Prophylactic (hydroxy)chloroquine in COVID-19: Potential relevance for cardiac arrhythmia risk

Abstract

of the Heart (ERN GUARDHEART; https://guardheart.ern-net.eu), and ‡ European Cardiac Arrhythmia Genetics Focus Group (ECGen) of the European Heart Rhythm Association (EHRA).(Hydroxy)chloroquine ((H)CQ) is being investigated as a treatment for COVID-19, but studies have so far demonstrated either no or a small benefit. However, these studies have been mostly performed in patients admitted to the hospital and hence likely already (severely) affected. Another suggested approach uses prophylactic (H)CQ treatment aimed at preventing either severe acute respiratory syndrome coronavirus 2 infection or the development of disease. A substantial number of clinical trials are planned or underway aimed at assessing the prophylactic benefit of (H)CQ. However, (H)CQ may lead to QT prolongation and potentially induce life-threatening arrhythmias. This may be of particular relevance to patients with preexisting cardiovascular disease and those taking other QTprolonging drugs. In addition, it is known that a certain percentage of the population carries genetic variant(s) that reduces their repolarization reserve, predisposing them to (H)CQ-induced QT prolongation, and this may be more relevant to female patients who already have a longer QT interval to start with. This review provides an overview of the current evidence on (H)CQ therapy in patients with COVID-19 and discusses different strategies for prophylactic (H)CQ therapy (ie, preinfection, postexposure, and postinfection). In particular, the potential cardiac effects, including QT prolongation and arrhythmias, will be addressed. Based on these insights, recommendations will be presented as to which preventive measures should be taken when giving (H)CQ prophylactically, including electrocardiographic monitoring.

Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments

“…Acidic endolysosomes are also important for autophagy, which is important for initiating innate immune responses and the degradation of viruses ( Dalpke and Helm, 2012 ; Choi et al, 2018a ). Accordingly, de-acidification of endolysosomes might hamper autophagy-mediated antiviral responses ( Kužnik et al, 2011 ) by deactivating RNA sensors ( Belizaire and Unanue, 2009 ; Kužnik et al, 2011 ; Kazi et al, 2013 ; Hussman, 2020 ; Offerhaus et al, 2020 ; Schrezenmeier and Dörner, 2020 ). Therefore, improving innate immune responses using synthetic RNAs, oligonucleotides, or small agonists of TLRs as well as type-I interferon treatment might improve clinical responses to CQ and HCQ ( Dalpke and Helm, 2012 ; Freund et al, 2019 ; Hussman, 2020 ; Lee and Shin, 2020 ).…”

COVID-19, hydroxychloroquine and sudden cardiac death: implications for clinical practice in patients with rheumatic diseases

“…In fact, a recent clinical trial conducted by Self et al concluded that HCQ did not improve clinical status at day 14 of COVID-19 patients; thus, its use was not supported [ 103 ]. However, several reasons may be associated with this trend, such as different in vitro and in vivo results and conduction of recent studies in critically ill patients and, hence, the administration of HCQ in the later stage of the disease; while, most of its mechanisms of inhibition of viral replication are effective during early disease [ 104 ]. Therefore, the data available for HCQ show both promising early therapeutic benefits and existing concerns.…”

“…HCQ is not only known to mildly block the human ether-à-go-go related gene (hERG) aka KCNH2 that codes for delayed rectifier potassium channel, but also the inward-rectifier potassium channel [ 111 ]. This interferes with ventricular repolarization, resulting in a continuous action potential which causes significant prolongation of QT interval [ 104 , 112 ]. Thus, HCQ is proarrhythmic, increasing the risk of torsades de pointes and other ventricular arrhythmias [ 66 ].…”

Nanomedicine Reformulation of Chloroquine and Hydroxychloroquine

“…While CQ and HCQ also have similar toxicity profiles and are equipotent, chloroquine is much more toxic (2-fold) [ 16 ]. Although short-term administration of either drug is generally well-tolerated, except in patients predisposed to arrhythmia, chronic dosing and high-dose regimens can cause severe side effects such as irreversible retinal toxicity [ 17 , 18 , 19 ]. CQ and HCQ have similar pharmacokinetic (PK) properties, including high volume of distribution and prolonged plasma half-lives between 40 and 50 days, which requires weeks of dosing to achieve steady-state therapeutic concentrations [ 20 ].…”