The link between abnormal calcium handling and electrical instability in acquired long QT syndrome - does calcium precipitate arrhythmic storms? (original) (raw)
Related papers
Circulation. Arrhythmia and electrophysiology, 2015
Background-Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca 2+-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source-sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias. Methods and Results-Optical maps of action potentials and Ca 2+-transients from Langendorff rabbit hearts were measured at low (150×150 μm 2 /pixel) and high (1.5×1.5 μm 2 /pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of I Kr (the rapid component of rectifying K + current), produced spontaneous Ca 2+-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca 2+waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca 2+elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca 2+ (40%-60% of peak-Ca 2+-transients), appeared first in small islands (0.5×0.5 mm 2) that enlarged and spread throughout the epicardium. Synchronous systolic Ca 2+elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca 2+-transient-durations and action potentialdurations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca 2+-dynamics (multiple chaotic Ca 2+-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca 2+-elevations and arrhythmias. Conclusions-The results indicate that systolic and diastolic Ca 2+-elevations emanate from sarcoplasmic reticulum Ca 2+release and systolic Ca 2+-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca 2+ , which overcomes source-sink mismatch to trigger arrhythmias in intact hearts.
2012
In numerous pathologies, spontaneous Ca 2+ release (SCR) emanating from the sarcoplasmic reticulum and occurring during the action potential (AP) plateau can drive voltage instability that initiates arrhythmias, but the direct interplay between SCRs and arrhythmogeneis has not been fully understood in bradycardia and in long QT type 2 (LQT2) models. Simultaneous optical measurement of intracellular Ca 2+ transient (Ca i T) and AP were performed in Langendorff-perfused rabbit hearts following AV node ablation. Bradycardia and/or LQT2 was/were induced and the spatial heterogeneity of intracellular Ca 2+ handling and its link to voltage dispersion were investigated. Upon switching from 120 to 50 beats/min, AP duration (APD) increased gradually with increasing occurrence of SCRs during the AP plateau (p<0.01, n=7). SCR was a) regionally heterogeneous, b) spatially correlated with APD prolongation, c) associated with enhanced dispersion of repolarization (DOR), d) reversed by pacing at 120 beats/min and e) suppressed with K201 (1µM) or flecainide (5µM), inhibitors of cardiac ryanodine receptors (RyR2) which reduced APD (p<0.01, n=5) and DOR (p<0.02, n=5). Western blots of Ca 2+ channels/transporters revealed intrinsic spatial distributions of Cav1.2α and NCX (but not RyR2, and SERCA2a) that correlate with the distribution of SCR and underlie the molecular mechanism responsible for SCRs.
The Journal of Physiology, 2002
The role of intracellular Ca 2+ (CaA) in triggering early afterdepolarizations (EADs), the origins of EADs and the mechanisms underlying Torsade de Pointes (TdP) were investigated in a model of long QT syndrome (Type 2). Perfused rabbit hearts were stained with RH327 and Rhod-2/AM to simultaneously map membrane potential (V m) and CaA with two photodiode arrays. The I Kr blocker E4031 (0.5 mM) together with 50 % reduction of [K + ] o and [Mg 2+ ] o elicited long action potentials (APs), V m oscillations on AP plateaux (EADs) then ventricular tachycardia (VT). Cryoablation of both ventricular chambers eliminated Purkinje fibres as sources of EADs. E4031 prolonged APs (0.28 to 2.3 s), reversed repolarization sequences (baseåapex) and enhanced repolarization gradients (30 to 230 ms, n = 12) indicating a heterogeneous distribution of I Kr. At low [K + ] o and [Mg 2+ ] o , E4031 elicited spontaneous CaAand V m spikes or EADs (3.5 ± 1.9 Hz) during the AP plateau (n = 6). EADs fired 'out-of-phase' from several sites, propagated, collided then evolved to TdP. Phase maps (CaAvs. V m) had counterclockwise trajectories shaped like a 'boomerang' during an AP and like ellipses during EADs, with V m preceding CaAby 9.2 ± 1.4 (n = 6) and 7.2 ± 0.6 ms (n = 5/6), respectively. After cryoablation, EADs from surviving epicardium (~1 mm) fired at the same frequency (3.4 ± 0.35 Hz, n = 6) as controls. At the origins of EADs, CaApreceded V m and phase maps traced clockwise ellipses. Away from EAD origins, V m coincided with or preceded CaA. In conclusion, overload elicits EADs originating from either ventricular or Purkinje fibres and 'out-of-phase' EAD activity from multiple sites generates TdP, evident in pseudo-ECGs.
