Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Abstract

BackgroundHeart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis.Methods and ResultsA model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol‐induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L‐type Ca2+ currents, increased Na+‐Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca2+ uniporter–specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+‐Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L‐type Ca2+ current, consistent with the experimental observations.ConclusionsMitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.

A Spatiotemporal Ventricular Myocyte Model Incorporating Mitochondrial Calcium Cycling

“…The overall ventricular myocyte model structure The spatiotemporal myocyte model ( Fig. 1 A) consists of a 3D coupled network of CRUs and mitochondria, modified from the model in our recent study (12), which contains 21,504 (64 Â 28 Â 12) CRUs and 5376 (64 Â 14 Â 6) mitochondria. These numbers can be changed for modeling different cell sizes.…”

“…1, B and C). The major improvements in the model from our previous study (12) are an incorporation of 1) a new, to our knowledge, stochastic MPTP gating model ( Fig. 1 F), a new, to our knowledge, model for mitochondrial Ca 2þ buffering, and simplified models for cytosolic ROS and ATP; 2) the MCU formulation by Williams et al (41) and the oxidized CaMKII signaling formulation by Foteinou et al (42) (Fig.…”

“…It has also been shown that mitochondrial depolarization and other metabolic stress affect the Ca 2þ cycling dynamics, including Ca 2þ spark (1,2), Ca 2þ alternans (3)(4)(5)(6)(7)(8), and spontaneous Ca 2þ release and waves (9,10). Mitochondrial depolarization and Ca 2þ cycling can also affect the action potential dynamics, such as promoting early afterdepolarizations (11,12), and lower membrane excitability by opening of K ATP channels (13)(14)(15) to promote arrhythmias or modulating the pacemaking activity of cardiomyocytes (16,17).…”

Role of mitochondrial Ca2+ homeostasis in cardiac muscles

“…It is well-documented that a dramatically increased mitochondrial Ca 2+ level (i.e., mitochondrial Ca 2+ overload) causes cardiac dysfunction, mainly via cardiomyocyte death in various animal disease models [9,11,[147][148][149]. There are at least two key mechanisms by which elevated [Ca 2+ ] m promotes cardiomyocyte dysfunction and/or death: 1) mitochondrial ROS generation and 2) mPTP opening.…”

“…For instance, cardiomyocyte-specific and inducible MCU deletion did not exhibit protective effects against surgical transverse aortic constriction [9,11], while pharmacological inhibition of MCU does provide some cardioprotective effects [153]. Xie and his colleagues used a non-ischemic heart failure model induced by hypertension resulting from unilateral nephrectomy, deoxycorticosterone acetate (DOCA) treatment, and addition of salt to drinking water and showed that cardiac mitochondria from this animal model has mitochondrial Ca 2+ overload and that pharmacological MCU inhibition or genetic MCU deletion protects the heart from early afterdepolarizations promoted by heart failure remodeling [148], though they used conventional MCU knockout mouse line [12] in this report. Elrod's group also showed that cardiomyocyte-specific and inducible NCLX deletion causes acute myocardial dysfunction and fulminant heart failure with a high incidence of sudden cardiac death [17].…”