Pharmacological Approach for Symptomatic Nonsustained Ventricular Tachycardia.

Nonsustained ventricular tachycardia (NSVT) is a common arrhythmia associated with heart failure, cardiomyopathy, coronary artery disease, electrolyte imbalances, and congenital heart disorders (Foth et al., 2023). NSVT is often asymptomatic depending on its burden percentage. However, typical NSVT presentation in the emergency department (ED) includes palpitations, near-syncope, dizziness, skipped beats, chest pain, and/or dyspnea (Katritsis et al., 2012). In some instances, NSVT can present with elevated or slightly elevated troponin from demand ischemia. A definite diagnosis of NSVT is not of high complexity; nevertheless, it is not always identified on electrocardiogram (ECG) by the time the patient arrives to the ED. Identification of NSVT usually requires prolonged cardiac monitoring, mobile cardiac telemetry (MCT), and in some instances internal loop recorder placement. The purpose of this case is to discuss the typical presentation and pharmacological approach of patients with stable NSVT.

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model.

BACKGROUND: The VICTORIA trial demonstrated a significant decrease in cardiovascular events through vericiguat therapy. This study aimed to assess the potential mechanisms responsible for the reduction of cardiovascular events with vericiguat therapy in a rabbit model of myocardial infarction (MI). METHODS: A chronic MI rabbit model was created through coronary artery ligation. Following 4 weeks, the hearts were harvested and Langendorff perfused. Subsequently, electrophysiological examinations and dual voltage-calcium optical mapping studies were conducted at baseline and after administration of vericiguat at a dose of 5 µmol/L. RESULTS: Acute vericiguat therapy demonstrated a significant reduction in premature ventricular beat burden and effectively suppressed ventricular arrhythmic inducibility. The electrophysiological influences of vericiguat therapy included an increased ventricular effective refractory period, prolonged action potential duration, and accelerated intracellular calcium (Cai) homeostasis, leading to the suppression of action potential and Cai alternans. The pacing-induced ventricular arrhythmias exhibited a reentrant pattern, attributed to fixed or functional conduction block in the peri-infarct zone. Vericiguat therapy effectively mitigated the formation of cardiac alternans as well as the development of reentrant impulses, providing additional anti-arrhythmic benefits. CONCLUSIONS: In the MI rabbit model, vericiguat therapy demonstrates anti-ventricular arrhythmia effects. The vericiguat therapy reduces ventricular ectopic beats, inhibiting the initiation of ventricular arrhythmias. Furthermore, the therapy successfully suppresses cardiac alternans, preventing conduction block and, consequently, the formation of reentry circuits.

Discovery and Structure-Activity Relationship of a Ryanodine Receptor 2 Inhibitor.

Ryanodine receptor 2 (RyR2) is a large Ca2+-release channel in the sarcoplasmic reticulum (SR) of cardiac muscle cells. It serves to release Ca2+ from the SR into the cytosol to initiate muscle contraction. RyR2 overactivation is associated with arrhythmogenic cardiac disease, but few specific inhibitors have been reported so far. Here, we identified an RyR2-selective inhibitor 1 from the chemical compound library and synthesized it from glycolic acid. Synthesis of various derivatives to investigate the structure-activity relationship of each substructure afforded another two RyR2-selective inhibitors 6 and 7, among which 6 was the most potent. Notably, compound 6 also inhibited Ca2+ release in cells expressing the RyR2 mutants R2474S, R4497C and K4750Q, which are associated with cardiac arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). This inhibitor is expected to be a useful tool for research on the structure and dynamics of RyR2, as well as a lead compound for the development of drug candidates to treat RyR2-related cardiac disease.

Antiarrhythmic and Anti-Inflammatory Effects of Sacubitril/Valsartan on Post-Myocardial Infarction Scar.

