Weightlessness and Cardiac Rhythm Disorders: Current Knowledge from Space Flight and Bed-Rest Studies

Isolatedepisodesofheartrhythmdisordershavebeenreportedduring40yearsofspaceflight,triggeringresearchtoevaluatetheriskofdevelopinglife-threateningarrhythmiasinducedbyprolongedexposuretoweightlessness.Infact,theseeventscouldcompromiseastronautperformanceduringexploratorymissions,aswellasposeatrisktheastronauthealth,duetolimitedoptionsofcareonboardtheInternationalSpaceStation.Startingfromoriginalobservations,thisminireviewwillexplorethelatestresearchinthisfield,consideringresultsobtainedbothduringspaceflightandonEarth,thelatterbysimulatinglong-termexposuretomicrogravitybyhead-downbedrestmaneuverinordertoelicitcardiovasculardeconditioningonnormalvolunteers

Stochastic Cardiac Pacing Increases Ventricular Electrical Stability—A Computational Study

AbstractThe ventricular tissue is activated in a stochastic rather than in a deterministic rhythm due to the inherent heart rate variability (HRV). Low HRV is a known predictor for arrhythmia events and traditionally is attributed to autonomic nervous system tone damage. Yet, there is no model that directly assesses the antiarrhythmic effect of pacing stochasticity per se. One-dimensional (1D) and two-dimensional (2D) human ventricular tissues were modeled, and both deterministic and stochastic pacing protocols were applied. Action potential duration restitution (APDR) and conduction velocity restitution (CVR) curves were generated and analyzed, and the propensity and characteristics of action potential duration (APD) alternans were investigated. In the 1D model, pacing stochasticity was found to sustain a moderating effect on the APDR curve by reducing its slope, rendering the tissue less arrhythmogenic. Moreover, stochasticity was found to be a significant antagonist to the development of concordant APD alternans. These effects were generally amplified with increased variability in the pacing cycle intervals. In addition, in the 2D tissue configuration, stochastic pacing exerted a protective antiarrhythmic effect by reducing the spatial APD heterogeneity and converting discordant APD alternans to concordant ones. These results suggest that high cardiac pacing stochasticity is likely to reduce the risk of cardiac arrhythmias in patients

Exercise-Induced Repolarization Alternans Heterogeneity in Patients with an Implanted Cardiac Defibrillator

Abstract Repolarization alternans (RA

Techniques for ventricular repolarization instability assessment from the ECG

Instabilities in ventricular repolarization have been documented to be tightly linked to arrhythmia vulnera- bility. Translation of the information contained in the repolar- ization phase of the electrocardiogram (ECG) into valuable clinical decision-making tools remains challenging. This work aims at providing an overview of the last advances in the pro- posal and quantification of ECG-derived indices that describe repolarization properties and whose alterations are related with threatening arrhythmogenic conditions. A review of the state of the art is provided, spanning from the electrophysio- logical basis of ventricular repolarization to its characteriza- tion on the surface ECG through a set of temporal and spatial risk markers

The Power of Exercise-Induced T-wave Alternans to Predict Ventricular Arrhythmias in Patients with Implanted Cardiac Defibrillator

ABSTRACT The power of exercise-induced T-wave alternans (TWA) to predict the occurrence of ventricular arrhythmias was evaluated in 67 patients with an implanted cardiac defibrillator (ICD). During the 4-year follow-up, electrocardiographic (ECG) tracings were recorded in a bicycle ergometer test with increasing workload ranging from zero (NoWL) to the patient's maximal capacity (MaxWL). After the follow-up, patients were classified as either ICD_Cases (n = 29), if developed ventricular tachycardia/fibrillation, or ICD_Controls (n = 38). TWA was quantified using our heart-rate adaptive match filter. Compared to NoWL, MaxWL was characterized by faster heart rates and higher TWA in both ICD_Cases (12−18 µ V vs. 20−39 µ V; P < 0.05) and ICD_Controls (9-15 µ V vs. 20−32 µ V; P < 0.05 ). Still, TWA was able to discriminate the two ICD groups during NoWL (sensitivity = 59−83%, specificity = 53−84%) but not MaxWL (sensitivity = 55−69%, specificity = 39−74%). Thus, this retrospective observational case-control study suggests that TWA's predictive power for the occurrence of ventricular arrhythmias could increase at low heart rates

