Risk Of QT Prolongation Research Articles

Diagnosing Torsades De Pointes Based on Correlation to QT Interval: A Systematic Review.

Torsades de Pointes (TdP) is a rare form of tachyarrhythmia which can potentially be fatal due to its tendency to degenerate into ventricular fibrillation. It is described as a polymorphic ventricular tachycardia characterized by twisting of the QRS complexes around the electrocardiogram (ECG) baseline in patients with a prolonged QT interval. Prolonged QT interval is known as long QT syndrome.Torsades de Poccurs most commonly in patients with an extended QT interval duration, and even though monitoring an ECG can assist in its prevention, there is no defined duration of a QT interval that can lead to an increased risk of Torsades de Pointes. So, it is hard to determine what QT interval constitutes enough risk for Torsades de Pointes to require intervention. The QT interval duration also depends on other factors, namely heart rate (HR) and other factors such as drugs, congenital diseases, and a combination of both.In this study, we considered various causes of QT prolongation but mainly focused on congenital diseases, drugs, or perioperative risk of QT prolongation and the correlation with the risk of impending TdP. By following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and researching studies on various databases, namely PubMed, Science Direct, Medline, and CiNii we were able to find various systematic reviews and articles showing the association between prolonged QT interval and its degeneration into TdP. This review encourages further research into this topic to understand the implications of QT prolongation and how it can help save the lives of patients with known long QT syndrome, or those on QT prolonging drugs with simple ECG monitoring and treatment for the respective cause.

204 Adverse events associated with hydroxychloroquine use in cicatricial alopecia patients

The anti-malarial hydroxychloroquine (HCQ) is a common treatment for cicatricial alopecias (CA). Serious adverse events include prolonged QT interval, ventricular arrythmias and irreversible retinopathy. There is limited literature on the incidence of adverse events in CA patients taking HCQ. A retrospective analysis was performed of 60 CA patients, mean age 60 years, prescribed HCQ. Alopecia diagnoses included lichen planopilaris, frontal fibrosing alopecia, discoid lupus, central centrifugal cicatricial alopecia and folliculitis decalvans. Average length of HCQ treatment was 2.98 years. Dosing ranged from 100 to 400 mg daily. 83.3% of patients did not experience an adverse event. Adverse events that occurred include GI distress (n=5), tinnitus or other hearing-related changes (n=2), and allergic skin rash (n=1). One patient developed non-sustained ventricular tachycardia (NSVT) 17 months after starting HCQ 400 mg daily. During her hospitalization, no structural cardiac abnormalities were revealed, and the cause of the NSVT was not determined. She was prescribed daily estradiol-norethindrone hormone replacement therapy (HRT) for several years prior to the NSVT. Her medical history was significant for congestive heart failure and remote history of pulmonary hypertension and left ventricular hypertrophy. The patient permanently discontinued both medications. She has not developed another NSVT episode and remains healthy. Within our cohort, there were no other cardiac related events despite some patients taking concomitant medications known to increase risk of QT prolongation. These patients were monitored with regular electrocardiograms. The risk of HCQ-associated retinopathy increases with > 5 years of cumulative use. No patients included in our analysis developed retinopathy, including the 6.67% taking HCQ for > 5 years. We demonstrate that while adverse events may occur during treatment, HCQ is generally well tolerated by CA patients. We hope this will help support treatment discussions with CA patients.

Isavuconazole for COVID-19-Associated Invasive Mold Infections.

Isavuconazole is a broad-spectrum antifungal drug recently approved as a first-line treatment for invasive aspergillosis and as a first or alternative treatment for mucormycosis. The purpose of this review was to report and discuss the use of isavuconazole for the treatment of COVID-19-associated aspergillosis (CAPA), and COVID-19-associated mucormycosis (CAM). Among all studies which reported treatment of CAPA, approximately 10% of patients were reportedly treated with isavuconazole. Considering 14 identified studies that reported the use of isavuconazole for CAPA, isavuconazole was used in 40% of patients (95 of 235 treated patients), being first-line monotherapy in over half of them. We identified six studies that reported isavuconazole use in CAM, either alone or in combination therapy. Overall, isavuconazole was used as therapy in 13% of treated CAM patients, frequently as combination or sequential therapy. The use of isavuconazole in CAPA and CAM is complicated by the challenge of achieving adequate exposure in COVID-19 patients who are frequently obese and hospitalized in the ICU with concomitant renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO). The presence of data on high efficacy in the treatment of aspergillosis, lower potential for drug–drug interactions (DDIs) and for subtherapeutic levels, and no risk of QT prolongation compared to other mold-active azoles, better safety profile than voriconazole, and the possibility of using an intravenous formulation in the case of renal failure are the advantages of using isavuconazole in this setting.