BACKGROUND: Sacubitril/valsartan (Sac/Val) is superior to angiotensin-converting enzyme inhibitors in reducing the risk of heart failure hospitalization and cardiovascular death, but its mechanistic data on myocardial scar after myocardial infarction (MI) are lacking. The objective of this work was to assess the effects of Sac/Val on inflammation, fibrosis, electrophysiological properties, and ventricular tachycardia inducibility in post-MI scar remodeling in swine. METHODS: After MI, 22 pigs were randomized to receive ß-blocker (BB; control, n=8) or BB+Sac/Val (Sac/Val, n=9). The systemic immune response was monitored. Cardiac magnetic resonance data were acquired at 2-day and 29-day post MI to assess ventricular remodeling. Programmed electrical stimulation and high-density mapping were performed at 30-day post MI to assess ventricular tachycardia inducibility. Myocardial samples were collected for histological analysis. RESULTS: Compared with BB, BB+Sac/Val reduced acute circulating leukocytes (P=0.009) and interleukin-12 levels (P=0.024) at 2-day post MI, decreased C-C chemokine receptor type 2 expression in monocytes (P=0.047) at 15-day post MI, and reduced scar mass (P=0.046) and border zone mass (P=0.043). It also lowered the number and mass of border zone corridors (P=0.009 and P=0.026, respectively), scar collagen I content (P=0.049), and collagen I/III ratio (P=0.040). Sac/Val reduced ventricular tachycardia inducibility (P=0.034) and the number of deceleration zones (P=0.016). CONCLUSIONS: After MI, compared with BB, BB+Sac/Val was associated with reduced acute systemic inflammatory markers, reduced total scar and border zone mass on late gadolinium-enhanced magnetic resonance imaging, and lower ventricular tachycardia inducibility.

Insights into adherence to medication and lifestyle recommendations in an international cohort of patients with catecholaminergic polymorphic ventricular tachycardia.

AIMS: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT. METHODS AND RESULTS: An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22-50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3-12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6-31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1-1.3, P < 0.001) were independently associated with non-adherence. CONCLUSION: The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education.

Relevance of mexiletine in the era of evolving antiarrhythmic therapy of ventricular arrhythmias.

Despite impressive developments in the field of ventricular arrhythmias, there is still a relevant number of patients with ventricular arrhythmias who require antiarrhythmic drug therapy and may, e.g., in otherwise drug and/or ablation refractory situations, benefit from agents known for decades, such as mexiletine. Through its capability of blocking fast sodium channels in cardiomyocytes, it has played a minor to moderate antiarrhythmic role throughout the recent decades. Nevertheless, certain patients with structural heart disease suffering from drug-refractory, i.e., mainly amiodarone refractory ventricular arrhythmias, as well as those with selected forms of congenital long QT syndrome (LQTS) may nowadays still benefit from mexiletine. Here, we outline mexiletine's cellular and clinical electrophysiological properties. In addition, the application of mexiletine may be accompanied by various potential side effects, e.g., nausea and tremor, and is limited by several drug-drug interactions. Thus, we shed light on the current therapeutic role of mexiletine for therapy of ventricular arrhythmias and discuss clinically relevant aspects of its indications based on current evidence.

Smartwatch detection of new-onset monomorphic ventricular tachycardia in pregnancy.

Smartwatches provide health tracking in various ways and there has been a recent rise in reporting cardiac arrhythmias. While original studies focused on atrial fibrillation, fewer reports have been made on other arrhythmias especially in pregnancy. We report a pregnant patient who presented at 34 weeks' gestation with palpitations. An ECG recorded through her Apple Watch showed ventricular tachycardia. Hospital ECG confirmed monomorphic ventricular tachycardia likely caused by increased sympathetic tone from the gravid state. She was admitted to the cardiac intensive care unit for close monitoring with intravenous anti-arrhythmic agents; however, the rhythm persisted. She underwent a caesarean delivery and the arrhythmia resolved post partum. She later underwent a catheter ablation, after which she discontinued all anti-arrhythmic medications with no recurrence. This case highlights the importance of requesting relevant digital health information, if available, from patients in our modern era. Controlled clinical studies are needed to validate such practices.

