Comparison of the cardiovascular presentations, complications and outcomes following different coronaviruses’ infection: A systematic review

Manifestations caused by coronavirus family have presented it in many ways during the previous years. The aim of this systematic review was to gather all possible cardiovascular manifestations of the coronavirus family in the literature. Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched PubMed, Scopus, Web of Science, Cochrane and ProQuest which were updated on May 1, 2020 for the last time. Regarding to the novelty and speed of publications on COVID-19, we searched Google Scholar and also references of included studies and review articles in the systematic search results were searched manually. The searched keywords were the combination of the following MeSH terms: "COVID-19", "SARS", "MERS" and "cardiovascular presentation". The systematic review was registered with ID CRD42020180736 in International Prospective Register of Systematic Reviews (PROSPERO). After screening, 28 original articles and ten case studies (five case reports and five case series) were included. Most of the studies were focused on COVID-19 (20 original articles and four case studies) while the only studies about Middle East Respiratory Syndrome (MERS) were a case report and a case series. Almost all the cardiovascular presentations and complications including acute cardiac injury, arrhythmias and the thrombotic complications were more prevalent in COVID-19 than severe acute respiratory syndrome (SARS) and MERS. The cardiac injury was the most common cardiovascular presentation and complication in COVID-19 whereas thrombotic complications were commonly reported in SARS. The cardiac injury was the predictor of disease severity and mortality in both COVID-19 and SARS.Coronavirus 2019 may present with cardiovascular manifestations and complications in signs and symptoms, laboratory data and other paraclinical findings. Also, cardiovascular complications in the course of COVID-19 may result in worse outcomes.


Introduction
The novel coronavirus disease 2019 (COVID- 19) pandemic has rapidly spread in many countries around the world. As of June 18, 2020, more than 8 million people have been infected, with near to 440 000 deaths. 1   is affecting adults more than children specially those younger than 15 years of age. The three main symptoms of the infection are cough, shortness of breath and fever. Some other symptoms include headache, malaise and sore throat which are less common. Most of these symptoms are presentations of respiratory tract infection. However, there have been reports about symptoms which overlap with cardiovascular symptoms. 2 Some of these patients have underlying cardiovascular diseases, which affects their disease progression and outcome, but others might also present with cardiovascular manifestations. They might either present with cardiovascular findings or develop cardiovascular complication. 2,3 But this is not the first time for cardiovascular presentations of coronavirus. There have been some studies reporting these presentations by previously known strains of the coronavirus family. Severe acute respiratory syndrome (SARS) caused by SARSassociated coronavirus has presented itself in many ways during the previous years. [4][5][6][7] Studying the previous presentations of coronavirus family and the recent cardiovascular manifestations of COVID-19 can help in predicting possible future challenges and taking measures to tackle these issues. The aim of this systematic review was to gather cardiovascular presentations of the coronavirus diseases including SARS, MERS and COVID-19 in the literature.

Search strategy
PubMed, Scopus, Web of Science, Cochrane and ProQuest were searched systematically based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and updated on May 1, 2020 for the last time. 8 Regarding to the novelty and speed of publications on COVID-19, we searched Google Scholar and also references of included studies and review articles in the systematic search results were searched manually. The searched keywords were the combination of the following MeSH terms: "COVID-19", "SARS", "MERS" and "cardiovascular presentation". The systematic review was registered with ID CRD42020180736 in PROSPERO International prospective register of systematic reviews and the complete search strategy is available online. On May 6, 2020, we added another researcher who helped in carrying on the systematic review to the PROSPERO. We also added the search strategy for all databases that were used. There were no changes in the protocol during the review.

Study selection
Interventional or descriptive studies on cardiovascular manifestations or complications of confirmed cases of three Coronaviruses including COVID-19, MERS and SARS were included in the study. There was no limitation on the year of publication or age of the study population. However, only articles in English Language were included. Case reports and letters were not excluded. Animal studies, reviews and guidelines were considered as exclusion criteria. Title, abstract and full text of search results were screened by two investigators independently and in any case of disagreement, the third senior investigator was asked to make the decision after discussion about the issue.
Our outcomes of interest were the various cardiovascular specific presentations, the cardiovascular related laboratory and imaging findings, complications and outcomes in SARS, MERS and COVID-19.

