Corrected QT Research Articles

Incidence and determinants of QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin.

Combined use of hydroxychloroquine and azithromycin was globally adopted, in part due to paucity and high cost of alternative therapies. However the utility of these medications has been questioned; and thus safety becomes a major concern given clinical equipoise regarding efficacy. Both hydroxychloroquine and azithromycin continue to be administered in US clinical trials examining their potential role in prevention of infection, treatment of mild infection in ambulatory patients, and in combination with other medical regimens in treatment of patients with severe disease. These drugs also continue to be clinically utilized in hospitalized patients around the globe, often without continuous telemetry due to lack of resources. Concern regarding use of hydroxychloroquine without adequate rhythm monitoring in clinical trials has been recently expressed.1 A review of clinicaltrials.gov at the time of submission of this correspondence reveals actively recruiting trials of combined hydroxychloroquine/azithromycin with or without additional COVID-19 therapies, for both ambulatory and hospitalized patients within and outside the US. The potential for hydroxychloroquine and azithromycin to cause QT prolongation is counterbalanced by very low risk of pro-arrhythmia in the general population, and emerging evidence of relatively low risk of Torsades de Pointes (TdP) in COVID-19 patients.2,3,4,5 Thus delineation of the determinants of significant QTc prolongation and pro-arrhythmic risk for hydroxychloroquine/azithromycin is very important, especially given mounting evidence of inefficacy in COVID-19 treatment.

Recurrent Occurrence of Idiopathic Ventricular Tachycardia after Extubation Undergoing Bile Duct Resection, Roux-en-Y Hepaticojejunostomy in Young Patient

Arrhythmias occurring during surgery are mostly benign and improve without special treatment, but sometimes life threatening and poor vital signs may require immediate antiarrhythmic or electrotherapy. In some cases, permanent arrhythmias may require continued treatment after surgery. A cardiac event occurred to a 28-year-old man who underwent Bile duct resection/Roux-en-Y hepaticojejunostomy due to cholelithiasis with cholecystitis and choledocholithiasis. He diagnosed mental retardation level 2. Pre-operation laboratory test is normal except liver function test (AST 64, ALT 141). Electrocardiography shows 57 bpm heart rate, sinus rhythm, first degree AV block and long corrected QT interval that was checked 462ms and echocardiography shows LVEF 67%, normal echocardiogram. When we prepared extubation after finishing operation, Sugammadex 200mg was injected. Suddenly, patient’s oxygen saturation was low at 85%. We started manual ventilation for oxygenation and saturation was increased at 100%. When we extubated endotracheal tube, his ECG changed normal sinus rhythm to idiopathic ventricular tachycardia (VT). Firstly we considered that is paroxysmal supraventricular tachycardia and infused adenosine 6mg twice and 12mg once. But arrhythmia was continuous and vital sign changed unstable. We performed reintubation and defibrillated at 200J. After defibrillation, arrhythmia converted sinus rhythm. We transferred the patient to the ICU and evaluated further to see if the patient had heart problems. During admission in ICU, attending surgeon tried to extubate endotracheal tube 2 more times. But, Idiopathic VT occurred whenever try to extubate. Finally, in the fourth attempt, extubation without occurrence of VT succeeded with continuous intravenous infusion of esmolol and dexmedetomidine. Keywords: Arrhythmia, Extubation, Idiopathic ventricular tachycardia

Electrocardiographic Changes Associated With Ibrutinib Exposure.

