Epicardial Activation Research Articles

High frame rate ultrasounds for electromechanical wave imaging to characterize and differentiate endocardial from epicardial activation of ventricular arrhythmia: A proof of concept study

Differentiating an epicardial from an endocardial ventricular tachycardia (VT) can be really challenging despite the latest technologies available. We intended to develop a new tool method based on electromechanical wave imaging (EWI) to improve arrhythmogenic substrate activation analysis. Experiments were conducted on a left ventricle of a swine isolated working heart model. Our protocol aimed to demonstrate that, thanks to ultrasounds, a different pattern of mechanical activation could be obtained whether the ventricle was in sinus rhythm, paced from the epicardium or from the endocardium. EWI electrocardiogram-gated systematically differentiated with success endocardial from epicardial foci. When in paced ventricle, the origin of the wave front was focal and coming from the endocardium or the epicardium. In sinus rhythm, wave front was global and activating from the entire endocardium towards the epicardium at a speed of 1.47 ± 0.42 ms −1 . Wave front speed through the thickness of the ventricle was similar when the endocardium was paced (1.42 ± 0.38 ms −1 ) and much slower when the epicardium was paced (0.59 ± 0.19 ms −1 ). EWI activation mapping can locate ventricular activation inside the left ventricular wall thickness and calculate the propagation of the wave front through the muscle. In the future, this technology might help to differentiate endocardial from epicardial VT during complex ablation procedures.

Trabecular Architecture Determines Impulse Propagation Through the Early Embryonic Mouse Heart.

Most embryonic ventricular cardiomyocytes are quite uniform, in contrast to the adult heart, where the specialized ventricular conduction system is molecularly and functionally distinct from the working myocardium. We thus hypothesized that the preferential conduction pathway within the embryonic ventricle could be dictated by trabecular geometry. Mouse embryonic hearts of the Nkx2.5:eGFP strain between ED9.5 and ED14.5 were cleared and imaged whole mount by confocal microscopy, and reconstructed in 3D at 3.4 μm isotropic voxel size. The local orientation of the trabeculae, responsible for the anisotropic spreading of the signal, was characterized using spatially homogenized tensors (3 × 3 matrices) calculated from the trabecular skeleton. Activation maps were simulated assuming constant speed of spreading along the trabeculae. The results were compared with experimentally obtained epicardial activation maps generated by optical mapping with a voltage-sensitive dye. Simulated impulse propagation starting from the top of interventricular septum revealed the first epicardial breakthrough at the interventricular grove, similar to experimentally obtained activation maps. Likewise, ectopic activation from the left ventricular base perpendicular to dominant trabecular orientation resulted in isotropic and slower impulse spreading on the ventricular surface in both simulated and experimental conditions. We conclude that in the embryonic pre-septation heart, the geometry of the A-V connections and trabecular network is sufficient to explain impulse propagation and ventricular activation patterns.

Neuropilin 1 mediates epicardial activation and revascularization in the regenerating zebrafish heart.

ABSTRACTUnlike adult mammals, zebrafish can regenerate their heart. A key mechanism for regeneration is the activation of the epicardium, leading to the establishment of a supporting scaffold for new cardiomyocytes, angiogenesis and cytokine secretion. Neuropilins are co-receptors that mediate signaling of kinase receptors for cytokines with crucial roles in zebrafish heart regeneration. We investigated the role of neuropilins in response to cardiac injury and heart regeneration. All four neuropilin isoforms (nrp1a, nrp1b, nrp2a and nrp2b) were upregulated by the activated epicardium and an nrp1a-knockout mutant showed a significant delay in heart regeneration and displayed persistent collagen deposition. The regenerating hearts of nrp1a mutants were less vascularized, and epicardial-derived cell migration and re-expression of the developmental gene wt1b was impaired. Moreover, cryoinjury-induced activation and migration of epicardial cells in heart explants were reduced in nrp1a mutants. These results identify a key role for Nrp1 in zebrafish heart regeneration, mediated through epicardial activation, migration and revascularization.

