Journal of the Practice of Cardiovascular Sciences

: 2021  |  Volume : 7  |  Issue : 2  |  Page : 97--107

COVID-19 and cardiovascular disease: Clinical implications of biochemical pathways

Shivani G Varmani1, Rimpy Kaur Chowhan2, Ishani Sharma3, Rajiv Narang4,  
1 Department of Biomedical Science, Bhaskaracharya College of Applied Sciences, Delhi, India
2 Department of Biomedical Science, Acharya Narendra Dev College, Delhi, India
3 Department of Microbiology, Bhaskaracharya College of Applied Sciences, University of Delhi, Delhi, India
4 Department of Cardiology, All India Institute of Medical Sciences, Delhi, India

Correspondence Address:
Shivani G Varmani
Department of Biomedical Science, Bhaskaracharya College of Applied Science, University of Delhi


Coronavirus disease of 2019 (COVID-19) is a viral pandemic which has taken away more than over 4 million lives all over the world as of July 9, 2021, with the USA, India, and Brazil being the most affected countries. Apart from the respiratory tract, the cardiovascular (CV) system is one of the important organ systems affected by this complex multisystem disease. Various studies have confirmed that COVID-19 predisposes an individual to increased risk of CV complications. In fact, hospitalized patients have been consistently reported to have modulated levels of biomarkers demonstrating coagulation and acute cardiac injury. Understanding of molecular mechanisms underlying CV involvement is strongly believed to be the foundation for developing strategies for early diagnosis and management of COVID-19-affected individuals. We review here various molecular mechanisms underlying CV involvement in COVID-19 and discuss several biochemical prognostic markers, as they have evidently revealed their importance in predicting severe prognosis such as mortality, mechanical ventilation, and ICU admission among severe acute respiratory syndrome coronavirus 2-infected patients with or without previous history of myocardial injury. The therapeutic strategies that could be employed to treat and manage CV manifestations in COVID-19-positive individuals are also discussed.

How to cite this article:
Varmani SG, Chowhan RK, Sharma I, Narang R. COVID-19 and cardiovascular disease: Clinical implications of biochemical pathways.J Pract Cardiovasc Sci 2021;7:97-107

How to cite this URL:
Varmani SG, Chowhan RK, Sharma I, Narang R. COVID-19 and cardiovascular disease: Clinical implications of biochemical pathways. J Pract Cardiovasc Sci [serial online] 2021 [cited 2023 Feb 3 ];7:97-107
Available from:

Full Text


In December 2019, the world witnessed the emergence of coronavirus disease of 2019 (COVID-19) disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in humans. It initially appeared as clusters of pneumonia-like cases in Wuhan, a city in the Hubei province of China,[1] and then massively spread to 220 countries across the globe infecting more than 186 million individuals as of July 9, 2021. Considering the severity of the situation, the World Health Organization escalated it from the level of a global health emergency to a pandemic in March 2020. SARS-CoV-2 virus is an enveloped positive-sense RNA virus belonging to the Betacoronavirus genus. It is the seventh known human coronavirus with about 79% and 50% similarity to SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV). It is believed that SARS-CoV-2 had a zoonotic transmission from bats to humans. This notion is corroborated by phylogenetic analysis that demonstrated SARS-CoV-2 to share 89% to 96% nucleotide homology with bat-derived SARS-like coronaviruses, namely bat-SL-CoVZXC21 and bat-SL-CoVZC45.[2] However, the absence of an intermediate host animal identification that transmitted the closest relative of SARS-CoV-2 (with more than 96% homology) to humans has sparked the possibility of lab leakage as the origin of coronavirus pandemic.[3] Investigations in this regard are ongoing.

In the past year and a half, the world has witnessed a rapid increase in COVID-19 transmission due to the emergence of novel variants with varying degrees of pathogenicity. Among these emerging variants, those identified to be of global concern include alpha (B.1.1.7), beta (B.1.351, B.1.351.2, and B.1.351.3), gamma (P. 1, P. 1.1, and P. 1.2), and delta (B.1.617) variants.[4] These variants have been reported to first appear and mostly affect the population in the United Kingdom, South Africa, Brazil, and India, respectively. However, it is the delta variant and its subtype delta plus (B.1.617.2) that is considered to be the most virulent with the highest infectivity, transmissibility, mortality rate, and tendency to escape from vaccines. In addition, there are several other variants that are being tracked by health organizations but have not posed to be a serious hazard that the wild-type SARS-CoV-2. These variants of interest are also labeled using the Greek alphabets, namely eta (B.1.525), iota (B.1.526), epsilon (B.1.427/B.1.429), zeta (P. 2), theta (P. 3, B.1.616), kappa (B.1.617.1), and lambda (C.37).

The genomic studies on alpha variant have revealed around 17 amino acid mutations, out of which 8 were found in the spike protein itself. The three mutations such as N501Y (reported to increase affinity of binding between spike protein-angiotensin-converting enzyme 2 [ACE2] receptor), deletion of 69–70 residue pair (reported to enable virus to be two times more infectious), and P681H (alters site of cleavage of spike protein before entering the host cell) are considered to be most significant for enhancing coronavirus pathogenicity.[4] Mutations in the spike protein region are appearing to be the major cause of enhanced virulence in other variants as well. The efforts to curb transmission and vaccinate the population require urgency as several new variants are emerging worldwide.