Although ibrutinib-associated atrial and ventricular arrhythmias have been well described, there is little information about ibrutinib’s effects on other electrocardiographic parameters, particularly the QT interval. Using our database of 137 patients treated with ibrutinib, we retrospectively identified 21 patients in whom an electrocardiogram (ECG) was obtained both prior to and after ibrutinib exposure. All traditional ECG parameters as well as QT dispersion were manually measured by an electrophysiologist. Compared to baseline ECGs, post ibrutinib ECGs demonstrated QT interval shortening from 386 ms to 356 ms (P = .007), corrected QT interval shortening using Bazett’s formula from 446 ms to 437 ms (P = .04), and corrected QT interval shortening using Fridericia’s formula from 425 ms to 407 ms (P = .003). QT dispersion also increased post ibrutinib exposure compared to baseline (39.8 ms vs 57.3 ms, P = .002). There was no significant change in other ECG parameters. In conclusion, both the absolute and corrected QT intervals significantly shortened after ibrutinib exposure, while there was a significant increase in QT dispersion. These findings may point to a common underlying electrophysiologic mechanism of ibrutinib-associated arrhythmias.

Lamotrigine Toxicosis Treated with Intravenous Lipid Emulsion Therapy in a Dog

A female spayed dachshund/mixed-breed dog was evaluated following ingestion of lamotrigine tablets with subsequent rapid onset of vomiting, diarrhea, and generalized tremoring. On initial examination, the dog was moderately obtunded and nonambulatory with intermittent myoclonus and hyperesthesia. Electrocardiogram revealed sinus tachycardia with prolongation of the QT interval. Intravenous lipid emulsion (ILE) infusion was initiated, with reduction in tremoring and improved patient mentation being noted after ∼20 min of therapy. An elevated cardiac troponin I value measured at 1.02 ng/mL the day after presentation. Serum toxicological assay revealed marked reduction in serum lamotrigine levels following ILE and continued reduction during hospitalization. The dog's clinical signs resolved, corrected QT interval returned to normal, and the patient was discharged 38 hr after presentation. Individual cases of lamotrigine toxicosis have not been fully reported in veterinary literature. This case report documents the rapid onset of clinical signs including neurologic dysfunction, cardiac arrhythmias, and transient corrected QT prolongation. Serial serum concentrations of lamotrigine showed a rapid reduction with ILE therapy and corresponded with clinical recovery, suggesting efficacy of ILE treatment in this case.

Effect of Chloroquine, Hydroxychloroquine, and Azithromycin on the Corrected QT Interval in Patients With SARS-CoV-2 Infection.

Background:The novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is responsible for the global coronavirus disease 2019 pandemic. Small studies have shown a potential benefit of chloroquine/hydroxychloroquine±azithromycin for the treatment of coronavirus disease 2019. Use of these medications alone, or in combination, can lead to a prolongation of the QT interval, possibly increasing the risk of Torsade de pointes and sudden cardiac death.Methods:Hospitalized patients treated with chloroquine/hydroxychloroquine±azithromycin from March 1 to the 23 at 3 hospitals within the Northwell Health system were included in this prospective, observational study. Serial assessments of the QT interval were performed. The primary outcome was QT prolongation resulting in Torsade de pointes. Secondary outcomes included QT prolongation, the need to prematurely discontinue any of the medications due to QT prolongation, and arrhythmogenic death.Results:Two hundred one patients were treated for coronavirus disease 2019 with chloroquine/hydroxychloroquine. Ten patients (5.0%) received chloroquine, 191 (95.0%) received hydroxychloroquine, and 119 (59.2%) also received azithromycin. The primary outcome of torsade de pointes was not observed in the entire population. Baseline corrected QT interval intervals did not differ between patients treated with chloroquine/hydroxychloroquine (monotherapy group) versus those treated with combination group (chloroquine/hydroxychloroquine and azithromycin; 440.6±24.9 versus 439.9±24.7 ms, P=0.834). The maximum corrected QT interval during treatment was significantly longer in the combination group versus the monotherapy group (470.4±45.0 ms versus 453.3±37.0 ms, P=0.004). Seven patients (3.5%) required discontinuation of these medications due to corrected QT interval prolongation. No arrhythmogenic deaths were reported.Conclusions:In the largest reported cohort of coronavirus disease 2019 patients to date treated with chloroquine/hydroxychloroquine±azithromycin, no instances of Torsade de pointes, or arrhythmogenic death were reported. Although use of these medications resulted in QT prolongation, clinicians seldomly needed to discontinue therapy. Further study of the need for QT interval monitoring is needed before final recommendations can be made.Visual Overview:A visual overview is available for this article.

