The Cardiorespiratory Effects of COVID-19

Direct Viral Toxicity

SARS-CoV-2 is transmitted mainly through direct or indirect respiratory tract exposure. Given the high expression of ACE2 in multiple epithelial cell types of the airway including alveolar epithelial type II cells in the lung parenchyma, SARS-CoV-2 has tropism for the respiratory tract. Live SARS-CoV-2 virus and viral subgenomic mRNA isolated from the upper airway can be detected by real-time polymerase chain reaction (RT-PCR). Later in the disease course, viral replication may occur in the lower respiratory tract, which manifests in severe cases as pneumonia and ARDS.

Studies have isolated viral RNA from fecal samples at high titers. It has been less commonly isolated from urine and blood. ^, Histopathological studies have confirmed organotropism of SARS-CoV-2 beyond the respiratory tract, including tropism to renal, myocardial, neurologic, pharyngeal, and gastrointestinal tissues. In addition, single-cell RNA sequencing studies have further verified expression of ACE2 and TMPRSS2 in lung alveolar epithelial type II cells, nasal goblet secretory cells, cholangiocytes, colonocytes, esophageal keratinocytes, gastrointestinal epithelial cells, pancreatic β-cells, and renal proximal tubules and podocytes. ^, These findings suggest that direct viral tissue damage may be at least partially responsible for the multiple organ injury.

Endothelial Cell Damage and Thromboinflammation

Endothelial cell damage through ACE2-mediated entry of SARS-CoV-2 with subsequent inflammation and the generation of a prothrombotic milieu is another proposed pathophysiologic mechanism of COVID-19. ACE2 expression has been demonstrated in the arterial and venous endothelium of several organs, and histopathological studies have found microscopic evidence of SARS-CoV-2 viral particles in endothelial cells of the kidneys and lungs. Infection-mediated endothelial injury (characterized by elevated levels of von Willebrand factor) and endothelialitis (marked by the presence of activated neutrophils and macrophages) found in multiple vascular beds (including the lungs, kidney, heart, small intestine, and liver of patients with COVID-19) can trigger excessive thrombin production, inhibit fibrinolysis, activate complement pathways, initiate thromboinflammation, and ultimately lead to microthrombi deposition and microvascular dysfunction.

Platelet–neutrophil cross-communication and activation of macrophages in this setting can also facilitate a variety of proinflammatory effects such as cytokine release, the formation of neutrophil extracellular traps (NETs), and fibrin and/or microthrombus formation. NETs further damage the endothelium and activate both extrinsic coagulation pathways and intrinsic coagulation pathways. They were detected at higher levels in patients hospitalized with COVID-19 in a study from the United States, and a ‘pro-NETotic state’ was positively correlated with severe illness. Hypoxia-mediated hyperviscosity and upregulation of the hypoxia-inducible factor 1 signaling pathway subsequent to acute lung injury may also contribute to the prothrombotic state. Finally, direct coronavirus-mediated effects may also lead to an imbalance of pro- and anticoagulant pathways. Small case reports and case series have demonstrated the presence of fibrinous exudates and microthrombi in histopathological examinations in patients with COVID-19.

Dysregulation of the Immune Response

The presentation of severe COVID-19 is characterized by a dysregulated immune response and cytokine release syndrome due to overactivation of innate immunity in the setting of T-cell lymphodepletion. Prior preclinical and human studies with pathogenic human coronaviruses have proposed rapid viral replication, antagonism of interferon signaling, and activation of neutrophils and monocyte-macrophages as mediators of hyperinflammation. Elevation of serum inflammatory markers such as C-reactive protein (CRP), ferritin, erythrocyte sedimentation rate, D-dimer, fibrinogen, and lactate dehydrogenase is predictive of subsequent critical illness and mortality in patients with COVID-19. Higher levels of the cytokine interleukin-6 (IL-6) in the serum have also been linked to a worse prognosis and have been found to correlate with fibrinogen levels in patients with COVID-19. Clinical trials for treating COVID-19 by targeting the IL-6 signaling pathway are underway with the hope of mitigating the deleterious effects linked to the activation of this pathway.

