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.

Direct and Indirect Mechanisms of Cardiac Injury in COVID-19.

There are two direct causes of cardiac injury—direct infection of the myocardium by the SARS-CoV-2 virus and direct renin-angiotensin system (RAS)–mediated injury, which is caused by the local cardiac RAS. The three indirect mechanisms are the cytokine-mediated cardiac injury, COVID-19 associated coagulation (thrombosis), and the injury resulting from systemic RAS. (Created with Biorender.)

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.

Renin-Angiotensin System (RAS).

Both the classic regulatory RAS pathway (Angiotensinogen → Angiotensin-1 → Angiotensin-2) and the counterregulatory pathway (Angiotensin-1 → Angiotensin 1-9, Angiotensin-2 → Angiotensin 1-7) are shown. The classic RAS arm can induce cardiac injury when excessive angiotensin-2 binds to AT1R. When SARS-CoV-2 saturates angiotensin-converting enzyme-2 (ACE2), which the virus binds for cellular entry, the counterregulatory arm is downregulated as less ACE2 is available. The counterregulatory RAS arm is cardioprotective. AT1R, Angiotensin type 1 receptor; AT2R, angiotensin-2 receptor angiotensin-2 receptor, MasR, MAS receptor. (Created with Biorender.)

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.

Expression Profile of Angiotensin-Converting Enzyme-2 (ACE2) in the Cardiovascular System.

ACE2 is expressed in the cardiomyocytes and pericytes of the heart and the endothelial and smooth muscle cells of the vasculature. The clinical and pathological manifestations resulting from SARS-CoV-2 infection of the heart and the vasculature are also enumerated. (Created with Biorender.)

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.

SARS-CoV-2 Viral Entry.

The virus enters the target cells—cardiomyocytes and pericytes—by binding to the angiotensin-converting enzyme-2 receptor. The viral entry and activation are facilitated by the cleavage of the SARS-CoV-2 S glycoprotein by TMPRSS2. Activation of the S2 domain of the S protein results in the fusion of the viral and host cell membrane, enabling entry of viral RNA into the host cell. TMPRSS2, Transmembrane protease serine 2. (Created with Biorender.)

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.

Cytokine Storm.

The immune response goes into overdrive after infection of the lung alveolar cells by SARS-CoV-2, resulting in cytokine release. The cytokines attract more immune cells, creating a vicious cycle causing large amounts of cytokines and chemokines to be released. Apart from local organ damage, a prolonged systemic elevation of large quantities of inflammatory cytokines and chemokines occurs, leading to damage to other vital organs such as the heart, liver, kidneys, and the brain. DC, Dendritic cell; IL-6R, interleukin-6 receptor; NK, natural killer (cell). (Modified from Lu L, Zhang H, Zhan M, et al. Preventing mortality in COVID-19 patients: which cytokine to target in a raging storm? Front Cell Dev Biol. 2020;8:677, with permission (creative common license. Created with Biorender.)

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 ).

Myocarditis

Myocarditis can result from direct viral myocardial invasion or consequent to systemic inflammation. A clinical diagnosis of myocarditis is arrived at based on laboratory and imaging markers of myocyte involvement such as elevated troponin levels and cardiac magnetic resonance (CMR) imaging features. ^{, ,} It is important to exclude CAD, and when CMR is not feasible, it is recommended that cardiac CT angiography may be performed. The clinical presentation of myocarditis can be variable from mild disease to fulminant myocarditis complicated by arrhythmias, HF, and cardiogenic shock. ^, Atrial and ventricular arrhythmias are quite common in the setting of myocarditis. ^, Various pathophysiological mechanisms have been postulated for the observed arrhythmicity in myocarditis. ^, Fig. 6.7 provides an illustration of these mechanisms leading to various types of arrhythmias in myocarditis. Myocarditis is an uncommon pathological diagnosis occurring in 5% to 10% of highly selected cases undergoing autopsy or EMB. ^{, ,} Elevated troponin levels have been shown to be associated with higher mortality in the setting of COVID-19. ^, The sequelae of myocarditis such as low-grade inflammation and fibrosis play a major role in disease progression leading to HF.

Pathophysiological Mechanisms of Arrhythmias in Myocarditis.

The figure illustrates four postulated mechanisms of arrhythmia generation in the setting of myocarditis: (1) direct injury to the cardiac muscle cells, (2) viral pericarditis with effusion, (3) microvascular disease due to infection of the pericytes by SARS-CoV-2, and (4) the systemic mechanism of cytokine storm. (Created with Wikimedia and Servier medical art icons under creative commons license.)

It is important to distinguish fulminant myocarditis from sepsis; other differential diagnoses include acute coronary syndrome and sepsis-related cardiomyopathy. Echocardiography, CMR, and cardiac computed tomography (CT) are useful in resolving the differential diagnosis; for a definitive diagnosis, EMB may be required.

