COVID‐19 and the heart: An update for clinicians

Abstract SARS‐CoV‐2, the cause of the COVID‐19 pandemic has significantly impacted cardiovascular healthcare. Patients with pre‐existing cardiovascular disease are at higher risk of morbidity and mortality. The virus may affect the heart directly and indirectly with clinical syndromes of acute myocardial injury, myocarditis, acute coronary syndromes, heart failure, arrhythmias, and venous thromboembolism. Some therapeutics under investigation for COVID‐19 may also have adverse cardiac effects. The involvement of the RAAS system in viral entry makes it pertinent to consider the effects of medications that modulate the system. Comprehensive knowledge of peculiar cardiovascular manifestations of COVID‐19 and the role of RAAS in the prognosis of COVID‐19 disease is needed for optimal patient management.

The clinical spectrum of COVID-19 appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness and severe viral pneumonia with respiratory failure, systemic inflammatory syndrome and even death. 2 The respiratory tract is the primary target for SARS-CoV-2 virus, however cardiovascular involvement has been documented in different studies and the heart is involved in 40% of patients dying from COVID-19 disease. 3 Cardiovascular complications of influenza and coronavirus infection, including myocarditis, acute myocardial infarction, and exacerbation of heart failure have been documented during previous epidemics with significant impact on both morbidity and mortality. 4 Underlying myocarditis has been described with electrocardiographic changes, troponin elevation, and echocardiographic evidence of diastolic and systolic dysfunction. In previous coronavirus epidemics, adverse outcomes including hypotension, arrhythmia, and sudden cardiac death have been reported in patients with pre-existing cardiovascular disease. 5 Patients with pre-existing comorbidities are thought to be at an increased risk of infection with SARS-CoV2 and also tend to have worse clinical outcomes. Specifically, patients with cardiovascular disease, diabetes and hypertension are thought to have a high complication rate with mortality rate of 10.5% reported in cardiac patients and mortality rates of 7.3% and 6.0% for diabetes and hypertension patients, respectively. 6 2 | COVID 19 AND THE HEART: EPIDEMIOLOGY

| Sex
Men are at higher risk in the COVID-19 epidemic. They are admitted to hospital at higher rates and suffer higher degrees of morbidity and mortality. United States data from the COVID-19 net dataset (May 9, 2020) found that men represented 52.9% of the hospitalized population as compared to 47.1% being women. A report of 5700 patients from a New York hospital system found that men represented 60.3% of the admitted patients. COVID-19 mortality in this study was higher in men than in women at every age. 7 The pathophysiology and significance of male predominance of COVID-19 disease is uncertain. Further study is ongoing in this area.

| Age
As age increases, so does the risk of developing severe COVID-19 disease. Data from the CDC in the United States reveal that patients with COVID-19 disease less than 19 years of age have a risk of hospitalization that is 2% to 3% compared to a risk of hospitalization that is greater than 31% in patients above the age of 85. 8 Furthermore, no patients in this cohort less than 19 years of age required ICU care. In the age group 20 to 45 years the hospitalization rate was 2% to 4% and in the 75 to 84 year cohort the rate of hospitalization increased to 11% to 31%. 9 A trend was noted for increasing mortality with age in the United States with case fatality rates of 0.1% to 0.2% in patients less than 44 years of age and 10.4% to 27.3% in patient 85 years or older. 9 Recently there have been reports of a rare multisystem inflammatory syndrome associated with COVID-19 disease resembling Kawasaki disease in children. 10 Much remains unclear about how commonly this occurs and what the risk factors may be.

| Co-morbidities
Patients with pre-existing co-morbidities are thought to be at an increased risk of infection with SARS-CoV2 and tend to have worse clinical outcomes. Specifically, patients with cardiovascular disease, diabetes and hypertension are thought to have a high complication rate with mortality rate of 10.5% reported in cardiac patients and mortality rates of 7.3% and 6.0% for diabetes and hypertension patients, respectively. 6

| Socio-economic factors
Aside from race and ethnicity other socio-economic factors have been shown to worsen outcome with COVID-19 disease. Nursing Homes and Assisted living facilities have proved to be areas of easy spread with high subsequent morbidity and mortality. Both inmates and correctional staff in US prisons have been documented to be at risk.
Homeless shelters have also been identified as being at risk for COVID-19 disease. 8

