Fatal arrhythmias: Another reason why doctors remain cautious about chloroquine/hydroxychloroquine..

Fatal arrhythmias: Another reason why doctors remain cautious about chloroquine/hydroxychloroquine for treating COVID-19

Introduction

The drugs chloroquine (CQ) and hydroxychloroquine (HCQ), a less toxic derivative of QC, are used to treat malaria and autoimmune conditions. They now have been proposed to have antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. Recent in vitro studies1 ,2 and a small nonrandomized clinical trial of 36 patients from France3 had promising results and initiated the trend of using CQ/HCQ to treat COVID-19. However, the integrity of the nonrandomized clinical trial has been questioned by the International Society of Antimicrobial Chemotherapy for the trial’s unclear inclusion criteria and triage of patients.4 Although a subsequent smaller randomized clinical trial of 30 patients showed little to no effect,5 a larger randomized clinical trial of 62 patients showed that HCQ significantly reduced the incidence and duration of COVID-19 pneumonia.6 These studies do not have sufficient statistical power to unequivocally prove the positive effects of HCQ on COVID-19. Nevertheless, the urgency of the pandemic has resulted in (1) the United States Food and Drug Administration (FDA) issuing an emergency use authorization for CQ/HCQ as treatment of COVID-19, an action that has been criticized by former FDA leaders; and (2) a call by the World Health Organization (WHO) for rapid, large, global CQ/HCQ clinical trials.


Results

In both preparations, HCQ increased the minimum CL at which pacing the hearts was possible, that is, as the wavelength increased due to the drug’s effect, conduction block was easier to elicit for longer periods with the drug, thereby predisposing the heart to arrhythmia. In the GP and rabbit, no fibrillation was obtained without the drug, and it was possible to pace with no arrhythmias at CL as short as 130 ms for GP heart and 140 ms for rabbit heart (Online Video 1). Shorter CLs led to conduction block but no arrhythmias. In contrast, tachycardia/fibrillation not only appeared in both hearts with HCQ, but it was inducible at longer CLs. Furthermore, marked alternans in APD developed with HCQ. Although APD alternans with variations >5 ms from beat to beat can be induced in rabbit ventricles, it is only possible at CL <220 ms. In GP, alternans is not common, but when observed it appears at CL <160 ms. With HCQ, APD alternans readily developed at CL <380 ms in rabbit and <350 ms in GP.

In rabbit, arrhythmias occurred with HCQ at CL <250 ms. Figure 1A and Online Video 2 show the initiation of fibrillation (multiple waves) by conduction block. Figure 2A compares the distribution of APD for CL of 250 ms between control and HCQ. The histograms show how APD dispersion increased with HCQ, with APDmax prolongation from 155 to 205 ms, and median APD changing from 124 ms to alternating APD values with medians of 125 and 132 ms. Morphologic changes in action potential (AP) also can be observed in the optical mapping voltage trace comparing the normal constant AP with the increased and alternating APs with HCQ. Online Video 3 shows the difference in wave propagation by periodic stimulation between control and HCQ. Without HCQ, continuous pacing is possible even at very short CL of 140 ms with propagation still smooth, whereas with HCQ at even relatively longer CL of 380 ms, large heterogeneities in wave propagation are present. These dynamic heterogeneities promote arrhythmia initiation at CL <250 ms and in some cases complex propagation at CL <350 ms (Online Video 4).



Fatal arrhythmias: Another reason why doctors remain cautious about chloroquine/hydroxychloroquine for treating COVID-19

Although ectopic beats were not observed in rabbit hearts, ectopic beats were seen in GP hearts. Figure 1B and Online Video 5 show 2 ectopic beats generated after 3 stimulations in GP heart. Online Video 6 shows an episode of VT initiation in rabbit heart.

Because hypokalemia has been shown to be prevalent in COVID-19 patients, we tested the effect of HCQ under hypokalemia by switching the Tyrode solution in the GP experiment from normal to lower potassium (from 4 to 2.5 mmol/L) and lower magnesium (from 1 to 0.8 mmol/L). We perfused with hypokalemia Tyrode solution twice, with normal Tyrode solution (washout) in between. In both instances, fibrillation occurred spontaneously under the hypokalemic conditions (the heart was defibrillated when back in normal Tyrode solution), highlighting a possible higher risk of HCQ in patients with hypokalemia and thus the importance of monitoring and treating low potassium levels because they can increase the probability of arrhythmic events.19



Fatal arrhythmias: Another reason why doctors remain cautious about chloroquine/hydroxychloroquine for treating COVID-19

Discussion

These experiments show that as QT interval/APD increased with HCQ, arrhythmias could be induced at CLs closer to physiological heart rates, thus demonstrating the potential dangers of HCQ. In particular, immediate arrhythmia initiation was observed when hypokalemia was induced with HCQ, but not only in the hypokalemia case. This is important because of particular concern about hypokalemia in COVID-19 disease.21 Hypokalemia seems to be present in almost all COVID-19 patients,22 likely due to the interaction of SARS-CoV2 with the renin-angiotensin system (RAS), binding to angiotensin I converting enzyme 2 receptor of RAS and causing prevalent hypokalemia.

With HCQ alone, spatial alternans was observed at longer CLs, including those of normal sinus heart rates without the drug. Although HCQ produces bradycardia that, in principle, may not allow these CLs to be reachable, sympathetic surges can easily lead to sudden increased heart rates that induce pause/bradycardia arrhythmias such as TdP. Furthermore, the increased APD heterogeneity induced by HCQ at bradycardic CLs also showed dramatic anisotropic conduction slowing even before alternans developed. This phenomenon can be seen clearly in Online Video 3. At CL of 380 ms, a marked slowing in conduction velocity is observed in a region of the heart that produces a nonsmooth propagation compared to the case without HCQ at a very short CL of 140 ms. Thus, HCQ induced complex repolarization heterogeneities and a substrate for arrhythmias such as TdP.

Study limitations

The most important limitation is the low number of experiments for rabbit and GP, and we are aware that our results are more descriptive because statistical analysis cannot be performed. However, because our results in normal rabbit and GP hearts compare well with those of other studies in both species,23 ,24 and in general when healthy these hearts do not go into fibrillation when slowly paced down (until conduction block) but did so under HCQ, we believe that our study has provided some mechanistic insights. Nevertheless, this study needs to be extended to allow for complete statistical analysis that can solidify the proarrhythmic mechanisms of HCQ as well as the possibility of any differences related to sex, given that female sex is known to be an independent risk factor for developing TdP.

Another limitation of our study is the use of animal models with small hearts and electrophysiologies different from human hearts. A major problem with using small hearts is the difficulty in inducing reentrant tachycardias due to the size mismatch between ventricles and reentrant wavelength. Therefore, a negative result in small hearts is not reassuring for the absence of arrhythmogenicity in humans. However, we observed polymorphic VT with characteristics similar to clinical TdP, which is a finding of concern because typically induction of TdP is easier in humans than in these models.

The most important ion channels in the genesis of TdP are the delayed rectifier potassium channels, especially IKr. Both rabbit and GP ventricles have dofetilide-sensitive IKr and are prone to exhibiting repolarization alternans as a result of potassium channel blockade.25 Therefore, these species are commonly used to test for drug-induced repolarization abnormalities28 that could affect humans.

Conclusion

A challenging aspect of COVID-19 treatment with respect to cardiac complications is the use of unusual drug combinations, such as HCQ with antibiotics such as azithromycin, which before the COVID-19 pandemic were rarely used together. The risk profiles of individual drugs with regard to QT prolongation have been characterized, but data on the combinations of those drugs are lacking. Only a few studies, just becoming available,30 indicate prolongation of LQTS. Although current trials have seldom required discontinuation of therapy, it remains imperative to investigate the safety of potentially effective drugs such as CQ/HCQ and their combinations before their widespread clinical use as treatment against SARS-CoV-2.

Based on the limited and contradictory evidence reported to date, the efficacy of CQ/HCQ against COVID-19 is questionable at best, and the safety is unclear due to the propensity for fatal arrhythmia. Until the results of large, well-designed clinical trials (such as the WHO Solidarity Trial) are available, clinicians have compelling reasons not to treat COVID-19 patients with CQ/HCQ.


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