Post COVID, Ergo Propter COVID?

Corresponding Author

Nearly 3 years into the COVID-19 pandemic, more than 97 million cases have occurred in the United States, with more than 1 million associated deaths.¹ Beyond the acute illness, COVID often has long-term impacts on patients’ functional status, economic and social productivity, and quality of life. Patients and clinicians have struggled with uncertainty regarding the natural history of long COVID, which can be highly variable, and have experienced frustration related to the limitations of current diagnostic methods and treatments.

In this issue of JACC: Case Reports, Safronenka et al² describe the clinical course of a patient with recrudescence of frequent symptomatic premature ventricular contractions (PVCs) accompanied by a constellation of symptoms including chest pain and shortness of breath, 3 weeks after she received a second COVID-19 vaccine. She subsequently underwent 2 PVC ablations and later tested positive for SARS-CoV-2, with symptoms including chest pain and joint pain persisting for months afterwards. The presence of a pericardial effusion on echocardiography and improvement of symptoms with nonsteroidal anti-inflammatory drugs supported a diagnosis of pericarditis. Serologic testing was notable for a positive antinuclear antibody titer, with negative titers for other autoantibodies, including double-stranded DNA.

Long COVID, or postacute sequelae of SARS-CoV-2 (PASC), is a multisystem syndrome including diverse symptoms such as fatigue, chest pain, dyspnea, palpitations, musculoskeletal pain, and headache, persisting 4 or more weeks after SARS-CoV-2 infection.³ Given the heterogeneous nature of PASC, defining an individual patient’s specific phenotype based on a thorough clinical assessment is critically important for risk stratification and management. PASC cardiovascular disease refers to cardiovascular conditions including, but not limited to, myocarditis and other myocardial involvement, pericarditis, new or worsening myocardial ischemia due to epicardial or microvascular coronary artery disease, left ventricular or right ventricular dysfunction, and arrhythmias. PASC cardiovascular syndrome encompasses cardiovascular symptoms and findings such as exercise intolerance, postexertional malaise, orthostasis, and tachycardia, in the absence of clear cardiovascular pathology based on standard diagnostic tests.³

Initial workup for a patient with persistent cardiovascular symptoms after COVID-19 should include basic laboratory testing (including serum cardiac troponin, preferably a high-sensitivity assay), electrocardiography, transthoracic echocardiography, and possibly ambulatory rhythm monitoring. The clinician should pursue further testing selectively, based on results of the initial evaluation and the patient’s clinical course. Particularly for a patient with frequent ventricular ectopy, cardiac magnetic resonance imaging is prudent to assess for myocarditis and other forms of myocardial involvement.

Myocarditis associated with COVID-19 mRNA vaccines is rare, occurs most often in male adolescents and young adults, and usually manifests with symptoms several days after the second vaccine dose.^3,4 The association between mRNA vaccines and pericarditis is less clear.⁵ The patient described by Safronenka et al² did not meet diagnostic criteria for myocarditis, and pericarditis was not diagnosed until months after vaccination.² Therefore, it is difficult to know precisely how the vaccination affected her individual clinical course.

However, on a population level, SARS-CoV-2 infection is clearly associated with an increase in incident cardiovascular disease. In a Veterans Affairs cohort of 153,760 individuals with COVID-19, new diagnoses of multiple cardiovascular disorders were more common, from 1 to 12 months after the illness, than in control subjects.⁶ New diagnoses of atrial fibrillation and heart failure were particularly common in this cohort (excess burden per 1,000 persons: 10.74 and 11.61, respectively). The proinflammatory and hyperadrenergic milieu such as that seen in SARS-CoV-2 infection can trigger atrial fibrillation and heart failure as acute or subacute manifestations of underlying, previously undiagnosed, structural heart disease. On a related note, patients with historically evident arrhythmias, like the patient in this case report, could plausibly become more symptomatic as a result of cardiovascular deconditioning after SARS-CoV-2 infection. Mechanisms underlying palpitations, a frequent component of PASC, may include decreased blood volume, cardiac atrophy, and decreased stroke volume, accompanied by compensatory tachycardia.³

The associations between SARS-CoV-2 infection and autoimmunity are under active investigation. Autoantibodies, including antinuclear and antiphospholipid antibodies, have been documented in patients with SARS-CoV-2 infection, suggesting that the virus can trigger autoimmune responses via molecular mimicry.⁷ The long-term impact of SARS-CoV-2 infection on autoimmune serologies deserves further study. Moreover, it remains unclear whether vaccines or antiviral pharmacotherapies (namely, nirmatrelvir-ritonavir) affect the probability of autoimmune phenomena following SARS-CoV-2 infection.

As we continue to grapple with COVID-19 and its sequelae, longitudinal studies such as the National Institute of Health’s Researching COVID to Enhance Recovery (RECOVER) will help to clarify disease mechanisms, identify prognostic indicators, and evaluate efficacy of treatments. Especially as new variants emerge and as the population’s immunity waxes and wanes with infections and booster vaccines, we will need repeated population-based studies to assess attributable risks of cardiovascular disorders. Post COVID, ergo propter COVID? For an individual patient, it may be impossible to answer this question with certainty. But with high-quality epidemiologic data, we as clinicians will be better equipped to educate and care for our patients.

Funding Support and Author Disclosures

The author has reported that she has no relationships relevant to the contents of this paper to disclose.