A minimally invasive hybrid approach for cardiac resynchronization of the systemic right ventricle.

Patients with systemic right ventricle (RV) often develop progressive heart failure and may benefit from cardiac resynchronization therapy (CRT); however, the optimal strategy for CRT has not been defined. A retrospective review of all the patients with systemic RV failure undergoing a hybrid transcatheter-surgical approach was performed. Procedural technique and outcomes are reported. Six patients underwent detailed electroanatomical mapping of the systemic RV followed by a new hybrid approach targeting latest endocardial activation, which was followed by focused epicardial mapping. The exact site of latest endocardial activation was variable but localized to the basolateral RV in all cases. Sites of latest activation tended to be more superior during contralateral ventricular pacing versus intact atrioventricular conduction (P=0.06). Latest endocardial activation at the targeted site occurred at 157ms (interquartile range [IQR]=120-181ms) and corresponding epicardial activation at 174ms (IQR=140-198ms), after the onset of the QRS complex. Following the hybrid CRT, the QRS duration decreased from a median of 193 to 147ms and the fractional area of change increased from a median of 15.5% to 30% (P<0.001). Patients were discharged to home after a median of 4 days. Of the three patients who were initially referred for transplant evaluation, two (66%) of them no longer met the criteria following CRT. Whereas latest endocardial activation for the systemic RV appears to localize to the basolateral region, the optimal lead position may be variable. An approach utilizing endocardial mapping followed by a limited surgical incision and confirmation of latest activation may result in minimally invasive surgery and a favorable acute CRT response.

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.

How Accurate Is Inverse Electrocardiographic Mapping? A Systematic In Vivo Evaluation.

Inverse electrocardiographic mapping reconstructs cardiac electrical activity from recorded body surface potentials. This noninvasive technique has been used to identify potential ablation targets. Despite this, there has been little systematic evaluation of its reliability. Torso and ventricular epicardial potentials were recorded simultaneously in anesthetized, closed-chest pigs (n=5), during sinus rhythm, epicardial, and endocardial ventricular pacing (70 records in total). Body surface and cardiac electrode positions were determined and registered using magnetic resonance imaging. Epicardial potentials were reconstructed during ventricular activation using experiment-specific magnetic resonance imaging-based thorax models, with homogeneous or inhomogeneous (lungs, skeletal muscle, fat) electrical properties. Coupled finite/boundary element methods and a meshless approach based on the method of fundamental solutions were compared. Inverse mapping underestimated epicardial potentials >2-fold (P<0.0001). Mean correlation coefficients for reconstructed epicardial potential distributions ranged from 0.60±0.08 to 0.64±0.07 across all methods. Epicardial electrograms were recovered with reasonable fidelity at ≈50% of sites (median correlation coefficient, 0.69-0.72), but variation was substantial. General activation spread was reproduced (median correlation coefficient, 0.72-0.78 for activation time maps after spatio-temporal smoothing). Epicardial foci were identified with a median location error ≈16 mm (interquartile range, 9-29 mm). Inverse mapping with meshless method of fundamental solutions was better than with finite/boundary element methods, and the latter were not improved by inclusion of inhomogeneous torso electrical properties. Inverse potential mapping provides useful information on the origin and spread of epicardial activation. However the spatio-temporal variability of recovered electrograms limit resolution and must constrain the accuracy with which arrhythmia circuits can be identified independently using this approach.

