Activation-recovery Intervals Research Articles

Non-invasive electrocardiographic imaging in patients with idiopathic premature ventricular contractions from the right ventricular outflow tract: New insights into arrhythmia substrate

AimsThe aim of this study was to use non-invasive electrocardiographic imaging (ECGI) to study the electrophysiological properties of right ventricular outflow tract (RVOT) in patients with frequent premature ventricular contractions (PVCs) from the RVOT and in controls. MethodsECGI is a combined application of body surface electrocardiograms and computed tomography or magnetic resonance imaging data. Unipolar electrograms are reconstructed on the epicardial and endocardial surfaces. Activation time (AT) was defined as the time of maximal negative slope of the electrogram (EGM) during QRS, recovery time (RT) as the time of maximal positive slope of the EGM during T wave, Activation recovery interval (ARI) was defined as the difference between RT and AT. ARI dispersion (Δ ARI) and RT dispersion (Δ RT) were calculated as the difference between maximal and minimal ARI and RT respectively. We evaluated those parameters in patients with frequent PVCs from the RVOT, defined as >10.000 per 24 h, and in a control group. ResultsWe studied 7 patients with frequent RVOT PVCs and 17 controls. Patients with PVCs from the RVOT had shorter median RT than controls, in the endocardium and in the epicardium, respectively 380 (239–397) vs 414 (372–448) ms, p = 0.047 and 275 (236–301) vs 330 (263–418) ms, p = 0.047. The dispersion of ARI and of RT in the epicardium was higher than in controls, Δ ARI of 145 (68–216) vs 17 (3–48) ms, p = 0.001 and Δ RT of 201 (160–235) vs 115 (65–177), p = 0.019. ConclusionIn this group of patients we found a shorter median RT in the endocardium and in the epicardium of the RVOT and a higher dispersion of the ARI and RT across the epicardium in patients with PVCs from the RVOT when comparing to controls.

Electrophysiological remodeling of the right ventricle in experimental heart failure of different etiologies

The aim of the study was to evaluate electrophysiological remodeling of the right ventricle in rats in experimental heart failure of different etiologies. Materials and methods. Isadrin-, doxorubicin- and monocrotaline-induced heart failure models were developed. Unipolar epicardial electrograms of the ventricles (256 recording sites) were recorded using a 144-channel system. The cardiac output and pressure in both ventricles of the heart were measured. Activation-recovery intervals were used as an index of duration of local repolarization, and the general and local dispersions of activation-recovery intervals were used as an index of heterogeneity of ventricular repolarization. Results. In all models of heart failure, the following were identified: 1) non-uniform prolongation of repolarization with the greatest elongation at the apex of the right ventricle; 2) an increase in apicobasal differences of repolarization with the greatest change in the right ventricle; 3) an increase in the heterogeneity of the repolarization of the epicardial layer of the ventricles with heterogeneous changes in the local heterogeneity of repolarization and a decrease in the interregional differences in the heterogeneity of the electrophysiological properties of the myocardium; 4) more pronounced changes in the repolarization of the right ventricle than in the repolarization of the left ventricle. Conclusion. Thus, irrespective of the cause of the heart failure, the following changes occur: 1) prolongation of the right ventricular repolarization occurs non-uniformly (mostly due to the apical area), which results in an increase in the right ventricular repolarization heterogeneity; 2) an increase in the heterogeneity of right ventricular repolarization is observed, which causes an increase in the overall heterogeneity of the ventricular epicardial surface.

Mechanisms Underlying Interactions Between Low-Frequency Oscillations and Beat-to-Beat Variability of Celullar Ventricular Repolarization in Response to Sympathetic Stimulation: Implications for Arrhythmogenesis.

Background and Objectives: Enhanced beat-to-beat variability of ventricular repolarization (BVR) has been linked to arrhythmias and sudden cardiac death. Recent experimental studies on human left ventricular epicardial electrograms have shown that BVR closely interacts with low-frequency (LF) oscillations of activation recovery interval during sympathetic provocation. In this work human ventricular computational cell models are developed to reproduce the experimentally observed interactions between BVR and its LF oscillations, to assess underlying mechanisms and to establish a relationship with arrhythmic risk.Materials and Methods: A set of human ventricular action potential (AP) models covering a range of experimental electrophysiological characteristics was constructed. These models incorporated stochasticity in major ionic currents as well as descriptions of β-adrenergic stimulation and mechanical effects to investigate the AP response to enhanced sympathetic activity. Statistical methods based on Automatic Relevance Determination and Canonical Correlation Analysis were developed to unravel individual and common factors contributing to BVR and LF patterning of APD in response to sympathetic provocation.Results: Simulated results reproduced experimental evidences on the interactions between BVR and LF oscillations of AP duration (APD), with replication of the high inter-individual variability observed in both phenomena. ICaL, IKr and IK1 currents were identified as common ionic modulators of the inter-individual differences in BVR and LF oscillatory behavior and were shown to be crucial in determining susceptibility to arrhythmogenic events.Conclusions: The calibrated family of human ventricular cell models proposed in this study allows reproducing experimentally reported interactions between BVR and LF oscillations of APD. Ionic factors involving ICaL, IKr and IK1 currents are found to underlie correlated increments in both phenomena in response to sympathetic provocation. A link to arrhythmogenesis is established for concomitantly elevated levels of BVR and its LF oscillations.

