Our findings provide a new mechanism for hypoosmotic-stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.
Heart failure is a highly prevalent syndrome of multiple etiologies and associated comorbidities, and aberrant intracellular Ca2+ homeostasis is a hallmark finding in heart failure patients. The cyclical changes in Ca2+ concentration within cardiomyocytes control cycles of cardiac contraction and relaxation, and dysregulation of Ca2+ handling processes leads to systolic dysfunction, diastolic dysfunction, and adverse remodeling. For this reason, greater understanding of Ca2+ handling mechanisms in heart failure is critical for selection of appropriate treatment strategies. In this review, we summarize the mechanisms of altered Ca2+ handling in two subsets of heart failure, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, and outline current and experimental treatments that target cardiomyocyte Ca2+ handling processes.
Aims Cardiovascular disease remains the greatest cause of mortality in Americans over 65. The stretch-activated Transient Receptor Potential Vanilloid-4 (TRPV4) ion channel is expressed in cardiomyocytes of the aged heart. This investigation tests the hypothesis that TRPV4 alters Ca2+ handling and cardiac function in response to increased ventricular preload and cardiomyocyte stretch. Methods and Results Left-ventricular maximal pressure (PMax) was monitored in isolated working hearts of Aged (24-27 months) mice following preload elevation from 5-20mmHg, with and without TRPV4 antagonist HC067047 (HC,1 µmol/L). In preload-responsive hearts, PMax prior to and immediately following preload elevation (i.e., Frank-Starling response) was similar between Aged and Aged+HC. Within 1 minute following preload elevation, Aged hearts demonstrated secondary PMax augmentation (Aged>Aged+HC) suggesting a role for stretch-activated TRPV4 in cardiac hypercontractility. However, after 20 minutes at 20mmHg Aged exhibited depressed PMax (Aged<Aged+HC) suggestive of TRPV4-dependent contractile dysfunction with sustained stretch. To examine stretch-induced Ca2+ homeostasis at the single-cell level, isolated cardiomyocytes were stretched 10-15% of slack length while measuring intracellular Ca2+ with fura-2. Uniaxial longitudinal stretch increased intracellular Ca2+ levels and triggered Ca2+ overload and terminal cellular contracture in Aged, but not Aged+HC. Preload elevation in hearts of young/middle-age (3-12 month) mice produced an initial PMax increase (Frank-Starling response) without secondary PMax augmentation, and cardiomyocyte stretch did not affect intracellular Ca2+ levels. Hearts of transgenic mice with cardiac-specific TRPV4 expression exhibited PMax similar to 3-12 month control mice prior to and immediately following preload elevation but displayed secondary PMax augmentation. Cardiomyocytes of mice with transgenic TRPV4 expression were highly sensitive to mechanical stimulation and exhibited elevated Ca2+ levels, Ca2+ overload, and terminal contracture upon cellular attachment and stretch. Conclusions TRPV4 contributes to a stretch-induced increase in cardiomyocyte Ca2+ and cardiac hypercontractility, yet sustained stretch leads to cardiomyocyte Ca2+ overload and contractile dysfunction in the aged heart.
