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Clinical Infection & Immunity

Review

Volume 5, Number 2, June 2020, pages 25-30

Disease, Drugs and Dilemma: A Review of Cardiovascular Implications of Novel COVID-19

The coronavirus disease 2019 (COVID-19) is caused by a new beta-coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 outbreak emerged from Wuhan City, Hubei Province of China, and it was reported on December 8, 2019. Having travelled across the globe, it is declared by the World Health Organization (WHO) as a pandemic disease on March 11, 2020 though not of international consequences. However sooner than later, COVID-19 has been recognized as one of the greatest threat to the mankind in the history with one possible exception when influenza epidemic alone plagued the world in 1918. According to WHO (accessed on May 10, 2020), COVID-19 already spread across 215 countries with 3,976,043 confirmed cases (including 277,708 deaths) and the number is still on the rise [1]. While this virus has strong predilection for the lungs, emerging reports showed that it does not spare the heart and may worsen the clinical outcome of already existing cardiovascular diseases (CVDs). COVID-19 may even initiate cascade of events leading to cardiovascular complications and sequelae.

COVID-19 is caused by a novel beta-coronavirus, which is a single-stranded positive-sense ribonucleic acid (RNA) virus of between 26 and 32 kb in length within the family Coronaviridae. This virus is the seventh coronavirus discovered to infect human. Considering genetic similarity to SARS coronavirus, the Coronavirus Study Group of the International Committee on Taxonomy of Viruses has proposed that this virus be designated SARS-CoV-2 [2]. Since more than 90% of its genome resembles that of a bat, the SARS-CoV-2 is now believed to be originated from bats. Like SARS and Middle East respiratory syndrome (MERS), it appears likely that SARS-CoV-2 moved from bats to an intermediate host and then to humans [3].

In order to understand the cardiovascular impact of COVID-19, it is pertinent to know the underlying basic pathophysiology of SARS-CoV-2 infection. This novel virus invades the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptors, following activation of the surface spike protein by transmembrane protease serine 2 (TMPRSS2), and then viral replication occurs via the RNA-dependent RNA polymerase [4]. Lungs appear to be the predominant portal of entry, as ACE2 is highly expressed in type II alveolar cells. Furthermore, ACE2 is also expressed in other organs like heart, vascular endothelium, intestinal epithelium, and kidney, thereby explaining the possible mechanism behind multiorgan dysfunction in COVID-19. Studies in animal models demonstrated that ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may up-regulate the expression of ACE2. Therefore, conceptual possibility of intensifying COVID-19 infection by these drugs was proposed, due to increased tissue level of the target molecule ACE2 for SARS-CoV-2 [5]. The exact mechanism through which COVID-19 affects the cardiovascular system is still not very clear. However, possible mechanisms of cardiovascular manifestations of COVID-19 have been proposed or explained (Fig. 1).

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Figure 1. Possible mechanisms of cardiovascular manifestations of COVID-19. COVID-19: coronavirus disease 2019.

The manifestation of COVID-19 may vary from person to person depending upon the presence of prior comorbidities. These symptoms are non-specific and can range from no symptoms (asymptomatic) to severe pneumonia and death. The main clinical features include fever, dry cough, breathlessness, fatigue, ageusia and anosmia. Flu-like symptoms such as sore throat, rhinorrhea, nasal congestion, myalgia, arthralgia and conjunctival congestion have also been reported [6].

The symptoms usually appear 5 - 6 days after infection, but the incubation period may range 1 - 14 days and as long as 24 days in certain cases. Shedding of the viral particles may persist till 34 days after the first symptoms [7]. Though the major route of spread of infection is via respiratory droplets and fomites, fecal-oral route has also been suggested as another possible route of viral transmission after having detected in the stool of some patients [8].

Fortunately, majority of the infected patients developed mild disease (80%) and recover. On the other hand, 13.8% develops severe disease (dyspnea, respiratory rate ≥ 30/min, blood oxygen saturation (SpO₂) ≤ 93%, partial pressure of oxygen (PaO₂)/fraction of inspired oxygen (FiO₂) ratio < 300, lung infiltrates > 50% of the lung field within 24 - 48 h) and 6.1% are critical (respiratory failure, septic shock, and/or multiple organ dysfunction/failure) [7]. The overall symptomatic secondary attack rate is 0.45% for close contacts and > 10% for household contacts [9].

