Psychological factors and cardiac repolarization instability during anger in implantable cardioverter defibrillator patients.

BACKGROUND: Evidence indicates that emotions such as anger are associated with increased incidence of sudden cardiac death, but the biological mechanisms remain unclear. We tested the hypothesis that, in patients with sudden death vulnerability, anger would be associated with arrhythmic vulnerability, indexed by cardiac repolarization instability. METHODS: Patients with coronary artery disease (CAD) and an implantable cardioverter defibrillator (ICD; n = 41) and healthy controls (n = 26) gave an anger-inducing speech (anger recall), rated their current (state) anger, and completed measures of trait (chronic) levels of Anger and Hostility. Repolarization instability was measured using QT Variability Index (QTVI) at resting baseline and during anger recall using continuous ECG. RESULTS: ICD patients had significantly higher QTVI at baseline and during anger recall compared with controls, indicating greater arrhythmic vulnerability overall. QTVI increased from baseline to anger recall to a similar extent in both groups. In ICD patients but not controls, during anger recall, self-rated anger was related to QTVI (r = .44, p = .007). Trait (chronic) Anger Expression (r = .26, p = .04), Anger Control (r = -.26, p = .04), and Hostility (r = .25, p = .05) were each associated with the change in QTVI from baseline to anger recall (ΔQTVI). Moderation analyses evaluated whether psychological trait associations with ΔQTVI were specific to the ICD group. Results indicated that Hostility scores predicted ΔQTVI from baseline to anger recall in ICD patients (ß = 0.07, p = .01), but not in controls. CONCLUSIONS: Anger increases repolarization lability, but in patients with CAD and arrhythmic vulnerability, chronic and acute anger interact to trigger cardiac repolarization lability associated with susceptibility to malignant arrhythmias.

Ventricular Arrhythmias Associated With Over-the-Counter and Recreational Opioids.

BACKGROUND: Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied. OBJECTIVES: In this study, we sought to explore opioid-associated arrhythmia reporting in North America. METHODS: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory. RESULTS: Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS. CONCLUSIONS: The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.

Cardiovascular Complications of Opioid Use: JACC State-of-the-Art Review.

Opioids are the most potent of all analgesics. Although traditionally used solely for acute self-limited conditions and palliation of severe cancer-associated pain, a movement to promote subjective pain (scale, 0 to 10) to the status of a "fifth vital sign" bolstered widespread prescribing for chronic, noncancer pain. This, coupled with rising misuse, initiated a surge in unintentional deaths, increased drug-associated acute coronary syndrome, and endocarditis. In response, the American College of Cardiology issued a call to action for cardiovascular care teams. Opioid toxicity is primarily mediated via potent µ-receptor agonism resulting in ventilatory depression. However, both overdose and opioid withdrawal can trigger major adverse cardiovascular events resulting from hemodynamic, vascular, and proarrhythmic/electrophysiological consequences. Although natural opioid analogues are devoid of repolarization effects, synthetic agents may be proarrhythmic. This perspective explores cardiovascular consequences of opioids, the contributions of off-target electrophysiologic properties to mortality, and provides practical safety recommendations.

Huffing and twist: Fatal Torsade de pointes associated with Tetrafluoroethane Inhalation and amphetamine use.

Many volatile chemicals inhaled for a recreational high have a chemical structure similar to chloroform and may lead to Ikr blockade and subsequent torsades de pointes. This is one potential mechanism of action for huffing-associated sudden death.

A Point-of-Care Algorithm to Guide Proper Device Selection for Ambulatory Electrocardiography.