Moxifloxacin concentration correlate with QTc interval in rifampicin-resistant tuberculosis patients on shorter treatment regimens

BackgroundDrug-resistant tuberculosis (DR-TB) continues to be a global threat. Moxifloxacin is one of the components of the shorter treatment regimen which is suspected to increase the risk of QT prolongation, although it is also likely to be the most effective against DR-TB. A study to evaluate the correlation between the concentration of moxifloxacin and QTc interval in RR-TB patients who received shorter regimens is needed. MethodsThis was an observational study in 2 groups of RR-TB patients on shorter treatment regimens (intensive phase and continuation phase), contain moxifloxacin with body weight-adjusted dose. Blood samples were collected at 2 h after taking the 48th-hour dose and 1 h before taking the 72nd-hour dose. ResultsForty-five RR-TB patients were included in this study. At 2 h after taking the 48th-hour dose, the mean of QTc interval in intensive phase and continuation phase was 444.38 ms vs. 467.94 ms, p = 0.026, while mean of moxifloxacin concentration in intensive phase and continuation phase was 4.3 µg/mL vs. 4.61 µg/mL, p = 0.686). At 1 h before taking the 72nd-hour dose, both moxifloxacin concentration and QTc interval in intensive phase and continuation showed no significant difference with p-value of 0.610 and 0.325, respectively. At 2 h after taking the 48th-dose, moxifloxacin concentration did not correlate with QTc interval, both in intensive phase (p = 0.576) and in continuation phase (p = 0.691). At 1 h before taking the 72nd-hour dose, moxifloxacin concentration also did not correlate with QTc interval in intensive phase (p = 0.531) and continuation phase (p = 0.209). ConclusionsOur study found that moxifloxacin concentration did not correlate with QTc interval, which indicates the safe use of moxifloxacin on QTc interval. In addition to close monitoring of QTc interval, the clinicians should also consider other variables which potentially increase risk for QTc prolongation in DR-TB patients who received shorter treatment regimens.

Interleukin-6 Elevation Is a Key Pathogenic Factor Underlying COVID-19-Associated Heart Rate-Corrected QT Interval Prolongation.

BackgroundHeart rate-corrected QT interval (QTc) prolongation is prevalent in patients with severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. Recent evidence suggests that the exaggerated host immune-inflammatory response characterizing the disease, specifically interleukin-6 (IL-6) increase, may have an important role, possibly via direct effects on cardiac electrophysiology. The aim of this study was to dissect the short-term discrete impact of IL-6 elevation on QTc in patients with severe COVID-19 infection and explore the underlying mechanisms.MethodsWe investigated the following mechanisms: (1) the QTc duration in patients with COVID-19 during the active phase and recovery, and its association with C-reactive protein (CRP) and IL-6 levels; (2) the acute impact of IL-6 administration on QTc in an in vivo guinea pig model; and (3) the electrophysiological effects of IL-6 on ventricular myocytes in vitro.ResultsIn patients with active severe COVID-19 and elevated IL-6 levels, regardless of acute myocardial injury/strain and concomitant QT-prolonging risk factors, QTc was significantly prolonged and rapidly normalized in correlation with IL-6 decrease. The direct administration of IL-6 in an in vivo guinea pig model acutely prolongs QTc duration. Moreover, ventricular myocytes incubated in vitro with IL-6 show evident prolongation in the action potential, along with significant inhibition in the rapid delayed rectifier potassium current (IKr).ConclusionFor the first time, we demonstrated that in severe COVID-19, systemic inflammatory activation can per se promote QTc prolongation via IL-6 elevation, leading to ventricular electric remodeling. Despite being transitory, such modifications may significantly contribute to arrhythmic events and associated poor outcomes in COVID-19. These findings provide a further rationale for current anti-inflammatory treatments for COVID-19, including IL-6-targeted therapies.