Although COVID-19 primarily emerged as an acute respiratory infectious disease, its significant manifestations in CV system have been well documented by now. It has been reported globally that COVID-19 patients with underlying CV disease or associated risk factors such as hypertension, diabetes, and thyroid have a higher risk of mortality.[5],[6] However, till date, the debate on how and exactly what all factors are involved in this viral infection and subsequent CV disease development is not settled. Neither, there has been any consolidated report reviewing all prognostic markers whose detection could prevent CV disease-associated deaths in COVID-19 patients via timely commemoration of a correct treatment plan.

The present review provides a comprehensive account of the molecular mechanisms underlying SARS-CoV-2 pathogenicity in CV system, biochemical prognostic markers, and their implications in COVID-19 patients. We have also discussed novel therapeutic strategies proposed to manage and combat CV manifestations in SARS-CoV-2-infected individuals.


A comprehensive literature exploration was carried out on various scientific literature databases including Medline/PubMed, Web of Science, and Google Scholar using several keywords: SARS-CoV-2, COVID-19, cardiovascular disease (CVD), myocarditis, heart failure, acute coronary syndrome, myocardial infarction, arrhythmia, embolism, coagulation, hypertension, antivirals, immunosuppressant, statins, anticoagulants, and COVID-19 drugs. All of these publications were scrutinized for their relevance to our theme of CV system and COVID-19, and the suitable case reports, systematic reviews, NIH/WHO guidelines, and original studies were used for preparing this review.

 Coronavirus Disease of 2019-Associated Cardiovascular Manifestations

COVID-19 was initially thought to primarily affect respiratory system, but with a rise in the number of infected individuals, its multiple physiological manifestations affecting various other organs including CV system, kidneys, brain, etc., have been reported. In fact, in certain individuals, cardiac manifestations have been seen as COVID-19 disease's first clinical presentation.[7] Ruan et al. have reported cardiac injury to contribute to 40% of deaths in COVID-19 patients.[8] In another study, more than 7% of admitted SARS-CoV-2 positive and 22% of critically ill patients were found to exhibit myocardial injury.[9] Another recent study done at Edinburgh University with more than 1200 patients (out of which 901 had no prior heart disease) from 69 countries has revealed abnormal changes in cardiac pumping in 55% of the patients, with around one in seven showing evidence of severe dysfunction.[10] The CV complications majorly observed in COVID-19 include acute myocardial injury evidenced by raised cardiac biomarkers, myocardial infarction, myocarditis, arrhythmia, thromboembolism, and even shock.[6],[11],[12] Wu et al., on the basis of a large cohort study with SARS-CoV-2-infected patients, have found 16.7% of patients to develop arrhythmia, 7.2% to develop acute cardiac injury, and 8.7% to exhibit shock and thromboembolism.[13] Another study has reported heart failure as one of the most commonly seen indications, with 49% incidence in COVID-19 patients who died.[14] The fatality rate of COVID-19 patients with underlying CVD (10.5%) is also found to be higher than other comorbidities including diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6%), and cancer (5.6%).[9],[15],[16]

 Molecular Mechanisms Underlying Severe Acute Respiratory Syndrome Coronavirus-2 Pathogenicity in Cardiovascular System

Renin–angiotensin–aldosterone system modulation

SARS-CoV-2 virus encodes as many as 29 different proteins, including a structural glycoprotein present on its surface, S glycoprotein, which plays an important role in viral attachment, entry, and disease pathogenesis [Figure 1]. S glycoprotein is a heterodimer with (a) S1 subunit that contains receptor binding domain and (b) S2 subunit that intercedes fusion between host cell and virus membranes.[13] The viral infection is initiated by binding of S1 subunit with the human ACE2 present on the host cell's surface. ACE2 is an important functional receptor protein involved in renin–angiotensin–aldosterone system (RAAS) signaling [Figure 2].[17] It is highly expressed in Type II alveolar cells of the lungs, intestinal epithelium, kidneys, heart myocytes, and vascular endothelium.[18] The greater pathogenicity of SARS-CoV-2 in contrast to its predecessors including common cold coronavirus, SARS, MERS, etc., is attributed majorly to substitutions in its ACE binding domain on S1 subunit and presence of 4 additional amino acid residues at S1 and S2 subunit's boundary.[13] While mutations at S1 account for stronger binding affinity to the ACE2 receptor, the insertions are responsible for creation of a furin cleavage site with close similarity to cleavage sites found in spike proteins of highly pathogenic avian influenza virus and Newcastle disease virus, and is believed to enhance viral virulence and pathogenicity.[17],[19] It appears that latter provides the transmembrane serine protease, TMPRSS2, the site to prime (or cleave) S glycoprotein at the S1/S2 boundary after the initial viral S1 and host ACE2 binding interaction. This leads to the release of S2 subunit which then mediates the fusion of virus and host cell membranes, and direct virus entry into the cell [Figure 1].[20] This novel cleavage site is also considered to be the reason for multi-organ effects of COVID-19.[17]{Figure 1}{Figure 2}

Interestingly, cardiomyocytes have been reported to express ACE2 at levels even higher than lungs, but TMPRSS2 expression is negligible, indicating an alternate route of infection in cardiomyocytes by SARS-CoV-2.[21] It is believed that the virus gains entry into the cardiomyocytes via the endocytic pathway, where viral and ACE2 complex is first translocated to endosomes followed by S protein priming via endosomal cysteine proteases (cathepsin L and cathepsin B), and subsequent viral release into the cytoplasm. This is supported by the fact that cathepsin L and B are expressed at extremely elevated levels in cardiomyocytes,[21] and viral RNAs are recurrently observed in hearts of nonsurviving COVID-19 patients.[22] Short-term use of cathepsin L or B protease inhibitors such as oxocarbazate and K11777 could be explored as an alternative therapeutic strategy to prevent viral infiltration in cardiomyocytes.[23]