Influence of dibornol-HES on electrophysiological parameters in the period of restoration of blood flow in rabbit myocardium

Objective. Dibornol-HES, a water-soluble drug based on the derivative of 2,6-diisobornyl-4-methylphenol Dibornol conjugated with hydroxyethyl starch, can reduce the occurrence and severity of arrhythmias by preventive intravenous administration, but it is unknown whether the drug could reduce the myocardial arrhythmogenicity once ischemia has developed at the developed ischemia.Materials and methods. In the model of acute ischemia / reperfusion of the rabbit heart, the effect of Dibornol-HEC (80 mg/kg body weight of the animal) on the electrophysiological indices characterizing myocardial arrhythmogenicity (global and border dispersion of repolarization) was studied during the restoration of blood flow. In the model of acute ischemia / reperfusion with 64 unipolar epicardial leads, the activation-recovery intervals were measured and global and border dispersion of repolarization in the native rabbits (control group, n = 9) and in the rabbits treated by Dibornol-HES (on the 25th minute of occlusion, the experimental group, n = 6).Results. The introduction of Dibornol-HES did not lead to a change in the electrocardiographic parameters of rabbits. By the 30th minute of the coronary occlusion on the ECG in the animals of the control and the experimental groups, the intervals RR, QT, QTc were shortened (p < 0.05). In the animals of both groups by the 30th minute of coronary occlusion, the global dispersion of repolarization increased (p < 0.05), the boundary dispersion of repolarization also increased (p < 0.05), due to the decrease in the duration of the activation-recovery intervals in the ischemic zone (p < 0.05). During the 30-minute reperfusion the magnitude of the global dispersion of repolarization did not change in animals of the both groups, and the magnitude of the border dispersion of repolarization in the control rabbits decreased (p < 0.05), while in the rabbits treated by Dibornol-HES the border dispersion of repolarization did not changed.Conclusion. In rabbits of the experimental group, the values of the global and border dispersions of repolarization did not differ from those of the animals in the control group. Therefore, the administration to Dibornol-HES just prior to reperfusion does not lead to the decrease in the dispersion of repolarization increased as a result of acute ischemic myocardial damage.

Left ventricular activation-recovery interval variability predicts spontaneous ventricular tachyarrhythmia in patients with heart failure

Enhanced beat-to-beat variability of repolarization is strongly linked to arrhythmogenesis and is largely due to variation in ventricular action potential duration (APD). Previous studies in humans have relied on QT interval measurements; however, a direct relationship between beat-to-beat variability of APD and arrhythmogenesis in humans has yet to be demonstrated. This study aimed to explore the beat-to-beat repolarization dynamics in patients with heart failure at the level of ventricular APD. Forty-three patients with heart failure and implanted cardiac resynchronization therapy - defibrillator devices were studied. Activation-recovery intervals as a surrogate for APD were recorded from the left ventricular epicardial lead while pacing from the right ventricular lead to maintain a constant cycle length. During a mean follow-up of 23.6±13.6 months, 11 patients sustained ventricular fibrillation/ventricular tachycardia (VT/VF) and received appropriate implantable cardioverter-defibrillator therapies (antitachycardia pacing or shock therapy). Activation-recovery interval variability (ARIV) was significantly greater in patients with subsequent VT/VF than in those without VT/VF (3.55±1.3 ms vs 2.77±1.09 ms; P=.047). Receiver operating characteristic curve analysis (area under the curve 0.71; P=.046) suggested high- and low-risk ARIV groups for VT/VF. Kaplan-Meier survival analysis demonstrated that the time until first appropriate therapy for VT/VF was significantly shorter in the high-risk ARIV group (P=.028). ARIV was a predictor for VT/VF in the multivariate Cox model (hazard ratio 1.623; 95% confidence interval 1.1-2.393; P=.015). Increased left ventricular ARIV is associated with an increased risk of VT/VF in patients with heart failure.

Pharmacological Modulation of Right Ventricular Endocardial-Epicardial Gradients in Brugada Syndrome.

