca 2+ transients in murine and human cardiomyocytes. Our data indicate that S36 and GM1869 are more suitable than dantrolene to directly modulate RyR2 activity, especially in RyR2 R2474S/+ mice. Remarkably, GM1869 may represent a new dual-acting lead compound for maintenance of diastolic Ca 2+ .

Ask AI

Helpful

Bookmark

View Full Paper