In the outpatient setting, ambulatory electrocardiography is the most frequently used diagnostic modality for the evaluation of patients in whom cardiac arrhythmias or conduction abnormalities are suspected. Proper selection of the device type and monitoring duration is critical for optimizing diagnostic yield and cost-effective resource utilization. However, despite guidance from major professional societies, the lack of systematic guidance for proper test selection in many institutions results in the need for repeat testing, which leads to not only increased resource utilization and cost of care, but also suboptimal patient care. To address this unmet need at our own institution, we formed a multidisciplinary panel to develop a concise, yet comprehensive algorithm, incorporating the most common indications for ambulatory electrocardiography, to efficiently guide clinicians to the most appropriate test option for a given clinical scenario, with the goal of maximizing diagnostic yield and optimizing resource utilization. The algorithm was designed as a single-page, color-coded flowchart to be utilized both as a rapid reference guide in printed form, and a decision support tool embedded within the electronic medical records system at the point of order entry. We believe that systematic adoption of this algorithm will optimize diagnostic efficiency, resource utilization, and importantly, patient care and satisfaction.

QTc interval screening in methadone treatment.

DESCRIPTION: An independent panel developed cardiac safety recommendations for physicians prescribing methadone. METHODS: Expert panel members reviewed and discussed the following sources regarding methadone: pertinent English-language literature identified from MEDLINE and EMBASE searches (1966 to June 2008), national substance abuse guidelines from the United States and other countries, information from regulatory authorities, and physician awareness of adverse cardiac effects. RECOMMENDATION 1 (DISCLOSURE): Clinicians should inform patients of arrhythmia risk when they prescribe methadone. RECOMMENDATION 2 (CLINICAL HISTORY): Clinicians should ask patients about any history of structural heart disease, arrhythmia, and syncope. RECOMMENDATION 3 (SCREENING): Obtain a pretreatment electrocardiogram for all patients to measure the QTc interval and a follow-up electrocardiogram within 30 days and annually. Additional electrocardiography is recommended if the methadone dosage exceeds 100 mg/d or if patients have unexplained syncope or seizures. RECOMMENDATION 4 (RISK STRATIFICATION): If the QTc interval is greater than 450 ms but less than 500 ms, discuss the potential risks and benefits with patients and monitor them more frequently. If the QTc interval exceeds 500 ms, consider discontinuing or reducing the methadone dose; eliminating contributing factors, such as drugs that promote hypokalemia; or using an alternative therapy. RECOMMENDATION 5 (DRUG INTERACTIONS): Clinicians should be aware of interactions between methadone and other drugs that possess QT interval-prolonging properties or slow the elimination of methadone.

Muscarinic modulation of the sodium-calcium exchanger in heart failure.

BACKGROUND: The Na-Ca exchanger (NCX) is a critical calcium efflux pathway in excitable cells, but little is known regarding its autonomic regulation. METHODS AND RESULTS: We investigated beta-adrenergic receptor and muscarinic receptor regulation of the cardiac NCX in control and heart failure (HF) conditions in atrially paced pigs. NCX current in myocytes from control swine hearts was significantly increased by isoproterenol, and this response was reversed by concurrent muscarinic receptor stimulation with the addition of carbachol, demonstrating "accentuated antagonism." Okadaic acid eliminated the inhibitory effect of carbachol on isoproterenol-stimulated NCX current, indicating that muscarinic receptor regulation operates via protein phosphatase-induced dephosphorylation. However, in myocytes from atrially paced tachycardia-induced HF pigs, the NCX current was significantly larger at baseline but less responsive to isoproterenol compared with controls, whereas carbachol failed to inhibit isoproterenol-stimulated NCX current, and 8-Br-cGMP did not restore muscarinic responsiveness. Protein phosphatase type 1 dialysis significantly reduced NCX current in failing but not control cells, consistent with NCX hyperphosphorylation in HF. Protein phosphatase type 1 levels associated with NCX were significantly depressed in HF pigs compared with control, and total phosphatase activity associated with NCX was significantly decreased. CONCLUSIONS: We conclude that the NCX is autonomically modulated, but HF reduces the level and activity of associated phosphatases; defective dephosphorylation then "locks" the exchanger in a highly active state.

QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.

BACKGROUND: Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects. METHODS: We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds. RESULTS: Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group). CONCLUSION: Buprenorphine is associated with less QTc prolongation than levomethadyl or methadone and may be a safe alternative.

Gender differences in Na/Ca exchanger current and beta-adrenergic responsiveness in heart failure in pig myocytes.

Clinical trials suggest females experience less heart failure (HF) progression, mortality, and arrhythmia frequency. HF increases Na/Ca exchanger (NCX) expression and activity contributing to both depressed contractility and ventricular arrhythmias, but whether gender modifies this effect is unknown. Left ventricular myocytes were isolated from control and from tachycardic pacing-induced failing swine hearts of both sexes. The Ni-sensitive NCX current (I(NCX)) was measured in voltage clamp after blocking other channels. In control myocytes there is no difference in basal I(NCX) and beta-adrenergic responsiveness between male and female animals. HF greatly increased I(NCX) and reduced beta-adrenergic responsiveness in males compared to females, an effect that was eliminated by PP1. Diuretic therapy (furosemide, 1 mg/kg/day) further enhanced I(NCX) and reduced beta-adrenergic responsiveness in females and eliminated the gender difference. Gender-specific differences in calcium handling may contribute to improved survival of females in HF.

Protein kinase A hyperphosphorylation increases basal current but decreases beta-adrenergic responsiveness of the sarcolemmal Na+-Ca2+ exchanger in failing pig myocytes.

The sodium-calcium exchanger (NCX) protein is the major cardiac calcium extrusion mechanism and is upregulated in heart failure (HF). NCX expression level and functional activity as regulated by beta-adrenergic receptor (beta-AR) stimulation in swine with and without tachycardia-induced heart failure were studied. The Ni2+-sensitive NCX current was measured in myocytes from HF and control animals in the basal state or in the presence of isoproterenol, forskolin, 8-Br-cAMP, okadaic acid, or protein phosphatase type 1. Western blot analysis revealed a significant increase in both the 120-kDa (29%) and 80-kDa (69%) fragments in HF (P<0.05 versus control). Despite this modest increase in protein, the basal peak outward NCX current was increased almost 5-fold in HF (P<0.05 versus control). Stimulation with isoproterenol, however, increased the control currents to a significantly greater extent than HF (500% increase in control versus 100% increase in HF, P<0.01); peak stimulated current was not different in HF and control. This reduction in responsiveness to beta-AR stimulation was refractory to forskolin, 8-Br-cAMP, or okadaic acid stimulation. In vitro protein kinase A back-phosphorylation revealed higher phosphorylation capacity of NCX protein in control versus HF, consistent with increased phosphorylation in vivo (hyperphosphorylation) in HF. Protein phosphatase type 1 exposure resulted in a significant reduction (73%) in peak basal current in HF (compared with no significant difference in controls), confirming that the increased basal NCX current in HF is predominantly attributable to hyperphosphorylation. NCX expression and activity are thus increased in HF, although beta-AR responsiveness is decreased because of NCX hyperphosphorylation.

Cardiovascular disorders associated with naloxone monotherapy and in fixed-dose combination with opioids: Data from international safety surveillance.

