Open-access database of literature derived drug-related Torsade de Pointes cases

Since an introduction of an ICH guidance in 2005, no new drugs were withdrawn from the market because of the causation of Torsade de Pointes (TdP). However, the risk of TdP is still a concern for marketed drugs. TdP is a type of polymorphic ventricular tachycardia which may lead to sudden cardiac death. QT/QTc interval prolongation is considered a sensitive, but not specific biomarker. To improve the effectiveness of studies’ workflow related to TdP risk prediction we created an extensive, structured, open-access database of drug-related TdP cases. PubMed, Google Scholar bibliographic databases, and the Internet, via the Google search engine, were searched to identify eligible reports. A total of 424 papers with a description of 634 case reports and observational studies were included. Each paper was manually examined and listed with up to 53 variables related to patient/population characteristics, general health parameters, used drugs, laboratory measurements, ECG results, clinical management, and its outcomes, as well as suspected drug’s properties and its FDA adverse reaction reports. The presented database may be considered as an extension of the recently developed and published database of drug cardiac safety-related information, part of the tox-portal project providing resources for cardiac toxicity assessment.

Clinical Characteristics, Genetic Findings and Arrhythmic Outcomes of Patients with Catecholaminergic Polymorphic Ventricular Tachycardia from China

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. The aim of this study is to examine the genetic basis and identify predictive factors for arrhythmic outcomes of CPVT patients from China. Methods: PubMed and MedRxiv were systematically searched for case reports or case series reporting on CPVT patients from China. Clinical characteristics, genetic findings and primary outcome of spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) were analyzed. Results: A total of 56 (median presentation age=9 [6-13] years old) patients were included. All patients except for one presented at or before 19 years of age. Fifty-three patients (94.6%) were initially symptomatic. PVCs were present in 40 out of 45 patients (88.9%) and VT in 51 out of 56 patients (91.1%). Genetic tests were performed in 50 patients (89.3%). RyR2, CASQ2 and TERCL mutations were found in 32 (57.1%), 11 (19.6%) and one (0.02%) patients, respectively. Fifty patients were treated with beta-blockers, eight patients received flecainide, four patients received amiodarone, two received verapamil and one received propafenone. Sympathectomy (n=10) and implantable-cardioverter defibrillator implantation (n=7) were performed. On follow-up, 17 patients developed incident VT/VF. Conclusion: This is the first systemic review and meta-analysis of CPVT patients from China. Most patients had symptoms on initial presentation, and around a third had VT as the presenting complaint. RyR2 mutation accounts for more than half of the CPVT cases, followed by CASQ2 and TERCL mutations. Some of these mutations have not been hitherto reported outside of China. Most patients received β-blocker therapy. Around 18% had sympathectomy and 13% had ICDs implanted.

Clinical features and antiarrhythmic therapy in patients with catecholaminergic polymorphic ventricular tachycardia

Aims. To evaluate the long-term efficacy of antiarrhythmic therapy in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT).Methods. CPVT was diagnosed in 11 patients between the ages of 3-12 years with a minimum follow-up of 10 years. The data analyzed was obtained from existing medical records that included symptoms, family screenings, treadmill tests, electrocardiography, echocardiography, implanted cardioverter-defibrillator data (ICD), and medical treatments.Results. Cardiac events were registered in 75% of patients on beta-blocker therapy. Supraventricular arrhythmias such as atrial and atrioventicular nodal tachycardia, atrial fibrillation and atrial flutter were detected using various ECG diagnostic methods in all patients, which is significantly higher than reported in similar studies. A combination of anti-arrhythmic therapy and beta-blocker treatment reduced the number of cardiac events by 50% as compared to only beta-blocker treatment.Conclusion. Multiple supraventricular arrhythmias have a high prevalence in patients with CPVT and can trigger ventricular arrhythmia. Combined antiarrhythmic therapy is effective because it prevents cardiac events in patients with CPVT. Combined antiarrhythmic therapy improves the prognosis of patients with CPVT and may help to avoid or postpone ICD implantation.

Clinical Characteristics, Genetic Findings and Arrhythmic Outcomes of Patients with Catecholaminergic Polymorphic Ventricular Tachycardia from China

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. The aim of this study is to examine the genetic basis and identify predictive factors for arrhythmic outcomes of CPVT patients from China. Methods: PubMed and MedRxiv were systematically searched for case reports or case series reporting on CPVT patients from China. Clinical characteristics, genetic findings and primary outcome of spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) were analyzed. Results: A total of 56 (median presentation age=9 [6-13] years old) patients were included. All patients except for one presented at or before 19 years of age. Fifty-three patients (94.6%) were initially symptomatic. PVCs were present in 40 out of 45 patients (88.9%) and VT in 51 out of 56 patients (91.1%). Genetic tests were performed in 50 patients (89.3%). RyR2, CASQ2 and TERCL mutations were found in 32 (57.1%), 11 (19.6%) and one (0.02%) patients, respectively. Fifty patients were treated with beta-blockers, eight patients received flecainide, four patients received amiodarone, two received verapamil and one received propafenone. Sympathectomy (n=10) and implantable-cardioverter defibrillator implantation (n=7) were performed. On follow-up, 17 patients developed incident VT/VF. Conclusion: This is the first systemic review and meta-analysis of CPVT patients from China. Most patients had symptoms on initial presentation, and around a third had VT as the presenting complaint. RyR2 mutation accounts for more than half of the CPVT cases, followed by CASQ2 and TERCL mutations. Some of these mutations have not been hitherto reported outside of China. Most patients received β-blocker therapy. Around 18% had sympathectomy and 13% had ICDs implanted.

Successful ablation of bifocal PVCs from both left bundle branches triggering polymorphic VT in LQTS 2—A case report

Background A 19-year-old woman with an established diagnosis of long QT syndrome (LQTS) 2 and underlying KCNH2-mutation was referred to our centre for recurrent polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) refractory to medical therapy and bilateral thoracic sympathectomy. Case summary Holter monitoring revealed a relevant PVC burden of two different morphologies. One PVC was originating from the left anterior fascicle, the other from the left posterior fascicle. Radiofrequency ablation resulted in complete suppression of both spontaneous PVC morphologies with a favourable clinical course over the next 2 years. Discussion This case presents two interesting insights: Firstly, the consistent bigeminal pattern of the torsade de pointes triggering PVC. These were retrieved from the device interrogation and correlated with the pattern that was seen at the time of the procedure. Secondly, PVC morphologies suggested an origin from both the left ventricular (posterior and anterior) fascicles, which has not been described so far. This was confirmed by the preceding Purkinje potentials seen at the successful ablation sites in sinus rhythm and during PVC. Ablation of triggering PVCs causing recurrent VT/VF in LQT 2 syndrome is feasible and effective over a mid-term Follow-up.

An unusual cause of electrical storm in a young woman

A 35-year-old woman was admitted for recurrent syncope. At admission multiples episodes of non-sustained polymorphic ventricular tachycardia were recorded. After exclusion of all possible aetiologies a carefully electrocardiogram analysis reveals the key for the diagnosis.

CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited condition that can cause fatal cardiac arrhythmia. Human mutations in the Ca2+ sensor calmodulin (CaM) have been associated with CPVT susceptibility, suggesting that CaM dysfunction is a key driver of the disease. However, the detailed molecular mechanism remains unclear. Focusing on the interaction with the cardiac ryanodine receptor (RyR2), we determined the effect of CPVT-associated variants N53I and A102V on the structural characteristics of CaM and on Ca2+ fluxes in live cells. We provide novel data showing that binding of both Ca2+/CaM-N53I and Ca2+/CaM-A102V to RyR23583-3603 is decreased. Ca2+/CaM:RyR23583-3603 high-resolution crystal structures highlight subtle conformational changes for the N53I variant, with A102V being similar to wild-type. We show that co-expression of CaM-N53I or CaM-A102V with RyR2 in HEK293 cells significantly increased the duration of Ca2+ events, CaM-A102V exhibited a lower frequency of Ca2+ oscillations. In addition, we show that CaMKIIδ phosphorylation activity is increased for A102V, compared to CaM-WT. This paper provides novel insight into the molecular mechanisms of CPVT-associated CaM variants and will facilitate development of strategies for future therapies.

An International Multi-Center Cohort Study on β-blockers for the Treatment of Symptomatic Children with Catecholaminergic Polymorphic Ventricular Tachycardia

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. Beta-blockers (BBs) decrease this risk, but studies comparing individual BBs in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of BB in a large cohort of symptomatic children with CPVT. Methods: From two international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest prior to BB initiation and age at start of BB therapy <18 years), treated with a BB were included. Cox-regression analyses with time-dependent covariates for BB and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 [interquartile range, 2.8-12.5] years. Two-hundred sixteen patients (66.0%) used a non-selective BB (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective BB (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial BB. Baseline characteristics did not differ. The HR for both the primary and secondary outcomes were higher for β1-selective compared with non-selective BBs (HR, 2.04 95% CI, 1.31-3.17; and HR, 1.99; 95% CI, 1.20-3.30, respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68; 95% CI, 1.44-4.99), bisoprolol (HR, 3.24; 95% CI, 1.47-7.18), and metoprolol (HR, 2.18; 95% CI, 1.08-4.40) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68; 95% CI, 1.30-5.55). Conclusions: B1-selective BBs were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with non-selective BBs, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred BB for treating symptomatic children with CPVT.