key: cord-1045115-06jr58kz authors: Lazaridis, Charalampos; Vlachogiannis, Nikolaos I.; Bakogiannis, Constantinos; Spyridopoulos, Ioakim; Stamatelopoulos, Kimon; Kanakakis, Ioannis; Vassilikos, Vassilios; Stellos, Konstantinos title: Involvement of Cardiovascular System As The Critical Point in Coronavirus Disease 2019 (COVID-19) Prognosis and Recovery date: 2020-06-10 journal: Hellenic J Cardiol DOI: 10.1016/j.hjc.2020.05.004 sha: 16f74d0eb9d4947902b8abae20a3808389365df9 doc_id: 1045115 cord_uid: 06jr58kz The novel coronavirus disease (COVID-19) pandemic has already caused more than 300,000 deaths worldwide. Several studies have elucidated the central role of cardiovascular complications in the disease course. Herein, we provide a concise review of current knowledge regarding the involvement of cardiovascular system in the pathogenesis and prognosis of COVID-19. We summarize data from 21 studies involving in total more than 21,000 patients from Asia, Europe and the USA indicating that severe disease is associated with the presence of myocardial injury, heart failure and arrhythmias. Additionally, we present the clinical and laboratory differences between recovered and deceased patients highlighting the importance of cardiac manifestations. For the infected patients, underlying cardiovascular comorbidities and especially existing cardiovascular disease seem to predispose to the development of cardiovascular complications, which are in turn associated with higher mortality rates. We provide mechanistic insights into the underlying mechanisms including direct myocardial damage by the virus and the consequences of the hyperinflammatory syndrome developed later in the disease course. Finally, we summarize current knowledge on therapeutic modalities and recommendations by scientific societies and experts regarding the cardiovascular management of COVID-19 patients. In early December 2019, the first cases of a pneumonia-like disease emerged in Wuhan, Hubei Province, China 1 . All cases were linked to a seafood market in the same city 2 and were confirmed to be associated with a novel RNA betacoronavirus, which was later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3,4 . On 11 February 2020, the novel disease was named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO) which declared a pandemic on 11 March 2020 5 . COVID-19's high reproduction number has led to worldwide expansion of the disease 6 and has gripped the world in a health and economic crisis 7,8 . SARS-CoV-2 is a round or elliptic betacoronavirus and has a diameter of approximately 60-140 nm 9 . It belongs to the large family of coronaviruses, which are responsible for 5-10% of all respiratory tract infections 10 . Coronaviruses have also been the cause of two previous infectious disease outbreaks; severe acute The high sequence homology of SARS-CoV-2 with bat coronavirus 13 and the vast number of coronaviruses carried by distinct bat species 32, 33 have suggested that SARS-CoV-2 has originated from bats 13 . The transmission of SARS-CoV-2 occurs mainly from person to person via respiratory droplets [34] [35] [36] and has an incubation period ranging from 2 to 14 days 37 or in extreme cases up to 32 days 38 . Li et al. analyzed the first 425 cases in Wuhan by 22 January 2020 and estimated the mean incubation period of COVID-19 at 5.2 days with the 95 th percentile of the distribution at 12.5 days 36 . Airborne transmission 39 and transmission through the oral-faecal route 40 higher R 0 in comparison to SARS-CoV, estimating the mean R 0 of SARS-CoV-2 at 3.28 by analyzing data from 12 studies 47 . However, since there has not been adequate evidence regarding how asymptomatic carriers contribute to the transmission rate of this novel infectious disease and how each treatment or preventive strategy affects it, the accurate estimation of R 0 is difficult. Gender differences have been reported in the epidemiology of COVID-19, as women have lower infection and mortality rates than men 29, 48 . A recent study in patients with heart failure found that circulating levels of ACE2 were higher in men than in women, suggesting increased ACE2 tissue expression which could contribute to susceptibility to SARS-CoV-2 infection and disease progress 49 . However, further studies are needed to elucidate the gap between sex difference and