The oral Ca/calmodulin-dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure.

ESC Heart Failure
J MustrophS Wagner

Abstract

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). 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 significan...Continue Reading

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Citations

Feb 18, 2021·Circulation Research·Julian MustrophStefan Wagner
Jun 19, 2021·Frontiers in Molecular Biosciences·Yingjie YangYaozu Xiang
Jul 25, 2021·International Journal of Molecular Sciences·Natthaphat Siri-AngkulJudith K Gwathmey

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Methods Mentioned

BETA
transgenic
biopsies
electrophoresis
force measurements
chromosomal aberrations

Software Mentioned

LabChart Pro
GraphPad Prism
SAS
WinNonlin
Analyst
GraphPad

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