Reduction of SR Ca2+ leak and arrhythmogenic cellular correlates by SMP-114, a novel CaMKII inhibitor with oral bioavailability.

Abstract

Sarcoplasmic reticulum (SR) Ca2+ leak induced by Ca2+/calmodulin-dependent protein kinase II (CaMKII) is centrally involved in atrial and ventricular arrhythmogenesis as well as heart failure remodeling. Consequently, treating SR Ca2+ leak has been proposed as a novel therapeutic paradigm, but compounds for use in humans are lacking. SMP-114 ("Rimacalib") is a novel, orally available CaMKII inhibitor developed for human use that has already entered clinical phase II trials to treat rheumatoid arthritis. We speculated that SMP-114 might also be useful to treat cardiac SR Ca2+ leak. SMP-114 significantly reduces SR Ca2+ leak (as assessed by Ca2+ sparks) in human atrial (0.72±0.33 sparks/100µm/s vs. control 3.02±0.91 sparks/100µm/s) and failing left ventricular (0.78±0.23 vs. 1.69±0.27 sparks/100µm/s) as well as in murine ventricular cardiomyocytes (0.30±0.07 vs. 1.50±0.28sparks/100µm/s). Associated with lower SR Ca2+ leak, we found that SMP-114 suppressed the occurrence of spontaneous arrhythmogenic spontaneous Ca2+ release (0.356±0.109 vs. 0.927±0.216 events per 30s stimulation cessation). In consequence, post-rest potentiation of Ca2+-transient amplitude (measured using Fura-2) during the 30s pause was improved by SMP-114 (52±5 vs. 37±4%). Noteworthy, SMP-114 has these beneficial effects without negatively impairing global excitation-contraction coupling: neither systolic Ca2+ release nor single cell contractility was compromised, and also SR Ca2+ reuptake, in line with resulting cardiomyocyte relaxation, was not impaired by SMP-114 in our assays. SMP-114 demonstrated potential to treat SR Ca2+ leak and consequently proarrhythmogenic events in rodent as well as in human atrial cardiomyocytes and cardiomyocytes from patients with heart failure. Further research is necessary towards clinical use in cardiac disease.