PP-308 - Pneumomediastinum After Epicardial Ventricular Tachycardia Ablation

A 77-year-old male with ventricular tachycardia storm, converted by multiple anti-tachycardia pacing and shock attempts was referred to our arrhythmia center. During electrophysiologic study clinical ventricular tachycardia with pseudo-delta waves was induced. Epicardial activation and voltage mappings using Carto-3 system were obtained via subxiphoid route. Critical isthmus was detected at basal inferior right ventricular epicardium near the atrioventricular groove and radiofrequency ablation immediately stopped the tachycardia. No recurrence was seen with control stimulations. Severe retrosternal pain occurred during catheter manipulations. Transthoracic echo showed no remarkable pericardial effusion. Chest computed tomography demonstrated air localized in the periaortic area compatible with pneumomediastinum without additional complication (Figure 1, white stars). Chest-surgeon advised conservative follow-up and the patient was discharged with pain relief on the fifth postoperative day.

Micro RNAs are involved in activation of epicardium during zebrafish heart regeneration

Zebrafish could be an interesting translational model to understand and improve the post-infarction trial and possible regeneration in humans. The adult zebrafish is able to regenerate efficiently after resecting nearly 20% of the ventricular apex. This process requires the concert activation of the epicardium and endocardium, as well as trans-differentiation of pre-existing cardiomyocytes that together replace the lost tissue. The molecular mechanisms involved in this activation process are not completely clarified. In this work, in order to investigate if the downregulation of these miRNAs (miRs) are linked with the activation of epicardium, the expressions of miR-133a, b and miR-1 during regeneration were analysed. qPCR analyses in whole-heart, or from distinct dissected epicardial cells comparing to regenerative clot (containing cardiomyocytes, fibroblasts and endocardial cells) by a laser-micro-dissector, have indicated that already at 24 h there is a downregulation of miRs: (1) miR-133a and miR-1 in the epicardium and (2) miR-133b and miR-1 in the regenerative clot. All the miRs remain downregulated until 7 days post-surgery. With the aim to visualize the activations of heart component in combination with miRs, we developed immunohistochemistry using antibodies directed against common markers in mammals as well as zebrafish: Wilms tumour 1 (WT1), a marker of epicardium; heat-shock protein 70 (HSP70), a chaperon activated during regeneration; and the Cardiac Troponin T (cTnT), a marker of differentiated cardiomyocytes. All these markers are directly or indirectly linked to the investigated miRs. WT1 and HSP70 strongly marked the regeneration site just at 2–3 days postventricular resection. In coherence, cTnT intensively marked the regenerative portion from 7 days onwards. miRs-1 and -133 (a,b) have been strongly involved in the activation of epicardium and regenerative clot during the regeneration process in zebrafish. This study can be a useful translational model to understand the early epicardial activation in which miRs-133a and miR-1 seem to play a central role as observed in the human heart.

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.

Endocardial Activation Drives Activation Patterns During Long-Duration Ventricular Fibrillation and Defibrillation.

Understanding the mechanisms that drive ventricular fibrillation is essential for developing improved defibrillation techniques to terminate ventricular fibrillation (VF). Distinct organization patterns of chaotic, regular, and synchronized activity were previously demonstrated in VF that persisted over 1 to 2 minutes (long-duration VF [LDVF]). We hypothesized that activity on the endocardium may be driving these activation patterns in LDVF and that unsuccessful defibrillation shocks may alter activation patterns. The study was performed using a 64-electrode basket catheter on the left ventricle endocardium and 54 6-electrode plunge needles inserted into the left ventricles of 6 dogs. VF was induced electrically, and after short-duration VF (10 seconds) and LDVF (7 minutes), shocks of increasing strengths were delivered every 10 seconds until VF was terminated. Endocardial activation patterns were classified as chaotic (varying cycle lengths and nonsynchronous activations), regular (highly repeatable cycle lengths), and synchronized (activation that spreads rapidly over the endocardium with diastolic periods between activations). The results showed that the chaotic pattern was predominant in early VF, but the regular pattern emerges as VF progressed. The synchronized pattern only emerged occasionally during late VF. Failed defibrillation shocks changed chaotic and regular activation patterns to synchronized patterns in LDVF but not in short-duration VF. The regular and synchronized patterns of activation were driven by rapid activations on the endocardial surface that blocked and broke up transmurally, leading to an endocardial to epicardial activation rate gradient as LDVF progressed.

