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

Background Systemic 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 Results We 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-ß 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-ß estradiol levels; in these patients, increased C-reactive protein and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Conclusions During 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.

Drug-Induced QTc Prolongation: What We Know and Where We Are Going.

Drug-induced QTc prolongation is a concerning electrocardiogram (ECG) abnormality. This cardiac disturbance carries a 10% risk of sudden cardiac death due to the malignant arrhythmia, Torsades de Pointes. The Arizona Center for Education and Research on Therapeutics (AzCERT) has classified QTc prolonging therapeutic classes, such as antiarrhythmics, antipsychotics, anti-infectives, and others. AzCERT criteria categorize medications into three risk categories: "known," "possible," and "conditional risk" of QTc prolongation and Torsades de Pointes. The list of QTc prolonging medications continues to expand as new drug classes are approved and studied. Risk factors for QTc prolongation can be delineated into modifiable or non-modifiable. A validated risk scoring tool may be utilized to predict the likelihood of prolongation in patients receiving AzCERT classified medication. The resultant risk score may be applied to a clinical decision support system, which offers mitigation strategies. Mitigation strategies including discontinuation of possible offending agents with a selection of an alternative agent, assessment of potential drug interactions or dose adjustments through pharmacokinetic and pharmacodynamic monitoring, and initiation of both ECG and electrolyte monitoring are essential to prevent a drug-induced arrhythmia. The challenges presented by the COVID-19 pandemic have led to the development of innovative continuous monitoring technology, increasing protection for both patients and healthcare workers. Early intervention strategies may reduce adverse events and improve clinical outcomes in patients identified to be at risk of QTc prolongation.

Safely Administering Potential QTc Prolonging Therapy Across a Large Health Care System in the COVID-19 Era.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) has resulted in a global pandemic. Hydroxychloroquine±azithromycin have been widely used to treat coronavirus disease 2019 (COVID-19) despite a paucity of evidence regarding efficacy. The incidence of torsade de pointes remains unknown. Widespread use of these medications forced overwhelmed health care systems to search for ways to effectively monitor these patients while simultaneously trying to minimize health care provider exposure and use of personal protective equipment. METHODS: Patients with COVID-19 positive who received hydroxychloroquine±azithromycin across 13 hospitals between March 1 and April 15 were included in this study. A comprehensive search of the electronic medical records was performed using a proprietary python script to identify any mention of QT prolongation, ventricular tachy-arrhythmias and cardiac arrest. RESULTS: The primary outcome of torsade de pointes was observed in 1 (0.015%) out of 6476 hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin. Sixty-seven (1.03%) had hydroxychloroquine±azithromycin held or discontinued due to an average QT prolongation of 60.5±40.5 ms from a baseline QTc of 473.7±35.9 ms to a peak QTc of 532.6±31.6 ms. Of these patients, hydroxychloroquine±azithromycin were discontinued in 58 patients (86.6%), while one or more doses of therapy were held in the remaining nine (13.4%). A simplified approach to monitoring for QT prolongation and arrythmia was implemented on April 5. There were no deaths related to the medications with the simplified monitoring approach and health care provider exposure was reduced. CONCLUSIONS: The risk of torsade de pointes is low in hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin therapy.

Saudi Heart Rhythm Society Task Force on Management of Potential Arrhythmogenicity Associated with Pharmacotherapy for COVID-19.

Evidence of cardiovascular complications associated with the COVID-19 global pandemic continues to evolve. These include direct and indirect myocardial injury with subsequent acute myocardial ischemia, and cardiac arrhythmia. Some results from a limited number of trials of antiviral medications, along with chloroquine/hydroxychloroquine and azithromycin, have been beneficial. However, these pharmacotherapies may cause drug-induced QT prolongation leading to ventricular arrhythmias and sudden cardiac death. Mitigation of the potential risk in these susceptible patients may prove exceptionally challenging. The Saudi Heart Rhythm Society established a task force to perform a review of this subject based on has recently published reports, and studies and recommendations from major medical organizations. The objective of this review is to identify high-risk patients, and to set clear guidelines for management of patients receiving these pharmacotherapies.