Restitution of Ca2+ Release and Vulnerability to Arrhythmias
Journal of Cardiovascular Electrophysiology, 2006
Ca 2+ Release Restitution. New information has recently been obtained along two essentially parallel lines of research: investigations into the fundamental mechanisms of Ca 2+ -induced Ca 2+ release (CICR) in heart cells, and analyses of the factors that control the development of unstable rhythms such as repolariza-tion alternans. These lines of research are starting to converge such that we can begin to understand unstable and potentially arrhythmogenic cardiac dynamics in terms of the underlying mechanisms governing not only membrane depolarization and repolarization but also the complex bidirectional interactions between electrical and Ca 2+ signaling in heart cells. In this brief review, we discuss the progress that has recently been made in understanding the factors that control the beat-to-beat regulation of cardiac Ca 2+ release and attempt to place these results within a larger context. In particular, we discuss factors that may contribute to unstable Ca 2+ release and speculate about how instability in CICR may contribute to the development of arrhythmias under pathological conditions.
Physiological Research, 2016
We aimed to determine the impact of Ca 2+-related disorders induced in intact animal hearts on ultrastructure of the cardiomyocytes prior to occurrence of severe arrhythmias. Three types of acute experiments were performed that are known to be accompanied by disturbances in Ca 2+ handling. Langedorffperfused rat or guinea pig hearts subjected to K +-deficient perfusion to induce ventricular fibrillation (VF), burst atrial pacing to induce atrial fibrillation (AF) and open chest pig heart exposed to intramyocardial noradrenaline infusion to induce ventricular tachycardia (VT). Tissue samples for electron microscopic examination were taken during basal condition, prior and during occurrence of malignant arrhythmias. Cardiomyocyte alterations preceding occurrence of arrhythmias consisted of non-uniform sarcomere shortening, disruption of myofilaments and injury of mitochondria that most likely reflected cytosolic Ca 2+ disturbances and Ca 2+ overload. These disorders were linked with non-uniform pattern of neighboring cardiomyocytes and dissociation of adhesive junctions suggesting defects in cardiac cell-to-cell coupling. Our findings identified heterogeneously distributed high [Ca 2+ ]i-induced subcellular injury of the cardiomyocytes and their junctions as a common feature prior occurrence of VT, VF or AF. In conclusion, there is a link between Ca 2+-related disorders in contractility and coupling of the cardiomyocytes pointing out a novel paradigm implicated in development of severe arrhythmias.
Intracellular Ca 2+ Dynamics and the Stability of Ventricular Tachycardia
Biophysical Journal, 1999
Ventricular fibrillation (VF), the major cause of sudden cardiac death, is typically preceded by ventricular tachycardia (VT), but the mechanisms underlying the transition from VT to VF are poorly understood. Intracellular Ca 2ϩ overload occurs during rapid heart rates typical of VT and is also known to promote arrhythmias. We therefore studied the role of intracellular Ca 2ϩ dynamics in the transition from VT to VF, using a combined experimental and mathematical modeling approach. Our results show that 1) rapid pacing of rabbit ventricular myocytes at 35°C led to increased intracellular Ca 2ϩ levels and complex patterns of action potential (AP) configuration and the intracellular Ca 2ϩ transients; 2) the complex patterns of the Ca 2ϩ transient arose directly from the dynamics of intracellular Ca 2ϩ cycling, and were not merely passive responses to beat-to-beat alterations in AP; 3) the complex Ca 2ϩ dynamics were simulated in a modified version of the Luo-Rudy (LR) ventricular action potential with improved intracellular Ca 2ϩ dynamics, and showed good agreement with the experimental findings in isolated myocytes; and 4) when incorporated into simulated two-dimensional cardiac tissue, this action potential model produced a form of spiral wave breakup from VT to a VF-like state in which intracellular Ca 2ϩ dynamics played a key role through its influence on Ca 2ϩ -sensitive membrane currents such as I Ca , I NaCa , and I ns(Ca) . To the extent that spiral wave breakup is useful as a model for the transition from VT to VF, these findings suggest that intracellular Ca 2ϩ dynamics may play an important role in the destabilization of VT and its degeneration into VF.
Arrhythmia Genesis: Aberrations of Voltage or Ca2+ Cycling?
Heart Rhythm, 2006
In the normal cardiac beat, the firing of an action potential (AP) at the surface membrane elicits a rise of intracellular free Ca 2ϩ (Ca i ) that controls force generation and the subsequent removal of cytosolic Ca 2ϩ imparts a state of relaxation. Great strides have been accomplished in our understanding of the ionic basis of the AP and the mechanisms responsible for Ca 2ϩ cycling from beat-to-beat. The robust control of Ca 2ϩ cycling by the AP under a wide range of physiological conditions highlights the tight coupling between electrical impulses and contractions. While the firing of the AP triggers Ca 2ϩ release from the sarcoplasmic reticulum (SR) by Ca 2ϩ -induced Ca 2ϩ -release (CICR), the Ca 2ϩ transient modulates the shape and duration of the AP by modulating Ca-sensitive ion channels such as increasing the rate of inactivation of I Ca,L , modulating the sodium/calcium exchange current (I NCX ), activating Ca 2ϩsensitive Cl Ϫ channels (I Cl ) and indirectly by enhancing the delayed rectifying K ϩ currents (I Ks ) via Ca-calmodulin. The inter-dependence between the AP and Ca i implies that an understanding of arrhythmia mechanisms must consider the role of aberrations in Ca i cycling either as a trigger of arrhythmias or an influence on the perpetuation of arrhythmias.