Antiarrhythmic properties of ivabradine in an experimental model of Short-QT- Syndrome.

The If channel inhibitor ivabradine is recommended for treatment of chronic heart failure. However, ivabradine also inhibits human ether-a-go-go (hERG) mediated potassium currents. The aim of the present study was to assess the electrophysiologic effects of ivabradine in an experimental model of short-QT-syndrome. Twelve rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, pinacidil, an IK-ATP channel opener, was infused (1μmol/L). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a significant abbreviation of QT interval (-32ms, P<.05) and shortening of action potential duration at 90% of repolarization (APD90; -22ms, P<.05). The shortening of ventricular repolarization was accompanied by a reduction of effective refractory period (ERP; -20ms, P<.05). Thereafter, hearts were additionally treated with ivabradine (5μmol/L) leading to an increase of QT interval (+31ms, P<.05), APD90 (+15ms, P<.05) as well as of ERP (+38ms, P<.05) and post-repolarization refractoriness (PRR, +33ms, P<.05) as compared with sole pinacidil infusion. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in 3 of 12 hearts (6 episodes). After application of 1μmol/L pinacidil, 6 of 12 hearts were inducible (22 episodes). Additional infusion of 5μmol/L ivabradine led to a significant suppression of VF. Only two episodes could be induced in 1 of 12 hearts. In the present study ivabradine reversed the electrophysiologic effects of pharmacologically simulated short-QT syndrome. Ivabradine demonstrated antiarrhythmic properties based on an increase of both ERP and PRR.

BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease

Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin β4 (Tβ4) and myocardial infarction (MI) by reactivating a fetal gene programme to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene (re-)activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of the SWI/SNF chromatin–remodelling complex, is required for expression of Wilms’ tumour 1 (Wt1), fetal EPDC activation and subsequent differentiation into coronary smooth muscle, and restores Wt1 activity upon MI. BRG1 physically interacts with Tβ4 and is recruited by CCAAT/enhancer-binding protein β (C/EBPβ) to discrete regulatory elements in the Wt1 locus. BRG1-Tβ4 co-operative binding promotes optimal transcription of Wt1 as the master regulator of embryonic EPDCs. Moreover, chromatin immunoprecipitation-sequencing reveals BRG1 binding at further key loci suggesting SWI/SNF activity across the fetal epicardial gene programme. These findings reveal essential functions for chromatin–remodelling in the activation of EPDCs during cardiovascular development and repair.

Abstract 86: Mapping and Inducing Ventricular Tachycardia in Cardiomyopathic Animal Models

Introduction: In the United States, one in three deaths is attributed to cardiovascular disease (CVD). With CVD, sudden cardiac death is a common cause of mortality, specifically by way of ventricular tachycardia (VT) and ventricular fibrillation. We propose the application of our custom software to evaluate the electrophysiologic (EP) properties of animal models of ischemic and non-ischemic dilated cardiomyopathies. Methods: Adult male Sprague-Dawley rats with left coronary artery ligation and adult male and female transgenic Fragile X cardiomyopathic mice were sedated with Inactin and Isoflurane, respectively, and underwent hemodynamic measurements and/or EP testing. Using a PowerLab system and LabChart software, three-lead electrocardiograms were recorded. Using a pressure catheter, hemodynamic parameters were calculated. Using a concentric microelectrode (World Precision Inc.), a clinical EP catheter (Bard Inc.), and custom MATLAB software, local epicardial monophasic action potentials (MAP) and local epicardial voltages were recorded. Using custom MATLAB software for programmed electrical stimulation (PES), VT was induced epicardially with a clinically-accepted drivetrain. Animals underwent eight equidistant ‘S1’ stimulations followed by a premature ‘S2’ stimulation. The S2 stimulation was decreased by 5 milliseconds until loss of capture, indicating the effective refractory period. Sustained ventricular tachycardia (sVT) has been defined as more than fifteen consecutive premature ventricular contractions. Results: The chronic heart failure (CHF) rats had documented hemodynamic heart failure with elevated LV EDPs, and decreased EFs. Mapping and PES was performed on the two groups of rats, namely CHF and Sham-operated. In the CHF group, 71% (27/39) of the rats exhibited sVT, while 0% (0/10) of the Sham-operated rats exhibited sVT. Mapping was also performed on the two groups of mice, namely Wild-Type and Fragile X. Conclusions: We have performed clinically-relevant EP studies in CHF rats and in Fragile X dilated cardiomyopathic mice. These EP studies demonstrate our ability to evaluate and validate the phenotypes of animal models of cardiomyopathies and demonstrate the potential to evaluate the effectiveness of new therapies.