Acute Coronary Syndrome

Severe systemic inflammation, increased levels of circulating cytokines, and a hypercoagulable state observed in COVID-19 have the potential for increased risk for AMI. Based on a study of 28 COVID-19 patients with ST-elevation myocardial infarction (STEMI) from the Lombardy region of Italy, Stefanini et al. reported that the first clinical manifestation of COVID-19 could be STEMI. Coronary angiography revealed a culprit lesion requiring revascularization in only 17 patients (61%), whereas the remaining 11 patients (39%) did not have obstructive CAD. Diaz-Arocutipa et al. performed a systematic review of 42 studies covering 161 COVID-19 patients with STEMI, which found obstructive CAD as the cause for ST elevation in 133 patients (83%). However, the mortality rate in the two groups, obstructive CAD, and nonobstructive CAD were similar (≈30%).

The causes of acute myocardial injury in patients without CAD in the context of COVID-19 include myocarditis, cytokine storm and stress cardiomyopathy; hypoxemia, microvascular dysfunction resulting from small vessel thrombosis, and endotheliitis also have been postulated as potential causes in this setting. ^,

Heart Failure

HF occurs commonly in patients hospitalized with COVID-19. The prevalence is 25% among patients hospitalized with COVID-19 and about a third in patients whose condition is critical. ^, SARS-CoV-2 infection can also worsen preexisting cardiac failure, leading to a decompensated heart. Based on a retrospective study of more than 132,000 hospitalized patients with a history of HF over a period of 6 months, the mortality rate among the three categories of hospitalized patients were as follows: (1) Non-COVID non-HF, 4512 deaths (4.5%); (2) non-COVID acute HF, 617 deaths (2.6%); and (3) COVID-19, 2026 deaths (24.2%). Among hospitalized COVID-19 patients with a history of HF, with a high risk for complications, 1 in 4 patients died during the course of hospitalization. As discussed earlier, SARS-CoV-2 uses the ACE2 receptor for cellular entry. The ACE2 receptor is known to be upregulated in the failing heart, and this makes patients with a history of HF more susceptible to SARS-CoV-2 and potentially a more severe form of COVID-19. Fig. 6.8 illustrates the pathophysiological mechanisms contributing to severe disease in COVID-19 patients presenting with a history of HF.

Adverse COVID-19 Outcomes in Patients With History of Heart Failure (HF).

Angiotensin-converting enzyme-2 (ACE2) receptor is upregulated in individuals with a history of HF, making them more susceptible to SARS-CoV-2 and a severe disease course of COVID-19. In HF, Toll-like receptor-4 (TLR-4) is upregulated, and both the innate and adaptive immune systems are also activated with release of cytokines and chemokines. The activation of the innate immune response is mediated through PAMPs (derived from SARS-CoV-2) and DAMPs (released from compromised myocytes) binding to TLR-4. The proinflammatory cytokines that are released produce a negative inotropic effect. The negative inotropic effect causing reduced myocardial contractility, combined with the release of chemokines and endothelial cell dysfunction, result in further aggravation of HF, causing more severe disease and adverse outcomes. DAMPs, Damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns. (Created with Servier medical art icon under creative commons license and Biorender.)

Cardiac Arrhythmias

Early reports of the incidence of arrhythmias occurring in hospitalized patients with COVID-19 in Wuhan varied from 6% for ventricular arrhythmias to 17% for all types of arrhythmias. Based on their study of 700 patients hospitalized with COVID-19 at the University of Pennsylvania Hospital, Bhatla et al. reported 53 arrhythmic events: 9 cardiac arrests, 25 atrial fibrillations, 9 clinically significant bradyarrhythmias, and 10 nonsustaining ventricular tachycardias. The cardiac arrests were independently associated with acute mortality whereas the other three types of arrhythmias did not independently contribute to increased mortality.

Based on a retrospective study of 4526 hospitalized patients worldwide with COVID-19, Coromilas et al. reported an incidence of arrhythmias in 827 (18%) patients, most without a history of arrhythmias. Atrial fibrillation, atrial flutter, and supraventricular tachycardia were observed in 82% of the patients, ventricular arrhythmias were seen in 21%, and 23% developed bradyarrhythmias. Presence of arrhythmias resulted in an adverse prognosis; approximately 40% had to be mechanically ventilated, and the mortality in the arrhythmia group was 50%.

Thromboembolic Events

VTE is common in hospitalized patients with COVID-19. Wichmann et al., in their postmortem study of 12 consecutive deceased patients who had been hospitalized with COVID-19, found a high incidence of VTE (7/12 [58%]). Piazza et al. observed an incidence of major arterial or venous thromboembolic event in in 60 of 170 (35%) patients with COVID-19 admitted to the intensive care unit (ICU), and in 6 of 229 (3%) in patients undergoing nonintensive care; DVT in 39 of 170 (23%) in the ICU setting and none in the non-ICU setting; PE in 3 of 170 (2%) in the ICU setting and 5 of 229 (2%) in the non-ICU setting. Ribes et al. in their review of thromboembolic events in COVID-19 reported a range of 25% to 69% for VTE in ICU setting, 15% to 53% for DVT in the non-ICU setting, 23% to 86% for DVT in the ICU setting, and an incidence of ≈20% for PE. In a multicenter cohort study of 1240 hospitalized patients with COVID-19, Fauvel et al. reported an incidence of PE in 103 cases (8.3%).

