Calcium-Dependent Arrhythmogenic Foci Created by Weakly Coupled Myocytes in the Failing Heart

Abstract

Rationale Intercellular uncoupling and Ca mishandling can initiate triggered ventricular arrhythmias. Spontaneous Ca release activates inward current which depolarizes membrane potential (Vm) and can trigger action potentials in isolated myocytes. However, cell-cell coupling in intact hearts limits local depolarization and may protect hearts from this arrhythmogenic mechanism. Traditional optical mapping lacks the spatial resolution to assess coupling of individual myocytes. Objective We investigate local intercellular coupling in Ca-induced depolarization in intact hearts, using confocal microscopy to measure local Vm and intracellular [Ca2+] ([Ca]i) simultaneously. Methods and Results We used isolated Langendorff-perfused hearts from control (CTL) and HF mice (HF induced by trans-aortic constriction). In CTL hearts, 1.4 % of myocytes were poorly synchronized with neighboring cells and exhibited asynchronous Ca2+ transients (AS). These AS myocytes were much more frequent in HF (10.8% of myocytes, p<0.05 vs. CTL). Local Ca waves depolarized Vm in HF but not CTL hearts, suggesting weaker gap junction coupling in HF-AS vs. CTL-AS myocytes. Cell-cell coupling was assessed by calcein fluorescence recovery after photobleach (FRAP) during [Ca]i recording. All regions in CTL hearts exhibited faster calcein diffusion than in HF, with HF-AS myocyte being slowest. In HF-AS, enhancing gap junction conductance (with rotigaptide) increased coupling and suppressed Vm depolarization during Ca waves. Conversely, in CTL hearts, gap junction inhibition (carbenoxolone) decreased coupling and allowed Ca-wave-induced depolarizations. Synchronization of Ca wave initiation and triggered action potentials were observed in HF hearts and computational models. Conclusions Well-coupled CTL myocytes are effectively voltage-clamped during Ca waves, protecting the heart from triggered arrhythmias. Spontaneous Ca waves are much more common in HF myocytes and these AS myocytes are also poorly coupled, enabling local Ca-induced inward current of sufficient source strength to overcome a weakened current sink to depolarize Vm and trigger action potentials.

Enhancement of Cardiac Store Operated Calcium Entry (SOCE) within Novel Intercalated Disk Microdomains in Arrhythmic Disease

“…IDs are emerging as versatile signaling hubs involved in mechanical and electrical communication among adjacent cardiomyocytes, mechanosensing as well as cell proliferation and development 38–43 . Thus, segregation to the ID, a spatially distinct compartment from the ECC domain, may confer upon SOCE a privileged role in modulating cardiac myocyte signaling and function.…”

“…For example, SOCE-derived intracellular Ca 2+ could modulate cell-to-cell adhesion and electrical coupling through influencing functions of ID-residing proteins such as N-Cadherin, desmoplakin 5,30,44,45 and or Cx43 40,46–48 . SOCE could also play a role in the maintenance of the ID structure and function via regulation of protein synthesis, trafficking and targeting 3,38,49 .…”

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

“…Finally, a recent study from the Bers’ lab has also highlighted that in HF there is a much higher density of ‘Ca 2+ asynchronous’ myocytes that are poorly coupled to the surrounding myocardium. These poorly coupled myocytes may also contribute to initiating triggered activity ( Lang et al, 2017 ).…”

Quantitative systems models illuminate arrhythmia mechanisms in heart failure: Role of the Na+‐Ca2+‐Ca2+/calmodulin‐dependent protein kinase II‐reactive oxygen species feedback

“…In failing cardiac tissue, Lang et al observed a higher than normal (vs. nonfailing cardiac tissue) number of myocytes that did not synchronize with neighboring myocytes, and these asynchronous myocytes also often exhibited independent spontaneous Ca 2+ waves. While in normal well‐coupled tissue asynchronous Ca 2+ waves did not produce detectable depolarizations, poor electrical coupling between failing myocytes enabled local Ca 2+ ‐induced inward current of sufficient source strength to overcome a weakened current sink to depolarize the membrane potential in the actual myocyte exhibiting the Ca 2+ wave, and even depolarize nearby neighboring myocytes appreciably (Lang et al, ).…”