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1.
Clin Pharmacol Ther ; 107(1): 102-111, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31709525

RESUMO

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.

2.
Biophys J ; 117(12): E1-E3, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31791548
3.
Phys Rev Lett ; 123(21): 218101, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31809131

RESUMO

We develop an iterated map model to describe the bifurcations and complex dynamics caused by the feedback between voltage and intracellular Ca^{2+} and Na^{+} concentrations in paced ventricular myocytes. Voltage and Ca^{2+} can form either a positive or a negative feedback loop, while voltage and Na^{+} form a negative feedback loop. Under certain diseased conditions, when the feedback between voltage and Ca^{2+} is positive, Hopf bifurcations occur, leading to periodic oscillatory behaviors. When this feedback is negative, period-doubling bifurcation routes to alternans and chaos occur.


Assuntos
Cálcio/metabolismo , Modelos Cardiovasculares , Miócitos Cardíacos/metabolismo , Sódio/metabolismo , Relógios Biológicos , Cátions Bivalentes/metabolismo , Cátions Monovalentes/metabolismo , Membrana Celular/metabolismo , Polaridade Celular , Retroalimentação Fisiológica , Ventrículos do Coração/citologia , Ventrículos do Coração/metabolismo , Potenciais da Membrana , Miócitos Cardíacos/citologia , Trocador de Sódio e Cálcio/metabolismo
4.
Circ Arrhythm Electrophysiol ; 12(12): e007571, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31838916

RESUMO

BACKGROUND: Long QT syndromes (LQTS) arise from many genetic and nongenetic causes with certain characteristic ECG features preceding polymorphic ventricular tachyarrhythmias (PVTs). However, how the many molecular causes result in these characteristic ECG patterns and how these patterns are mechanistically linked to the spontaneous initiation of PVT remain poorly understood. METHODS: Anatomic human ventricle and simplified tissue models were used to investigate the mechanisms of spontaneous initiation of PVT in LQTS. RESULTS: Spontaneous initiation of PVT was elicited by gradually ramping up ICa,L to simulate the initial phase of a sympathetic surge or by changing the heart rate, reproducing the different genotype-dependent clinical ECG features. In LQTS type 2 (LQT2) and LQTS type 3 (LQT3), T-wave alternans was observed followed by premature ventricular complexes (PVCs). Compensatory pauses occurred resulting in short-long-short sequences. As ICa,L increased further, PVT episodes occurred, always preceded by a short-long-short sequence. However, in LQTS type 1 (LQT1), once a PVC occurred, it always immediately led to an episode of PVT. Arrhythmias in LQT2 and LQT3 were bradycardia dependent, whereas those in LQT1 were not. In all 3 genotypes, PVCs always originated spontaneously from the steep repolarization gradient region and manifested on ECG as R-on-T. We call this mechanism R-from-T, to distinguish it from the classic explanation of R-on-T arrhythmogenesis in which an exogenous PVC coincidentally encounters a repolarizing region. In R-from-T, the PVC and the T wave are causally related, where steep repolarization gradients combined with enhanced ICa,L lead to PVCs emerging from the T wave. Since enhanced ICa,L was required for R-from-T to occur, suppressing window ICa,L effectively prevented arrhythmias in all 3 genotypes. CONCLUSIONS: Despite the complex molecular causes, these results suggest that R-from-T is likely a common mechanism for PVT initiation in LQTS. Targeting ICa,L properties, such as suppressing window ICa,L or preventing excessive ICa,L increase, could be an effective unified therapy for arrhythmia prevention in LQTS.

5.
Sci Rep ; 9(1): 14849, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619700

RESUMO

The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in transgenic rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn-1 + α2CLn-2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn-1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.

