key: cord-271653-4q2olzx1
authors: Libby, Peter
title: The Heart in COVID19: Primary Target or Secondary Bystander?
date: 2020-04-10
journal: JACC Basic Transl Sci
DOI: 10.1016/j.jacbts.2020.04.001
sha: 
doc_id: 271653
cord_uid: 4q2olzx1

Summary: In the throes of the current COVID-19 pandemic, interest has burgeoned in the cardiovascular complications of this virulent viral infection. As troponin, a biomarker of cardiac injury, often rises in hospitalized patients, its interpretation and actionability require careful consideration. Fulminant myocarditis due to direct viral infection can certainly occur, but patients with increased oxygen demands due to tachycardia and fever, and reduced oxygen delivery due to hypotension and hypoxemia can cause myocardial injury indirectly. Cytokines released during the acute infection can elicit activation of cells within pre-existing atherosclerotic lesions, augmenting thrombotic risk and risk of ischemic syndromes. Moreover, microvascular activation by cytokines can cause not only myocardial injury but harm other organ systems commonly involved in COVID-19 infections including the kidneys. Dealing with the immense challenge of COVID-19 disease, confronted with severely ill patients in dire straits with virtually no rigorous evidence base to guide our therapy, we must call upon our clinical skills and judgment. These touchstones can help guide us in selecting patients who might benefit from the advanced imaging and invasive procedures that present enormous logistical challenges in the current context. Lacking a robust evidence base, pathophysiologic reasoning can help guide our choices of therapy for individual clinical scenarios. We must exercise caution and extreme humility, as often plausible interventions fail when tested rigorously. But act today we must, and understanding the multiplicity of mechanisms of myocardial injury in COVID-19 infection will help us meet our mission unsupported by the comfort of strong data.

In the throes of the current COVID-19 pandemic, interest has burgeoned in the cardiovascular complications of this virulent viral infection. As troponin, a biomarker of cardiac injury, often rises in hospitalized patients, its interpretation and actionability require careful consideration. Fulminant myocarditis due to direct viral infection can certainly occur, but patients with increased oxygen demands due to tachycardia and fever, and reduced oxygen delivery due to hypotension and hypoxemia can cause myocardial injury indirectly. Cytokines released during the acute infection can elicit activation of cells within pre-existing atherosclerotic lesions, augmenting thrombotic risk and risk of ischemic syndromes. Moreover, microvascular activation by cytokines can cause not only myocardial injury but harm other organ systems commonly involved in COVID-19 infections including the kidneys. Dealing with the immense challenge of COVID-19 disease, confronted with severely ill patients in dire straits with virtually no rigorous evidence base to guide our therapy, we must call upon our clinical skills and judgment. These touchstones can help guide us in selecting patients who might benefit from the advanced imaging and invasive procedures that present enormous logistical challenges in the current context. Lacking a robust evidence base, pathophysiologic reasoning can help guide our choices of therapy for individual clinical scenarios. We must exercise caution and extreme humility, as often plausible interventions fail when tested rigorously. But act today we must, and understanding the multiplicity of mechanisms of myocardial injury in COVID-19 infection will help us meet our mission unsupported by the comfort of strong data.

In the throes of the current pandemic, intense interest has burgeoned in cardiovascular involvement by the novel coronavirus known as COVID-19. Cardiologists as well as other practitioners who care for those with this virulent viral infection, and indeed the general public as To approach this question, we need to distinguish myocarditis due to infection of cardiac cells from myocardial ischemic injury. Flow embarrassment to the heart muscle can result from lesions in epicardial coronary arteries or in the heart's microvasculature. Cardiac ischemia can also arise from an imbalance between oxygen supply and demand, a type 2 acute coronary syndrome, a situation that can prevail in acute infections, particularly those that affect the lungs like COVID19. Several of these pathophysiologic pathways to myocardial ischemia may affect those without substantial or obstructive coronary artery atherosclerosis. Hence, the distinction between these various mechanisms has important clinical consequences. The need for arduous imaging studies and invasive evaluation may vary considerably in these different scenarios, an issue of great import in acute care facilities stretched to or beyond their limits during a pandemic with a readily contagious and virulent infectious agent such as COVID19. Considering the pathophysiologic paths to cardiac injury can inform judgement regarding the necessity of transport of severely ill patients and the performance invasive procedures. 

