Cardiovascular complications of COVID-19: evidence, misconceptions, and new opportunities.

Abstract

On June 01, 2020, the outbreak of COVID-19 caused by SARS-CoV-2 has escalated to 6.3 million cases worldwide, including 374,000 deaths. Severe lung disease with acute respiratory distress syndrome represents one of the most common complications. Additionally, myocardial injury is present in more than a quarter of critical cases, manifesting either acutely on presentation or more insidiously as illness severity intensifies (1, 2, 3, 4). Clinical signs of cardiovascular disease include chest pain, fulminant myocarditis, arrhythmias, acute coronary artery disease, and heart failure. More recently, microvascular disease syndromes have been reported, including cutaneous reticular livedo (5, 6). Some cases of Kawasaki disease, in which blood vessels throughout the body become inflamed and can form aneurysms, have been also reported. However, this figure is lower than would be normally expected at this time of year when Kawasaki disease generally peaks (https://www.rcpch. ac.uk/news-events/news/college-responds-recent-reportscovid-19-children). Media articles on Kawasaki disease were confusing and have caused public concern. This calls for cautious interpretation and communication of research outputs, a difficult task in a global emergency requiring immediate medical solutions. Two COVID-19 priority studies in the UK (DIAMONDS (Central Portfolio Management System 45537) and ISARIC (UK Clinical Research Network 14152)) are collaborating in a study exploring prevalence of the disease and underpinning mechanisms. Researchers around the world are racing to learn how the virus behaves and which health factors put people most at risk. The crucial question they are trying to work out is whether there may be some specific mechanism in cells of the lung and heart that could mean some people suffer respiratory complications and heart attacks more than others. While the increased frailty of cardiovascular patients may account for the susceptibility to infection and organ damage, the reason why COVID-19 causes cardiovascular complications is less obvious. SARS-CoV-2 has adopted a successful tactic to infect, damage, and spread. The virus binds with its spike protein to the surface receptor angiotensin converting enzyme 2 (ACE2) to unlock human cells and begin infection. We know relatively little of the stoichiometry of the virus – human cell receptor interaction. The minimum number necessary for infection varies between different viruses and it is not clear what is minimum infectious dose for COVID-19. Likewise, it remains to be established whether repeated exposures or a single contact with massive doses of the virus, like in the case of clinical staff caring patients who are not known to be infected, can increase the risk of developing severe forms of the disease. The second element to consider is the binding affinity of the viral spike protein for the human cell receptor. The binding of SARS-CoV-2 to ACE2 is stronger than previous coronaviruses, due to difference in key amino acid residues allowing for enhanced interactions between the virus and human cells. This may explain the larger global impact of COVID-19 as compared with SARS. Interfering with binding of SARS-CoV-2 to ACE2 could be a means to attenuate infection, while waiting for vaccine availability. In this respect, the use of the extracellular domain of ACE2 could represent a solution to sponge the virus before it can reach cell membrane bound ACE2 receptors. It is not clear whether having high circulating levels of ACE2 are protective, neutral, or negative in terms -20-0008 ID: XX-XXXX;