Action Potential Duration Dynamics Research Articles

Intracellular ion accumulation in the genesis of complex action potential dynamics under cardiac diseases.

Intracellular ions, including sodium (Na^{+}), calcium (Ca^{2+}), and potassium (K^{+}), etc., accumulate slowly after a change of the state of the heart, such as a change of the heart rate. The goal of this study is to understand the roles of slow ion accumulation in the genesis of cardiac memory and complex action-potential duration (APD) dynamics that can lead to lethal cardiac arrhythmias. We carry out numerical simulations of a detailed action potential model of ventricular myocytes under normal and diseased conditions, which exhibit memory effects and complex APD dynamics. We develop a low-dimensional iterated map (IM) model to describe the dynamics of Na^{+}, Ca^{2+}, and APD and use it to uncover the underlying dynamical mechanisms. The development of the IM model is informed by simulation results under the normal condition. We then use the IM model to perform linear stability analyses and computer simulations to investigate the bifurcations and complex APD dynamics, which depend on the feedback loops between APD and intracellular Ca^{2+} and Na^{+} concentrations and the steepness of the APD response to the ion concentrations. When the feedback between APD and Ca^{2+} concentration is positive, a Hopf bifurcation leading to periodic oscillatory behavior occurs as the steepness of the APD response to the ion concentrations increases. The negative feedback loop between APD and Na^{+} concentration is required for the Hopf bifurcation. When the feedback between APD and Ca^{2+} concentration is negative, period-doubling bifurcations leading to high periodicity and chaos occurs. In this case, Na^{+} accumulation plays little role in the dynamics. Finally, we carry out simulations of the detailed action potential model under two diseased conditions, which exhibit steep APD responses to ion concentrations. Under both conditions, Hopf bifurcations leading to slow oscillations or period-doubling bifurcations leading to high periodicity and chaotic APD dynamics occur, depending on the strength of the ion pump-Na^{+}-Ca^{2+} exchanger. Using functions reconstructed from the simulation data, the IM model accurately captures the bifurcations and dynamics under the two diseased conditions. In conclusion, besides using computer simulations of a detailed high-dimensional action-potential model to investigate the effects of slow ion accumulation and short-term memory on bifurcations and genesis of complex APD dynamics in cardiac myocytes under diseased conditions, this study also provides a low-dimensional mathematical tool, i.e., the IM model, to allow stability analyses for uncovering the underlying mechanisms.

Acute Effects of Ibrutinib on Ventricular Arrhythmia in Spontaneously Hypertensive Rats

BackgroundThe Bruton's Tyrosine Kinase Inhibitor ibrutinib is associated with ventricular arrhythmia (VA) and sudden death. However, the pro-arrhythmic electrophysiological dysregulation that results from ibrutinib with age and cardiovascular disease is unknown. ObjectivesThis study sought to investigate the acute effects of ibrutinib on left ventricular (LV) VA vulnerability, cytosolic calcium dynamics, and membrane electrophysiology in old and young spontaneous hypertensive rats (SHRs). MethodsLangendorff-perfused hearts of young (10 to 14 weeks) and old (10 to 14 months) SHRs were treated with ibrutinib (0.1 μmol/l) or vehicle for 30 min. Simultaneously, LV epicardial action potential and cytosolic calcium transients were optically mapped following an incremental pacing protocol. Calcium and action potential dynamics parameters were analyzed. VA vulnerability was assessed by electrically inducing ventricular fibrillations (VFs) in each heart. Western blot analysis was performed on LV tissues. ResultsIbrutinib treatment resulted in higher vulnerability to VF in old SHR hearts (27.5 ± 7.5% vs. 5.7 ± 3.7%; p = 0.026) but not in young SHR hearts (8.0 ± 4.9% vs. 0%; p = 0.193). In old SHR hearts, following ibrutinib treatment, action potential duration (APD) alternans (p = 0.008) and APD alternans spatial discordance (p = 0.027) were more prominent. Moreover, calcium transient duration 50 was longer (p = 0.032), calcium amplitude alternans ratio was significantly lower (p = 0.001), and time-to-peak of calcium amplitude was shorter (p = 0.037). In young SHR hearts, there were no differences in calcium and APD dynamics. ConclusionsIbrutinib-induced VA is associated with old age in SHR. Acute dysregulation of calcium and repolarization dynamics play important roles in ibrutinib-induced VF.

