Cardiovascular Implications of Coronavirus Disease 2019 ( COVID-19 ) : A Systematic Review


 Background: World Health Organization has declared Coronavirus disease (COVID-19) as a Public Health Emergency of International Concern. It has killed thousands and millions are infected worldwide. Though COVID-19 is supposed to be primarily a disease of respiratory system, it also has widespread implications on other systems as well. The aim of this systematic review is to summarize the cardiovascular implications of COVID-19. Methods: PubMed, PubMed Central, EMBASE, and Google Scholar were searched for peer-reviewed articles which aimed to delineate the cardiovascular implications of COVID-19.Results: A total of six articles (five original articles and one case report) were included. We found diverse cardiovascular implications of COVID-19 ranging from acute cardiac injury to death. New onset abnormalities in electrocardiogram or echocardiogragram, elevated plasma levels of cardiac troponin, NT-proBNP, and D-dimer have role in early identification of acute cardiac injury in such patients. Additionally, cardiac troponin and NT-proBNP can be used to evaluate prognosis and possible need for intensive care in these patients.Conclusion: Acute cardiac injury is common in patients with COVID-19. Aggressive supportive management based on prognostic indicators along with management of heart failure, arrhythmias, acute coronary syndrome and thrombosis can improve clinical outcomes in such patients.


Introduction
In late 2019, a cluster of cases of 'pneumonia of unknown origin' emerged which was linked to seafood wholesale and wet market in Wuhan, China (1), that heralded the onset of Coronavirus disease . The disease has now spread rapidly to several countries around the globe and has already been declared a pandemic by WHO (2). Till April 8, 2020, a total of 1,441,589 con rmed cases of COVID-19 with mortality of 82,933 have been reported (2). COVID-19 is probably the greatest threat to mankind of 21 st century that has not only challenged the current medical practices, but also has imposed a huge psychological and socio-economic burden to the entire world.
Coronavirus is one of the major pathogens that primarily target the human respiratory system (3). However, previous outbreaks of coronaviruses i.e. severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) have already shown multisystem involvement including cardiovascular system as well (4)(5)(6). Given that, with increasing number of con rmed cases and death due to COVID-19, it is important to be acquainted with cardiovascular manifestations induced by this viral infection. However, there is only limited published data pertaining to cardiovascular presentations of COVID-19. The present systematic review aims to describe the cardiovascular implications of COVID-19 and ll the gap in the knowledge regarding understanding of varied cardiovascular manifestations of COVID-19.

Protocol and registration
We followed the recommendations established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (7). The systematic review protocol was not registered due to the urgency of the matter and very limited available evidence on the topic.

Eligibility criteria
Published peer-reviewed articles from January 1, 2020 until March 30, 2020 which aimed to assess cardiovascular implications in patients with COVID-19 were included. Article language restrictions were not imposed. In addition to original articles; case reports, and case series were also included. Editorials, letters to editor, and correspondences were excluded.

Study selection and data abstraction
First of all, we screened articles by title and abstract. Then, we examined full texts of relevant articles for inclusion and exclusion criteria. The data abstraction spreadsheet using Microsoft Excel version 2013 was developed; which included the following information: author, year of publication, journal, and country where the study was done, study design, sample size, baseline characteristics and laboratory parameters of the patients and cardiovascular implications of COVID-19. Any duplicated article was counted as a single article.

Study characteristics
All the studies were conducted in China in 2020 and all of them were original articles except for one case report of Cui, et al. (8). Among the original articles, all were retrospective studies except study by Huang,et al. (9) which was prospective, observational study. All the studies have categorized patients into two groups: non-ICU/non-critical/without myocardial injury/with normal cardiac Troponin group and ICU/critical/with myocardial injury/with elevated cardiac Troponin group. Wang, et al. (10) and Huang,et al. (9) de ned acute cardiac injury as blood levels of hypersensitive troponin I above the 99th percentile upper reference limit (>28 pg/mL) or new abnormalities shown on electrocardiography and echocardiography. Xingwei, et al. (11) de ned myocardial injury as blood levels of myocardial troponin ≥3 times the upper reference limit (34.2 ng / L). However, Chen, et al. (12) and Guo,et al. (13) de ned myocardial injury as serum levels of troponin above the 99th percentile upper reference limit [ Table 1].
Baseline characteristics and co-morbidities of the patients  (13). All the studies have included the underlying co-morbidities of the patients [ Table 2].
Besides, ICU patients demonstrated signi cantly high levels of creatine phosphokinase (CPK), and D-dimer. Number of patients who had procalcitonin levels >0.05 ng/mL and cTnI >28 pg/mL (99th percentile) were more in ICU group compared with non-ICU group [ Table 4].
Similarly, Chen, et al. (12) discovered that among the 150 patients, 22 (7.1%) patients had acute cardiac injury. In the same study, out of 24 patients in critical group, 15 (62.5%) had acute cardiac injury and 7 (5.6%) out of 126 patients in non-critical group had acute cardiac injury and the difference was statistically signi cant (p-value <0.001) [ Table 3]. Hypersensitive C-reactive protein (hs-CRP), N-terminal-pro brain natriuretic peptide (NT-proBNP) and cTnI levels of the patients were signi cantly higher in critical care cases than in mild cases (p-value <0.001) [ Table 4]. On univariate logistic regression analysis, critical disease status had a signi cant correlation with age, male gender, elevated NT-proBNP, elevated cTnI, elevated hs-CRP, hypertension, and coronary artery disease (all p<0.05). Multivariate logistic regression analysis revealed that elevated cTnI (OR = 26.909, 95%CI 4.086-177.226, p = 0.001) and coronary artery disease (OR = 16.609, 95%CI 2.288-120.577, p = 0.005) were the independent risk factors of critical disease status.
In study performed by Xingwei, et al. (11) among the 54 severe/critically severe patients, acute myocardial injury was discovered in 24 (44.4%) patients while 26 (48.1%) patients died during hospital stay. In-hospital mortality rate was signi cantly higher in myocardial injury group compared to the group without myocardial injury [75.0% (18/24) vs. 26.7% (8/30), p-value = 0.001]. In myocardial injury group, C-reactive protein (CRP) and NT-proBNP levels were also found to be signi cantly higher than those without myocardial injury (all p-value<0.01) Cui, et al (8) has described a case report of acute cardiac injury in an infant infected with COVID-19 as suggested by elevated plasma levels of CPK-MB, and cTnI.

Discussion
In previous outbreaks of in uenza and coronavirus i.e. MERS and SARS coronavirus, cardiovascular implications like myocarditis, acute myocardial infarction, and acute exacerbation of heart failure (both systolic and diastolic) have been well-recognized (4, 14-17) [ Table 5]. Based on the studies analyzed, we found that patients with COVID-19 too have a diverse cardiovascular implications ranging from acute cardiac injury to death. The incidence of acute cardiac injury ranges from 7% to 44 % in different studies and the incidence were higher in patients admitted to ICU compared with non-ICU patients [ Table 3]. Additionally, other co-morbid illness are more prone to experience myocardial injury during the course of COVID-19. In these patients, superimposed viral illness damages the myocardial cells by enhancing the systemic in ammatory responses, aggravating hypoxia, and destabilizing coronary plaque. The exact pathophysiology of myocardial injury in previously healthy patients with COVID-19 infection is not fully understood. Cardiac injury can occur via direct or indirect mechanisms [ Figure 2]. Direct mechanism is exhibited by in ltration of virus into myocardial cells and myocardial in ammation, resulting into cardiomyocyte death. Indirect mechanisms include respiratory failure and hypoxemia, multi-organ dysfunction, hyper-in ammation accompanied by cytokine storm, which ultimately lead to myocardial injury (18). Cytokine storm during infection possibly cause reduction in coronary blood ow, destabilization of coronary plaque and microthrombogenesis (19).
In ammatory markers like CRP/ hs-CRP, and procalcitonin were found to be signi cantly elevated in patients with myocardial injury/critical patients/ICU patients; suggesting role of in ammation in COVID-19 mediated cardiac injury. Increased plasma levels of cardiac troponin, NT-proBNP, and D-dimer or new onset abnormalities in electrocardiogram or echocardiogragram can be helpful in early identi cation of acute cardiac injury in patients of COVID-19. Besides, cardiac troponin and NT-proBNP may play role in prognostication and possible need for intensive care in such patients. Aggressive supportive management based on prognostic indicators can improve clinical outcomes in such patients. Management of heart failure, arrhythmias, acute coronary syndrome and thrombosis is important.
The present work is, to the best of our knowledge, the rst systematic review of the latest published peer reviewed studies, addressing the cardiovascular implications of COVID-19.

Limitations of the review
Our review has included limited number of available studies with small sample size. Hence, the result of our systematic review should be considered with caution. All studies included in our review were conducted in China and most of them were retrospective. Thus, our review lacks heterogeneous and diverse population. We recommend multicenter, multi-national, prospective studies be carried on cardiovascular implications of COVID-19. It is di cult to postulate myocardial injury as the sole cause of death as it may have occurred due to multi-organ dysfunction.

Conclusion
Acute cardiac injury is common in patients with COVID-19 and when it occurs, has a poor prognosis. Monitoring of myocardial injury markers and cardiac function is of utmost importance, and attention should be paid to the early identi cation and comprehensive management of myocardial injury in such patients.

Declarations
Ethics approval and consent to participate: Not applicable. Consent to publish: Not applicable.

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

Competing interests:
Authors declare no competing interests.

Funding: None
Authors' contribution: RRP, AKY, and SM contributed to writing and reviewing data, data extraction, analysis of the results, and screening articles. RRP and AKY supervised and conceptualized the project. Speci cally, all authors have (i) made substantial contributions to conception and design or acquisition of data or analysis and interpretation of data, (ii) been involved in drafting the manuscript or revising it critically for important intellectual content, (iii) given nal approval of the version to be published, and (iv) agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.     Pathophysiology of myocardial injury in patients with COVID-19