The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
David S Rosenbaum - One of the best experts on this subject based on the ideXlab platform.
-
heart failure enhances susceptibility to arrhythmogenic cardiac Alternans
Heart Rhythm, 2009Co-Authors: Lance D Wilson, Kenneth R Laurita, Darwin Jeyaraj, Gregory S Hoeker, Tamer H Said, Matthew Gittinger, David S RosenbaumAbstract:Background Although heart failure (HF) is closely associated with susceptibility to sudden cardiac death (SCD), the mechanisms linking contractile dysfunction to cardiac electrical instability are poorly understood. Cardiac Alternans has also been closely associated with SCD, and has been linked to a mechanism for amplifying electrical heterogeneities in the heart. However, previous studies have focused on Alternans in normal rather than failing myocardium. Objective This study sought to investigate the hypothesis that HF enhances susceptibility to arrhythmogenic cardiac Alternans. Methods High-resolution transmural optical mapping was performed in canine wedge preparations from normal (n = 8) and HF (n = 8) hearts produced by rapid ventricular pacing. Results HF significantly ( P P P P P Conclusion Heart failure increases the susceptibility to arrhythmogenic cardiac Alternans, which arises from HF-induced impairment in calcium cycling.
-
cellular mechanisms of arrhythmogenic cardiac Alternans
Progress in Biophysics & Molecular Biology, 2008Co-Authors: Kenneth R Laurita, David S RosenbaumAbstract:Despite the strong association between mechanical dysfunction of the heart and sudden death due to arrhythmias, the causal relationship is not well understood. Cardiac Alternans has been linked to arrhythmogenesis and can be mediated by intracellular calcium handling. Given the integral role intracellular calcium plays in contractile function, calcium-mediated Alternans may represent an important mechanistic link between mechanical dysfunction and electrical instability. This relationship, however, is not well understood due to complex feedback between membrane currents, intracellular calcium, and contraction. This manuscript describes the cellular mechanisms of cardiac Alternans. Through several pathways, calcium transient Alternans is coupled to repolarization Alternans that can form a substrate for reentrant excitation. Abnormal intracellular calcium cycling, either impaired release or impaired reuptake of sarcoplasmic reticulum calcium, is a cellular mechanism of calcium transient Alternans. Thus, cardiac Alternans is an important mechanistic link between mechanical dysfunction and sudden cardiac death.
-
role of calcium cycling versus restitution in the mechanism of repolarization Alternans
Circulation Research, 2004Co-Authors: Etienne Pruvot, David S Rosenbaum, Rodolphe P Katra, Kenneth R LauritaAbstract:T-wave Alternans, a powerful marker of arrhythmic events, results from alternation in action potential duration (APD). The underlying cellular mechanism of APD Alternans is unknown but has been attributed to either intracellular calcium (Ca 2+ ) cycling or membrane ionic currents, manifested by a steep slope of cellular APD restitution. To address these mechanisms, high-resolution optical mapping techniques were used to measure action potentials and Ca 2+ transients simultaneously from hundreds of epicardial sites in the guinea pig model of pacing-induced T-wave Alternans (n=7). The pacing rates (ie, Alternans threshold) at which T-wave (369±11 bpm), APD (369±21 bpm), and Ca 2+ (371±29 bpm) Alternans first appeared were comparable. Importantly, the site of origin of APD Alternans and Ca 2+ Alternans consistently occurred together near the base of the left ventricle, not where APD restitution was steepest. In addition, APD and Ca 2+ Alternans were remarkably similar both spatially and temporally during discordant Alternans. In conclusion, the mechanism underlying T-wave Alternans in the intact heart is more closely associated with intracellular Ca 2+ cycling rather than APD restitution.