Small-conductance Ca2+-activated K+ channels promote J-wave syndrome and phase 2 reentry

Small-conductance Ca2+-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca2+ channels, yet how this colocalization affects cardiac arrhythmogenesis is unknown. The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca2+ channels in promoting J-wave syndrome and ventricular arrhythmias. We carried out computer simulations of single-cell and tissue models. SK channels in the model were assigned to preferentially sense Ca2+ in the bulk cytosol, subsarcolemmal space, or junctional cleft. When SK channels sense Ca2+ in the bulk cytosol, the SK current (ISK) rises and decays slowly during an action potential, the action potential duration (APD) decreases as the maximum conductance increases, no complex APD dynamics and phase 2 reentry canbe induced by ISK. When SK channels sense Ca2+ in the subsarcolemmal space or junctional cleft, ISK can rise and decay rapidly during an action potential in a spike-like pattern because of spiky Ca2+ transients in these compartments, which can cause spike-and-dome action potential morphology, APD alternans, J-wave elevation, and phase 2 reentry. Our results can account for the experimental finding that activation of ISK induced J-wave syndrome and phase 2 reentry in rabbit hearts. Colocalization of SK channels with L-type Ca2+ channels so that they preferentially sense Ca2+ in the subsarcolemmal or junctional space may result in a spiky ISK, which can functionally play a similar role of the transient outward K+ current in promoting J-wave syndrome and ventricular arrhythmias.

Restitution and Stability of Human Ventricular Action Potential at High and Variable Pacing Rate

Despite the key role of beat-to-beat action potential (AP) variability in the onset of ventricular arrhythmias at high pacing rate, the knowledge of the involved dynamics and of effective prognostic parameters is largely incomplete. Electrical restitution (ER), the way AP duration (APD) senses changes in preceding cycle length (CL), has been used to monitor transition to arrhythmias. The use of standard ER (sER), though, is controversial, not always suitable for in vivo and only rarely for clinical applications. By means of simulations on a human ventricular AP model, I investigate the dynamics of APD at high pacing rate under sinusoidally, saw-tooth, and randomly variable pacing CLs. AP sequences were compared in terms of beat-to-beat restitution (btb-ER) and of the collections of sER curves generated from each beat. A definition of APD stability is also proposed, based on successive APD changes introduced in an AP sequence by a premature beat. The explored CL range includes values leading to APD alternans under constant pacing. Three different types of response to CL variability were found, corresponding to progressively higher rate of beat-to-beat CL changes. Low rates (∼1 ms/beat) generate a btb-ER dominated by steady-state rate dependence of APD (type 1), intermediate rates (∼5 ms/beat) lead to a btb-ER similar to a single sER (type 2), and high rates (∼20 ms/beat) to hysteretic btb-ER under periodic pacing and to a vertically spread btb-ER in the case of random pacing (type 3). Stability of AP repolarization always increases with the rate of CL changes. Thus, rather than looking at sER slope, which requires additional interventions during the recording of cardiac electrical activity, this study provides rationale for the use of btb-ER representations as predictors of repolarization stability under extreme pacing conditions, known to be critical for the arrhythmia development.

Effects of antiarrhythmics and hypokalemia on the rate adaptation of cardiac repolarization

Objectives. In normal conditions, sudden heart rate acceleration provokes a rapid reduction in ventricular action potential duration (APD). The protracted APD rate adaptation favors early afterdepolarizations and precipitates arrhythmia. Nevertheless, it is uncertain as to whether the rate-dependent changes of ventricular repolarization can be adversely modified by arrhythmogenic drugs (quinidine and procainamide) and hypokalemia, in comparison to the agents with safe therapeutic profile, such as lidocaine. Design. The rate adaptation of QT interval and monophasic APD obtained from the left ventricular (LV) and the right ventricular (RV) epicardium was examined during rapid cardiac pacing applied in isolated, perfused guinea-pig heart preparations. Results. At baseline, an abrupt increase in cardiac activation rate was associated with a substantial reduction of the QT interval and ventricular APD in the first two cardiac cycles, which was followed by a gradual shortening of repolarization over subsequent pacing intervals. The time constants of the fast (τfast) and slow (τslow) components of the APD dynamics determined from a double exponential fit were longer in RV compared to LV chamber. Quinidine, procainamide, and hypokalemia prolonged ventricular repolarization and delayed the rate adaptation of the QT interval and APD in LV and RV, as evidenced by increased τfast and τslow values. In contrast, lidocaine had no effect on the dynamic changes of ventricular repolarization upon heart rate acceleration. Conclusions. The rate adaptation of ventricular repolarization is delayed by arrhythmogenic interventions, such as quinidine, procainamide, and hypokalemia, but not changed by lidocaine, a clinically safe antiarrhythmic agent.

Organization of ventricular fibrillation in the human heart: experiments and models

Sudden cardiac death is a major health problem in the industrialized world. The lethal event is typically ventricular fibrillation (VF), during which the co-ordinated regular contraction of the heart is overthrown by a state of mechanical and electrical anarchy. Understanding the excitation patterns that sustain VF is important in order to identify potential therapeutic targets. In this paper, we studied the organization of human VF by combining clinical recordings of electrical excitation patterns on the epicardial surface during in vivo human VF with simulations of VF in an anatomically and electrophysiologically detailed computational model of the human ventricles. We find both in the computational studies and in the clinical recordings that epicardial surface excitation patterns during VF contain around six rotors. Based on results from the simulated three-dimensional excitation patterns during VF, which show that the total number of electrical sources is 1.4 +/- 0.12 times greater than the number of epicardial rotors, we estimate that the total number of sources present during clinically recorded VF is 9.0 +/- 2.6. This number is approximately fivefold fewer compared with that observed during VF in dog and pig hearts, which are of comparable size to human hearts. We explain this difference by considering differences in action potential duration dynamics across these species. The simpler spatial organization of human VF has important implications for treatment and prevention of this dangerous arrhythmia. Moreover, our findings underline the need for integrated research, in which human-based clinical and computational studies complement animal research.

