Introduction
The AMA Guides® Newsletter has published six articles reflecting impairment for long-COVID issues. In 2020, Talmage et al1 described methods for rating permanent impairment. In the same issue, Snyder2 discussed causation issues. A second general article was written by Caruso et al3 in 2021. Also in 2021, Talmage et al4 updated their earlier 2020 article, titling it “COVID-19: Achieving Maximum Medical Improvement and Assessing Permanent Impairment.” These four articles described methodologies for a variety of clinical conditions, including those involving the cardiac and the pulmonary systems. In 2021, Gulick et al5 described the psychological effects of COVID-19 infections, and in 2022, Hirsch et al6 discussed neurological and psychological issues. This article focuses on cardiac issues associated with long COVID, updating much of the medical literature since early 2021.
Cardiac problems associated with long COVID can occur de novo or present with worsened problems in individuals with pre-existing cardiac problems. An article by Caforio7 in UpToDate states:
Patients with acute COVID-19 may present with a broad spectrum of clinical cardiac presentations: some patients manifest no clinical evidence of heart disease, some have no symptoms of heart disease but have cardiac test abnormalities (such as serum cardiac troponin elevation, asymptomatic cardiac arrhythmias, or abnormalities on cardiac imaging), and some have symptomatic heart disease. Cardiac complications include myocardial injury, heart failure, cardiogenic shock, and cardiac arrhythmias including sudden cardiac arrest.
Most patients with COVID-19 with abnormalities on cardiac testing have typical symptoms of COVID-19, including cough, fever, myalgia, headache, and dyspnea… A minority of patients with COVID-19 present with symptoms that may suggest heart disease (such as palpitations or chest pain). These symptoms may or may not be accompanied by prior or concurrent symptoms typical of COVID-19 infection. Symptoms such as dyspnea and chest pain may be caused by noncardiac and/or cardiac causes.
Most patients with COVID-19 with cardiac test abnormalities (such as cardiac troponin elevation, electrocardiographic [ECG] abnormalities, or cardiac imaging findings) lack symptoms of heart disease.
The Centers for Disease Control and Prevention (CDC) defines long COVID as “an umbrella term for the wide range of health consequences that are present 4 or more weeks after infection with SARS-CoV-2. The timeframe of 4 or more weeks provides a rough approximation of effects that occur beyond the acute period, but that timeframe might change as we learn more.”8 The World Health Organization (WHO) defines long COVID as a condition occurring in individuals with a history of probable or confirmed SARS-CoV-2 infection. It occurs “usually” 3 months from the onset, with symptoms lasting for at least 2 months that cannot be explained by alternative diagnoses. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction.9
New and Persisting Problems Generally Associated With COVID-19
A position paper from the Society of Occupational Medicine dated August 2022 stated that “long COVID is a massive public health problem.”10 The prevalence is greatest in individuals aged 35 to 69 years. That review stated that 80% of individuals with COVID-19 had mild symptoms whereas 10% to 15% developed more severe symptoms, such as pneumonia, acute respiratory distress, or multiorgan system failure. The review also noted that 5% to 36% of individuals recovering from COVID-19 still experienced a variety of symptoms weeks to months following the acute infection and provided the following table of long-term symptoms.
| Median and Range | <3 Months | 3-6 Months | >6 Months |
|---|---|---|---|
| Hospitalized | 32% (5%-36%) | 57% (13%-92%) | 60% |
| Nonhospitalized | 51% (32%-78%) | 26% (2%-62%) | 25% (13%-53%) |
In 2021, Ramadan et al11 reviewed 35 studies representing 52,609 patients. Twenty-nine studies used objective cardiac assessments such as cardiac magnetic resonance imaging (CMR) (used in 16 studies), echocardiography (used in 15), electrocardiography (used in 16), and cardiac biomarkers (used in 18). The median time from the date of diagnosis to the date of cardiac assessment was 48 days. Individuals younger than 18 years were excluded. Table 1 is derived from their data. It is organized by the test and the timing of the evaluation (<3 months or 3-6 months); the proportion of patients is given by the percent testing positive for any given test.
