Cardiotoxicity of chloroquine and hydroxychloroquine through mitochondrial pathway.

BACKGROUND: Medical therapies can cause cardiotoxicity. Chloroquine (QC) and hydroxychloroquine (HQC) are drugs used in the treatment of malaria and skin and rheumatic disorders. These drugs were considered to help treatment of coronavirus disease (COVID-19) in 2019. Despite the low cost and availability of QC and HQC, reports indicate that this class of drugs can cause cardiotoxicity. The mechanism of this event is not well known, but evidence shows that QC and HQC can cause cardiotoxicity by affecting mitochondria and lysosomes. METHODS: Therefore, our study was designed to investigate the effects of QC and HQC on heart mitochondria. In order to achieve this aim, mitochondrial function, reactive oxygen species (ROS) level, mitochondrial membrane disruption, and cytochrome c release in heart mitochondria were evaluated. Statistical significance was determined using the one-way and two-way analysis of variance (ANOVA) followed by post hoc Tukey to evaluate mitochondrial succinate dehydrogenase (SDH) activity and cytochrome c release, and Bonferroni test to evaluate the ROS level, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling. RESULTS: Based on ANOVA analysis (one-way), the results of mitochondrial SDH activity showed that the IC50 concentration for CQ is 20 µM and for HCQ is 50 µM. Based on two-way ANOVA analysis, the highest effect of CQ and HCQ on the generation of ROS, collapse in the MMP, and mitochondrial swelling were observed at 40 µM and 100 µM concentrations, respectively (p < 0.05). Also, the highest effect of these two drugs has been observed in 60 min (p < 0.05). The statistical results showed that compared to CQ, HCQ is able to cause the release of cytochrome c from mitochondria in all applied concentrations (p < 0.05). CONCLUSIONS: The results suggest that QC and HQC can cause cardiotoxicity which can lead to heart disorders through oxidative stress and disfunction of heart mitochondria.

Review of Hydroxychloroquine Cardiotoxicity: Lessons From the COVID-19 Pandemic.

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has popularized the usage of hydroxychloroquine and chloroquine (HCQ/CQ) as treatments for COVID-19. Previously used as anti-malarial and now commonly used in rheumatologic conditions, preliminary in vitro studies have demonstrated these medications also have anti-viral properties. Retinopathy and neuromyopathy are well recognized complications of using these treatments; however, cardiotoxicity is under-recognized. This review will discuss the implications and cardiotoxicity of HCQ/CQ, their mechanisms of action, and their utility in COVID-19. RECENT FINDINGS: Early clinical trials demonstrated a modest benefit of HCQ in COVID-19, causing a push for the usage of it. However, further large multi-center randomized control centers, demonstrated no benefit, and even a trend towards worse outcomes. The predominant cardiac complication observed with HCQ in COVID-19 was cardiac arrhythmias and prolonging of the QT interval. However, with chronic usage of HCQ/CQ, the development of heart failure (HF) and cardiomyopathy (CM) can occur. Although, most adverse cardiac events related to HCQ/CQ usage in COVID-19 were secondary to conduction disorders given the short duration of treatment, HCQ/CQ can cause CM and HF, with chronic usage. Given the insufficient evidence, HCQ/CQ usage in COVID-19 is not routinely recommended, especially with novel therapies now being developed and used. Additionally, usage of HCQ/CQ should prompt initial cardiac evaluation with ECG, and yearly monitoring, with consideration for advanced imaging if clinically warranted. The diagnosis of HCQ/CQ cardiomyopathy is important, as prompt cessation can allow for recovery when these changes are still reversible.

Investigating and Resolving Cardiotoxicity Induced by COVID-19 Treatments using Human Pluripotent Stem Cell-Derived Cardiomyocytes and Engineered Heart Tissues.

Coronavirus disease 2019 continues to spread worldwide. Given the urgent need for effective treatments, many clinical trials are ongoing through repurposing approved drugs. However, clinical data regarding the cardiotoxicity of these drugs are limited. Human pluripotent stem cell-derived cardiomyocytes (hCMs) represent a powerful tool for assessing drug-induced cardiotoxicity. Here, by using hCMs, it is demonstrated that four antiviral drugs, namely, apilimod, remdesivir, ritonavir, and lopinavir, exhibit cardiotoxicity in terms of inducing cell death, sarcomere disarray, and dysregulation of calcium handling and contraction, at clinically relevant concentrations. Human engineered heart tissue (hEHT) model is used to further evaluate the cardiotoxic effects of these drugs and it is found that they weaken hEHT contractile function. RNA-seq analysis reveals that the expression of genes that regulate cardiomyocyte function, such as sarcomere organization (TNNT2, MYH6) and ion homeostasis (ATP2A2, HCN4), is significantly altered after drug treatments. Using high-throughput screening of approved drugs, it is found that ceftiofur hydrochloride, astaxanthin, and quetiapine fumarate can ameliorate the cardiotoxicity of remdesivir, with astaxanthin being the most prominent one. These results warrant caution and careful monitoring when prescribing these therapies in patients and provide drug candidates to limit remdesivir-induced cardiotoxicity.

Role of cardiac MRI in the diagnosis of immune checkpoint inhibitor-associated myocarditis.

Immune checkpoint inhibitor (ICI)-induced cardiotoxicity is a rare immune-related adverse event (irAE) characterized by a high mortality rate. From a pathological point of view, this condition can result from a series of causes, including binding of ICIs to target molecules on nonlymphocytic cells, cross-reaction of T lymphocytes against tumor antigens with off-target tissues, generation of autoantibodies and production of proinflammatory cytokines. The diagnosis of ICI-induced cardiotoxicity can be challenging, and cardiac magnetic resonance (CMR) represents the diagnostic tool of choice in clinically stable patients with suspected myocarditis. CMR is gaining a central role in diagnosis and monitoring of cardiovascular damage in cancer patients, and it is entering international cardiology and oncology guidelines. In this narrative review, we summarized the clinical aspects of ICI-associated myocarditis, highlighting its radiological aspects and proposing a novel algorithm for the use of CMR.

The new HFA/ICOS risk assessment tool to identify patients with chronic myeloid leukaemia at high risk of cardiotoxicity.

AIMS: Tyrosine kinase inhibitors (TKIs) used to treat chronic myeloid leukaemia (CML) can cause cardiovascular adverse events. So far, the Systematic Coronary Risk Evaluation (SCORE) charts of the European Society of Cardiology (ESC) have been used to identify cancer patients at increased cardiovascular risk. The primary aim of our study was to evaluate the usefulness of the new cardiovascular risk assessment model proposed by the Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the ESC in collaboration with the International Cardio-Oncology Society (ICOS) to stratify the cardiovascular risk in CML patients, compared with SCORE risk charts. The secondary aim was to establish the incidence of adverse arterial events (AEs) in patients with CML treated with TKIs and the influence of preventive treatment with aspirin. METHODS AND RESULTS: A retrospective single-centre observational study was carried out on 58 patients (32 men and 26 women; mean age ± SD: 59 ± 15 years) with CML treated with TKIs for a median period of 43 ± 31 months. Cardiological evaluation was performed and cardiovascular risk was estimated with SCORE risk charts and with the new risk assessment tool proposed by HFA/ICOS. AEs were recorded. According to SCORE charts and the new HFA/ICOS risk stratification tool, respectively, 46% (Group A1) and 60% (Group A2) of patients were at high-very high risk, and 54% (Group B1) and 40% (Group B2) at low-moderate risk. AEs were significantly more frequent in Group A1 than Group B1 (P value < 0.01) when considered overall; they were significantly more frequent in Group A2 than Group B2 either overall or considered individually. HFA/ICOS risk stratification tool was significantly more sensitive than SCORE (P < 0.01) in identifying patients at higher risk of cardiovascular toxicity. In addition, we did not find AEs in patients pretreated with aspirin. CONCLUSIONS: The new HFA/ICOS risk stratification model allows a more tailored cardiovascular risk stratification in patients with CML and it is more sensitive than SCORE charts.

Interleukin-1 blocking agents as promising strategy for prevention of anticancer drug-induced cardiotoxicities: possible implications in cancer patients with COVID-19.

Cytokines in cardiac tissue plays a key role in progression of cardiometabolic diseases and cardiotoxicity induced by several anticancer drugs. Interleukin-1ß is one on the most studied regulator of cancer progression, survival and resistance to anticancer treatments. Recent findings indicate that interleukin1-ß exacerbates myocardial damages in cancer patients treated with chemotherapies and immune check-point inhibitors. Interleukin1-ß blocking agent canakinumab reduces major adverse cardiovascular events and cardiovascular death in recent cardiovascular trials. We focalized on the main biological functions of interleukin1-ß in cancer and cardiovascular diseases, summarizing the main clinical evidence available to date in literature. Especially in the era of SARS-CoV-2 infection, associated to coagulopathies, myocarditis and heart failure, cancer patients have an increased risk of cardiovascular complications compared to general population, therefore, the pharmacological inhibition of interleukin1-ß should be discussed and considered.

American College of Rheumatology White Paper on Antimalarial Cardiac Toxicity.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are well-established medications used in treating systemic lupus erythematosus and rheumatoid arthritis, as well as skin conditions such as cutaneous lupus erythematosus. In rare cases, arrhythmias and conduction system abnormalities, as well as cardiomyopathy, have been reported in association with HCQ/CQ use. Recently, however, the corrected QT interval (QTc)-prolonging potential of these medications, and risk of torsade de pointes (TdP) in particular, have been highlighted in the setting of their experimental use for COVID-19 infection. This report was undertaken to summarize the current understanding of HCQ/CQ cardiac toxicity, describe QTc prolongation and TdP risks, and discuss areas of priority for future research. A working group of experts across rheumatology, cardiology, and dermatology performed a nonsystematic literature review and offered a consensus-based expert opinion. Current data clearly indicate that HCQ and CQ are invaluable medications in the management of rheumatic and dermatologic diseases, but they are associated with QTc prolongation by directly affecting cardiac repolarization. Prescribing clinicians should be cognizant of this small effect, especially in patients taking additional medications that prolong the QTc interval. Long-term use of HCQ/CQ may lead to a cardiomyopathy associated with arrhythmias and heart failure. Risk and benefit assessment should be considered prior to initiation of any medication, and both initial and ongoing risk-benefit assessments are important with regard to prescription of HCQ/CQ. While cardiac toxicity related to HCQ/CQ treatment of rheumatic diseases is rarely reported, it can be fatal. Awareness of the potential adverse cardiac effects of HCQ and CQ can increase the safe use of these medications. There is a clear need for additional research to allow better understanding of the cardiovascular risk and safety profile of these therapies used in the management of rheumatic and cutaneous diseases.

Cardiotoxicity of Immune Checkpoint Inhibitors.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) have improved the survival of several cancers. However, they may cause a wide range of immune-related adverse events (irAEs). While most irAEs are manageable with temporary cessation of ICI and immunosuppression, cardiovascular toxicity can be associated with high rates of morbidity and mortality. As ICIs evolve to include high-risk patients with preexisting cardiovascular risk factors and disease, the risk and relevance of ICI-associated cardiotoxicity may be even higher. RECENT FINDINGS: Several cardiovascular toxicities such as myocarditis, stress cardiomyopathy, and pericardial disease have been reported in association with ICIs. Recent findings also suggest an increased risk of atherosclerosis with ICI use. ICI-associated myocarditis usually occurs early after initiation and can be fulminant. A high index of suspicion is required for timely diagnosis. Prompt treatment with high-dose corticosteroids is shown to improve outcomes. Although the overall incidence is rare, ICI cardiotoxicity, particularly myocarditis, is associated with significant morbidity and mortality, making it a major therapy-limiting adverse event. Early recognition and prompt treatment with the cessation of ICI therapy and initiation of high-dose corticosteroids are crucial to improve outcomes. Cardio-oncologists will need to play an important role not just in the management of acute cardiotoxicity but also to reduce the risk of long-term sequelae.

Hydroxychloroquine in the post-COVID-19 era: will this pandemic upset decades of clinical practice?

In the early stage of the COVID-19 pandemic, Belgian health authorities endorsed the interim guidelines for the treatment of COVID-19 pneumonia: hydroxychloroquine (HCQ) recommended for treatment of hospitalized patients with moderate to severe disease. As a growing number of patients were admitted, inevitably, our internal medicine team questioned the efficacy and safety of HCQ, especially with regard to cardiac side effects. In parallel with our concerns, data regarding the safety and efficacy of HCQ were published, with discordant results and debate in the medical community. Media coverage of the possible risks and benefits of HCQ use in COVID-19 also caused confusion amongst the public. In this Perspectives in Rheumatology article, we review the use and safety of HCQ in autoimmune disease and its putative efficacy and toxicity in COVID-19. Finally, we share our concern about the future of this widely used and inexpensive drug after the COVID-19 pandemic has passed.

Protective effect of Rosuvastatin on Azithromycin induced cardiotoxicity in a rat model.

AIMS: Azithromycin is widely used broad spectrum antibiotic recently used in treatment protocol of COVID-19 for its antiviral and immunomodulatory effects combined with Hydroxychloroquine or alone. Rat models showed that Azithromycin produces oxidative stress, inflammation, and apoptosis of myocardial tissue. Rosuvastatin, a synthetic statin, can attenuate myocardial ischemia with antioxidant and antiapoptotic effects. This study aims to evaluate the probable protective effect of Rosuvastatin against Azithromycin induced cardiotoxicity. MAIN METHOD: Twenty adult male albino rats were divided randomly into four groups, five rats each control, Azithromycin, Rosuvastatin, and Azithromycin +Rosuvastatin groups. Azithromycin 30 mg/kg/day and Rosuvastatin 2 mg/kg/day were administrated for two weeks by an intragastric tube. Twenty-four hours after the last dose, rats were anesthetized and the following measures were carried out; Electrocardiogram, Blood samples for Biochemical analysis of lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). The animals sacrificed, hearts excised, apical part processed for H&E, immunohistochemical staining, and examined by light microscope. The remaining parts of the heart were collected for assessment of Malondialdehyde (MDA) and Reduced Glutathione (GSH). KEY FINDINGS: The results revealed that Rosuvastatin significantly ameliorates ECG changes, biochemical, and Oxidative stress markers alterations of Azithromycin. Histological evaluation from Azithromycin group showed marked areas of degeneration, myofibers disorganization, inflammatory infiltrate, and hemorrhage. Immunohistochemical evaluation showed significant increase in both Caspase 3 and Tumor necrosis factor (TNF) immune stain. Rosuvastatin treated group showed restoration of the cardiac muscle fibers in H&E and Immunohistochemical results. SIGNIFICANCE: We concluded that Rosuvastatin significantly ameliorates the toxic changes of Azithromycin on the heart.

Cardiotoxicity induced by the combination therapy of chloroquine and azithromycin in human embryonic stem cell-derived cardiomyocytes.

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].

Cardiac arrest and drug-related cardiac toxicity in the Covid-19 era. Epidemiology, pathophysiology and management.

SARS-CoV-2 (Covid-19) infection has recently become a worldwide challenge with dramatic global economic and health consequences. As the pandemic is still spreading, new data concerning Covid-19 complications and related mechanisms become increasingly available. Accumulating data suggest that the incidence of cardiac arrest and its outcome are adversely affected during the Covid-19 period. This may be further exacerbated by drug-related cardiac toxicity of Covid-19 treatment regimens. Elucidating the underlying mechanisms that lead to Covid-19 associated cardiac arrest is imperative, not only in order to improve its effective management but also to maximize preventive measures. Herein we discuss available epidemiological data on cardiac arrest during the Covid-19 pandemic as well as possible associated causes and pathophysiological mechanisms and highlight gaps in evidence warranting further investigation. The risk of transmission during cardiopulmonary resuscitation (CPR) is also discussed in this review. Finally, we summarize currently recommended guidelines on CPR for Covid-19 patients including CPR in patients with cardiac arrest due to suspected drug-related cardiac toxicity in an effort to underscore the most important common points and discuss discrepancies proposed by established international societies.

Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019.

Hydroxychloroquine, initially used as an antimalarial, is used as an immunomodulatory and anti-inflammatory agent for the management of autoimmune and rheumatic diseases such as systemic lupus erythematosus. Lately, there has been interest in its potential efficacy against severe acute respiratory syndrome coronavirus 2, with several speculated mechanisms. The purpose of this review is to elaborate on the mechanisms surrounding hydroxychloroquine. The review is an in-depth analysis of the antimalarial, immunomodulatory, and antiviral mechanisms of hydroxychloroquine, with detailed and novel pictorial explanations. The mechanisms of hydroxychloroquine are related to potential cardiotoxic manifestations and demonstrate potential adverse effects when used for coronavirus disease 2019 (COVID-19). Finally, current literature associated with hydroxychloroquine and COVID-19 has been analyzed to interrelate the mechanisms, adverse effects, and use of hydroxychloroquine in the current pandemic. Currently, there is insufficient evidence about the efficacy and safety of hydroxychloroquine in COVID-19. KEY MESSAGES HCQ, initially an antimalarial agent, is used as an immunomodulatory agent for managing several autoimmune diseases, for which its efficacy is linked to inhibiting lysosomal antigen processing, MHC-II antigen presentation, and TLR functions. HCQ is generally well-tolerated although severe life-threatening adverse effects including cardiomyopathy and conduction defects have been reported. HCQ use in COVID-19 should be discouraged outside clinical trials under strict medical supervision.

Insights on the Evidence of Cardiotoxicity of Hydroxychloroquine Prior and During COVID-19 Epidemic.

The recent empirical use of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19) revived the interest in its cardiac toxicity, increasingly sidelined over time. We aimed to assess and compare the profile of cardiac adverse drug reactions (CADRs) associated with HCQ before and during COVID-19. We performed a retrospective comparative observational study using the French Pharmacovigilance network database between 1985 and May 2020 to assess all postmarketing CADRs associated with HCQ notified before COVID-19 in its approved indications for lupus and rheumatoid arthritis (preCOV), and those concerning its empirical use in COVID-19 (COV). Eighty-five CADR in preCOV were compared with 141 CADRs in COV. The most common CADR of preCOV were cardiomyopathies (42.4%) and conduction disorders (28.2%), both statistically more frequent than in COV (P < 0.001). COV notifications significantly highlighted repolarization and ventricular rhythm disorders (78.0%, P < 0.001) as well as sinus bradycardias (14.9%, P = 0.01) as compared with preCOV. Estimated incidence of CADR was significantly higher among patients exposed to off-label use of HCQ in COVID-19 (2.9%) than before COVID-19 in its approved indications (0.01%, P < 0.001). The use of HCQ in COVID-19 sheds a new light on the spectrum of its cardiac toxicity. This fosters the value of a closer monitoring of all patients treated with HCQ, regardless of its indication, and the importance of an update of its summary of product characteristics.

Safety of hydroxychloroquine in COVID-19 and other diseases: a systematic review and meta-analysis of 53 randomized trials.

INTRODUCTION: Many concerns still exist regarding the safety of hydroxychloroquine (HCQ) in the treatment of Coronavirus Disease 2019 (COVID-19). OBJECTIVES: The purpose of this study was to evaluate the safety of HCQ in the treatment of COVID-19 and other diseases by performing a systematic review and meta-analysis. METHODS: Randomized controlled trials (RCTs) reporting the safety of HCQ in PubMed, Embase, and Cochrane Library were retrieved starting from the establishment of the database till June 5, 2020. Literature screening, data extraction, and assessment of risk bias were performed independently by two reviewers. RESULTS: We identified 53 eligible studies involving 5496 patients. The meta-analysis indicated that the risk of adverse effects (AEs) in the HCQ group was significantly increased compared with that in the control group (RD 0.05, 95%CI, 0.02 to 0.07, P = 0.0002), and the difference was also statistically significant in the COVID-19 subgroup (RD 0.15, 95%CI, 0.07 to 0.23, P = 0.0002) as well as in the subgroup for other diseases (RD 0.03, 95%CI, 0.01 to 0.04, P = 0.003). CONCLUSIONS: HCQ is associated with a high total risk of AEs compared with the placebo or no intervention in the overall population. Given the small number of COVID-19 participants included, we should be cautious regarding the conclusion stating that HCQ is linked with an increase incidence of AEs in patients with COVID-19, which we hope to confirm in the future through well-designed and larger sample size studies.

The Cardiovascular Effects of Treatment with Hydroxychloroquine and Azithromycin.

Hydroxychloroquine combined with azithromycin has been investigated for activity against coronavirus disease 2019 (COVID-19), but concerns about adverse cardiovascular (CV) effects have been raised. This study evaluated claims data to determine if risks for CV events were increased with hydroxychloroquine alone or combined with azithromycin. We identified data from 43,752 enrollees that qualified for analysis. The number of CV events increased by 25 (95% confidence interval [CI]: 8, 42, p=0.005) per 1000 people per year of treatment with hydroxychloroquine alone compared with pretreatment levels and by 201 (95% CI: 145, 256, p<0.001) events per 1000 people per year when individuals took hydroxychloroquine and azithromycin. These rates translate to an additional 0.34 (95% CI: 0.11, 0.58) CV events per 1000 patients placed on a 5-day treatment with hydroxychloroquine monotherapy and 2.75 (95% CI: 1.99, 3.51) per 1000 patients on a 5-day treatment with both hydroxychloroquine and azithromycin. The rate of adverse events increased with age following exposure to hydroxychloroquine alone and combined with azithromycin. For females aged 60 to 79 years prescribed hydroxychloroquine, the rate of adverse CV events was 0.92 per 1000 patients on 5 days of therapy, but it increased to 4.78 per 1000 patients when azithromycin was added. The rate of adverse CV events did not differ significantly from zero for patients 60 years of age or younger. These data suggest that hydroxychloroquine with or without azithromycin is likely safe in individuals under 60 years of age if they do not have additional CV risks. However, the combination of hydroxychloroquine and azithromycin should be used with extreme caution in older patients.