Bloqueo del ganglio estrellado como tratamiento de la tormenta arrítmica: estudio observacional / Stellate ganglion block as a treatment for arrhythmic storm: an observational study

Introducción: La tormenta arrítmica (TA) es una situación de emergencia potencialmente letal, con una elevada tasa de mortalidad. Cuando el tratamiento convencional agudo es inefectivo, el bloqueo del ganglio estrellado puede ayudar a controlar la arritmia, aportando un bloqueo simpático cervicotorácico visceral. El objetivo de este estudio es valorar la efectividad y seguridad de los bloqueos del ganglio estrellado (BGE) para el tratamiento de la TA refractaria. Método: Seguimiento de una cohorte de pacientes con TA refractaria que cumplieron los criterios para la realización de BGE. Dicho bloqueo fue ecoguiado al nivel de C6, utilizando un anestésico y un esteroide, de manera unilateral izquierda en primer lugar, y bilateral de no existir respuesta, realizándose posteriormente ablación mediante radiofrecuencia (RFC) guiada por fluoroscopio en C7 de no existir respuesta favorable, sino recidiva subsiguiente. Resultados: Se incluyeron siete pacientes, con una tasa de mortalidad durante el ingreso de 14,29%. Cuatro pacientes recibieron bloqueos unilaterales del ganglio estrellado, y en tres pacientes se realizaron bloqueos bilaterales. En seis de ellos se aplicó ablación, y uno de ellos tenía implantado un cardioversor-desfibrilador. La TA fue controlada temporalmente, más allá del efecto del anestésico local en todos los pacientes. Tres de ellos recibieron ablación por RFC, y dos simpatectomías torácicas quirúrgicas. El único efecto secundario fue el síndrome de Horner, que se observó en todos los casos tras realizar el bloqueo del ganglio estrellado con anestésico local. Dos pacientes murieron tras recibir el alta, y cuatro siguen en sus casas, tres de ellos sin haber sido ingresados a causa de episodios ventriculares durante más de dos años. Conclusión: El bloqueo ecoguiado del ganglio estrellado es una técnica efectiva y segura para el tratamiento de la TA refractaria, como complemento del tratamiento cardiológico habitual.(AU)

Introduction: Arrhythmic storm is a life-threatening emergency with a high mortality rate. When acute conventional treatment is ineffective, a stellate ganglion block can contribute to the control of the arrhythmia by providing a visceral cervicothoracic sympathetic block. The objective of the study is to assess the effectiveness and safety of stellate ganglion blocks for the treatment of refractory arrhythmic storm. Method: Follow-up of a cohort of patients with refractory arrhythmic storm that met the criteria for performing stellate ganglion blocks. The block was ultrasound-guided at C6-level using local anaesthetic and a steroid, left unilateral first, bilateral if no response, and followed by fluoroscopy-guided radiofrequency ablation at C7 if there was a favourable response but subsequent relapse. Results: Seven patients were included, with a mortality rate during admission of 14.29%. Four patients received unilateral and three bilateral stellate ganglion blocks. Six were ablated and one of them had an implanted cardioverter-defibrillator. Arrhythmic storm was controlled temporarily beyond the effect of the local anaesthetic in all patients. Three underwent radiofrequency ablation and two underwent surgical thoracic sympathectomy. The only side effect was Horner's syndrome, which was observed in all cases after administering a stellate ganglion block with local anaesthetic. Two died after discharge and four are still at home, three of them without further admission due to ventricular events for more than two years. Conclusion: An ultrasound-guided stellate ganglion block is an effective and safe technique in the treatment of refractory arrhythmic storm as a complement to the usual cardiological treatment.(AU)

Combined modified Valsalva maneuver with adenosine supraventricular tachycardia: A comparative study.

BACKGROUND AND IMPORTANCE: Paroxysmal supraventricular tachycardia (PSVT) is an arrhythmia commonly seen in the emergency department. Both modified Valsalva maneuver (MVM) and intravenous adenosine are the first line treatment, of which the former has e lower success rate while the latter has a higher success rate but some risks and adverse effects. Given both of these reverse rhythms quickly, combining them may achieve a better effect. OBJECTIVE: The objective of this study is to evaluate the success rate and potential risk of combining the use of intravenous adenosine while patients were doing MVM as a treatment for paroxysmal supraventricular tachycardia(pSVT). DESIGN, SETTINGS AND PARTICIPANTS: We recruited patients with pSVT from 2017 to 2022, and randomly assigned them into 3 groups, MVM group, intravenous adenosine group, and combination therapy group, in which MVM was allowed to be performed twice, while intravenous adenosine was given in a titration manner to repeat three times, recorded the success rate and side effects in each group. MAIN RESULTS: The success rate of the MVM group, adenosine group, and combination group are 42.11%, 75.00 and 86.11%, respectively. The success rate of the adenosine group and combination group is significantly higher than the n MVSM group (p < 0.01, p < 0.001), while the success rate of the combination group is higher than the adenosine group, it has no significant difference (p = 0.340). In terms of safety, the longest RR durations (asystole period) are 1.61 s, 1.60s, and 2.27 s, there is a statistical difference among the three groups (p < 0.01) and between the adenosine and combination group (0.018). CONCLUSION: Therefore, we can conclude that combination therapy has a relatively high success rate and good safety profile, but the current study failed to show its superiority to adenosine.

Clinical and genetic profiles of chinese pediatric patients with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUNDS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but lethal cardiac ion channelopathy. Delayed diagnosis and misdiagnosis remain a matter of concern due to its rarity and insufficient recognition of this disorder, particularly in developing countries like China. AIMS AND METHODS: We reported six catecholaminergic polymorphic ventricular tachycardia (CPVT) children diagnosed in our center along with a comprehensive review of Chinese pediatric CPVT patients reported in domestic and overseas literature between January 2013 and December 2021 to provide an essential reference for physicians to deepen their understanding of pediatric CPVT. RESULTS: A total of 95 children with CPVT, including our six patients from 21 medical centers were identified. The median age of symptom onset is 8.7 ± 3.0 years. Diagnosis occurred at a median age of 12.9 ± 6.8 years with a delay of 4.3 ± 6.6 years. Selective beta-blockers (Metoprolol and Bisoprolol) were prescribed for 38 patients (56.7%) and 29 (43.3%) patients received non-selective beta-blocker (Propranolol and Nadolol) treatment. Six patients accepted LCSD and seven received ICD implantation at the subsequent therapy. A total of 13 patients died during the disease course. Of the 67 patients with positive gene test results, variants in RYR2 were 47 (70.1%), CASQ2 were 11 (16.4%), and RYR2 accompanied SCN5A were 7 (10.4%). Patients with CASQ2 gene mutations presented with younger symptom onset age, higher positive family history rate and better prognosis than those with RYR2 mutations. CONCLUSION: Chinese pediatric patients with CPVT had a poorer prognosis than other cohorts, probably due to delayed/missed diagnosis, non-standard usage of beta-blockers, unavailability of flecainide, and a lower rate of LCSD and ICD implantation.

Insights on the mechanism of flecainide in catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by defective cardiac ryanodine receptor (RyR2) calcium release during times of adrenergic stimulation, resulting in bidirectional or polymorphic ventricular tachycardia. Flecainide is a class 1c anti-arrhythmic drug that has demonstrated therapeutic efficacy in treating CPVT. However, its mechanism of action remains disputed. One group proposes a direct effect of flecainide on RyR2-mediated calcium release, while another proposes an indirect effect via sodium channel blockade and modulation of intracellular calcium dynamics. In light of recent studies, this commentary aims to explore and discuss the evidence base for these potential mechanisms.

Use of mexiletine in therapy-refractory recurrent ventricular tachycardia storm.