Aims Cardiomyocyte Ca2+ homoeostasis is altered with ageing and predisposes the heart to Ca2+ intolerance and arrhythmia. Transient receptor potential vanilloid 4 (TRPV4) is an osmotically activated cation channel with expression in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in Ca2+ handling and arrhythmogenesis following ischaemia–reperfusion (I/R), a pathological scenario associated with osmotic stress. Methods and results Cardiomyocyte membrane potential was monitored prior to and following I/R in Langendorff-perfused hearts of Aged (19–28 months) male and female C57BL/6 mice ± TRPV4 inhibition (1 μM HC067047, HC). Diastolic resting membrane potential was similar between Aged and Aged HC at baseline, but following I/R Aged exhibited depolarized diastolic membrane potential vs. Aged HC. The effects of TRPV4 on cardiomyocyte Ca2+ signalling following I/R were examined in isolated hearts of Aged cardiac-specific GCaMP6f mice (±HC) using high-speed confocal fluorescence microscopy, with cardiomyocytes of Aged exhibiting an increased incidence of pro-arrhythmic Ca2+ signalling vs. Aged HC. In the isolated cell environment, cardiomyocytes of Aged responded to sustained hypoosmotic stress (250mOsm) with an increase in Ca2+ transient amplitude (fluo-4) and higher incidence of pro-arrhythmic diastolic Ca2+ signals vs. Aged HC. Intracardiac electrocardiogram measurements in isolated hearts following I/R revealed an increased arrhythmia incidence, an accelerated time to ventricular arrhythmia, and increased arrhythmia score in Aged vs. Aged HC. Aged exhibited depolarized resting membrane potential, increased pro-arrhythmic diastolic Ca2+ signalling, and greater incidence of arrhythmia when compared with Young (3–5 months). Conclusion TRPV4 contributes to pro-arrhythmic cardiomyocyte Ca2+ signalling, electrophysiological abnormalities, and ventricular arrhythmia in the aged mouse heart.
We have recently identified a critical role of mitochondria to shape intracellular Ca 2þ signals and to regulate cardiac rhythmicity. Activation of mitochondrial Ca 2þ uptake by efsevin, an agonist of the voltage-dependent anion channel 2 in the outer mitochondrial membrane, restored rhythmic cardiac contractions in a zebrafish cardiac arrhythmia model. Here we investigated the potential of pharmacological activation of mitochondrial Ca 2þ uptake as a novel pharmacological strategy for human cardiac arrhythmia in a translational approach. To this aim we first used a murine model of ryanodine receptor 2 (RyR2)-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). In freshly isolated cardiomyocytes of RyR2 R4496C/WT mice, harboring the human RyR2 R4496C mutation associated with CPVT, efsevin restricted diastolic Ca 2þ sparks and prevented the formation of propagating Ca 2þ waves and spontaneous, diastolic action potentials. This anti-arrhythmic effect was abolished in the presence of mitochondrial Ca 2þ uniporter (MCU) blocker Ru360 , but could be reproduced with the MCU activator kaempferol, demonstrating an immediate role of mitochondrial Ca 2þ uptake for the anti-arrhythmic effect of efsevin. In RyR2 R4496C/WT mice both mitochondrial Ca 2þ uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of ventricular tachycardia after catecholaminergic stimulation by a bolus injection of epinephrine and caffeine in vivo while baseline ECG was unaffected. Finally, we used stem cell-derived cardiomyocytes from a CPVT patient to show efficacy of MiCUps in a human model. Both MiCUps abolished arrhythmogenic events in human CPVT cardiomyocytes. Our results demonstrate that enhancement of mitochondrial Ca 2þ uptake by MiCUps is a promising pharmacological strategy for treatment and prevention of Ca 2þ -triggered arrhythmias, such as CPVT. The antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), has been associated with increased risk of sudden cardiac death. Epidemiological data from the Danish population suggest that in patients taking citalopram, co-administration of carvedilol reduced sudden death risk compared to two other beta-blockers, metoprolol and bisoprolol. Since carvedilol is the only beta blocker that suppresses store overloadinduced calcium release, we hypothesized that citalopram promotes calcium release from sarcoplasmic reticulum (SR) calcium stores. Left ventricular myocytes were isolated from black 6 mice, permeabilized, and loaded with the calcium indicator, Fluo-4. Incubation of citalopram or escitalopram (S-enantiomer) for 20 minutes significantly increased calcium wave frequency and decreased calcium wave amplitude in a dose-dependent manner. This response was more sensitive to escitalopram, indicating selectivity for the S-enantiomer in the high nanomolar range. At 30 mM, calcium waves were no longer evident, however cytosolic calcium was elevated approximately two-fold, indicating possible constitutive calcium release from the SR stores...
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