6.
Biophys J ; 117(12): 2349-2360, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623883

RESUMO

Intracellular calcium (Ca2+) cycling dynamics in cardiac myocytes are spatiotemporally generated by stochastic events arising from a spatially distributed network of coupled Ca2+ release units that interact with an intertwined mitochondrial network. In this study, we developed a spatiotemporal ventricular myocyte model that integrates mitochondria-related Ca2+ cycling components into our previously developed ventricular myocyte model consisting of a three-dimensional Ca2+ release unit network. Mathematical formulations of mitochondrial membrane potential, mitochondrial Ca2+ cycling, mitochondrial permeability transition pore stochastic opening and closing, intracellular reactive oxygen species signaling, and oxidized Ca2+/calmodulin-dependent protein kinase II signaling were incorporated into the model. We then used the model to simulate the effects of mitochondrial depolarization on mitochondrial Ca2+ cycling, Ca2+ spark frequency, and Ca2+ amplitude, which agree well with experimental data. We also simulated the effects of the strength of mitochondrial Ca2+ uniporters and their spatial localization on intracellular Ca2+ cycling properties, which substantially affected diastolic and systolic Ca2+ levels in the mitochondria but exhibited only a small effect on sarcoplasmic reticulum and cytosolic Ca2+ levels under normal conditions. We show that mitochondrial depolarization can cause Ca2+ waves and Ca2+ alternans, which agrees with previous experimental observations. We propose that this new, to our knowledge, spatiotemporal ventricular myocyte model, incorporating properties of mitochondrial Ca2+ cycling and reactive-oxygen-species-dependent signaling, will be useful for investigating the effects of mitochondria on intracellular Ca2+ cycling and action potential dynamics in ventricular myocytes.

7.
Heart Rhythm ; 16(4): 615-623, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30445170

RESUMO

BACKGROUND: The apamin-sensitive small-conductance calcium-activated K (SK) current IKAS modulates automaticity of the sinus node. IKAS blockade by apamin causes sinus bradycardia. OBJECTIVE: The purpose of this study was to test the hypothesis that IKAS modulates ventricular automaticity. METHODS: We tested the effects of apamin (100 nM) on ventricular escape rhythms in Langendorff-perfused rabbit ventricles with atrioventricular block (protocol 1) and on recorded transmembrane action potential of pseudotendons of superfused right ventricular endocardial preparations (protocol 2). RESULTS: All preparations exhibited spontaneous ventricular escape rhythms. In protocol 1, apamin decreased the atrial rate from 186.2 ± 18.0 bpm to 163.8 ± 18.7 bpm (N = 6; P = .006) but accelerated the ventricular escape rate from 51.5 ± 10.7 bpm to 98.2 ± 25.4 bpm (P = .031). Three preparations exhibited bursts of nonsustained ventricular tachycardia and pauses, resulting in repeated burst termination pattern. In protocol 2, apamin increased the ventricular escape rate from 70.2 ± 13.1 bpm to 110.1 ± 2.2 bpm (P = .035). Spontaneous phase 4 depolarization was recorded from the pseudotendons in 6 of 10 preparations at baseline and in 3 in the presence of apamin. There were no changes of phase 4 slope (18.37 ± 3.55 mV/s vs 18.93 ± 3.26 mV/s, N = 3; P = .231, ), but the threshold of phase 0 activation (mV) reduced from -67.97 ± 1.53 to -75.26 ± 0.28 (P = .034). Addition of JTV-519, a ryanodine receptor 2 stabilizer, in 5 preparations reduced escape rate back to baseline. CONCLUSION: Contrary to its bradycardic effect in the sinus node, IKAS blockade by apamin accelerates ventricular automaticity and causes repeated nonsustained ventricular tachycardia in normal ventricles. ryanodine receptor 2 blockade reversed the apamin effects on ventricular automaticity.

8.
Chaos ; 28(11): 113122, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30501225

RESUMO

Sudden cardiac death is known to be associated with dynamical instabilities in the heart, and thus control of dynamical instabilities is considered a potential therapeutic strategy. Different control methods were developed previously, including time-delayed feedback pacing control and constant diastolic interval pacing control. Experimental, theoretical, and simulation studies have examined the efficacy of these control methods in stabilizing action potential dynamics. In this study, we apply these control methods to control complex action potential (AP) dynamics under two diseased conditions: early repolarization syndrome and long QT syndrome, in which voltage-driven instabilities occur in the presence of short-term cardiac memory. In addition, we also develop a feedback pacing method to stabilize these instabilities. We perform theoretical analyses using iterated map models and carry out numerical simulations of AP models. We show that under the normal condition where the memory effect is minimal, all three methods can effectively control the action potential duration (APD) dynamics. Under the two diseased conditions where the memory effect is exacerbated, constant diastolic pacing control is least effective, while the feedback pacing control is most effective. Under a very strong memory effect, all three methods fail to stabilize the voltage-driven instabilities. The failure of effective control is due to memory and the all-or-none AP dynamics which results in very steep changes in APD.