COVID-19 susceptibility and prognosis. Myocardial injury has been a remarkable finding, which contributes to worse prognosis (Figures 3 & 4) , in most patient cohorts with COVID-19 so far 34 As already described, high ACE2 expression is detected in cardiac tissue 63 and may therefore facilitate cellular entry of the virus resulting in endothelial dysfunction and myocardial damage ( Table 6 ). In particular, ACE2 is widely expressed in cardiomyocytes, cardiac pericytes and coronary endothelial cells 64 . Therefore, SARS-CoV-2 could directly enter cardiomyocytes and provoke myocardial injury. Further, pericytes, which are perivascular mural cells with high ACE2 expression, have been suggested as target host cells by SARS-CoV-2 64 . Considering the essential role of cardiac pericytes in maintaining endothelial cell function in capillary vessels, their infection could lead to coronary microvascular dysfunction and cardiac injury 64 . SARS-CoV-2 has also been shown to infect human blood vessel organoids in vitro 65 . Recent pathology reports provided evidence of direct endothelial cell infection and diffuse endothelial inflammation, which could suggest the induction of "endotheliitis" and endothelial dysfunction, potentially contributing to destabilization of coronary plaques, atherothrombosis and vascular disease 66 . Viral infections are recognized as one of the most frequent causes of infectious myocarditis which trigger the activation of the host antiviral immune response, including natural killer cells, macrophages and virus-specific T lymphocytes 67 . Similarly, an aberrant T-cell and monocyte response has been observed in COVID-19 patients leading to a systemic hyper-inflammatory response characterized by increased proinflammatory cytokine and chemokine production (tumor necrosis factor, IL-2, IL-6, IL-7 and CCL2 among others) 34, 48, 50, 68, 69 (Table 5) , (Figure 2 The binding of SARS-CoV-2 to ACE2 is expected to lead to internalization of ACE2 and loss of the external ACE2 catalytic effect 24, 93 . Therefore, the possible downregulation of ACE2 and the subsequent increase of the pro-atherosclerotic angiotensin II together with the decrease of the cardioprotective angiotensin 1-7 in patients with COVID-19 may ultimately compromise heart function 94,95 . Remarkably, severe COVID-19 has been associated with hypokalemia and higher blood pressure, supporting suggestions of decreased ACE2 function and augmented levels of angiotensin II after SARS-CoV-2 infection 96 . Current data regarding the incidence of heart failure among patients with COVID-19 are limited (Table 1) . Viral infections are the most common cause of myocarditis 97 . Despite the high recovery rates, nearly one out of three biopsy-proven myocarditis patients will later develop dilated cardiomyopathy 98 There are limited data to guide the clinical treatment strategies for COVID-19 and its cardiovascular complications. The best possible approach should be reached with a multidisciplinary team, which includes specialized infectious disease advice, and should be based upon the available information provided by the World Health Organization or reputable societies ( Table 7) . Numerous clinical trials are currently testing experimental therapies or re-purposing of current drugs for the treatment of COVID-19 131 . The participation of ACE2 in the pathogenesis of COVID-19, acting as a cell receptor for SARS-CoV-2 13 has caused increasing concern about the role of antihypertensive therapy with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II Chloroquine, an antimalarial agent with known anti-viral effects 141 Epidemiologists have forecasted that 40-70% of the world's population will be infected by SARS-CoV-2 in the coming year and will present with a wide range of clinical manifestations 157 . Apart from the direct effects of SARS-CoV-2 infection, patients who avoid infection may be affected by self-isolation and social distancing 158 . Hospital attendance and hospital admissions for diseases other than COVID-19 have been significantly decreased since the beginning of the pandemic 159 . There have been reports of significant decrease in the number of patients with acute coronary syndromes as well as large delays in presentation 160 163 , particularly in the era of a pandemic. 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