key: cord-0757374-7f3gyt5p
authors: Liu, Jing; Virani, Salim S.; Alam, Mahboob; Denktas, Ali E.; Hamzeh, Ihab; Khalid, Umair
title: Coronavirus disease‐19 and cardiovascular disease: A risk factor or a risk marker?
date: 2020-09-22
journal: Rev Med Virol
DOI: 10.1002/rmv.2172
sha: 9d12d7f9934abe3a00c436a0b79326f9f5f35dcf
doc_id: 757374
cord_uid: 7f3gyt5p

Severe acute respiratory syndrome coronavirus‐2 causes the clinical syndrome of coronavirus disease of 2019 (COVID‐19) which has become a global pandemic resulting in significant morbidity and mortality. While the virus primarily affects the respiratory system, it also causes a wide variety of complex cardiac manifestations such as acute myopericarditis, acute coronary syndrome, congested heart failure, cardiogenic shock and cardiac arrhythmias. There are numerous proposed mechanisms of cardiac injury, including direct cellular injury, pro‐inflammatory cytokine storm, myocardial oxygen‐demand mismatch, and systemic inflammation causing multi‐organ failure. Additionally, medications commonly used to treat COVID‐19 patients have various cardiovascular side effects. We aim to provide a succinct review about the pathophysiology and cardiac manifestations of COVID‐19, as well as treatment considerations and the various adaptations made to the current healthcare structure as a result of the pandemic.

On a cellular level, the hallmark of COVID-19 is a state of hyperinflammation mediated by the cytokine storm. Numerous key inflammatory markers have been found to be elevated in these patients with systemic illness, including IL-6, IL-2, IL-7, TNF-α, IFN-γ, granulocyte-colony stimulating factor (G-CSF), C-reactive protein (CRP), procalcitonin and ferritin. 2 Several mechanisms of cardiac injury have been proposed. First, it has been hypothesized that SARS-CoV-2 can cause direct myocardial injury by entering human cells via binding with the angiotensin-converting enzymes 2 (ACE2) receptor on cell membrane. Subsequently, this can lead to acute myocardial injury by affecting the neurohumoral pathways of the cardiovascular system. 7, 8 The virus may also increase myocardial metabolic demand in the setting of systemic infection and hypoxia, leading to oxygen supply-demand mismatch and acute myocardial injury. Additionally, systemic inflammation caused by increased levels of pro-inflammatory cytokines may also cause multi-organ failure, including the heart. 9,10 Furthermore, severe illness caused by the virus can lead to significant electrolyte abnormalities, predisposing the patient to cardiac arrhythmia. 11 Increased coronary blood flow and systemic inflammation may also increase shear stress on the vascular endothelium, increasing the risk of plaque rupture and thrombosis, leading to acute myocardial infarction. 12 Finally, COVID-19 is associated with a hypercoagulable state. Case reports have found positive anticardiolipin IgA and anti-β2-glycoprotein I IgA and IgG antibodies in patients tested positive for the infection who suffered multiple infarcts. [13] [14] [15] 

Elevation of cardiac markers are common among patients with COVID-19, and several cardiac markers have been found to be helpful in predicting prognosis in these patients. A study conducted in Wuhan, China, including 273 COVID-19 patients, found that increased serum levels of creatinine kinase myocardial band (CK-MB), myosin, ultra-TnI and N-terminal (NT)-pro hormone BNP (NT-proBNP) correlated directly with increased disease severity and case-fatality rate. 16 Highsensitivity cardiac troponin (s-cTn) level has also been found to be independently associated with mortality. In a cohort study of 191 patients with COVID-19, the univariable odds ratio for mortality when s-cTnI concentrations were above the 99th percentile upper reference limit was 80.1 (95% confidence interval [CI] 10.3-620.4, p < 0.0001). This odds ratio was higher than those of all other biomarkers tested, including D-dimer. 9 Additionally, a separate study including 416 patients hospitalized for COVID-19 found that patients with elevated troponin on presentation are more likely to require invasive or non-invasive ventilation (22% vs. 4% and 46% vs. 4%), to develop acute respiratory distress syndrome (ARDS; 59% vs. 15%) or acute kidney injury (9% vs. 0%, p < 0.001 for all). The mortality was also 10-fold higher in those with elevated markers indicating cardiac injury on presentation (51% vs. 5%), adjusted hazard ratio 3.41 (95% CI 1. 62-7.16 ). 17 However, while the rise of cardiac enzymes has been associated with worse prognosis, it is worth noting that presence of cardiac markers is fairly non-specific in COVID-19 patients and is expected to be elevated in both non-ischemic and ischemic myocardial injury. This has been identified as pathophysiologic basis of acute cardiac injury in COVID-19 patients, with non-ischemic injury (secondary to cytokine storm, stress cardiomyopathy, viral myocarditis, or hypoxia induced cardiac myocyte death) being the predominant mechanism. 18 Abnormal troponin, in particular, has been found in more than half of the patients diagnosed with COVID-19. Thus, clinicians are only advised to measure troponin if acute myocardial infarction is suspected; abnormal troponin alone should not be considered evidence of acute myocardial infarction without other corroborating clinical evidence. 19 