Data extraction
For each included study, the type of Coronavirus infection, year and country of publication, and the name of the first author were summarized into a table. Reported cardiac presentations and complications with their prevalence in the study population if available, were gathered and their impact on outcomes of the disease were added to the table. The data extraction was performed by two investigators independently and the third investigator was asked to participate in the case of disagreement.

Quality assessment
For quality assessment, the Quality Assessment Tool for Studies with Diverse Designs (QATSDD) was used. 9 Two investigators assessed each study independently and the third investigator was asked to make the decision in the case of disagreement. The quality assessment was only done for original articles and case studies were not assessed. Also, quality assessment was not done for excluded articles. The QATSDD consists of 16 questions that 2 of them are for qualitative studies only. For each question there is a possible score 0 to 3 that makes the highest possible score to be 42. After scoring each question, the overall score for each article was calculated and then the percentage of the 42 was determined.

Results
After screening, 28 original articles and 10 case studies (5 case reports and 5 case series) were included. Most of the studies were focused on COVID-19 (20 original articles and four case studies), and 12 articles (eight original and four case studies) were focused on SARS. While there were only two studies about MERS. The PRISMA flow diagram is shown in Figure 1. Quality of most 20 studies was more than 70%. The range of the percent of quality was 40% to 88%. Original studies were retrospective in 22 articles and China was the origin of most of the articles. The original articles and case reports are summarized in Table 1 and Table 2 respectively.

Cardiovascular presentation
Ten COVID-19 manuscripts reported cardiac injury as the cardiovascular presentation of patients. However, only three manuscripts reported elevated creatine kinase levels in SARS patients without a significant increase in the MB isoform. Seven (one original study and six case studies) manuscripts reported electrocardiography changes and arrhythmias such as ventricular fibrillation and tachycardia as the presentation of patients infected with coronaviruses.

Cardiovascular complication
From the COVID-19 manuscripts, eight studies reported cardiac injury as a complication of the infection with incidence of 7.4%-77% according to the included patients' disease severity. Heart failure was reported as the complication in four manuscripts with an incidence of 1%-49%. Regarding arrhythmias, only two studies reported them as the complication of COVID-19 infection with an incidence of 10.4%-60%. Studies related to SARS infection reported ischemic strokes, deep vein thrombosis (DVT), pulmonary embolism and cardiomegaly as cardiovascular complications of the infection.

Cardiovascular outcome
Most studies reported cardiac injury as predictors of disease severity and mortality. Some studies indicated that patients who had cardiac injury needed more intensive care unit hospitalization. Acute myocardial infarction, arrhythmias and heart failure were regarded as the cause of death in some patients. Table 2 summarizes the different cases reported with COVID-19, SARS and MERS infection and their cardiovascular presentations, complications or outcomes. Overall, the cases included patients experiencing cardiogenic shock, myocarditis, ischemic stroke, myocardial infarction, DVT and pulmonary embolism.

