Torsades Research Articles

Abstract #1591722: Primary Hyperaldosteronism Revealed by a Torsade de Pointes: A Case Report and Review of the Literature

Abstract #1591722: Primary Hyperaldosteronism Revealed by a Torsade de Pointes: A Case Report and Review of the Literature

Role of Pharmacokinetics and Pharmacogenetics of Antidepressant-Induced Prolongation of the QT Interval and Torsade de Pointes in Patients with Mental Disorders

Antidepressants (ADs) include drugs of various pharmacological groups, which are mainly used for the treatment of mental disorders (major depressive disorder, obsessive-compulsive disorder, social phobia, panic disorder, generalized anxiety disorder, post-traumatic stress disorder), chronic pain and addiction diseases. Chronic use of ADs can lead to the development of cardiotoxic adverse drug reactions (ADRs). The most important cardiotoxic AD-induced ADRs are prolongation of the QT interval, ventricular tachycardia of the "pirouette" type (Torsades de Pointes - TdP). This narrative review analyzes and summarizes the results of studies on pharmacokinecis and pharmacogenetics of ADs on QT interval prolongation and updates physicians' knowledge of the risk of developing AD-induced TdP in patients with psychiatric disorders.

Thyroid gland dysfunction in heart rhythm disorders

Thyroid gland dysfunction is estimated to occur in approximately 5% of the population and affects people of different ages. Cardiovascular diseases can occur in diseases such as hyperthyroidism as well as hypothyroidism. Increased thyroid hormone levels precipitate sympathetic nervous system activation, potentially culminating in heightened heart rate (tachycardia) and disruptions in electrical conduction. This influence can induce QT interval shortening and provoke premature ventricular contractions (PVCs), amplifying the propensity for more severe arrhythmic manifestations. Insufficiency of thyroid hormones decelerates metabolic activity, potentially leading to bradycardia. Hypothyroidism elevates the risk of atrial fibrillation occurrence and additionally elongates QT intervals, enhancing the susceptibility to torsade de pointes. Untreated hormone disorders affect severe cardiac complications, which can occur in patients with previously diagnosed heart disease. Effective management of cardiac arrhythmias in patients with thyroid dysfunction necessitates interdisciplinary collaboration between endocrinologists and cardiologists.

Roles of atrial arrhythmias in triggering torsade de pointes in patients with acquired long QT syndrome

Abstract Background Little is known about a role of atrial arrhythmias (AAs) in triggering Torsade de Pointes (TdP) in patients with long QT syndrome (LQTS). Purpose To determine the prevalence of AAs-induced TdP in acute acquired LQTS patients and to classify the AAs’ roles in the development of TdP. Methods Initiation patterns of 81 episodes of TdP obtained from 34 consecutive acquired LQTS patients (14 men; median age, 69 years; median QTc, 645.5 ms) with documented TdP were analysed. The patients were divided into 2 groups based on the presence or absence of AAs involvement in triggering TdP: AAs-induced and non-AAs-induced groups. Results AAs-induced group comprised 52.9% (18/34) of the patients studied. TdP was preceded by AAs-induced short-long sequences (SLSs) in 41.2% (14/34) of the patients and directly induced by R-on-T AAs (AAs coincidentally encounter a vulnerable repolarizing region during the T wave) in 23.5% (8/34). AAs-induced group experienced TdP after initiating therapy more frequently than non-AAs-induced group (2.5 vs. 1, p=0.008). AAs triggered 48 (59.3%) of the 81 TdP episodes. AAs-induced SLS comprised 67.8% (40 /59) of the SLS-induced TdP episodes. R-on-T AAs accounted for 23.5% (19/81) of the TdP episodes. Conclusions Our observations suggest that AAs are associated with the onset mechanism of TdP in more than half of acute acquired LQTS patients and even increase TdP frequency. Thus, AAs are not benign but rather can be lethal in acute acquired LQTS patients.Representative casesAnalysis of Torsade de Pointes episodes