Outcome of patients with chlorpyrifos intoxication.

There is a paucity of literature analyzing outcome of chlorpyrifos intoxication. A total of 40 patients with chlorpyrifos intoxication were seen at Chang Gung Memorial Hospital between 2008 and 2017. Patients were stratified into two subgroups according to their prognosis, as good (n = 12) or poor (n = 28). Good prognosis group were defined as patients who survived without serious complications, and poor prognosis group included patients who died and survived after development of severe complications. Demographic, clinical, laboratory, and mortality data were obtained for analysis. Patients aged 53.8 ± 16.3 years and most were male (80.0%). All patients (100.0%) developed acute cholinergic crisis such as emesis (45.0%), respiratory failure (42.5%), tachycardia (30.0%), kidney injury (22.5%), and seizure (7.5%). Intermediate syndrome developed in 12.5% of patients, but none had delayed neuropathy (0%). The poor prognosis group suffered higher incidences of respiratory failure (p = 0.011), kidney injury (p = 0.026), and prolonged corrected QT interval (p = 0.000), and they had higher blood urea nitrogen level (p = 0.041), lower Glasgow coma scale score (p = 0.011), and lower monocyte count (p = 0.023) than good prognosis group. All patients were treated with atropine and pralidoxime therapy, but six patients (15.0%) still died of intoxication. In a multivariate logistic regression model, blood urea nitrogen was a significant risk factor for poor prognosis (odds ratio: 1.375, 95% confidence interval: 1.001-1.889, p = 0.049). Nevertheless, no mortality risk factor could be identified. The mortality rate of patients with chlorpyrifos intoxication was 15.0%. Furthermore, acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 12.5%, and 0% of patients, respectively.

Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society

The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.

Drug-specific risk of severe QT prolongation following acute drug overdose

Background: Severe QT prolongation (SQTP) has been identified as a strong predictor of adverse cardiovascular events in acute drug overdose, but drug-specific causes of SQTP in the setting of acute drug overdose remain unclear. We aimed to perform the most definitive study to date describing drug-specific risk of SQTP following acute drug overdose.Methods: This was a prospective multicenter cohort study at >50 hospital sites across the US using the ToxIC Registry between 2015 and 2018. Inclusion criteria were adults (≥18 years) receiving medical toxicology consultation for acute drug overdose. The primary outcome was SQTP, which was defined using the computer automated Bazett QT correction (QTc) on the ECG with the previously validated cut point of 500 milliseconds. Mean difference in QTc was also calculated for specific drugs. Drugs associated with SQTP were analyzed using multivariable logistic regression to control for known confounders of QT risk (age, sex, race, cardiac disease).Results: From 25,303 patients screened, 6473 met inclusion criteria with SQTP occurring in 825 (13%). Drugs associated with increased adjusted odds of SQTP included Class III antidysrhythmics (sotalol), sodium channel blockers (amitriptyline, diphenhydramine, doxepin, imipramine, nortriptyline), antidepressants (bupropion, citalopram, escitalopram, trazodone), antipsychotics (haloperidol, quetiapine), and the antiemetic serotonin antagonist ondansetron.Conclusions: This large US cohort describes drug-specific risk of SQTP following acute drug overdose. Healthcare providers caring for acute drug overdoses from any of these implicated drugs should pay close attention to cardiac monitoring for occurrence of SQTP.

Thorough QTc Study of a Single Supratherapeutic Dose of Relebactam in Healthy Participants.

The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single-dose, double-blind (relebactam only), randomized, placebo- and positive-controlled, 3-period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (≥4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open-label positive control), and IV placebo. Least squares mean and 2-sided 90% confidence interval for change from baseline in population-derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population-derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150-mg supratherapeutic dose (4.6-fold above the 250-mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a β-lactamase inhibitor in antimicrobial therapy.

