Uncoupling cytosolic calcium from membrane voltage by transient receptor potential melastatin 4 channel (TRPM4) modulation: A novel strategy to treat ventricular arrhythmias.

The current antiarrhythmic paradigm is mainly centered around modulating membrane voltage. However, abnormal cytosolic calcium (Ca2+) signaling, which plays an important role in driving membrane voltage, has not been targeted for therapeutic purposes in arrhythmogenesis. There is clear evidence for bidirectional coupling between membrane voltage and intracellular Ca2+. Cytosolic Ca2+ regulates membrane voltage through Ca2+-sensitive membrane currents. As a component of Ca2+-sensitive currents, Ca2+-activated nonspecific cationic current through the TRPM4 (transient receptor potential melastatin 4) channel plays a significant role in Ca2+-driven changes in membrane electrophysiology. In myopathic and ischemic ventricles, upregulation and/or enhanced activity of this current is associated with the generation of afterdepolarization (both early and delayed), reduction of repolarization reserve, and increased propensity to ventricular arrhythmias. In this review, we describe a novel concept for the management of ventricular arrhythmias in the remodeled ventricle based on mechanistic concepts from experimental studies, by uncoupling the Ca2+-induced changes in membrane voltage by inhibition of this TRPM4-mediated current.

Restoration of calcium release synchrony: A novel target for heart failure and ventricular arrhythmia.

Myocardial calcium (Ca2+) signaling plays a crucial role in contractile function and membrane electrophysiology. An abnormal myocardial Ca2+ transient is linked to heart failure and ventricular arrhythmias. At the subcellular level, the synchronous release of Ca2+ sparks from sarcoplasmic Ca2+ release units determines the configuration and amplitude of the global Ca2+ transient. This narrative review evaluates the role of aberrant Ca2+ release synchrony in the pathophysiology of cardiomyopathies and ventricular arrhythmias. The potential therapeutic benefits of restoration of Ca2+ release synchrony in heart failure and ventricular arrhythmias are also discussed.

Pro-arrhythmic role of adrenergic spatial densities in the human atria: An in-silico study.

Chronic stress among young patients (≤ 45 years old) could result in autonomic dysfunction. Autonomic dysfunction could be exhibited via sympathetic hyperactivity, sympathetic nerve sprouting, and diffuse adrenergic stimulation in the atria. Adrenergic spatial densities could alter atrial electrophysiology and increase arrhythmic susceptibility. Therefore, we examined the role of adrenergic spatial densities in creating arrhythmogenic substrates in silico. We simulated three 25 cm2 atrial sheets with varying adrenergic spatial densities (ASD), activation rates, and external transmembrane currents. We measured their effects on spatial and temporal heterogeneity of action potential durations (APD) at 50% and 20%. Increasing ASD shortens overall APD, and maximum spatial heterogeneity (31%) is achieved at 15% ASD. The addition of a few (5% to 10%) adrenergic elements decreases the excitation threshold, below 18 µA/cm2, while ASDs greater than 10% increase their excitation threshold up to 22 µA/cm2. Increase in ASD during rapid activation increases APD50 and APD20 by 21% and 41%, respectively. Activation times of captured beats during rapid activation could change by as much as 120 ms from the baseline cycle length. Rapidly activated atrial sheets with high ASDs significantly increase temporal heterogeneity of APD50 and APD20. Rapidly activated atrial sheets with 10% ASD have a high likelihood (0.7 ± 0.06) of fragmenting otherwise uniform wavefronts due to the transient inexcitability of adrenergically stimulated elements, producing an effective functional block. The likelihood of wave fragmentation due to ASD highly correlates with the spatial variations of APD20 (ρ = 0.90, p = 0.04). Our simulations provide a novel insight into the contributions of ASD to spatial and temporal heterogeneities of APDs, changes in excitation thresholds, and a potential explanation for wave fragmentation in the human atria due to sympathetic hyperactivity. Our work may aid in elucidating an electrophysiological link to arrhythmia initiation due to chronic stress among young patients.

Decrement Evoked Potential (DEEP) Mapping of the Atria: Unmasking Atrial Fibrillation Substrate.

