On March 11, 2020, the World Health Organization (WHO) declared the novel coronavirus disease (COVID-19) to be a pandemic. Initial reports consisted primarily of COVID-19 pneumonia cases. However, an explosion of research has led to the understanding that COVID-19 can, in addition to respiratory illness, cause widespread systemic effects by initiating a cascade of deleterious events, including direct infection of the heart, microthrombus formation, and an overzealous inflammatory response. These events are associated with cardiac injury, arrhythmia, and cardiac arrest, and they contribute to nearly half of COVID-19-related deaths in hospitalized patients. Here, we review the pathophysiology of COVID-19-induced cardiac injury through both direct and indirect mechanisms, and highlight the therapeutic role of existing cardioprotective interventions.
Incorporation of pharmacotherapies that prevent cardiovascular harm may substantially improve COVID-19 patient outcomes.
Key words: arrhythmia, ACE2 receptor, COVID-19, myocarditis, thromboembolism
The COVID-19 pandemic recently surpassed 95 million global cases and 2 million deaths worldwide, with over 24 million total infections and over 398,000 deaths in the United States.1 Enough time has passed to justify a retrospective glance at a few of the defining events that shaped the early days of the pandemic (Figure 1).2-9 In particular, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was isolated and reported in roughly a week, demonstrating the remarkable speed of modern science and the powerful effect that collaborative efforts in research can achieve.7
A study of evacuees from China estimates that about 30.8% (95% confidence interval: 7.7-53.8%) of cases are asymptomatic.10,11 Symptomatic COVID-19 patients commonly present with a flu-like syndrome, with patients most frequently reporting dyspnea, dry cough, and fever.12 A subset of patients also report palpitations, chest pain, or both, and hospitals are accumulating evidence of increased cardiovascular disease morbidity and mortality in COVID-19 patients.12-14
The ACE2 Receptor
Like many members of the coronavirus family, SARS-CoV-2 gains entry into cells via binding to the receptor of membrane-bound angiotensin-converting enzyme 2 (ACE2; Figure 2).15 ACE2 is a zinc metalloprotease and contains a single transmembrane spanning alpha helix, an extracellular N-terminal domain containing the active site, and a short intracellular C-terminal tail.16 The spike protein of SARS-CoV-2 binds to the active site of ACE2, inducing endocytosis. It is the antigen currently targeted by the 2 COVID-19 vaccines being administered in the United States to induce a host immune response that combats viral entry.17 Upon entry, the single-stranded, positive-sense RNA of SARS-CoV-2 uses host ribosomes to translate viral proteins, including an RNA-dependent RNA polymerase that replicates the viral genome.18
ACE2 is expressed on cardiomyocytes, lung endothelial cells, enterocytes of the small intestines, arterial and venous endothelial cells, and arterial smooth muscle cells throughout the body.19–22 This widespread expression of ACE2 is consistent with the clinical observation that COVID-19 is a multisystemic disease with broad and seemingly unrelated symptoms. The clinical presentation includes acute kidney injuries, gastrointestinal symptoms, cardiac arrhythmias, cardiomyopathy, cardiac arrest, and widespread blood clotting. ACE2 is also expressed in cortical neurons and glia, which may be the basis of anosmia, dysgeusia, and other neurological defects seen in patients with COVID-19.23,24
ACE2 has been shown to have a protective effect against coronavirus-induced lung injury by increasing levels of the vasodilator angiotensin-(1-7) and by downstream anti-inflammatory effects, including reducing oxidative stress.25 ACE2 is considered to confer a protective benefit in heart failure, diabetes, and hypertension. Conversion of angiotensin II to angiotensin-(1-7) by ACE2 can reduce cytokine release and inhibit signaling pathways of tissue fibrosis in experimental models of atherosclerosis and obesity.26 Binding of SARS-CoV-2 to ACE2 leads to ACE2 downregulation and increased angiotensin II levels, which are associated with respiratory distress in COVID-19 patients.27,28 In animal models, ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression and thereby enhance production of angiotensin-(1-7).25,29 Subsequent downregulation of inflammatory cytokine release may be responsible for the lower risk of mortality in hypertensive patients with COVID-19 receiving ACEIs/ARBs, as compared to those who did not.30 It is therefore plausible that inhibition of cytokine storm by ACEIs/ARBs may have cardioprotective effects in COVID-19 patients.13,31
A history of underlying cardiovascular disease, including hypertension, is associated with COVID-19 severity.12,32,33 One large-scale report from China found that patients who needed intensive care unit (ICU) admission were more likely to have cardiovascular comorbidities, and the case fatality rate for patients with underlying cardiovascular disease was larger than that for patients with underlying chronic respiratory illness (10.5% and 6.3%, respectively).34 Infection with SARS-CoV-2 has been shown to cause acute cardiac complications, including a higher risk of myocarditis, cardiac arrest, acute heart failure, arrhythmias, and thromboembolism (Figure 3).35-37 A case report of a previously healthy 11-year-old girl who developed cardiac failure and died from COVID-19 infection was found to have SARS-CoV-2 viral particles in cardiac tissue associated with myocardial and endocardial thickening.38 Viral infection of myocardial tissue was also observed in 24 of 39 (61.5%) deceased individuals with SARS-CoV-2 infection in an autopsy study conducted in Germany.39 COVID-19 may also cause cardiac complications by increasing the body’s metabolic demand and imparting stress on the heart through added physiological workload. The pneumonia induced by COVID-19 and subsequent right heart strain may further contribute.40 Hemostatic abnormalities may result from intense COVID-19-associated inflammation and present as the formation of microthrombi in the lungs and heart, leading to strained function and necrotic tissue formation.41,42 Over-aggressive host responses to SARS-CoV-2 infection likely contribute to COVID-19 cardiac events as well.