BACKGROUND: The widespread use of opioids has resulted in sharp rise of associated complications, particularly opioid-induced constipation (OIC). Opioid receptor antagonists have been proposed to treat OIC, but could precipitate rapid opioid withdrawal. As cardiovascular safety data are lacking, we assessed disproportionate reporting of adverse cardiac events associated with naloxone across large, international pharmacovigilance systems. METHODS: Post-marketing data from the World Health Organization (WHO) and FDA Adverse Events Reporting System (FAERS) were evaluated for naloxone and the synthetic opioids oxycodone and tilidine. The proportional reporting ratio (PRR), a measure of reporting frequency analogous to an odds ratio, was assessed. The primary outcome was reporting frequency of the MedDRA System Organ Class (SOC) 'Cardiac Disorders' for naloxone alone and in fixed-dose combination with opioids. Opioid mono-preparations served as quasi-experimental controls. A PRR greater than 2.0 was considered significant. RESULTS: In total, 14,827,374 million adverse drug event reports were reviewed. In WHO, there were 1757 reports of SOC cardiac disorders among 10,866 total reports for oxycodone (PRR 2.38 [95% CI 2.28-2.49, χ(2)=1504]). For oxycodone-naloxone, there were 43/453 reports of SOC cardiac disorders (PRR 1.45 [95% CI 1.09-1.92, χ(2)=6.4]). For the synthetic opioid tilidine there were 13/179 reports (PRR 1.13 [95% CI 0.67-1.91, χ(2)=0.2]) and for tilidine-naloxone, 30/505 reports (PRR 0.92 [95% CI 0.65-1.31, χ(2)=0.2]). In FAERS, the PRR for SOC cardiac disorders was 0.95 [95% CI 0.89-1.01, χ(2)=2.1] for naloxone (all administration routes) and 1.16 [95% CI 0.93-1.45, χ(2)=1.3] for naloxone (oral only). In comparison, the PRR was 1.66 [95% CI 1.63-1.69, χ(2)=4278] for oxycodone and 1.52 [CI 1.28-1.80, χ(2)=1500] for oxycodone-naloxone. CONCLUSIONS: Available pharmacovigilance data do not suggest disproportionate reporting of adverse cardiovascular events for opioid antagonists used to treat OIC.

Potent Inhibition of hERG Channels by the Over-the-Counter Antidiarrheal Agent Loperamide.

OBJECTIVES: The aim of this study was to determine the in vitro electrophysiological properties of loperamide. The authors' hypothesis was that loperamide is a potent blocker of the current carried by the human ether-à-go-go-related gene (hERG) potassium channel. BACKGROUND: Loperamide is a peripherally-acting µ-opioid agonist available worldwide as an over-the-counter treatment for diarrhea. Like most opioids, it is not currently known to be proarrhythmic. Recent cases of torsade de pointes in association with high-dose loperamide raise concern given its structural similarity to methadone, another synthetic opioid with an established arrhythmia risk. METHODS: Effects of loperamide on blockade of the hERG potassium channel ion current were assessed in Chinese Hamster Ovary (CHO) cells stably expressing hERG to elucidate current amplitude and kinetics. The concentration required to produce 50% inhibition of hERG current was assessed from the amplitude of tail currents and the impact on action potential duration was assessed in isolated swine ventricular cardiomyocytes. RESULTS: The 50% inhibitory concentration for loperamide inhibition of hERG ionic tail currents was approximately 40 nmol/l. In current-voltage measurements, loperamide reduced steady and tail currents and shifted the current activation to more negative potentials. Loperamide (10 nmol/l) also increased the action potential duration, assessed at 90% of repolarization, in ventricular myocytes by 16.4 ± 1.7% (n = 6; p < 0.004). The maximum rate of rise of phase 0 of the action potential, however, was not significantly altered at any tested concentration of loperamide. CONCLUSIONS: Loperamide is a potent hERG channel blocker. It significantly prolongs the action potential duration and suggests a causal association between loperamide and recent clinical cases of torsade de pointes.

Cytosolic free magnesium modulates Na/Ca exchange currents in pig myocytes.