Assuntos
Potenciais de Ação , Síndrome do QT Longo/fisiopatologia , Modelos Cardiovasculares , Miócitos Cardíacos/metabolismo , Animais , Humanos , Síndrome do QT Longo/patologia , Miócitos Cardíacos/patologia
9.
JCI Insight ; 3(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429367

RESUMO

The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (IKAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. IKAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (INa) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent IKAS blockade by apamin reduced J wave elevation and eliminated SVF. ß-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0°C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that IKAS activation contributes to the development of JWS in rabbit ventricles.


Assuntos
Arritmias Cardíacas/etiologia , Doença do Sistema de Condução Cardíaco/etiologia , Sistema de Condução Cardíaco , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Sódio/metabolismo , Animais , Feminino , Masculino , Potássio/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Coelhos , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , Síndrome , Taquicardia Ventricular/etiologia , Fibrilação Ventricular/etiologia
10.
PLoS Comput Biol ; 14(11): e1006382, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30475801

RESUMO

Early afterdepolarizations (EADs) are spontaneous depolarizations during the repolarization phase of an action potential in cardiac myocytes. It is widely known that EADs are promoted by increasing inward currents and/or decreasing outward currents, a condition called reduced repolarization reserve. Recent studies based on bifurcation theories show that EADs are caused by a dual Hopf-homoclinic bifurcation, bringing in further mechanistic insights into the genesis and dynamics of EADs. In this study, we investigated the EAD properties, such as the EAD amplitude, the inter-EAD interval, and the latency of the first EAD, and their major determinants. We first made predictions based on the bifurcation theory and then validated them in physiologically more detailed action potential models. These properties were investigated by varying one parameter at a time or using parameter sets randomly drawn from assigned intervals. The theoretical and simulation results were compared with experimental data from the literature. Our major findings are that the EAD amplitude and takeoff potential exhibit a negative linear correlation; the inter-EAD interval is insensitive to the maximum ionic current conductance but mainly determined by the kinetics of ICa,L and the dual Hopf-homoclinic bifurcation; and both inter-EAD interval and latency vary largely from model to model. Most of the model results generally agree with experimental observations in isolated ventricular myocytes. However, a major discrepancy between modeling results and experimental observations is that the inter-EAD intervals observed in experiments are mainly between 200 and 500 ms, irrespective of species, while those of the mathematical models exhibit a much wider range with some models exhibiting inter-EAD intervals less than 100 ms. Our simulations show that the cause of this discrepancy is likely due to the difference in ICa,L recovery properties in different mathematical models, which needs to be addressed in future action potential model development.


Assuntos
Simulação por Computador , Ventrículos do Coração/metabolismo , Modelos Biológicos , Miócitos Cardíacos/fisiologia , Potenciais de Ação , Humanos , Transporte de Íons
11.
Phys Rev E ; 97(4-1): 042414, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29758700

RESUMO

Excitable cells, such as cardiac myocytes, exhibit short-term memory, i.e., the state of the cell depends on its history of excitation. Memory can originate from slow recovery of membrane ion channels or from accumulation of intracellular ion concentrations, such as calcium ion or sodium ion concentration accumulation. Here we examine the effects of memory on excitation dynamics in cardiac myocytes under two diseased conditions, early repolarization and reduced repolarization reserve, each with memory from two different sources: slow recovery of a potassium ion channel and slow accumulation of the intracellular calcium ion concentration. We first carry out computer simulations of action potential models described by differential equations to demonstrate complex excitation dynamics, such as chaos. We then develop iterated map models that incorporate memory, which accurately capture the complex excitation dynamics and bifurcations of the action potential models. Finally, we carry out theoretical analyses of the iterated map models to reveal the underlying mechanisms of memory-induced nonlinear dynamics. Our study demonstrates that the memory effect can be unmasked or greatly exacerbated under certain diseased conditions, which promotes complex excitation dynamics, such as chaos. The iterated map models reveal that memory converts a monotonic iterated map function into a nonmonotonic one to promote the bifurcations leading to high periodicity and chaos.


