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Introduction: Ventricular ectopic beats and corrected QT interval (QTc) prolongation are both relatively common entities that are typically benign. It is difficult to predict subsequent dysrhythmias from either electrocardiogram (ECG) feature. The combination of both features may better predict the risk of torsades de pointes. We highlight a case of torsades preceded by a bizarre bigeminal rhythm with QTc prolongation likely caused by memantine use and hypokalemia. Case Report: An 84-year-old female presented to the emergency department with a fall. A syncope workup revealed an ECG demonstrating bigeminy with a prolonged QTc interval. Several minutes after obtaining the ECG, the patient went into torsades. She had multiple subsequent cardiac arrests during the rest of her hospital stay. This case report details the importance of recognizing ventricular bigeminy in the context of QTc prolongation as a harbinger of torsades. Conclusion: While premature ventricular contractions including bigeminy may be a benign finding, when accompanied by prolonged QTc intervals, they warrant immediate investigation and treatment of potential underlying pathology to prevent torsades and subsequent cardiac arrest.

The author comments on calculating a corrected QT interval (QTc) in acute care settings and the significant role of pharmacists in QTc interpretation. Topics discussed include standards for pharmacists in assessing the risk of QTc prolongation, the methods used to correct QT values, and factors to be considered in assessing the risk of torsades de pointes.

Proton pump inhibitors (PPI) are widely used medications for gastrointestinal disorders. Recent research suggests a potential association between long-term PPI use and increased cardiovascular (CV) risk, creating a complex clinical dilemma. This review critically evaluates the current evidence for this association, considering the limitations of observational studies and the lack of definitive confirmation from randomized controlled trials. This review delves into the reported association between PPIs and adverse CV events, examining proposed mechanisms such as drug interactions, electrolyte imbalances induced by PPIs and their potential impact on cardiac and vascular function. Evidence suggests these mechanisms converge, with varying influence depending on patient populations. Clinicians require a risk-benefit analysis for each patient considering their CV risk profile. Alternative gastrointestinal therapies should be explored for high-bleeding risk patients. Medications with lower cytochrome-P450 interaction potential may be preferable among essential PPI users. Elucidating the specific mechanisms by which PPIs might influence CV health, assessing long-term vascular effects and investigating interactions with newer anticoagulant medications are crucial for future research. Plain Language Summary Proton pump inhibitors (PPIs) are commonly used medications for gastrointestinal problems. However, recent studies have shown that long-term use of PPIs might increase the risk of heart problems. While this link hasn't been definitively proven, it's important to be aware of it. Researchers think that several factors could contribute to this increased risk. PPIs might interact with other medications, cause electrolyte imbalances, or affect the way the heart and blood vessels work through multiple mechanisms. Doctors need to carefully weigh the benefits of PPIs against the potential risks for each patient. For people at high risk of heart problems, alternative treatments might be better. If someone requires a PPI due to increased risk of gastrointestinal bleeding, providers need to take into account concurrent medications and carefully select those with the least risk of interactions. Future research should focus on understanding how PPIs might impact the heart and blood vessels in the long term, especially considering the increasing use of newer blood-thinning medications. Graphical Abstract Article highlights The widespread use of proton pump inhibitors (PPI) has risen dramatically in recent years, yet their potential cardiovascular risks remain uncertain. PPIs can influence the metabolism of clopidogrel, an antiplatelet agent, by affecting hepatic cytochrome P450 (CYP) enzymes, particularly CYP2C19. PPIs may elevate cardiovascular risk through mechanisms beyond drug interactions. Chronic PPI use has been associated with electrolyte imbalances, notably hypocalcemia and hypomagnesemia, which are crucial for maintaining cellular homeostasis. PPI-induced intracellular disturbances can precipitate life-threatening arrhythmias, including torsade de pointes. PPIs, through both direct and indirect mechanisms, can disrupt cellular electrolyte balance, thereby impairing myocyte function and potentially contributing to the development of heart failure. PPIs may exert a direct influence on vascular regulation, potentially accelerating vascular senescence through intricate cellular mechanisms. Future research should investigate these mechanisms and potential interactions with novel cardiovascular medications. [ABSTRACT FROM AUTHOR]

Implantable loop records allow continuous heart rhythm monitoring with the ability to be stored and viewed remotely. The limited use in the pediatric population stems from the unknown indications of use and feasibility of implantation. We describe the case of a 2.7kg female with Long QT3. A loop recorder helped identify breakthrough tachycardia and helped her transition to the next stage of care. Placement was at the left subscapular region with no complications. Implantable loop recorder placement is achievable in a 2.7 kg patient at corrected gestational age 38 weeks for LQT3 syndrome monitoring and management. Article highlights Long QT 3 may present with neonatal arrhythmias. Implantable loop recorders may help in identifying control of arrhythmias in smaller patients with Long QT3. The subscapular region may be helpful when patient size may predispose to higher risk of erosion from an implantable loop recorder. [ABSTRACT FROM AUTHOR]