Interindividual Variability of Anticonvulsant-Induced QT Prolongation Risk

In connection with the widespread use of anticonvulsants (antiepileptic drugs – AEDs) in psychiatric and neurological practice and the need for their long-term use to treat a wide range of mental disorders and neurological diseases, the question of their safety profile, including the assessment of the risk of developing life-threatening conditions and adverse reactions (ADRs), becomes relevant. In this regard, from the position of personalized medicine, it is critical to develop an interdisciplinary approach with the participation of doctors of various specialties and a new strategy of a personalized approach to predicting AED-induced prolongation of the QT interval as one of the most prognostically unfavorable cardiological ADRs (including sudden death syndrome – SDS). We searched for full-text publications for the period from 2011 to 2021 databases using the following keywords and its combination. We have found and systematized monogenic and multifactorial forms of long QT syndrome (LQTS) and candidate genes that slow down AEDs metabolism in the liver. Identification of risk alleles of single nucleotide variants (SNVs) of the candidate genes predisposing to the development of AED-induced LQTS and SDS will make it possible to adjust the choice and dosage of these drugs and prevent the development of ADRs, which will improve the quality of life of patients and prevent SDS in the patients with psychiatric and neurological disorders.

PO-715-04 HIGHER BODY MASS INDEX IS ASSOCIATED WITH UNSAFE DOFETILIDE INITIATION

Early rhythm control strategies may improve cardiovascular outcomes for patients with atrial fibrillation. Dofetilide is one effective strategy, but its risk of QT prolongation and torsades de pointes necessitates a hospital-based initiation. Detecting patients who do not have sufficient “repolarization reserve” to safely tolerate dofetilide would alter shared decision-making regarding rhythm control strategies using this drug.

Hydroxyzine Initiation Following Drug Safety Advisories on Cardiac Arrhythmias in the UK and Canada: A Longitudinal Cohort Study.

IntroductionRegulatory advisories on hydroxyzine and risk of QT prolongation and Torsade de pointes (TdP) were issued in the UK in April 2015 and Canada in June 2016. We hypothesized patients with risk factors for QT prolongation and TdP, compared with those without risk factors, would be less likely to initiate hydroxyzine in the UK and in British Columbia (BC), Canada, following advisories.MethodsWe conducted a longitudinal study with repeated measures, and evaluated hydroxyzine initiation in a UK cohort and a concurrent BC control cohort (April 2013–March 2016) as well as in a BC advisory cohort (June 2014–May 2017).ResultsThis study included 247,665 patients in the UK cohort, 297,147 patients in the BC control cohort, and 303,653 patients in the BC advisory cohort. Over a 12-month post-advisory period, hydroxyzine initiation decreased by 21% in the UK (rate ratio 0.79, 95% confidence interval 0.66–0.96) relative to the expected level of initiation based on the pre-advisory trend. Hydroxyzine initiation did not change in the BC control cohort or following the Canadian advisory in the BC advisory cohort. The decrease in hydroxyzine initiation in the UK in the 12 months after the advisories was not significantly different for patients with risk factors compared with those without risk factors.ConclusionHydroxyzine initiation decreased in the UK, but not in BC, in the 12 months following safety advisories. The decrease in hydroxyzine initiation in the UK was not significantly different for patients with versus without risk factors for QT prolongation and TdP.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-022-01175-2.

POTENTIAL INTERACTIONS BETWEEN CARDIOVASCULAR AND COVID-19 MEDICATION REGIMENS AMONG PATIENTS WITH HEART FAILURE

Since December 2019, the COVID-19 pandemic has led to significant mortality in the world. Based on epidemiological data from China, 20% or more of COVID-19 patients had cardiovascular comorbidities. Life-threatening complications due to COVID-19 can develop in these patients. Meanwhile, the risk of complications may be higher in patients with heart failure (HF), who usually have older people and more comorbidities. COVID-19 can lead to myocardial injury and disease exacerbation in HF patients due to a cytokine storm-related hyper-inflammation syndrome.1 Hence, most studies only addressed the prevalence of the cardiovascular disease among COVID-19 patients and less specifically the prevalence of HF. A study in China found that 23% of COVID-19 patients had HF, of which 52% died.2 On the other hand, it has been suggested that COVID-19 may cause heart damage due to the specific condition of HF patients and the characteristics of this syndrome.3 Therefore, it is important to pay attention to the cardiovascular consequences of COVID-19. Despite, the effect of different drug therapies on the outcomes of COVID-19 patients with HF, management of potential interactions between cardiovascular and COVID-19 medication regimens among patients with HF remains an important and challenging clinical issue. In the early pandemic, antiviral drugs such as hydroxychloroquine were widely used to manage COVID-19 infection. Chloroquine and hydroxychloroquine are potassium channel blockers that can prolong QTc and play a role in sudden cardiac death. This process becomes especially dangerous when combined with other treatments, including the QTc prolonging azithromycin and lopinavir/ritonavir. Therefore, HF patients may be at particular risk for sudden cardiac death. In addition, in advanced treatments of HF patients, interactions may occur between COVID-19 and the cardiovascular medication regimen. For example, patients with left ventricular assist devices (LVAD) are usually treated with anticoagulation drugs such as warfarin. Warfarin is a vitamin k antagonist that can interact with some antiviral drugs in the treatment of COVID-19.4 Previous evidences have shown that chloroquine and hydroxychloroquine interactions with cardiovascular drugs such as digoxin and antiarrhythmic drugs are associated with the possibility of HF, QT prolongation, and cardiac arrhythmias.5,6 On the other hand, Remdesivir, which is made to treat Ebola, has shown little potential effect against SARS-CoV-2. Despite the lack of interaction of Remdesivir with HF drugs, it has been suggested that patients receiving Remdesivir be closely monitored due to the risk of QT prolongation and electrolyte disturbances. 1 In sum, previous evidence regarding the potential interactions between cardiovascular and COVID-19 medication regimens among patients with HF are limited and no strong evidence is available. Therefore, further studies are needed to identify these interactions. Given the increasing incidence of COVID-19 in HF patients, it is essential to better understand the interactions between this disease and SARS-CoV-2 in order to manage these patients. Also, a multidisciplinary approach including members of the HF team may lead to better management of HF patients in this pandemic.

Evaluation of the Citalopram levels on QTc Interval in Rats using with Radio-telemetry

Long QT syndrome is an arrhythmogenic disease characterized by prolonged QT interval. Citalopram (CIT) was reported to prolong QT interval dose-dependently. Omeprazole (OMP), inhibits CIT metabolizing enzyme CYP2C19, thereby increases serum concentrations which may increase the risk of QT prolongation. These are commonly co-prescribed and recent studies have raised the safety concerns about. We aimed to investigate the dose dependent effects of citalopram alone and in combination with OMP. Forty male, Sprague Dawley rats were divided into 5 groups (n=8). CIT (10 mg/kg or 30 mg/kg) was given for 2 weeks alone or in combination with OMP (100 mg/kg) starting from the 2nd week. ECG recordings and blood samples were collected. QT interval significantly increased in all groups compared to control. The plasma level of CIT in the CIT30 group was significantly higher than CIT10 group (p<0.01) and was significantly higher in the CIT10+OMP group than that of the CIT10 group (p<0.01). In treatment groups, the increase in plasma citalopram level correlated positively with the increase in QT (r=0.844, r2=0.713). It was determined that CIT caused prolongation of QT interval, the addition of OMP increased QT interval more, and these increases correlated positively with CIT plasma concentration. Therefore, it would be appropriate to routinely measure CIT plasma levels in addition to ECG, particularly in patients with additional risk factors for QT prolongation.

Data-driven drug-induced QT prolongation surveillance using adverse reaction signals derived from 12-lead and continuous electrocardiogram data.