New risk predictor of arrhythmias in patients with congenital Long-QT Syndrome

Abstract Congenital long-QT syndrome (LQTS), is an inherited cardiac channelopathy characterized by delayed ventricular repolarization, which may lead to Torsade de pointes (TdP), that may degenerate into ventricular fibrillation. Determination of risk remains unrefined. It is well established that the repolarizing current Iks is increased during adrenergic stimulation, as occurs during exercise, thereby playing an important role in shortening the QT interval as an adaptation to increased heart rate. Accordingly, patients with LQTS, in particular those with LQT1 are at high arrhythmic risk during exercise. We hypothesized that changes in QTc during exercise stress test (EST) may be useful for risk stratification in LQTS. Furthermore, we hypothesized that as changes in IKs impact on repolarization reserve, the predictive capacity of the EST may extend to other LQTS genetic subtypes. Aim assessing the potential value of QT dynamics during EST to identify high risk patients in patients with LQT1 and LQTS2. Methods This study included genotype-positive LQT1 and LQT2 patients from the Netherlands, Italy and Germany. Symptomatic patients; patients whom experienced an arrhythmic syncope, sustained ventricular arrhythmia or (aborted) sudden cardiac death. Twelve-lead ECGs were digitally acquired during exercise testing. QT measurements were determined at specific time points. Statistical analyses were performed using R software. Logistic regression and cox proportional hazards models were used to calculate the predictive value and hazard ratio per ms increase in ΔQTc. Covariates included age, QTc, sex, beta-blocker use, center and genetic variant location. Results A total of 222 patients with LQT1 and 164 patients with LQT2 (Table 1), with a pathogenic or likely pathogenic variant in KCNQ1 or KCNH2, were included. In both LQTS1 and LQTS2 patients, the ΔQTc between rest and at 3-4 minutes recovery was the most relevant and significant EST predictor. For LQT1, the ΔQTc was significantly increased in symptomatic patients versus non-symptomatic ones (46 ms ± 35 vs 18 ms ± 36, p = < 0.001)(figure 1 panel A). Logistic regression model shows a predictive value (AUC) of 89.2% for ΔQTc. Survival analysis showed a hazard ratio of 1.02 with 95% CI of 1.01 – 1.03 for each ms ΔQTc increase. For LQTS 2 patients, the ΔQTc between rest and 3-4 minutes recovery was also increased in symptomatic patients versus non-symptomatoc ones (27 ms ± 40 vs 12 ms ± 40, p = 0.03). Logistic regression analysis; OR per ms: 1.02 (1.01 – 1.04 95%CI) AUC 78.3%. Survival analysis showed a hazard ratio of 1.02 (1.01 - 1.03 CI) for each ms ΔQTc increase. Conclusion The ΔQTc between rest and at 3-4 minutes recovery was significantly increased in symptomatic LQT1 and LQT2 patients compared to non-symptomatic patients, and is a promising risk marker to identify high risk patients, in both LQT1 and LQT2.Table 1

Abstract 11698: Torsades de Aortique Pustule: A Case of Aortic Abscess Leading to 2:1 AV Block and Torsades de Pointes

Introduction: Endocarditis of the aortic valve has a propensity to create A-V conduction disturbances in up to 10% of cases. Torsades de pointes (TdP) is polymorphic ventricular tachycardia in the setting of prolonged QT interval and bradycardia that is typically preceded by a short-long-short sequence of ventricular activation. We present a case of infective endocarditis with aortic root abscess leading to acute 2:1 A-V conduction and culminating in TdP. Case Summary: A 30-year-old male with history of IV drug use and bioprosthetic aortic valve repair presented with pleuritic chest pain, nausea and vomiting. He was febrile and tachycardic with a systolic murmur at the right upper sternal border. Initial electrocardiogram showed sinus rhythm with no conduction abnormalities. A Transthoracic echocardiography showed a large aortic valve vegetation with an abscess cavity. E Blood cultures grew Streptococcus oralis. Two days later, he developed VT/VF arrest requiring external defibrillation. Preceding ECGs and telemetry showed sinus tachycardia with new left bundle branch block and prolonged QTc. B This progressed to 2:1 AV block C with abrupt transition to relative bradycardia and ventricular ectopy leading to short-long-short ventricular intervals and subsequent TdP. D A temporary pacemaker was placed, and he underwent an aortic root reconstruction with valve replacement. Discussion: While both the etiology of TdP and aortic root abscesses leading to conduction system disease are well described, this case exhibits the real time progression of aortic abscess involvement. The patient presented with a normal QRS morphology. During hospitalization, he developed new LBBB, and the appropriate sinus tachycardia then deteriorated into 2:1 AV conduction leading to relative bradycardia. This abrupt transition with QTc prolongation sets up the nidus for ventricular ectopy (due to early after depolarizations) with salvos of short-long-short sequences causing TdP.

