COVID-19 and the Cardiovascular System

Pathophysiology and Potential Mechanisms of Cardiovascular Injury From COVID-19

SARS-CoV-2 is primarily a respiratory virus, and its predominant target is the lung. Like any major extrapulmonary organ, the heart and the general vasculature are also broadly susceptible in two ways: (1) direct infection of the cardiac tissue by the virus; and (2) indirect or systemic effects resulting from the host inflammatory response, endothelial activation, thrombotic changes, and coagulation dysfunction. ^, Fig. 6.1 provides an overview of these mechanisms of cardiac injury. The pathophysiology of cardiovascular injury is largely dependent on the renin-angiotensin system (RAS), which plays a key role in cardiovascular homeostasis.

Renin-Angiotensin System

The local RAS ^, plays a key role in mediating and channeling the mechanistic forces responsible for cardiovascular injury. The RAS system and more specifically the hormone angiotensin is responsible for the maintenance of the cardiovascular homeostasis. The classic and counterregulatory renin-angiotensin (RA) pathways play key regulatory roles in this modulation of cardiovascular physiology. The key components of the classic RA pathway are (1) angiotensinogen is converted to angiotensin-1 by renin and (2) angiotensin-1 is further processed by the angiotensin-converting enzyme (ACE) to angiotensin-2. Angiotensin-2 induces vasoconstriction by binding to angiotensin-1 receptors (AT1Rs) on the vascular smooth muscle cells and also by the release of aldosterone from the adrenal cortex. In addition to vasoconstriction, activation of AT1R results in sympathetic stimulation, cardiac hypertrophy, fibrosis, and inflammation.

The counterregulatory RA pathway has two salient components: (1) Angiotensin-1 is cleaved by angiotensin-converting enzyme 2 (ACE2) to generate angiotensin 1-9; (2) angiotensin 1-7 is formed by cleavage of angiotensin-2 by ACE2. Angiotensin 1-9 activates angiotensin-2 receptors (AT2R) to trigger nitric oxide production resulting in vasodilatation and concomitant lowering of BP. Angiotensin 1-7 binds to the proto-oncogene Mas receptor (MasR) causing dilatation of blood vessels and a reduction in BP. Both angiotensin 1-9 and angiotensin 1-7 peptides are cardioprotective and reduce inflammation, cardiac hypertrophy, and fibrosis. Both receptors AT1R and AT2R are expressed in the heart and blood vessels. Fig. 6.2 shows the regulatory and counterregulatory arms of the RAS.

ACE2 is a key element of the counterregulatory arm of RAS and is an essential regulator of heart function. ACE2 is also the functional receptor for SARS-CoV-2; the SARS-CoV-2 spike protein binds to ACE2 for cellular entry of the virus. ACE2 has been shown to be upregulated in HF and ACE2 mRNA levels are elevated in myocardial infarction (MI). Inflammatory processes play a key role in the pathogenesis and natural history of many CVDs, including atherosclerosis, hypertension, cardiomyopathy, MI, and cardiac failure. ^, SARS-CoV-2 infection causes a functional depletion of ACE2 as the virus binds to ACE2 receptors for cellular entry. This causes downregulation of the counterregulatory arm of RAS and accumulation of angiotensin-2. Angiotensin-2 in turn binds to AT1R, triggering cardiac injury.

Direct Infection of the Myocardium

Direct entry of SARS-CoV-2 into cells is facilitated by the affinity of the viral spike protein S to the host cell ACE2 receptor, with the host protease transmembrane protease serine 2 (TMPRSS2), acting as the enabler. ^, Many organs and tissues of the body express both ACE2 and TMPRSS2, including the lungs, heart, gut, liver, kidney, neurons, joints, and eye, and this explains the tropism and potential of the virus to cause injury to these organs and tissues. Moreover, Chen et al. showed that although the expression levels of ACE2 are lower in the heart compared with the gut and kidney, the levels were higher in the heart than in the lungs, which act as the primary targets for SARS-CoV-2. Fig. 6.3 presents the ACE2 receptor expression profile in the cardiovascular system.

Different studies and case reports have demonstrated the presence of SARS-CoV-2 genomic RNA or viral particles morphologically identified as SARS-CoV-2 in myocardial tissue obtained from biopsy-confirmed myocarditis patients. ^{, ,} Tavazzi et al. reported one of the earliest cases of biopsy-proven myocardial localization of viral particles with the morphology of a coronavirus in a COVID-19 patient who presented with cardiogenic shock. Escher et al. identified SARS-CoV-2 genomic RNA in 5 of 104 endomyocardial biopsy (EMB) samples of patients with suspected myocarditis or unexplained HF. A more recent study by Bearse et al. looked at 41 consecutive autopsies of patients who died from COVID-19 to understand the relationship of myocardial injury to SARS-CoV-2 infection. Based on in situ hybridization (ISH) and NanoString transcriptomic (NST) profiling, the researchers determined that endomyocardial infection by SARS-CoV-2 was present in 30 of 41 cases (73%). Cellular targets for SARS-CoV-2 include cardiomyocytes, pericytes, fibroblasts, and resident macrophages of the heart. Fig. 6.4 provides additional details of the mechanism of SARS-CoV-2 entry into the heart and blood vessels.

Based on ISH, NST profiling for virus positivity and histopathological findings of inflammatory infiltrates characteristic of myocyte injury for defining myocarditis, the researchers partitioned their study sample (n = 41) in three groups—virus-positive with myocarditis (n = 4), virus-positive without myocarditis (n = 26), and virus-negative without myocarditis (n = 11) to study the relationship between cardiac pathological changes and cardiac infection by the SARS-CoV-2 virus. Table 6.1 presents the details of the pathological findings in the various groups. Electrocardiographic (ECG) abnormalities in the form of atrial fibrillation, premature atrial complexes, prolongation of QTc, and nonspecific ST segment and T wave alterations were observed disproportionately in patients whose hearts were infected with SARS-CoV-2.

Pellegrini et al. in their histopathological study of 40 patients hospitalized with COVID-19 who subsequently died, report that SARS-CoV-2 RNA was much more prevalent in the lung tissue (34/40 [85%]) compared with cardiac tissue (8/40 [20%])

Cytokine-Mediated Cardiac Injury

The systemic inflammatory response, and the resulting concomitant cytokine storm, is a major contributor to cardiac injury from SARS-CoV-2 infection. ^{, , , ,} The aggravated inflammatory reaction resulting in increased cytokine production and release occurring in critically ill patients leads to the development of disseminated intravascular coagulopathy (DIC). In a study of 183 hospitalized patients with COVID-19 pneumonia, Tang et al. reported that DIC was observed in most of the 21 patients who did not survive. DIC could lead to microvascular thrombosis in coronary vessels resulting in myocardial injury. ^, Fig. 6.5 provides a summary of the cytokine storm phenomenon and its salient characteristics.

COVID-19–Associated Thrombosis

Critically ill hospitalized patients are at a high risk for thromboembolic complications. ^, In a cohort of 170 COVID-19 patients in intensive care in Boston area hospitals, more than 35% developed arterial or venous thromboemblism. COVID-19–associated coagulopathy (CAC) has been postulated as a distinct condition separate from DIC and coagulation abnormalities resulting from acute respiratory distress syndrome (ARDS). ^{, ,} In the natural history of COVID-19, dysregulated coagulation has been documented in various studies as contributing to increased disease severity and higher mortality. ^{, ,} The causative mechanisms of CAC are multifactorial. Direct invasion of the vascular endothelium by SARS-CoV-2, inflammatory cytokines such as interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha, and coagulation factors such as factor VIII, von Willebrand factor, and angiopoietin-2 are all significant contributors to the prothrombotic state, resulting in thrombus formation in COVID-19. ^,

DIC is characterized by a marked elevation in d -dimer and prothrombin time (PT) with concomitant reduction in fibrinogen and significant thrombocytopenia. In CAC, d -dimer and fibrinogen are elevated and the PT is not markedly increased. Thrombocytopenia is also not a characteristic feature of CAC. However, the CAC can evolve into a decompensated coagulopathy in critically ill COVID-19 patients. Fibrinolysis suppression leading to fibrinolytic shutdown also has been observed in severe COVID-19 complicated by CAC. ^, There seems to be significant overlap in the pathophysiology of DIC and CAC. However, arterial thrombosis and vascular complications are characteristic of CAC and microvascular thrombosis in coronary arteries is a distinct possibility.

Bois et al. in their histopathological study of 15 COVID-19 patients found nonocclusive fibrin microthrombi without ischemic injury in 12 cases, but its clinical significance is not clear. A larger histopathological study by Pellegrini et al. that studied the hearts of 40 patients who died from COVID-19 reported that 14 of 40 subjects (35%) had evidence of cardiac injury in the form of myocyte necrosis. Most of them, 11 of 14 (79%), demonstrated focal myocyte necrosis; the major cause of myocyte necrosis was cardiac microthrombi, which were observed in 9 of 14 (64%) hearts with myocyte necrosis. Both of these studies demonstrate the significance of microvascular thrombosis as a cause of cardiac injury in hospitalized patients with COVID-19.

Another potential pathophysiological mechanism of cardiac injury is the downregulation of ACE2 in SARS-CoV-2 infection. This was demonstrated in the mouse model by Oudit et al. As mentioned earlier, ACE2 has been shown to have a protective effect on the heart and blood vessels based on its antiinflammatory, antifibrotic, antioxidative, and vasodilatory properties. ACE2 converts angiotensin-2 to angiotensin 1-7, which reduces vasoconstriction mediated by the RAS. The downregulation of ACE2 causes angiotensin-2 to be upregulated, which results in an increased production of inflammatory cytokines ^, (see Fig. 6.2 ).