key: cord-0761561-axgnqwl0 authors: Sheth, Aakash R; Grewal, Udhayvir S; Patel, Harsh P; Thakkar, Samarthkumar; Garikipati, Subhash; Gaddam, Jashwanth; Bawa, Danish title: Possible Mechanisms Responsible for Acute Coronary Events in COVID-19 date: 2020-07-21 journal: Med Hypotheses DOI: 10.1016/j.mehy.2020.110125 sha: ad5aa8ec8f16fe6c7762bb31d8ee07ed217b9a2d doc_id: 761561 cord_uid: axgnqwl0 The novel coronavirus (SARS-CoV-2) is primarily a respiratory pathogen and its clinical manifestations are dominated by respiratory symptoms, the most severe of which is acute respiratory distress syndrome (ARDS). However, COVID-19 is increasingly recognized to cause an overwhelming inflammatory response and cytokine storm leading to end organ damage. End organ damage to heart is one of the most severe complications of COVID-19 that increases the risk of death. We proposed a two-fold mechanism responsible for causing acute coronary events in patients with COVID-19 infection: Cytokine storm leading to rapid onset formation of new coronary plaques along with destabilization of pre-existing plaques and direct myocardial injury secondary to acute systemic viral infection. A well-coordinated immune response is the first line innate immunity against a viral infection. However, an uncoordinated response and hypersecretion of cytokines and chemokines lead to immune related damage to the human body. Human Coronavirus (HCoV) infection causes infiltration of inflammatory cells that cause excessive production of cytokines, proteases, coagulation factors, oxygen radicals and vasoactive molecules causing endothelial damage, disruption of fibrous cap and initiation of formation of thrombus. Systemic viral infections also cause vasoconstriction leading to narrowing of vascular lumen and stimulation of platelet activation via shear stress. The resultant cytokine storm causes secretion of hypercoagulable tissue factor without consequential increase in counter-regulatory pathways such as AT-III, activated protein C and plasminogen activator type 1. Lastly, influx of CD4+ T-cells in cardiac vasculature results in an increased production of cytokines that stimulate smooth muscle cells to migrate into the intima and generate collagen and other fibrous products leading to advancement of fatty streaks to advanced atherosclerotic lesions. Direct myocardial damage and cytokine storm leading to destabilization of pre-existing plaques and accelerated formation of new plaques are the two instigating mechanisms for acute coronary syndromes in COVID-19. The novel coronavirus (SARS-CoV-2) is primarily a respiratory pathogen and its clinical manifestations are dominated by respiratory symptoms, the most severe of which is acute respiratory distress syndrome (ARDS). However, COVID-19 is increasingly recognized to cause an overwhelming inflammatory response and cytokine storm leading to end organ damage. End organ damage to heart is one of the most severe complications of COVID-19 that increases the risk of death. We proposed a two-fold While there is a lack of medical literature regarding the association of acute coronary events in COVID-19 patients, data can be extrapolated from previous clinical and epidemiological studies in Influenza and acute inflammatory conditions 6-9 that are also known to cause systemic inflammatory stress. Existing studies have proposed multiple pathophysiologic mechanisms for AMI in the setting of these viral infections. These include, inflammatory and increased shear stress causing plaque rupture leading to acute coronary event, aggravation of pre-existing coronary artery disease causing more severe cardiac injury and other direct and indirect causes of myocardial injuries. In this piece, we aim to further hypothesize and discuss possible pathophysiologic mechanisms for acute coronary events in COVID-19 infection. Respiratory viral infections have been known to be associated with an increased risk of cardiovascular morbidity and mortality 7 . Systemic inflammation caused by the viral infections plays a key role in the pathogenesis of acute coronary syndromes in these patients 19 . We hypothesize a bi-faced mechanism for the occurrence of acute coronary events in an acute systemic viral infection: 1. Rapid new onset formation of coronary plaques along with acute plaque change (APC) in pre-existing plaques, Acute myocardial infarction in influenza and human coronavirus like infections is well studied. 7 Given the scarcity of information about COVID-19 and its stark similarity with respiratory viral syndromes, it is prudent to extrapolate information to better understand the pathophysiology behind cardiovascular complications of COVID-19. A pivotal step in the evolution of acute coronary syndrome is the activation of platelets and formation of platelet thrombi. Platelets can be directly activated by pathogens which can in-turn augment the inflammatory process 25, 26 . Acute infections such as influenza also cause coronary vasoconstriction and stimulate platelet activation via shear stress 27 . Cytokine storm induced by respiratory viral infections also leads to increased secretion of tissue factor without consequential increase in counter-regulatory pathways such as anti-thrombin III activity, activated protein C and plasminogen activator inhibitor type 1 [28] [29] [30] [31] [32] . This leads to the formation of new onset thrombi that can propagate in size causing myocardial ischemia. Furthermore, severe hypoxemia induced by respiratory viral infections, increased cardiac metabolic demands induced by the subsequent cytokine storm and the eventual decrease in mean arterial pressure owing to sepsis causes further development of myocardial ischemia 33 . There is some evidence suggesting presence of heightened plasma viscosity during fever 34 , which further increases the chances of myocardial ischemia. Atherosclerosis is an inflammatory condition that begins with endothelial injury. A variety of stimuli are known to cause endothelial injury and help accelerate plaque formation. Improved understanding of underlying mechanisms by which COVID-19 causes myocardial injury will help thousands of individuals currently infected by the SARS-CoV2 to take preventive measures and follow up more intensively to achieve early detection, prevention and treatment of subsequent atherosclerotic disease and new onset myocardial injury. While it is known that repeated influenza infections cause proportionally increased risk of MI, it is yet to be determined if repeated infection with SARS-CoV2 is associated with increased risk of MI. However, based on the knowledge of common mechanisms by which systemic viral infections cause multi-organ damage, it is rational to assume that re-infection with SARS-CoV2 and subsequent infection with other viruses will lead to super-added myocardial injury. Therefore, further research is needed to study in detail, the pathophysiologic mechanisms underlying this association and identify high risk groups that can possibly benefit from intensive cardiovascular screening and follow-up. The authors have no disclosures or conflicts of interest. 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