Methadone-induced mortality in the treatment of chronic pain: Role of QT prolongation

Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual’s propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone-associated arrhythmia and to assess the feasibility of current risk mitigation strategies

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 (β = 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

Sleep-disordered Breathing Destabilizes Ventricular Repolarization: Cross-sectional, Longitudinal, and Experimental Evidence – The Role of Intermittent Hypoxemia

Sleep-disordered breathing (SDB) increases the risk of cardiac arrhythmias and sudden cardiac death. To characterize the associations between SDB, intermittent hypoxemia, and the beat-to-beat QT variability index (QTVI), a measure of ventricular repolarization lability associated with cardiac arrhythmias and sudden cardiac death. Three distinct cohorts were used: (1) a matched sample of 122 participants with and without severe SDB for cross-sectional analysis, (2) a matched sample of 52 participants with and without incident SDB for longitudinal analysis, and (3) a sample of 19 healthy adults exposed to acute intermittent hypoxia and ambient air on two separate days. The cross-sectional and longitudinal cohorts were the Sleep Heart Health Study participants with no known comorbidities who were not on any drugs known to affect cardiac repolarization and satisfied the inclusion criteria. Electrocardiographic measures were calculated from one-lead electrocardiograms. Participants with severe SDB had greater QTVI than those without SDB (P = 0.027). Total sleep time with less than 90% oxygen saturation, but not the arousal frequency, was a predictor of QTVI. QTVI during sleep was predictive of all-cause mortality. With incident SDB, mean QTVI increased from -1.23 to -0.86 over 5 years (P = 0.017). Finally, experimental exposure of healthy adults to acute intermittent hypoxia for four hours progressively increased QTVI (P = 0.016). The results show that both prevalent and incident SDB are associated with ventricular repolarization instability and suggest intermittent hypoxemia as the underlying mechanism that may contribute to increased mortality in SDB

Sleep-Disordered Breathing Destabilizes Ventricular Repolarization

Sleep-disordered breathing (SDB) increases the risk of cardiac arrhythmias, sudden death, and all-cause mortality. To characterize the associations between SDB, intermittent hypoxemia, and the QT variability index (QTVI), a measure of ventricular repolarization lability associated with a higher risk for cardiac arrhythmias, sudden death, and cardiovascular mortality. Polysomnograms from three cohorts were used: a matched sample of 122 participants with and without severe SDB, a matched sample of 52 participants with and without incident SDB, and a cohort of 19 healthy adults exposed to intermittent hypoxia and ambient air on two separate days. Electrocardiographic measures were calculated from one-lead electrocardiograms. Compared to those without SDB, participants with severe SDB had larger QTVI (-1.19 vs. -1.43, =0.027), heart rate (68.34 vs. 64.92 beats/minute; =0.028), and hypoxemia burden during sleep as assessed by the total sleep time with oxygen saturation less than 90% (TST ; 11.39% vs. 1.32%, <0.001). TST , but not the frequency of arousals, was a predictor of QTVI. Heart rate and QTVI during sleep were predictive of all-cause mortality. In the cohort with incident SDB, the mean QTVI increased from -1.23 to -0.86 over 5 years ( =0.017). Finally, in the cohort of healthy adults, exposure to intermittent hypoxia for four hours increased QTVI (-1.85 vs. -1.64; =0.016). Prevalent and incident SDB are associated with ventricular repolarization instability, which predisposes to ventricular arrhythmias and sudden cardiac death. Intermittent hypoxemia can destabilize ventricular repolarization and may mediate the increased mortality in SDB