Background We explored the hypothesis that increased cholinergic tone exerts its proarrhythmic effects in Brugada syndrome (BrS) through increasing dispersion of transmural repolarization in patients with spontaneous and drug-induced BrS. Methods BrS and supraventricular tachycardia patients were studied after deploying an Ensite Array in the right ventricular outflow tract and a Cardima catheter in the great cardiac vein to record endo and epicardial signals, respectively. S1-S2 restitution curves from the right ventricular apex were conducted at baseline and after edrophonium challenge to promote increased cholinergic tone. The local unipolar electrograms were then analyzed to study transmural conduction and repolarization dynamics. Results The study included 8 BrS patients (5 men:3 women; mean age, 56 years) and 8 controls patients with supraventricular tachycardia (5 men:3 women; mean age, 48 years). Electrophysiological studies in controls demonstrated shorter endocardial than epicardial right ventricular activation times (mean difference: 26 ms; P<0.001). In contrast, patients with BrS showed longer endocardial than epicardial activation time (mean difference: -15 ms; P=0.001). BrS hearts, compared with controls, showed significantly larger transmural gradients in their activation recovery intervals (mean intervals, 20.5 versus 3.5 ms; P<0.01), with longer endocardial than epicardial activation recovery intervals. Edrophonium challenge increased such gradients in both controls (to a mean of 16 ms [ P<0.001]) and BrS (to 29.7 ms; P<0.001). However, these were attributable to epicardial and endocardial activation recovery interval prolongations in control and BrS hearts, respectively. Dynamic changes in repolarization gradients were also observed across the BrS right ventricular wall in BrS. Conclusions Differential contributions of conduction and repolarization were identified in BrS which critically modulated transmural dispersion of repolarization with significant cholinergic effects only identified in the patients with BrS. This has important implications for explaining the proarrhythmic effects of increased vagal tone in BrS, as well as evaluating autonomic modulation and epicardial ablation as therapeutic strategies.

RESULTS OF NON-INVASIVE ACTIVATION MAPPING OF THE HEART IN “IDIOPATHIC” VENTRICULAR ARRHYTHMIAS IN COMPARISON WITH STRUCTURAL CHARACTERISTICS OF MYOCARDIUM BY MAGNETIC RESONANCE IMAGING

Aim.To compare the results of non-invasive activational mapping in patients with “idiopathic” ventricular arrhythmias (IVA) with the data on myocardial structure obtained by late enhancement magnetic resonance tomography (MRI).Material and methods.Twenty eight IVA patients, mean age 37 y. o. [26; 45], with ventricular arrhythmias of the heart (VA) of 2nd or higher grade by Lown, and 5 healthy volunteers (HV), mean age 29 [29; 30], underwent surface epiand endocardial non-invasive mapping (SEENIM) of the heart with the system for noninvasive electrophysiological investigation of the heart “Amicard 01C” with the analysis of duration of the activation-recovery interval (ARI) of the ventricles, and high resolution MRI (voxel 1,25x1,25x2,5mm) with delayed contrasting.Results.The number of VA in IVA group was 20196 [11479; 29834] for 24 hours. In 11 patients there were episodes of non-sustained ventricular tachycardia (VT). By SEENIM, predominating morphological type of ventricular ectopic activity in 22 patients sourced from the right ventricle myocardium (RV), of those in 20 from outflow tract of the LV (OTLV). There was significantly prolonged ARI in OTLV patients with IVA comparing to HV (p&lt;0,05). In IVA and non-sustained ventricular tachycardia patients, by contrast MRI of the heart, in LV myocardium there were small foci of contrast retention found. There was no correlation of the areas of contrast retention and topography of VA sources.Conclusion.In most of IVA patients the source of VA was outflowing tract of the RV. The revealed prolongation of the ARI of this area in IVA patients can be an important factor of IVA onset. Small foci of LV fibrosis, found in late enhancement MRI of the heart and episodes of so called idiopathic VT, might be the earliest presentation of the “tachycardiopathy” at the step of pathology development when there are no signs of LV dilation.

The effect of repolarization duration on the indices of the pump function of the heart ventricles in animals with different types of activation of the myocardium under ectopic excitation of ventricles

Background — The aim of the work was to study the influence of myocardial repolarization on the indices of the pump function in animals with different types of the myocardial activation (dog, amphibians) under ectopic excitation of the ventricles. Material and Methods — Intraventricular blood pressure in animals was measured using a hemodynamic Prucka MacLab 2000 system under basal and apical locations of the stimulating electrode on the ventricles of the heart. The activation-recovery intervals (ARIs) were determined from unipolar myocardial electrograms recorded in the intramural layers of apical and basal parts of the ventricles in dog (n=16) and amphibians (toads Bufo bufo, n=11; frogs Rana temporaria, n=23). Data are presented as median with lower and upper quartiles. Results — The pacing of the left ventricle apical area in dogs with more prolonged ARIs, as compared with the base, does not change the isovolumic indices of the left ventricle pump function. However, ARIs were longer at the ventricular base – 248 (206, 260) ms for dog’s right ventricle and 742 (680, 929) ms for froggy ventricle, as compared with the apex in the canine right ventricle – 238 (219, 249) ms, and the ventricle in the amphibians – 692 (637, 860) ms. Therefore, pacing of the right ventricle in the apical area in dog and ventricular apex in amphibians leads to a significant decrease of their pump function. Conclusion — In the animals with successive (amphibians) and flash-successive (dog) types of activation of the myocardium, parameters of the pump function of ventricles were better at pacing of the area with the longest repolarization at the baseline and worse at pacing of the shortest repolarization area.

Bridging Organ- and Cellular-Level Behavior in Ex Vivo Experimental Platforms Using Populations of Models of Cardiac Electrophysiology

The inability to discern between pathology and physiological variability is a key issue in cardiac electrophysiology since this prevents the use of minimally invasive acquisitions to predict early pathological behavior. The goal of this work is to demonstrate how experimentally calibrated populations of models (ePoM) may be employed to inform which cellular-level pathologies are responsible for abnormalities observed in organ-level acquisitions while accounting for intersubject variability; this will be done through an exemplary computational and experimental approach. Unipolar epicardial electrograms (EGM) were acquired during an ex vivo porcine heart experiment. A population of the Ten Tusscher 2006 model was calibrated to activation–recovery intervals (ARI), measured from the electrograms, at three representative times. The distributions of the parameters from the resulting calibrated populations were compared to reveal statistically significant pathological variations. Activation–recovery interval reduction was observed in the experiments, and the comparison of the calibrated populations of models suggested a reduced L-type calcium conductance and a high extra-cellular potassium concentration as the most probable causes for the abnormal electrograms. This behavior was consistent with a reduction in the cardiac output (CO) and was confirmed by other experimental measurements. A proof of concept method to infer cellular pathologies by means of organ-level acquisitions is presented, allowing for an earlier detection of pathology than would be possible with current methods. This novel method that uses mathematical models as a tool for formulating hypotheses regarding the cellular causes of observed organ-level behaviors, while accounting for physiological variability has been unexplored.

Effect of electroacupuncture on porcine cardiac excitability induced by left stellate ganglion stimulation

Augmentation of cardiac sympathetic tone has been shown to induce ventricular arrhythmias. Acupuncture has been clinically used to treat hypertension, angina pectoris, and atrial arrhythmias. However, the effects of acupuncture on ventricular electrophysiology and autonomic tone remain unknown. We hypothesized that acupuncture attenuates cardiac excitability and corrects the imbalance of autonomic tone during sympathetic hyperactivity. Fourteen Yorkshire pigs were randomized to electroacupuncture (EA, 2 Hz, 0.3-0.5 mA, 0.5 ms duration) or control (without EA) groups. Animals were sedated with terazol. General anesthesia consisted of isoflurane and fentanyl during surgical preparation and was transitioned to α-chloralose during experimental protocols. Through a median sternotomy, the heart was exposed and fitted with an elastic epicardial 56-electrode sock. Cardiac excitability was measured via activation recovery interval (ARI) and dispersion of repolarization (DOR) while autonomic balance was evaluated by heart rate variability (HRV) power spectrum analysis at baseline and during left stellate ganglion stimulation (LSS) with and without EA delivered at P 5-6 acupoints. 30-min of EA did not alter the baseline ARI and DOR, but significantly suppressed cardiac excitability during LSS through attenuation of ARI shortening (EA 2.1 ± 0.3% vs. control 5.2 ± 0.7%, P < 0.05) and DOR (EA 74.3 ± 26.9% vs., control 110.1 ± 22.9%, P < 0.05). EA significantly attenuated the increase in LF/HF (EA 0.6 ± 0.1 vs. control 1.1 ± 0.2, P < 0.05). In conclusion, EA reduces the cardiac excitability induced by LSS through correction of cardiac sympathovagal balance. This study provides mechanistic insights underlying cardiac neuromodulation of EA during sympathoexcitation.

Beat-to-Beat Variability of Ventricular Action Potential Duration Oscillates at Low Frequency During Sympathetic Provocation in Humans.

Background: The temporal pattern of ventricular repolarization is of critical importance in arrhythmogenesis. Enhanced beat-to-beat variability (BBV) of ventricular action potential duration (APD) is pro-arrhythmic and is increased during sympathetic provocation. Since sympathetic nerve activity characteristically exhibits burst patterning in the low frequency range, we hypothesized that physiologically enhanced sympathetic activity may not only increase BBV of left ventricular APD but also impose a low frequency oscillation which further increases repolarization instability in humans.Methods and Results: Heart failure patients with cardiac resynchronization therapy defibrillator devices (n = 11) had activation recovery intervals (ARI, surrogate for APD) recorded from left ventricular epicardial electrodes alongside simultaneous non-invasive blood pressure and respiratory recordings. Fixed cycle length was achieved by right ventricular pacing. Recordings took place during resting conditions and following an autonomic stimulus (Valsalva). The variability of ARI and the normalized variability of ARI showed significant increases post Valsalva when compared to control (p = 0.019 and p = 0.032, respectively). The oscillatory behavior was quantified by spectral analysis. Significant increases in low frequency (LF) power (p = 0.002) and normalized LF power (p = 0.019) of ARI were seen following Valsalva. The Valsalva did not induce changes in conduction variability nor the LF oscillatory behavior of conduction. However, increases in the LF power of ARI were accompanied by increases in the LF power of systolic blood pressure (SBP) and the rate of systolic pressure increase (dP/dtmax). Positive correlations were found between LF-SBP and LF-dP/dtmax (rs = 0.933, p < 0.001), LF-ARI and LF-SBP (rs = 0.681, p = 0.001) and between LF-ARI and LF-dP/dtmax (rs = 0.623, p = 0.004). There was a strong positive correlation between the variability of ARI and LF power of ARI (rs = 0.679, p < 0.001).Conclusions: In heart failure patients, physiological sympathetic provocation induced low frequency oscillation (~0.1 Hz) of left ventricular APD with a strong positive correlation between the LF power of APD and the BBV of APD. These findings may be of importance in mechanisms underlying stability/instability of repolarization and arrhythmogenesis in humans.

The assessment of electrophysiological indices and ECG parameters as predictors of fatal arrhythmias under ischemia/reperfusion setting in multivariate regression model.

IntroductionThere are many factors predisposing to arrhythmia. The reentry mechanism is determined by dispersion of repolarization, unidirectional conduction block and activation slowing which can be documented as QRS widening. Similarly, the duration of repolarization and heart rate could favor the triggered activity or afterdepolarization proarrhythmic mechanism. The great interest for clinically application is the evaluation of noninvasive markers of fatal arrhythmias such as Tpeak‐Tend interval, QT dispersion and others but often they give unsatisfactory or conflicting results.The aim of the study was to find out which of the electrophysiological indices and ECG parameters contribute significantly to the genesis of fatal arrhythmias under experimental coronary occlusion and reperfusion using multivariate regression model.MethodsUsing needle plunge electrodes unipolar electrograms were recorded in intramural ventricular layers of 24 anesthetized open‐chest cats. Activation times (ATs) as dV/dt min during QRS, end of repolarization times (RTs) as dV/dt max during ST‐T, and activation‐recovery intervals (ARIs) as the time interval between the ATs and RTs were measured in total of 88 myocardial leads. The global, apicobasal, border RT dispersions were calculated as electrophysiological indices. The data were obtained at baseline, at 1 and 30 min of coronary occlusion and at 1 and 30 min of reperfusion.ResultsThe ventricular tachycardia and/or ventricular fibrillation (VT/VF) arose in a total of 10 animals at 1–5 minutes after reperfusion onset. During ischemia RTs progressively decreased and ATs increased in the ischemic zone and then progressively restored during reperfusion (P&lt;0.05). The global, apicobasal, border dispersion of repolarization, QRS, Tpeak‐Tend intervals increased in all animals during ischemia and at the reperfusion onset (P&lt;0.05). Under ischemia/reperfusion episode, the VT/VF group of animals demonstrated the greater global, border, apicobasal dispersion of RT, RTs in nonischemic and ischemic areas, QRS and Tpeak‐Tend intervals, and the lower heart rate as compared with the nonVT/VF animals (P&lt;0.05). Using the multivariate logistic regression analysis we assessed the association between the dispersions of RT, RTs and ATs of ischemic and nonischemic zone under the 1 min of reperfusion and the occurrence of VT/VF. It was found that RTs of nonischemic zone (P=0.024) and global dispersion of RT (P=0.046) demonstrated significant association with the reperfusion VT/VF. The following ECG parameters as predictors of arrhythmias were tested (heart rate, Tpeak‐Tend, QRS and QTc intervals, Tpeak‐Tend/QT ratio). The QRS interval (P=0.01) and heart rate (P=0.009) were found to have the significant link with the occurrence of VT/VF.ConclusionThe multivariate regression model showed that the genesis of VT/VF was independently predicted by the repolarization duration in nonischemic area and the global dispersion of repolarization at the reperfusion onset. The QRS and heart rate were the independent ECG predictors of the occurrence of reperfusion VT/VF.Support or Funding InformationThe study was supported by the Program for Fundamental Research of RAS project № AAAA‐A17‐117012310154‐6, № AAAA‐A18‐118012290365‐2.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Antiarrhythmic effects of vagal nerve stimulation after cardiac sympathetic denervation in the setting of chronic myocardial infarction