| PATHOPHYSIOLOGY OF COVID-19 AND CARDIAC INVOLVEMENT
Progression of COVID-19 disease is divided into three intermingling phases; early infection phase, a pulmonary phase, and a hyperinflammation phase 13 (Figure 1). The first phase features virus spread and proliferation in lung tissues with initial innate immunity including recruitment of monocytes and macrophages, characterized by mild constitutional symptoms. Some early phase symptomatic patients suffer from mild respiratory symptoms and may require supportive care like supplemental oxygen followed by an adaptive immunity stage with falling titers of the virus and resolution of symptoms. The second stage includes several mechanisms leading to pulmonary tissue injury, vasodilation, endothelial permeability and leukocyte recruitment that cause further pulmonary damage, hypoxemia, and cardiovascular stress. Ten percent of patients in the second stage may experience further exacerbation of immune response (hyperinflammation stage) become critically-ill, and they may suffer from acute respiratory distress syndrome (ARDS), acute cardiac injury, multi-organ failure, secondary bacterial infections, sepsis and require intensive care . 13 The mechanisms of cardiac injury are not well established. Acute myocardial injury is the most common cardiovascular complication in COVID-19 manifested by elevation of high-sensitivity cardiac troponin I and the incidence of acute myocardial injury has been reported to be around 8% to 12%. 14 Acute myocardial injury has been shown to be a strong negative prognostic marker in patients with COVID-19. 2 Several mechanisms are thought to be responsible.: A. Direct myocardial injury-SARS-CoV-2 viral invasion of cardiomyocytes is thought to occur by binding to angiotensin-converting enzyme 2 (ACE2). The binding of SARS-CoV-2 to ACE2 can result in alteration of ACE2 signaling pathways, leading to acute myocardial and lung injury, however, autopsy studies have thus far failed to confirm this pathway. 15 This will be discussed in detail in a later section of this article.
B. Indirect myocardial injury-which is expressed in two ways.  16 2 Severe hypoxia from acute respiratory damage which may result in oxidative stress and increased cardiometabolic demand that leads to acute myocardial injury. 15

| Histopathology of COVID-19 and cardiac involvement
There are only few postmortem studies, however, histopathologic changes are consistent with diffuse alveolar damage, reactive type II pneumocyte hyperplasia, hyaline membrane formation, intra-alveolar fibrin exudates, epithelial damage, along with loose interstitial fibrosis and chronic inflammatory infiltrates. 17 Intravascular coagulopathy was noted in an autopsy study with fibrin thrombosis of small arterial vessels in 87% of specimens. Microvascular thrombosis and hemorrhage linked to extensive alveolar and interstitial inflammation that shares features with the macrophage activation syndrome. This may explain the severe hypoxemia which characterizes the clinical feature of ARDS in COVID-19 patients. 18 Limited cardiac autopsies have shown some interstitial mononuclear inflammatory infiltrates, but no virus has been identified in cardiac tissues. 17

| Arrhythmias
The most commonly reported arrhythmia in COVID-19 disease is symptomatic/asymptomatic tachycardia. Bradycardia has been also reported. Arrythmia may occur in the setting of myocarditis, myocardial ischemia and in critically ill patients with hypoxia and shock. 23 Other forms of arrythmias have been reported. Several mechanisms may trigger or aggravate arrhythmias in subjects with COVID 19.
Potential causes include electrolyte disturbance (mainly hypokalemia), adverse effects of therapies (eg, chloroquine/hydroxychloroquine and azithromycin) that prolong QT interval with potential development of polymorphic ventricular tachycardia (VT) 24 and fever which may unmask cases of cardiac channelopathies such as Brugada syndrome and long QT syndrome. 6

| Acute coronary syndrome
There are no clear statistics on the incidence of ST segment elevation myocardial infarction (STEMI) from intracoronary plaque rupture or obstruction in the setting of COVID 19 disease and it is likely low.
Acute coronary events may be triggered by plaque rupture and coronary thrombosis due to inflammation/increased shear stress in high risk patients. Tam et al, reported a significant decline in the number of patients with STEMI seeking medical care at their institute. 25 They attributed this to the reluctance of patients to go to a hospital during the COVID-19 outbreak, delays in evaluating patients with STEMI after hospital arrival due to precautions such as detailed travel and contact history, symptomatology, and chest X-ray. Taken together, this may delay patient transfer to catheterization laboratory. Additional precautions taken in catheterization laboratory such as time needed to wear protective gear may further delay intervention. 25

| Heart failure
There is a lack of data on the incidence of left ventricular systolic dysfunction, acute left ventricular failure, and cardiogenic shock. One study demonstrated heart failure in 52% of deceased patients and 12% of discharged patients. 2 Many critically ill patients may develop reversible sepsis-related cardiomyopathy with left ventricular dilatation, impaired systolic function and recovery within 7 to 10 days. 21 COVID-19 infection can cause decompensation of underlying heart failure and may lead to mixed shock syndrome (combination of septic shock and cardiogenic shock). Invasive hemodynamic monitoring, if feasible, may be helpful to manage the cardiac component of shock in such cases. 26

| Long-term cardiovascular outcome
It is too early to predict long term cardiovascular outcome for patients who have recovered from COVID 19 infection, However, the potential outcome may be similar to that seen in the severe acute respiratory syndrome (SARS) caused by the SARS-CoV virus. The outcome studies of patients who recovered from SARS and were followed for 12 years showed that 40% had cardiovascular abnormalities, 60% with altered glucose metabolism and 68% with abnormal lipid metabolism. 25

| Cerebrovascular disease
COVID-19 infection is associated with a prothrombotic state causing venous and arterial thrombosis and elevated D-dimer. The reported incidence of cerebrovascular disease among severe COVID-19 F I G U R E 2 Pathophysiology of COVID-19 cardiac related complications patients varied from 2.3% to 22%. 27 Increased production of antiphospholipid antibodies has been suggested as a possible cause of ischemic stroke. 28 Stroke has been found to be associated with a 2.5-fold increased disease severity in patients with COVID-19. 27  showed good in-vitro activity against the virus and there was great excitement about the potential of these medications in the early stages of the pandemic. 29 However, the RCTs so far have not shown any benefit for chloroquine or hydroxychloroquine, rather, a study had to be stopped mid-trial due to side effects of therapy as 11 patients died in the group taking chloroquine. In an analysis of a multinational registry of 96 032 patients from 671 hospitals in six continents, Mehra and colleagues 30 found no benefit of Hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcome for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19. Complications of the drug include severe cardiac electrical abnormalities electrical irregularities in the heart such as polymorphic VT (Torsade de Pointes), long QT syndrome, and increased risk of sudden death. 19 Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases and which was initially developed to treat the Ebola virus has also shown good in-vitro activity against the SARS-CoV-2 virus. 29 Clinical trials on Remdesivir are currently ongoing and two trials have reported a reduction in time to clinical improvement in patients who took the drug compared to placebo. 31 Convalescent plasma and tocilizumab (a monoclonal antibody against interleukin-6) are other therapies that have shown some promise in reducing severity of illness in case series but the results of RCTs on these are still awaited. 32

| COVID-19 AND THE RAAS SYSTEM
The renin angiotensin aldosterone system (RAAS) is a complex hormonal system that is comprised of the interactions of renin, angiotensinogen, angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), angiotensin II, and aldosterone. In summary, RAAS is a system that responds to a physiologic state of hypovolemia, hyponatremia, adrenergic activation and hypotension and activates a system that increases vasoconstriction and fluid retention. 33  ACEi and ARB cause upregulation of ACE2 and this is thought to increase viral entry . 35 On the other hand, markedly elevated angiotensin II levels were noted in plasma samples from SARS-CoV-2 infected patients and were linearly associated with viral load and lung injury. Indeed, enhanced ACE activity and decreased ACE2 activity have been shown to contribute to lung injury in mouse models 33  should not discontinue them with CoVID-19 disease. 36

| STATINS AND COVID-19
Statins are effective cholesterol lowering drugs that act primarily by blocking the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase enzyme. It was found that statins, particularly pitavastatin, bind strongly to and inhibit the SARS-CoV-2 main protease (Mpro), a key coronavirus enzyme, which is a potential drug target. 37 This will need to be explored in further studies.

| COVID-19 AND NSAIDS
Non-steroidal anti-inflammatory drugs (NSAIDs) are medications that work by inhibiting the cyclo-oxygenase enzyme that produces prostaglandins and are commonly used for the relief of pain and fever. Initial public concern for these medications in the context of COVID-19 was raised by the French Minister of Health in mid-March and the basis of his concern appeared to be an anecdotal report of four patients who had appeared to worsen in the context of NSAID use. These medications have been shown to increase the expression of ACE2 on the cellular membranes and could theoretically increase viral entry into respiratory cells. 38 However, aside from case reports, there is no other evidence that NSAIDs lead to poor outcomes in COVID-19 patients and in contrast, one NSAID, Indomethacin has shown in vitro evidence of inhibition of RNA synthesis of the SARS-CoV-1 virus independent of its cyclooxygenase activity. 39 More studies will be needed on this, but given this concern, many European countries have suggested that in patients with respiratory tract infections, acetaminophen should be used in preference to NSAIDs for control of pain and fever. 40

| CONCLUSION
This review has examined the cardiac complications of COVID-19 and also sheds a light on peculiar characteristics of the virus and its relationship with cardiac therapies particularly ACEi and ARBs. More research is ongoing on various aspects of this novel coronavirus and clinicians are watching keenly to learn as much as they can in the process.