Dynamics Study of Constant DI and Constant TR Control for Cardiac Alternans Based on a Two Dimensional Cellular Automata Model

As a precursor for cardiac arrhythmias such as atrial and ventricular fibrillations, which could cause sudden cardiac death (SCD), cardiac alternans is essentially an unstable heart rhythm with alternating long and short action potential durations (APD) of cardiac myocytes that usually occurs under fast pacing conditions. In this paper, the constant TR control method based on global pseudo-electrocardiogram (ECG) is studied and compared with the local constant diastolic interval (DI) control method using a 2-dimensional (2-D) cellular automata model (CAM), aiming at preventing or eliminating cardiac alternans before arrhythmias. The results show that both the constant TR and constant DI control methods are effective in stabling the alternans to a smaller basic cycle length (BCL). Also, the efficacy of the two control approaches depends on the “decrease step” Δ in the downsweep protocol, and a smaller Δ could significantly improve their performance. Besides, in general, constant TR control is superior to constant DI control in alternans prevention when a relatively large Δ is adopted.

A dataset of dual calcium and voltage optical mapping in healthy and hypertrophied murine hearts

Pathological hypertrophy underlies sudden cardiac death due to its high incidence of occurrence of ventricular arrhythmias. The alteration of transmural electrophysiological properties in hypertrophic cardiac murine tissue has never been explored previously. In this dataset, we have for the first time conducted high-throughput simultaneous optical imaging of transmembrane potential and calcium transients (CaT) throughout the entire hypertrophic murine hearts at high temporal and spatial resolution. Using ElectroMap, we have conducted multiple parameters analysis including action potential duration/calcium transient duration, conduction velocity, alternans and diastolic interval. Voltage-calcium latency was measured as time difference between action potential and CaT peak. The dataset therefore provides the first high spatial resolution transmural electrophysiological profiling of the murine heart, allowing interrogation of mechanisms driving ventricular arrhythmias associated with pathological hypertrophy. The dataset allows for further reuse and detailed analyses of geometrical, topological and functional analyses and reconstruction of 2-dimensional and 3-dimentional models.

Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243

Human Ether-à-go-go (hERG) channels contribute to cardiac repolarization, and inherited variants or drug block are associated with long QT syndrome type 2 (LQTS2) and arrhythmia. Therefore, hERG activator compounds present a therapeutic opportunity for targeted treatment of LQTS. However, a limiting concern is over-activation of hERG resurgent current during the action potential and abbreviated repolarization. Activators that slow deactivation gating (type I), such as RPR260243, may enhance repolarizing hERG current during the refractory period, thus ameliorating arrhythmogenicity with reduced early repolarization risk. Here, we show that, at physiological temperature, RPR260243 enhances hERG channel repolarizing currents conducted in the refractory period in response to premature depolarizations. This occurs with little effect on the resurgent hERG current during the action potential. The effects of RPR260243 were particularly evident in LQTS2-associated R56Q mutant channels, whereby RPR260243 restored WT-like repolarizing drive in the early refractory period and diastolic interval, combating attenuated protective currents. In silico kinetic modeling of channel gating predicted little effect of the R56Q mutation on hERG current conducted during the action potential and a reduced repolarizing protection against afterdepolarizations in the refractory period and diastolic interval, particularly at higher pacing rates. These simulations predicted partial rescue from the arrhythmic effects of R56Q by RPR260243 without risk of early repolarization. Our findings demonstrate that the pathogenicity of some hERG variants may result from reduced repolarizing protection during the refractory period and diastolic interval with limited effect on action potential duration, and that the hERG channel activator RPR260243 may provide targeted antiarrhythmic potential in these cases.

Information Flow Between Heart Rhythm, Repolarization, and the Diastolic Interval Series for Healthy Individuals and LQTS1 Patients

Using information theoretic measures, relations between heart rhythm, repolarization in the tissue of the heart, and the diastolic interval time series are analyzed. These processes are a fragment of the cardiovascular physiological network. A comparison is made between the results for 84 (42 women) healthy individuals and 65 (45 women) long QT syndrome type 1 (LQTS1) patients. Self-entropy, transfer entropy, and joint transfer entropy are calculated for the three time series and their combinations. The results for self-entropy indicate the well-known result that regularity of heart rhythm for healthy individuals is larger than that of QT interval series. The flow of information depends on the direction with the flow from the heart rhythm to QT dominating. In LQTS1 patients, however, our results indicate that information flow in the opposite direction may occur—a new result. The information flow from the heart rhythm to QT dominates, which verifies the asymmetry seen by Porta et al. in the variable tilt angle experiment. The amount of new information and self-entropy for LQTS1 patients is smaller than that for healthy individuals. However, information transfers from RR to QT and from DI to QT are larger in the case of LQTS1 patients.