Like other viral infections, cardiovascular complication such as myocarditis, acute coronary syndrome (ACS), exacerbation of heart failure and arrhythmia are not uncommon in COVID-19. In a recently published multinational observational study (involving 8,910 patients), the death rate of COVID-19 was 5.8%. This study also revealed that underlying CVD is independently associated with poor outcome. The factors found to be independently associated with an increased risk of death were the age older than 65 years (10.0% vs. 4.9%), coronary artery disease (CAD) (10.2% vs. 5.2%), heart failure (15.3% vs.5.6%), cardiac arrhythmia (11.5% vs. 5.6%), chronic obstructive pulmonary disease (14.2% vs. 5.6%), and current smoking (9.4% vs. 5.6%). In contrast, an immunosuppressed condition, the race or ethnic group, hyperlipidemia and diabetes mellitus (DM) were not associated with increased mortality [10]. One cohort study showed that the incidence of acute cardiac injury, shock and arrhythmia were 7.2%, 8.7% and 16.7%, respectively [11]. Activation of coagulation pathways, pro-inflammatory effects, and endothelial cell dysfunction are found responsible for higher incidences of such complications.

One multinational study showed that in-hospital death rate is significantly higher among those patients with pre-existing coronary arterial disease (10.2% vs. 5.2%) [10]. But the existing literature is limited regarding the pathogenesis of ACS in the setting of COVID-19. Like other viral infections, type 2 myocardial infarction (MI) may be responsible for most ACS, as viral infection intensifies the mismatch between myocardial oxygen supply and metabolic demand. Therefore, the usefulness of invasive strategy remains a challenge for an interventional cardiologist during the pandemic crisis. Also, tremendous release of inflammatory mediators (cytokine storm) in response to viral infection may destabilize the atherosclerotic plague and cause MI especially among those patients with pre-existing atherosclerotic disease [12]. Therefore, plague stabilizing agents like statins, anti-platelets, β-blockers and ACEIs remain the mainstay of treatment in this condition. In addition to cytokine storm, microvascular dysfunction due to direct local microvascular inflammation may also contribute to myocardial infarction with non-obstructive coronary arteries (MINOCA).

Myocardial injury comprises of various conditions causing cardiomyocyte necrosis. Clinically it is suspected when there is significant rise of cardiac biomarkers, specifically cardiac troponin value above the 99th percentile upper reference limit (URL), in accordance with Fourth Universal Definition of Myocardial Infarction [13]. A recent study reported that 17% of hospitalized COVID-19 patients sustained acute myocardial injury [14]. The mechanisms underlying myocardial injury remain unknown and it is unclear whether they reflect systemic/local and/or ischemic/inflammatory process. In a meta-analysis of four studies, cardiac troponin I (cTnI) levels were much higher among those who survived than those who did not [15]. Presumptive causes of myocardial injury in the setting of COVID-19 include myocarditis, hypoxic injury, Takotsubo cardiomyopathy, ischemic injury caused by cardiac microvascular damage or epicardial CAD (with plaque rupture or demand ischemia), and systemic inflammatory response syndrome (SIRS).

Heart failure has been reported as an outcome in 23% of COVID-19 subjects in a recent report from in-hospital Chinese cohorts. Approximately 52% of non-survivors had heart failure as compared with 12% of survivors [14]. Similarly, in a recent multinational cohort, the mortality rate was higher among COVID-19 patients with heart failure (15.3%) than those without heart failure (5.6%) [10]. The clinical presentation of myocarditis is non-specific and difficult to distinguish from other causes of cardiac injury in most patients. Thus, it is usually suspected when ACS is ruled out angiographically. As it is in most viral myocarditis, biopsy/autopsy is not very specific for establishing the case of COVID-19 myocarditis and hence the prevalence and exact mechanism of cardiomyocyte injury remain a dilemma. Though the confirmation of COVID-19-related myocarditis relies upon cardiac magnetic resonance imaging (MRI) and endomyocardial biopsy (EMB), these diagnostic tools are inappropriate during the pandemic crisis. There is no established therapy for clinically suspected myocarditis; however investigational cases had been reported in which patients responded well to immunoglobulins and steroids [16].

According to some report, the prevalence of arrhythmias among hospitalized patients was as high as 16.7-44%. The possible reasons for vulnerabilities to arrhythmias may be due to cardiac injury, hypoxic injury, electrolyte imbalance, neuro-hormonal imbalance and administration of drugs causing arrhythmia. However, data related to specific types of arrhythmias are not well recorded and therefore, the exact prevalence and consequences remain unclear [17]. The risk of in-hospital death is significantly higher among COVID-19 patients with cardiac arrhythmia (11.5%) than those without arrhythmia (5.6%) [10]. Only a few patients (7.3%) reported palpitations as a presenting symptom [11].

The incidence of venous thromboembolism (VTE) is very common (20-43%) in acutely ill patients with COVID-19, despite prophylactic anticoagulation. Abnormalities in coagulation measures specially prolonged activated partial thromboplastin time (aPTT) have been reported in patients with COVID-19. This finding could be the reason for avoidance of use of anticoagulation at therapeutic and prophylactic doses. The most common reported VTE is pulmonary embolism (PE) [18]. The pathogenesis of hypercoagulability in COVID-19 is incompletely understood. Unlike disseminated intravascular coagulation (DIC) where bleeding is the major manifestation, the most common clinical finding in COVID-19 is thrombosis. Hypercoagulable state in patients with COVID-19 is supported by presence of coagulation abnormalities such as high D-dimers, von Willebrand factor (VWF) antigen and activity, and factor VIII activity along with increased incidence of VTE [19]. Interestingly, pulmonary autopsy finding from northern Italy revealed the presence of platelet-fibrin thrombi in 86% of the cases (33/38), especially in small arteries with diameter < 1 mm. This might explain the presence of severe hypoxemia in critically ill COVID-19 patients. Therefore, early initiation of adequate anticoagulation may provide survival benefit in patients with severe pulmonary complications [20]. A prolonged aPTT should not be a barrier to the use of anticoagulation therapies in the prevention and treatment of venous thrombosis in patients with COVID-19. Clinicians should not withhold use of anticoagulants for thrombosis while waiting for further investigation/evaluations of a prolonged aPTT, nor thrombolytic therapy should be withheld in the face of a high-risk PE on the basis of a prolonged aPTT alone [21].

The occurrence of hypertension was high among patients with COVID-19 and is presumed to be associated with more severe illness and death. According to the Chinese cohort, the prevalence of hypertension was reported as 12.8%, out of which 39.7% succumbed to their illness [22]. However, the recent multinational cohort did not mention hypertension as an independent factor of in-hospital death, where the reported prevalence of hypertension was 26.3%. Therefore, when the association is adjusted for other risk factors, there is no clear evidence to indicate increased susceptibility of patients with hypertension to SARS-CoV-2 infection [10].

The concern has been raised regarding the harmful effect of certain drugs like ACEIs and ARBs in patients with COVID-19. This hypothesis is based on animal studies, which demonstrated high expression of ACE2, the target molecule of SARS-CoV-2 in the tissue level by ACEIs and ARBs. Recent analysis of three large studies showed that neither ACEIs nor ARBs were associated with the likelihood of infection, the risk of severe disease and death among those with a positive test for COVID-19 [23]. Therefore, it is important to highlight that till date there is no clear evidence to support ACEIs or ARBs are harmful to human. Hence, there is no reason for stopping these drugs in a confirmed case and patients at risk of COVID-19 [24].

Based on a promising result in the French cohort, many countries have begun using hydroxychloroquine alone or in combination with azithromycin to treat COVID-19. These drugs are known to prolong QT interval, thereby raising concern about the risk of arrhythmia in patients receiving those drugs. Chloroquine and hydroxychloroquine are structurally similar to quinidine and have QT-prolonging effects by blocking the rapidly activating delayed rectifier potassium channel (I_Kr). Though azithromycin lacks strong pharmacodynamic evidence of I_Kr inhibition, it is also notorious for inducing prolonged QT interval [25]. Therefore, scientifically the combination of these drugs seems unsafe as far as the risk of arrhythmia is concerned.

However, the short-term side effect use of these medications for patients without these underlying conditions is unclear, as most available data related to the side effects and toxicities come from treatment of chronic diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). One study reported that the incidence of prolonged QTc > 500 ms in COVID-19 patients who received the combination of azithromycin and high dose of chloroquine (600 mg twice daily for 10 days) was 18.9 %, while it was 11.1% in those receiving low dose of chloroquine (450 mg twice daily for 1 day, then 450 mg daily for 4 days). However, only two recipients of high-dose chloroquine developed ventricular tachycardia (VT), and no torsades de pointes (TdP) was reported [26]. Various factors like electrolyte imbalance, chronic renal insufficiency, QT prolonging medications and those with congenital long QT syndrome contributes to increased risk of drug-induced TdP. Tisdale et al proposed a risk score for prediction of drug-associated QT prolongation so that the safety of QT prolonging medications may be optimize and prevent life-threatening arrhythmias [27]. Patients those who have QTc interval ≥ 500 ms (with QRS ≤ 120 ms) are at increased risk for significant QT prolongation and polymorphic VT. Hence, it is necessary to obtain baseline QTc value before administration of the aforementioned medicines. If the QTc subsequently increases to ≥ 500 ms after 2 - 3 h of taking medications, or if the change in QT interval is ≥ 60 ms from the baseline electrocardiogram (ECG), to ensure whether the risk outweigh the benefits, reassessment must be done.

It is preferable to keep a dedicated echocardiography machine within the isolation ward where suspected or confirmed COVID-19 patients are being treated to assess left ventricle (LV) function and volume status regularly. Shifting of patients to separate echo laboratory increases the chance of spread of infection. Patients with suspected COVID-19 infection at initial presentation may be considered for echocardiography. However, the person performing the echocardiography must be well protected depending upon the level of clinical condition or presentation of the patient. In confirmed cases of COVID-19 use of personal protection equipment (PPE) must be mandatory with eye protection. Patients must be encouraged to wear mask irrespective of their COVID-19 test status.

Patients with known COVID-19 or suspected COVID-19 should wear an appropriate surgical mask when they are required to come to catheterization laboratory and require urgent intervention. In such instance, all staffs of catheterization laboratory team should wear PPE as the procedures as well as cardiopulmonary resuscitation (CPR) and intubation can result in aerosolization of respiratory secretions which increases the exposure to medical personnel. If possible, elective procedures are to be postponed especially in patients with significant comorbidities. The decision for elective procedures has to be individualized. The treating medical team has to consider the risk to the treating medical team versus the risk of delay in diagnosis or treatment to the patient. All the staffs should be trained in the proper techniques for donning and doffing of PPE including eye protection. In cases where there is possibility to consider intubation especially in a patient with borderline respiratory status, the threshold to consider intubation may have to be lowered and preferably should be done prior to transfer to the laboratory so as to reduce the chance of aerosol transmission during emergency intubation.

The implication of COVID-19 infection is wider than the effect of the disease itself on patients. Individuals with pre-existing CVDs are found to be at increased risk of complications of COVID-19. Henceforth intensive preventive and precautionary measures should be followed in accordance with the WHO, Centers for Disease Control and Prevention (CDC), as well as local guidelines. The most common cardiac complications include arrhythmia, myocarditis, cardiac injury (elevated high-sensitivity cTnI (hs-cTnI) and creatine kinase (CK)), ACS and heart failure. Usually cardiac complications are seen after more than 15 days of initiation of fever or symptoms. Some of the medications like hydroxychloroquine and azithromycin used in management of COVID-19 may contribute to cardiac toxicity, while the effectiveness of these medications is unconfirmed. Patients who are on ARBs/ACEIs should continue the use of medications as there is no evidence that these medicines are associated with worse prognosis. It is interesting to see that a molecule, ACE2, which was underappreciated in cardiovascular pathology, is becoming a center stage in understanding and potentially managing COVID-19. The exact mechanism through which CVDs worsen COVID-19 prognosis is still not clear, and it remains to be addressed that to what extent individual CVDs are exacerbated by COVID-19. Regarding follow-up in patients who had cardiovascular involvement, while there are no evidence-based recommendations, it is reasonable to propose that patients should be seen every 1 - 3 months. Periodic evaluation should include 12-lead ECG, two-dimensional echocardiography and MRI with gadolinium enhancement, if required.

Acknowledgments

We would like to acknowledge our family members for their constant support and encouragement.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Author Contributions

TE, AM, and VF were involved in conception or design of the work. TE, VF, AB, UK, SAK, and AK collected the data. TE, AB, UK, SAK, AK, VF, and DB analyzed and interpreted data. VF, AM, TE, and DB drafted the article. AM, TE, and VF critically revised the article. TE and AM were the final approvers of the version to be published.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ACE: angiotensin-converting enzyme; ACS: acute coronary syndrome; ARB: angiotensin receptor blocker; CAD: coronary artery disease; COVID-19: coronavirus disease 2019; DM: diabetes mellitus; MI: myocardial infarction; MINOCA: myocardial infarction with non-obstructive coronary arteries; PE: pulmonary embolism; SIRS: systemic inflammatory response syndrome; TMPRSS-2: transmembrane protease serine 2; VTE: venous thromboembolism; WHO: World Health Organization

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