Continued Problems Separated by Test, Symptoms, Diagnosis, and Time
| <3 mo | 3-6 mo | <3 mo | 3-6 mo | ||||
|---|---|---|---|---|---|---|---|
| CMR | Increased T-1 | 30% | <1% | ECG | ST changes/elevation | 4% | 1% |
| Increased T-2 | 16% | 3% | RBBB | 4% | <1% | ||
| Pericardial enhancement | 10% | <1% | T wave abnormalities | 7% | <1% | ||
| Pericardial effusion | 15% | 1% | |||||
| Decreased EF | 3% | <1% | Cardiac biomarkers | Elevated troponin | 4% | <1% | |
| Myocardial enhancement | 10% | <1% | Elevated NT-proBNP | 6% | 18% | ||
| LGE | 11% | 10% | |||||
| Elevated ECV | 1% | 9% | Symptoms | Chest pain | 25% | 5% | |
| Reduced GLS | 2% | 30% | Dyspnea | 36% | 3% | ||
| Palpitations | 6% | 9% | |||||
| Echocardiography | Decreased EF | 2% | 4% | ||||
| Pericardial effusion | 1% | 4% | Diagnoses | Myocarditis | 13% | <1% | |
| Biventricular dysfunction | <1% | 1% | Pericarditis | <1% | 3% | ||
| Diastolic dysfunction | 5% | 40% | Myopericarditis | <1% | 11% | ||
| Pulmonary hypertension | <1% | 7% |
Abbreviations: CMR, cardiac magnetic resonance; ECG, electrocardiogram; ECV, extracellular volume; EF, ejection fraction; GLS, global longitudinal strain; LGE, late gadolinium enhancement; RBBB, right bundle branch block
As outlined in Table 1, many abnormalities detected within 3 months would have remitted within 3 to 6 months. The exceptions were elevated extracellular volume, reduced global longitudinal strain, diastolic dysfunction, pulmonary hypertension, elevated natriuretic hormone, the diagnosis of myopericarditis, and symptomatic palpitations. The incidence of longer duration of symptoms was significantly associated with the need for hospitalization during the acute phase of the COVID-19 infection.
An article by Mikkelsen and Abramoff12 in UpToDate is an invaluable resource for cutting edge information regarding the cardiovascular manifestations of long COVID, the diagnostic evaluation for those manifestations, and accepted treatment protocols. Oronsky et al13 provided a review of the potential immunochemical mechanisms and mechanistic factors.
Other than continued test abnormalities or persisting symptoms, many published articles have suggested that there is an increased incidence of cardiac and/or vascular problems, including cerebrovascular disorders (transient ischemic attacks [TIAs] and strokes), arrhythmias (usually atrial), ischemic heart disease, heart failure, myocarditis, pericarditis, and thrombotic disorders between 1 and 12 months following a COVID-19 infection, in comparison to control cohorts.11,12,14-16
Wang et al16 studied 126 patients who averaged 5 months post–COVID-19 diagnosis. The most common symptoms were dyspnea (52%), chest pain and pressure (40%), palpitations (44%), and fatigue (42%), which were usually associated with exertion or exercise intolerance. New cardiovascular diseases were present in 23% of cases.
Visco et al14 noted that approximately 10% of individuals recovering from acute COVID-19 infections may have persistent symptoms lasting more than 3 months. “The original cause of the persistence of symptoms has yet to be recognized, but several hypotheses have been produced.” The articles they reviewed suggested the following etiologies:
Aberrant immune responses
Virus-specific pathophysiological alterations
Inflammatory damage
Viral persistence in certain tissues
SARS-CoV-2 interactions with the host microbiome and virome communities
Clotting/coagulation issues
Dysfunctional brainstem and vagus nerve signaling
Unknown cause(s) for increased risk in certain populations including:
Severity of the acute infection
Symptom load
Level of hospital care and the need for mechanical ventilation
Female gender
Older age
Presence of comorbidities
Minority ethnicities
Tudoran et al17 reviewed the cases of 383 patients, all younger than 55 years and without a history of cardiovascular disease. All were diagnosed with post-acute COVID-19 syndrome (ie, long COVID) and were evaluated by transthoracic echocardiography (TTE). Of those individuals studied, 102 patients (26.6%) had various TTE abnormalities. Those patients were reevaluated at 3 and 6 months to determine the evolution of abnormalities such as left ventricular function, diastolic dysfunction, elevated systolic pulmonary artery pressures, right ventricular dysfunction, and pericardial effusion or thickening. Gradual improvement was seen at 3 months but more significant at 6 months. At 6 months, only 5.7% of patients had abnormalities consistent with mildly abnormal left ventricular function. Diastolic dysfunction persisted in approximately 33%; those patients were primarily female, overweight, and with less severe lung injury during the acute illness. Significant improvements were also seen in the pericardial abnormalities and elevated pulmonary artery pressures.
Xie et al18 reviewed cases in the database of the US Department of Veterans Affairs, identifying 153,760 individuals with COVID 19: “Beyond the first 30 days after infection, people with COVID-19 exhibited increased risks and 12-month burdens of incident cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease and other cardiac disorders. The risks were evident regardless of age, race, sex and other cardiovascular risk factors, including obesity, hypertension, diabetes, chronic kidney disease and hyperlipidemia; they were also evident in people without any cardiovascular disease before exposure to COVID-19, providing evidence that these risks might manifest even in people at low risk of cardiovascular disease.” Unfortunately, while all individuals were studied between 30 and 365 days following their acute infection, the amount of time was not broken into intervals. In other words, all the results were for individuals between 30 and 365 days without specifying possible changes in the risk profile at 1 to 3 months, 3 to 6 months, etc.18
Arrhythmias and Other ECG Abnormalities
Saha et al19 published a review of the dysrhythmias associated with acute COVID-19 infections but failed to discuss the dysrhythmias found in individuals with long COVID. Tobler et al15 stated that “arrhythmia has been noted in up to 10.4% of COVID-19 patients with moderate to severe COVID-19 disease,” with the most frequently observed being atrial fibrillation, nonsustained ventricular tachycardia, and bradyarrhythmias.
Coromilas et al20 reviewed the records of 4,526 patients worldwide and found that most patients with arrhythmias during acute COVID-19 did not have a prior history of arrhythmia. Of those who did develop an arrhythmia, the majority (81.8%) had atrial arrhythmias, 20.7% had ventricular arrhythmias, and 22.6% had bradyarrhythmias. Musikantow et al21 retrospectively studied the incidence of atrial fibrillation and flutter in almost 4,000 hospitalized patients with COVID-19 or influenza and found similar rates in both groups, with an association between arrhythmia and elevations in inflammatory markers, myocardial injury, and death. Atrial fibrillation or flutter was seen in approximately 10% of patients; the incidence in patients without a history of atrial arrhythmias was 4%. The authors stated that the results suggested that atrial fibrillation and flutter during COVID-19 hospitalization may occur secondary to systemic inflammation associated with a severe viral illness.
However, there is less information regarding arrhythmias associated with long COVID. Ingul et al22 performed 24-hour electrocardiogram (ECG) on 204 patients 3 to 4 months after COVID-19 and detected arrhythmias in 27% of patients, primarily premature ventricular contractions (80%) and nonsustained ventricular tachycardia (5%). Atrial fibrillation and flutter were seen in 4%, and supraventricular tachycardia lasting longer than 30 seconds was seen in 2%.
In a study of 29 patients by Marazzato et al,23 two patients had atrial fibrillation “after full recovery.” Furthermore, persistent ECG abnormalities were common, including nonspecific repolarization abnormalities (93%) reflecting pericardial involvement on TTE (86%).
In their review, Ramadan et al11 found nine studies (excluding case reports) reporting ECG abnormalities. The median time to assessment was 41 days postinfection. A study of 678 patients revealed:
T wave changes in 43 patients (6.3%); median = 0% with a range of 0% to 27%
ST segment changes, including elevation and depression, in 26 patients (3.8%); median = 0% with a range of 0% to 10%
Right bundle branch block in 26 patients (3.8%); median = 0% with a range of 0% to 18%
Sinus tachycardia in 2 patients (6.3%); median = 0% with a range of 0% to 2%
Included in their review were four studies of 150 participants who had a median time to assessment of 44 days and reported no abnormalities on ECG.
Dysautonomia
On the first page of their review, Palma and Kaufmann24 stated:
When autonomic reflexes are impaired or intravascular volume is markedly depleted, a significant reduction in blood pressure occurs upon standing, a phenomenon termed “orthostatic hypotension.” Orthostatic hypotension can be asymptomatic or symptomatic. Symptoms include dizziness, lightheadedness, syncope, muscle ache in the neck and shoulders, and even angina. Symptomatic falls in blood pressure after standing or eating are frequent problems. The prevalence of orthostatic hypotension varies from 5% to 20% in different reports. Chronic orthostatic intolerance (COI) describes the association of lightheadedness, dizziness, faintness, or syncope that occurs with prolonged standing or upright posture. The symptoms may sometimes be associated with an exaggerated tachycardia but no fall in blood pressure, a disorder called postural orthostatic tachycardia syndrome (POTS).
Saha et al19 published a review of this subject in individuals with acute COVID-19 infections but did not discuss the presence or persistence of dysautonomia found in individuals with long COVID.
Vernon et al25 stated that symptoms of orthostatic intolerance (OI) include lightheadedness, nausea, cognitive problems, disruptive sleep, headache, palpitations, and exercise intolerance. In individuals with OI, symptoms may also be experienced that are not associated with upright posture. This condition generally reflects dysfunction of the autonomic nervous system. During formal testing, some individuals with OI meet the criteria for POTS. The authors studied 42 patients between the ages of 18 to 65 years with more than 3 months of persistent symptoms following acute COVID-19 infection. The majority were white (90%) and women (90%); the patients were tested using the NASA lean test (NLT). Immediately after this test, there was a significant worsening of symptoms, but not in the healthy control subjects. This test caused an increase in diastolic blood pressure, which caused a reduced pulse pressure and an abnormally narrowed blood pressure ratio. The authors stated that these abnormalities “may reflect autonomic dysfunction—either increase sympathetic output and/or inadequate compensatory parasympathetic response.”25
In an early study of a few individuals, Barizien et al26 concluded that “long COVID-19 participants with fatigue may exhibit a dysautonomia characterized by dysregulation of the HRV [heart rate variability], that is reflected by the NOI [nociception index] index measurements, compared to control participants. Dysautonomia may explain the persistent symptoms observed in long COVID-19 patients, such as fatigue and hypoxia.”
Bisaccia et al27 stated that “signs of cardiovascular autonomic dysfunction appear to be common in PASC (post-acute sequelae of SARS-CoV-2) and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia.”
Marques et al28 reviewed the records of 155 long COVID patients studied at less than 3, 3 to 6, and more than 6 months. The authors stated that their findings “indicate that long COVID leads to sympathetic excitation influence and parasympathetic reduction. The excitation can increase the heart rate and blood pressure and predispose to cardiovascular complications. Short-term HRV analysis showed good reproducibility to verify the cardiac autonomic involvement.”
In a study of 85 individuals (mean age, 46 years; 74% female) with OI, Monaghan et al29 noted that OI appeared to be associated with fatigue and depressive symptoms and an inability to perform activities of daily living. In the study, individuals underwent a three-minute active stand test. The authors concluded that individuals with OI had a higher initial heart rate during the active stand test, which equalized within 1 minute. POTS was infrequent (2%).
In a 2022 review, Carmona-Torre et al30 stated:
Autonomic dysfunction associated with SARS-CoV-2 infection occurs at different temporal stages. Some proposed pathophysiological mechanisms include direct tissue damage, immune dysregulation, hormonal disturbances, elevated cytokine levels, and persistent low-grade infection. Acute autonomic dysfunction directly impacts the mortality risk, given its repercussions on the respiratory, cardiovascular, and neurological systems. Iatrogenic autonomic dysfunction is a side effect caused by the drugs used and/or admission to the intensive care unit. Finally, late dysautonomia occurs in 2.5% of patients with post–COVID-19 conditions. While orthostatic hypotension and neurally mediated syncope should be considered, postural orthostatic tachycardia syndrome (POTS) appears to be the most common autonomic phenotype among these patients.
This article reviewed dysautonomia and other manifestations of long COVID. It also discussed possible pathogenetic mechanisms, the methods of diagnosis, and possible treatments in long COVID patients.
In another 2022 review, Ormiston et al31 stated that POTS is a complex multisystem disorder characterized by OI and tachycardia. A viral infection may trigger it; they reviewed reports suggesting that 2 to 14% of COVID-19 survivors developed POTS within 6 to 8 months of the acute infection. Hypothetical causes included autoimmunity related to the SARS-CoV-2 infection, autonomic dysfunction, direct toxic injury by SARS-CoV-2 on the autonomic nervous system, and invasion of the central nervous system by this virus.
Right Heart Failure and Pulmonary Hypertension
Khetpal et al32 stated:
COVID-19 has been associated with pulmonary hypertension and right heart failure in those hospitalized during the acute phase of the disease. Multiple mechanisms for developing pulmonary hypertension have been postulated, including inflammation, cytokine storm, endothelial injury, hypercoagulability causing venous thromboembolism, thrombotic microangiopathy, and vasoconstriction. These pathophysiologic mechanisms are postulated to lead to either pre-capillary pulmonary hypertension or chronic thromboembolic pulmonary hypertension. In addition, pulmonary hypertension may result from hypoxia and significant lung injury from the acute disease. However, data on pulmonary hypertension and right heart failure are limited as long-term manifestations of PACS [post-acute COVID syndrome].
Tobler et al15 stated:
Pulmonary hypertension and right ventricular dysfunction have been observed in up to 12% and 14%-33%, respectively, of patients admitted for COVID-19. Both findings are observed more frequently in those with prior cardiac comorbidities and have been associated with more severe lung disease and higher in-hospital mortality rates. Though described, the incidence of left ventricular dysfunction is not entirely clear.
Furthermore, they stated:
One investigation of individuals recovered from acute COVID-19 infection revealed that at one year follow-up, new-onset hypertension and de novo heart failure were present in 2% of patients, and there was an increased need for readmission for heart failure medication augmentation. Additionally, 2.7% of patients in this same study developed new right-sided heart failure in the absence of hypertension of left heart failure. Given the findings of frequently abnormal echocardiograms in the acute setting, however, it is difficult to know if this represents structural change in the post-infectious setting or dysfunction that was simply not assessed during the index admission. While pulmonary hypertension is often seen in the acute phase of the illness, this has not been frequently seen on follow-up echocardiography.15
In the study by Marazzato et al,23 ECG abnormalities consistent with pericardial involvement were found in 93% of patients, and pericardial abnormalities were found in 86% by TTE “after full recovery from COVID-19 pneumonia.” Pulmonary hypertension was found in 55% of patients despite the absence of prior core morbidities in 44%.
Pela et al33 studied 160 patients following discharge. At an average follow-up of 5 months, echocardiographic evidence of abnormalities in the right and left ventricles, such as right ventricular dilation, increased pressure in the pulmonary circulation, and biventricular systolic and diastolic dysfunction, were found.
Tudoran et al17 found diastolic dysfunction in 100 patients, initially decreasing to 81 patients at 3 months and 59 patients at 6 months.