Drug-induced QT prolongation is one of the most common side effects of drug use and can cause fatal outcomes such as sudden cardiac arrest. This study adopts the data-driven approach to assess the QT prolongation risk of all the frequently used drugs in a tertiary teaching hospital using both standard 12-lead ECGs and intensive care unit (ICU) continuous ECGs. We used the standard 12-lead ECG results (n = 1,040,752) measured in the hospital during 1994-2019 and the continuous ECG results (n = 4,835) extracted from the ICU's patient-monitoring devices during 2016-2019. Based on the drug prescription frequency, 167 drugs were analyzed using 12-lead ECG data under the case-control study design and 60 using continuous ECG data under the retrospective cohort study design. Whereas the case-control study yielded the odds ratio, the cohort study generated the hazard ratio for each candidate drug. Further, we observed the possibility of inducing QT prolongation in 38 drugs in the 12-lead ECG analysis and 7 drugs in the continuous ECG analysis. The seven drugs (vasopressin, vecuronium, midazolam, levetiracetam, ipratropium bromide, nifedipine, and chlorpheniramine) that showed a significantly higher risk of QT prolongation in the continuous ECG analysis were also identified in the 12-lead ECG data analysis. The use of two different ECG sources enabled us to confidently assess drug-induced QT prolongation risk in clinical practice. In this study, seven drugs showed QT prolongation risk in both study designs.

A tiered approach to population-based in vitro testing for cardiotoxicity: Balancing estimates of potency and variability

Population-wide in vitro studies for characterization of cardiotoxicity hazard, risk, and population variability show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a powerful and high-throughput testing platform for drugs and environmental chemicals alike. However, studies in multiple donor-derived hiPSC-CMs, across large libraries of chemicals tested in concentration-response are technically complex, and study design optimization is needed to determine sufficient and fit-for-purpose population size considerations. Therefore, we tested a hypothesis that a computational down-sampling analysis based on the data from hiPSC-CM screening of 136 diverse compounds in a population of 43 non-diseased donors, including multiple replicates of the “standard” donor hiPSC-CMs, will inform optimal study designs depending on the decision context (hazard, risk and/or inter-individual variability in cardiotoxicity). Through 50 independent random subsamples of 5, 10, or 20 donors, we estimated accuracy and precision for quantifying potency, inter-individual variability, and QT prolongation risk; the results were compared to the full 43-donor cohort. We found that for potency and clinical risk of QT prolongation, a cohort of 5 randomly-selected unique donors provides accurate and precise estimates. Larger cohort sizes afforded marginal improvements, and 5 replicates of a single donor performed worse. For estimating inter-individual variability, cohorts of at least 20 donors are needed, with smaller populations on average showing bias towards underestimation in population variance. Collectively, this study shows that a variable-size hiPSC-CM-based population-wide in vitro model can be used in a number of decision scenarios for identifying cardiotoxic hazards of drugs and environmental chemicals in the population context.

Chronic toxicity assessment of BCR-ABL tyrosine kinase inhibitors using human-induced pluripotent stem cell-derived cardiomyocytes

Tyrosine kinase inhibitors (TKIs) have contributed to the improvement of the survival of patients with chronic myelogenous leukemia (CML). Growing evidence suggest that cancer therapy-related cardiac dysfunction has become important as the most undesirable side effects of chemotherapy. BCR-ABL TKIs, such as nilotinib and imatinib, has been reported to have a risk of QT prolongation associated with Torsades des Pointes and cardiac failure. We have previously reported that nilotinib caused QT prolongation and early afterdepolarization (EAD) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). However, chronic cardiotoxicity of BCR-ABL TKIs has not been fully understood. In this study, we evaluated the chronic toxicity of imatinib and nilotinib using hiPSC-CMs. We used iCell Cardiomyocyte 2.0 (Cellular Dynamics International). To assess whether imatinib and nilotinib induced chronic cardiotoxicity, we investigated the QT interval recorded by multi-electrode array system (MED64, Alpha MED Scientific) and contractility velocity recorded by motion vector analysis (SI8000, Sony). We found that the imatinib decreased contraction velocity for long-term treatment. In addition, long-term treatment with nilotinib caused QT prolongation and decrease in contraction velocity in a concentration-dependent manner. These results suggest that hiPSC-CMs can be the useful tool for chronic cardiotoxicity assessment. We are planning to evaluate other types of BCR-ABL TKIs with hiPSC-CMs.

Seven day continuous ambulatory electrocardiographic telemetric study with pocket electrocardiographic recording device for detecting hydroxychloroquine induced arrhythmias.