Abstract 18979: Calm Before the Storm: Exploring the Risk of Torsades De Pointes With Dexmedetomidine Administration

Introduction: Corrected QT interval (QTc) prolongation is the known side effect of multiple medications especially in antipsychotic and antiarrhythmic family. Patients with either inherited or secondary prolonged QTc should be monitored closely as they can develop life threatening complications like Torsades de-pointes and ventricular fibrillation. Here we present a case of cardiac arrest secondary to dexmedetomidine. Case: A 49-year-old female with history of bipolar disorder was admitted to intensive unit for seizure after intentional ingestion of uncounted amount of diphenhydramine pills. Patient was intubated for airway protection and started on propofol. Her vitals at the time of admission included the pulse rate of 76, blood pressure of 102/49 mmHg. Her urine drug screen was positive for TCA and cannabinoids. Her ECG at the time of admission was significant for prolonged QTC of 600msec that improved to 460msec in the consecutive ECGs after administration of total of 4mg intravenous magnesium. Continuous EEG was negative for seizure and she was weaned off sedation. After awakening, she became agitated, after pushes of benzodiazepines, was eventually started on dexmedetomidine. Twenty minutes after starting low dose dexmedetomidine, patient was noted to be in cardiac arrest. Reviewing telemetry prior to event, revealed the R on T phenomenon and Torsades de pointes that lasted for few seconds with progression into ventricular fibrillation. Discussion: Currently dexmedetomidine is labeled with a low to possible risk of Torsade de pointes and QTC prolongation. Dexmedetomidine induced Torsade de pointes might be explained by bradycardia in patients which causes further prolongation of QT interval. Studies have shown that continuous IV infusion of dexmedetomidine at rate of 0.3 mcg/kg/hour can worsen QTC prolongation. Conclusions: In this case we present a case of VFib arrest secondary to Torsade after twenty minutes of infusion of dexmedetomidine without any sign of bradycardia prior to the event. This carries a significant importance as it shows this drug carries a potential risk of QTc prolongation similar to previous studies. Whether this side effect is dose dependent or not requires further investigation.

Abstract 18257: Arrhythmias in Tumor Lysis Syndrome

Background: Tumor lysis syndrome (TLS) is a common complication seen among hospitalized patients with acute promyelocytic leukemia (APL) undergoing induction therapy. Question: What is the incidence and type of arrhythmias in patients with TLS? Methods: This study utilized the National Inpatient Sample Database between 2015-2019 to identify patients hospitalized with APL and further subclassify them into those with and without TLS. ICD-10 codes were used to identify different types of arrhythmias in both groups. A multivariate logistic regression model was constructed to assess adjusted odds ratio for all-cause mortality and cardiac/renal complications. Results: A total of 9938 hospitalizations with APL were identified. Of those, 415 patients had TLS (4.2%). APL patients with TLS were older and more likely to be males. CVA, CHF, CAD, HTN and higher comorbidity scores were more frequent among patients with TLS (Table 1). On adjusted analysis, Patients with TLS had ~2.7-fold increase in all-cause mortality (aOR 2.74, 95% CI [2.12 - 3.55], p< 0.01). In addition, TLS patients had higher rates of cardiac arrhythmias (33.7% vs 21.4%, p<0.01). Atrial fibrillation was the most common arrhythmia (45%), followed by ventricular arrhythmias (11.3%), and lastly, torsade de pointes (8.2%). Finally, TLS patients were more likely to have AKI (aOR 4.13, 95% [3.31 - 5.16], and need hemodialysis (aOR 3.44, 95% CI [2.34 - 5.05], p<0.01). Conclusion: Patients with TLS are at high risk for arrhythmias, all-cause mortality and cardiac morbidity. Preventive strategies like continuous telemetry monitoring may allow for early identification of arrhythmias and may help improve outcomes.