Cardiac effects of repeated focal seizures in rats induced by intrahippocampal tetanus toxin: Bradyarrhythmias, tachycardias, and prolonged interictal QT interval.

To determine electrical changes in the heart in a chronic, nonstatus model of epilepsy. Electrocorticography (ECoG) and electrocardiography (ECG) of nine animals (five made epileptic by intrahippocampal injection of tetanus neurotoxin (TeNT) and four controls), are monitored continuously by radiotelemetry for up to 7weeks. Epileptic animals develop a median of 168 seizures, with postictal tachycardias reaching a mean of 487 beats/min and lasting a mean of 661seconds. Ictal changes in heart rate include tachycardia and in the case of convulsive seizures, bradyarrhythmias resembling Mobitz type 1second-degree atrioventricular block; notably the P-R interval increased before block. Postictally, the amplitude of T wave increases. Interictally, QT dependence on RR is modest and conventional QT corrections prove ineffective. Interictal QT intervals, measured at a heart rate of 400bpm, increased from 65 to 75ms, an increase dependent on seizure incidence over the preceding 10-14days. Repeated seizures induce a sustained tachycardia and increase in QT interval of the ECG and evoke arrhythmias including periods of atrioventricular block during Racine type 4 and 5 seizures. These changes in cardiac function may predispose to development in fatal arrhythmias and sudden death in humans with epilepsy.

SUN-083 ELECTROCARDIOGRAPHIC INDICES AND PERIPHERAL VASCULAR DISEASE AMONG PREDIALYTIC CKD PATIENTS

Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. It is not known whether abnormalities of cardiac rhythm are associated with bio-impedance measurements or whether resting electrocardiographic findings are associated with peripheral vascular disease (PVD) in the CKD setting. The study design was cross-sectional, case-control in nature. After exclusion of heart disease, atrial fibrillation, implantable pacemaker, or use of anti-arrhythmic drugs, 90 participants were analysed comprising of 45 predialytic CKD patients and 45 age- and sex-matched controls. CKD was defined by an estimated eGFR < 60ml/min/1.73m2. All patients underwent 12 lead electrocardiogram (ECG) and bioelectric impedance assessment. ECG abnormalities were defined based on accepted standard criteria. Phase angle was calculated as arctangent of (X/R). Peripheral vascular disease was estimated using ankle-brachial index (ABI). Baseline characteristics of study participants is as shown in table 1. Patients with CKD had prolonged QRS interval [Median (IQR); 92.0 (86.0-96.0) vs 82.0 (77.0-86.0), p<0.001], higher prevalence of left ventricular hypertrophy (33.3% vs 8.9%, p=0.004) and lower impedance values [Median (IQR); 471.0 (427.0-516.0) vs 512.0 (470.5-571.5), p=0.018] compared with those without CKD. Prevalence of PVD was 31.1% in CKD patients compared to 11.1% in non-CKD patients. Phase angle correlated with heart rate (r = -0.351; p=0.001), prolonged QRS duration (r=0.278; p=0.010) and prolonged corrected QT (QTc) interval (r = -0.248; p=0.022) while eGFR correlated with impedance (r=0.313; p=0.004), prolonged QRS duration (r = -0.404; p<0.001), prolonged QTc (r = -0.224; p=0.036), ABI (right; r = -0.284; p=0.008, left: r = -0.262; p=0.014). After adjustment for eGFR, age, gender, blood pressure, and phase angle, LVH was associated with 65-fold greater risk for PVD (95% CI: (1.05 – 4073.54, p=0.047) while prolonged QRS interval was associated with 1.2 fold rise in PVD (95% CI: (1.02 – 1.39, p=0.023). Resting electrocardiographic abnormalities are common in predialytic CKD patients, correlated with BIA parameters and independently predict PVD in predialytic CKD.

Antipsychotic Use in the Prevention and Treatment of Intensive Care Unit Delirium in Pediatric Patients.