Methadone, a well-known drug used for pain control and as a treatment for opioid addiction, can cause arrhythmias, including torsades de pointes (TdP), which may progress to ventricular fibrillation and sudden death. We present a case of a middle-aged woman with a long history of methadone use who presented to the emergency department after experiencing cardiac arrest at home. During her hospitalization, she experienced multiple episodes of TdP that improved with isoproterenol and potassium correction. The initial diagnosis was methadone-induced prolonged QT. However, even with discontinuation of methadone, her QTc remained prolonged. Congenital long QT syndrome was suspected, and genetic testing was instructed to test in the outpatient setting. She was discharged on nadolol and a LifeVest. [ABSTRACT FROM AUTHOR]

Background: The safety of triple antiemetic therapy consisting of ondansetron, haloperidol, and a steroid, to surgical patients is unknown. Objective: To determine the incidence of torsade de pointes (TdP) or death following perioperative administration of triple antiemetic therapy. Methods: A retrospective cohort study identified 19,874 patients who received 22,202 doses of triple antiemetics during the 2.5-year time frame from March 4, 2020 to September 7, 2022 for surgical nausea prophylaxis or treatment of nausea. These patients above were cross-matched with an electrocardiogram and adverse outcome database; this identified 226 patients with documentation of a QTc > 450 ms, all ventricular tachycardias including TdP within 48 hours of receiving triple antiemetic therapy, or death within 7 days of receiving ondansetron. Results: There were 3 patients who had documented VT (n = 3), but there were no documented incidents of TdP (n = 0). There were 9 codes called on patients within 48 hours of medication administration, and none of them were due to ventricular arrythmias (n = 0). A total of 11 patients died within 7 days of triple antiemetic therapy. Ten of the 11 deaths were determined to not be from the triple antiemetic. One patient died at home within 24 hours of the procedure of an unknown cause (n = 1). Conclusions and Relevance: No episodes of TdP were identified in patients receiving triple antiemetic therapy perioperatively, though the cause of death in 1 patient could not be determined. This suggest that low-dose triple antiemetic therapy is low risk for the development of TdP. [ABSTRACT FROM AUTHOR]

Hypothyroidism can have a significant impact on cardiac contractility, vascular resistance, blood pressure, and cardiac rhythm. Ventricular arrhythmias induced by hypothyroidism are infrequently reported, especially in pediatric cases. A 15-year-old girl with autoimmune hypothyroidism experienced pulseless ventricular arrhythmias on 2 separate occasions because of nonadherence to levothyroxine medication. Subsequent investigations revealed an SCN5A mutation associated with Brugada syndrome. A loop recorder captured polymorphic ventricular tachycardia (PMVT), specifically Torsades de Pointes during her second event. Both arrhythmias were addressed only after stabilizing her thyroid hormone levels with replacement therapy. Although rare, patients with uncontrolled hypothyroidism may present with ventricular arrhythmias, particularly PMVT. The cornerstone of treatment for hypothyroidism-induced ventricular arrhythmia is thyroid replacement therapy. The identification of an SCN5A mutation unmasked by overt hypothyroidism emphasizes the need for a comprehensive cardiac evaluation in patients with hypothyroidism being assessed for PMVT. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the high-quality literature on the frequency and nature of major adverse cardiac events (MACE) associated with either hydroxychloroquine (HCQ) or chloroquine (CQ). Data sources: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onward using search strategies created in collaboration with medical science librarians. Study selection and data extraction: Randomized controlled trials (RCTs) published in English language from January 1996 to September 2022, involving adult patients at least 18 years of age, were selected. Outcomes of interest were death, arrhythmias, syncope, and seizures. Random-effects meta-analyses were performed with a Treatment Arm Continuity Correction for single and double zero event studies. Data synthesis: By study drug, there were 31 HCQ RCTs (n = 6677), 9 CQ RCTs (n = 622), and 1 combined HCQ-CQ trial (n = 105). Mortality was the most commonly reported MACE at 220 of 255 events (86.3%), with no reports of torsades de pointes or sudden cardiac death. There was no increased risk of MACE with exposure to HCQ-CQ compared with control (risk ratio [RR] = 0.90, 95% CI = 0.69-1.17, I 2 = 0%). Relevance to patient care and clinical practice: These findings have important implications with respect to patient reassurance and updated guidance for prescribing practices of these medications. Conclusions: Despite listing as QT-prolonging meds, HCQ-CQ did not increase the risk of MACE. [ABSTRACT FROM AUTHOR]

Background: During takotsubo syndrome (TS), QTc prolongation is common, reflecting repolarization injury and providing the substrate for torsades de pointes (TdP). TdP has been reported sporadically in TS, yet QTc prolongation and TdP risk are often overlooked during management. Objectives: In TS patients, we sought to document TdP incidence, characteristics of patients with TdP, and association of QTc with postdischarge survival. Methods: Among consecutive TS patients at a single institution, we documented admission and discharge QTc, TdP incidence, and postdischarge 1-year mortality from 2006 to 2019. For perspective regarding TdP-TS risk, we characterized all published TdP cases from 2003 to 2022. Results: Of 259 patients, median age was 68 (range: 59-77) years; 92% were female. The QTc interval was prolonged (≥460 ms) on admission in 129 (49.8%) patients and at discharge in 140 (54%) patients. QTc was ≥500 ms either on admission or at discharge in 98 (37.8%) patients. In-hospital TdP incidence was 0.8%. Postdischarge mortality was associated with admission but not discharge, QTc: 98% survival at 1-year postdischarge.

