Protective Effects of Meldonium in Experimental Models of Cardiovascular Complications with a Potential Application in COVID-19.

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients.

The impact of hydroxychloroquine-azithromycin combination on Tpeak-to-end and Tpeak-to-end/QT ratio during a short treatment course.

BACKGROUND: Since there was no proven treatment of coronavirus disease 2019 (COVID-19), hydroxychloroquine-azithromycin (HCQ-AZM) combination is being used in different countries as a treatment option. Many controversies exist related to the safety and effectiveness of this combination, and questions about how HCQ-AZM combination affects the ventricular repolarization are still unknown. OBJECTIVE: The aim of the study was to show whether the hydroxychloroquine-azithromycin (HCQ-AZM) combination prolonged Tpeak-to-end (TpTe) duration and TpTe/QT interval ratio or not. METHODS: One hundred and twenty-six consequent COVID-19(+) patients meeting the study criteria were enrolled in this study. Baseline ECGs were obtained immediately after hospitalization and before commencing the HCQ-AZM combination. On-treatment ECG was obtained 24-48 hr after the loading dose of HCQ/AZM. ECG parameters including PR interval, QRS duration, QT interval, QTc interval, TpTe duration, and TpTe/QT interval ratio were assessed. Demographic and laboratory findings were collected from an electronic recording system. RESULTS: ECGs of 126 COVID-19(+) patients who received HCQ-AZM combination were assessed. Mean baseline QTc (by Fridericia formula), TpTe, and TpTe/QT ratio were 420.0 ± 26.5 ms, 82.43 ± 9.77 ms, and 0.22 ± 0.02, respectively. On-treatment QTc, TpTe and TpTe/QT ratio were 425.7 ± 27.18 ms, 85.17 ± 11.17 ms, and 0.22 ± 0.03, respectively. No statistically significant acute impacts of HCQ-AZM combination on TpTe duration and TpTe/QT interval ratio were observed compared with baseline values. No ventricular tachycardia/fibrillation and the significant conduction delays were seen during in-hospital follow-up. CONCLUSION: HCQ-AZM combination increased TpTe duration. However, no significant impact on TpTe/QT interval ratio was observed.

Cardiac Arrest Risk During Acute Infections: Systemic Inflammation Directly Prolongs QTc Interval via Cytokine-Mediated Effects on Potassium Channel Expression.

BACKGROUND: During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K+ channel expression. METHODS: We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K+ channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time. RESULTS: In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K+ channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients. CONCLUSIONS: During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.