BACKGROUND: Atrial myopathy may underlie the progression of atrial fibrillation (AF) from a treatable disease to an irreversible condition with poor ablation outcomes. Electrophysiological methods to unmask areas prone to re-entry initiation could be key to defining latent atrial myopathy. METHODS: Consecutive patients referred for AF ablation were prospectively included at four institutions. Decrement evoked potential mapping (DEEP) was performed in eight left atrial sites and five right atrial sites, from two different pacing locations (endocardially from the left atrial appendage, epicardially from the proximal coronary sinus). The electrograms (EGMs) during S1 600 ms drive and after an extra stimulus (S2 at +30 ms above atrial refractoriness) were studied at each location and assessed for decremental properties. Follow-up was 12 months. RESULTS: Seventy-four patients were included and 85% had persistent AF. A total of 17,614 EGMs were individually analysed and measured. Nine percent of the EGMs showed DEEP properties (local delay of >10 ms after S2) with a mean decrement of 33±26 ms. DEEPs were more frequent in the left atrium than the right atrium (9.4% vs 8.0%; p<0.001) and more prevalent in persistent AF patients than paroxysmal AF patients (9.8% vs 4.6% p=0.001). Atrial DEEPs were more frequently unmasked in normal bipolar voltage areas and by epicardial pacing than endocardial pacing (9.6% vs 8.4%, respectively; p=0.004). Within the left atrium, the roof had the highest prevalence of DEEP EGMs. CONCLUSIONS: DEEP mapping of both atria is useful for highlighting areas with a tendency for unidirectional block and re-entry initiation. Those areas are more easily unmasked by epicardial pacing from the coronary sinus and more prevalent in persistent AF patients than in paroxysmal AF patients.

Maturation of iPSC-derived cardiomyocytes in a heart-on-a-chip device enables modeling of dilated cardiomyopathy caused by R222Q-SCN5A mutation.

To better understand sodium channel (SCN5A)-related cardiomyopathies, we generated ventricular cardiomyocytes from induced pluripotent stem cells obtained from a dilated cardiomyopathy patient harbouring the R222Q mutation, which is only expressed in adult SCN5A isoforms. Because the adult SCN5A isoform was poorly expressed, without functional differences between R222Q and control in both embryoid bodies and cell sheet preparations (cultured for 29-35 days), we created heart-on-a-chip biowires which promote myocardial maturation. Indeed, biowires expressed primarily adult SCN5A with R222Q preparations displaying (arrhythmogenic) short action potentials, altered Na+ channel biophysical properties and lower contractility compared to corrected controls. Comprehensive RNA sequencing revealed differential gene regulation between R222Q and control biowires in cellular pathways related to sarcoplasmic reticulum and dystroglycan complex as well as biological processes related to calcium ion regulation and action potential. Additionally, R222Q biowires had marked reductions in actin expression accompanied by profound sarcoplasmic disarray, without differences in cell composition (fibroblast, endothelial cells, and cardiomyocytes) compared to corrected biowires. In conclusion, we demonstrate that in addition to altering cardiac electrophysiology and Na+ current, the R222Q mutation also causes profound sarcomere disruptions and mechanical destabilization. Possible mechanisms for these observations are discussed.

Orientation of conduction velocity vectors on cardiac mapping surfaces.

AIMS: Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using two-dimensional (2D) mapping tools. We studied the accuracy of mapping surface 2D CV, compared to the three-dimensional (3D) vectors, and the influence of mapping resolution in non-scarred animal and human heart models. METHODS AND RESULTS: Two models were used: a healthy porcine Langendorff model with transmural needle electrodes and a computer stimulation model of the ventricles built from an MRI-segmented, excised human heart. Local activation times (LATs) within the 3D volume of the mesh were used to calculate true 3D CVs (direction and velocity) for different pixel resolutions ranging between 500 µm and 4 mm (3D CVs). CV was also calculated for endocardial surface-only LATs (2D CV). In the experimental model, surface (2D) CV was faster on the epicardium (0.509 m/s) compared to the endocardium (0.262 m/s). In stimulation models, 2D CV significantly exceeded 3D CVs across all mapping resolutions and increased as resolution decreased. Three-dimensional and 2D left ventricle CV at 500 µm resolution increased from 429.2 ± 189.3 to 527.7 ± 253.8 mm/s (P < 0.01), respectively, with modest correlation (R = 0.64). Decreasing the resolution to 4 mm significantly increased 2D CV and weakened the correlation (R = 0.46). The majority of CV vectors were not parallel (<30°) to the mapping surface providing a potential mechanistic explanation for erroneous LAT-based CV over-estimation. CONCLUSION: Ventricular CV is overestimated when using 2D LAT-based CV calculation of the mapping surface and significantly compounded by mapping resolution. Three-dimensional electric field-based approaches are needed in mapping true CV on mapping surfaces.

