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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2019)

Arrhythmias and sudden cardiac death (SCD) represent a leading cause of mortality in the US and worldwide. Currently, the most effective therapy for preventing SCD is the implantable cardioverter-defibrillator (ICD). ICDs however can only terminate arrhythmias after they have already occurred and have numerous severe side effects and poor cost-effectiveness. Therefore, the ideal anti-arrhythmic strategy is the prevention of arrhythmia initiation, or arrhythmogenesis, in the first place. Unfortunately, multiple clinical trials have demonstrated that many of the currently available anti-arrhythmic drugs are not generally effective in the prevention of ventricular arrhythmias, and in some cases may even be pro-arrhythmic unintuitively causing increased mortality. Thus, improved anti-arrhythmic strategies are needed which require improved mechanistic understanding of the arrhythmogenesis process.

Computational modeling is a powerful research tool, complementary to experimental and clinical studies, to study the underlying mechanisms of arrhythmias. In this dissertation, we use computer modeling and patch clamp experiments to investigate the spontaneous initiation of triggered and reentrant ventricular arrhythmias as related to delayed afterdepolarizations (DADs) and long QT syndrome (LQTS). We first describe a dynamical threshold for DAD-mediated triggered activity which is lower than the sodium channel threshold and manifests under conditions of hypokalemia and slow spontaneous calcium release. Next, we investigate the critical factors that determine DAD-mediated triggered activity formation in cardiac tissue. Thirdly, we study whether sub-threshold DADs can act as an arrhythmogenic trigger and find that DADs can generate both triggers and a reentry substrate simultaneously. And finally, we detail a novel common mechanism of arrhythmia initiation across different genotypes of LQTS called “R-from-T”, which blurs the usual notions between arrhythmia trigger and substrate beyond the traditional paradigm. The mechanistic insights gained from these studies help inform the development of new arrhythmia prevention strategies.

  • 10 supplemental videos
Cover page: Multiscale Modeling of Cardiac Arrhythmogenesis: Beyond the Trigger-Substrate Paradigm
  • Article
  • Peer Reviewed
UCLA Previously Published Works (2018)
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.
    Cover page: Transverse tubular network structures in the genesis of intracellular calcium alternans and triggered activity in cardiac cells
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2016)
    Intracellular calcium (Ca2+) alternans is a dynamical phenomenon in ventricular myocytes, which is linked to the genesis of lethal arrhythmias. Iterated map models of intracellular Ca2+ cycling dynamics in ventricular myocytes under periodic pacing have been developed to study the mechanisms of Ca2+ alternans. Two mechanisms of Ca2+ alternans have been demonstrated in these models: one relies mainly on fractional sarcoplasmic reticulum Ca2+ release and uptake, and the other on refractoriness and other properties of Ca2+ sparks. Each of the two mechanisms can partially explain the experimental observations, but both have their inconsistencies with the experimental results. Here we developed an iterated map model that is composed of two coupled iterated maps, which unifies the two mechanisms into a single cohesive mathematical framework. The unified theory can consistently explain the seemingly contradictory experimental observations and shows that the two mechanisms work synergistically to promote Ca2+ alternans. Predictions of the theory were examined in a physiologically-detailed spatial Ca2+ cycling model of ventricular myocytes.
      Cover page: A unified theory of calcium alternans in ventricular myocytes
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2021)
      QT prolongation, due to lengthening of the action potential duration in the ventricles, is a major risk factor of lethal ventricular arrhythmias. A widely known consequence of QT prolongation is the genesis of early afterdepolarizations (EADs), which are associated with arrhythmias through the generation of premature ventricular complexes (PVCs). However, the vast majority of the EADs observed experimentally in isolated ventricular myocytes are phase-2 EADs, and whether phase-2 EADs are mechanistically linked to PVCs in cardiac tissue remains an unanswered question. In this study, we investigate the genesis of PVCs using computer simulations with eight different ventricular action potential models of various species. Based on our results, we classify PVCs as arising from two distinct mechanisms: repolarization gradient (RG)-induced PVCs and phase-2 EAD-induced PVCs. The RG-induced PVCs are promoted by increasing RG and L-type calcium current and are insensitive to gap junction coupling. EADs are not required for this PVC mechanism. In a paced beat, a single or multiple PVCs can occur depending on the properties of the RG. In contrast, phase-2 EAD-induced PVCs occur only when the RG is small and are suppressed by increasing RG and more sensitive to gap junction coupling. Unlike with RG-induced PVCs, in each paced beat, only a single EAD-induced PVC can occur no matter how many EADs in an action potential. In the wide parameter ranges we explore, RG-induced PVCs can be observed in all models, but the EAD-induced PVCs can only be observed in five of the eight models. The links between these two distinct PVC mechanisms and arrhythmogenesis in animal experiments and clinical settings are discussed.
        Cover page: Mechanisms of Premature Ventricular Complexes Caused by QT Prolongation
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2015)