Myocarditis/myopericarditis in COVID-19 patients have been reported in case reports or case series. In a case series including 150 hospitalized patients in Wuhan, China, 7% of deaths were attributable to myocarditis and associated circulatory failure, while in 33% of these cases myocarditis were thought to play a role, if not directly causal for the patients' demise. 20 However, despite increasing number of case reports, the true prevalence of COVID-19 myocarditis remains unknown. 21 Presenting symptoms are broad and nonspecific, including fatigue, chest discomfort, dyspnoea, heart failure as well as fulminant myocarditis with hemodynamic instability. [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] Patients are often found to have ST-T wave changes on electrocardiogram or diffuse ST-segment elevation mimicking ST-elevation myocardial infarction (STEMI), as well as increased levels of cardiac enzymes, such as NT-proBNP and high-sensitivity troponin T. Echocardiogram may demonstrate left ventricular or biventricular systolic dysfunction, with or without regional wall motion abnormalities.

Inversion recovery and T2-mapping sequences on cardiac magnetic resonance imaging (MRI) can show marked biventricular myocardial interstitial edema, with diffuse late gadolinium enhancement involving the entire biventricular wall. [22] [23] [24] [25] Autopsy studies have suggested pathological evidence of myocarditis in these patients. In the first autopsy series in the United States including four patients who expired from COVID-19, cardiomegaly was found to be a salient feature. While sections of the myocardium did not show large area of necrosis, cardiac histopathology did show scattered individual cell myocyte necrosis in each heart examined. In rare areas, lymphocytes were found adjacent to the degenerating myocytes. The clinical significance of these pathologic findings is not immediately clear but may represent early manifestation of viral myocarditis. 34 Treatment regimen for patients with suspected acute myocarditis/pericarditis from COVID-19 varied from case to case. Use of standard guidelinedirected heart failure regimen, inotropes, antiviral medications (lopinavir/ritonavir), steroids, chloroquine, or mechanical circulatory support devices have been reported. 26 indicating potential acute myocardial infarction were studied. 36 Among these patients, 10 had ST-segment elevation on presentation, while the other 8 patients developed ST-elevation during hospitalization. Nine patients underwent coronary angiography, of whom 6 had obstructive disease, and 5 underwent percutaneous coronary intervention (PCI). It is worth noting the high prevalence of nonobstructive disease on coronary angiography, possibly secondary to coronary spasm, microthrombi, hypoxic injury, or direct endothelial injury. The prognosis among these patients were poor, with 13 patients having in-hospital mortality. 36 There was also one case report of spontaneous coronary artery dissection in France in a patient with COVID-19 presenting as ACS. 37 In light of the pandemic, cardiology societies of the United States and other countries have proposed guidelines regarding triage, management, and utilization of the cardiac catheterization laboratories, which will be explored further in the following sections.

Development of new onset heart failure or cardiogenic shock have also been reported in patients with COVID-19. In a cohort study including 191 hospitalized COVID-19 patients in Wuhan, China, 44 (23%) developed new onset heart failure. 9 In a separate case series involving 21 patients admitted to the intensive care unit (ICU), cardiomyopathy developed in 7 (33%) of the patients, 38 and heart failure was more common among those who did not survive the hospitalization compared to those who survived (51.9% vs. 11.7%).

Additionally, right-sided heart failure can develop in the setting of concomitant lung disease as well as acute respiratory distress syndrome. 39 Cardiogenic shock secondary to COVID-19 has been described in isolated case reports. For instance, there is a case report of a 68-year-old patient with confirmed COVID-19 infection who presented with flu-like illness then rapidly degenerated into ARDS and cardiogenic shock requiring venous-arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation. Endomyocardial biopsy in this patient demonstrated myocardial inflammation as well as viral particles. 40 Given that COVID-19 patients commonly present with pneumonia and ARDS, it is sometimes difficult to differentiate pulmonary edema from cardiogenic shock from ground glass opacities as a result of ARDS. Clinical presentation, laboratory markers such as BNP, echocardiography, or right heart catheterization in selected cases to determine cardiac output and filling pressures may be helpful in distinguishing the two and guide clinical decision making. 41 

Self-quarantine and shelter-at-home orders in response to COVID-19 pandemic have also played an adverse role in the cardiovascular outcomes of patients. Dramatic reduction in physical activity because of the shelter-at-home order is seen. The lock-down has had effects not only on individuals who routinely performed recreational sports but also for individuals who commuted to work by walking or cycling.

Fitbit data showed that the severity of decline in steps varied country by country. The United States had a 12% decline in steps count, and the European countries had decline in steps count ranging from 7% to LIU ET AL.

-3 of 9 38%, during the week ending 22 March 2020. 47 The reduction in physical activity in turn can lead to development of insulin resistance, decreased muscle mass, bone loss, decreased aerobic capacity, worsening hypertension, and dyslipidaemia. Additionally, as weight gain has been reported during extensive leave-periods in the past, it has been hypothesized as one of the adverse consequences of the current pandemic, driven by physical inactivity, unhealthy diet, and prolonged television viewing. Social isolation and depression can also amplify the burden on the cardiovascular system. 48 Echocardiographic protocols should be as focused as possible to answer the clinical questions without need to return for further images, and scan time should be minimized by excluding students or novice practitioners from performing imaging. 69 

Many medications have been trialed in COVID-19 positive patients with hope to improve outcomes. However, many of these medications have considerable cardiovascular side effects. Among these are the anti-viral medications (ribavirin and lopinavir/ritonavir), whose potential cardiac side effects (with incidence >0.01%) include tachycardia, myocardial infarction, cardiomyopathy, arrhythmia, mL/min, HCQ dose should be reduced by 50%, and any significant electrolyte abnormalities should be corrected prior to administration of the medication. Additionally, it is also reasonable to temporarily stop class III anti-arrhythmic while the patient is on HCQ. Electrocardiogram monitoring should also be considered as an additional precautionary step. 46, 74 Azithromycin, a macrolide and frequently used antibiotic, has pro-arrhythmic properties, with epidemiologic studies estimating over 47 cardiovascular deaths presumed arrhythmic per 1 million completed courses. 75, 76 The data evaluating the pro-arrhythmic effect of chloroquine and azithromycin combination is limited. However, an in vivo study has not shown synergistic arrhythmic effect of azithromycin with or without chloroquine. 77 Cardiovascular side effect of the above-mentioned medications are summarized in Table 1 .

In summary, the ongoing COVID-19 pandemic poses an almost unprecedented challenge to the healthcare community. The infection can lead to a variety of complex cardiovascular complications and has caused significant morbidity and mortality to numerous patients. It is important for healthcare providers to be familiar with these cardiac manifestations, diagnostic criteria as well as management considerations in order to provide timely and adequate care to patients.

However, much remains to be learned about this novel virus and its clinical presentations, as well as options in prevention and treatment.

As the medical community gains more experience with COVID-19, information and best-practice experiences should be shared in a timely manner.

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The authors declare no conflict of interest. No funding was received for this project. 

No data has been shared other than with the co-authors or RMV editorial board.

https://orcid.org/0000-0001-5898-3706