CaMKII Activation Promotes Cardiac Electrical Remodeling and Increases the Susceptibility to Arrhythmia Induction in High-fat Diet-Fed Mice With Hyperlipidemia Conditions.

Background:Obesity/hyperlipidemia is closely related to both atrial and ventricular arrhythmias. CaMKII, a multifunctional serine/threonine kinase, has been involved in cardiac arrhythmias of different etiologies. However, its role in obesity/hyperlipidemia-related cardiac arrhythmia is unexplored. The aim of this was to determine the involvement of CaMKII in the process.Methods:Adult male APOE−/− mice were fed a high-fat diet (HFD), administrated with KN93 (10 mg·kg−1·2d−1), a specific inhibitor of CaMKII. Serum lipid and glucose profile, cardiac function, and surface electrocardiogram were determined. Electrophysiological study and epicardial activation mapping were performed in Langendorff-perfused heart. Expression of cardiac ion channels, gap junction proteins, Ca2+ handling proteins, and CaMKII were evaluated, coupled with histological analysis.Results:A hyperlipidemia condition was induced by HFD in the APOE−/− mice, which was associated with increased expression and activity of CaMKII in the hearts. In Langendorff-perfused hearts, HFD-induced heart showed increased arrhythmia inducibility, prolonged action potential duration, and decreased action potential duration alternans thresholds, coupled with slow ventricular conduction, connexin-43 upregulation, and interstitial fibrosis. Downregulation of ion channels including Cav1.2 and Kv4.2/Kv4.3 and disturbed Ca2+ handling proteins were also observed in HFD-induced heart. Interestingly, all these alterations were significantly inhibited by KN93 treatment.Conclusion:Our results demonstrated an adverse effect of metabolic components on cardiac electrophysiology and implicated an important role of CaMKII underlying this process.

Electrical and Structural Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a significant cause of sudden cardiac death in the young. Improved noninvasive assessment of ARVC and better understanding of the disease substrate are important for improving patient outcomes. We studied 20 genotyped ARVC patients with a broad spectrum of disease using electrocardiographic imaging (a method for noninvasive cardiac electrophysiology mapping) and advanced late gadolinium enhancement cardiac magnetic resonance scar imaging. Compared with 20 healthy controls, ARVC patients had longer ventricular activation duration (median, 52 versus 42 ms; P=0.007) and prolonged mean epicardial activation-recovery intervals (a surrogate for local action potential duration; median, 275 versus 241 ms; P=0.014). In these patients, we observed abnormal and varied epicardial activation breakthrough locations and regions of nonuniform conduction and fractionated electrograms. Nonuniform conduction and fractionated electrograms were present in the early concealed phase of ARVC. Electrophysiological abnormalities colocalized with late gadolinium enhancement scar, indicating a relationship with structural disease. Premature ventricular contractions were common in ARVC patients with variable initiation sites in both ventricles. Premature ventricular contraction rate increased with exercise, and within anatomic segments, it correlated with prolonged repolarization, electric markers of scar, and late gadolinium enhancement (all P<0.001). Electrocardiographic imaging reveals electrophysiological substrate properties that differ in ARVC patients compared with healthy controls. A novel mechanistic finding is the presence of repolarization abnormalities in regions where ventricular ectopy originates. The results suggest a potential role for electrocardiographic imaging and late gadolinium enhancement in early diagnosis and noninvasive follow-up of ARVC patients.