        Background

        Delayed afterdepolarizations (DADs) have been well characterized as arrhythmia triggers, but their role in generating a tissue substrate vulnerable to reentry is not well understood.

        Objective

        The purpose of this study was to test the hypothesis that random DADs can self-organize to generate both an arrhythmia trigger and a vulnerable substrate simultaneously in cardiac tissue as a result of gap junction coupling.

        Methods

        Computer simulations in 1-dimensional cable and 2-dimensional tissue models were performed. The cellular DAD amplitude was varied by changing the strength of sarcoplasmic reticulum calcium release. Random DAD latency and amplitude in different cells were simulated using gaussian distributions.

        Results

        Depending on the strength of spontaneous sarcoplasmic reticulum calcium release and other conditions, random DADs in cardiac tissue resulted in the following behaviors: (1) triggered activity (TA); (2) a vulnerable tissue substrate causing unidirectional conduction block and reentry by inactivating sodium channels; (3) both triggers and a vulnerable substrate simultaneously by generating TA in regions next to regions with subthreshold DADs susceptible to unidirectional conduction block and reentry. The probability of the latter 2 behaviors was enhanced by reduced sodium channel availability, reduced gap junction coupling, increased tissue heterogeneity, and less synchronous DAD latency.

        Conclusion

        DADs can self-organize in tissue to generate arrhythmia triggers, a vulnerable tissue substrate, and both simultaneously. Reduced sodium channel availability and gap junction coupling potentiate this mechanism of arrhythmias, which are relevant to a variety of heart disease conditions.
          Cover page: Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2016)
          Ventricular myocytes are excitable cells whose voltage threshold for action potential (AP) excitation is ∼-60 mV at which INa is activated to give rise to a fast upstroke. Therefore, for a short stimulus pulse to elicit an AP, a stronger stimulus is needed if the resting potential lies further away from the INa threshold, such as in hypokalemia. However, for an AP elicited by a long duration stimulus or a diastolic spontaneous calcium release, we observed that the stimulus needed was lower in hypokalemia than in normokalemia in both computer simulations and experiments of rabbit ventricular myocytes. This observation provides insight into why hypokalemia promotes calcium-mediated triggered activity, despite the resting potential lying further away from the INa threshold. To understand the underlying mechanisms, we performed bifurcation analyses and demonstrated that there is a dynamical threshold, resulting from a saddle-node bifurcation mainly determined by IK1 and INCX. This threshold is close to the voltage at which IK1 is maximum, and lower than the INa threshold. After exceeding this dynamical threshold, the membrane voltage will automatically depolarize above the INa threshold due to the large negative slope of the IK1-V curve. This dynamical threshold becomes much lower in hypokalemia, especially with respect to calcium, as predicted by our theory. Because of the saddle-node bifurcation, the system can automatically depolarize even in the absence of INa to voltages higher than the ICa,L threshold, allowing for triggered APs in single myocytes with complete INa block. However, because INa is important for AP propagation in tissue, blocking INa can still suppress premature ventricular excitations in cardiac tissue caused by calcium-mediated triggered activity. This suppression is more effective in normokalemia than in hypokalemia due to the difference in dynamical thresholds.
            Cover page: A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity.
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2017)
            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.
              Cover page: Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2020)

              Background

              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.

              Objective

              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.

              Methods

              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.

              Results

              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 can be 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.

              Conclusion

              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.
                Cover page: Small-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels promote J-wave syndrome and phase 2 reentry.
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