Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes

Abstract

Substantial efforts have been recently committed to develop COVID-19 medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. While these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluated the pro-arrhythmia risk and inotropic effects of these drugs in the cardiomyocyte contractility-based model of the human heart. We found Hydroxychloroquine to have a low pro-arrhythmia risk, while Chloroquine and Azithromycin were associated with high risk. Hydroxychloroquine pro-arrhythmia risk changed to high with low level of K+, while high level of Mg2+ protected against pro-arrhythmic effect of high Hydroxychloroquine concentrations. Moreover, therapeutic concentration of Hydroxychloroquine caused no enhancement of elevated temperature-induced pro-arrhythmia. Polytherapy of Hydroxychloroquine plus Azithromycin and sequential application of these drugs were also found to influence pro-arrhythmia risk categorization. Hydroxychloroquine pro-arrhythmia risk changed to high when combined with Azithromycin at therapeutic concentration. However, Hydroxychloroquine at therapeutic concentration impacted the cardiac safety profile of Azithromycin and its pro-arrhythmia risk only at concentrations above therapeutic level. We also report that Hydroxychloroquine and Chloroquine, but not Azithromycin, decreased contractility while exhibiting multi-ion channel block features, and Hydroxychloroquine’s contractility effect was abolished by Azithromycin. Thus, this study has the potential to inform clinical studies evaluating repurposed therapies, including those in the COVID-19 context. Additionally, it demonstrates the translational value of the human cardiomyocyte contractility-based model as a key early discovery path to inform decisions on novel therapies for COVID-19, malaria, and inflammatory diseases.

Assessment of proarrhythmogenic risk for chloroquine and hydroxychloroquine using the CiPA concept

“… Cardiac ion current IC50 (μM) Preparation Ref. own data Literature Chloroquine I Kr 1.82 at RT 1.29 at PT 0.96 at RT HEK293 Borsini et al (2012) 1.03 at PT CHO Delaunois et al (2021) 1.47 at PT CHO TeBay et al (2021) 1.6 at PT (65% block at 3 μM) cat Purkinje fibers Sánchez-Chapula et al (2001) 2.5 at RT HEK293 Traebert et al (2004) 7.77 CHO Jordaan et al (2021) 8.4 Xenopus laevis oocytes Sánchez-Chapula et al (2002) I Ks >100 >80.9 (11% block at 10 μM) cat Purkinje fibers Sánchez-Chapula et al (2001) 115 (8% block at 10 μM) human atrial myocytes Borsini et al (2012) >300 CHO Delaunois et al (2021) I K1 5.86 0.35 (74% block at 1 μM) cat Purkinje fibers Sánchez-Chapula et al (2001) 1.2 HEK293 …”

Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart

“…Given the cross-species differences we have discussed between human and animal cardiomyocytes with regards to the properties and amplitude of the late INa conductance, therapeutic development efforts that are exclusively reliant on animal models run the risk of selecting molecules with limited utility for the treatment of human atrial fibrillation 77 – 80 . The availability of human primary cardiac tissue and cells for healthy and atrial fibrillation donors provides a unique opportunity to identify and optimize novel molecules with the activity profile needed for effective treatment of specific atrial fibrillation patient populations 4 , 8 – 15 , 81 , 82 .…”

Outcome and death risk of diabetes patients with Covid-19 receiving pre-hospital and in-hospital metformin therapies

“…In Brazil the use of chloroquine has been strongly recommended by the federal government, however, in this study the use of CHLO/HCQ instead of having a protective potential, was associated with a significantly increase of both the need for mechanical ventilation and death risk (Table 2 ). One of the concerns of chloroquine and azithromycin are their cardiotoxic potential [ 30 ]. It has been also observed that chloroquine/hydroxychloroquine increases corrected QT interval (QTc) in COVID-19 patients, however, this change was not associated with death risk [ 31 ].…”