Infection may stimulate a severe immune reaction called “cytokine storm,” in which the body dissipates too many cytokines in the blood very quickly and uncontrollably. As a result, the production of neutrophils, proinflammatory cytokines (IL-1b, IL-6, tissue necrosis factor [TNF] α, etc.), and chemokines (chemokine ligand [CCL] 1, C-X-C motif chemokine ligand 10 [CXCL] 10, CCL3, etc.) exceeds the levels of antiinflammatory cytokines in the body, which in turn leads to multiorgan damage. A majority of patients are reported to exhibit diffuse bilateral pneumonia surrounded with ground-glass opacity either progressing or coexisting with consolidation. Histological examinations have also evidenced that the lower respiratory tract holds a higher overall viral load than the upper respiratory tract. In addition, pathological findings in the infected lungs have indicated the appearance of proteinaceous exudates in lung tissues as well as in bronchial lavage fluids, development of pulmonary edema, bilateral diffuse alveolar damage, interstitial thickening, and the infiltration of T cells or inflammatory monocytes, etc., in comparison to a healthy lung. Moreover, COVID-19 patients have been marked with relatively low levels of lymphocytic T cells (CD4+ and CD8+) and natural killer (NK) cells, i.e., overall low levels of lymphocyte counts in the blood profile. Two of the most prominent reasons for low lymphocytes are hypokalemia and hypophosphatemia, metabolic derangements induced by the impact of SARS-CoV-2 on patients’ ACE-angiotensin-II (ACE-Ang-II) that prevents the degradation of intact ACE-Ang-II within the system. As a result, aldosterone production triggers frequent vomiting, diarrhea, and urination as part of multiple organ injury. People with comorbidities such as diabetes, hypertension, hypothyroidism, chronic lung diseases, malignancy, and obesity are at a significantly higher risk of severe COVID-19 infection due to altered immune response.

Dysregulation of the Renin–Angiotensin–Aldosterone System

Maladaptive functions of the RAAS constitute another plausible pathophysiological mechanism of SARS-CoV-2 infection–related tissue damage. The RAAS is composed of a cascade of regulatory peptides that participate in key physiological processes of the body, including fluid and electrolyte balance, blood pressure (BP) regulation, vascular permeability, and tissue growth. ACE2 has emerged as a potent counterregulator of the RAAS pathway. ACE2 cleaves angiotensin I into inactive angiotensin 1–9 and cleaves angiotensin II into angiotensin 1–7 that has vasodilatory, antiproliferative, and antifibrotic properties. While the pathophysiology of SARS-CoV-2 may not be limited exclusively to ACE2-related pathways, these findings may have implications for the organ-specific clinical manifestations of COVID-19. Recent findings suggest that bradykinin and the kinin–kallikrein system may also play a prominent role in COVID-19 via a newly described bradykinin storm. Bradykinin storm could be the result of the SARS-CoV-2–mediated reduction in ACE2 availability and the downregulation of des-Arg -bradykinin degradation. This is associated with BP dysfunction as well as inflammation. An accumulation of bradykinin has been detected in bronchoalveolar lavage fluid from COVID-19 patients, and this has been correlated to symptoms associated with COVID-19.

Clinical Manifestations

SARS-CoV-2 can cause both direct and indirect cardiovascular sequelae including myocardial injury, acute coronary syndrome (ACS), cardiomyopathy, acute cor pulmonale, arrhythmias, cardiogenic shock, and thrombotic complications. Myocardial injury with elevation of cardiac biomarkers above the 99th percentile of the upper reference limit occurred in 20% to 30% of hospitalized patients with COVID-19. Preexisting cardiovascular disease increased this rate to 55%. A greater frequency and magnitude of troponin elevations in hospitalized patients have been associated with disease severity and poorer outcomes. Biventricular cardiomyopathy has been reported in 7% to 33% of critically ill patients with COVID-19. Isolated right ventricular (RV) failure with and without confirmed pulmonary embolism has also been reported. A study of 138 patients in Wuhan, China, demonstrated that cardiac arrhythmias, including new-onset atrial fibrillation, heart block, and ventricular arrhythmias, are prevalent, occurring in 17% of hospitalized patients and 44% of patients in the intensive care unit (ICU) setting. In a multicenter New York City cohort, 6% of 4250 patients with COVID-19 had prolonged QTc (corrected QT; >500 ms) at the time of admission. Among 393 patients with COVID-19 from a separate cohort from New York City, atrial arrhythmias were more common among patients who required mechanical ventilation than among those who did not (17.7% versus 1.9%). Reports from Lombardi, Italy, showed an increase of nearly 60% in the rate of out-of-hospital cardiac arrest during the 2020 COVID-19 pandemic relative to a similar period in 2019, which suggested the etiology to be either COVID-19 or another untreated pathology related to patients’ reluctance to seek care ( Fig. 4.4 ). Acute cardiac injury in COVID-19 is associated with poor prognosis. Shi et al. showed that patients with acute cardiac injury had a significantly higher risk of in-hospital mortality compared to patients without cardiac injury from the time of symptom onset (hazard ratio 4.26, 95% CI, 1.92–9.49) or hospital admission (hazard ratio 3.41, 95% CI, 1.62–7.16). Box 4.1 summarizes COVID-19 cardiac manifestations’ clinical presentations, COVID-19 specific considerations, and general considerations.