To describe the antipsychotics, route of administration, dosage regimen, and outcomes reported to prevent or treat delirium in hospitalized children. Medline, Embase, and International Pharmaceutical Abstracts were searched using the keywords "haloperidol," "olanzapine," "quetiapine," "risperidone," "ziprasidone," and "delirium." Articles evaluating the use of these agents to manage delirium in hospitalized children that were published between 1946 and August 2019 were included. Two authors independently screened each article for inclusion. Reports were excluded if they were published abstracts or included fewer than 3 patients in the report. Thirteen reports that included 370 children receiving haloperidol, quetiapine, olanzapine, and/or risperidone for delirium treatment were reviewed. Most children received haloperidol (n = 131) or olanzapine (n = 125). Significant variability in dosing was noted. A total of 23 patients (6.2%) had an adverse drug event, including 13 (56.5%) who experienced dystonia and 3 (13.0%) with a prolonged corrected QT interval. Most reports described improvement in delirium symptoms; however, only 5 reports used a validated screening tool for PICU delirium to evaluate antipsychotic response. Most reports noted efficacy with antipsychotics, but these reports were limited by sample size and lacked a validated PICU delirium tool. Future research is needed to determine the optimal agent and dosage regimen to treat PICU delirium.

Summary: QT Corrections for Long QT Risk Assessment: Implications for the Preparticipation Examination1

Summary: QT Corrections for Long QT Risk Assessment: Implications for the Preparticipation Examination1

Electrocardiography Findings in Children with Febrile Convulsion

AbstractFebrile convulsion (FC) is a seizure associated with body temperature that leads to electrocardiography changes. This article aimed to study electrocardiographic changes in children with FC as compared with healthy children. In this case–control study, 90 children aged 6 to 60 months were matched with equal healthy ones in “Ali Ebne Abi Talib” hospital in Zahedan, Iran. FC was confirmed by a neurologist based on its definition by the International League Against Epilepsy. Electrocardiogram (ECG) was captured by a pediatric cardiologist. Data were analyzed using SPSS 19. Sex distribution in groups was similar (p = 0.232). QT correction (QTc) was normal in 97.8 and 76.7% of controls and FC children, respectively (p &lt; 0.001). QT dispersion (QTd) was normal in all controls when it was prolonged in 0.6% of children (p&lt; 0.316). Calculated QT (QTcd) prolonged in controls and FC of 4.4 and 27.8% of children, respectively (p &lt; 0.001). RR interval (p = 0.001), heart rate (p&lt; 0.001), S in V1 (p = 0.004), R in aVL (p = 0.007), S in V3(p&lt; 0.001), left ventricular mass (LVM) (p&lt; 0.001), QTd (p&lt; 0.001), QTc max (p&lt; 0.001), and QTcd (p&lt; 0.001) were significant. Means of LVM were 46.00 ± 1.86, 47.22 ± 2.24, and 51.45 ± 2.41 for age groups of &lt;12, 12–24, and &gt;24 months, respectively (p &lt; 0.001). We conclude that QTd, QTc, and QTcd were higher in FC compared with those of healthy children. The rate of FC in children with higher level of QTcd increased compared with controls.

Screening for QT Prolongation in the Emergency Department: Is There a Better “Rule of Thumb?”