Assuntos
Cardiopatias/patologia , Modelos Cardiovasculares , Dinâmica não Linear , Potenciais de Ação , Miócitos Cardíacos/patologia
12.
PLoS One ; 13(5): e0196714, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29715271

RESUMO

Multicellular spheroids generated through cellular self-assembly provide cytoarchitectural complexities of native tissue including three-dimensionality, extensive cell-cell contacts, and appropriate cell-extracellular matrix interactions. They are increasingly suggested as building blocks for larger engineered tissues to achieve shapes, organization, heterogeneity, and other biomimetic complexities. Application of these tissue culture platforms is of particular importance in cardiac research as the myocardium is comprised of distinct but intermingled cell types. Here, we generated scaffold-free 3D cardiac microtissue spheroids comprised of cardiac myocytes (CMs) and/or cardiac fibroblasts (CFs) and used them as building blocks to form larger microtissues with different spatial distributions of CMs and CFs. Characterization of fusing homotypic and heterotypic spheroid pairs revealed an important influence of CFs on fusion kinetics, but most strikingly showed rapid fusion kinetics between heterotypic pairs consisting of one CF and one CM spheroid, indicating that CMs and CFs self-sort in vitro into the intermixed morphology found in the healthy myocardium. We then examined electrophysiological integration of fused homotypic and heterotypic microtissues by mapping action potential propagation. Heterocellular elongated microtissues which recapitulate the disproportionate CF spatial distribution seen in the infarcted myocardium showed that action potentials propagate through CF volumes albeit with significant delay. Complementary computational modeling revealed an important role of CF sodium currents and the spatial distribution of the CM-CF boundary in action potential conduction through CF volumes. Taken together, this study provides useful insights for the development of complex, heterocellular engineered 3D tissue constructs and their engraftment via tissue fusion and has implications for arrhythmogenesis in cardiac disease and repair.


Assuntos
Potenciais de Ação/fisiologia , Fibroblastos/fisiologia , Coração/fisiologia , Miócitos Cardíacos/fisiologia , Esferoides Celulares/fisiologia , Animais , Técnicas de Cultura de Células/métodos , Matriz Extracelular/fisiologia , Miocárdio/citologia , Ratos , Ratos Sprague-Dawley , Engenharia Tecidual/métodos
13.
Circ Arrhythm Electrophysiol ; 11(6): e005414, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29769222

RESUMO

BACKGROUND: Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymorphic ventricular tachycardia (pVT). We investigated ionic mechanisms that underlie pVT in LQT1 using a transgenic rabbit model of LQT1. METHODS: Optical mapping, cellular patch clamping, and computer modeling were used to elucidate the mechanisms of EADs in transgenic LQT1 rabbits. RESULTS: The results showed that shorter action potential duration in the right ventricle (RV) was associated with focal activity during pVT initiation. RV cardiomyocytes demonstrated higher incidence of EADs under 50 nmol/L isoproterenol. Voltage-clamp studies revealed that the transient outward potassium current (Ito) magnitude was 28% greater in RV associated with KChiP2 but with no differences in terms of calcium-cycling kinetics and other sarcolemmal currents. Perfusing with the Ito blocker 4-aminopyridine changed the initial focal sites of pVT from the RV to the left ventricle, corroborating the role of Ito in pVT initiation. Computer modeling showed that EADs occur preferentially in the RV because of the larger conductance of the slow-inactivating component of Ito, which repolarizes the membrane potential sufficiently rapidly to allow reactivation of ICa,L before IKr has had sufficient time to activate. CONCLUSIONS: Ito heterogeneity creates both triggers and an arrhythmogenic substrate in LQT1. In the absence of IKs, Ito interactions with ICa,L and IKr promote EADs in the RV while prolonging action potential duration in the left ventricle. This heterogeneity of action potential enhances dispersion of refractoriness and facilitates conduction blocks that initiate pVTs.