MECHANISM UNDERLYING BRADYCARDIA AND LONG QT 2 RELATED ARRHYTHMIAS: INTERPLAY BETWEEN Ca2+ OVERLOAD AND ELECTRICAL DYSFUNCTION

In numerous pathologies, spontaneous Ca2+ release (SCR) emanating from the sarcoplasmic reticulum and occurring during the action potential (AP) plateau can drive voltage instability that initiates arrhythmias, but the direct interplay between SCRs and arrhythmogeneis has not been fully understood in bradycardia and in long QT type 2 (LQT2) models. Simultaneous optical measurement of intracellular Ca2+ transient (CaiT) and AP were performed in Langendorff-perfused rabbit hearts following AV node ablation. Bradycardia and/or LQT2 was/were induced and the spatial heterogeneity of intracellular Ca2+ handling and its link to voltage dispersion were investigated. Upon switching from 120 to 50 beats/min, AP duration (APD) increased gradually with increasing occurrence of SCRs during the AP plateau (p<0.01, n=7). SCR was a) regionally heterogeneous, b) spatially correlated with APD prolongation, c) associated with enhanced dispersion of repolarization (DOR), d) reversed by pacing at 120 beats/min and e) suppressed with K201 (1µM) or flecainide (5µM), inhibitors of cardiac ryanodine receptors (RyR2) which reduced APD (p<0.01, n=5) and DOR (p<0.02, n=5). Western blots of Ca2+ channels/transporters revealed intrinsic spatial distributions of Cav1.2α and NCX (but not RyR2, and SERCA2a) that correlate with the distribution of SCR and underlie the molecular mechanism responsible for SCRs. In LQT2, lability of Cai, voltage, and ECG signals increased during paced rhythm, before the appearance of early afterdepolarizations (EADs). When EADs appeared, Cai occasionally rose before voltage upstrokes at the origins of propagating EADs. Localized, areas of SCRs appeared in LQT2 and corresponded to areas of prolonged CaiT and APD. Triggered activity appeared after 3-5 min of LQT2 and emanated only at sites with steep membrane potential (Vm) gradients (ΔVm gradient percentile: 94.9 ± 3.2%, n=6). Pre- or post-treatment with K201 suppressed SCRs and decreased DOR, ΔVm and ΔCai. The reduction of ΔVm suppressed triggered activity (n=8/9 hearts). The results show that bradycardia and LQT2 elicit spatially discordant SCR, which is tightly correlated with AP instability. The SCR mediated-enhancement of repolarization gradients and AP prolongation can promote arrhythmogenesis. These findings underscore the importance of a detailed understanding of Ca2+-dependent arrhythmogenic mechanisms for the development of rational treatment strategies

Mechano-electrical feedback in the clinical setting: Current perspectives

Mechano-electric feedback (MEF) is an established mechanism whereby myocardial deformation causes changes in cardiac electrophysiological parameters. Extensive animal, laboratory and theoretical investigation has demonstrated that abnormal patterns of cardiac strain can induce alteration of electrical excitation and recovery through MEF, which can potentially contribute to the establishment of dangerous arrhythmias. However, the clinical relevance of MEF in patients with heart disease remains to be established. This paper reviews upto date experimental evidence describing the response to different types of mechanical stimuli in the intact human heart with the support of new data collected during cardiac surgery. It discusses modulatory effects of MEF that may contribute to increase the vulnerability to arrhythmia and describes MEF interaction with clinical conditions where mechanically induced changes in cardiac electrophysiology are likely to be more relevant. Finally, directions for future studies, including the need for in-vivo human data providing simultaneous assessment of the distribution of structural, functional and electrophysiological parameters at the regional level, are identified

Multiphoton Imaging of Ca2+ Instability in Acute Myocardial Slices from a RyR2R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca2+ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca2+ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca2+ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2R2474S knock-in mice, electrically paced at different rates (1-5 Hz), to identify arrhythmogenic Ca2+ dynamics, from the sub- to the multicellular perspective. In both models, RyR2R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca2+ alternans and synchronous Ca2+ release events in neighboring cardiomyocytes. Analysis of Ca2+ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with 'leaky' RyR2