OBJECTIVE: Cardiac Na/Ca exchanger (NCX) protein is up-regulated and intracellular free magnesium ([Mg(2+)](i)) is significantly reduced in experimental heart failure. We asked whether changes in [Mg(2+)](i) in a physiologically relevant range could alter the I(NCX). METHODS: The nickel-sensitive current was measured in voltage-clamped myocytes (Yorkshire pig; left ventricular) exposed to ramp pulses at 37 degrees C in Tyrode's solution containing ouabain, nifedipine and +/- Ni(2+) (5 mmol/l). The intracellular free [Ca(2+)] and [Mg(2+)] concentrations were set at 50 nmol/l and 1.25 mmol/l (HiMg) or 0.13 mmol/l (LoMg), respectively, through pipette dialysis. RESULTS: Reducing [Mg(2+)](i) resulted in a significant increase in both outward and inward Ni-sensitive current without a shift in the reversal potential. This effect was not due to the inadvertent reduction of intracellular free [ATP] secondary to binding of ATP to Mg(2+); reducing intracellular [ATP] in LoMg cells from 1.35 mmol/l to 0.18 mmol/l did not affect I(NCX). The intracellular free [Ca(2+)] was raised from 50 to 200 nmol/l, resulting in augmented inward and outward current due to calcium activation. HiMg attenuated both inward and outward currents significantly compared to LoMg, suggesting that [Mg(2+)](i) competes with [Ca(2+)](i) at the allosteric regulatory site. CONCLUSION: Cytosolic free magnesium modulates the I(NCX) over a physiologic range independent of [ATP](i). Reduced [Mg(2+)](i) in heart failure could contribute to altered calcium regulation of the NCX, contributing to the altered heart failure phenotype through enhanced NCX activity.

Catheter ablation of atrial fibrillation should be offered as primary therapy: what's your hurry?

The appropriate initial treatment of a middle-aged individual with symptomatic paroxysms of atrial fibrillation, diabetes, and hypertension should focus on eliminating the underlying causes of disease to safely reduce morbidity and prolong life. An initial strategy using ablation temporarily reduces arrhythmia symptoms and exposes the individual to potentially needless risk and repeat procedures. Randomized trials have not established the superiority of ablation to antiarrhythmic drugs with respect to prolonging life or reducing serious morbidity. It is appropriate to treat modestly symptomatic individuals with antiarrhythmic drugs while performing aggressive risk factor modification.

Arrhythmia associated with buprenorphine and methadone reported to the Food and Drug Administration.

AIM: To assess the relative frequency of reporting of adverse events involving ventricular arrhythmia, cardiac arrest, corrected QT interval (QTc) prolongation or torsade de pointes to the US Food and Drug Administration (FDA) between buprenorphine and methadone. DESIGN: Retrospective pharmacoepidemiological study. SETTING: Adverse drug events reported spontaneously to the FDA between 1969 and June 2011 originating in 196 countries (71% events from the United States). CASES: Adverse event cases mentioning methadone (n = 14 915) or buprenorphine (n = 7283) were evaluated against all other adverse event cases (n = 4 796 017). MEASUREMENTS: The primary outcome was the composite of ventricular arrhythmia or cardiac arrest. The secondary outcome was the composite of QTc prolongation or torsade de pointes. The proportional reporting ratio (PRR) was used to identify disproportionate reporting defined as a PRR > 2, χ(2) error > 4, with ≥ 3 cases. FINDINGS: There were 132 (1.8%) ventricular arrhythmia/cardiac arrest and 19 (0.3%) QTc prolongation/torsade de pointes cases associated with buprenorphine compared with 1729 (11.6%) ventricular arrhythmia/cardiac arrest and 390 (2.6%) QTc prolongation/torsade de pointes cases involving methadone. PRRs associated with buprenorphine were not significant for ventricular arrhythmia/cardiac arrest (1.10, 95%, confidence interval (0.93-1.31, χ(2) = 1.2) or QTc prolongation/torsade de pointes (1.03, 95% CI = 0.66-1.62, χ(2) = 0.01), but were for methadone (7.20, 95% CI = 6.88-7.52, χ(2) = 8027; 10.7, 95% CI = 9.66-11.8, χ(2) = 1538, respectively). CONCLUSION: In spontaneously reported adverse events, methadone is associated with disproportionate reporting of cardiac arrhythmias, whereas buprenorphine is not. Although these findings probably reflect clinically relevant differences, a causal connection cannot be presumed and disproportionality analysis cannot quantify absolute risk per treatment episode. Population-based studies to definitively quantify differential incidence rates are warranted.