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Since an introduction of an ICH guidance in 2005, no new drugs were withdrawn from the market because of the causation of Torsade de Pointes (TdP).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.

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.

555 Torsade-de-pointes electrical storm late after treatment with hydroxychloroquine and azithromycin for COVID-19

A 78-year-old woman was admitted to our hospital due to multiple brief episodes of transient loss of consciousness. She was recently hospitalized elsewhere for SARS-CoV-2 infection and she had been discharged two days before. During the previous hospitalization she had been treated with hydroxychloroquine 400 mg twice daily on Day 1, followed by Hydroxychloroquine 400 mg daily together with azithromycin 500 mg daily for 7 days, leading to symptomatic resolution and two consecutive negative RT-PCR tests at discharge. Her medical history included dilated cardiomyopathy and in 2017 she underwent CRT-D implantation for primary prevention; over the past 3 years, she did not experience any ICD intervention. Her home therapy included amiodarone, bisoprolol, warfarin, and trazodone. Baseline ECG obtained 6 month before admission is shown in Figure 1, Panel A. On admission, her ECG showed sinus bradycardia with biventricular pacing and significant QT prolongation (i.e. 640 ms, Figure 1 B). On day 2 of hospitalization, she reported multiple brief episodes of transient loss of consciousness. An interrogation of her device revealed 27 torsade-de-pointes episodes in a 48-hour period, treated with 11 shocks. All episodes were preceded by a variable period of bigeminal rhythm due to one or two premature ventricular beats coupled to the prolonged QT segment of the preceding basic beat in a ‘short-long-short’ sequence (Figure 2). The patient experienced a torsade-de-pointes TdP during COVID-19 disease. She had multiple concomitant factors for QT prolongation (TISDALE SCORE 13): mainly, female sex, cardiac disease, inflammation, electrolyte imbalances and multiple QT-prolonging drugs. Amiodarone and bisoprolol were subsequently stopped and potassium and magnesium were supplemented, with rapid resolution of torsade-de-pointes. No more episodes of TdP were detected after two weeks of hospitalization. The remote monitoring assessment of her device did not show any further episodes during subsequent follow-up. To our best knowledge, this is the first ICD-documented report of a TdP electrical storm in a COVID-19 patient, treated with HCQ/AZT, who had multiple concomitant factors for QT prolongation. 555 Figure 1

Safe electrophysiologic profile of dexmedetomidine in different experimental arrhythmia models

Previous studies suggest an impact of dexmedetomidine on cardiac electrophysiology. However, experimental data is sparse. Therefore, purpose of this study was to investigate the influence of dexmedetomidine on different experimental models of proarrhythmia. 50 rabbit hearts were explanted and retrogradely perfused. The first group (n = 12) was treated with dexmedetomidine in ascending concentrations (3, 5 and 10 µM). Dexmedetomidine did not substantially alter action potential duration (APD) but reduced spatial dispersion of repolarization (SDR) and rendered the action potentials rectangular, resulting in no proarrhythmia. In further 12 hearts, erythromycin (300 µM) was administered to simulate long-QT-syndrome-2 (LQT2). Additional treatment with dexmedetomidine reduced SDR, thereby suppressing torsade de pointes. In the third group (n = 14), 0.5 µM veratridine was added to reduce the repolarization reserve. Further administration of dexmedetomidine did not influence APD, SDR or the occurrence of arrhythmias. In the last group (n = 12), a combination of acetylcholine (1 µM) and isoproterenol (1 µM) was used to facilitate atrial fibrillation. Additional treatment with dexmedetomidine prolonged the atrial APD but did not reduce AF episodes. In this study, dexmedetomidine did not significantly alter cardiac repolarization duration and was not proarrhythmic in different models of ventricular and atrial arrhythmias. Of note, dexmedetomidine might be antiarrhythmic in acquired LQT2 by reducing SDR.

Life-Threatening Cardiac Arrhythmias during Anesthesia and Surgery

Life-threatening arrhythmias are frequently encountered during anesthesia for cardiac or non-cardiac surgery. They result in a significant cause of morbidity and mortality, particularly in elderly patients. Predisposing factors like electrolytes abnormalities, pre-existing cardiac disease, intubation procedure, anesthetic medications, and various surgical stimulation need to be determined. Early diagnosis and commencement of an appropriate treatment protocol may be lifesaving. Treatment usually involves correction of the underlying causes, cardiac electroversion, and the use of one or more antiarrhythmic agents. Although ventricular tachycardia, ventricular fibrillation, torsade de pointes, and pulseless electrical activity are considered malignant arrhythmias that can lead to cardiac arrest, other types of Brady and tachyarrhythmias are also included in this chapter to enable adopting a more objective approach in the management of arrhythmias intraoperatively, avoiding risks of inappropriate management strategies.