BOX 4.1

COVID-19 Cardiac Manifestations

Adapted from Gupta A, Madhavan MV, Sehgal K, et al. Extrapulmonary manifestations of COVID-19. Nat Med . 2020;26(7):1017-1032.

ACE , angiotensin-converting enzyme; ARBs , angiotensin receptor blockers; MI , myocardial infarction; NSTEACS , non–ST segment elevation acute coronary syndrome; STEMI , ST segment elevation MI; GRACE , Global Registry of Acute Coronary Events.

Clinical Presentations

• Myocardial ischemia and MI (type 1 and 2)

• Myocarditis

• Arrhythmia: new-onset atrial fibrillation and flutter, sinus tachycardia, sinus bradycardia, QTc prolongation (often drug induced), torsades de pointes, sudden cardiac death, pulseless electrical activity

• Cardiomyopathy: biventricular, isolated right or left ventricular dysfunction

• Cardiogenic shock

COVID-19–Specific Considerations

• Do not routinely discontinue ACE inhibitors or ARBs in patients already on them at home; assess on a case-by-case basis

• Perform an electrocardiogram or telemetry monitoring for patients at medium to high risk for torsades de pointes who are being treated with QTc-prolonging drugs

• Carefully consider the utility of diagnostic modalities, including cardiac imaging, invasive hemodynamic assessments, and endomyocardial biopsies, to minimize the risk of viral transmission

• Primary percutaneous coronary intervention remains the preferred approach for most patients with STEMI; consider fibrinolytic therapy in select patients, especially if personal protective equipment is not available

General Considerations

• Utilize noninvasive hemodynamic assessments, and measurement of lactate, troponin, and beta-natriuretic peptide concentrations, with sparing use of routine echocardiography for guidance about fluid resuscitation, vasoactive agents, and mechanical circulatory support

• Minimize invasive hemodynamic monitoring, but can consider in select patients with mixed vasodilatory and cardiogenic shock

• Consider point-of-care ultrasound to assess regional wall motion abnormalities to help distinguish type 1 MI from myocarditis

• Early catheterization and revascularization is recommended for high-risk patients with NSTEACS (e.g., GRACE score >140)

• Consider medical therapy for low-risk patients with NSTEACS, particularly if the suspicion for type 1 MI is low

• Monitor and correct electrolyte abnormalities to mitigate arrhythmia risk

Pathophysiology

The pathophysiology underlying cardiovascular manifestations is likely multifactorial. ACE2 has high expression in cardiovascular tissues, including cardiac myocytes, fibroblasts, endothelial cells, and smooth muscle cells, which supports a possible mechanism of direct viral injury. Patients with preexisting cardiovascular disease may have higher levels of ACE2, which would potentially predispose them to more severe COVID-19. Myocarditis is a presumed etiology of cardiac dysfunction, and the development of myocarditis may relate to viral load. While isolation of the virus from myocardial tissue has been reported in a few autopsy studies, other pathological reports have described inflammatory infiltrates without myocardial evidence of SARS-CoV-2. In addition, the finding of direct viral infection of the endothelium and accompanying inflammation as reported in a patient with circulatory failure and MI lead to the possibility of virus-mediated endothelial cell damage as an underlying mechanism. Systemic inflammatory response syndrome (cytokine storm) is another putative mechanism of myocardial injury. Lastly, isolated RV dysfunction may occur as a result of elevated pulmonary vascular pressures secondary to ARDS, pulmonary thromboembolism, or virus-mediated injury to vascular endothelial and smooth muscle tissue.

Other potential etiologies of myocardial damage not specific to COVID-19 include severe ischemia or MI in patients with preexisting coronary artery disease, stress-mediated myocardial dysfunction, tachycardia-induced cardiomyopathy, and myocardial stunning after resuscitation or prolonged hypotension. While patients with viral infections are at risk for MI in general, this risk may be amplified in patients with COVID-19 given its propensity to create hypercoagulability and thus potentially increase thrombotically mediated MI. Moreover, distinguishing the presentation of atherosclerotic plaque rupture MI (type 1 MI) from myonecrosis due to supply–demand mismatch (type 2 MI) in the setting of severe hypoxia, hemodynamic instability, and myocarditis can be challenging. This was especially evident in a recent case series of 18 patients with COVID-19 who developed ST segment elevation on electrocardiogram with 10 of these patients diagnosed with noncoronary myocardial injury ( Fig. 4.5 ).

