key: cord-0910145-v61c2ovm authors: Liu, Yang; Wu, Shaohui; Qin, Mu; Jiang, Weifeng; Liu, Xu title: Prevalence of Cardiovascular Comorbidities in Coronavirus Disease 2019, Severe Acute Respiratory Syndrome, and Middle East Respiratory Syndrome: Pooled Analysis of Published Data date: 2020-08-20 journal: J Am Heart Assoc DOI: 10.1161/jaha.120.016812 sha: d9e205c6b2b5af3bfc532489658a8191ca217269 doc_id: 910145 cord_uid: v61c2ovm BACKGROUND: Coronavirus disease 2019 (COVID‐19) is spreading widely around the world. We conducted this meta‐analysis to explore the prevalence of cardiovascular comorbidities in COVID‐19, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS) cases. METHODS AND RESULTS: Relevant reports updated to April 17, 2020, were searched from PubMed, Embase, Web of Science, and the Cochrane Library with no restriction on language. A random‐effects model was used in this meta‐analysis to obtain pooled proportions of cardiovascular comorbidities in COVID‐19, SARS, and MERS. A total of 22 studies (12 for COVID‐19, 4 for SARS, and 6 for MERS) were included in this analysis, and the average age of patients with COVID‐19, SARS, and MERS was 46.41±1.79, 39.16±2.25, and 52.51±4.64 years, respectively. Proportions of cardiovascular comorbidities in coronavirus diseases were as follows: COVID‐19: proportion of hypertension was 17.1% (95% CI, 13.2%–20.9%), proportion of cardiac disease was 4.5% (95% CI, 3.6%–5.5%) and proportion of diabetes mellitus was 8.5% (95% CI, 5.5%–11.4%); SARS: proportion of hypertension was 4.5% (95% CI, 2.0%–7.0%), proportion of cardiac disease was 2.1% (95% CI, 0.6%–3.7%) and proportion of diabetes mellitus was 3.7% (95% CI, 1.0%–6.4%); MERS: proportion of hypertension was 30.3% (95% CI, 18.3%–42.2%), proportion of cardiac disease was 20.9% (95% CI, 10.7%–31.1%), and proportion of diabetes mellitus was 45.4% (95% CI, 27.3%–63.5%). CONCLUSIONS: The prevalence of cardiovascular comorbidities varies among different coronavirus‐associated diseases. With the development of time, proportions of cardiovascular comorbidities in COVID‐19 need further attention. Middle East respiratory syndrome (MERS). 4 2019-nCoV is a new strain of coronavirus not previously identified in humans. Coronaviruses are zoonotic and are a large family of viruses that cause illness ranging from the common cold to more severe diseases, such as MERS and SARS. 5 In 2002, the SARS epidemic originated from an animal market in South China and then affected more than 8000 people, with 916 deaths in 29 countries, 6 and the mortality was nearly 11%. After the emergence of SARS, MERS was the second coronavirus resulting in a major global public health crisis. It first emerged in 2012 in Saudi Arabia when a 60-year-old man presented with severe pneumonia. 7 Since 2012, 2494 laboratory confirmed cases of MERS have been reported, and 858 associated deaths have occurred (34.4% case-fatality ratio). 8 COVID-19 appears to have greater infectivity and a lower case fatality rate when compared with SARS and MERS. 9 Between countries, case fatality rates of COVID-19 vary significantly, but it could range from about 0.17% to 15.34%. 10 The present study was undertaken to provide a systematic evaluation and detailed estimate of the prevalence of cardiovascular comorbidities (hypertension, cardiac disease, and diabetes mellitus) in SARS, MERS and COVID-19 cases. Lessons learned from the MERS and SARS outbreaks can provide valuable insight into how to handle the current epidemic. This assessment may aid the public health sector while formulating policies for surveillance, preparedness, and response to COVID-19. The authors declare that all supporting data are available within the article. We searched MEDLINE via PubMed, Embase, Web of Science, and the Cochrane Library, with no restriction on language for articles published until April 17, 2020. The keywords of the search included "COVID-19," "2019 novel coronavirus,""SARS," and "MERS." Articles were eligible for inclusion if they met the following criteria: (1) those that were clinical studies or consecutive cases about human; (2) required clinical data could be extracted from articles; and (3) at least 3 cases were reported in an article. Articles that met the following criteria were excluded: (1) reports published as review articles, letters, editorials, conference abstracts, vaccination trials, or family-based studies; (2) studies that did not contain data of specific comorbidities; and (3) articles containing data that were also included by other larger studies (eg, if data of article A were also included in article B, which contained more patients, article A would be excluded, while article B would be included). Two researchers (Y.L., S.W.) extracted data independently for each identified article, and any disagreements were resolved by discussion. The following data were recorded: first author's name, year of publication; screening time; number, age, and sex of participants; and number of cardiovascular comorbidities, referring to hypertension, cardiac disease (mainly referred to coronary heart disease), and diabetes mellitus. We used the Newcastle-Ottawa Scale to assess the quality of included articles. 11 We identified 1654 reports; 85 full-text articles were retrieved for in-depth review. A total of 22 studies that reported the prevalence of cardiovascular comorbidities in COVID-19 12-23 (n=51 268 cases from 12 studies) and SARS 24-27 (n=1608 cases from 4 studies) and MERS 28-33 (n=597 cases from 6 studies) were selected. All cases included in this meta-analysis were laboratory-confirmed cases. Figure 1 shows the selection of articles. All 22 articles were available as full reports (all in English). The assessment of the quality of reports is given in Table 1 . Characteristics of included studies are given in (Figure 4 ). Twenty-two studies were included in this meta-analysis, and we found out that the prevalence of cardiovascular comorbidities varies among different coronavirusassociated diseases. The proportions of hypertension, cardiac disease, and diabetes mellitus in MERS were all higher than those in COVID-19 and SARS. It could also be obtained from the meta-analysis that COVID-19 had an apparently higher prevalence of hypertension than SARS. As MERS was prevalent mainly in the Middle East, the varying rates of cardiovascular comorbidities between MERS and COVID-19 and SARS cases may relate to their different patterns of regional spread. Another reason for this difference may relate to the highest average age of MERS cases given that older age is a known risk factor for hypertension, cardiac disease, and diabetes mellitus. Remarkably, a cardinal difference among SARS, MERS, and COVID-19 is the frequency of cardiovascular involvement. The viral illness could cause a general consequence of the imbalance between infection-induced increased metabolic demand and reduced cardiac reserve, along with superimposed pneumonia will directly and indirectly affect the cardiovascular system. The viral illness can also potentially destabilize coronary plaques and deteriorate the heart failure through several mechanisms including systemic inflammatory responses, which have been recently documented with COVID-19. 34 Both SARS and MERS have been linked to acute myocarditis, acute myocardial infarction, and rapid-onset heart failure. Reversible, subclinical diastolic left ventricular impairment in acute SARS even among those without underlying cardiac disease appears common, likely the result of systemic inflammatory immune response; however, lower ejection fraction upon admission was predictive of later mechanical ventilation. 35 According to previous research on SARS-CoV, cardiac disease, and diabetes mellitus increased the risk of death by twice as much as other risk factors. 36 A large study from mainland China indicated that the overall case fatality rate of COVID-19 was 2.3%, but the mortality reached 10.5% in patients with underlying cardiovascular disease. 37 For patients with underlying cardiovascular disease, including hypertension, coronary heart disease, and cardiomyopathy, viral illness can damage myocardial cells through several mechanisms including direct damage by the virus, systemic inflammatory responses, destabilized coronary plaque, and aggravated hypoxia. 38 Patients with cardiovascular disease are more susceptible to cardiac injury after COVID-19 infection. Cardiac injury can in turn further aggravate the pneumonia and increase the severity of symptoms. Therefore, patients with cardiovascular disease account for a large proportion of deaths from COVID-19. 39 Proportion of hypertension was very different between COVID-19 and SARS according to this analysis. Despite the evidence suggesting an influence of age on proportion of hypertension, the rate of hypertension in COVID-19 cases (average age 46.41±1.79 years) was still nearly 4-fold higher than that in the SARS cases (average age 39.16±2.25 years) (17.1% versus 4.5%). In accordance with a report, 40 the prevalence of hypertension at 40 to 49 years of age was 22.1% and that at 35 to 39 years of age was 12.6% in China. The ratio between them was 1.8, which was lower than the ratio of hypertension prevalence between COVID-19 and SARS (3.8) . Therefore, there may be some other reasons contributing to the difference of hypertension prevalence between COVID-19 and SARS apart from age. Scientists have confirmed that 2019-nCoV uses the same cell entry receptor, angiotensin-converting enzyme 2 (ACE2), as SARS coronavirus. 41 This finding has important implications for our understanding of 2019-nCoV transmissibility and pathogenesis. ACE2, the receptor for SARS-CoV-2 and SARS coronavirus, is a surface molecule localized on arterial and venous endothelial cells, arterial smooth muscle cells, and epithelia of the small intestine and the respiratory tract. 42 In the respiratory tract, ACE2 receptor is expressed on the epithelial cells of alveoli, trachea, and bronchi, bronchial serous glands, and alveolar monocytes and macrophages. 43 Downregulation of ACE2, as occurs during COVID-19 infection, is believed to contribute to pathological changes in the lung. Expression of the ACE2 receptor is also found in many extrapulmonary tissues including heart, kidney, endothelium, intestine, and liver. SARS-CoV-2 could invade cells of the above tissues and injure these organs. 44, 45 Target cells of the MERS coronavirus infection in the lung include pneumocytes, multinucleated epithelial cells, and bronchial submucosal gland cells. 46 All of these cells express a multifunctional cell surface protein, called dipeptidyl peptidase 4 (also known as CD26), constituting the primary entry receptor of MERS coronavirus. 47 Dipeptidyl peptidase 4, the entry receptor of MERS coronavirus, is widely expressed on epithelial cells in the kidney, alveoli, small intestine, liver, and prostate, suggesting that the range of MERS coronavirus tissue tropism is broader than SARS coronavirus and 2019-nCoV. There are several limitations in this meta-analysis. First, the studies included in this analysis indicated a wide among-studies variance in the prevalence of comorbidities, which may have facilitated the appearance of significant heterogeneity. Furthermore, the large variation among studies in the sample size (30-44 672 2019-nCoV cases, 138-801 SARS cases and 12-348 MERS cases) may be additional sources of heterogeneity. Third, different studies may define cardiac disease slightly differently, which may increase heterogeneity to some extent. For example, some studies referred only to coronary heart disease, while other studies included several cardiac diseases. Last but not least, further studies are needed to illustrate the discrepancy of the prevalence of comorbidities among different coronavirus diseases more accurately. As COVID-19 is spreading in many regions of the world currently, it is reasonable to advise patients with comorbidities of the potential increased risk and to encourage additional, reasonable precautions in geographies with active COVID-19 transmission. 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From the Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. None.