Neuraxial modulation with cardiac sympathetic denervation (CSD) can potentially reduce burden of ventricular tachyarrhythmia (VT). However, despite catheter ablation and CSD, VT can recur in patients with cardiomyopathy and the role of vagal nerve stimulation (VNS) in this setting is unclear. The purpose of this study was to evaluate the electrophysiological effects of VNS after CSD in normal and infarcted hearts. In 10 normal and 6 infarcted pigs, electrophysiological and hemodynamic parameters were evaluated before and during intermittent VNS pre-CSD (bilateral stellectomy and T2-T4 thoracic ganglia removal) as well as post-CSD. The effect of VNS during isoproterenol was also assessed pre- and post-CSD. Multielectrode ventricular activation recovery interval (ARI) recordings, a surrogate of action potential duration, were obtained. VT inducibility was tested during isoproterenol infusion after CSD with and without VNS. VNS increased the global ARI by 4% ± 4% pre-CSD and by5% ± 6% post-CSD, with enhanced effects observed during isoproterenol infusion (10% ± 8% pre-CSD and 12% ± 9% post-CSD) in normal animals. In infarcted animals pre-CSD, VNS increased ARI by 6% ± 7% before and by 13% ± 8% during isoproterenol infusion. Post-CSD, VNS increased ARI by 6% ± 5% before and by 11% ± 7% during isoproterenol infusion. VT was inducible in all infarcted animals post-CSD during isoproterenol infusion; this inducibility was reduced by 67% with VNS (P = .01). In all animals, the hemodynamic effects of VNS remained after CSD. After CSD, the beneficial electrophysiological effects of VNS remain. Furthermore, VNS can reduce VT inducibility beyond CSD in the setting of circulating catecholamines, suggesting a role for additional parasympathetic modulation in the treatment of ventricular arrhythmias.

Cardiac vanilloid receptor-1 afferent depletion enhances stellate ganglion neuronal activity and efferent sympathetic response to cardiac stress.

Afferent fibers expressing the vanilloid receptor 1 (VR1) channel have been implicated in cardiac nociception; however, their role in modulating reflex responses to cardiac stress is not well understood. We evaluated this role in Yorkshire pigs by percutaneous epicardial application of resiniferatoxin (RTX), a toxic activator of the VR1 channel, resulting in the depletion of cardiac VR1-expressing afferents. Hemodynamics, epicardial activation recovery intervals, and in vivo activity of stellate ganglion neurons (SGNs) were recorded in control and RTX-treated animals. Stressors included inferior vena cava or aortic occlusion and rapid right ventricular pacing (RVP) to induce dyssynchrony and ischemia. In the epicardium, stellate ganglia, and dorsal root ganglia, immunostaining for the VR1 channel, calcitonin gene-related peptide, and substance P was significantly diminished by RTX. RTX-treated animals exhibited higher basal systolic blood pressures and contractility than control animals. Reflex responses to epicardial bradykinin and capsaicin were mitigated by RTX. Cardiovascular reflex function, as assessed by inferior vena cava or aortic occlusion, was similar in RTX-treated versus control animals. RTX-treated animals exhibited resistance to hemodynamic collapse induced by RVP. Activation recovery interval shortening during RVP, a marker of cardiac sympathetic outflow, was greater in RTX-treated animals and exhibited significant delay in returning to baseline values after cessation of RVP. The basal firing rate of SGNs and firing rates in response to RVP were also greater in RTX-treated animals, as was the SGN network activity in response to cardiac stressors. These data suggest that elimination of cardiac nociceptive afferents reorganizes the central-peripheral nervous system interaction to enhance cardiac sympathetic outflow. NEW & NOTEWORTHY Our work demonstrates a role for cardiac vanilloid receptor-1-expressing afferents in reflex processing of cardiovascular stress. Current understanding suggests that elimination of vanilloid receptor-1 afferents would decrease reflex cardiac sympathetic outflow. We found, paradoxically, that sympathetic outflow to the heart is instead enhanced at baseline and during cardiac stress.

Repolarization abnormalities unmasked with exercise in sudden cardiac death survivors with structurally normal hearts.

Models of cardiac arrhythmogenesis predict that nonuniformity in repolarization and/or depolarization promotes ventricular fibrillation and is modulated by autonomic tone, but this is difficult to evaluate in patients. We hypothesize that such spatial heterogeneities would be detected by noninvasive ECG imaging (ECGi) in sudden cardiac death (SCD) survivors with structurally normal hearts under physiological stress. ECGi was applied to 11 SCD survivors, 10 low-risk Brugada syndrome patients (BrS), and 10 controls undergoing exercise treadmill testing. ECGi provides whole heart activation maps and>1,200 unipolar electrograms over the ventricular surface from which global dispersion of activation recovery interval (ARI) and regional delay in conduction were determined. These were used as surrogates for spatial heterogeneities in repolarization and depolarization. Surface ECG markers of dispersion (QT and Tpeak-end intervals) were also calculated for all patients for comparison. Following exertion, the SCD group demonstrated the largest increase in ARI dispersion compared to BrS and control groups (13 ± 8ms vs. 4 ± 7ms vs. 4 ± 5ms; P=0.009), with baseline dispersion being similar in all groups. In comparison, surface ECG markers of dispersion of repolarization were unable to discriminate between the groups at baseline or following exertion. Spatial heterogeneities in conduction were also present following exercise but were not significantly different between SCD survivors and the other groups. Increased dispersion of repolarization is apparent during physiological stress in SCD survivors and is detectable with ECGi but not with standard ECG parameters. The electrophysiological substrate revealed by ECGi could be the basis of alternative risk-stratification techniques.