Acute COVID-19 Cardiovascular Syndrome

Acute COVID-19 cardiovascular syndrome (ACovCS) includes acute cardiac injury, thromboembolic complications, atrial and ventricular arrhythmias, hemodynamic instability, and sudden cardiac death ( Fig. 4.6 ). The clinical presentation of acute cardiac injury may be chest pain, shortness of breath, syncope/near syncope, tachycardia, elevated myocardial troponins and natriuretic peptides, regional wall motion abnormalities or global left ventricular (LV) dysfunction on echocardiography, ST segment depression or elevation, or T-wave abnormalities on electrocardiogram (ECG). Cardiac injury in COVID-19 patients may occur both with and without acute obstruction of the coronary arteries (irrespective of a preceding atherosclerotic coronary artery disease), which portends poor prognosis. It is believed that virally induced thrombi may result in ACSs (NSTEMI or STEMI), although other causes have been described including type 2 MI related to tachycardia, hypotension, and hypoxemia; microvascular damage secondary to diffuse microembolism; cardiotoxic effects of an inflammation-induced cytokine storm; and stress-induced cardiomyopathy (also termed Takotsubo syndrome) ( Fig. 4.7 ). ^, Acute heart failure syndromes (systolic RV and LV dysfunction with or without cardiogenic shock), myopericarditis, and myocarditis ( Fig. 4.8 ) are also common and may be induced by direct viral invasion of the myocardium (primary cardiomyocyte injury) or by an enhanced inflammatory response (cytokine-mediated injury). Recently, severe cases of acute perimyocarditis with subsequent cardiac tamponade in patients with COVID-19 infection have been reported. However, the prevalence of myocarditis in COVID-19 is extremely rare, and larger retrospective multicenter cohort studies have found it to be 1% or less.

COVID-19 may also affect the RV, but it has been less extensively studied in comparison to the LV. ^, RV dysfunction was the most common abnormality seen in a multicenter international cohort of over 300 hospitalized patients with COVID-19 at a rate of approximately 26%. Use of speckle tracking echocardiography found reduced basal longitudinal strain to be present in 52% of patients in one single-center study; patients who were obese, black or had hypertension and diabetes were more likely to present with reduced basal longitudinal strain. Another echocardiographic study of COVID-19 patients found that the most prevalent abnormality was reduced longitudinal strain in more than one basal LV segment (71%). This pattern reminded of a “reverse Takotsubo” morphology that is not typical for other viral myocarditis presentations. Although the tricuspid annular plane systolic excursion (TAPSE) was found to be preserved in hospitalized COVID-19 patients, a cohort of COVID-19 ARDS patients from the United Kingdom demonstrated a specific phenotype of RV radial dysfunction with sparing of longitudinal function. Notably, in these patients, the RV–pulmonary artery coupling as reflected by the fractional area change divided by RV systolic pressure (RV afterload) was an important marker of disease severity. In addition, RV longitudinal strain has been identified as a powerful predictor of mortality in COVID-19 patients.

Limited data are available on the prevalence of spontaneous coronary dissection in COVID-19 patients. Spontaneous dissection is linked to risk factors that are also highly prevalent in COVID-19 including systemic inflammatory response, hemodynamic stress, and hypertension. There is also lack of evidence pertaining to COVID-19–related native and prosthetic valve endocarditis. It is important to highlight that COVID-19 can cause decompensation of an underlying heart failure. This may lead to a mixed shock and require specific therapeutic approaches. Differentiating COVID-19–related acute lung injury from patients with acute pulmonary edema and preexisting heart failure is crucial as continuous positive airway pressure is contraindicated in heart failure patients and beneficial in lung injury patients. Finally, it is important to note that the clinical presentation of some fulminant myocarditis, such as giant cell myocarditis, may resemble COVID-19 myocarditis.

Diagnosis of Acute COVID-19 Cardiovascular Syndrome

Detectable troponin elevation carries prognostic value in acute COVID-19 infection. Shi and colleagues reported higher mortality in those with troponin elevation from a single-center cohort in Wuhan, China, finding a threefold to fourfold increased risk of death. Later, Lombardi and colleagues validated these findings in a multicenter cohort in Italy with over 600 patients, with a more attenuated hazard ratio of 1.7. In one of the most diverse cohorts studied with over 2000 patients admitted to a New York City hospital system, Smilowitz and colleagues illustrated that the risk of death was twofold higher among patients with troponin elevation. Importantly, the degree of troponin elevation was associated with more severe critical illness (defined as ICU admission, need for mechanical ventilation, discharge to hospice, or death). While these seminal studies defined troponin elevation as greater than the 99 ^th percentile of the upper limit of normal, Qin and colleagues illustrated that troponin elevation in COVID-19 infection was associated with mortality even at thresholds 19% to 50% lower than those traditionally used in clinical settings.