COVID-19 elicits an excessive secretion of cytokines that lead to injury across multiple organ systems.43 These cytokines include interleukins (IL-2, IL-6, and IL-7), tumor necrosis factor (TNF)-α, and interferon, among others.31,32,44 They activate pathways involved in immune cell differentiation, trafficking, and expansion at injured sites, but they can also trigger tissue edema, endothelial injury, and fibrotic repair processes in bystander organs.45
A report on 35 COVID-19-positive children found that severe inflammatory state [elevated C-reactive protein (CRP), D-Dimer, and IL-6] after infection was associated with acute heart failure.46-48 The children were admitted to the pediatric ICU for cardiogenic shock, left ventricular (LV) dysfunction, and severe inflammatory state.49 They were also found to have mild to moderate troponin I elevation with normal right ventricular (RV) function. The children improved with intravenous steroids, IL-1 antagonist (anakinra), intravenous immunoglobulin, and inotropic support.
The severe inflammatory state associated with COVID-19 in children has been termed multisystem inflammatory syndrome in children (MIS-C) and compared with acute phase Kawasaki disease (KD). Echocardiographic comparison found that LV systolic and diastolic function were worse in MIS-C compared to KD, especially when myocardial injury was present. Within 3-8 days, LV systolic function improved in the MIS-C patients, but diastolic dysfunction persisted. Only 1 of the 28 MIS-C patients in the study exhibited coronary artery dilatation, which was not observed during follow-up examination.50
Widespread hyperinflammation from COVID-19 has been associated with myocardial injury in adults. One group at Mount Sinai studied troponin I levels in hospitalized COVID-19 patients within 24 hours of admission.51 They found that troponin elevation was more prevalent in patients with pre-existing cardiovascular disease and associated with worse outcomes. Even mild troponin elevation (0.03 to 0.09 ng/mL) was associated with an increased risk of death.51 However, very few of these patients met the criteria for acute myocardial infarction (MI), and it is likely that the myocardial damage was mediated through myocardial microthrombi (in the absence of epicardial coronary obstruction), injurious cytokine overactivity, or both.
Cardiac magnetic resonance (CMR) imaging of 26 COVID-19-positive athletes found evidence of myocarditis in 4 athletes and late gadolinium enhancement (suggesting prior myocardial injury) in 8 athletes.52 While most of the athletes were asymptomatic, 12 reported mild symptoms (sore throat, shortness of breath, myalgias, fever). These results raise concern of myocardial inflammation after recovery, which may interfere with returning to competitive play. Although myocarditis is traditionally associated with lymphocytic abundance, lymphopenia has been documented in over 80% of COVID-19 patients and is believed to be an important prognostic indicator.53-55 The presence of lymphopenia may indicate an increased likelihood of cytokine storm and subsequent myocardial injury.55
Major echocardiographic abnormalities, including LV wall motion abnormalities, global LV dysfunction, LV diastolic dysfunction, RV dysfunction, and pericardial effusions, have been linked with COVID-19-associated myocardial injury.56 Overall, the presence of acute cardiac injury, evidenced by elevated cardiac biomarkers, electrocardiographic abnormalities, and echocardiographic abnormalities, is associated with more severe COVID-19 symptoms and worse prognosis.14
The prevailing view holds that myocardial damage may directly increase the risk of arrhythmia in COVID-19 patients.14 In March 2020, studies from China reported an overall cardiac arrhythmia incidence of 17% in hospitalized COVID-19 patients, with a 44% rate in COVID-19 patients in the ICU.12 Arrhythmias were identified as the leading cause of complications after acute respiratory distress syndrome (ARDS) in hospitalized COVID-19 patients.14 The presence of atrial fibrillation or flutter is associated with mechanical ventilation or death within 48 hours of COVID-19 presentation.57 A study of 700 hospitalized COVID-19 patients over the course of 9 weeks observed 9 cardiac arrests, 25 atrial fibrillation events, 9 clinically significant bradyarrhythmias, and 10 non-sustained ventricular tachycardia events.58
Although myocardial damage may play a role in the pro-arrhythmic effect of COVID-19, only a subset of ICU COVID-19 patients presenting with arrhythmias also presented with evidence of acute cardiac injury.12 Therefore, it is likely that COVID-19 enhances the risk of arrhythmia through additional mechanisms. IL-6, TNF-α, and IL-1 have been found to prolong ventricular action potential duration by modulating cardiomyocyte ion channels.59 Increased availability of inflammatory cytokines has been identified as a risk factor for QT prolongation.60 IL-6, in particular, has been shown to inhibit the cytochrome P450 enzyme, CYP3A4, increasing the bioavailability of QT-prolonging drugs.61
Although estimates of the risk of arterial and venous thromboembolic complications are still preliminary, one group in the Netherlands studying 184 COVID-19 patients in the ICU (receiving standard thromboprophylaxis) estimated a 31% incidence of thrombotic complications, with pulmonary embolism as the most frequently observed pathology.62 Autopsy evidence of widespread intramyocardial capillary microthrombi mediating myocardial necrosis further supports a role for anticoagulation in COVID-19 management.41 Evidence of cardiac injury, such as troponin elevation or wall motion abnormalities, without detectable coronary occlusion, may be attributed to the formation of microvascular thrombi.