Antifibrillatory effects of renal denervation on ventricular fibrillation in a canine model of pacing-induced heart failure.

What is the central question of this study? In the present study, we investigated the effects of renal denervation on the vulnerability to ventricular fibrillation and the ventricular electrical properties in a rapid pacing-induced heart failure canine model. What is the main finding and its importance? Renal denervation significantly attenuated the process of heart failure and improved left ventricular systolic dysfunction, stabilized ventricular electrophysiological properties and decreased the vulnerability of the heart to ventricular fibrillation during heart failure. Thus, renal denervation can attenuate ventricular electrical remodelling and exert a potential antifibrillatory action in a pacing-induced heart failure canine model. In this study, we investigated the effects of renal denervation (RDN) on the vulnerability to ventricular fibrillation (VF) and the ventricular electrical properties in a canine model of pacing-induced heart failure (HF). Eighteen beagles were divided into the following three groups: control (n=6), HF (n=6) and HF+RDN (n=6). Heart failure was induced by rapid right ventricular pacing. Renal denervation was performed simultaneously with the pacemaker implantation in the HF+RDN group. A 64-unipolar basket catheter was used to perform global endocardial mapping of the left ventricle. The restitution properties and dispersion of refractoriness were estimated from the activation recovery intervals (ARIs) by a pacing protocol. The VF threshold (VFT) was defined as the maximal pacing cycle length required to induce VF using a specific pacing protocol. The defibrillation threshold (DFT) was measured by an up-down algorithm. Renal denervation partly restored left ventricular systolic function and attenuated the process of HF. Compared with the control group, the VFT in the HF group was decreased by 27% (106±8.0 versus 135±10ms, P<0.01). However, RDN increased the VFT by 13% (135±10 versus 118±7.5ms, P<0.05) and decreased the DFT by 27% (30±6.3 versus 21.8±4.7J, P<0.05) in the treated hearts compared with the failing hearts. Renal denervation significantly flattened the ventricular ARI restitution curve by 15% (1.48±0.2 versus 1.26±0.11, P<0.05) and decreased the dispersion of ARI by 25% (0.08±0.02 versus 0.06±0.01, P<0.01) in the treated group compared with the HF group. The findings of this study suggest that RDN can attenuate ventricular electrical remodelling and exert a potential antifibrillatory action on VF in a canine model of pacing-induced HF.

Beat-to-beat variations in activation-recovery interval derived from the right ventricular electrogram can monitor arrhythmic risk under anesthetic and awake conditions in the canine chronic atrioventricular block model

In the chronic atrioventricular block (CAVB) dog model, beat-to-beat variation of repolarization in the left ventricle (LV) quantified as short-term variability of the left monophasic action potential duration (STVLVMAPD) increases abruptly upon challenge with a proarrhythmic drug. This increase occurs before the first ectopic beat (EB), specifically in subjects who demonstrate subsequent repetitive torsades de pointes arrhythmias (TdP). The purpose of this study was to demonstrate that STV is feasible to monitor arrhythmic risk through use of the intracardiac electrogram (EGM) derived from the right ventricular (RV) lead from pacemakers or implantable cardioverter-defibrillators. In 30 anaesthetized, inducible (≥3 TdP) CAVB dogs, STV between LV and RV monophasic action potential duration (STVLVMAPD and STVRVMAPD) was compared. In prospectively enrolled CAVB dogs, STV of the activation-recovery interval (ARI) derived from the RV EGM (STVRVARI) was measured before and after a challenge with dofetilide under anesthesia (2a; n = 10) and cisapride under awake conditions (2b; n = 8). Both STVLVMAPD and STVRVMAPD increased before the first EB (1.29 ± 0.58 ms to 3.05 ± 1.70 ms and 1.11 ± 0.53 ms to 2.18 ± 1.43 ms, respectively; P = 0.001). STVRVARI increased from 2.82 ± 0.33 ms to 3.77 ± 0.69 ms (P = .001). Inducible subjects (4/8) showed an increase in STVRVARI from 2.65 ± 0.55 ms to 3.45 ± 0.33 ms (in the first hour; P = .02) and 4.20 ± 1.33 ms (before the first EB; P = .04). Behavior of STV from the RV and LV is comparable. STVRVARI increases significantly before the occurrence of an arrhythmia in awake and anaesthetized conditions. This finding can be integrated into devices to monitor arrhythmic risk.