Background Fluoroquinolones (FQs) are widely used in the management of several bacterial infections including urinary tract infections (UTIs), upper respiratory tract infections (URTIs), lower respiratory tract infections (LRTIs), skin and soft tissue, gastrointestinal tract infections (GITIs), and many other infections. Objective This review article focuses on some serious side effects notified by United States Food and Drug Administration (US FDA) in different warning statements. Methods The literature was searched, in databases such as Medline/PubMed/PMC, Google Scholar, Science Direct, Ebsco, Scopus, Web of science, Embase, and reference lists to identify publications relevant to the serious side effects associated with the use of FQs. Results Several epidemiological studies and meta-analyses have documented the occurrence of serious side effects of FQs including tendinopathy, peripheral neuropathy, aortic aneurysm/dissection, hypoglycemia, QT prolongation, retinal detachment, and worsening of myasthenia gravis. Conclusion The clinicians should be aware of serious side effects of FQs. The US FDA and European Medicines Agency recommend against the use of FQs as first-line therapies to treat infections such as acute sinusitis, acute bronchitis, and uncomplicated UTIs, as the risks outweigh the benefits. The risk of incidence of serious side effects of FQs is higher among patients with advanced age, renal insufficiency, and certain concomitant medications. To avoid occurrence of any serious side effects of FQs, the clinicians should prefer non-FQ antibacterial drugs to manage uncomplicated UTIs, respiratory tract infections, and other infections for which alternatives available. [ABSTRACT FROM AUTHOR]

Safety pharmacology examines the potential for new drugs to have unusual, rare side effects such as torsade de pointes (TdP). Recently, as a part of the Comprehensive in vitro Proarrhythmia Assay (CiPA) project, techniques for predicting the development of druginduced TdP through computer simulations have been proposed and verified. However, CiPA assessment generally does not consider the effect of cardiac cell inter-individual variability, especially related to metabolic status. The study aimed to explore whether rare proarrhythmic effects may be linked to the inter-individual variability of cardiac cells and whether incorporating this variability into computational models could alter the prediction of drugs' TdP risks. This study evaluated the contribution of two biological characteristics to the proarrhythmic effects. The first was spermine concentration, which varies with metabolic status; the second was L-type calcium permeability that could occur due to mutations. Twenty-eight drugs were examined throughout this study, and qNet was analyzed as an essential feature. Even though there were some discrepancies of TdP risk predictions from the baseline model, we found that considering the inter-individual variability might change the TdP risk of drugs. Several drugs in the high-risk drugs group were predicted to affect as intermediate and low-risk drugs in some individuals and vice versa. Also, most intermediaterisk drugs were expected to act as low-risk drugs. When compared, the effects of interindividual variability of L-type calcium were more significant than spermine in altering the TdP risk of compounds. These results emphasize the importance of considering interindividual variability to assess drugs. [ABSTRACT FROM AUTHOR]

An implantable loop recorder (ILR) is now widely used for differential diagnosis of unexplained syncope or recurrent syncope with unknown causes. In the inherited arrhythmia syndromes, ILR may be useful for management of the therapeutic strategies; however, there is no obvious evidence to uncover arrhythmic syncope by ILR in long-QT syndrome (LQTS) patients. Here we experienced a 19-year-old female patient with LQTS type 1 who had recurrent syncope even after beta-blocker therapy but no arrhythmias were documented, and some episodes might be due to non-cardiogenic causes. Implantable cardioverter defibrillator (ICD) therapy was also recommended; however, she could not accept ICD but was implanted with ILR for further continuous monitoring. Two years later, she suffered syncope during a brief run, and ILR recorded an electrocardiogram at that moment. Thus a marked QT interval prolongation as well as T-wave alternance resulting in development of torsades de pointes could be detected. Although ILR is just a diagnostic tool but does not prevent sudden cardiac death, most arrhythmic events in LQTS are transient and sometimes hard to be diagnosed as arrhythmic syncope. ILR may provide direct supportive evidence to select the optimal therapeutic strategy in cases where syncope is difficult to diagnose. Long-QT syndrome (LQTS) patients often suffer recurrent syncope even after beta-blocker therapy, but torsades de pointes (TdP) is not always detected by standard 12‑lead electrocardiogram or Holter monitoring, and some syncope might be non-cardiogenic. In this case, implantable loop recorder (ILR) documented the evidence of QT interval prolongation and beat-by-beat T-wave alternance subsequent TdP. Thus, ILR may provide useful evidence for the optimal treatment strategy in LQTS cases where syncope is difficult to diagnose. [ABSTRACT FROM AUTHOR]

Rationale: Little is known about the prescribing of medications with potential to cause QTc‐prolongation in the ambulatory care settings. Understanding real‐world prescribing of QTc‐prolonging medications and actions taken to mitigate this risk will help guide strategies to optimize safety and appropriate prescribing among ambulatory patients. Objective: To evaluate the frequency of clinician action taken to monitor and mitigate modifiable risk factors for QTc‐prolongation when indicated. Methods: This retrospective, cross‐sectional study evaluated clinician action at the time of prescribing prespecified medications with potential to prolong QTc in adult patients in primary care. The index date was defined as the date the medication was ordered. Electronic health record (EHR) data were evaluated to assess patient, clinician and visit characteristics. Clinician action was determined if baseline or follow‐up monitoring was ordered or if action was taken to mitigate modifiable risk factors (laboratory abnormalities or electrocardiogram [ECG] monitoring) within 48 h of prescribing a medication with QTc‐prolonging risk. Descriptive statistics were used to describe current practice. Results: A total of 399 prescriptions were prescribed to 386 patients, with a mean age of 51 ± 18 years, during March 2021 from a single‐centre, multisite health system. Of these, 17 (4%) patients had a known history of QTc‐prolongation, 170 (44%) did not have a documented history of QTc‐prolongation and 199 (52%) had an unknown history (no ECG documented). Thirty‐nine patients (10%) had at least one laboratory‐related risk factor at the time of prescribing, specifically hypokalemia (16 patients), hypomagnesemia (8 patients) or hypocalcemia (19 patients). Of these 39 patients with laboratory risk factors, only 6 patients (15%) had their risk acknowledged or addressed by a clinician. Additionally, eight patients' most recent QTc was ≥500 ms and none had an ECG checked at the time the prescription was ordered. Conclusion: Despite national recommendations, medication monitoring and risk mitigation is infrequent when prescribing QTc‐prolonging medications in the ambulatory care setting. These findings call for additional research to better understand this gap, including reasons for the gap and consequences on patient outcomes. [ABSTRACT FROM AUTHOR]

We present a case of a 45-year-old female with advanced heart failure due to nonischemic cardiomyopathy, an ejection fraction of 15% complicated by ventricular arrhythmias degenerating into an electrical storm. The treatment approach involved antiarrhythmic medications, inotrope support, diuretics, and the placement of an Impella 5.5 device for mechanical circulatory support. Due to persistent polymorphic ventricular tachycardia, a bilateral stellate ganglion blockade was performed along with intensified antiarrhythmic therapy and deep sedation. This case highlights the role of axillary mechanical circulatory support with the Impella 5.5 in providing unfettered hemodynamic stability and the potential added benefit of stellate ganglion blockade in managing malignant ventricular arrhythmias.

Case reports suggest that quetiapine or haloperidol use is associated with severe QT prolongation (SQTP) and torsades de pointes. The purpose of this study was to examine the incidences, risk factors, and outcomes of SQTP in quetiapine and haloperidol users. This study accessed electronic medical records from a multicenter health-care hospital system in Taiwan and included patients who received quetiapine or haloperidol therapy and had both baseline and follow-up electrocardiograms. SQTP was defined as a posttreatment corrected QT (QTc) interval exceeding 500 ms or an increase in QTc interval of >60 ms compared with the baseline value. We analyzed the risk factors and outcomes of SQTP using multivariate logistic regression. Mean increases in QTc interval were +8.3 ± 51.8 and +8.9 ± 44.0 ms after the administration of quetiapine (n = 8832) and haloperidol (n = 2341). Among these users, 1149 (13.0%) and 333 (14.2%) developed SQTP, respectively. Common risk factors for SQTP included old age, heart failure, hypokalemia, amiodarone use, and baseline QTc interval. SQTP in quetiapine users was significantly associated with ventricular arrhythmias (odds ratio 2.84; 95% confidence interval 1.95–4.13) and sudden cardiac death (odds ratio 2.29; 95% confidence interval 1.44–3.66). More than 10% of patients receiving quetiapine or haloperidol therapy developed SQTP, and many of them were exposed to risk factors for SQTP. SQTP in quetiapine users was significantly associated with increased risks of ventricular arrhythmias and sudden cardiac death. Clinicians should be vigilant for ventricular arrhythmias in quetiapine users who have risk factors for SQTP. [Display omitted] [ABSTRACT FROM AUTHOR]

Myocardial infarction is among the top causes of mortality worldwide. Survivors may also experience several complications. Infarct-related torsade de pointes (TdP) is an uncommon complication. In the context of myocardial infarction, coronary artery bypass graft (CABG) surgery is the prevalent therapeutic modality associated with several early and late complications. Ventricular tachyarrhythmias, including TdP, because of electrical inhomogeneity, would potentially be a lethal complication of CABG. Here, we report the occurrence of medically intractable TdP in the presence of an uncommon case of a post-CABG retrosternal hematoma. Arrhythmia was properly resolved after hematoma removal surgically. It showed the possibility of a “cause and effect” relationship between these two complications. This unique case emphasizes the post-CABG medically-resistant TdP, considering the mechanical pressure effect of retrosternal hematoma that stimulates this potentially malignant arrhythmia, especially in the absence of electrolyte disturbances and evident symptoms of ongoing ischemia.