Objective:The use of hydroxychloroquine (HCQ) for COVID-19 treatment and prophylaxis raised issues concerning its cardiac safety owing to the possibility of QT prolongation and arrhythmias. There was no study on long-term electrocardiographic telemetry monitoring of patients taking HCQ. We planned a continuous electrocardiographic Holter telemetry of these patients for 7 days.Material and Methods:Health care workers taking HCQ as pre exposure prophylaxis and patients on HCQ were monitored using seven day Holter electrocardiographic telemetry with continuous beat to beat analysis. Telemetry can instantly convey any arrhythmic event or significant QT prolongation to the medical faculty.Results:Twenty-five participants with a mean age of 42.4 ± 14.1 years were included in the study; 40% were females. Twenty percent of participants needed to stop HCQ. Four patients developed QT prolongation >500 ms and needed to stop HCQ, one patient had accelerated idioventricular rhythm and stopped treatment, and one had short episodes of atrial fibrillation. No malignant arrhythmia or ventricular arrhythmia, or torsade de pointis were noted. No episode of significant conduction disturbance and arrhythmic death was noted. Baseline mean QTc was 423.96 ± 32.18 ms, mean QTc corrected at 24 h was 438.93 ± 37.95, mean QTc was 451.879 ± 37.99 at 48 h, and change in baseline mean QTc to max QTc was 30.74 ± 21.75 ms at 48 h. All those who developed QTc prolongation >500 ms were greater than 50 years of age.Conclusion:Ambulatory telemetry ECG monitoring detects early QT prolongation, and stopping drugs prevents malignant arrhythmias. HCQ seems to have less risk of QT prolongation in young, healthy individuals.

Toxicity assessment of tyrosine kinase inhibitors using human-induced pluripotent stem cell-derived cardiomyocytes

BCR-ABL tyrosine kinase inhibitors (TKIs) have contributed to the improvement of the survival of patients with chronic myelogenous leukemia (CML). Growing evidence suggests that cancer therapy-related cardiac dysfunction has become important as the most undesirable side effect of chemotherapy. For example, one of BCR-ABL TKIs, nilotinib, has been reported to have a risk of QT prolongation associated with Torsades des Pointes and cardiac failure. We have previously reported that nilotinib causes QT prolongation and early afterdepolarization (EAD) using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). In this study, we evaluated the effect of BCR-ABL TKIs on contractility using hiPSC-CMs.

Transient Hypogonadism Is Associated With Heart Rate-Corrected QT Prolongation and Torsades de Pointes Risk During Active Systemic Inflammation in Men.

BackgroundSystemic inflammation and male hypogonadism are 2 increasingly recognized “nonconventional” risk factors for long‐QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate–corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc.Methods and ResultsWe investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C‐reactive protein and interleukin‐6 levels. Reduction of testosterone levels, which also inversely correlated with 17‐β estradiol over time, significantly contributed to inflammation‐induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C‐reactive protein, testosterone, and 17‐β estradiol levels; in these patients, increased C‐reactive protein and reduced testosterone were associated with a worse short‐term outcome of the arrhythmia.ConclusionsDuring systemic inflammatory activation, interleukin‐6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen‐to‐estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long‐QT syndrome/TdP risk in men.

Prevalence of drug to drug induced QT interval prolongation in critically Ill cardiac patients in a tertiary cardiac center in Malaysia

Drug-drug interactions (DDIs) involving CYP3A4 are particularly concerning, in view of their enzyme system which could metabolize up to 50% of utilized medications which could predispose to the hazard of QT prolongation. Some drugs do not affect the repolarization or affect the QT interval themselves. However, it can increase the risk of QT prolongation when taken with drugs that block the metabolic breakdown particularly. Predisposing factors of QT prolongation include female sex, age over 65 years, brady-arrhythmia, electrolyte disturbances (hypokalemia, hypomagnesaemia), cardiac disease (congestive heart failure, ventricular hypertrophy, myocardial infarction, and atrial fibrillation), impaired hepatic/renal function and hypothyroidism.