-
hysteresis effect implicates calcium cycling as a mechanism of repolarization Alternans
Circulation, 2003Co-Authors: Mariah L Walker, Xiaoping Wan, Glenn E Kirsch, David S RosenbaumAbstract:Background— T-wave Alternans is due to alternation of membrane repolarization at the cellular level and is a risk factor for sudden cardiac death. Recently, a hysteresis effect has been reported in patients whereby T-wave Alternans, once induced by rapid heart rate, persists even when heart rate is subsequently slowed. We hypothesized that Alternans hysteresis is an intrinsic property of cardiac myocytes, directly related to an underlying mechanism for repolarization Alternans that involves intracellular calcium cycling. Methods and Results— Stepwise pacing was used to induce Alternans in Langendorff-perfused guinea pig hearts from which optical action potentials were recorded simultaneously at 256 ventricular sites with voltage-sensitive dyes and in whole-cell patch-clamped cardiac myocytes treated with or without BAPTA-AM (1,2-bis[2-aminophenoxy]ethane-N,N,N′,N′-tetraacetic acid tetrakis [acetoxymethyl ester]). Alternans hysteresis was observed in every isolated heart: threshold heart rate for Alternans...
-
role of structural barriers in the mechanism of Alternans induced reentry
Circulation Research, 2000Co-Authors: Joseph M Pastore, David S RosenbaumAbstract:Abstract —Previously, using an animal model of T-wave Alternans in structurally normal myocardium, we demonstrated that repolarization can alternate with opposite phase between neighboring myocytes (ie, discordant Alternans), causing spatial dispersions of repolarization that form the substrate for functional block and reentrant ventricular fibrillation (VF). However, the mechanisms responsible for cellular discordant Alternans and its electrocardiographic manifestation (ie, T-wave Alternans) in patients with structural heart disease are unknown. We hypothesize that electrotonic uncoupling between neighboring regions of cells by a structural barrier (SB) is a mechanism for discordant Alternans. Using voltage-sensitive dyes, ventricular action potentials were recorded from 26 Langendorff-perfused guinea pig hearts in the absence (ie, control) and presence of an insulating SB produced by an epicardial laser lesion. Quantitative analysis of magnitude and phase of cellular Alternans revealed that in controls, action potential duration alternated in phase at all ventricular sites above a critical heart rate (269±17 bpm), ie, concordant Alternans. Also, above a faster critical heart rate threshold (335±24 bpm), action potential duration alternated with opposite phase between sites, ie, discordant Alternans. In contrast, only discordant but not concordant Alternans was observed in 80% of hearts with the SB, and discordant Alternans always occurred at a significantly slower heart rate (by 68±28 bpm) compared with controls. Therefore, the SB had a major effect on the Alternans–heart rate relation, which served to facilitate the development of discordant Alternans. Whether a SB was present or not, discordant Alternans produced considerable increases (by ≈170%) in the maximum spatial gradient of repolarization, which in turn formed the substrate for unidirectional block and reentry. However, by providing a structural anchor for stable reentry, discordant Alternans in the presence of a SB led most often to sustained monomorphic ventricular tachycardia rather than to VF, whereas in the absence of a SB discordant Alternans caused VF. SBs facilitate development of discordant Alternans between cells with different ionic properties by electrotonically uncoupling neighboring regions of myocardium. This may explain why arrhythmia-prone patients with structural heart disease exhibit T-wave Alternans at lower heart rates. These data also suggest a singular mechanism by which T-wave Alternans forms a substrate for initiation of both VF and sustained monomorphic ventricular tachycardia.
Zhilin Qu - One of the best experts on this subject based on the ideXlab platform.
-
mechanisms linking t wave Alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long qt syndrome
The Journal of Physiology, 2018Co-Authors: Gideon Koren, Xiaodong Huang, Bumrak Choi, Zhilin QuAbstract:KEY POINTS: T-wave Alternans (TWA) and T-wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD Alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD Alternans and chaos can exacerbate pre-existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in transgenic long QT rabbits show that PVC Alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. ABSTRACT: T-wave Alternans (TWA) and irregular beat-to-beat T-wave variability or T-wave lability (TWL), the ECG manifestations of action potential duration (APD) Alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization-mediated APD Alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD Alternans and chaos exacerbated pre-existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L , resulted in a tissue-scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate-induced PVC Alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions.