Effect of thoracic epidural anesthesia on heart rate variability in a porcine model.

Heart rate variability (HRV) is increasingly recognized as a means of evaluating autonomic tone. Thoracic epidural anesthesia (TEA) has been previously demonstrated to suppress the electrical storms in patients. However, the effect of TEA on HRV during sympathoexcitation remains unknown. In this study, we aimed to determine the effects of TEA on HRV response to left stellate ganglion stimulation (LSS) in a porcine model. In 12 anesthetized pigs after insertion of an epidural catheter to T1 level, a median sternotomy was performed to expose the heart and the left stellate ganglion. A 56‐electrode sock was used for obtaining epicardial activation recovery interval (ARI). Animal received LSS at 4 Hz for 30 sec. After 30 min of bupivacaine epidural injection, LSS was performed in the same way as the baseline condition. LSS significantly increased low‐frequency normalized units (LF: 44.9 ± 6.7 vs. 13.6 ± 3.1 msec2 baseline, P < 0.05) and decreased high‐frequency normalized units (HF: 11.5 ± 4.6 vs. 41.9 ± 5.1 msec2 baseline, P < 0.05). As a result, LF/HF significantly increased from 0.3 ± 0.2 to 3.9 ± 1.4 during LSS. TEA significantly attenuated the LF/HF from 3.9 ± 1.4 to 1.6 ± 0.8 with increased HF components from 11.5 ± 4.6 to 26.5 ± 3.2 msec2. LF component significantly correlates with global ARI (r = −0.81) and dispersion of repolarization (r = 0.85). HRV can precisely reflect the cardiac autonomic tone and TEA modulates the HRV by enhancing the HF components probably through a parasympathetic nerve system.

Mesenchymal stem cell-loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium.

Cardiac patch is considered a promising strategy for enhancing stem cell therapy of myocardial infarction (MI). However, the underlying mechanisms for cardiac patch repairing infarcted myocardium remain unclear. In this study, we investigated the mechanisms of PCL/gelatin patch loaded with MSCs on activating endogenous cardiac repair. PCL/gelatin patch was fabricated by electrospun. The patch enhanced the survival of the seeded MSCs and their HIF‐1α, Tβ4, VEGF and SDF‐1 expression and decreased CXCL14 expression in hypoxic and serum‐deprived conditions. In murine MI models, the survival and distribution of the engrafted MSCs and the activation of the epicardium were examined, respectively. At 4 weeks after transplantation of the cell patch, the cardiac functions were significantly improved. The engrafted MSCs migrated across the epicardium and into the myocardium. Tendency of HIF‐1α, Tβ4, VEGF, SDF‐1 and CXCL14 expression in the infarcted myocardium was similar with expression in vitro. The epicardium was activated and epicardial‐derived cells (EPDCs) migrated into deep tissue. The EPDCs differentiated into endothelial cells and smooth muscle cells, and some of EPDCs showed to have differentiated into cardiomyocytes. Density of blood and lymphatic capillaries increased significantly. More c‐kit+ cells were recruited into the infarcted myocardium after transplantation of the cell patch. The results suggest that epicardial transplantation of the cell patch promotes repair of the infarcted myocardium and improves cardiac functions by enhancing the survival of the transplanted cells, accelerating locality paracrine, and then activating the epicardium and recruiting endogenous c‐kit+ cells. Epicardial transplantation of the cell patch may be applied as a novel effective MI therapy.

Severe Proarrhythmic Potential of the Antiemetic Agents Ondansetron and Domperidone.