IntroductionIdentification of QT prolongation in the emergency department (ED) is critical for appropriate monitoring, disposition, and treatment of patients at risk for torsades de pointes (TdP). Unfortunately, identifying prolonged QT is not straightforward. Computer algorithms are unreliable in identifying prolonged QT. Manual QT-interval assessment methods, including QT correction formulas and the QT nomogram, are time-consuming and are not ideal screening tools in the ED. Many emergency clinicians rely on the “rule of thumb” or “Half the RR” rule (Half-RR) as an initial screening method, but prior studies have shown that the Half-RR rule performs poorly as compared to other QT assessment methods. We sought to characterize the problems associated with the Half-RR rule and find a modified screening tool to more safely assess the QT interval of ED patients for prolonged QT.MethodsWe created graphs comparing the prediction of the Half-RR rule to other common QT assessment methods for a spectrum of QT and heart rate pairs. We then proposed various modifications to the Half-RR rule and assessed these modifications to find an improved “rule of thumb.”ResultsWhen compared to other methods of QT correction, the Half-RR rule appears to be more conservative at normal and elevated heart rates, making it a safe initial screening tool. However, in bradycardia, the Half-RR rule is not sufficiently sensitive in identifying prolonged QT. Adding a fixed QT cutoff of 485 milliseconds (ms) increases the sensitivity of the rule in bradycardia, creating a safer initial screening tool.ConclusionFor a rapid and more sensitive screening evaluation of the QT interval on electrocardiograms in the ED, we propose combining use of the Half-RR rule at normal and elevated heart rates with a fixed uncorrected QT cutoff of 485 ms in bradycardia.

Electrocardiogram Characteristics and Arrhythmic Events during Fever in Patients with Fever-Induced Brugada Syndrome

Introduction: Changes in electrocardiogram (ECG) parameters and the incidence of arrhythmic events in patients with fever-induced Brugada syndrome (BrS) remain unknown. Objective: We aimed to investigate the effect of hyperthermia on the ECG pattern and the occurrence of fever-triggered arrhythmic events (FTAEs) in patients with fever-induced BrS. Methods: We retrospectively analyzed a series of fever-induced BrS cases from January 1966 to November 2018. Clinical characteristics and ECG parameters were evaluated in the presence or absence of fever. Results: Syncope and implantable cardioverter defibrillator implantation occurred more frequently in BrS patients with FTAEs than in patients without FTAEs. In BrS patients <16 years old, more arrhythmia events occurred in patients with FTAEs than in patients without FTAEs (p = 0.04). During follow-up, 2 patients in the FTAEs group suffered new malignant arrhythmic events. Compared to the afebrile state, the J point increased significantly in precordial leads V1, V2, and V3 during the febrile state (all p < 0.01). The corrected QTpeak intervals in V1 and V2 were significantly longer in the FTAEs group than in the non-FTAEs group (354.5 ± 37.0 vs. 334.3 ± 45.5 ms, p < 0.01 and 368.0 ± 43.4 vs. 330.9 ± 41.5 ms, p < 0.01, respectively). An increased corrected QT dispersion and a lengthened corrected Tpeak-Tend dispersion were also observed during fever. Conclusions: Fever may not only reveal BrS but also induce life-threatening arrhythmic events, especially in children and adolescents.

Elevated Plasma Adiponectin Levels Are Associated with Abnormal Corrected QT Interval in Patients with Stable Angina.

Low-circulating levels of adiponectin (ADPN) are associated with obesity, diabetes mellitus, and coronary artery disease. On the contrary, some studies have demonstrated a link between relatively high levels of plasma ADPN and heart failure, atrial fibrillation, and adverse outcome. However, little is known about the relationship between ADPN level and prolonged QT interval. The aim of this study was to investigate the association between plasma ADPN levels and prolonged QT interval in patients with stable angina.In this retrospective study, because the diverse disease severity and condition of the study population may have affected the results, we chose individuals with stable angina. Plasma ADPN concentrations were measured using enzyme-linked immunosorbent assays. A 12-lead ECG recording was obtained from each patient.We enrolled 479 stable-angina patients. Patients with an abnormal corrected QT (QTc) interval had higher median plasma ADPN levels than those with normal QTc intervals. Age- and sex-adjusted ADPN levels were positively associated with heart rate, QTc interval, left ventricular mass index, and creatinine but negatively associated with left ventricular ejection fraction, waist circumference, current smoking, total cholesterol, triglycerides, low-density lipoprotein cholesterol, albumin, and estimated glomerular filtration rate. A multiple logistic regression analysis revealed ADPN as an independent association factor for abnormal QTc interval. Increasing concentrations of sex-specific ADPN were independently and significantly associated with abnormal QTc interval, even after full adjustment of known biomarkers.Our results indicate that ADPN may play a role in the pathogenesis of abnormal QTc interval in patients with stable angina.

Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program.

BackgroundAn intranasal formulation of esketamine, combined with an oral antidepressant, is approved in the USA and the European Union for adults with treatment-resistant depression (TRD). Transient cardiovascular stimulatory effects have been reported with ketamine.MethodsCardiovascular effects of esketamine nasal spray, combined with an oral antidepressant, were evaluated in 1708 esketamine-treated adults with TRD in six trials (five double-blind, placebo-controlled (486 placebo-treated patients); one open-label) of 4–52 weeks’ duration. Patients with established cardiovascular disease, including uncontrolled hypertension (> 140/> 90 mmHg), history of hypertensive crisis, or clinically significant electrocardiogram (ECG) abnormalities, were excluded from enrollment. Effects on cardiac repolarization were assessed in a phase I randomized, positive- and active-controlled thorough corrected QT (QTc) interval study. For adverse events, odds ratio (OR) [95% confidence interval] for esketamine/antidepressant versus antidepressant/placebo was calculated.ResultsAdverse events related to increased BP were reported in 12.8% of all esketamine-treated patients (in double-blind trials: esketamine/antidepressant 11.6% vs. antidepressant/placebo 3.9%; OR 3.2 [1.9–5.8]). Among the patients without a history of hypertension, new antihypertensive medication was initiated by 2.1% (6/280) of patients in the esketamine/antidepressant group versus 1.2% (2/171) of patients in the antidepressant/placebo group, in the double-blinded studies. Adverse events related to abnormal heart rate were reported in 3.0% of all esketamine-treated patients (in double-blind trials: 1.6% vs. 0.8%; OR 1.9 [0.5–8.6]). Overall, three cardiovascular adverse events related to BP increase were reported as serious and severe, and there was one fatal event considered unrelated (acute cardiac failure). BP increases reached the maximum postdose value within ~ 40 min of esketamine dosing and returned to the predose range by ~ 1.5 h postdose. In two studies (4-week duration, age 18–64 years), the largest mean maximum systolic/diastolic postdose BP increases were 13.3/8.7 mmHg for esketamine/antidepressant and 6.1/4.9 mmHg for antidepressant/placebo, and in a short-term elderly study (age ≥ 65 years) were 16.0/9.5 and 11.1/6.8 mmHg, respectively. Across studies/study phases, < 2% of patients discontinued esketamine due to adverse events of increased BP and tachycardia. No clinically relevant effect on ECG parameters was observed. Therapeutic and supratherapeutic doses of esketamine did not prolong the QTcF (QT corrected by Fridericia’s equation) interval (baseline-corrected values of − 2.02 to 2.16 ms, and − 3.51 to 4.89 ms, respectively).ConclusionsBP elevations following esketamine dosing are generally transient, asymptomatic, and not associated with serious cardiovascular safety sequalae. Further evaluation of long-term cardiovascular outcomes is warranted.

Protective role of cardiac-specific overexpression of caveolin-3 in cirrhotic cardiomyopathy.

Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TGneg) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TGneg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TGneg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TGneg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TGneg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis.NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for successful liver transplantation. This study shows cardiac myocyte specific overexpression of caveolin-3 (Cav-3) provides better cardiac contractile responses and less corrected QT prolongation during adrenergic stress in a cirrhotic cardiomyopathy model, suggesting beneficial effects of Cav-3 expression in cirrhotic cardiomyopathy.

Quetiapine and QTc prolongation in critically ill patients

Antipsychotics are commonly used in the management of delirium, generally in order to ameliorate agitation and other behavioral disturbances. However, the rare but potentially life‐threatening atypical ventricular tachycardia known as torsade de pointes can be associated with the use of antipsychotics, as a result of their effect on delaying cardiac conduction, as evidenced by a prolonged corrected QT interval (QTc) on the electrocardiogram.