Assuntos
Frequência Cardíaca , Ventrículos do Coração/metabolismo , Canal de Potássio KCNQ1/metabolismo , Potássio/metabolismo , Síndrome de Romano-Ward/metabolismo , Taquicardia Ventricular/metabolismo , Função Ventricular Direita , Potenciais de Ação , Animais , Animais Geneticamente Modificados , Sinalização do Cálcio , Simulação por Computador , Modelos Animais de Doenças , Feminino , Ventrículos do Coração/fisiopatologia , Canal de Potássio KCNQ1/genética , Masculino , Modelos Cardiovasculares , Mutação , Miócitos Cardíacos/metabolismo , Coelhos , Síndrome de Romano-Ward/genética , Síndrome de Romano-Ward/fisiopatologia , Taquicardia Ventricular/genética , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo
14.
J Am Heart Assoc ; 7(8)2018 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-29627768

RESUMO

BACKGROUND: Heart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis. METHODS AND RESULTS: A model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol-induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L-type Ca2+ currents, increased Na+-Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 µmol/L Ru360, a mitochondrial Ca2+ uniporter-specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+-Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L-type Ca2+ current, consistent with the experimental observations. CONCLUSIONS: Mitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.


Assuntos
Arritmias Cardíacas/etiologia , Cardiomiopatias/metabolismo , Ventrículos do Coração/metabolismo , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Modelos Animais de Doenças , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Trocador de Sódio e Cálcio/metabolismo
15.
J Physiol ; 596(8): 1341-1355, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29377142

RESUMO

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.


Assuntos
Síndrome do QT Longo/fisiopatologia , Potenciais de Ação , Animais , Eletrocardiografia , Modelos Cardiovasculares , Contração Miocárdica , Coelhos , Disfunção Ventricular/fisiopatologia
16.
J Mol Cell Cardiol ; 114: 288-299, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29217432

RESUMO

RATIONALE: The major role of a transverse-tubular (TT) network in a cardiac cell is to facilitate effective excitation-contraction coupling and signaling. The TT network structures are heterogeneous within a single cell, and vary between different types of cells and species. They are also remodeled in cardiac diseases. However, how different TT network structures predispose cardiac cells to arrhythmogenesis remains to be revealed. OBJECTIVE: To systematically investigate the roles of TT network structure and the underlying mechanisms in the genesis of intracellular calcium (Ca2+) alternans and triggered activity (TA). METHODS AND RESULTS: Based on recent experimental observations, different TT network structures, including uniformly and non-uniformly random TT distributions, were modeled in a cardiac cell model consisting of a three-dimensional network of Ca2+ release units (CRUs). Our simulations showed that both Ca2+ alternans and Ca2+ wave-mediated TA were promoted when the fraction of orphaned CRUs was in an intermediate range, but suppressed in cells exhibiting either well-organized TT networks or low TT densities. Ca2+ alternans and TA could be promoted by low TT densities when the cells were small or the CRU coupling was strong. Both alternans and TA occurred more easily in uniformly random TT networks than in non-uniformly random TT networks. Subcellular spatially discordant Ca2+ alternans was promoted by non-uniformly random TT networks but suppressed by increasing CRU coupling strength. These mechanistic insights provide a holistic understanding of the effects of TT network structure on the susceptibility to arrhythmogenesis. CONCLUSIONS: The TT network plays important roles in promoting Ca2+ alternans and TA, and different TT network structures may predispose cardiac cells differently to arrhythmogenesis.


Assuntos
Sinalização do Cálcio , Espaço Intracelular/metabolismo , Miócitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismo , Canais de Cálcio Tipo L/metabolismo , Tamanho Celular , Átrios do Coração/citologia , Ventrículos do Coração/citologia , Modelos Cardiovasculares , Trocador de Sódio e Cálcio/metabolismo
17.
Biophys J ; 112(9): 1949-1961, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28494965