Electrical storm due to recurrent ventricular tachycardias (VTs) is a life-threatening arrhythmic emergency. The authors present a case report of a 69-year-old male patient with VT storm of non-ischemic etiology. Despite optimal medical treatment escalated by amiodarone antiarrhythmic drug therapy, the patient experienced multiple implantable cardioverter defibrillator (ICD) shocks. An electrophysiological study revealed an epicardial substrate; however, considering the patient's extreme obesity and active anticoagulant effect, catheter ablation was deemed to be unfeasible. Subsequently, mexiletine was added to the patient's drug regimen, resulting in successful control of arrhythmias during the following 6 months. Although the most recent European guidelines for the management of patients with ventricular arrhythmias mention mexiletine only for the treatment of LQT3 patients, its use for treatment-refractory VT storm seems to also be an important indication area.

Effect of ivabradine on ventricular arrhythmias in heart failure patients with reduced ejection fraction.

BACKGROUND/INTRODUCTION: Heart failure patients with reduced ejection fraction are at high risk for ventricular arrhythmias and sudden cardiac death. Ivabradine, a specific inhibitor of the If current in the sinoatrial node, provides heart rate reduction in sinus rhythm and angina control in chronic coronary syndromes. OBJECTIVE: The effect of ivabradine on ventricular arrhythmias in heart failure patients with reduced ejection fraction patients has not been fully elucidated. The aim of this study was to investigate the effect of ivabradine use on life-threatening arrhythmias and long-term mortality in heart failure patients with reduced ejection fraction patients. METHODS: In this retrospective study, 1,639 patients with heart failure patients with reduced ejection fraction were included. Patients were divided into two groups: ivabradine users and nonusers. Patients presenting with ventricular tachycardia, the presence of ventricular extrasystole, and ventricular tachycardia in 24-h rhythm monitoring, appropriate implantable cardioverter-defibrillator shocks, and long-term mortality outcomes were evaluated according to ivabradine use. RESULTS: After adjustment for all possible variables, admission with ventricular tachycardia was three times higher in ivabradine nonusers (95% confidence interval 1.5-10.2). The presence of premature ventricular contractions and ventricular tachycardias in 24-h rhythm Holter monitoring was notably higher in ivabradine nonusers. According to the adjusted model for all variables, 4.1 times more appropriate implantable cardioverter-defibrillator shocks were observed in the ivabradine nonusers than the users (95%CI 1.8-9.6). Long-term mortality did not differ between these groups after adjustment for all covariates. CONCLUSION: The use of ivabradine reduced the appropriate implantable cardioverter-defibrillator discharge in heart failure patients with reduced ejection fraction patients. Ivabradine has potential in the treatment of ventricular arrhythmias in heart failure patients with reduced ejection fraction patients.

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.

Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes.

BACKGROUND: Polymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death, typically exercise-induced. We previously showed a link between the RyR2-H29D mutation and a clinical phenotype of short-coupled PMVT at rest using patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs). In the present study, we evaluated the effects of clinical and experimental anti-arrhythmic drugs on the intracellular Ca2+ handling, contractile and molecular properties in PMVT hiPSC-CMs in order to model a personalized medicine approach in vitro. METHODS: Previously, a blood sample from a patient carrying the RyR2-H29D mutation was collected and reprogrammed into several clones of RyR2-H29D hiPSCs, and in addition we generated an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. Here, we tested 4 drugs with anti-arrhythmic properties: propranolol, verapamil, flecainide, and the Rycal S107. We performed fluorescence confocal microscopy, video-image-based analyses and biochemical analyses to investigate the impact of these drugs on the functional and molecular features of the PMVT RyR2-H29D hiPSC-CMs. RESULTS: The voltage-dependent Ca2+ channel inhibitor verapamil did not prevent the aberrant release of sarcoplasmic reticulum (SR) Ca2+ in the RyR2-H29D hiPSC-CMs, whereas it was prevented by S107, flecainide or propranolol. Cardiac tissue comprised of RyR2-H29D hiPSC-CMs exhibited aberrant contractile properties that were largely prevented by S107, flecainide and propranolol. These 3 drugs also recovered synchronous contraction in RyR2-H29D cardiac tissue, while verapamil did not. At the biochemical level, S107 was the only drug able to restore calstabin2 binding to RyR2 as observed in the isogenic control. CONCLUSIONS: By testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca2+ release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest.