Differential conditions for early after‐depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits

Abstract

Non-technical summary Long QT syndrome (LQTS) is a genetic disorder characterized by recurrent syncope and sudden cardiac death (SCD). Type 1 (LQT1) and Type 2 (LQT2) LQTS account for 90% of the genotyped mutations in patients with this disorder. These syndromes have been associated with different sympathetic modes for initiation of cardiac arrest. Using isolated cardiomyocytes and Langendorff-perfused hearts from transgenic rabbit models of LQT1 and LQT2, we have identified differential conditions and cellular mechanisms for the generation of early afterdepolarizations (EADs), abnormal depolarizations during the plateau and repolarization phase of action potentials and the hallmark of the arrhythmias in LQTS. These differences explain why different types of increased autonomic nervous system activity, i.e. sympathetic surge vs. high sympathetic tone, are associated with the initiation of polymorphic ventricular tachycardia in LQTS patients with different genetic background.Abstract Early after-depolarization (EAD), or abnormal depolarization during the plateau phase of action potentials, is a hallmark of long-QT syndrome (LQTS). More than 13 genes have been identified as responsible for LQTS, and elevated risks for EADs may depend on genotypes, such as exercise in LQT1 vs. sudden arousal in LQT2 patients. We investigated mechanisms underlying different high-risk conditions that trigger EADs using transgenic rabbit models of LQT1 and LQT2, which lack I Ks and I Kr (slow and fast components of delayed rectifying K + current), respectively. Single-cell patch-clamp studies show that prolongation of action potential duration (APD) can be further enhanced by lowering extracellular potassium concentration ([K + ] o ) from 5.4 to 3.6 mM. However, only LQT2 myocytes developed spontaneous EADs following perfusion with lower [K + ] o , while there was no EAD formation in littermate control (LMC) or LQT1 myocytes, although APDs were also prolonged in LMC myocytes and LQT1 myocytes. Isoprenaline (ISO) prolonged APDs and triggered EADs in LQT1 myocytes in the presence of lower [K + ] o . In contrast, continuous ISO perfusion diminished APD prolongation and reduced the incidence of EADs in LQT2 myocytes. These different effects of ISO on LQT1 and LQT2 were verified by optical mapping of the whole heart, suggesting that ISO-induced EADs are genotype specific. Further voltage-clamp studies revealed that ISO increases L-type calcium current (I Ca ) faster than I Ks (time constant 9.2 s for I Ca and 43.6 s for I Ks ), and computer simulation demonstrated a high-risk window of EADs in LQT2 during ISO perfusion owing to mismatch in the time courses of I Ca and I Ks , which may explain why a sympathetic surge rather than high sympathetic tone can be an effective trigger of EADs in LQT2 perfused hearts. In summary, EAD formation is genotype specific, such that EADs can be elicited in LQT2 myocytes simply by lowering [K + ] o , while LQT1 myocytes require sympathetic stimulation. Slower activation of I Ks than of I Ca by ISO may expla...

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

“…6 as well as previous experiments (sample voltage traces are shown in Fig. S3) (3,31,37). Note that in Fig.…”

Nonlinear and stochastic dynamics in the heart

“…EADs are often associated with life-threatening arrhythmias such as Torsade de Pointes in the setting of cardiac diseases [307–309], including acquired and congenital long QT syndromes [310, 311] and heart failure [312, 313]. EADs were identified more than a half century ago [307, 314, 315] and have been the subject of many experimental and computational studies.…”

“…Conversely, some drugs cause EADs without significantly prolonging APD. Figure 31a shows EADs recorded from a single myocyte isolated from the ventricles of a transgenic long QT rabbit [311], illustrating the voltage oscillations during the plateau phase. These oscillations eventually cease, allowing the myocyte to repolarize.…”

“…Action potentials recorded from a ventricular myocyte of transgenic long QT rabbit heart before (dashed) and after (solid) isoproterenol [311]. b .…”

A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias

“…Ventricular myocytes were isolated from the septal portions of hearts of 2-4-kg New Zealand White female rabbits as previously described (Liu et al, 2012). For peak and late I Na , myocytes were depolarized from a holding potential of 2120 mV to a test potential of 220 mV for 20 or 220 ms, respectively, at a frequency of 0.1 Hz.…”