RESUMO

Spontaneous calcium (Ca) waves in cardiac myocytes underlie delayed afterdepolarizations (DADs) that trigger cardiac arrhythmias. How these subcellular/cellular events overcome source-sink factors in cardiac tissue to generate DADs of sufficient amplitude to trigger action potentials is not fully understood. Here, we evaluate quantitatively how factors at the subcellular scale (number of Ca wave initiation sites), cellular scale (sarcoplasmic reticulum (SR) Ca load), and tissue scale (synchrony of Ca release in populations of myocytes) determine DAD features in cardiac tissue using a combined experimental and computational modeling approach. Isolated patch-clamped rabbit ventricular myocytes loaded with Fluo-4 to image intracellular Ca were rapidly paced during exposure to elevated extracellular Ca (2.7 mmol/L) and isoproterenol (0.25 µmol/L) to induce diastolic Ca waves and subthreshold DADs. As the number of paced beats increased from 1 to 5, SR Ca content (assessed with caffeine pulses) increased, the number of Ca wave initiation sites increased, integrated Ca transients and DADs became larger and shorter in duration, and the latency period to the onset of Ca waves shortened with reduced variance. In silico analysis using a computer model of ventricular tissue incorporating these experimental measurements revealed that whereas all of these factors promoted larger DADs with higher probability of generating triggered activity, the latency period variance and SR Ca load had the greatest influences. Therefore, incorporating quantitative experimental data into tissue level simulations reveals that increased intracellular Ca promotes DAD-mediated triggered activity in tissue predominantly by increasing both the synchrony (decreasing latency variance) of Ca waves in nearby myocytes and SR Ca load, whereas the number of Ca wave initiation sites per myocyte is less important.


Assuntos
Sinalização do Cálcio/fisiologia , Potenciais da Membrana/fisiologia , Miócitos Cardíacos/metabolismo , Compostos de Anilina , Animais , Arritmias Cardíacas/metabolismo , Cafeína/farmacologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Simulação por Computador , Corantes Fluorescentes , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Modelos Cardiovasculares , Miócitos Cardíacos/efeitos dos fármacos , Técnicas de Patch-Clamp , Coelhos , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Imagens com Corantes Sensíveis à Voltagem , Xantenos
18.
Phys Rev Lett ; 118(13): 138101, 2017 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-28409990

RESUMO

Excitable systems display memory, but how memory affects the excitation dynamics of such systems remains to be elucidated. Here we use computer simulation of cardiac action potential models to demonstrate that memory can cause dynamical instabilities that result in complex excitation dynamics and chaos. We develop an iterated map model that correctly describes these dynamics and show that memory converts a monotonic first return map of action potential duration into a nonmonotonic one, resulting in a period-doubling bifurcation route to chaos.


Assuntos
Potenciais de Ação , Coração/fisiologia , Simulação por Computador , Humanos , Memória , Dinâmica não Linear
20.
Proc Natl Acad Sci U S A ; 114(3): E270-E279, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28049836

RESUMO

Cardiac myocytes normally initiate action potentials in response to a current stimulus that depolarizes the membrane above an excitation threshold. Aberrant excitation can also occur due to spontaneous calcium (Ca2+) release (SCR) from intracellular stores after the end of a preceding action potential. SCR drives the Na+/Ca2+ exchange current inducing a "delayed afterdepolarization" that can in turn trigger an action potential if the excitation threshold is reached. This "triggered activity" is known to cause arrhythmias, but how it is initiated and terminated is not understood. Using computer simulations of a ventricular myocyte model, we show that initiation and termination are inherently random events. We determine the probability of those events from statistical measurements of the number of beats before initiation and before termination, respectively, which follow geometric distributions. Moreover, we elucidate the origin of randomness by a statistical analysis of SCR events, which do not follow a Poisson process observed in other eukaryotic cells. Due to synchronization of Ca2+ releases during the action potential upstroke, waiting times of SCR events after the upstroke are narrowly distributed, whereas SCR amplitudes follow a broad normal distribution with a width determined by fluctuations in the number of independent Ca2+ wave foci. This distribution enables us to compute the probabilities of initiation and termination of bursts of triggered activity that are maintained by a positive feedback between the action potential upstroke and SCR. Our results establish a theoretical framework for interpreting complex and varied manifestations of triggered activity relevant to cardiac arrhythmias.


Assuntos
Modelos Cardiovasculares , Miócitos Cardíacos/fisiologia , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Sinalização do Cálcio/fisiologia , Simulação por Computador , Fenômenos Eletrofisiológicos , Retroalimentação Fisiológica , Humanos , Canais Iônicos/fisiologia , Processos Estocásticos
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