Diastolic dysfunction and arrhythmias caused by overexpression of CaMKIIδC can be reversed by inhibition of late Na+ current

Abstract

Transgenic (TG) Ca2+/calmodulin-dependent protein kinase II (CaMKII) δC mice develop systolic heart failure (HF). CaMKII regulates intracellular Ca2+ handling proteins as well as sarcolemmal Na+ channels. We hypothesized that CaMKII also contributes to diastolic dysfunction and arrhythmias via augmentation of the late Na+ current (late INa) in early HF (8-week-old TG mice). Echocardiography revealed severe diastolic dysfunction in addition to decreased systolic ejection fraction. Premature arrhythmogenic contractions (PACs) in isolated isometrically twitching papillary muscles only occurred in TG preparations (5 vs. 0, P < 0.05) which could be completely terminated when treated with the late INa inhibitor ranolazine (Ran, 5 μmol/L). Force–frequency relationships revealed significantly reduced twitch force amplitudes in TG papillary muscles. Most importantly, diastolic tension increased with raising frequencies to a greater extent in TG papillary muscles compared to WT specimen (at 10 Hz: 3.7 ± 0.4 vs. 2.5 ± 0.3 mN/mm2; P < 0.05). Addition of Ran improved diastolic dysfunction to 2.1 ± 0.2 mN/mm2 (at 10 Hz; P < 0.05) without negative inotropic effects. Mechanistically, the late INa was markedly elevated in myocytes isolated from TG mice and could be completely reversed by Ran. In conclusion, our results show for the first time that TG CaMKIIδC overexpression induces diastolic dysfunction and arrhythmogenic triggers possibly via an enhanced late INa. Inhibition of elevated late INa had beneficial effects on arrhythmias as well as diastolic function in papillary muscles from CaMKIIδC TG mice. Thus, late INa inhibition appears to be a promising option for diastolic dysfunction and arrhythmias in HF where CaMKII is found to be increased.

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

“…Elevated [Na + ] i , caused by increased persistent Na + current, is a hallmark of both animal models and human heart failure (18)(19)(20). In humans, some gain-of-function SCN5A mutations are associated with familial dilated cardiomyopathy.…”

Myocyte repolarization modulates myocardial function in aging dogs

“…The composition of the pipette solution was the following (in mM): 10 NaCl, 113 KCl, 0.5 MgCl2, 5 K2-ATP, 5.5 glucose, 10 HEPES, 10 EGTA, and 1 CaCl2 (pH 7.2 with KOH). INaL was studied in voltage-clamp mode (36,43,53). Myocytes were bathed with a modified Tyrode solution in which KCl was replaced with CsCl and 4 M nicardipine were added to block L-type Ca 2ϩ current.…”

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

“…48,53 Furthermore, inhibition of I Na,late by ranolazine reduces the incidence of DADs and prevents triggered activity. 16,48,[53][54][55] Delayed afterdepolarizations have been observed in several types of cardiac tissue, including both atrial and ventricular myocytes, where they can lead to triggered activity and tachyarrhythmias. 56 The second mechanism of arrhythmia in the heart is abnormal conduction and includes conduction block and reentry.…”

“…44,[66][67][68][69][70][71][72] I Na,late and CaMKII I Na,late is thought to be modulated in several ways, including by toxins (for example ATX-II), hypoxia, ischemia, reactive oxygen species, the expression of different channel subunits, and also CaMKII. 20,21,55,[73][74][75][76][77][78][79] Calmodulin-dependent protein kinase II is a signaling molecule, and the predominant isoform in the heart is CaMKIId c . It has been shown to be a key protein in the regulation of various aspects of cardiac excitation-contraction coupling.…”

“…87,88 Overexpression of CaMKIId c has been shown to cause arrhythmias, hypertrophy, and diastolic dysfunction, implying that CaMKII upregulation may play a significant role in the manifestation of cardiac pathologies and heart failure. 55,77,82,[89][90][91] There is extensive evidence that CaMKII phosphorylates the ryanodine receptor (RyR) at Ser 2815 , altering its open probability. 92 In particular, increased SR Ca 2þ leak via phosphorylated RyR is believed to be associated with heart failure, 81,[93][94][95][96][97] and CaMKII has been shown to mediate this increase in Ca 2þ leak.…”