Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue

Liu, Michael B.; Lange, Enno de; Garfinkel, Alan; Weiss, James N.; Qu, Zhilin

doi:10.1016/j.hrthm.2015.06.019

Cited by 60 publications

(66 citation statements)

References 35 publications

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“…Once intracellular Ca 2þ rises and activates sufficient I NCX to depolarize the myocyte past the dynamical threshold, the voltage continues to automatically depolarize to above the I Na threshold due to a steep negative slope of the I K1 -V curve. Thus, despite decreased excitability in response to short current pulses, DAD-mediated TA is whose random latencies were drawn from a Gaussian distribution with time to onset t 0,onset ¼ 300 ms and standard deviation s latency ¼ 50 ms. See Liu et al (22) for details. Note also that in Liu et al (22), t 0 corresponds to the Ca 2þ release onset (t 0,onset ), not the Ca 2þ transient peak as in this article.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, despite decreased excitability in response to short current pulses, DAD-mediated TA is whose random latencies were drawn from a Gaussian distribution with time to onset t 0,onset ¼ 300 ms and standard deviation s latency ¼ 50 ms. See Liu et al (22) for details. Note also that in Liu et al (22), t 0 corresponds to the Ca 2þ release onset (t 0,onset ), not the Ca 2þ transient peak as in this article. This particular example shows a paced beat propagating through the entire cable, followed by the central region exhibiting suprathreshold DADs that trigger a propagating PVC.…”

Section: Discussionmentioning

confidence: 99%

“…Liu et al (22). Briefly, a SR release conductance was added with a certain strength and duration to release Ca 2þ from the SR.…”

Section: Computer Simulationsmentioning

confidence: 99%

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A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity

Liu

Song

et al. 2016

Biophysical Journal

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Ventricular myocytes are excitable cells whose voltage threshold for action potential (AP) excitation is~À60 mV at which I Na 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 I Na 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 I Na 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 I K1 and I NCX . This threshold is close to the voltage at which I K1 is maximum, and lower than the I Na threshold. After exceeding this dynamical threshold, the membrane voltage will automatically depolarize above the I Na threshold due to the large negative slope of the I K1 -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 I Na to voltages higher than the I Ca,L threshold, allowing for triggered APs in single myocytes with complete I Na block. However, because I Na is important for AP propagation in tissue, blocking I Na 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity

Liu

Song

et al. 2016

Biophysical Journal

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“…On one hand, depolarization of resting potential bring the cells closer to the threshold of the fast sodium current facilitating propagation [39]. On the other hand, long lasting DADs ultimately lead to inactivation of sodium channels promoting conduction block [17,40]. Indeed, simulation results (see Supplementary Results, Figure S1 in supplementary materials) demonstrate that propagation of an AP initiated within the thinnest isthmus, w isth = 0.2 mm, to the myocardium depended on the amplitude of DADs at the exit site.…”

Section: The Role Of Electrotonic Loadmentioning

confidence: 99%

Microscopic Isthmuses and Fibrosis Within the Border Zone of Infarcted Hearts Promote Calcium-Mediated Ectopy and Conduction Block

et al. 2018

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Ventricular tachycardia (VT) secondary to myocardial infarction (MI) remain a major cause of sudden death in adults. Premature ventricular complexes (PVCs), the first initiating beats of a portion of these arrhythmias, arise from triggered activity in the infarct border zone (BZ). At the cellular scale, spontaneous calcium release (SCR) events are a known cause of triggered activity and have been reported in cells that survive MI. At the tissue scale, fibrosis has been shown to play an important role in creating the substrate for VT. However, the interplay between SCR-mediated triggered activity and fibrosis upon VT formation in infarcted hearts has not been fully investigated. Here, we conduct in-silico experiments to assess how macroscopic and microscopic anatomical properties of the BZ can create a substrate for SCR-mediated VT formation. To study this question, we employ a stochastic subcellular-scale model of SCR events and action potential to simulate different cardiac preparations. Within 2D sheet models with idealized infarct scars and BZ we show that the probability of PVCs is higher, 55%, in preparations with thin conducting isthmuses (0.2 mm) transcending the scar. In an anatomically-detailed model of the rabbit ventricles with a realistic representation of intramural scars, we show that the heart's protective source-sink mismatch prevents ectopy. Furthermore, we demonstrate that fibrosis disrupts this antiarrhythmic mechanism making PVCs more likely. PVC probability is highest (≥25%) when fibrosis accounts for 60 and 90% of the BZ in the 2D sheet and the 3D anatomical model, respectively. Above these thresholds, PVC occurrence decreases because of: (1) the reduced number of myocytes in the BZ; (2) conduction block. Block is caused either by disconnection of BZ cells from the myocardium or due to source-sink mismatches at regions of rapid tissue expansion. Moreover, while outward propagation to healthy tissue may fail, PVCs traveling inward through the scar might encounter more favorable loading conditions. These PVCs may exit to the myocardium and reenter back at the region of block. Overall, our findings indicate that thin isthmuses and strands of myocytes interspersed with fibrosis can be arrhythmogenic. Ablation of these microscopic structures may prevent VT formation.

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“…As shown in a recent study (31), subthreshold DADs can locally reduce excitability by inactivating the Na current, leading to conduction block and initiation of reentry. Thus, the same DAD-mediated process can produce both the trigger and vulnerable substrate (due to dispersion of excitability) promoting initiation of reentry and cardiac fibrillation.…”

Section: Discussionmentioning

confidence: 68%

Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue

Liu

Song

et al. 2017

Biophysical Journal

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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 mmol/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.

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Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue

Cited by 60 publications

References 35 publications

A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity

A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity

Microscopic Isthmuses and Fibrosis Within the Border Zone of Infarcted Hearts Promote Calcium-Mediated Ectopy and Conduction Block

Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue

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