Statins Protect Against Early Stages of Doxorubicin-induced Cardiotoxicity Through the Regulation of Akt Signaling and SERCA2.

Background: Doxorubicin-induced cardiomyopathy (DICM) is one of the complications that can limit treatment for a significant number of cancer patients. In animal models, the administration of statins can prevent the development of DICM. Therefore, the use of statins with anthracyclines potentially could enable cancer patients to complete their chemotherapy without added cardiotoxicity. The precise mechanism mediating the cardioprotection is not well understood. The purpose of this study is to determine the molecular mechanism by which rosuvastatin confers cardioprotection in a mouse model of DICM. Methods: Rosuvastatin was intraperitoneally administered into adult male mice at 100 µg/kg daily for 7 days, followed by a single intraperitoneal doxorubicin injection at 10 mg/kg. Animals continued to receive rosuvastatin daily for an additional 14 days. Cardiac function was assessed by echocardiography. Optical calcium mapping was performed on retrograde Langendorff perfused isolated hearts. Ventricular tissue samples were analyzed by immunofluorescence microscopy, Western blotting, and quantitative polymerase chain reaction. Results: Exposure to doxorubicin resulted in significantly reduced fractional shortening (27.4% ± 1.11% vs 40% ± 5.8% in controls; P < 0.001) and re-expression of the fetal gene program. However, we found no evidence of maladaptive cardiac hypertrophy or adverse ventricular remodeling in mice exposed to this dose of doxorubicin. In contrast, rosuvastatin-doxorubicin-treated mice maintained their cardiac function (39% ± 1.26%; P < 0.001). Mechanistically, the effect of rosuvastatin was associated with activation of Akt and phosphorylation of phospholamban with preserved sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 (SERCA2)-mediated Ca2+ reuptake. These effects occurred independently of perturbations in ryanodine receptor 2 function. Conclusions: Rosuvastatin counteracts the cardiotoxic effects of doxorubicin by directly targeting sarcoplasmic calcium cycling.

Contexte: La cardiomyopathie induite par la doxorubicine (CMID) est l'une des complications pouvant limiter le traitement d'un nombre considérable de patients atteints de cancer. Dans des modèles animaux, l'administration de statines peut prévenir l'apparition d'une CMID. Ainsi, l'utilisation de statines avec les anthracyclines pourrait vraisemblablement permettre aux patients de compléter leur chimiothérapie en évitant une cardiotoxicité supplémentaire. Le mécanisme précis qui sous-tend cet effet cardioprotecteur n'est pas entièrement élucidé. Cette étude a pour objectif de déterminer dans un modèle murin de CMID le mécanisme moléculaire par lequel la rosuvastatine confère une cardioprotection. Méthodologie: La rosuvastatine a été administrée par voie intrapéritonéale à des souris adultes mâles à une dose de 100 µg/kg par jour pendant sept jours, suivie d'une dose unique de doxorubicine de 10 mg/kg administrée par injection intrapéritonéale. Les animaux poursuivaient ensuite le traitement par la rosuvastatine une fois par jour pendant 14 jours supplémentaires. La fonction cardiaque a été mesurée par échocardiographie. Une cartographie optique du calcium a été réalisée sur des cœurs isolés soumis à une perfusion rétrograde selon la méthode de Langendorff. Des échantillons de tissu ventriculaire ont été analysés par microscopie en immunofluorescence, par buvardage de western et par mesure quantitative de l'amplification en chaîne par polymérase. Résultats: L'exposition à la doxorubicine a entraîné une diminution significative de la fraction de raccourcissement (27,4 % ± 1,11 % vs 40 % ± 5,8 % dans le groupe témoin; p < 0,001) et la réexpression du programme génique fœtal. Toutefois, aucune hypertrophie cardiaque inadaptée ni aucun remodelage ventriculaire indésirable n'ont été observés chez les souris ayant été exposées à la dose de doxorubicine étudiée. En revanche, la fonction cardiaque a été préservée chez les souris traitées par l'association rosuvastatine-doxorubicine (39 % ± 1,26 %; p < 0,001). Sur le plan du mode d'action, l'effet de la rosuvastatine a été associé à une activation de l'Akt et à une phosphorylation du phospholambane, avec préservation du recaptage de Ca2+ médié par la pompe SERCA2 (sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2). Ces effets sont survenus indépendamment des perturbations de la fonction du récepteur RyR2 (ryanodine receptor 2). Conclusions: La rosuvastatine neutralise les effets cardiotoxiques de la doxorubicine en ciblant directement la circulation sarcoplasmique du calcium.