The potential of ondansetron and domperidone, both clinically established antiemetic agents, to increase the QT-interval has been described in several case reports. Therefore, the aim of the present study was to investigate whether these drugs may provoke polymorphic ventricular tachycardia in a sensitive experimental model of drug-induced proarrhythmia. In 10 female rabbits, ondansetron (1, 5 and 10µM, n=10) or domperidone (0.5, 1 and 2µM, n=8) was infused after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG reproduced the clinically observed QT-prolongation (ondansetron: 1µM:+17ms, 5µM:+41ms, 10µM:+78ms, p<0.01; domperidone: 0.5µM:+57ms, 1µM:+79ms, 2µM:+99ms, p<0.01). This was accompanied by a significant increase in action potential duration at 90% of repolarization. Administration of both agents also increased dispersion of repolarization (ondansetron: 1µM:+12ms, 5µM:+17ms; 10µM:+18ms, p<0.05; domperidone: 0.5µM:+19ms, 1µM:+27ms; 2µM:+23ms p<0.05). Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 9 of 10 ondansetron-treated hearts and induced polymorphic ventricular tachycardia (VT) resembling torsade de pointes in 7 of 10 ondansetron-treated hearts (86 episodes). Under the influence of domperidone, EAD and polymorphic VT occurred in 7 of 8 hearts (131 episodes). In the present study, both ondansetron and domperidone demonstrated a severe proarrhythmic potential. A significant prolongation of cardiac repolarization as well as a marked increase in spatial dispersion of repolarization represents the underlying electrophysiologic mechanisms. These results imply that application of ondansetron should be handled carefully. For regular administration, ECG monitoring should be mandatory.

Colchicine Increases Ventricular Vulnerability in an Experimental Whole‐Heart Model

The traditional gout medication colchicine has been reported to effectively prevent atrial fibrillation recurrence after atrial fibrillation ablation or cardiac surgery in a few clinical trials. Severe adverse events have not yet been reported. The aim of the present study was to assess possible direct electrophysiological effects in an experimental whole-heart model. Ten rabbit hearts were isolated and Langendorff-perfused. Thereafter, colchicine was administered in two concentrations (1 and 3 μM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a stable QT interval and action potential duration during colchicine infusion. Furthermore, there was no significant increase in dispersion of repolarization. However, colchicine induced a dose-dependent significant decrease of effective refractory period (ERP; 1 μM: -19 ms, 3 μM: -22 ms; p < 0.05). In the present study, acute infusion of colchicine in isolated rabbit hearts resulted in a reduction of ERP in the presence of a stable myocardial repolarization. This led to a significantly elevated inducibility of ventricular fibrillation. In 4 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a pro-arrhythmic or toxic effect of colchicine and underline that further clinical studies on potential adverse effects should be conducted before the drug can be recommended for routine use after atrial fibrillation ablation.

Expecting the Expected: Electrocardiographic Identification for Ablation Targets.

An invariable hallmark of an experienced invasive electrophysiologist is his or her ability to thoroughly examine preprocedural data so as to anticipate the likely site of successful ablation. Indeed, teaching rounds for electrophysiology at any institution is likely replete with examples of how careful analysis of the ECG and structural imaging data are used to anticipate not only where to ablate but also the specific anatomic hurdles that may be encountered, facilitating planning to avoid complications. Although advanced imaging has become increasingly useful to understand substrate abnormalities, the mainstay for preprocedural prediction of successful ablation remains the ECG. See Article by Namdar et al From the outset, the field of electrophysiology has relied heavily on the ECG for clinical and invasive diagnoses. Every student’s knowledge base includes ECG localization for accessory pathways and detailed ECG vector analysis to diagnose the origin of monomorphic ventricular tachycardia and atrial tachycardia.1 In this installment of Teaching Rounds in Cardiac Electrophysiology, Namdar et al2 add to this legacy instructing us on an advanced multielectrode surface ECG analysis system that allowed a surprisingly high degree of spatial resolution in identifying a coronary venous epicardial ventricular tachycardia focus. The authors elegantly instruct us on the use of the new system, but, more importantly, provide a …