Macrophage-Dependent Interleukin-6-Production and Inhibition of IK Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart

In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel IK, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered IK in the heart, using electrophysiology to evaluate changes in IK in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of IKr and IKs densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of IKr did a proarrhythmic phenotype of IKs depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.

Kv1.3 Channel Blockade Improves Inflammatory Profile, Reduces Cardiac Electrical Remodeling, and Prevents Arrhythmia in Type 2 Diabetic Rats

Purpose Kv1.3 channel regulates the activity of lymphocytes, macrophages, or adipose tissue and its blockade reduces inflammatory cytokine secretion and improves insulin sensitivity in animals with metabolic syndrome and in genetically obese mice. Thus, Kv1.3 blockade could be a strategy for the treatment of type 2 diabetes. Elevated circulating levels of TNFα and IL-1b mediate the higher susceptibility to cardiac arrhythmia in type 2 diabetic rats. We hypothesized that Kv1.3 channel blockade with the psoralen PAP1 could have immunomodulatory properties that prevent QTc prolongation and reduce the risk of arrhythmia in type 2 diabetic rats. Methods Type 2 diabetes was induced to Sprague-Dawley rats by high-fat diet and streptozotocin injection. Diabetic animals were untreated, treated with metformin, or treated with PAP1 for 4 weeks. Plasma glucose, insulin, cholesterol, triglycerides, and cytokine levels were measured using commercial kits. ECG were recorded weekly, and an arrhythmia-inducing protocol was performed at the end of the experimental period. Action potentials were recorded in isolated ventricular cardiomyocytes. Results In diabetic animals, PAP1 normalized glycaemia, insulin resistance, adiposity, and lipid profile. In addition, PAP1 prevented the diabetes-induced repolarization defects through reducing the secretion of the inflammatory cytokines IL-10, IL-12p70, GM-CSF, IFNγ, and TNFα. Moreover, compared to diabetic untreated and metformin-treated animals, those treated with PAP1 had the lowest risk of developing the life-threatening arrhythmia Torsade de Pointes under cardiac challenge. Conclusion Kv1.3 inhibition improves diabetes and diabetes-associated low-grade inflammation and cardiac electrical remodeling, resulting in more protection against cardiac arrhythmia compared to metformin.

Cardiovascular Toxicity of Carfilzomib: The Real-World Evidence Based on the Adverse Event Reporting System Database of the FDA, the United States

Background: Carfilzomib, an effective proteasome inhibitor agent for the therapy of relapsed and refractory multiple myeloma, has been related to a significant number of cardiovascular events. However, patterns of cardiovascular complications associated with this agent remain poorly characterized in real-world settings.Objective: To gain further insight into the frequency, spectrum, clinical features, timing, and outcomes of carfilzomib-related cardiovascular toxicities.Methods: This disproportionality (case/non-case) study was conducted leveraging records from FAERS database from 2014 to 2019. Cardiovascular events were defined and broadly categorized eight entities using narrow version of the Standardized MedDRA Queries (SMQs). Reporting odds ratios (ROR) and information component (IC) were calculated to measure disproportionality. Additionally, statistical shrinkage was applied to reduce false-positive signals.Results: The final number of records involved was 28,479,963, with 3,370 records submitted for carfilzomib related cardiovascular events. Significant disproportionality association between carfilzomib administration and cardiovascular events was captured (IC025/ROR025 = 0.85/1.95) when exploring in the entire database. Upon further analysis, all eight broad categories of cardiovascular toxicities were disproportionately associated with carfilzomib with varying frequencies, time-to-onset, and severities. Cardiomyopathy-related complications (N = 1,301, 38.61%), embolic and thrombotic events (N = 821, 24.36%), and cardiac failure (N = 765, 22.70%) largely comprised the reported problems. Notably, the strongest signal was detected for cardiac failure (IC025/ROR025 = 1.33/2.59), followed by pulmonary hypertension (IC025/ROR025 = 1.19/2.34). Median onset time of cardiovascular events was 41days (Q1-Q3: 9-114 days), with the shortest median time being 16 days (Q1–Q3: 4–85 days) for ischemic heart disease, with the longest time being 68 days (Q1–Q3: 21–139 days) for embolic and thrombotic events. Torsade de pointes/QT prolongation was identified as a new complication (IC025/ROR025 = 0.33/1.29) and was particularly noteworthy for highest death proportion (44.11%).Conclusions: Treatment with carfilzomib can lead to severe and versatile cardiovascular events. Early and intensive monitoring is important, particularly in the first 3 months after carfilzomib initiation. Maximizing the benefit while reducing potential cardiovascular harms of carfilzomib should become a priority.