Clinical Potential of Beat‐to‐Beat Diastolic Interval Control in Preventing Cardiac Arrhythmias

Life‐threatening ventricular arrhythmias and sudden cardiac death are often preceded by cardiac alternans, a beat‐to‐beat oscillation in the T‐wave morphology or duration. However, given the spatiotemporal and structural complexity of the human heart, designing algorithms to effectively suppress alternans and prevent fatal rhythms is challenging. Recently, an antiarrhythmic constant diastolic interval pacing protocol was proposed and shown to be effective in suppressing alternans in 0‐, 1‐, and 2‐dimensional in silico studies as well as in ex vivo whole heart experiments. Herein, we provide a systematic review of the electrophysiological conditions and mechanisms that enable constant diastolic interval pacing to be an effective antiarrhythmic pacing strategy. We also demonstrate a successful translation of the constant diastolic interval pacing protocol into an ECG‐based real‐time control system capable of modulating beat‐to‐beat cardiac electrical activity and preventing alternans. Furthermore, we present evidence of the clinical utility of real‐time alternans suppression in reducing arrhythmia susceptibility in vivo. We provide a comprehensive overview of this promising pacing technique, which can potentially be translated into a clinically viable device that could radically improve the quality of life of patients experiencing abnormal cardiac rhythms.

Reverse use dependence of calcium sensitizer levosimendan on action potential duration shortening prevents ventricular arrhythmia during therapeutic hypothermia

Background Therapeutic hypothermia (TH) increases the risk of ventricular arrhythmia (VA) by prolonging action potential duration (APD) and steepening the APD restitution (APDR). The calcium sensitizer levosimendan, a medication for heart failure treatment, has been reported to shorten APD by enhancing ATP-sensitive K current and affect the APDR. Purpose We hypothesized that levosimendan might shorten the already prolonged APD particularly at long pacing cycle length (PCL), thus decreases the maximal slope of APDR, and prevent VA during TH. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, APD was evaluated by S1 pacing and APDR curve was plotted using APD70 versus diastolic interval. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s at the shortest PCL that achieved 1:1 ventricular capture. Results The APD was shortened from 259±8 ms at TH to 241±18 ms after levosimendan infusion at long PCL of 400 ms (p=0.024). However, at short PCL of 280 ms, the APD was not changed before (194±19) and after (188±23) levosimendan during TH (p=0.61). Levosimendan decreases the maximal slope of APDR curve from 1.99±0.65 at TH to 1.41±0.32 after adding levosimendan (p=0.034). The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% with levosimendan (p=0.023). In control hearts, the maximal slope of APDR (p=0.75) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusion Levosimendan might protect the hearts against VA during TH by shortening APD at long PCL and flattening the APDR. Enhancing ATP-sensitive K current with levosimendan during TH might be a novel approach to prevent VA during TH. Funding Acknowledgement Type of funding source: None

Complete Electroanatomic Imaging of the Diastolic Pathway Is Associated With Improved Freedom From Ventricular Tachycardia Recurrence

Background: The development of multielectrode mapping catheters has expanded the spectrum of mappable ventricular tachycardias (VTs). Full diastolic pathway recording has been associated with a high rate of VT termination during radiofrequency ablation as well as noninducibility at study end. However, the role of diastolic pathway mapping on VT recurrence has yet to be clearly elucidated. We aimed to explore the role of complete diastolic pathway activation mapping on VT recurrence. Methods: Eighty-five consecutive patients who underwent VT ablation guided by high-density mapping were enrolled. During activation mapping, the presence of electrical activity in all segments of diastole defined the evidence of having had recorded the whole diastolic interval. Patients were categorized as having recorded the full diastolic pathway, partial diastolic pathway, or no diastolic pathway map performed. Recurrences of VT were defined as appropriate implantable cardioverter defibrillator therapies or on the basis of ECG-documented arrhythmia. Results: Eighty-five patients were included. Complete recording of the diastolic pathway was achieved in 36/85 (42.4%) patients. Partial recording of the diastolic pathway of the clinical VT was achieved in 24/85 (28.2%) patients. No recording of the diastolic pathway of the clinical VT was feasible in 25/85 patients (29.4%). At a mean of 12.8 months, freedom from VT recurrence was 67% in the overall cohort. At a mean of 12.8 months, freedom from VT recurrence was 88%, 50%, and 55% in patients who had full diastolic activity recorded, partial diastolic activity recorded, or underwent substrate modification, respectively; the observed differences were statistically significant ( P =0.02). Conclusions: Mapping of the entire diastolic pathway was associated with a higher freedom from VT recurrence as compared with partial diastolic pathway recording and substrate modification. The use of multielectrode mapping catheters in recording diastolic activity may help predict those VTs employing intramural circuits and further optimize ablation strategies.