Moreover, risk for mortality and adverse outcomes appears to be continuous with the degree of troponin elevation; higher troponin continues to amplify risk, providing clinicians with not only a qualitative risk assessment for patients, but a quantitative assessment as well. As such, measuring troponin for hospitalized COVID-19 patients has been integrated into routine clinical practice and management algorithms. For hospitals, it serves to forecast trajectory and identify patients that may require more intensive resources in times of scarcity. Several societal guidelines including the World Health Organization and the Chinese Clinical Guidance for COVID-19 recommend measuring troponin for all admitted patients, while others including the American College of Cardiology (ACC) recommend testing when clinically indicated.

The clinical presentation of other forms of fulminant myocarditis may resemble COVID myocarditis. An endomyocardial biopsy might be considered in patients presenting with life-threatening arrhythmias and cardiogenic shock; however, in the presence of COVID-19, such an approach may not be feasible due to patient instability, procedural risk, and risk of healthcare staff exposure, especially if the biopsy results would not change clinical management. Patterns of delayed myocardial enhancement consistent with acute myocarditis have been described in contrast-enhanced ECG-gated multidetector computed tomography (CT) in non–COVID-19 cases. This rapid, noninvasive testing may be useful for the assessment of myocardial injury in patients with COVID-19 and warrants further investigation.

Given the extremely contagious nature of COVID-19, a priority is placed on minimizing COVID-19 exposure for healthcare staff and non-COVID patients while successfully managing the care of COVID patients. This goal can be facilitated by limiting testing and patient transfer for diagnostic procedures, especially for procedures that do not directly influence patient management. Consideration is also given to limit testing that requires terminal room cleaning necessitated by patient transfer, as that process can add significant delays to diagnostic testing for other patients. Such strategies may result in increased uncertainty about the diagnosis but are unlikely to increase adverse short-term outcomes in patients without fulminant presentations. For example, if a type 1 MI can be excluded on clinical grounds for a patient noted to have acutely elevated troponins, then a biopsy is unlikely to change immediate clinical management no matter the ultimate pathology. This strategy is aligned with recent ACC recommendations. An exception to that approach may be warranted in a COVID-19 patient with hemodynamic or electrophysiological instability who undergoes coronary angiography to exclude obstructive coronary artery disease. As the patient is already in the catheterization laboratory, incremental infectious risk of patient transport is reduced. A biopsy may be useful to gain insight into the mechanism of the acute myocardial injury, including the possibility of giant cell myocarditis.

In accordance with these guiding principles, the majority of patients with an abnormal troponin in the setting of COVID-19 infection can be followed up with expectant management until recovery from the acute viral syndrome. Patients with COVID-19 and myocardial injury who are hemodynamically and electrophysiologically stable with mild to moderate elevations of troponin should not routinely undergo an echocardiogram, angiography, or cardiac imaging. These diagnostic studies can be delayed until recovery from COVID-19 or avoided altogether unless the patient clinically deteriorates and develops hemodynamic instability, shock, ventricular arrhythmias, or concerning troponin levels ( Fig. 4.9 ). Point-of-care cardiac ultrasonography (POCUS) may be a viable alternative to the aforementioned modalities as it can be performed at bedside without the aerosolization risk of transesophageal echocardiography (TEE). Determination of ejection fraction and cardiac tamponade could help identify higher-risk patients and support earlier initiation of guideline-directed medical therapy once the patient is stable. The European and American Societies of Cardiology recommend POCUS for COVID-19 patients and consider bedside critical care echocardiography as an effective option to screen for cardiovascular complications in the COVID-19 infection. However, unnecessary or repeated imaging not vital to clinical decision-making should be avoided in accordance with the American Society of Echocardiography COVID-19 statement. Patients discovered to have newly diagnosed depressed LV systolic function (low LV ejection fraction) without elevated troponin are more likely to have preexisting cardiomyopathy than myocarditis. Although the lack of definitive diagnostic studies may temporarily increase diagnostic uncertainty, it reduces the risk of COVID-19 transmission to staff and seems unlikely to compromise short-term (<60 days) patient outcomes in clinically stable patients.