-
t tubule disruption promotes calcium Alternans in failing ventricular myocytes mechanistic insights from computational modeling
Journal of Molecular and Cellular Cardiology, 2015Co-Authors: Michael Nivala, James N. Weiss, Zhen Song, Zhilin QuAbstract:In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the mechanisms of TT disruption and other HF remodeling factors on Ca Alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in “orphaned” RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted Alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, Alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca Alternans; 2) for down-regulated SERCA, Alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca Alternans. In conclusion, the mechanisms of Ca Alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca Alternans by both mechanisms, which may contribute to Alternans at different stages of HF.
-
calcium Alternans in cardiac myocytes order from disorder
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Zhilin Qu, Michael Nivala, James N. WeissAbstract:Abstract Calcium Alternans is associated with T-wave Alternans and pulsus Alternans, harbingers of increased mortality in the setting of heart disease. Recent experimental, computational, and theoretical studies have led to new insights into the mechanisms of Ca Alternans, specifically how disordered behaviors dominated by stochastic processes at the subcellular level become organized into ordered periodic behaviors. In this article, we summarize the recent progress in this area, outlining a holistic theoretical framework in which the complex effects of Ca cycling proteins on Ca Alternans are linked to three key properties of the cardiac Ca cycling network: randomness, refractoriness, and recruitment. We also illustrate how this ‘3R theory’ can reconcile many seemingly contradictory experimental observations. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.
-
t wave Alternans and arrhythmogenesis in cardiac diseases
Frontiers in Physiology, 2010Co-Authors: Zhilin Qu, Alan Garfinkel, James N. WeissAbstract:T-wave Alternans, a manifestation of repolarization Alternans at the cellular level, is associated with lethal cardiac arrhythmias and sudden cardiac death. At the cellular level, several mechanisms can produce repolarization Alternans, including: 1) electrical restitution resulting from collective ion channel recovery, which usually occurs at fast heart rates but can also occur at normal heart rates when action potential is prolonged resulting in a short diastolic interval; 2) the transient outward current, which tends to occur at normal or slow heart rates; 3) the dynamics of early afterdepolarizations, which tends to occur during bradycardia; and 4) intracellular calcium cycling Alternans through its interaction with membrane voltage. In this review, we summarize the cellular mechanisms of Alternans arising from these different mechanisms, and discuss their roles in arrhythmogenesis in the setting of cardiac disease.
-
spark induced sparks as a mechanism of intracellular calcium Alternans in cardiac myocytes
Circulation Research, 2010Co-Authors: Robert J Rovetti, Alan Garfinkel, James N. Weiss, Zhilin QuAbstract:Rationale: Intracellular calcium (Ca) Alternans has been widely studied in cardiac myocytes and tissue, yet the underlying mechanism remains controversial. Objective: In this study, we used computational modeling and simulation to study how randomly occurring Ca sparks interact collectively to result in whole-cell Ca Alternans. Methods and Results: We developed a spatially distributed intracellular Ca cycling model in which Ca release units (CRUs) are locally coupled by Ca diffusion throughout the myoplasm and sarcoplasmic reticulum (SR) network. Ca sparks occur randomly in the CRU network when periodically paced with a clamped voltage waveform, but Ca Alternans develops as the pacing speeds up. Combining computational simulation with theoretical analysis, we show that Ca Alternans emerges as a collective behavior of Ca sparks, determined by 3 critical properties of the CRU network from which Ca sparks arise: “randomness” (of Ca spark activation), “refractoriness” (of a CRU after a Ca spark), and “recruit...
Richard J Cohen - One of the best experts on this subject based on the ideXlab platform.