Although d -dimer is a nonspecific marker of inflammation, a high level of d -dimer has been shown to be associated with adverse outcomes of severe and critical illness and higher mortality in hospitalized patients with COVID-19. ^{, ,} Prolonged PT also has been well-documented in hospitalized patients with COVID-19, ^, with worse prognosis and higher mortality associated with increase in PT. ^, The reduction in platelet count in hospitalized patients with COVID-19 has been mild to moderate but not clearly associated with severity of the disease. However, Zhou et al. reported that moderate thrombocytopenia was more frequent in nonsurvivors than among survivors.

Coronary Artery Disease

Based on their study of 8438 patients hospitalized with COVID-19 in the New York City area, of whom 9% had CAD, Kuno et al. reported that patients with CAD had significantly higher rates of mechanical ventilation and mortality. The relative risk for CAD was markedly higher for both mechanical ventilation and death in patients 50 years and younger. Phelps et al., in their study of 4090 COVID-19–positive patients in Denmark, found that among patients who had severe disease or who died within 30 days of COVID-19 diagnosis, 20% had a history of CAD, and the representation of patients with a history of CAD in the nonsevere disease manifestation group was only 10%.

Hypertension

Although the risk for infection with SARS-CoV-2 remains the same for hypertensive and normotensive individuals, patients with hypertension are at higher risk for developing a more severe disease and increased mortality. However, Savoia et al. and Kreutz et al. argued that a direct role for hypertension as an independent risk factor for higher mortality in COVID-19 has not been clearly established. Because the prevalence of hypertension is higher in the older population, who have disproportionately suffered severe manifestations of COVID-19 resulting in increased mortality, the reported association between hypertension and severity of COVID-19 could be confounded by age and other comorbidities.

Myocardial Injury and Acute Coronary Syndromes

The assessment of troponin elevations with coexisting COVID-19 infection can be difficult in eliciting the cause. Myocardial injury defined as any cardiac troponin elevation is associated with significant morbidity and mortality. ^, Myocardial injury from COVID-19 is potentially from plaque rupture MI, inflammation, hypoxic injury, myocarditis, stress cardiomyopathy, microthrombi, or endothelial injury. ^{, ,} Management of troponin elevations in association with COVID-19 is mostly extrapolated from pre–COVID-19 existing recommendations. ^, Acute myocardial injury should initially be assessed for clinical deterioration, hemodynamic instability, and arrhythmias. Imaging modalities should initially be performed with echocardiography and then consideration given for CMR imaging or CT scan based on clinical suspicion of the cause. ^, The majority of care is supportive in those with non–acute coronary syndrome troponin elevation. In general, supportive measures, including mechanical support, should be considered on a case-by-case basis.

Troponin elevations in COVID-19 patients can be related to plaque rupture that is consistent with an AMI. During the COVID-19 pandemic, patients presenting with an AMI should be treated as probable or possible COVID-19 positive. Those presenting with a probable STEMI should be treated with a primary percutaneous coronary intervention (PCI) strategy in the standard of care fashion. ^, In those with ST elevations on electrocardiography and unclear diagnosis of STEMI, additional testing, including point-of-care ultrasound to evaluate for regional wall motion abnormality or coronary CT angiography (CCTA) in cases with conflicting information, may have to be considered. The likelihood of having acute coronary syndromes versus nonacute coronary syndrome–associated troponin elevations should be weighed to help guide appropriate treatments. Non–ST-elevation myocardial infarct (NSTEMI) management should be guided by risk stratification and identification of high-risk features. A NSTEMI due to plaque rupture with high-risk features should be managed with an early invasive strategy with the intention of performing PCI; those without high-risk features should be carefully evaluated for alternative diagnoses. This should be undertaken along with management recommendations according to existing guidelines for noninvasive studies such as echocardiography or CCTA. ^,

Myocarditis

COVID-19 is associated with myocarditis, which can range from mild disease to fulminant myocarditis. The mechanism, risk factors, and prevalence are not well understood. ^{, ,} Myocarditis has a wide range of presentations but should be considered with new-onset HF, cardiogenic shock, and arrhythmias. ^, Troponin levels will be elevated and suggestive of myocardial injury but given the wide range of presentations, ischemia will often need to be ruled out first. The troponin elevation associated with COVID-19 infections can be difficult to discern, creating a challenging diagnostic dilemma. Fig. 6.9 is useful in the approach to this management issue.

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