Abstract 10689: C-src Contributes to Mitochondrial Ca 2+ Uniporter Increase and Arrhythmic Risk in Ischemic Cardiomyopathy

Introduction: We have described previously an arrhythmic mechanism in nonischemic heart failure (HF) involving an increased mitochondrial Ca 2+ uptake that results in QT prolongation and lethal arrhythmias during cardiomyopathy. This arrhythmic mechanism is associated with mitochondrial Ca 2+ uniporter (MCU) tyrosine phosphorylation (p-Tyr). Hypothesis: Here, we determined which kinase was responsible for MCU phosphorylation in ischemic cardiomyopathy. Methods: Ischemic HF was induced in wild type FVB/NJ mice for three weeks by ligated left anterior descending coronary artery. Western blot, immunoprecipitation, fluorescence resonance energy transfer (FRET) and patch-clamp techniques were employed in isolated mouse cardiomyocytes. Results: When compared to sham hearts, the protein level of p-Src increased significantly in ischemic HF mouse hearts. In a heterologous expression system, c-Src could bind MCU and tyrosine phosphorylate MCU. This phosphorylation was blocked by a c-Src inhibitor, PP1. Overexpression of constitutive active c-Src (Src-Y527F) significantly increased MCU inward current at -160 mV. Downregulation of C-terminal Src kinase (CSK), a regulatory kinase inversely related to c-Src activity, increased p-Src, enhanced mitochondrial and SR contact, and facilitated mitochondrial Ca 2+ uptake in ischemic HF mouse cardiomyocytes. Protein expression of CaMKII, PyK2, and p-PyK2 did not change during ischemic HF. MI activated c-Src by S-nitrosylation of caveolin-1 with subsequent release of the kinase. c-Src activation was associated with APD prolongation and arrhythmia following myocardial infarction in mice. Human heart tissue showed that ischemic HF patients had significantly increased p-Src associated with increased QTc prolongation and arrhythmia. Conclusions: During ischemic HF, c-Src activation directly increased MCU current that contributed to QT prolongation and arrhythmic risk in ischemic cardiomyopathy.

Cardioversion of recent-onset atrial fibrillation using intravenous antiarrhythmics: A European perspective.

Pharmacological cardioversion using intravenous antiarrhythmic agents is commonly indicated in symptomatic patients with recent-onset atrial fibrillation (AF). Except in hemodynamically unstable patients who require emergency direct current electrical cardioversion, for the majority of hemodynamically stable patients, pharmacological cardioversion represents a valid option and requires the clinician to be familiar with the properties and use of antiarrhythmic agents. The main characteristics of selected intravenous antiarrhythmic agents for conversion of recent-onset AF, the reported success rates, and possible adverse events are discussed. Among intravenous antiarrhythmics, flecainide, propafenone, amiodarone, sotalol, dofetilide, ibutilide, and vernakalant are commonly used. Antazoline, an old antihistaminic agent with antiarrhythmic properties was also reported to give encouraging results in Poland. Intravenous flecainide and propafenone are the only Class I agents still recommended by recent guidelines. Intravenous new Class III agents as dofetilide and ibutilide have high and rapid efficacy in converting AF to sinus rhythm but require strict surveillance with electrocardiogram (ECG) monitoring during and after intravenous administration because of the potential risk of QT prolongation and Torsades de Pointes, which can be prevented and properly managed. Vernakalant, a partial atrial selective was shown to have a high success rate and to be safe in real-life use.

Safety considerations for prescribing SSRI antidepressants to patients at increased cardiovascular risk

ABSTRACT Introduction With the development of selective serotonin reuptake inhibitors (SSRI), a relatively uncomplicated treatment of depression and a safer alternative to tricyclic antidepressants was introduced. Any medical treatment has potential safety risks, however, and these risks should also be considered when prescribing SSRIs. Areas covered The present review focuses on safety considerations when prescribing SSRIs to patients with previous stroke and myocardial infarction, as depression, and the need for antidepressant treatment, is common in these patients. At the same time, patients with stroke and myocardial infarction may be at increased risk of developing adverse events due to higher age, comorbidity, and co-medication. Specifically, the evidence of the risk of QT prolongation and bleeding versus thrombotic events will be discussed in the present review. Expert opinion No medical treatment comes without risk and SSRIs are no exception. Depression, a common complication after vascular events, is a potentially life-threatening condition in itself and relevant and sufficient treatment is imperative. SSRIs are often the first medical treatment choice in the ambulatory setting, also in patients at increased cardiovascular risk. Relevant comorbidity and co-medication, however, should always be taken into account when initiating treatment and when choosing a specific SSRI.