-
predictive value of t wave Alternans for arrhythmic events in patients with congestive heart failure
The Lancet, 2000Co-Authors: Thomas Klingenheben, Ralph B Dagostino, Markus Zabel, Richard J Cohen, Stefan H HohnloserAbstract:Summary Measurement of microvolt level T-wave Alternans in the surface electrocardiogram is a novel way to assess the risk of ventricular arrhythmias. Seven tests of arrhythmic risk, including T-wave Alternans, were undertaken in 107 consecutive patients with congestive heart failure and no history of sustained ventricular arrhythmias; the patients were followed up for arrhythmic events during the next 18 months. Of the patients with events, 11 had positive and two indeterminate T-wave Alternans results; there were no arrhythmic events among patients with negative T-wave Alternans results. Of the seven tests, only T-wave Alternans was a significant (p=0·0036) and independent predictor of arrhythmic events.
-
t wave Alternans and dispersion of the qt interval as risk stratification markers in patients susceptible to sustained ventricular arrhythmias
American Journal of Cardiology, 1998Co-Authors: Antonis A Armoundas, David S Rosenbaum, Motohisa Osaka, Theofanie Mela, Jeremy N Ruskin, Hasan Garan, Richard J CohenAbstract:T-wave Alternans and QT dispersion were compared as predictors of the outcome of electrophysiologic study and arrhythmia-free survival in patients undergoing electrophysiologic evaluation. T-wave Alternans was a highly significant predictor of these 2 outcome variables, whereas QT dispersion was not.
-
electrical Alternans during rest and exercise as predictors of vulnerability to ventricular arrhythmias
American Journal of Cardiology, 1997Co-Authors: N Mark A Estes, Greg Michaud, Ferdinand J Venditti, Paul Albrecht, Douglas P. Zipes, David S Rosenbaum, Nabil Elsherif, Paul J Wang, Richard J CohenAbstract:This investigation was performed to evaluate the feasibility of detecting repolarization Alternans with the heart rate elevated with a bicycle exercise protocol. Sensitive spectral signal-processing techniques are able to detect beat-to-beat alternation of the amplitude of the T wave, which is not visible on standard electrocardiogram. Previous animal and human investigations using atrial or ventricular pacing have demonstrated that T-wave Alternans is a marker of vulnerability to ventricular arrhythmias. Using a spectral analysis technique incorporating noise reduction signal-processing software, we evaluated electrical Alternans at rest and with the heart rate elevated during a bicycle exercise protocol. In this study we defined optimal criteria for electrical Alternans to separate patients from those without inducible arrhythmias. Alternans and signal-averaged electrocardiographic results were compared with the results of vulnerability to ventricular arrhythmias as defined by induction of sustained ventricular tachycardia or fibrillation at electrophysiologic evaluation. In 27 patients Alternans recorded at rest and with exercise had a sensitivity of 89%, specificity of 75%, and overall clinical accuracy of 80% (p <0.003). In this patient population the signal-averaged electrocardiogram was not a significant predictor of arrhythmia vulnerability. This is the first study to report that repolarization Alternans can be detected with heart rate elevated with a bicycle exercise protocol. Alternans measured using this technique is an accurate predictor of arrhythmia inducibility.
-
predicting sudden cardiac death from t wave Alternans of the surface electrocardiogram promise and pitfalls
Journal of Cardiovascular Electrophysiology, 1996Co-Authors: S David M D Rosenbaum, Paul Albrecht, Richard J CohenAbstract:T Wave Alternans and Sudden Cardiac Death. Sudden cardiac death remains a preeminent public health problem. Despite advances in preventative treatment for patients known to be at risk, to date we have been able to identify, and thus treat, only a small minority of these patients. Therefore, there is a major need to develop noninvasive diagnostic technologies to identify patients at risk. Recent studies have demonstrated that measurement of microvolt-level T wave Alternans is a promising technique for the accurate identification of patients at risk for ventricular arrhythmias and sudden cardiac death. In this article, we review the clinical data establishing the relationship between microvolt T wave Alternans and susceptibility to ventricular arrhythmias. We also review the methods and technology that have been developed to measure microvolt levels of T wave Alternans noninvasively in broad populations of ambulatory patients. In particular, we examine techniques that permit the accurate measurement of T wave Alternans during exercise stress testing.
