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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.

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]

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]

BACKGROUND: Drug-induced or acquired long QT syndrome occurs as a result of the unintended disruption of cardiac repolarization due to drugs that block cardiac ion channels. These side effects have been responsible for the withdrawal of a range of drugs from market and are a common reason for termination of the development of new drugs in the preclinical stage. Existing approaches to risk prediction are expensive and overly sensitive meaning that recently there have been renewed efforts, largely driven by the comprehensive proarrhythmic assay initiative, to develop more accurate methods for allocation of proarrhythmic risk. METHODS: In this study, we aimed to quantify changes in the morphology of the repolarization phase of the cardiac action potential as an indicator of proarrhythmia, supposing that these shape changes might precede the emergence of ectopic depolarizations that trigger arrhythmia. To do this, we describe a new method of quantifying action potential morphology by measuring the radius of curvature of the repolarization phase both in simulated action potentials, as well as in action potentials measured from induced pluripotent stem cell-derived cardiomyocytes. Features derived from the curvature signal were used as inputs for logistic regressions to predict proarrhythmic risk. RESULTS: Optimal risk classifiers based on morphology were able to correctly classify risk to drugs in the comprehensive proarrhythmic assay initiative panels with very high accuracy (0.9375) and outperformed conventional metrics based on action potential duration at 90% repolarization, triangulation, and charge movement (qNet). CONCLUSIONS: Analysis of action potential morphology in response to proarrhythmic drugs improves prediction of torsadogenic risk. Furthermore, morphology metrics can be measured directly from the action potential, potentially eliminating the burden of undertaking complex screens of potency and drug-binding kinetics against multiple cardiac ion channels. As such, this method has the potential to improve and streamline regulatory assessment of proarrhythmia in preclinical drug development. [ABSTRACT FROM AUTHOR]

Azithromycin has been adopted as a component of the COVID-19 management protocol throughout the global healthcare settings but with a questionable if not downright unsubstantiated evidence base. In order to amalgamate and critically appraise the conflicting evidence around the clinical efficacy of Azithromycin (AZO) vis a vis COVID-19 management outcomes, a meta-analysis of meta-analyses was carried out to establish an evidence-based holistic status of AZO vis a vis its efficacy as a component-in-use of the COVID-19 management protocol. A comprehensive systematic search was carried out through PubMed/Medline, Cochrane and Epistemonikos with a subsequent appraisal of abstracts and full-texts, as required. The Quality of Reporting of Meta-analyses (QUOROM) checklist and the Assessment of Multiple Systematic Reviews (AMSTAR) methodology were adopted to assess the methodological quality of the included meta-analyses. Random-effects models were developed to calculate summarized pool Odds Ratios (with 95% confidence interval) for the afore determined primary and secondary outcomes. AZO, when compared with best available therapy (BAT) including or excluding Hydroxychloroquine, exhibited statistically insignificant reduction in mortality [(n= 27,204 patients) OR= 0.77 (95% CI: 0.51-1.16) (I2= 97%)] , requirement of mechanical ventilation [(n= 14,908 patients) OR= 1.4 (95% CI: 0.58-3.35) (I2= 98%)] , induction of arrhythmia [(n= 9,723 patients) OR= 1.21 (95% CI: 0.63-2.32) (I2= 92%)] and QTc prolongation (a surrogate for torsadogenic effect) [(n= 6,534 patients) OR= 0.62 (95% CI: 0.23-1.73) (I2= 96%)]. The meta-analysis of meta-analyses portrays AZO as a pharmacological agent that does not appear to have a comparatively superior clinical efficacy than BAT when it comes to COVID-19 management. Secondary to a very real threat of anti-bacterial resistance, it is suggested that AZO be discontinued and removed from COVID-19 management protocols. [ABSTRACT FROM AUTHOR]

Ivabradine is used to control heart rate in patients of heart failure with reduced ejection fraction. Although considered safe, it is reported to prolong QTc interval when given with other QTc prolonging drugs or in setting of hypokalemia or hypomagnesemia. Ivabradine causing isolated QTc interval prolongation without any provoking condition is rare. Our patient developed Torsades de Pointes after initiating Ivabradine and her QTc interval reduced after stopping Ivabradine. This may be due to a potential independent dose dependent effect of Ivabradine on QTc interval by its effects on its effects on human Ether-à-go-go-Related Gene (hERG) potassium channels.