Ajmaline blocks INa and IKr without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters

The class Ia anti-arrhythmic drug ajmaline is used clinically to unmask latent type I ECG in Brugada syndrome (BrS) patients, although its mode of action is poorly characterised.Our aims were to identify ajmaline's mode of action in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), and establish a simple BrS hiPSC platform to test whether differences in ajmaline response could be determined between BrS patients and controls.Control hiPSCs were differentiated into spontaneously contracting cardiac clusters. It was found using multi electrode array (MEA) that ajmaline treatment significantly lengthened cluster activation-recovery interval. Patch clamping of single CMs isolated from clusters revealed that ajmaline can block both INa and IKr.Following generation of hiPSC lines from BrS patients (absent of pathogenic SCN5A sodium channel mutations), analysis of hiPSC-CMs from patients and controls revealed that differentiation and action potential parameters were similar. Comparison of cardiac clusters by MEA showed that ajmaline lengthened activation-recovery interval consistently across all lines.We conclude that ajmaline can block both depolarisation and repolarisation of hiPSC-CMs at the cellular level, but that a more refined integrated tissue model may be necessary to elicit differences in its effect between BrS patients and controls.

ST-Elevation Magnitude Correlates With Right Ventricular Outflow Tract Conduction Delay in Type I Brugada ECG.

The substrate location and underlying electrophysiological mechanisms that contribute to the characteristic ECG pattern of Brugada syndrome (BrS) are still debated. Using noninvasive electrocardiographical imaging, we studied whole heart conduction and repolarization patterns during ajmaline challenge in BrS individuals. A total of 13 participants (mean age, 44±12 years; 8 men), 11 concealed patients with type I BrS and 2 healthy controls, underwent an ajmaline infusion with electrocardiographical imaging and ECG recordings. Electrocardiographical imaging activation recovery intervals and activation timings across the right ventricle (RV) body, outflow tract (RVOT), and left ventricle were calculated and analyzed at baseline and when type I BrS pattern manifested after ajmaline infusion. Peak J-ST point elevation was calculated from the surface ECG and compared with the electrocardiographical imaging-derived parameters at the same time point. After ajmaline infusion, the RVOT had the greatest increase in conduction delay (5.4±2.8 versus 2.0±2.8 versus 1.1±1.6 ms; P=0.007) and activation recovery intervals prolongation (69±32 versus 39±29 versus 21±12 ms; P=0.0005) compared with RV or left ventricle. In controls, there was minimal change in J-ST point elevation, conduction delay, or activation recovery intervals at all sites with ajmaline. In patients with BrS, conduction delay in RVOT, but not RV or left ventricle, correlated to the degree of J-ST point elevation (Pearson R, 0.81; P<0.001). No correlation was found between J-ST point elevation and activation recovery intervals prolongation in the RVOT, RV, or left ventricle. Magnitude of ST (J point) elevation in the type I BrS pattern is attributed to degree of conduction delay in the RVOT and not prolongation in repolarization time.

Normal 123 I-MIBG uptake areas may be associated with hyperinnervation and arrhythmia risk in phenol model rabbit hearts.

Iodine-123 metaiodobenzylguanidine (123 I-MIBG) is useful for detecting sympathetic innervation in the heart, and has been closely associated with fatal arrhythmias. However, such imaging is typically calibrated to the area of highest uptake and thus is unable to identify areas of hyperinnervation. We hypothesized that normal 123 I-MIBG uptake regions in the denervated heart would demonstrate nerve sprouting and correlate with the potential for arrhythmogenesis. Twenty New Zealand white rabbits treated with phenol or sham were prepared under anesthesia. Sympathetic innervation was quantified using autoradiography and immunostaining 4weeks after phenol application, and electrophysiological study was performed. 123 I-MIBG revealed maximal local differences in isotope uptake in the border zone between areas with attenuated and abundant MIBG compared with that seen between adjacent regions within the lowest uptake areas. On immunostaining, heterogeneous and decreased expressions of growth-associated protein 43 signal were observed in the MIBG-attenuated areas; however, abundant signals were recognized in the MIBG-abundant areas. Upregulation of the tyrosine hydroxylase signal was observed at the part of the MIBG-abundant area. In electrophysiological study, the dispersion of activation recovery interval (ARI) was increased in the phenol-applied areas by norepinephrine infusion. Stellate stimulation exacerbated the ARI dispersion in both the phenol-applied and nonapplied areas, and was associated with increased inducibility of ventricular tachycardia and ventricular fibrillation. The presence of hyperinnervation in the nondenervated regions of denervated rabbit hearts suggests that heterogeneous neural remodeling occurs in regions with seemingly normal 123 I-MIBG uptake and contributes to electrical instability.