Torsades de Pointes (TdP) is a malignant polymorphic ventricular tachycardia with heart rate corrected QT interval (QTc) prolongation, which may be attributed to congenital and acquired factors. Although various acquired factors for TdP have been summarized, levosimendan administration in complex postoperative settings is relatively uncommon. Timely identification of potential causes and appropriate management may improve the outcome. Herein, we describe the postoperative case of a 56-year-old female with initial normal QTc who accepted the administration of levosimendan for heart failure, suffered TdP, cardiac arrest, and possible Takotsubo cardiomyopathy, further genetically confirmed as long QT syndrome type 1 (LQT1). The patient was successfully treated with magnesium sulfate, atenolol, and implantable cardioverter defibrillator implantation. There should be a careful evaluation of the at-risk populations and close monitoring of the electrocardiograms, particularly the QT interval, to reduce the risk of near-fatal arrhythmias during the use of levosimendan.

ABSTRACT Adenosine is an antiarrhythmic drug that slows conduction through the atrioventricular node and acts as a coronary blood vessel dilator. This case report highlights two unusual life-threatening events following the use of adenosine to revert supraventricular tachycardia in a structurally normal heart: non-sustained polymorphic ventricular tachycardia and myocardial infarction. A 46-year-old woman presented to the emergency department with a two-hour history of palpitations and was diagnosed with supraventricular tachycardia. Vagal maneuvers were ineffective, and after intravenous adenosine administration, the patient presented with chest pain and hypotension. The rhythm degenerated into non-sustained polymorphic ventricular tachycardia and spontaneously reverted to sinus rhythm with ST elevation in lead aVR and ST depression in the inferior and anterolateral leads. The patient spontaneously recovered within a few minutes. Despite successful arrhythmia reversal, the patient was admitted to the intensive care unit because of an infarction without obstructive atherosclerosis. This report aims to alert emergency physicians about the potential complications associated with supraventricular tachycardia and its reversal with adenosine.

BackgroundThe short-coupled variant of torsade de pointes (sc-TdP) is a malignant arrhythmia that frequently presents with ventricular fibrillation (VF) electrical storm. Verapamil is considered the first-line therapy of sc-TdP while catheter ablation is not widely adopted. The aim of this study was to determine the origin of sc-TdP and to assess the outcome of catheter ablation using 3D-mapping.Methods and resultsWe retrospectively analyzed five patients with sc-TdP who underwent 3D-mapping and ablation of sc-TdP at five different institutions. Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope as the first manifestation. All patients demonstrated a monomorphic premature ventricular contraction (PVC) with late transition left bundle branch block pattern, superior axis, and a coupling interval of less than 300 ms. triggering recurrent TdP and VF. In four patients, the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients. Catheter ablation using 3D-mapping and intracardiac echocardiography eliminated sc-TdP in all patients, with no recurrence at mean 2.7 years (range 6 months to 8 years) of follow-up.Conclusion3D-mapping and intracardiac echocardiography demonstrate that sc-TdP predominantly originates from the MB free wall insertion and its Purkinje network. Catheter ablation of the culprit PVC at the MB free wall junction leads to excellent short- and long-term results and should be considered as first-line therapy in recurrent sc-TdP or electrical storm.

BackgroundEpileptic seizures can be difficult to distinguish from other etiologies that cause cerebral hypoxia, especially cardiac diseases. Long QT syndrome (LQTS), especially LQTS type 2 (LQT2), frequently masquerades as seizures because of the transient cerebral hypoxia caused by ventricular arrhythmia. The high rate of sudden death in LQTS highlights the importance of accurate and early diagnosis; correct diagnosis of LQTS also prevents inappropriate treatment with anti-epileptic drugs (AEDs).Case presentationWe report a case of congenital LQT2 with potassium voltage-gated channel subfamily H member 2 gene (KCNH2) mutation misdiagnosed as refractory epilepsy and treated with various AEDs for 22 years. The possibility of cardiac arrhythmia was suspected after the patient presented to the emergency room and the electrocardiograph (ECG) monitor showed paroxysmal ventricular tachycardia during attacks. Atypical seizure like attacks with prodromal uncomfortable chest sensation and palpitation, triggered by auditory stimulation, and typical ventricular tachycardia monitored by ECG raised suspicion for LQT2, which was confirmed by exome sequencing and epileptic seizure was ruled out by 24-h EEG monitoring. Although the patient rejected implantation of an implantable cardioverter defibrillator, β blocker was given and the syncope only attacked 1-2 per year when there was an incentive during the 5 years follow up.ConclusionsOur case illustrates how long LQTS can masquerade convincingly as epilepsy and can be treated wrongly with AEDs, putting the patient at high risk of sudden cardiac death. Careful ECG evaluation is recommend for both patients with first seizure and those with refractory epilepsy.

AIMS: With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA). METHODS AND RESULTS: We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967-83 to 15 070 in 2014-18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P

Torsades de Pointes (TdP) refers to a polymorphic ventricular tachycardia (VT) with undulating QRS axis that occurs in long QT syndrome (LQTS), although the term has been used to describe polymorphic ventricular tachyarrhythmias in which QT intervals are not prolonged, such as short-coupled variant of TdP currently known as short-coupled ventricular fibrillation (VF) and Brugada syndrome. Extensive works on LQTS-related TdP over more than 50 years since it was first recognized by Dessertennes who coined the French term meaning “twisting of the points”, have led to current understanding of the electrophysiological mechanism that TdP is initiated by triggered activity due to early afterdepolarization (EAD) and maintained by reentry within a substrate of inhomogeneous repolarization. While a recently emerging notion that steep voltage gradients rather than EADs are crucial to generate premature ventricular contractions provides additions to the initiation mode, the research to elucidate the maintenance mechanism hasn't made much progress. The reentrant activity that produces the specific form of VT is not well characterized. We have conducted optical mapping in a rabbit model of electrical storm by electrical remodeling (QT prolongation) due to chronic complete atrioventricular block and demonstrated that a tissue-island with prolonged refractoriness due to enhanced late Na+ current (INa−L) contributes to the generation of drifting rotors in a unique manner, which may explain the ECG characteristic of TdP. Moreover, we have proposed that the neural Na+ channel NaV1.8-mediated INa−L may be a new player to form the substrate for TdP. Here we discuss TdP mechanisms by comparing the findings in electrical storm rabbits with recently published studies by others in simulation models and human and animal models of LQTS.

With the improving life expectancy of patients with human immunodeficiency virus (HIV), there is an increasing health concern of potential toxicity and drug interactions of long-term antiretroviral therapies. We describe a female patient with HIV, who was admitted to the emergency department following an unexplained loss of consciousness. This patient had been on antiretroviral therapy comprising tenofovir disoproxil fumarate, lamivudine, and lopinavir/ ritonavir for 12 years. Coincidentally, she had been prescribed terfenadine for urticaria recently. After 3 days on this medication, she suddenly lost her consciousness, with a distinctive electrocardiogram alteration characterized by QT prolongation and torsade de pointes. This symptom recurred several times over a span of 2 days. We postulate that the primary instigator was an elevated concentration of terfenadine, which can be traced back to her antiretroviral therapy regimen comprising lopinavir/ritonavir. This drug is known to impede the metabolism of cytochrome P450 3A4 substrates and consequently elevate terfenadine concentrations. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course. Background: Myxedema coma is a rare, life-threatening condition caused by a severe form of hypothyroidism. The dangerously low levels of circulating thyroid hormone can lead to progressive mental status changes and numerous organ dysfunctions, including serious cardiac abnormalities. Case Report: We present a case of a 59-year-old woman who presented with altered mental status and fall who was originally thought to have a cerebrovascular accident but was later diagnosed with myxedema coma, after multiple cardiac arrests. It was discovered that the patient had not been taking any of her medications for the last several weeks, after her primary care provider retired from practice. Initial laboratory evaluation was significant for a TSH level of 159.419 mIU/L and an undetectable free T4 level. Complications of the myxedema coma resulted in QTC interval prolongation, causing torsades de pointes and sustained polymorphic ventricular tachycardia, requiring cardioversion. Conclusions: This case demonstrates the importance of early detection and treatment of myxedema coma, as it can cause life-threatening cardiac arrhythmias. It also emphasizes the need to ensure proper medication adherence in patients with chronic medical conditions, as non-compliance can result in dire consequences. [ABSTRACT FROM AUTHOR]

Drug-induced QT-prolongation increases the risk of TdP arrhythmia attacks and sudden cardiac death. However, measuring the QT-interval and determining a precise cut-off QT/QTc value that could put a patient at risk of TdP is challenging and influenced by many factors including female sex, drug-free baseline, age, genetic predisposition, and bradycardia. This paper presents a novel approach for intuitively and visually monitoring QT-prolongation showing a potential risk of TdP, which can be adjusted according to patient-specific risk factors, using a pseudo-coloring technique and explainable artificial intelligence (AI). We extended the development and evaluation of an explainable AI-based technique− visualized using pseudo-color on the ECG signal, thus intuitively 'explaining' how its decision was made −to detect QT-prolongation showing a potential risk of TdP according to a cut-off personalized QTc value (using Bazett's ∆ QTc > 60 ms relative to drug-free baseline and Bazett's QTc > 500 ms as examples), and validated its performance using a large number of ECGs (n = 5050), acquired from a clinical trial assessing the effects of four known QT-prolonging drugs versus placebo on healthy subjects. We compared this new personalized approach to our previous study that used a more general approach using the QT-nomogram. The explainable AI-based algorithm can accurately detect QT-prolongation when adjusted to a personalized patient-specific cut-off QTc value showing a potential risk of TdP. Using ∆ QTc > 60 ms relative to drug-free baseline and QTc > 500 ms as examples, the algorithm yielded a sensitivity of 0.95 and 0.79, and a specificity of 0.95 and 0.98, respectively. We found that adjusting pseudo-coloring according to Bazett's ∆QTc > 60 ms relative to a drug-free baseline personalized to each patient provides better sensitivity than using Bazett's QTc > 500 ms, which could underestimate a potentially clinically significant QT-prolongation with bradycardia. [ABSTRACT FROM AUTHOR]

Objective: Delirium is an acute, life-threatening neuropsychiatric disorder frequently occurring among hospitalized patients. Antipsychotic medications are often recommended for delirium management but are associated with cardiovascular risks. This study aimed to investigate the frequency and magnitude of QTc interval prolongation and clinically relevant side effects occurring in delirium patients managed with haloperidol and/or pipamperone. Methods: This descriptive retrospective cohort study evaluated 102 elderly (mean age: 73.2 years) inpatients with delirium treated with either haloperidol, pipamperone, a combination of both, or neither in a naturalistic setting over the course of up to 20 days or until the end of delirium. Results: A total of 86.3% of patients were treated with haloperidol and/or pipamperone at a mean daily haloperidol-equipotent dose of 1.2 ± 1 mg. Noncardiovascular side effects were registered in 2.9% of all patients and correlated with higher scores on the Delirium Observation Screening Scale. They did not occur more frequently under antipsychotic treatment. The frequency of QTc interval prolongation was comparably common among all groups, but prolongation magnitude was higher under antipsychotic treatment. It was positively correlated with antipsychotic dosage and the total number of QTc interval-prolonging substances administered. Critical QTc interval prolongation was registered in 21.6% (n = 19) of patients in the group treated with antipsychotics compared to 14.3% (n = 2) of patients in the unmedicated group; however, the difference was not statistically significant. Polypharmacy was associated with a higher risk of critical QTc interval prolongation and increased mortality during delirium. Conclusion: Delirium treatment with haloperidol and/or pipamperone was not associated with a higher risk of QTc-interval prolongation in this naturalistic patient sample but was greater in magnitude and correlated with equipotent dosage and the number of QT interval-prolonging substances used. Polypharmacy was associated with higher mortality and increased risk of critical QTc prolongation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. Although this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly under-represented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (i) TdP classifiers require different features in females vs. males; (ii) male-based classifiers perform more poorly when applied to female data; and (iii) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially life-threatening consequences for the female population.

Hydroxychloroquine has been widely prescribed to treat patients with COVID-19 pneumonia. A 73-year-0ld woman with COVID-19 pneumonia was treated with dexamethasone and hydroxychloroquine. Her home medications, citalopram and donepezil, were continued. The ECG prior to starting hydroxychloroquine showed normal sinus rhythm with prolonged corrected QT (QTc) of 497 ms, due to citalopram and donepezil therapy. Repeat ECG on days 3 and 4 of hydroxychloroquine therapy showed significantly prolonged QTc of 557 ms and 538 ms, respectively, despite normal serum electrolytes. All QT-prolonging medications including hydroxychloroquine were discontinued on day 4; however, she suffered a transient torsades de pointes lasting for about 15 s, which resolved before any intervention. QTc improved to 477 ms, after discontinuation of QT-prolonging medications. The patient had QTc prolongation and torsades de pointes due to therapy with multiple QT-prolonging medications. Medicine reconciliation and careful monitoring of QTc may help prevent cardiac complications in patients with COVID-19 treated with hydroxychloroquine.

Introduction: Long QT syndrome (LQTS) is an uncommon disorder that can lead to potentially life-threatening dysrhythmias. LQTS can be genetic, acquired, or both.Case Report: A 44-year-old female with well-controlled hypertension and asthma presented with chest tightness. An initial electrocardiogram yielded a normal corrected QT interval of 423 milliseconds (ms) (normal

A 42-year-old female patient with a psychiatric history presented with recurrent near syncope episodes, revealing a significantly prolonged QTc (>750 msec) and baseline sinus bradycardia on ECG. The severe QTc prolongation was attributed to the side effect of high-dose methadone, a QTc-prolonging medication the patient had been on for her psychiatric conditions. The patient developed torsades de pointes (TdP) and was stabilized with intravenous magnesium sulfate. The alarming QTc prolongation necessitated an urgent medication reassessment. A multidisciplinary approach facilitated the patient's transition to a non-QT prolonging psychiatric medication, effectively mitigating the risk of further QTc prolongation, TdP, and potential fatality. This case underscores the critical need for vigilant monitoring and management of patients on QTc-prolonging medications, especially methadone, to preclude severe cardiac complications. [ABSTRACT FROM AUTHOR]

Synthetic cannabinoid receptor agonists (SCRAs) have been associated with QT interval prolongation. Limited preclinical information on SCRA effects on cardiac electrogenesis results from the rapid emergence of new compounds and restricted research availability. We used two machine-learning-based tools to evaluate seven novel SCRAs' interaction potential with the hERG potassium channel, an important drug antitarget. Five SCRAs were predicted to have the ability to block the hERG channel by both prediction tools; ADB-FUBIATA was predicted to be a strong hERG blocker. ADB-5Br-INACA and ADB-4en-PINACA showed varied predictions. These findings highlight potentially proarrhythmic hERG block by novel SCRAs, necessitating detailed safety evaluations.

Congenital long QT syndrome is a cardiac disorder leading to arrhythmias and sudden cardiac death. We present a case of a 55-year-old woman with altered mental status experiencing cardiac arrest caused by congenital long QT syndrome, coincidentally found with Mycobacterium avium complex lung infection. Genetic testing identified a pathogenic mutation in the KCNH2 gene. (Level of Difficulty: Intermediate.)

Abstract 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.

ObjectiveDelirium is an acute, life-threatening neuropsychiatric disorder frequently occurring among hospitalized patients. Antipsychotic medications are often recommended for delirium management but are associated with cardiovascular risks. This study aimed to investigate the frequency and magnitude of QTc interval prolongation and clinically relevant side effects occurring in delirium patients managed with haloperidol and/or pipamperone.MethodsThis descriptive retrospective cohort study evaluated 102 elderly (mean age: 73.2 years) inpatients with delirium treated with either haloperidol, pipamperone, a combination of both, or neither in a naturalistic setting over the course of up to 20 days or until the end of delirium.ResultsA total of 86.3% of patients were treated with haloperidol and/or pipamperone at a mean daily haloperidol-equipotent dose of 1.2 ± 1 mg. Non-cardiovascular side effects were registered in 2.9% of all patients and correlated with higher scores on the Delirium Observation Screening Scale. They did not occur more frequently under antipsychotic treatment. The frequency of QTc interval prolongation was comparably common among all groups, but prolongation magnitude was higher under antipsychotic treatment. It was positively correlated with antipsychotic dosage and the total number of QTc interval-prolonging substances administered. Critical QTc interval prolongation was registered in 21.6% (n = 19) of patients in the group treated with antipsychotics compared to 14.3% (n = 2) of patients in the unmedicated group; however, the difference was not statistically significant. Polypharmacy was associated with a higher risk of critical QTc interval prolongation and increased mortality during delirium.ConclusionDelirium treatment with haloperidol and/or pipamperone was not associated with a higher risk of QTc-interval prolongation in this naturalistic patient sample but was greater in magnitude and correlated with equipotent dosage and the number of QT interval-prolonging substances used. Polypharmacy was associated with higher mortality and increased risk of critical QTc prolongation.

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. [Display omitted] • History or meds don't differ between long QTc patients who do or don't suffer TdP. • Serum chemistries don't differ between long QTc patients who do or don't suffer TdP. • Increased ventricular ectopy commonly precedes TdP. • Increased ventricular ectopy and its characteristics could be used to predict TdP TdP = Torsades de Pointes. [ABSTRACT FROM AUTHOR]

Contact dermatitis is a severe complication of cardiac-device implantation that may be observed in patients with metal allergies. Some studies have suggested that wrapping cardiac devices with expanded polytetrafluoroethylene (ePTFE) sheets is effective in preventing contact dermatitis. Most of these studies involved pacemakers, whereas those on implantable cardioverter-defibrillators (ICDs) are rare. Herein, we report a method for the successful implantation of an ICD wrapped with an ePTFE sheet in a patient with metal allergy. The metal part of the ICD generator was tightly wrapped with an ePTFE sheet, which was sewn with ePTFE sutures approximating the edges of the generator. After the wrapping procedure, the patient entered the operating room, and the generator and an ePTFE-coated dual-coil shock lead were implanted via a standard procedure. The shock impedance in the coil-to-can vector was high immediately after the implantation, but it reduced to less than half of its initial value over a period of two weeks post-surgery. The patient did not develop any new skin problems during the 20-month follow-up. This is a method for successfully preventing contact dermatitis; however, attention to the associated high risk of infection is required. Wrapping an implantable cardioverter-defibrillator with an expanded polytetrafluoroethylene sheet was effective in preventing contact dermatitis after implantation. The shock impedance in the coil-to-can vector was high immediately after implantation but reduced to approximately half of its initial value with time. [ABSTRACT FROM AUTHOR]