Highlights Sex differences exist from the cardiac structure and function to the presentation and progression of cardiac diseases. After puberty, QTC difference between boy and girls visible, but diminish with age and disappears after 75 years of age. Sex hormones play an important role in the sex-specific differences mainly by affecting cardiac repolarization Women have a higher risk of developing a special type of ventricular tachycardia associated with adverse effects of drugs that prolong ventricular repolarization time. HiPSC-CMs offer a robust human-based platform for studying sex-specific drug responses and for studying the mechanisms of sex differences at cellular and tissue levels.

The number of women of childbearing age who have been diagnosed in childhood with ion channelopathy and effectively treated using beta blockers, cardiac sympathectomy, and life-saving cardiac pacemakers/defibrillators is increasing. Since many of these diseases are inherited as autosomal dominant, offspring have about a 50% risk of having the disease, though many will be only mildly impacted during fetal life. However, highly complex delivery room preparation is increasingly needed in pregnancies with inherited arrhythmia syndromes (IASs). However, specific Doppler techniques show meanwhile a better understanding of fetal electrophysiology. The advent of fetal magnetocardiography (FMCG) now allows the detection of fetal Torsades de Pointes (TdP) ventricular tachycardia and other LQT-associated arrhythmias (QTc prolongation, functional second AV block, T-wave alternans, sinus bradycardia, late-coupled ventricular ectopy and monomorphic VT) in susceptible fetuses during the second and third trimester. These types of arrhythmias can be due to either de novo or familial Long QT Syndrome (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), or other IAS. It is imperative that the multiple specialists involved in the antenatal, peripartum, and neonatal care of these women and their fetuses/infants have the optimal knowledge, training and equipment in order to care for these highly specialized pregnancies and deliveries. In this review, we outline the steps to recognize symptomatic LQTS in either the mother, fetus or both, along with suggestions for evaluation and management of the pregnancy, delivery, or post-partum period impacted by LQTS. [ABSTRACT FROM AUTHOR]

Cardiotoxicity, particularly drug-induced Torsades de Pointes (TdP), is a concern in drug safety assessment. The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (human iPSC-CMs) has become an attractive human-based platform for predicting cardiotoxicity. Moreover, electrophysiological assessment of multiple cardiac ion channel blocks is emerging as an important parameter to recapitulate proarrhythmic cardiotoxicity. Therefore, we aimed to establish a novel in vitro multiple cardiac ion channel screening-based method using human iPSC-CMs to predict the drug-induced arrhythmogenic risk. To explain the cellular mechanisms underlying the cardiotoxicity of three representative TdP high-(sotalol), intermediate- (chlorpromazine), and low-risk (mexiletine) drugs, and their effects on the cardiac action potential (AP) waveform and voltage-gated ion channels were explored using human iPSC-CMs. In a proof-of-principle experiment, we investigated the effects of cardioactive channel inhibitors on the electrophysiological profile of human iPSC-CMs before evaluating the cardiotoxicity of these drugs. In human iPSC-CMs, sotalol prolonged the AP duration and reduced the total amplitude (TA) via selective inhibition of IKr and INa currents, which are associated with an increased risk of ventricular tachycardia TdP. In contrast, chlorpromazine did not affect the TA; however, it slightly increased AP duration via balanced inhibition of IKr and ICa currents. Moreover, mexiletine did not affect the TA, yet slightly reduced the AP duration via dominant inhibition of ICa currents, which are associated with a decreased risk of ventricular tachycardia TdP. Based on these results, we suggest that human iPSC-CMs can be extended to other preclinical protocols and can supplement drug safety assessments. [ABSTRACT FROM AUTHOR]

Myotonic Dystrophy (DM) is the most common form of muscular dystrophy with onset in adults. Cardiac manifestations are common in DM, but ventricular arrhythmias are uncommon and torsades de pointes is rarely described. Here we describe a patient with primary presentation of syncope, with recurrent polymorphic ventricular tachycardias and with torsades de pointes configuration.