-
Predicting sudden cardiac death from T wave Alternans of the surface electrocardiogram: promise and pitfalls.
Journal of cardiovascular electrophysiology, 1996Co-Authors: David S Rosenbaum, Paul Albrecht, Richard J CohenAbstract:Sudden cardiac death remains a preeminent public health problem. Despite advances in preventative treatment for patients known to be at risk, to date we have been able to identify, and thus treat, only a small minority of these patients. Therefore, there is a major need to develop noninvasive diagnostic technologies to identify patients at risk. Recent studies have demonstrated that measurement of microvolt-level T wave Alternans is a promising technique for the accurate identification of patients at risk for ventricular arrhythmias and sudden cardiac death. In this article, we review the clinical data establishing the relationship between microvolt T wave Alternans and susceptibility to ventricular arrhythmias. We also review the methods and technology that have been developed to measure microvolt levels of T wave Alternans noninvasively in broad populations of ambulatory patients. In particular, we examine techniques that permit the accurate measurement of T wave Alternans during exercise stress testing.
Donald M. Bers - One of the best experts on this subject based on the ideXlab platform.
-
dynamical effects of calcium sensitive potassium currents on voltage and calcium Alternans
The Journal of Physiology, 2017Co-Authors: Matthew Kennedy, Donald M. Bers, Nipavan Chiamvimonvat, Daisuke SatoAbstract:Cardiac Alternans is a precursor to life-threatening arrhythmias. Alternans can be caused by instability of the membrane voltage (Vm), instability of the intracellular Ca (Cai) cycling, or both. Vm dynamics and Cai dynamics are coupled via Ca-sensitive currents. In cardiac myocytes, there are several Ca-sensitive potassium (K) currents such as the slowly activating delayed rectifier current (IKs) and the small conductance Ca-activated potassium (SK) current (ISK). However, the role of these currents in the development of arrhythmias is not well understood. In this study, we investigated how these currents affect voltage and Ca Alternans using a physiologically detailed computational model of the ventricular myocyte and mathematical analysis. We define the coupling between Vm and Cai cycling dynamics (Cai→Vm coupling) as positive (negative) when a larger Ca transient at a given beat prolongs (shortens) the action potential duration (APD) of that beat. While positive coupling predominates at baseline, increasing IKs and ISK promote negative Cai→Vm coupling at the cellular level. Specifically, when Alternans is Ca-driven, electromechanically (APD-Ca) concordant Alternans becomes electromechanically discordant Alternans as IKs or ISK increase. These cellular level dynamics lead to different types of spatially discordant Alternans in tissue. These findings help to shed light on the underlying mechanisms of cardiac Alternans especially when relative strength of these currents becomes larger under pathological conditions or drug administrations. This article is protected by copyright. All rights reserved
-