The demographic most often affected by life-threatening and fatal COVID-19 has a high prior probability of pre-existing atherosclerotic lesions: the elderly, evident male predominance, and those with pre-existing lung disease including that associated with cigarette smoking, a risk factor for atherosclerosis. Remote infections such as the severe pneumonitis that too commonly complicates COVID-19 can elicit an acute exacerbation of the chronic smoldering inflammation that characterizes coronary atherosclerotic lesions ( Figure 2 ). The inflammatory cells at a site of regional infection such as the lungs in COVID19 pneumonitis can produce cytokines such as interleukins (IL)-1 and -6, and tumor necrosis factor, mediators that not only propagate local inflammation but can enter the systemic circulation. Such circulating cytokines can stimulate macrophages within the plaque to augment local cytokine production and provoke an increase in tissue factor expression that renders lesions more thrombogenic. We have referred to this local response to systemic stimuli as an "echo" phenomenon. 4, 6 These same systemic cytokines can stimulate leukocyte adhesion molecule expression on the endothelial cells overlying established atheroma, boosting local recruitment of these inflammatory cells. These alterations in preexisting plaques can enhance their propensity to disrupt, be it by fibrous cap fissure or by superficial erosion, and provoke an acute coronary syndrome.

Even in individuals without pre-existing epicardial coronary artery disease, systemic cytokines released from sites of local infections such as in pneumonitis can affect intermural coronary vessels. They also can activate the microvascular endothelium, predisposing to vasomotor abnormalities, augmented thrombosis, reduced fibrinolysis, increased leukocyte adhesion, and other aspects of dysfunction of the microvessels of the coronary circulation. These effects wrought by distant infection can contribute to myocardial ischemia even in the absence of epicardial atherosclerosis, and could compound cardiac injury in those with flow limitation due to plaque in the larger coronary arteries.

The cardinal signs of infection include fever and tachycardia, circumstances that increase the oxygen requirements of the myocardium (Figure 3 ). Hypoxemia produced by pneumonitis can decrease oxygen delivery to the myocardium. Hypotension in sepsis and in cytokine storm can impair coronary perfusion. Together these systemic effects of infection conspire to limit blood flow in the coronary arteries, and reduce oxygen supply while augmenting myocardial oxygen demand. These consequences of infection predispose to myocardial ischemia. They may aggravate the consequences of plaques that would not limit flow or provoke ischemia under usual conditions, and could produce ischemic injury even in those with little or no coronary artery atherosclerosis.

At one end of the spectrum, a young individual with pristine coronary arteries might suffer severe myocardial injury due to a fulminant myocarditis caused by direct infection with COVID-19 (Figure 1, left) . At the other extreme, a person with advanced coronary atherosclerosis could suffer a type 1 or type 2 acute myocardial infarction without direct viral infection of cardiac cells (Figure 1, right) . Although we are early in our experience with this novel coronavirus disease, most patients affected by COVID-19 encountered by cardiologists may have more secondary cardiac involvement then primary infective myocarditis. Thus, many of our patients may fall into the zone between the two bookends depicted in Figure 1 .

It behooves us to consider the multiple mechanisms of cardiac injury in patients with COVID-19 disease ( Figure 4) . As in the BC (before COVID) era, interpretation of rises in cardiac troponin requires consideration of the context of the clinical situation. Not all rises in this biomarker of cardiac injury will result from coronary artery disease requiring invasive assessment or intervention. We urgently need randomized clinical trials to assess the value of interventions including anti-inflammatory therapies ranging from glucocorticoids to cytokine antagonism in addition to antiviral agents as outlined in the elegant exposition of Atri et al. 3 Dealing with the immense challenge of COVID-19 disease, and confronted with severely ill patients in dire straits with virtually no rigorous evidence base to guide our therapy, we need to call upon our clinical skills and judgment. These touchstones can help guide us in selecting patients who might benefit from the advanced imaging and invasive procedures that present enormous logistical challenges in the current context. In the absence of a robust evidence base, we will also need to invoke pathophysiologic reasoning to guide our choices of therapy for each individual clinical scenario. We must do so with caution and extreme humility, recognizing how often plausible interventions fail when tested rigorously. But act today we must, and the overview of Atri et al. and other recent compendia will help us meet our mission unsupported by the comfort of strong data. 3 

Coronavirus fulminant myocarditis treated with glucocorticoid and human immunoglobulin

Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19)

COVID-19 for the Cardiologist: A State-of-the-Art Review of the Virology, Clinical Epidemiology, Cardiac and Other Clinical Manifestations and Potential Therapeutic Strategies. JACC: Basic to Translational Science

Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research

Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week

Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease