Key result
Oral RA608 preserves LVEF by ~11 points and curbs arrhythmogenesis in HF mice.
Why the study?
Excessive CaMKII activation is critical in HF and AF, but clinical inhibitor development has been hindered by a lack of selectivity, specificity, and bioavailability.
Does the oral CaMKII inhibitor RA608 improve contractile function and prevent arrhythmias in preclinical models of heart failure?
Does the oral CaMKII inhibitor RA608 improve contractile function and prevent arrhythmias in preclinical models of heart failure?
RA608 is an orally available CaMKII inhibitor that demonstrates efficacy in improving contractile function and reducing arrhythmogenesis in preclinical models of heart failure.
RA608 benefits in mice should not change practice; leaves open whether CaMKII inhibition improves human heart failure outcomes.
Aims Excessive activation of Ca/calmodulin-dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKIIδ/CaMKIIɣ-selective, ATP-competitive, orally available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC). Methods and results In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 ± 3.7% (RA608) vs. 34.9 ± 2.6% (vehicle), n = 9 vs. n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKIIδ transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608, P < 0.05, 'n − 1' χ2 test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608, P < 0.05, 'n − 1' χ2 test. Conclusions RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in mice in vivo.
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Mustroph et al. (2020) studied Heart Failure and Atrial Fibrillation (n=119). RA608 vs. Vehicle was evaluated on Ejection fraction at 3 weeks after transverse aortic constriction (TAC) in mice (p=<0.05). Oral administration of RA608 prevented the deterioration of ejection fraction (46.1% vs 34.9%) and reduced arrhythmogenesis in mouse models of heart failure.
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