Cardiovascular implications of coronavirus disease 2019: a systematic review [version 1; peer review: 1 not approved]

Background: World Health Organization has declared coronavirus disease 2019 (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 the 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. Conclusions: Acute cardiac injury is common in patients with COVID19. 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 been declared a pandemic by WHO 2 . By April 8, 2020, a total of 1,441,589 confirmed cases of COVID-19 with mortality of 82,933 were reported 2 . COVID-19 is probably the greatest threat to mankind of 21 st century; it has not only challenged the current medical practices, but also imposed a huge psychological and socio-economic burden to the entire world.
Coronaviruses are a group of pathogen 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 of the cardiovascular system, as well [4][5][6] . Given the increasing number of confirmed 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 fill 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 7,8 . The systematic review protocol was not registered due to the urgency of the matter and very limited available evidence on the topic.

Assessment of methodological quality and risk of bias
For quality assessment, we used the Newcastle-Ottawa scale (NOS). The total score was found to be 9 and all the studies are of high quality 9 .

Eligibility criteria
Published peer-reviewed articles from January 1, 2020 until June 15, 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. A 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. A third researcher checked the article list and data abstraction spreadsheet to ensure there were no duplicate articles. Any duplicated article was counted as a single article.

Study selection
A total of 315 articles were retrieved using the search strategy. After screening by abstract and title, 52 articles were selected for full-text assessment. Of these, 46 articles were excluded as they were not relevant to research aims and objectives ( Figure 1).

Study characteristics
All the studies were conducted in China in 2020 and all of them were original articles except for one case report, by Cui et al. 10 . Among the original articles, all were retrospective studies except study by Huang et al. 11 , which was a 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 and severe/with myocardial injury/with elevated cardiac Troponin group. Critical and severe COVID-19 was defined as presence of one of the following conditions: respiratory failure requiring mechanical ventilation; shock; failure of other organs that requires treatment in ICU. Wang et al. 12 and Huang et al. 11 defined 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. 13 defined myocardial injury as blood levels of myocardial troponin ≥3 times the upper reference limit (34.2 ng/L). However, Chen et al. 14 and Guo et al. 15 defined myocardial injury as serum levels of troponin above the 99th percentile upper reference limit (Table 1).
Baseline characteristics and co-morbidities of the patients The median age of the patients in all the studies was above 50 years, except in the studies by Huang et al. 11 (median age, 49 years) and Cui et al. 10 (patient's age; 55 days). In all studies, patients requiring ICU/critical care or patients with myocardial injury/elevated cardiac troponin were older comparatively, except in study conducted by Huang et al. 11 (median ages of patients in non-ICU and ICU groups were same). Male predominance was seen in all studies except those by Cui et al. 10 and Guo et al. 15 . All the studies have included the underlying co-morbidities of the patients (Table 2).

Cardiovascular complications associated with COVID-19
Wang et al. 12 established that among the 138 patients, acute cardiac injury was seen in n=10 (7.2%), shock in n=12 (8.7%), and arrhythmia in n=23 (16.7%) patients. ICU patients were more likely to have one of these complications than non-ICU patients (p < 0.001) [ Table 3]. ICU patients demonstrated significantly high levels of creatine phosphokinase myocardial band (CPK-MB), cardiac troponin I (cTnI) and D-dimer. Similarly, the number of patients who had procalcitonin levels >0.05 ng/mL was higher in the ICU group compared with the non-ICU group (n=27 [75%] vs n=22 [21.6%]) ( Table 4).
Similarly, Chen et al. 14 observed that among the n=150 patients, n=22 (7.1%) had acute cardiac injury. In the same study, out of n=24 patients in the critical group, n=15 (62.5%) had acute cardiac injury and n=7 (5.6%) out of 126 patients in non-critical group had acute cardiac injury and the difference was

Author Complications All patients (%) ICU patients (%) Non-ICU patients (%) p-value
Wang, et al. 12 Table 3). Hypersensitive C-reactive protein (hs-CRP), N-terminal-pro brain natriuretic peptide (NT-proBNP) and cTnI levels of the patients were significantly higher in critical care cases than in mild cases (p-value <0.001) ( In study performed by Xingwei et al. 13 , among the n=54 severe/ critically severe patients, acute myocardial injury was discovered in 24 (44.4%) patients while 26 (48.1%) patients died during hospital stay. The in-hospital mortality rate was significantly higher in the 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 significantly higher than those without myocardial injury (all p-value<0.01) Cui et al. 10 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 influenza 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) are well-recognized 4,[16][17][18][19] (Table 5). Based on the studies analyzed, we found that patients with COVID-19 have 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, cardiovascular involvement was more commonly seen in elderly males. Patients with underlying coronary artery disease, hypertension, cardiomyopathy and other co-morbidities 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 inflammatory 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 infiltration of virus into myocardial cells and myocardial inflammation, resulting into cardiomyocyte death. Indirect mechanisms include respiratory failure and hypoxemia, multi-organ dysfunction, hyper-inflammation accompanied by cytokine storm, which ultimately lead to myocardial injury 20 .   Cytokine storm during infection possibly causes a reduction in coronary blood flow, destabilization of coronary plaque and microthrombogenesis 21 .
Inflammatory markers like CRP/hs-CRP, and procalcitonin were found to be significantly elevated in patients with myocardial injury/critical patients/ICU patients; suggesting a role for inflammation 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 identification of acute cardiac injury in patients of COVID-19. Besides, cardiac troponin and NT-proBNP may have a 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.

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 difficult 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 identification and comprehensive management of myocardial injury in such patients.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required. strengthen the review.

Reporting guidelines
There are several papers published on this topic, therefore it is advised to include better key words and perform better systematic review.

8.
Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly

Is the statistical analysis and its interpretation appropriate? Partly
Are the conclusions drawn adequately supported by the results presented in the review? Partly