To evaluate the relationship between a modified Tisdale QTc-risk score (QTc-RS) and inpatient mortality and length of stay in a broad inpatient population with an order for a medication with a known risk of torsades de pointes (TdP). Managing the risk of TdP is challenging due to the number of medications with known risk of TdP and the complexity of precipitating factors. A model to predict risk of mortality may be useful to guide treatment decisions. This was a retrospective observational study using inpatient data from 28 healthcare facilities in the western United States. This risk score ranges from zero to 23 with weights applied to each risk factor based on a previous validation study. Logistic regression and a generalized linear model were performed to assess the relationship between QTc-RS and mortality and length of stay. Between April and December 2020, a QTc-RS was calculated for 92,383 hospitalized patients. Common risk factors were female (55.0%); age > 67 years (32.1%); and receiving a medication with known risk of TdP (24.5%). A total of 2770 (3%) patients died during their hospitalization. Relative to patients with QTc-RS < 7, the odds ratio for mortality was 4.80 (95%CI:4.42–5.21) for patients with QTc-RS = 7–10 and 11.51 (95%CI:10.23–12.94) for those with QTc-RS ≥ 11. Length of hospital stay increased by 0.7 day for every unit increase in the risk score (p < 0.0001). There is a strong relationship between increased mortality as well as longer duration of hospitalization with an increasing QTc-RS. • Length of hospital stays increases with higher risk scores. • Risk of death for patients with high scores was 11-fold higher than those with low scores. • Among risk factors, sepsis was associated with the highest risk of mortality, whereas hypokalemia and female sex were not associated with increased risk of mortality. [ABSTRACT FROM AUTHOR]

Background: Female gender, degree of QT prolongation, and genetic susceptibility are known risk factors for developing torsades de pointes (TdP) during high-grade atrioventricular block (HG-AVB). Our objective was to analyze the prevalence and clinical characteristics of patients presenting with TdP and AVB (TdP [+]) in comparison with non-TdP patients with AVB (TdP [−]). Methods: All the ECGs from patients prospectively admitted for AVB (2 to 1, HG, and complete) at the University Hospital of Nice were analyzed. Automated corrected QT (QTc), manual measurements of QT and JT intervals, and Tpeak-to-end were performed at the time of the most severe bradycardia. Results: From September 2020 to November 2021, 100 patients were admitted for HG-AVB. Among them, 17 patients with TdP were identified (8 men; 81 ± 10 years). No differences could be identified concerning automated QTc, manual QTc (Bazett correction), baseline QRS width, or mean left ventricular ejection fraction between the two groups. Potassium serum level on admission and mean number of QT-prolonging drugs per patient were not significantly different between the two groups, respectively: 4.34 ± 0.5 mmol/L in TdP [+] versus 4.52 ± 0.6 mmol/L (p = 0.33); and 0.6 ± 0.7 in TdP [+] versus 0.3 ± 0.5 (p = 0.15). In contrast, manual QTcFR (Fridericia correction), JT (Fridericia correction), Tpeak-to-end, and Tpe/QT ratio were significantly increased in the TdP [+] group, respectively: 486 ± 70 ms versus 456 ± 53 ms (p = 0.04); 433 ± 98 ms versus 381 ± 80 ms (p = 0.02); 153 ± 57 ms versus 110 ± 40 ms (p < 0.001); and 0.27 ± 0.08 versus 0.22 ± 0.06 (p < 0.001). Conclusions: The incidence of TdP complicating acquired AVB was 17%. Longer QTcFR, JT, and Tpeak-to-end were significantly increased in the case of TdP but also in the presence of permanent AVB during the hospitalization. [ABSTRACT FROM AUTHOR]

Introduction: Torsades de Pointes (TdP) is a potentially lethal polymorphic ventricular tachydysrhythmia associated with and caused by prolonged myocardial repolarization. However, prediction of TdP is challenging. We sought to determine if electrocardiographic myocardial repolarization heterogeneity is necessary and predictive of TdP. Methods: We performed a case control study of TdP at a large urban hospital. We identified cases based on a hospital center electrocardiogram (ECG) database search for tracings from 1/2005 to 6/2019 with heart rate corrected QT (QTc) > 500, QRS < 120, and heart rate (HR) < 60, and a subsequent natural language search of electronic health records for the terms: TdP, polymorphic ventricular tachycardia, sudden cardiac death, and relevant variants. Controls were drawn in a 2:1 ratio to cases from a similar pool of ECGs, and matching for QTc, heart rate, sex, and age. We abstracted historical, laboratory, and ECG data using detailed written instructions and an electronic database. We included a second blinded data abstractor to test data abstraction and manual ECG measurement reliability. We used General Electric (GE) QT Guard software for automated repolarization measurements. We compared groups using unpaired statistics. Results: We included 75 cases and 150 controls. The number of current QTc prolonging medications and serum electrolytes were substantially the same between the two groups. We found no significant difference in measures of QT or T wave repolarization heterogeneity. Conclusion: Electrocardiographic repolarization heterogeneity is not greater in otherwise unselected patients with QTc prolongation who suffer TdP and does not appear predictive of TdP. However, previous observations suggest specific repolarization characteristics may be useful for defined patient subgroups at risk for TdP. [ABSTRACT FROM AUTHOR]

Objectives HCQ is recommended for all patients with SLE, but reports of cardiac toxicity in severe acute respiratory syndrome coronavirus 2 patients raised concerns. We aimed to study the relationship between HCQ blood levels and QTc intervals. Methods A retrospective review of 90 SLE patients (cohort 1) was conducted with data collected regarding demographics, QTc interval and chronic kidney disease (CKD). A prospective study of 84 SLE patients (cohort 2) was conducted with data collected regarding demographics, dose of HCQ, duration of HCQ treatment, presence of echocardiographic abnormalities and CKD simultaneous with whole blood HCQ levels measured by HPLC. Statistical analysis utilized one-way analysis of variance, Pearson's correlation coefficient and t tests. Results In cohort 1 there was no significant difference in mean QTc based on 75 HCQ-treated [437.91 msec (s. d. 20.02)] as compared with 15 untreated patients [434.6 msec (s. d. 27.49)]. In patients with CKD, the mean QTc in HCQ users [448 (s. d. 23.37)] as compared with non-users [444.5 msec (s. d. 24.61)] also had no significant difference. In cohort 2, HCQ levels did not correlate with QTc interval (r  = 0.017) and this applied regardless of the dose prescribed (r  = 0.113 for 400 mg and r  = 0.06 for 200 mg), duration of exposure (P  = 0.36 for 0–5, >5–10 or >10 years), CKD (r  = 0.482) or underlying cardiac abnormalities (r  = 0.430). Conclusions This is the first study relying on measured blood levels demonstrating the absence of a clinically consequential increase in QTc levels in HCQ-treated SLE patients. [ABSTRACT FROM AUTHOR]

Clozapine is an atypical neuroleptic used to manage treatment-resistant schizophrenia which is known to inhibit cardiac hERG/KV11.1 potassium channels, a pharmacological property associated with increased risk of potentially fatal Torsades de Pointes (TdP) and sudden cardiac death (SCD). Yet, the long-standing clinical practice of clozapine does not show a consistent association with increased incidence of TdP, although SCD is considerably higher among schizophrenic patients than in the general population. Here, we have established the inhibitory profile of clozapine at the seven cardiac ion currents proposed by the ongoing comprehensive in vitro pro-arrhythmia (CiPA) initiative to better predict new drug cardio-safety risk. We found that clozapine inhibited all CiPA currents tested with the following rank order of potency: KV11.1 > NaV1.5 (late current) ≈ CaV1.2 ≈ NaV1.5 (peak current) ≈ KV7.1 > KV4.3 > Kir2.1 (outward current). Half-maximal inhibitory concentrations (IC50) at the repolarizing KV11.1 and KV7.1 channels, and at the depolarizing CaV1.2 and NaV1.5 channels fell within a narrow half-log 3–10 µM concentration range, suggesting that mutual compensation could explain the satisfactory arrhythmogenic cardio-safety profile of clozapine. Although the IC50 values determined herein using an automated patch-clamp (APC) technique are at the higher end of clozapine plasmatic concentrations at target therapeutic doses, this effective antipsychotic appears prone to distribute preferentially into the cardiac tissue, which supports the clinical relevance of our in vitro pharmacological findings. [ABSTRACT FROM AUTHOR]

Hydroxychloroquine (HCQ) is a common medication used for the treatment of rheumatic diseases. As a result of its widespread use during COVID-19, there are increasing concerns about its cardiotoxicity. HCQ is known to cause QTc prolongation, and its long-term use has been associated with cardiomyopathy and conduction abnormalities. Despite reports of ventricular arrhythmia in COVID-19 patients taking HCQ, there have been reassuring data in approved indications. HCQ has been in use for several decades with a good safety profile. In addition to better disease control and prevention of flares, it is associated with decreased risk of cardiovascular diseases. But given its small risk of cardiotoxicity, clinicians should be aware of this effect and monitor patients for developing cardiac symptoms. [ABSTRACT FROM AUTHOR]

There is an overwhelming number of medications that can affect the morphology of the beating heart by delaying the ventricular depolarization and repolarization processes, resulting in an elongated QT interval. This circumstance, in turn, can lead to ventricular arrhythmias, which can result in the patient's death, as was overwhelmingly the case at the beginning of the coronavirus pandemic. In this regard, this document presents an innovative expert system-based application devoted to estimating the level of risk of fatal ventricular arrhythmia as a consequence of QT prolonging treatments. For this purpose, the use of a fuzzy rule-based system has been considered for the decision-making process, establishing three different risk levels regarding the QT interval obtained from an electrocardiogram, its evolution from a basal electrocardiogram, and other significant clinical information of the patient such as age, sex, among others. This novel expert system-based application has been designed by considering the criteria of several specialist physicians from four different Spanish private and public hospitals. The proposed application can be especially important in primary health care centers, where the absence of specialists is remarkable because it provides clinical staff with a powerful tool for estimating the level of risk of fatal ventricular arrhythmia with 96.5% accuracy when comparing its decisions to those of specialist physicians, which could imply a significant reduction in the risk of death due to fatal ventricular arrhythmias in patients with QT prolonging treatment. In this respect, the developed application is currently used in some primary health care centers in Spain. [ABSTRACT FROM AUTHOR]

Abstract Background Hypothyroidism can manifest as several important cardiac abnormalities. There are few reports of ventricular dysrhythmias (VDs) in hypothyroidism. We described a rare case of VDs in severe hypothyroidism and reviewed the literature behind its management. Case presentation A 67-year-old gentleman, with poor compliance to treatment for Hashimoto’s thyroiditis, presented with palpitations to the Emergency Department. He had runs of non-sustained ventricular tachycardia (NSVT). He was treated with intravenous (IV) amiodarone and admitted to the intensive care unit for observation. He then developed recurrent Torsades de Pointes (Tdp) despite treatment with several anti-arhythmics. He required electrical cardioversion and eventual transvenous overdrive pacing (OP). VT recurred while he was on OP. VT resolved and he was weaned off OP only after adequate thyroid hormone replacement. Conclusions VDs, including NSVT, Tdp, and VT, are rare and potentially lethal in hypothyroidism. Our case demonstrates important challenges in the management of severe hypothyroidism. Here, VDs are often refractory to treatment with drugs and electrical means. The choice(s) of anti-arrhthymics requires careful consideration and can be difficult before thyroid function tests are known. Amiodarone use should be cautioned as it is associated with thyroid dysfunction and QT interval prolongation. There is no literature to guide thyroid hormone replacement in this disease. Aggressive replacement is associated with adverse cardiovascular effects. Our case showed a fine balance between the risk of rapid thyroid hormone replacement and the urgency to terminate VDs. Its administration should be carefully monitored amidst bridging strategies like electrical cardioversion and OP to manage life-threatening VDs.

Abstract Background Acquired long QT syndrome is an important and preventable cause of cardiac arrest. Certain medications and electrolyte disturbance are common contributors, and often coexist. In this case, we report five contributors to cardiac arrest. Case presentation This case is of a 51-year-old Caucasian female patient who presented with vomiting associated with hypokalemia and hypomagnesemia. She subsequently received ondansetron and metoclopramide, on the background of chronic treatment with fluoxetine. She then suffered an in-hospital monitored cardiac arrest, with features of long QT and torsades de pointes retrospectively noted on her prearrest electrocardiogram. She was diagnosed with acquired long QT syndrome, and her QT interval later normalized after removal of offending causes. Conclusions This case highlights the importance of proper consideration prior to prescribing QT prolonging medications, especially in patients who have other risk factors for prolonged QT, such as electrolyte disturbances and pretreatment with QT prolonging medications.

Background Catastrophic antiphospholipid syndrome and lupus myocarditis are two rare life-threatening conditions. Case summary We present a case of a 47-year-old woman admitted in profound cardiogenic shock due to catastrophic antiphospholipid syndrome and lupus myocarditis requiring advanced heart failure therapies, including early mechanical circulatory support. She improved with steroids, immunoglobulins, mycophenolate, and eculizumab. Discussion This case highlights the importance of early identification of cardiogenic shock secondary to catastrophic antiphospholipid syndrome and lupus myocarditis, the arrhythmogenic complications of myocarditis, and the subsequent management of the disease progression with mechanical and medical support. [ABSTRACT FROM AUTHOR]