Pro-arrhythmic Effects Of Fibroblast-myocyte Coupling In Simulated Cardiac Tissue

Fibroblasts comprise the majority of non-cardiac cells in normal heart and mediate the structural remodeling underlying progressive fibrosis in cardiac diseases. Recent experimental studies have shown that fibroblasts can electronically couple to myocytes via gap junctions and alter myocyte electrophysiology. However, the implications for cardiac arrhythmias are incompletely understood. In this study, we used mathematical modeling and computer simulation to investigate how fibroblast-myocyte coupling affects the dynamics of action potential duration (APD), excitation-contraction coupling, and alternans. Our major findings are: 1) Fibroblast-myocyte coupling shortens APD when fibroblast membrane conductance is high and resting membrane potential is low, but prolongs APD for other choices of conductance and resting potential. 2) Depending on the membrane conductance and resting potential of fibroblasts, fibroblast-myocyte coupling can either promote or suppress APD alternans by steepening or flattening APD restitution. 3) When alternans is calcium-driven, fibroblast-myocyte coupling always promotes alternans, and can result in electromechanically discordant alternans. 4) In cardiac tissue, fibroblast-myocyte coupling slows conduction velocity and broadens its restitution, promoting spatially discordant alternans. Spatially discordant alternans can also arise from electromechanically concordant alternans and electromechanically discordant alternans in different regions of the tissue. In conclusion, fibroblast-myocyte coupling has multiple pro-arrhythmic effects on electrophysiological properties in cardiac tissue.

Altered Action Potential Dynamics in Electrically Remodeled Canine Atria Evidence for Altered Intracellular Ca2+ Handling

Electrical instability following sustained rapid excitation has been attributed to altered ion channels. Alterations of Ca(2+) handling could also contribute to abnormal dynamics of action potential, favoring the initiation and perpetuation of arrhythmia. Transmembrane action potentials and twitch force (TF) were recorded from normal (n=6) and remodeled (6-week atrial pacing at 400 beats/min, n=6) canine atria. When the cycle length (CL) was suddenly prolonged in normal atria, both TF and action potential duration (APD) increased on the first beat, and decreased subsequently. Opposite changes were observed with sudden CL shortening. These dynamics in both APD and TF were abolished by ryanodine, but augmented by cyclopiazonic acid, an inhibitor of the sarcoplasmic reticulum (SR) Ca(2+) pump. In remodeled atria (RA), dynamic changes in APD were also concordant with dynamic changes in TF. The transient increases in APD and TF were enhanced, and the transient decreases were reduced compared to normal atria. The maximal slopes of APD and TF restitution curves were flatter and the magnitude of alternans was reduced in RA. The protein expression of SR Ca(2+) ATPase and SR Ca(2+)-release channel in RA was significantly reduced. Altered Ca(2+) handling may underlie abnormal APD dynamics in RA.

Dynamic restitution of action potential duration during electrical alternans and ventricular fibrillation.

The restitution kinetics of action potential duration (APD) were investigated in paced canine Purkinje fibers (P; n = 9) and endocardial muscle (M; n = 9), in isolated, perfused canine left ventricles during ventricular fibrillation (VF; n = 4), and in endocardial muscle paced at VF cycle lengths (simulated VF; n = 4). Restitution was assessed with the use of two protocols: delivery of a single extrastimulus after a train of stimuli at cycle length = 300 ms (standard protocol), and fixed pacing at short cycle lengths (100-300 ms) that induced APD alternans (dynamic protocol). The dynamic protocol yielded a monotone increasing restitution function with a maximal slope of 1.13 +/- 0.13 in M and 1.14 +/- 0.17 in P. Iteration of this function reproduced the APD dynamics found experimentally, including persistent APD alternans. In contrast, the standard protocol yielded a restitution relation with a maximal slope of 0.57 +/- 0.18 in M and 0.84 +/- 0.20 in P, and iteration of this function did not reproduce the APD dynamics. During VF, the restitution kinetics at short diastolic interval were similar to those determined with the dynamic protocol (maximal slope: 1.72 +/- 0.47 in VF and 1.44 +/- 0.49 in simulated VF). Thus APD dynamics at short coupling intervals during fixed pacing and during VF were accounted for by the dynamic, but not the standard, restitution relation. These results provide further evidence for a strong relationship among the kinetics of electrical restitution, the occurrence of APD alternans, and complex APD dynamics during VF.