Synchronizing systolic calcium release with azumolene in an experimental model.

Background: Post-defibrillation myocardial contractile dysfunction adversely affects the survival of patients after cardiac arrest. Attenuation of diastolic calcium (Ca2+) overload by stabilization of the cardiac ryanodine receptor (RyR2) is found to reduce refibrillation after long-duration ventricular fibrillation (LDVF). Objective: In the present study, we explored the effects of RyR2 stabilization by azumolene on systolic Ca2+ release synchrony and myocardial contractility. Methods: After completion of baseline optical mapping, Langendorff-perfused rabbit hearts were subjected to global ischemia followed by reperfusion with azumolene or deionized distilled water (vehicle). Following reperfusion, LDVF was induced with burst pacing. In the first series of experiments (n = 16), epicardial Ca2+ transient was analyzed for Ca2+ transient amplitude alternans and dispersion of Ca2+ transient amplitude alternans index (CAAI). In the second series of experiments following the same protocol (n = 12), ventricular contractility was assessed by measuring the left ventricular pressure. Results: Ischemic LDVF led to greater CAAI (0.06 ± 0.02 at baseline vs 0.12 ± 0.02 post-LDVF, P < .01) and magnitude of dispersion of CAAI (0.04 ± 0.01 vs 0.09 ± 0.01, P < .01) in control hearts. In azumolene-treated hearts, no significant changes in CAAI (0.05 ± 0.01 vs 0.05 ± 0.01, P = .84) and dispersion of CAAI (0.04 ± 0.01 vs 0.04 ± 0.01, P = .99) were noted following ischemic LDVF. Ischemic LDVF was associated with reduction in left ventricular developed pressure (100% vs 36.8% ± 6.1%, P = .002) and dP/dtmax (100% vs 45.3% ± 6.5%, P = .003) in control hearts, but these reductions were mitigated (left ventricular developed pressure: 100% vs 74.0% ± 8.1%, P = .052, dP/dtmax: 100% vs 80.8% ± 7.9%, P = .09) in azumolene-treated hearts. Conclusion: Treatment with azumolene is associated with improvement of systolic Ca2+ release synchrony and myocardial contractility following ischemic LDVF.

Automated Identification of Ventricular Tachycardia Ablation Targets: Multicenter Validation and Workflow Characterization.

Decrement evoked potentials (EPs) (DeEPs) constitute an accepted method to identify physiological ventricular tachycardia (VT) ablation targets without inducing VT. The feasibility of automated software (SW) in the detection of arrhythmogenic VT substrate has been documented. However, multicenter validation of automated SW and workflow has yet to be characterized. The objective of this study was to describe the functionality of a novel DeEP SW (Biosense Webster, Diamond Bar, CA, USA) and evaluate the independent performance of the automated algorithm using multicenter data. VT ablation cases were performed in the catheterization laboratory and retrospectively analyzed using the DeEP SW. The algorithm indicated and mapped DeEPs by first identifying capture in surface electrocardiograms (ECGs). Once capture was confirmed, the EPs of S1 paces were detected. The algorithm checked for the stability of S1 EPs by comparing the last 3 of the 8 morphologies and attributing standard deviation values. The extra-stimulus EP was then detected by comparing it to the S1 EP. Once detected, the DeEP value was computed from the extra-stimulus and displayed as a sphere on a voltage map. A total of 5,885 DeEP signals were extracted from 21 substrate mapping cases conducted at 3 different centers (in Spain, Canada, and Australia). A gold standard was established from ECGs manually marked by subject experts. Once the algorithm was deployed, 91.6% of S2 algorithm markings coincided with the gold standard, 1.9% were false-positives, and 0.1% were false-negatives. Also, 6.4% were non-specific DeEP detections. In conclusion, the automated DeEP algorithm identifies and displays DeEP points, revealing VT substrates in a multicenter validation study. The automation of identification and mapping display is expected to improve efficiency.

Overdrive pacing in the acute management of osimertinib-induced ventricular arrhythmias: A case report and literature review.

QT interval prolongation and ventricular arrhythmias (VAs) induced by osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, are life-threatening complications. However, no consensus has been achieved regarding their management. Overdrive pacing has been shown to be effective in shortening the QT interval and terminating torsade de pointes (TdP). Here, we report a case of osimertinib-induced QT prolongation accompanied by frequent VAs and TdP. Osimertinib was immediately discontinued after it was identified as the etiology for QT prolongation and VAs. A temporary pacemaker and overdrive pacing were used after other anti-arrhythmia treatments had failed and successfully shortened the QTc interval and terminated VAs. Repeated Holter monitoring at 1 week showed no remaining VAs or TdP, and the pacemaker was removed. Routine electrocardiography (ECG) surveillance was conducted afterward, and three- and 6-month follow-ups showed good recovery and normal ECG results. Vigilance is required for rare vital arrhythmias in patients taking osimertinib, and ECG surveillance should be conducted.

An In-Silico model for evaluating the directional shock vectors in terminating and modulating rotors.

Out-of-hospital cardiac arrest (OHCA) accounts for a majority of mortality worldwide. Survivability from an OHCA highly depends on timely and effective defibrillation. Most of the OHCA cases are due to ventricular fibrillation (VF), a lethal form of cardiac arrhythmia. During VF, previous studies have shown the presence of spatiotemporally organized electrical activities called rotors and that terminating these rotor-like activities could modulate or terminate VF in an in-hospital or research setting. However, such an approach is not feasible for OHCA scenarios. In the case of an OHCA, external defibrillation remains the main therapeutic option despite the low survival rates. In this study, we evaluated whether defibrillation effectiveness in an OHCA scenario could be improved if a shock vector directly targets rotor-like, spatiotemporal electrical activities on the myocardium. Specifically, we hypothesized that the position of defibrillator pads with respect to a rotor's core axis and shock current density could influence the likelihood of rotor termination and thereby result in successful defibrillation. We created a bidomain cardiac model based on porcine heart data using Aliev-Panfilov bidomain equations. We simulated localized rotors, which we attempted to terminate using different defibrillation pad orientations relative to the rotor axis (i.e., perpendicular, parallel, and oblique). In addition, we gradually increased current densities for each defibrillation pad orientation from 4 to 12 A/m2. We repeated the above defibrillation procedure for rotors originating from four different locations on the ventricles. The shock parameters and the outcomes were analyzed using a Generalized Linear Mixed Model (GLMM) with Logistic Regression to link rotor termination with the defibrillation pad orientation and current density. Our results suggest the highest average likelihood of terminating rotors during VF is when defibrillator pads are placed perpendicular to the rotor axis (0.99 ± 0.03), with an average current density of 7.2 A/m2, compared to any other orientation (parallel: 0.76 ± 0.26 and oblique: 0.08 ± 0.12). Our simulations suggest that optimal defibrillator pad orientation, combined with sufficient current density magnitude, could improve the likelihood of rotor termination during VF and thereby improving defibrillation success in OHCA patients.