Hemostatic abnormalities associated with COVID-19 include mild thrombocytopenia and increased D-dimer levels, and are associated with more severe disease prognosis.63,64 Tang et al published a retrospective study of 28-day mortality among 449 COVID-19 patients that found that at least 1 week of therapeutic heparin anticoagulation was associated with better prognosis in patients with markedly high D-dimer levels or patients with a sepsis-induced coagulopathy score of 4 or greater.65 The WHO recommends prophylactic low-molecular-weight heparins (LMWHs) or twice daily subcutaneous unfractionated heparin for hospitalized COVID-19 patients.66 Interestingly, LMWH has anti-inflammatory properties (distinct from its anticoagulant properties) which may counteract some of the hyperinflammation associated with COVID-19.67
On October 22, 2020, the U.S. Food and Drug Administration (FDA) approved remdesivir for treatment of hospitalized COVID-19 patients.68 Remdesivir is an antiviral drug that competes for incorporation into RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, resulting in delayed chain termination during viral RNA replication.69 Hospitalized patients with COVID-19 requiring respiratory support were found to have a reduced likelihood of death when treated with dexamethasone, a corticosteroid with well-characterized anti-inflammatory effects in the lungs.70 Pharmacologically targeting host inflammatory responses may benefit COVID-19 patients with severe disease, but more research is needed to better understand how to effectively dampen host inflammatory responses without compromising necessary immune defenses.
Current management of COVID-19 is primarily supportive and focused on preventing respiratory demise. However, cardiovascular disease, hypertension, and diabetes are closely related to severe and fatal outcomes in COVID-19.33 Preliminary evidence supports incorporation of known cardioprotective agents into COVID-19 treatment plans.30,71 Anticoagulation may be associated with lower intubation and mortality in hospitalized COVID-19 patients.62,72 Limited evidence supports a possible beneficial role for ACEIs/ARBs, leading some groups to explore the possibility of using soluble recombinant ACE2 to limit SARS-CoV-2 attachment and entry into host cells (Figure 2).73 Early experiments in tissue culture suggest that this approach may be promising.74
Of course, prevention of SARS-CoV-2 infection is the most effective method of protecting against COVID-19. Universal face coverings, social distancing, and handwashing may help prevent the spread of disease.75-77 Following SARS-CoV-2 genome sequencing in January 2020, international data sharing and collaboration has led to vaccine development at a remarkable pace.78 Current COVID-19 vaccines incorporate both viral vector and nucleic acid-based modalities (Figure 4).79,80 The viral vector vaccines involve an attenuated recombinant virus encoding genes to the spike protein, stimulating both humoral and cellular immune responses. Both adenovirus vectors carrying DNA and a recombinant vesicular stomatitis virus carrying RNA are undergoing clinical trials. Nucleic acid-based vaccines, consisting of mRNA encased in lipid nanoparticles for transport, self-replicate to also stimulate both humoral and cellular immune responses to the spike protein, but require 2 doses.80,81 In December 2020, the FDA approved emergency use authorization for distribution of mRNA COVID-19 vaccines developed by Pfizer in collaboration with BioNTech and Moderna in collaboration with the National Institutes of Health for use in the U.S.9,82
When symptomatic, COVID-19 is a multisystemic illness that produces cardiac manifestations that contribute to 40% of deaths in hospitalized patients.83-85 Based on publications to date on cardiac effects, some centers are routinely checking biomarkers (troponin, CRP) and ordering diagnostic tests (electrocardiography, echocardiography, CMR) to evaluate patients hospitalized with COVID-19. Our information leads us to advocate for a collaborative approach to cardiac manifestation and treatment as well as randomized controlled trials to evaluate the effectiveness of these approaches.
Disclosures: The authors have no conflicts of interest to report regarding the content herein.
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