Beyond being the virus's portal of entry, ACE2 is also a carboxypeptidase whose principal function is to convert angiotensin II into angiotensin (1–7) and maintain CV homeostasis by counteracting the excessive angiotensin II production by RAAS [Figure 2]. It prevents vasoconstriction, thrombosis, and excessive inflammation caused by angiotensin II and angiotensin Type-1 receptor interaction.[24] The importance of ACE2 expression in heart function can be gauged from the fact that ACE2 knockout mice develop severe left ventricular dysfunction.[25] Moreover, studies reporting downregulation of ACE2 expression, because of SARS-CoV-2 infection, suggests that its successor, SARS-CoV-2, upon binding with ACE2 receptor while infecting new cells would also reduce ACE2 availability, distress ACE signaling pathway, and impede cardiac homeostasis, subsequently resulting in severe CV complications in critically ill patients.[26]


Another plausible mechanism for myocardial injury in COVID-19 patients seems to be an imbalanced immunological response of the host to eradicate virus [Figure 3]. Prolonged activation of our immune system to reduce the pathogen burden is known to generate cytokine storm along with excessive production of complement proteins that mediate innocent-bystander lysis, thereby killing nearby host cells and tissues. A similar process occurs with SARS-CoV-2 infection, where elevated viral burden causes persistent inflammation in the pulmonary, cardiac, brain, kidney, and liver tissues.[13],[27] This inflammation is further aggravated by the mitochondrial damage caused by hypoxia due to respiratory dysfunction in critically ill COVID-19 patients.[28],[29] In cardiac cells, however, due to high cardiometabolic demand, this damage increases multifold, thereby triggering acute myocardial damage.[30] The pro-inflammatory cytokines released post induction of host immune response are also believed to activate coagulation pathway, leading to intravascular thrombi formation that can also dislodge and embolize to critical organs such as lungs, heart, and brain.[27] The initial autopsies in COVID-19-related deaths have also indicated microvascular thrombosis as the causative factor for the multi-organ failure, a major commonality among nonsurvivors.[31] Therefore, for COVID-19 management and prevention of downstream CV complication development, the current treatment plans focus on antivirals such as remdesivir and favipiravir that could limit viral growth.[32] It is to be noted, however, that these antivirals can effectively restrain SARS-CoV-2 spread within the host mostly when taken in the 1st week after the appearance of initial COVID-19 symptoms.[33],[34] In scenarios, where antiviral therapies fail or are not administered timely and one could see the active signs of excessive inflammation, the patients are often prescribed with steroidal anti-inflammatory and immunosuppressive drugs (methylprednisolone, dexamethasone, tocilizumab, etc.).[35] Unfortunately, despite our understanding of SARS-CoV-2 pathogenesis and availability of so many drugs, medical practitioners and researchers all over the world have been failing to prevent COVID-19-associated fatalities. This is majorly because of the spontaneity of our own immune system towards this virus and then our limitation to timely gauge the spread and development of extra-pulmonary complications. The need of the day, therefore, is to identify good prognostic markers and timely deliverance of treatments specifically aiming for nonpulmonary manifestations.{Figure 3}

 Biochemical Prognostic Markers

Electrocardiogram (ECG), one of the most convenient investigations for cardiac diagnosis, is restrictively used in patients with COVID-19 because of instrument unavailability for day-to-day analysis, and high infection risk to health-care workers. Hence, biochemical markers that can act as surrogate tools for detecting CVD complications in COVID-19 patients become even more important.[6] They happen to be especially useful if they could differentiate cardiac and pulmonary causes of COVID-19-associated respiratory distress in severely ill patients. This differentiation has diagnostic, therapeutic, and prognostic implications. Recent studies have shown successful employment of the following biochemicals as sensitive CVD prognostic markers in infected individuals with prominent respiratory involvement [Table 1].[6],[21],[36]{Table 1}


Troponins constitute a group of three types of proteins, namely troponin C, troponin T, and troponin I, found in cardiac and skeletal muscle fibers that regulate muscular contraction.[53] Whereas troponin C of skeletal and cardiac muscles is phenotypically similar, cardiac muscles have specific isoforms of troponin T and I. In a normal individual, these muscle proteins are found in undetectable amounts in the blood. However, damage of heart muscle cells leads to release of these troponins in blood such that the severity of the damage is directly proportional to troponin concentrations. Detection of CV system-specific troponin isoforms in blood has been used for the past 20 years to evaluate myocardial infarction or other forms of cardiac injury.[54] High sensitivity of the assay can be assessed by the fact that cardiac-specific isoforms of troponin T and I elevate in blood within 3 or 4 h post injury and stay prominently high for the next 10–14 days, thereby making it one of the best biomarker candidates for CVD prognosis. Interestingly, there has been a report, where troponin T has also been observed to elevate in non-CVD's, thereby cautioning against the usage of troponins as the only prognosis marker, especially in patients with non-CVD comorbidities.[55]

Several investigations have been carried out so far to assess the efficiency of blood troponin level measurement as a biochemical marker to diagnose the severity of CVD manifestations in COVID-19 patients and evaluate their likelihood of survival.[56] An independent study done in China has reported the presence of elevated cardiac troponin levels in approximately 12%–28% of SARS-CoV-2-positive patients.[47] They found that patients of older age or those with preexisting conditions such as diabetes, coronary artery disease, and hypertension had relatively higher cardiac troponin levels. Large number of such patients have been reported to either be admitted in intensive care units (ICUs) or have a higher mortality rate.[6],[14],[21]

Other studies have also corroborated the association of elevated troponin levels with high mortality and severity of CVD complications in COVID-19 patients. For instance, the meta-analysis of 341 patients from 4 studies revealed cardiac troponin I level to be much higher in critically ill patients than other SARS-CoV-2-positive patients (standardized mean difference of 25.6 ng/L; 95% confidence interval, 6.8–44.5 ng/L).[57] Taken together, it is clear that higher troponin levels can be taken as a warning sign during hospitalization and help in the prognosis of disease severity. The increase in troponin levels indicates both acute coronary syndrome postinfectious state and myocardial injury due to COVID-19-related pro-inflammatory and prothrombotic states. In one study, patients with troponin elevation above the sex-specific 99th percentile upper reference limit were identified to suffer from myocardial injury.[58] This threshold may differ among varied populations, especially in patients with comorbidities like renal disease or pulmonary complications, which show persistent troponin levels, thereby increasing the comparative nominal value. It must also be noted here that the mere presence of troponin in blood does not reflect an increased risk of cardiac disease as high-sensitivity assays usually detect it in minute concentration even in healthy individuals.[30]

In addition to troponins, cardiac enzymes including lactate dehydrogenase, creatine kinase-muscle/brain activity (CK-MB), myoglobin, and α-hydroxybutyrate dehydrogenase are also discharged into circulation upon myocardial necrosis and hence are often suggested to be used conjointly for better prognosis of myocardial injury. A recent study done with 2954 patients receiving treatment for COVID-19 has reported the abnormal level of such biomarkers to be highly correlated with mortality and ICU admission rate.[59] However, as per the American College of Cardiology Force (ACCF)/American Heart Association Task Force guidelines, only troponin I (because of its superior cardiospecificity, accuracy, and sensitivity) is recommended as a biomarker/gold standard for diagnosis of acute myocardial injury.[60] This is the reason that patients with negative CK-MB values and no visible ECG changes but elevated troponin levels are now reclassified as non-ST-segment elevation myocardial injury, rather than unstable angina or minor myocardial injury.[60] Therefore, measurement of serum levels of these biomarkers for CVD prognosis should be done cautiously while keeping in mind the clinical background and relative scientific literature.

B-type natriuretic peptide

Ventricular or brain or B-type natriuretic peptide (BNP), along with atrial natriuretic peptide (ANP) and C-type natriuretic peptides (NPs), belongs to the family of hormones that maintain hemodynamics and cardio-renal homeostasis and prevent cardioremodeling (i.e. alteration in size, mass, geometry, or function of heart due to injury). These peptides are synthesized as a prohormone, also referred to as N-terminal-pro NPs (NT-pro-NP), mainly by the cardiomyocytes (synthesize A and B-type NPs) and epithelial cells (synthesize C-type NPs). Collectively, both ANP and BNP decrease systemic vascular resistance and central venous pressure, leading to low blood pressure and abridged cardiac output. Their escalated levels are therefore believed to have a pathogenic causal link with major CV complications, such as left ventricular hypertrophy, heart failure, hypertension, and coronary artery disease. However, for diagnostic purposes, it is the blood levels of NT-pro-BNP and BNP that are preferred and not ANPs, as the latter tends to have the least stability in the blood.[41]

Comparative estimation of BNP and NT-pro-BNP has been identified as an efficient preliminary biochemical marker for assessing heart damage. It can also differentiate between pulmonary and cardiac cause respiratory distress seen in severe COVID-19 cases. One of the initial studies done in China has reported an association of escalated BNP levels with a high risk of cardiac damage and mortality (58.7%) among COVID-19 patients.[61] Another study demonstrating a positive correlation between blood NT-pro-NP levels with that of troponin T in COVID-19 patients justified monitoring of prohormone of BNP to assess myocardial injury.[7] Interestingly, the prohormone was found to constantly upsurge on serial measurements in nonsurvivors and remain constant in survivors, indicating its ability as a marker for prognosis of survivability in high-risk individuals. However, like any other biomarker prognosis, one must use this test outcome for screening purpose only and not as a concrete evidence for cardiac failure.

D-dimers and fibrin degradation product

Deep-vein thrombosis and pulmonary embolism are observed in more than 25% of critically ill COVID-19 patients.[12],[45] Furthermore, infected patients developing CVD complications have been observed to display right ventricular dysfunction most likely due to embolization or thrombotic occlusion in the pulmonary vasculature with resultant pulmonary artery hypertension.[62] A study on 153 patients in Wuhan has reported the presence of markers of hypercoagulation, such as D-dimers, fibrin degradation product, and fibrinogen along with low antithrombin and longer prothrombin time in more than 70% of the nonsurvivors.[12],[46] Measurement of hypercoagulability in COVID-19 patients via these markers could prove clinically useful for diagnostic and prognostic purposes.


Electrolyte imbalances have been frequently seen in several COVID-19 cases, the reason for which could be majorly attributed to hyperinflammation and gastrointestinal manifestations. However, COVID-related hypokalemia, i.e. increased urinary loss of K+, has been found to be directly associated with viral spike protein and host ACE2 receptor interaction and subsequent activation of the RAAS.[49] A cohort study done with 175 confirmed cases of COVID-19 has found approximately 85% of the severely and critically ill patients to be hypokalemic.[50] Potassium loss is also believed to be the major instigator of arrhythmias seen in COVID-19 patients with underlying heart conditions. Such hypokalemic patients need potassium supplementation to reduce the risk of arrhythmias. Patients generally respond well to potassium supplements as they recover[50] though hypokalemia may sometimes be refractory. Early detection and correction of potassium deficiency in hospitalized COVID-19 patients is important for prevention of CV complications. Moreover, since potassium levels share an inverse relationship with CV manifestations, the termination of urinary loss of K+ may also be used as a sensitive biomarker for tracking recovery in such patients.[51]

 Cardiovascular Drugs and Coronavirus Disease of 2019

Antithrombotic agents

Thromboembolism is considered as a major causative factor for multi-organ failure witnessed in critical COVID-19 cases. Pulmonary embolism can result in reduced cardiac output with shock leading to ischemic-hypoxic injury and resulting in multi-organ failure. Markers of hypercoagulation are usually increased in such patients. In this scenario, most clinicians administer anticoagulants such as low-molecular weight or unfractioned heparin to reduce thrombosis-associated complications.[62] While some centers counsel prophylactic anticoagulation for all positive patients, others advocate therapeutic anticoagulation only for high-risk patients.[63] This is likely related to concerns about bleeding risk of these agents, especially in higher dosages. Interactions of heparin with anti-inflammatory and antiviral agents being given for COVID-19 also have to be kept in mind.

While heparin is effective in prophylaxis, thrombolytic agents can lyse clots already formed in the blood vessels. Thrombolytic therapy for critically ill COVID-19 patients though has significant theoretical ground, there are very limited data and these agents can also cause serious bleeding events. Papamichalis in a case study has recently reported a 68-year old male diabetic patient with severe COVID-19 and enhanced hypercoagulation markers to show successful recovery with the usage of anticoagulants, recombinant tissue plasminogen activator, and tocilizumab, without any major toxic effects.[64] However, more studies are needed to establish the role of thrombolytic therapy in case of severe COVID-19.

Antiplatelet therapy

Induction of procoagulant state due to hyperinflammation in COVID-19 often coincides with increased platelet reactivity.[65] Platelet aggregation, however, is an important thrombotic event in the arterial tree system, which can lead to catastrophic consequences including acute myocardial infarction and brain stroke. Therefore, there is a strong theoretical basis for using antiplatelet agents as an adjunct treatment for thrombosis management in COVID-19 patients. Most of the randomized clinical trials investigating antiplatelet agents are principally testing aspirin, prasugrel, and clopidogrel in hospitalized or ambulatory patients.[66] Despite a strong theoretical pathophysiological basis, the trials completed up till now, after adjusting all compounding factors, haven't found any major benefit of antiplatelet drugs in mitigating thrombosis in COVID-19 patients with CV manifestations.[65] The results of other ongoing trials are expected to clarify the efficacy of antitplatelet therapy in improving patient outcomes.

Renin–angiotensin–aldostreone system inhibitors

RAAS is a hormonal cascade whose primary physiological product, angiotensin II is a potent vasoconstrictor. In healthy adults, ACE2 balances and modulates the effect of angiotensin II by converting it into angiotensin (1–7) [Figure 2]. The absence of ACE2 allows unchecked production of Angiotensin II, thereby causing vasoconstriction, and cytokine-induced and hyperinflammation-associated organ damage.[18] Inhibitors of RAAS including mineralocorticoid receptor antagonists, ACE-inhibitors, and angiotensin II receptor blockers (ARBs) are often used for hypertension, diabetes, myocardial infarction, and chronic kidney conditions.[2],[6],[67]

SARS-CoV-2 imitates its predecessor SARS-CoV such that after binding with ACE2 present on the host surface, it reduces the enzyme's functional efficiency.[2],[68],[69] This autonomously affects the regulatory role of ACE2 in counterbalancing the physiological effects of angiotensin II (synthesized by RAAS cascade). Deficiency of functional ACE2 in infected individuals enhances susceptibility to the harmful consequences of angiotensin II accumulation. This is believed to be partially responsible for the CV complications and lung injury seen in many COVID-19 patients.[5] The hypothesis, if true, indicates the use of RAAS inhibitors as an alternate treatment stratagem for alleviating severe COVID-19 complications including CV indications, especially hypertension, heart failure, and thromboembolism.

Since SARS-COV2 virus interacts closely with ACE-receptors, there could be a relation between the outcome of COVID-19 and intake of RAAS inhibitors. This is especially important since many patients with hypertension, diabetes, and CAD are on RAAS inhibitors. The relation between RAAS inhibitor usage and mortality from COVID-19 is still not clear. The previous study with viral pneumonia patients shows ARBs to be beneficial in reducing mortality rate and inflammatory response[70] and forms a strong theoretical basis for RAAS inhibitors as a potential COVID-19 drug candidate. The case series with more than 180 COVID-19 patients (out of which 27.8% patients had myocardial injury) presenting a slightly higher mortality rate in patients using ARBs (36.8%) than those without it (21.4%) conflicts with the usage of RAAS inhibitors as a safe therapeutic regimen.[11] Latter is hypothesized to be the result of increased availability of ACE2 for incoming viruses to interact with, thereby enhancing the risk of viral infection. Similar observations have been made earlier as well, where angiotensin II blockade in normotensive rat models was found to result in upregulation of ACE2 either via the modulatory effect of augmented angiotensin (1–7) or direct blockade of angiotensin II Type 1 receptors.[71] Such observations in fact suggest ARBs as a potential risk factor that could enhance COVID-19 disease severity. However, as per the scientific brief by WHO (based on 11 observational studies conducted with COVID-19 patients), there is not much certain evidence that patients on long-term use of ARBs or ACE inhibitors are not at an increased risk of COVID-19-associated harmful consequences.[72] The need of the hour is to conduct clinical trials to directly assess the effect of chronic usage of ARBs for CVD in COVID-19 patients. Nevertheless, the American College of Cardiology, for now, has advised against the indiscriminate withdrawal of these medications where they were preadministered to treat CVDs before SARS-CoV-2 infection. It is recommended that RAAS inhibitors should be continued by patients already taking them and these agents can be started by patients who have clear established indications for these agents, irrespective of COVID status.[73]


Statins are the drugs of choice in the vast majority of CVD patients to treat dyslipidemia by reducing low-density lipid-cholesterol levels. They are also often prescribed to patients with chronic kidney disease and diabetes for primary prevention against CVD development. Apart from being potent lipid biosynthesis inhibitors, statins exhibit pleotropic physiological effects including inhibition of TLR-MYD88-NF-kB pro-inflammatory pathway and amplification of ACE2 expression. These anti-inflammatory effects of statins have been proved useful for reducing disease severity among hospitalized patients during the 2009 H1N1 pandemic.[11],[74],[75] Beta-coronaviruses too are known to induce severe pro-inflammatory responses in the host by activating TLR-MYD88-NF-kB pathway. Earlier studies done with SARS-CoV-1 murine models have shown an increased chance of survival with the usage of statins.[76]

Fortuitously, apart from upregulating ACE2 activity and alleviating inflammation, statins can also corroborate against SARS-CoV-2 pathogenicity by countering endothelial dysfunction and subsequent deep-vein thrombosis, conditions commonly seen in critically ill COVID-19 patients.[63] In fact, during the Ebola outbreak in Africa, statins in conjugation with ARBs have been observed to work by preventing endothelial barrier damage.[77] The antithrombotic properties of statins are believed to be the consequence of reduced platelet aggregation, decreased tissue factor expression, and enhanced thrombomodulin expression on endothelial cells.[78]

Despite all these perceivable positive effects of statins for treating CV complications in COVID-19 patients, currently, their use is permitted only in patients who are already on statin therapy. This might be because of safety concerns over statin's side effects, such as myotoxicity and liver and kidney injury,[79] which might be compounded in COVID-19 patients consuming antiviral drugs. Latter being inhibitor of CYP3A4 hepatic isoenzyme have the potential to decrease the metabolism of CYP3A4-dependent statins and upsurge statin-associated toxicity.[80] Nevertheless, there is an urgent need to investigate the role of statins in preventing COVID-19-associated fatal CV manifestations.

Hydroxychloroquine and azithromycin

Some preliminary data suggested the antiviral effect of hydroxychloroquine (HCQ) against coronavirus.[81] Due to lack of any effective therapies for COVID-19, the high infectivity and mortality from the disease (as compared with common influenza illness), and low cost of HCQ, this agent was used by many for treatment of COVID-19 illness and its prophylaxis, even though large randomized controlled trials were lacking. HCQ also received emergency use authorization by the US Food and Drug Administration for this purpose.

However, subsequent randomized trials did not support the use of HCQ for COVID-19 and suggested an adverse outcome with this agent.[82],[83] Patients receiving HCQ in combination with azithromycin (Azt), which was given to prevent bacterial pulmonary infection, were found to be more often admitted to intensive care, require mechanical ventilation, exhibit ECG abnormalities, or undergo cardiac arrest than those who took HCQ or Azt alone.[84] This might be because both these drugs individually can cause QT segment prolongation and when given in conjugation, may cause additive or synergistic effect leading to life-threatening arrhythmias.[85] The HCQ arm of the solidarity trial (WHO global clinical trial aimed to identify the best COVID-19 treatment) has also been stopped (


COVID-19-associated research is a fast-evolving scientific field; hence, further advances, updates, and deeper insights are anticipated in near future. To maintain reliability, we have focussed on published reports and have not included preprints in our review. Moreover, most of the COVID-19-associated clinical data are from nonrandomized studies. Therefore, potential biases and confounding factors associated with observational data such as variations in health-care systems, diagnostic methods, and patient background must be taken into account by the clinician before deciding on an individual patient's therapeutic strategy.


COVID-19, the global pandemic which brought the entire world to a standstill, is now accepted to be not just a respiratory disorder but a complex multi-organ system disease with high risk for the elderly and individuals with comorbidities such as diabetes, hypertension, CVD, cancer, and immunodeficiency. A lot has been learned about the pathogenic mechanism of this disease, which has helped in determining new prognostic markers and treatment regimes. Reduction of functional ACE2, systemic inflammation, hypercoagulation, and drug toxicity has been found to be the major inducers of CV manifestations in COVID-19 patients. Prognostic and diagnostic biomarkers such as troponin, BNP, D-dimer, and urinary potassium enable early detection of high-risk status and complications in COVID-19 patients allowing more aggressive measures to be taken before multi-organ dysfunction becomes irreversible. Thus, development of tests that can rapidly determine the variation in levels of these prognostic markers would help in better allocation of the limited resources available at the moment.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239-42.
2Zhou P, Lou YX, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3.
3Maxmen A, Mallapaty S. The COVID lab-leak hypothesis: What scientists do and don't know. Nature 2021;594:313-5.
4World Health Organization. Tracking SARS-CoV-2 Variants. World Health Organization 2021;
5Singh AK, Gupta R, Misra A. Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes Metab Syndr Clin Res Rev 2020;14:283-7.
6Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17:259-60.
7Deng Q, Hu B, Zhang Y, Wang H, Zhou X, Hu W, et al. Suspected myocardial injury in patients with COVID-19: Evidence from front-line clinical observation in Wuhan, China. Int J Cardiol 2020;311:116-21.
8Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846-8.
9Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. COVID-19 and cardiovascular disease. Circulation 2020;141:1648-55.
10Dweck MR, Bularga A, Hahn RT, Bing R, Lee KK, Chapman AR, et al. Global evaluation of echocardiography in patients with COVID-19. Eur Heart J Cardiovasc Imaging 2020;21:949-58.
11Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:811-8.
12Klok FA, Kruip MJ, van der Meer NJ, Arbous MS, Gommers DA, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020;191:145-7.
13Wu L, O'Kane AM, Peng H, Bi Y, Motriuk-Smith D, Ren J. SARS-CoV-2 and cardiovascular complications: From molecular mechanisms to pharmaceutical management. Biochem Pharmacol 2020;178:114114.
14Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ 2020;368:m1091.
15Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239-42.
16Kendir C, van den Akker M, Vos R, Metsemakers J. Cardiovascular disease patients have increased risk for comorbidity: A cross-sectional study in the Netherlands. Eur J Gen Pract 2018;24:45-50.
17Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8.
18Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept 2012;2012:256294.
19Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nat Med 2020;26:450-2.
20Glowacka I, Bertram S, Muller MA, Allen P, Soilleux E, Pfefferle S, et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. Virol 2011;85:4122-34.
21Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: From basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020;17:543-58.
22Schaller T, Hirschbühl K, Burkhardt K, Braun G, Trepel M, Märkl B, et al. Postmortem examination of patients with COVID-19. JAMA 2020;323:2518-20.
23Liu T, Luo S, Libby P, Shi GP. Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients. Pharmacol Ther 2020;213:107587.
24Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Internal Med 2020;76:14-20.
25Patel VB, Bodiga S, Basu R, Das SK, Wang W, Wang Z, et al. Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: A critical role of the angiotensin II/AT1 receptor axis. Circ Res 2012;110:1322-35.
26Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, et al. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest 2009;39:618-25.
27Jose RJ, Manuel A. COVID-19 cytokine storm: The interplay between inflammation and coagulation. Lancet Respir Med 2020;8:e46-7.
28Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci 2020;250:117583.
29Gu X, Li X, An X, Yang S, Wu S, Yang X, et al. Elevated serum aspartate aminotransferase level identifies patients with coronavirus disease 2019 and predicts the length of hospital stay. Clin Lab Anal 2020;34:e23391.
30Bansal M. Cardiovascular disease and COVID-19. Diabetes Metab Syndr Clin Res Rev 2020;14:247-50.
31Wichmann D, Sperhake JP, Lütgehetmann M, Steurer S, Edler C, Heinemann A, et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med 2020;173:268-277.
32Kivrak A, Ulaş B, Kivrak H. A comparative analysis for anti-viral drugs: Their efficiency against SARS-CoV-2. Int Immunopharmacol 2021;90:107232.
33Wu J, Li W, Shi X, Chen Z, Jiang B, Liu J, et al. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID-19). J Intern Med 2020;288:128-38.
34Hung IF, Yuen KY. Early triple antiviral therapy for COVID-19 Authors' reply. Lancet 2020;396:1488.
35COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health 2021;
36Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020;26:1017-32.
37Aboughdir M, Kirwin T, Abdul Khader A, Wang B. Prognostic value of cardiovascular biomarkers in COVID-19: A review. Viruses 2020;12:527.
38Dawson D, Dominic P, Sheth A, Modi M. Prognostic value of cardiac biomarkers in COVID-19 infection: A meta-analysis. Res Sq 2020 ;
39Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
40Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020;5:802-10.
41Gao L, Jiang D, Wen XS, Cheng XC, Sun M, He B, et al. Prognostic value of NT-proBNP in patients with severe COVID-19. Respir Res 2020;21:83.
42Nakagawa Y, Nishikimi T, Kuwahara K. Atrial and brain natriuretic peptides: Hormones secreted from the heart. Peptides 2019;111:18-25.
43Han H, Xie L, Liu R, Yang J, Liu F, Wu K, et al. Analysis of heart injury laboratory parameters in 273 COVID-19 patients in one hospital in Wuhan, China. J Med Virol 2020;92:819-23.
44Mahajan K, Negi PC. The role of natriuretic peptide estimation in severe COVID-19. Monaldi Arch Chest Dis 2020;90:208-9.
45Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020;18:1421-4.
46Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LF, de Oliveira EP, Saldiva PH, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost 2020;18:1517-9.
47Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.
48Yao Y, Cao J, Wang Q, Shi Q, Liu K, Luo Z, et al. D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: A case control study. J Intensive Care 2020;8:49.
49Alfano G, Ferrari A, Fontana F, Perrone R, Mori G, Ascione E, et al. Hypokalemia in Patients with COVID-19. Clin Exp Nephrol 2021; 25(4):401-409.
50Chen D, Li X, Song Q, Hu C, Su F, Dai J, et al. Assessment of hypokalemia and clinical characteristics in patients with coronavirus disease 2019 in Wenzhou, China. JAMA Netw Open 2020;3:e2011122.
51Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol 2020;92:424-32.
52Moreno PO, Leon-Ramirez JM, Fuertes-Kenneally L, Perdiguero M, Andres M, Garcia-Navarro M, et al. Hypokalemia as a sensitive biomarker of disease severity and the requirement for invasive mechanical ventilation requirement in COVID-19 pneumonia: A case series of 306 Mediterranean patients. Int J Infect Dis 2020;100:449-54.
53Katrukha IA. Human cardiac troponin complex. Structure and functions. Biochemistry (Moscow) 2013;78:1447-65.
54Katus HA, Looser S, Hallermayer K, Remppis A, Scheffold T, Borgya A, et al. Development and in vitro characterization of a new immunoassay of cardiac troponin T. Clin Chem 1992;38:386-93.
55Welsh P, Preiss D, Hayward C, Shah AS, McAllister D, Briggs A, et al. Cardiac troponin T and troponin I in the general population. Circulation 2019;139:2754-64.
56Tersalvi G, Vicenzi M, Calabretta D, Biasco L, Pedrazzini G, Winterton D. Elevated troponin in patients with coronavirus disease 2019: Possible mechanisms. J Card Fail 2020;26:470-5.
57Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis. Prog Cardiovasc Dis 2020;63:390-1.
58Gore MO, Seliger SL, Defilippi CR, Nambi V, Christenson RH, Hashim IA, et al. Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay. Am Coll Cardiol 2014;63:1441-8.
59Li P, Wu W, Zhang T, Wang Z, Li J, Zhu M, et al. Implications of cardiac markers in risk-stratification and management for COVID-19 patients. Crit Care 2021;25:158.
60Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 130(25):2354-94.
61Ma M., Xu Y., Su Y., Ong SB, Hu X., Chai M, et al. Single-Cell Transcriptome Analysis Decipher New Potential Regulation Mechanism of ACE2 and NPs Signaling Among Heart Failure Patients Infected With SARS-CoV-2. Front Cardiovasc Med 2021; 8:628885.
62Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of coronavirus disease 2019. Crit Care Med 2020;48:1358-64.
63Lee KC, Sewa DW, Phua GC. Potential role of statins in COVID-19. Int J Infect Dis 2020;96:615-7.
64Papamichalis P, Papadogoulas A, Katsiafylloudis P, Skoura AL, Papamichalis M, Neou E, et al. Combination of thrombolytic and immunosuppressive therapy for coronavirus disease 2019: A case report. Int J Infect Dis 2020;97:90-3.
65Banik J, Mezera V, Köhler C, Schmidtmann M. Antiplatelet therapy in patients with Covid-19: A retrospective observational study. Thromb Updat 2021; 2:100026.
66Talasaz AH, Sadeghipour P, Kakavand H, Aghakouchakzadeh M, Kordzadeh-Kermani E, Van Tassell BW, et al. Recent randomized trials of antithrombotic therapy for patients with COVID-19: JACC state-of-the-art review. J Am Coll Cardiol 2021;77:1903-21.
67de Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, Aguilar M, García-Luque A, et al. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: A case-population study. Lancet 2020;395:1705-14.
68Hirano T, Murakami M. COVID-19: A new virus, but a familiar receptor and cytokine release syndrome. Immunity 2020;52:731-3.
69Dijkman R, Jebbink MF, Deijs M, Milewska A, Pyrc K, Buelow E, et al. Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63. Gen Virol 2012;93:1924-9.
70Henry C, Zaizafoun M, Stock E, Ghamande S, Arroliga AC, White HD. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc (Bayl Univ Med Cent) 2018;31:419-23.
71Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 2004;43:970-6.
72World Health Organization. COVID-19 and the use of angiotensin-converting enzyme inhibitors and receptor blockers: scientific brief, 7 May 2020. World Health Organization 2020;
73Solaru KW, Wright JT Jr. COVID-19 and Use of Drugs Targeting the Renin-Angiotensin-System-American College of Cardiology. Available from: [Last accessed on 2021 Apr 14].
74Fedson DS. Treating influenza with statins and other immunomodulatory agents. Antiviral Res 2013;99:417-35.
75Fedson DS. How will physicians respond to the next influenza pandemic? Clin Infect Dis 2014;58:233-7.
76Kuster GM, Pfister O, Burkard T, Zhou Q, Twerenbold R, Haaf P, et al. SARS-CoV2: Should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J 2020;41:1801-3.
77Fedson DS, Opal SM, Rordam OM. Hiding in plain sight: An approach to treating patients with severe COVID-19 infection. MBio 2020;11:e00398-20.
78Arslan F, Pasterkamp G, De Kleijn DP. Unraveling pleiotropic effects of statins: Bit by bit, a slow case with perspective. Circ Res 2008;103:334-6.
79Li J, Fan JG. Characteristics and mechanism of liver injury in 2019 coronavirus disease. J Clin Transl Hepatol 2020;8:13-7.
80Dashti-Khavidaki S, Khalili H. Considerations for statin therapy in patients with COVID-19. Pharmacotherapy 2020;40:484-6.
81Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6:16.
82Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med 2020;383:517-25.
83Saleh M, Gabriels J, Chang D, Soo Kim B, Mansoor A, Mahmood E, et al. Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection. Circ Arrhythm Electrophysiol 2020;13:e008662.
84Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020;323:2493-502.
85Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:1036-41.