Abstract 17871: Heterozygous Carriers of KCNQ1 Variants Associated With the Jervell-Lange-Nielsen Syndrome Have a Better Outcome When Compared to Other Type 1 LQTS Patients

Background: KCNQ1 mutations are associated with a risk of life-threatening torsade de Pointes. In the most common presentation, the mutation is heterozygous (type 1 LQTS). The homozygous expression causes type 1 Jervell-Lange-Nielsen syndrome (JLNS) with deafness and higher risk of sudden cardiac death. Hypothesis: Heterozygous carriers of JLN mutations would have different phenotype expression than patients carrying other KCNQ1 variants. Aims: To evaluate QTc duration and incidence of LQTS-related cardiac events according to genetic presentation. Methods: All patients with class 4 or 5 KCNQ1 variants for LQT1 or JLNS followed in our center (September 1993 to January 2023) were included. Lifelong Severe Cardiac events (ACA, SCD, appropriate shocks) and cardiac events (severe event + cardiac syncope) were collected.Quantitative data were compared between groups by ANOVA. Kaplan-Meier survival curves with the log-rank test were used to compare survival between the groups. Results: Three groups were identified among 741 LQT1 patients (55.3% female, age at diagnosis 25.2 years); 30 JLNS (group 1), 557 LQT1 carrying heterozygous mutations not found in the JLNS population (group 2), and 154 heterozygous carriers of mutations found in the JLNS population (group 3). QTc interval duration was different between groups (548±60ms, 467±36ms and 450±31ms in group 1, 2, 3 respectively, p<0.001).Patients carrying heterozygous JLN mutations (group 3) had a lower risk for cardiac events than patients with heterozygous non JLN mutations (group2) (HR 0.36 [0.23-0.57]; p<0.01) (Figure). Four parameters were independently associated with cardiac events: QTc (HR 1.01 [1.01-1.01]; p<0.01, haploinsufficiency (HR 0.57 [0.36-0.92]; p<0.05), pore localization (HR 1.63 [1.16-2.30]; p<0.01), and group (HR 0.50 [0.32-0.81]; p<0.01). Conclusion: Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events that other type 1 LQTS patients.

TakoTsubo secondary to acute kidney disease.

We report the case of a 62-year-old man who was admitted to the Cardiac Department for TakoTsubo and ACC by torsades de point, secondary to acute kidney disease. We decide to discharge with a portable defibrillator. One month after cardiac magnetic resonance showed a complete recovery of left ventricular function.

Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity

Background and ObjectiveIn silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models tended not to account for inter-individual response variability due to demographic covariates, such as sex, or physiologic covariates, such as renal function, which may be crucial when predicting TdP. This study aims to compare the effects of drugs in male and female populations with normal and impaired renal function using in silico methods. MethodsPharmacokinetic models considering sex and renal function as covariates were implemented from data published in pharmacokinetic studies. Drug effects were simulated using an electrophysiologically calibrated population of cellular models of 300 males and 300 females. The population of models was built by modifying the endocardial action potential model published by O'Hara et al. (2011) according to the experimentally measured gene expression levels of 12 ion channels. ResultsFifteen pharmacokinetic models for CiPA drugs were implemented and validated in this study. Eight pharmacokinetic models included the effect of renal function and four the effect of sex. The mean difference in action potential duration (APD) between male and female populations was 24.9 ms (p<0.05). Our simulations indicated that women with impaired renal function were particularly susceptible to drug-induced arrhythmias, whereas healthy men were less prone to TdP. Differences between patient groups were more pronounced for high TdP-risk drugs. The proposed in silico tool also revealed that individuals with impaired renal function, electrophysiologically simulated with hyperkalemia (extracellular potassium concentration [K+]o = 7 mM) exhibited less pronounced APD prolongation than individuals with normal potassium levels. The pharmacokinetic/electrophysiological framework was used to determine the maximum safe dose of dofetilide in different patient groups. As a proof of concept, 3D simulations were also run for dofetilide obtaining QT prolongation in accordance with previously reported clinical values. ConclusionsThis study presents a novel methodology that combines pharmacokinetic and electrophysiological models to incorporate the effects of sex and renal function into in silico drug simulations and highlights their impact on TdP-risk assessment. Furthermore, it may also help inform maximum dose regimens that ensure TdP-related safety in a specific sub-population of patients.

THU619 Atypical Clinical Presentation Of Adrenal Hemorrhage

Abstract Disclosure: T.L. Madsen-Barbosa: None. F.H. Antoni: None. A. Ghazi: None. Introduction: Adrenal hemorrhage (AH) is an uncommon condition that is challenging to diagnose due to its nonspecific findings. We illustrate a case of AH that presented with acute clinical deterioration and had catecholamine overproduction. Case: A 58-year-old woman with a history of migraine headaches and prediabetes presented to the emergency department for “the worst headache of her life” and palpitations of 4 hours duration. On admission, her blood pressure was 224/139 mmHg and heart rate was 102 bpm. Her physical examination was significant for diaphoresis and active vomiting. Initial laboratory tests showed hyperglycemia and leukocytosis. Her ECG, non-contrast CT scan of the head and CT angiography of the head and neck were unremarkable. Her hospital course was complicated by recurrent hypertensive episodes, arrhythmias including Torsades de pointes, and left flank pain. A CT chest, abdomen, and pelvis revealed a large left retroperitoneal hemorrhagic collection which seemed to arise from the inferior aspect of the left adrenal gland. She subsequently underwent successful IR embolization of the left inferior suprarenal artery. Further workup showed elevated urinary fractionated metanephrine and normetanephrine levels, as well as elevated levels of plasma free metanephrine and normetanephrine. Given concern for pheochromocytoma, phenoxybenzamine was started. A repeat CT abdomen after six days demonstrated shrinkage in hematoma and a 7 mm hypoattenuating nodule arising from the medial limb of the left adrenal gland. Outpatient follow-up CT abdomen showed left adrenal thickening with a 2.3 cm nodular area with 78.9 Hounsfield units and absolute washout of 60.9% suggestive of adenoma. After one month, repeat catecholamine levels normalized. Discussion: The clinical manifestation of AH varies widely. Acute adrenal insufficiency is seen if bilateral glands and 90% of the cortices are compromised. However, unilateral AH is most often asymptomatic - found incidentally on imaging. Having elevated catecholamines is described in 30% of patients in one case series. Differentiating spontaneous AH from hemorrhagic adrenal tumors is also a dilemma. Among the hemorrhagic adrenal masses, pheochromocytoma is the most common. Conclusion: This case highlights that clinicians should be aware of clinical manifestations of catecholamine excess when evaluating patients with AH. A catecholamine producing adrenal mass (pheochromocytoma) should also be ruled out in these situations. Reference:1- Elhassan YS, Ronchi C, Wijewickrama P, Balvedeweg SE. Approach to the patient with adrenal hemorrhage. J Clin Endocrinol Metab. 2023, 108 (4):995-1006.2- Karwacka IM, Obolonczyk L, Sworczak K. Adrenal hemorrhage: a single center experience and literature review. Adv Clin Exp Med. 2018; 27 (5): 681-687. Presentation: Thursday, June 15, 2023

Machine learning approach to evaluate TdP risk of drugs using cardiac electrophysiological model including inter-individual variability.

Introduction: Predicting ventricular arrhythmia Torsade de Pointes (TdP) caused by drug-induced cardiotoxicity is essential in drug development. Several studies used single biomarkers such as qNet and Repolarization Abnormality (RA) in a single cardiac cell model to evaluate TdP risk. However, a single biomarker may not encompass the full range of factors contributing to TdP risk, leading to divergent TdP risk prediction outcomes, mainly when evaluated using unseen data. We addressed this issue by utilizing multi-in silico features from a population of human ventricular cell models that could capture a representation of the underlying mechanisms contributing to TdP risk to provide a more reliable assessment of drug-induced cardiotoxicity. Method: We generated a virtual population of human ventricular cell models using a modified O'Hara-Rudy model, allowing inter-individual variation. and Hill coefficients from 67 drugs were used as input to simulate drug effects on cardiac cells. Fourteen features (, , , , , , , , , , , , qNet, qInward) could be generated from the simulation and used as input to several machine learning models, including k-nearest neighbor (KNN), Random Forest (RF), XGBoost, and Artificial Neural Networks (ANN). Optimization of the machine learning model was performed using a grid search to select the best parameter of the proposed model. We applied five-fold cross-validation while training the model with 42 drugs and evaluated the model's performance with test data from 25 drugs. Result: The proposed ANN model showed the highest performance in predicting the TdP risk of drugs by providing an accuracy of 0.923 (0.908-0.937), sensitivity of 0.926 (0.909-0.942), specificity of 0.921 (0.906-0.935), and AUC score of 0.964 (0.954-0.975). Discussion and conclusion: According to the performance results, combining the electrophysiological model including inter-individual variation and optimization of machine learning showed good generalization ability when evaluated using the unseen dataset and produced a reliable drug-induced TdP risk prediction system.

Psychotherapeutic drug-induced life-threatening arrhythmias: A retrospective analysis using the Japanese adverse drug eventreport database.

Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious cardiac side effects. Psychotherapeutic drugs are known to be risk factors for arrhythmias. The aim of this study was to evaluate psychotherapeutic drugs associated with life-threatening ventricular arrhythmias using the Japanese Adverse Drug Event Report (JADER) database. From the JADER database (April 2004 to September 2022), cases of TdP, VT, VF, and QT prolongation in patients taking psychotherapeutic drugs as 'suspected drugs' were extracted. The adjusted reported odds ratio (aROR) was calculated to identify potential drugs involved in combined TdP/VF/VT or combined QT prolongation/TdP. Of the 4,530,772 cases reported, life-threatening arrhythmia-related adverse events were reported in 1760 cases (QT prolongation 1261, TdP 192, VF 108, VT 199) among 909 patients; 58.9% of patients were female, and the highest incidence was among patients aged 80-89 years (18.6%), followed by patients aged 70-79 years (15.4%). The highest aROR for TdP/VF/VT was found for trazodone (17.1), followed by sulpiride (10.8), haloperidol (9.8), donepezil (9.1), and fluvoxamine (7.9). The highest aROR for QT prolongation/TdP was found for guanfacine (87.8), followed by sultopride (60.1), escitalopram (21.0), trazodone (12.8), and donepezil (9.3). This study showed that typical antipsychotics, antidepressants, and antidementia drugs were associated with life-threatening arrhythmia-related adverse events in a Japanese clinical setting. These events were more frequent in women and elderly individuals.

Agreement of Computerized QT and QTc Interval Measurements Between Both Bedside and Expert Nurses Using Electronic Calipers.

In hospitalized patients, QT/QTc (heart rate corrected) prolongation on the electrocardiogram (ECG) increases the risk of torsade de pointes. Manual measurements are time-consuming and often inaccurate. Some bedside monitors automatically and continuously measure QT/QTc; however, the agreement between computerized versus nurse-measured values has not been evaluated. The aim of this study was to examine the agreement between computerized QT/QTc and bedside and expert nurses who used electronic calipers. This was a prospective observational study in 3 intensive care units. Up to 2 QT/QTc measurements (milliseconds) per patient were collected. Bland-Altman test was used to analyze measurement agreement. A total of 54 QT/QTc measurements from 34 patients admitted to the ICU were included. The mean difference (bias) for QT comparisons was as follows: computerized versus expert nurses, -11.04 ± 4.45 milliseconds (95% confidence interval [CI], -2.3 to -19.8; P = .016), and computerized versus bedside nurses, -13.72 ± 6.70 (95% CI, -0.70 to -26.8; P = .044). The mean bias for QTc comparisons was as follows: computerized versus expert nurses, -12.46 ± 5.80 (95% CI, -1.1 to -23.8; P = .035), and computerized versus bedside nurses, -18.49 ± 7.90 (95% CI, -3.0 to -33.9; P = .022). Computerized QT/QTc measurements calculated by bedside monitor software and measurements performed by nurses were in close agreement; statistically significant differences were found, but differences were less than 20 milliseconds (on-half of a small box), indicating no clinical significance. Computerized measurements may be a suitable alternative to nurse-measured QT/QTc. This could reduce inaccuracies and nurse burden while increasing adherence to practice recommendations. Further research comparing computerized QT/QTc from bedside monitoring to standard 12-lead electrocardiogram in a larger sample, including non-ICU patients, is needed.

ICH S7B In Vitro Assays Do Not Address Mechanisms of QTC Prolongation for Peptides and Proteins - Data in Support of Not Needing Dedicated QTC Studies.

Current cardiac safety testing focuses on detecting drug-induced QTC prolongation as a surrogate for risk of Torsade de Pointes. The nonclinical strategy, described in International Conference on Harmonization (ICH) S7B, includes in vitro assessment of hERG block or ventricular repolarization delay and in vivo QT prolongation. Several studies have reported predictive values of ICH S7B results for clinical QTC outcomes for small molecules; none has examined peptides and proteins other than monoclonal antibodies. To address this knowledge gap, information for peptides and proteins submitted to the US Food and Drug Administration (FDA) was collected. Results of hERG assays, ventricular repolarization assays, and in vivo QT assessment were compared with clinical QTC study outcomes. The results show that 14% clinical QTC studies for approved and investigational products failed to exclude 10-ms QTC prolongation. Clinical QTC prolongation for these molecules lacked concentration-dependence which is expected for hERG block-mediated mechanism or QTC prolongation could not be excluded due to characterization in the clinical study. The hERG and ventricular repolarization assays do not identify clinical QTC prolongation potential for peptides and proteins. Lack of alignment between hERG and ventricular repolarization assay results and clinical QTC outcomes suggests that the mechanisms of QTC prolongation by some peptides and proteins are unrelated to direct cardiac ion channel block. Similar to large targeted proteins and monoclonal antibodies, peptides and proteins regardless of size have a low likelihood of direct cardiac ion channel interactions. This characteristic supports waiving the requirement for thorough QT assessment for products comprised of naturally occurring amino acids unless proarrhythmia potential is suggested by nonclinical or clinical data.

Efficacy and safety of in-hospital treatment of Covid-19 infection with low-dose hydroxychloroquine and azithromycin in hospitalized patients: A retrospective controlled cohort study

ObjectivesIn this study we evaluate the efficacy and safety of a treatment protocol with standard dose of hydroxychloroquine plus azithromycin in patients hospitalized with COVID-19 infection. MethodsWe conducted a retrospective analysis to compare the 28-day mortality rate in 352 patients treated with hydroxychloroquine with or without azithromycin (HCQ-group) in our hospital with a contemporary control group of 3533 patients receiving standard of care from the Belgian Collaborative Group on COVID-19 Hospital Surveillance. ResultsAll patients who received at least one dose of treatment were included in the analysis. A statistically significant reduction in crude mortality rate at 28 days was observed in the HCQ-group compared to standard of care (16.8% vs 25.9%,p ​= ​0.001).Patients in the treatment group were on average younger (69,7 vs73,1 years, p ​= ​0,0002), were less likely to smoke or to have malignancy and more likely to be male. Patients in the treatment group were more likely to be obese, immunocompromised or to have arterial hypertension, liver disease and lung disease.After adjustment for these variables the OR for mortality was 0.635 (95%CI 0.464–0.875). Patients who did not receive HCQ had a 57% higher risk of mortality. A survival benefit in the treatment group was consistent across all age groups. 13 patients discontinued treatment due to side effects (4 with QTc-prolongation>60msec (1.1%) and 9 because of gastro-intestinal symptoms (2.55%)). No episodes of ventricular arrhythmia or torsade de pointes were recorded during treatment. ConclusionTreatment of COVID-19 using a combination of hydroxychloroquine plus azithromycin was safe and was associated with a statistically significant mortality benefit in the treatment of COVID-19 infection in hospitalized patients. Our findings do not support the current negative recommendations regarding this treatment.

Polypharmacy, Gender Disparities, and Ethnic and Racial Predispositions in Long QT Syndrome: An In-Depth Review.

Long QT syndrome (LQTS) is a complex disorder of cardiac electrophysiology. It is characterized by delayed myocardial polarization leading to QT prolongation and alterations on the ST segment and Twave visible on electrocardiogram (ECG). Syncope is a common manifestation, and torsade de pointes (TdP) can lead to sudden cardiac death. Three major LQTS genes (KCI31, KCNH2, and SCN5) lead to most of the cases of LQTS. Lifestyle modifications, beta blockers, and implantable cardioverterdefibrillator(ICD) placement are the main treatments for LQTS. Polypharmacy, including QT-prolonging drugs, has been shown to worsen LQTS. The impact on potassium channels and the human ether-a-go-go-related gene (hERG) is the mechanism behind the QT interval prolongation caused by these medications. There is an increased incidence of LQTS among African-American men and women as compared to Caucasians. Women with LQTS tend to have a higher mortality rate from the condition, especially during menstruation and shortly after giving birth. Genetic testing is reserved to those patientswho exhibit either a strong clinical index of suspicion or experience persistent QT prolongation despite their lack of symptoms. Knowing the genetics, racial, and gender discrepancies can help improve patient management and a better comprehension on each case. Proper understanding of how ion channels function and their interaction with medications will lead to a better comprehension and to develop effective forms to treat those patients.

Rapid changes of mRNA expressions of cardiac ion channels affected by Torsadogenic drugs influence susceptibility of rat hearts to arrhythmias induced by Beta-Adrenergic stimulation.

Drug-induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug-induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)-inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12-h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff-perfused heart method under basal conditions and subsequently under beta-adrenergic stimulation. Gene expression was measured using real-time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug-induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + -ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta-adrenergic stimulation.

Increased ventricular ectopy precedes Torsades de Pointes in patients with prolonged QT.

Torsades de Pointes (TdP) is a potentially lethal ventricular tachydysrhythmia. Prolonged heartrate corrected QT interval (QTc) predicts TdP; however, with poor specificity. We performed this study to identify other predictors of TdP among patients with prolonged QTc. We performed a retrospective case control study with 2:1 matching at an urban academic hospital. We searched our hospital electrocardiogram (ECG) database for tracings with heartrate ≤ 60, QTc≥500, and QRS<120, followed by a natural language search for electronic records with "Torsades," "polymorphic VT," or similar to identify TdP cases from 2005 to 19. We identified controls from a similar ECG database search matching for QTc, heartrate, age, and sex. We compared cardiologic and historical factors, medications, laboratory values, and ECG measurements including ectopy using univariate statistics. For those cases with saved telemetry strips that included preceding beats or TdP onset, we compared ectopy and TdP onset characteristics between the ECG and telemetry strips using mixed linear modeling. Seventy-five cases including 50 with telemetry strips and 150 controls were included. Historical, pharmacologic, laboratory, and cardiologic testing results were similar between cases and controls. The proportion of telemetry tracings with premature ventricular contractions (PVC's) preceding TdP was 0.78 compared to 0.16 for case ECG's (difference 0.62(95%CI 0.44-0.75)) and 0.10 for control ECGs (difference 0.68(95%CI 0.56-0.80)). Average telemetry heartrate was 72 and QTc 549 immediately preceding TdP, similar to the ECG values. Clinical factors don't differentiate patients with long QTc who develop TdP, however, an increase in PVC's in patients with prolonged QTc may usefully predict imminent TdP.