Discussion
As experience with COVID-19 grows, the management of cardiovascular problems has become one of the most important challenges in caring process of these patients. While the world is in the grip of the COVID-19 pandemics, we took a look back at SARS and MERS and tried to show differences and similarities between the three kind of Coronavirus infection in terms of cardiovascular manifestations and outcomes.
A similar pathogenesis has been suggested for three viruses. It has also been shown that the presence of cardiovascular comorbidities is accompanied with more severe illness and mortality in all three cases of Coronavirus infection.  However, although the pandemics of COVID-19 has not ended, besides its reproductive number which is significantly higher in COVID-19 than SARS and MERS and their similarities such as more infection in adult and men, it seems that COVID19 compared to the other Coronavirus infections is more possible to manifest with a cardiovascular sign and symptom . 3,4,10,41-42,44-45 Interestingly, although it has been suggested that the three viruses may cause myocardial damage in victims, compared to SARS and COVID-19, the data regarding the cardiovascular manifestations of MERS were scarce and we could find limited reports regarding the presentation of MERS with cardiovascular manifestation. [40][41]46 The acute cardiac injury or a myocarditis like syndrome which would be the most common cardiac involvement during Coronavirus infections has been more prevalently reported in those with COVID-19. The development of cardiovascular complications later in the course of the disease has also been reported more frequently in COVID-19. 2,3,10,13-14, [47][48] As far as we searched, the acute cardiac injury was not reported as initial presentation of SARS. Regarding the MERS, Alhogbani et al reported a 60-year-old man with fever, respiratory symptoms, left ventricular systolic dysfunction, pericardial effusion and elevated cardiac biomarkers with final diagnosis of acute myocarditis based on the cardiac MR findings. 40 In a case series by Al-Abdallat et al a fatal case of MERS with pericarditis, pericardial and pleural effusions, and supraventricular tachycardia late in the course of illness has been reported. 41 Thrombotic complications seem to be the point of  Non-productive cough and shortness of breath for two days.
Symptoms improved significantly. One week later, normal heart size on chest x ray.
Echocardiography showed that the size and function of the heart had returned to normal.
Markers of myocardial injury dropped significantly after 1 week of treatment.
After 3 weeks, the myocardial injury markers had fully recovered to the normal range.
Severe fatigue for 2 previous days. She denied chest pain, dyspnea, and further symptoms.
She reported having fever and cough the week before.

Case 4:
A 63-year-old man, with diabetes hypertension and IHD. Brain CT: massive right MCA infarction with oedema and early hydrocephalus.

Case 3:
Brain CT: large infarctions in left PCA and bilateral MCA territories.

Case 5:
At autopsy: an infarction in the inferior lateral part of right occipital lobe was noted.
Sterile vegetations in multiple cardiac valves, deep venous thrombosis and pulmonary embolism were detected.

Case 1:
Aspirin was started and LMWH discontinued.
She remains aphasic and hemiplegic.
She was weaned off the ventilator two months later.
Died 1 week later.

Case 3:
Her blood pressure dropped to systolic 60mmHg, but responded promptly to desmopression acetate (DDAVP), intravenous fluids and inotropic drugs. LMWH.

Case 4:
No IVIG/No LMWH. Discharge  It is suggested that the thrombotic complications may be due to excessive inflammation, cytokine storm, platelet activation, endothelial dysfunction, and stasis. Also, the limited data in MERS suggests that the hematologic and coagulation disorders as the cause of the thrombotic complications in fatal cases. 3,7,29,39,42,46,[49][50][51] Conclusion In this study we tried to show the similarities and differences between the three types of Coronavirus. At the beginning the COVID-19 pandemic, the lessons from other Coronavirus epidemics suggested that the infection can be more severe and even fatal in those with cardiovascular co morbidities and a trigger for acute coronary syndromes, thrombotic complications and heart failure exacerbations; however, COVID-19 seems to be able to induce new cardiovascular pathologies and cardiovascular complications and appears to be a serious threat in addition to respiratory problems. It should also be clarified whether the nature of novel Coronavirus 2019 in terms of being more contagious and its spreading into different ethnicities and genetic backgrounds would be the cause of differences with its other ancestors. The long-term cardiovascular effects of COVID-19, along with the effect of future specific antiviral therapies are subject for further investigation. Further investigation is also needed to determine how patients with COVID-19 related cardiovascular complications should be followed in the long-term. Is there a possibility of recurrence in cases of myocarditis caused by the COVID-19? Will asymptomatic patients, with mild symptoms and people who have just suffered from respiratory problems without cardiovascular involvement, be at greater risk for heart diseases in the future?

Ethical approval
The study was approved at the institutional research ethics committee with IR.RHC.REC.1399.005 ethical code.