Open AccessThe oral Ca/calmodulin‐dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure
Author(s) -
Mustroph Julian,
Drzymalski Marzena,
Baier Maria,
Pabel Steffen,
Biedermann Alexander,
Memmel Bernadette,
Durczok Melanie,
Neef Stefan,
Sag Can Martin,
Floerchinger Bernhard,
Rupprecht Leopold,
Schmid Christof,
Zausig York,
Bégis Guillaume,
Briand Veronique,
Ozoux MarieLaure,
Tamarelle Dorothee,
Ballet Veronique,
Janiak Philip,
Beauverger Philippe,
Maier Lars S.,
Wagner Stefan
Publication year - 2020
Publication title -
esc heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.787
H-Index - 25
ISSN - 2055-5822
DOI - 10.1002/ehf2.12895
Subject(s) - medicine , heart failure , ejection fraction , atrial fibrillation , cardiology , calsequestrin , endocrinology , ryanodine receptor , calcium
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' χ 2 test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608, P < 0.05, ' n − 1' χ 2 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 .