optical mapping of sarcoplasmic reticulum ca2 in the intact heart ryanodine receptor refractoriness during Alternans and fibrillation
Circulation Research, 2014Co-Authors: Lianguo Wang, Rachel C Myles, Nicole M De Jesus, Alex K P Ohlendorf, Donald M. Bers, Crystal M. RipplingerAbstract:Rationale: Sarcoplasmic reticulum (SR) Ca 2+ cycling is key to normal excitation-contraction coupling but may also contribute to pathological cardiac Alternans and arrhythmia. Objective: To measure intra-SR free [Ca 2+ ] ([Ca 2+ ] SR ) changes in intact hearts during Alternans and ventricular fibrillation (VF). Methods and Results: Simultaneous optical mapping of Vm (with RH237) and [Ca 2+ ] SR (with Fluo-5N AM) was performed in Langendorff-perfused rabbit hearts. Alternans and VF were induced by rapid pacing. SR Ca 2+ and action potential duration (APD) Alternans occurred in-phase, but SR Ca 2+ Alternans emerged first as cycle length was progressively reduced (217±10ms vs. 190±13ms, p 2+ Alternans, with SR Ca 2+ release Alternans routinely occurring without changes in diastolic [Ca 2+ ] SR . Sensitizing RyR with caffeine (200μM) significantly reduced the pacing threshold for both SR Ca 2+ and APD Alternans (188±15ms and 173±12ms, p 2+ Alternans, but not APD Alternans, the pacing threshold for discordance, or threshold for VF. During VF, [Ca 2+ ] SR was high, but RyR remained nearly continuously refractory, resulting in minimal SR Ca 2+ release throughout VF. Conclusions: In intact hearts RyR refractoriness initiates SR Ca 2+ release Alternans, that can be amplified by diastolic [Ca 2+ ] SR Alternans and lead to APD Alternans. Sensitizing RyR suppresses spatially concordant, but not discordant SR Ca 2+ and APD Alternans. Despite increased [Ca 2+ ] SR during VF, SR Ca 2+ release was nearly continuously refractory. This novel method provides insight into SR Ca 2+ handling during cardiac Alternans and arrhythmia.
-
optical mapping of sarcoplasmic reticulum ca2 in the intact heart ryanodine receptor refractoriness during Alternans and fibrillation
Circulation Research, 2014Co-Authors: Lianguo Wang, Rachel C Myles, Nicole M De Jesus, Alex K P Ohlendorf, Donald M. Bers, Crystal M. RipplingerAbstract:Rationale:Sarcoplasmic reticulum (SR) Ca2+ cycling is key to normal excitation–contraction coupling but may also contribute to pathological cardiac Alternans and arrhythmia. Objective:To measure intra-SR free [Ca2+] ([Ca2+]SR) changes in intact hearts during Alternans and ventricular fibrillation (VF). Methods and Results:Simultaneous optical mapping of Vm (with RH237) and [Ca2+]SR (with Fluo-5N AM) was performed in Langendorff-perfused rabbit hearts. Alternans and VF were induced by rapid pacing. SR Ca2+ and action potential duration (APD) Alternans occurred in-phase, but SR Ca2+ Alternans emerged first as cycle length was progressively reduced (217±10 versus 190±13 ms; P<0.05). Ryanodine receptor (RyR) refractoriness played a key role in the onset of SR Ca2+ Alternans, with SR Ca2+ release Alternans routinely occurring without changes in diastolic [Ca2+]SR. Sensitizing RyR with caffeine (200 μmol/L) significantly reduced the pacing threshold for both SR Ca2+ and APD Alternans (188±15 and 173±12 ms; P<0....
