Burst Emergence of Intracellular Ca ²⁺ Waves Evokes Arrhythmogenic Oscillatory Depolarization via the Na ⁺ –Ca ²⁺ Exchanger

Abstract

Abstract-Intracellular Ca 2ϩ waves (CaWs) of cardiomyocytes are spontaneous events of Ca 2ϩ release from the sarcoplasmic reticulum that are regarded as an important substrate for triggered arrhythmias and delayed afterdepolarizations. However, little is known regarding whether or how CaWs within the heart actually produce arrhythmogenic membrane oscillation because of the lack of data confirming direct correlation between CaWs and membrane potentials (V m ) in the heart. On the hypothesis that CaWs evoke arrhythmogenic oscillatory depolarization when they emerge synchronously and intensively in the heart, we conducted simultaneous fluorescence recording of intracellular Ca 2ϩ ([Ca 2ϩ ] i ) dynamics and V m of ventricular myocytes on subepicardial surfaces of Langendorff-perfused rat hearts using in situ dual-view, rapid-scanning confocal microscopy. In intact hearts loaded with fluo4/acetoxymethyl ester and RH237 under perfusion with cytochalasin D at room temperature, individual myocytes exhibited Ca 2ϩ transients and action potentials uniformly on ventricular excitation, whereas low-K ϩ -perfused (2.4 mmol/L) hearts exhibited CaWs sporadically between Ca 2ϩ transients without discernible membrane depolarization. Further [Ca 2ϩ ] i loading of the heart, produced by rapid pacing and addition of isoproterenol, evoked triggered activity and subsequent oscillatory V m , which are caused by burst emergence of CaWs in individual myocytes. Such arrhythmogenic membrane oscillation was abolished by ryanodine or the Na ϩ -Ca 2ϩ exchanger inhibitor SEA0400, indicating an essential role of CaWs and resultant Na ϩ -Ca 2ϩ exchanger-mediated depolarization in triggered activity. In summary, we demonstrate a mechanistic link between intracellular CaWs and arrhythmogenic oscillatory depolarizations in the heart. Our findings provide a cellular perspective on abnormal [Ca 2ϩ ] i handling in the genesis of triggered arrhythmias in the heart. (Circ Res. 2008;103:509-518.)Key Words: Ca 2ϩ wave Ⅲ delayed afterdepolarization Ⅲ triggered activity Ⅲ Na ϩ -Ca 2ϩ exchange Ⅲ confocal microscopy I ntracellular Ca 2ϩ waves (CaWs) in cardiomyocytes are wave-like propagation of spontaneous, local Ca 2ϩ -release events from the sarcoplasmic reticulum (SR) within the cells as a result of Ca 2ϩ overload. [1][2][3][4][5] Previous electrophysiological studies in isolated ventricular myocytes suggested that CaWs can evoke triggered arrhythmias by generating oscillatory depolarization via Ca 2ϩ -activated transient inward currents, 5 which consist of the Na ϩ -Ca 2ϩ exchanger (NCX) current 6,7 and other Ca 2ϩ -activated currents. 8,9 When the depolarized membrane potential (V m ) reaches the threshold of firing, myocytes exhibit nondriven action potentials (APs) and subsequent oscillations called triggered activity and delayed afterdepolarizations (DADs), respectively. 6,10 -12 Although extensive studies have been conducted on CaWs for their electrogenic and proarrhythmic potentials, most studies were focused on isolated cardiomyocytes or sma...

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

“…It is widely accepted that DADs are mediated by Ca waves (47)(48)(49)(50), in which spontaneous SR Ca release from a group of adjacent CRUs recruits neighboring CRUs to initiate a propagating wave (51,52). On the other hand, the simulations in Fig.…”

Evaluation of the effects of power-frequency magnetic fields on the electrical activity of cardiomyocytes differentiated from human induced pluripotent stem cells

“…Low-frequency EMFs were found to change intracellular calcium concentration levels and the frequency of calcium transients in nonhuman CMs. Based on the strong correlation between the results of intracellular calcium imaging and those of extracellular FP recordings (Fujiwara et al, 2008), MFs of 50 Hz at 400 mT might not affect intracellular calcium transients in hiPS-CMs. This discrepancy might be explained by interspecies differences described above.…”

Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue

“…Our major finding is that for a given diastolic Ca-voltage coupling gain, the most influential factors determining whether a DAD in tissue reaches the threshold to trigger an AP are the latency period variance determining the synchrony of cellular Ca waves in a region of tissue and the SR Ca load, with the number of Ca release sites producing a Ca wave playing a minor role. It has previously been shown in confocal imaging studies in intact rat ventricular muscle that isolated Ca waves in individual myocytes during slow pacing caused no detectable changes in membrane potential due to the source-sink mismatch, and only when the majority of myocytes developed Ca waves synchronously did detectable DADs and TA result (15,16). Here we show in simulated tissue that even when 100% of the myocytes in the tissue develop Ca transients after a paced beat, the synchronicity of Ca waves still remains a predominant factor determining whether the DAD reaches sufficient amplitude to trigger an AP.…”

“…Because each ventricular myocyte is coupled through gap junctions to an average of 11 other myocytes (14), a single myocyte exhibiting a Ca wave will be voltage-clamped by neighboring quiescent myocytes, attenuating the DAD amplitude by more than an order of magnitude. Only when a large number of myocytes in a region of tissue all develop Ca waves quasi-synchronously within an overlapping time window can the source-sink mismatch be overcome to generate a DAD of appreciable magnitude in the tissue (11)(12)(13)15,16). Thus, after rapid pacing in cardiac tissue, the timing of Ca waves (i.e., the latency period, defined as the time interval between the last paced Ca transient and the onset of a spontaneous diastolic Ca wave) (16,17) in populations of adjacent myocytes plays a key role.…”