Comprehensive preclinical evaluation of how cardiac safety profiles of potential COVID-19 drugs are modified by disease associated factors.

Background and Purpose: Hydroxychloroquine and chloroquine, alone or in combination with azithromycin, have been proposed as therapies for COVID-19. However, there is currently scant and inconsistent data regarding their proarrhythmic potential in these patients. Moreover, their risk profile in the setting of altered physiological states encountered in patients with COVID-19 (i.e. febrile state, electrolyte imbalances, and/or acidosis) is unknown. Experimental approach: Potency of hERG block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from three separate individuals. Key Results: Chloroquine and hydroxychloroquine blocked hERG with IC50 of 1.47±0.07 µM and 3.78±0.17 µM respectively, indicating proarrhythmic risk at concentrations effective against SARS-CoV-2 in vitro and proposed in COVID-19 clinical trials. Hypokalaemia and hypermagnesemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs (i.e. reduced proarrhythmic risk), whereas increased temperature decreased potency of chloroquine and hydroxychloroquine but increased potency for azithromycin. In silico simulations across genetically diverse populations predicted that 17% of individuals exhibit action potential durations >500 ms at the highest proposed therapeutic levels, equating to significant QT prolongation. Conclusion and Implications: Significant proarrhythmic risk is predicted for hydroxychloroquine and chloroquine at doses proposed to treat COVID-19. Clinicians should carefully consider the risk of such treatments, and implement long term QT interval monitoring in trials, particularly in patients with electrolyte imbalances.

Diurnal variation in autonomic regulation among patients with genotyped Rett syndrome

BackgroundRett syndrome is a severe neurological disorder with a range of disabling autonomic and respiratory symptoms and resulting predominantly from variants in the methyl-CpG binding protein 2 gene on the long arm of the X-chromosome. As basic research begins to suggest potential treatments, sensitive measures of the dynamic phenotype are needed to evaluate the results of these research efforts. Here we test the hypothesis that the physiological fingerprint of Rett syndrome in a naturalistic environment differs from that of controls, and differs among genotypes within Rett syndrome.MethodsA comprehensive array of heart rate variability, cardiorespiratory coupling and cardiac repolarisation measures were evaluated from an existing database of overnight and daytime inhome ambulatory recordings in 47 cases and matched controls.ResultsDifferences between girls with Rett syndrome and matched controls were apparent in a range of autonomic measures, and suggest a shift towards sympathetic activation and/or parasympathetic inactivation. Daily temporal trends analysed in the context of circadian rhythms reveal alterations in amplitude and phase of diurnal patterns of autonomic balance. Further analysis by genotype class confirms a graded presentation of the Rett syndrome phenotype such that patients with early truncating mutations were most different from controls, while late truncating and missense mutations were least different from controls.ConclusionsComprehensive autonomic measures from extensive inhome physiological measurements can detect subtle variations in the phenotype of girls with Rett syndrome, suggesting these techniques are suitable for guiding novel therapies.