-
cardiac Alternans do not rely on diastolic sarcoplasmic reticulum calcium content fluctuations
Circulation Research, 2006Co-Authors: Eckard Picht, Jaime Desantiago, Lothar A Blatter, Donald M. BersAbstract:Cardiac Alternans are thought to be a precursor to life-threatening arrhythmias. Previous studies suggested that alterations in sarcoplasmic reticulum (SR) Ca 2+ content are either causative or not associated with myocyte Ca 2+ Alternans. However, those studies used indirect measures of SR Ca 2+ . Here we used direct continuous measurement of intra-SR free [Ca 2+ ] ([Ca 2+ ] SR ) (using Fluo5N) during frequency-dependent Ca 2+ Alternans in rabbit ventricular myocytes. We tested the hypothesis that alternating [Ca 2+ ] SR is required for Ca 2+ Alternans. Amplitudes of [Ca 2+ ] SR depletions alternated in phase with cytosolic Ca 2+ transients and contractions. Some cells showed clear alternation in diastolic [Ca 2+ ] SR during Alternans, with higher [Ca 2+ ] SR before the larger SR Ca 2+ releases. However, the extent of SR Ca 2+ release during the small beats was smaller than expected for the modest decrease in [Ca 2+ ] SR . In other cells, clear Ca 2+ Alternans was observed without alternations in diastolic [Ca 2+ ] SR . Additionally, alternating cells were observed, in which diastolic [Ca 2+ ] SR fluctuations occurred interspersed by depletions in which the amplitude was unrelated to the preceding diastolic [Ca 2+ ] SR . In all forms of Alternans, the SR Ca 2+ release rate was higher during large depletions than during small depletions. Although [Ca 2+ ] SR exerts major influence on SR Ca 2+ release, alternations in [Ca 2+ ] SR are not required for Ca 2+ Alternans to occur. Rather, it seems likely that some other factor, such as ryanodine receptor availability after a prior beat (eg, recovery from inactivation), is of greater importance in initiating frequency-induced Ca 2+ Alternans. However, once such a weak SR Ca 2+ release occurs, it can result in increased [Ca 2+ ] SR and further enhance SR Ca 2+ release at the next beat. In this way, diastolic [Ca 2+ ] SR Alternans can enhance frequency-induced Ca 2+ Alternans, even if they initiate by other means.
James N. Weiss - One of the best experts on this subject based on the ideXlab platform.
-
stochastic pacing reveals the propensity to cardiac action potential Alternans and uncovers its underlying dynamics
The Journal of Physiology, 2016Co-Authors: Yann Prudat, Roshni V Madhvani, Marina Angelini, Nils P Borgstom, Enno Lange, Hrayr S Karagueuzian, James N. Weiss, Riccardo Olcese, Alan Garfinkel, Jan KuceraAbstract:KEY POINTS: Beat-to-beat alternation (Alternans) of the cardiac action potential duration is known to precipitate life-threatening arrhythmias and can be driven by the kinetics of voltage-gated membrane currents or by instabilities in intracellular calcium fluxes. To prevent Alternans and associated arrhythmias, suitable markers must be developed to quantify the susceptibility to Alternans; previous theoretical studies showed that the eigenvalue of the alternating eigenmode represents an ideal marker of Alternans. Using rabbit ventricular myocytes, we show that this eigenvalue can be estimated in practice by pacing these cells at intervals varying stochastically. We also show that stochastic pacing permits the estimation of further markers distinguishing between voltage-driven and calcium-driven Alternans. Our study opens the perspective to use stochastic pacing during clinical investigations and in patients with implanted pacing devices to determine the susceptibility to, and the type of Alternans, which are both important to guide preventive or therapeutic measures. ABSTRACT: Alternans of the cardiac action potential (AP) duration (APD) is a well-known arrhythmogenic mechanism. APD depends on several preceding diastolic intervals (DIs) and APDs, which complicates the prediction of Alternans. Previous theoretical studies pinpointed a marker called λalt that directly quantifies how an alternating perturbation persists over successive APs. When the propensity to Alternans increases, λalt decreases from 0 to -1. Our aim was to quantify λalt experimentally using stochastic pacing and to examine whether stochastic pacing allows discriminating between voltage-driven and Ca(2+) -driven Alternans. APs were recorded in rabbit ventricular myocytes paced at cycle lengths (CLs) decreasing progressively and incorporating stochastic variations. Fitting APD with a function of two previous APDs and CLs permitted us to estimate λalt along with additional markers characterizing whether the dependence of APD on previous DIs or CLs is strong (typical for voltage-driven Alternans) or weak (Ca(2+) -driven Alternans). During the recordings, λalt gradually decreased from around 0 towards -1. Intermittent Alternans appeared when λalt reached -0.8 and was followed by sustained Alternans. The additional markers detected that Alternans was Ca(2+) driven in control experiments and voltage driven in the presence of ryanodine. This distinction could be made even before Alternans was manifest (specificity/sensitivity >80% for -0.4 > λalt > -0.5). These observations were confirmed in a mathematical model of a rabbit ventricular myocyte. In conclusion, stochastic pacing allows the practical estimation of λalt to reveal the onset of Alternans and distinguishes between voltage-driven and Ca(2+) -driven mechanisms, which is important since these two mechanisms may precipitate arrhythmias in different manners.
-
t tubule disruption promotes calcium Alternans in failing ventricular myocytes mechanistic insights from computational modeling
Journal of Molecular and Cellular Cardiology, 2015Co-Authors: Michael Nivala, James N. Weiss, Zhen Song, Zhilin QuAbstract:In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the mechanisms of TT disruption and other HF remodeling factors on Ca Alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in “orphaned” RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted Alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, Alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca Alternans; 2) for down-regulated SERCA, Alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca Alternans. In conclusion, the mechanisms of Ca Alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca Alternans by both mechanisms, which may contribute to Alternans at different stages of HF.
-
calcium Alternans in cardiac myocytes order from disorder
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Zhilin Qu, Michael Nivala, James N. WeissAbstract:Abstract Calcium Alternans is associated with T-wave Alternans and pulsus Alternans, harbingers of increased mortality in the setting of heart disease. Recent experimental, computational, and theoretical studies have led to new insights into the mechanisms of Ca Alternans, specifically how disordered behaviors dominated by stochastic processes at the subcellular level become organized into ordered periodic behaviors. In this article, we summarize the recent progress in this area, outlining a holistic theoretical framework in which the complex effects of Ca cycling proteins on Ca Alternans are linked to three key properties of the cardiac Ca cycling network: randomness, refractoriness, and recruitment. We also illustrate how this ‘3R theory’ can reconcile many seemingly contradictory experimental observations. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.
-
t wave Alternans and arrhythmogenesis in cardiac diseases
Frontiers in Physiology, 2010Co-Authors: Zhilin Qu, Alan Garfinkel, James N. WeissAbstract:T-wave Alternans, a manifestation of repolarization Alternans at the cellular level, is associated with lethal cardiac arrhythmias and sudden cardiac death. At the cellular level, several mechanisms can produce repolarization Alternans, including: 1) electrical restitution resulting from collective ion channel recovery, which usually occurs at fast heart rates but can also occur at normal heart rates when action potential is prolonged resulting in a short diastolic interval; 2) the transient outward current, which tends to occur at normal or slow heart rates; 3) the dynamics of early afterdepolarizations, which tends to occur during bradycardia; and 4) intracellular calcium cycling Alternans through its interaction with membrane voltage. In this review, we summarize the cellular mechanisms of Alternans arising from these different mechanisms, and discuss their roles in arrhythmogenesis in the setting of cardiac disease.
-
spark induced sparks as a mechanism of intracellular calcium Alternans in cardiac myocytes
Circulation Research, 2010Co-Authors: Robert J Rovetti, Alan Garfinkel, James N. Weiss, Zhilin QuAbstract:Rationale: Intracellular calcium (Ca) Alternans has been widely studied in cardiac myocytes and tissue, yet the underlying mechanism remains controversial. Objective: In this study, we used computational modeling and simulation to study how randomly occurring Ca sparks interact collectively to result in whole-cell Ca Alternans. Methods and Results: We developed a spatially distributed intracellular Ca cycling model in which Ca release units (CRUs) are locally coupled by Ca diffusion throughout the myoplasm and sarcoplasmic reticulum (SR) network. Ca sparks occur randomly in the CRU network when periodically paced with a clamped voltage waveform, but Ca Alternans develops as the pacing speeds up. Combining computational simulation with theoretical analysis, we show that Ca Alternans emerges as a collective behavior of Ca sparks, determined by 3 critical properties of the CRU network from which Ca sparks arise: “randomness” (of Ca spark activation), “refractoriness” (of a CRU after a Ca spark), and “recruit...