Hypercoagulability and Thromboembolism
Many individuals demonstrate laboratory evidence of hypercoagulability during the acute phase of COVID-19 illness. Some individuals develop venous and arterial thrombosis, especially in individuals with severe or critical acute clinical courses. The duration of hypercoagulability is unknown.11 Some individuals develop a disseminated intravascular coagulopathy (DIC)–like coagulopathy during the acute illness.13 Ambrosino et al34 stated:
Data in recent studies have demonstrated that severe pulmonary manifestations in COVID-19 patients are not only due to ARDS [acute respiratory distress syndrome], but also to macro- and microvascular involvement, with vascular endothelial injury and subsequent dysfunction. Vascular damage is probably related both to the direct cytopathic effect of the virus on endothelial cells (ECs) and to the high levels of cytokines and other inflammatory markers, inducing systemic endotheliitis, platelet activation, leucocyte adhesion, and reduced nitric oxide (NO) bioavailability. Overall, it is evident that in COVID-19 the pathological process is not limited to the lungs, and the systemic inflammatory process is responsible for an imbalance between the prothrombotic and anticoagulant properties of the endothelium, leading to arterial and venous thrombosis. Indeed, patients with severe COVID-19 frequently suffer from pulmonary and systemic vascular complications, including pulmonary embolism, deep vein thrombosis, and major CV events.
This review described micro- and macrovascular involvement, vascular endothelial injury, and subsequent dysfunction. It also discussed the physiological and biochemical aspects of these issues. Similar remarks were made by Santoro et al.35
According to Oronsky et al,13 “some patients with severe COVID-19 infection develop a DIC-like coagulopathy with fulminant activation of coagulation and consumption of coagulation factors. This is characterized by delayed clotting times (PT [prothrombin time] and aPTT [activated partial thromboplastin time]), low platelets, and decreased fibrinogen (<1.0 g/L) due to their consumption. Thrombotic complications include pulmonary embolism and strokes.”
Xiang et al36 reviewed alterations in clotting during acute COVID-19 infections. They stated that “[t]hrombus is a crucial factor in the progression of COVID-19 to severe disease, and its importance in long COVID has not been fully assessed. Early treatment of microthrombi can reduce not only mortality but also reduce the incidence of sequelae.”
Persistent fatigue, breathlessness, and reduced exercise tolerance have been reported following acute COVID-19 infections. In a study by Townsend et al,37 150 patients were studied 44 to 155 days following acute infection (the median was 80.5 days). Of the individuals studied, 69 had been hospitalized and 81 were managed as outpatients. Clinical examinations, chest X rays, and 6-minute walks were performed. The authors stated that ongoing symptoms consistent with long COVID were common; 51% met the case definition for fatigue (56% of those individuals were in the “mild symptoms” category and were managed entirely as outpatients). This study's purpose was to review various blood tests associated with coagulation, including the prothrombin time (PT), aPTT, fibrinogen, and D-dimer levels. Serum C-reactive protein (CRP), soluble CD25 (sCD25), and interleukin-6 (IL-6) were also measured. The authors found elevated D-dimer levels that could not be explained by low-grade DIC, systemic coagulation activation, or evidence of ongoing acute phase responses. Elevated levels were found in 38 patients (25.3%) at the time of follow-up and were more common in individuals who had been hospitalized. However, those individuals who had been hospitalized and had elevated levels at follow-up were not found to have any correlation with coagulation abnormalities during their hospitalization. Individuals with elevated D-dimer levels were more likely to have abnormal chest X rays during convalescence. A computed tomography (CT) pulmonary angiogram was performed on 8 of the 38 patients (21%) of the total cohort with increased D-dimer levels. None of the scans was positive for pulmonary embolus. However, subsequently, two of those individuals developed vascular problems (bilateral pulmonary emboli and a non-ST elevation myocardial infarction). The authors concluded that an elevation in the D-dimer level is a common finding in the convalescent period. “Importantly, this increase in D-dimer was seen at a median of greater than two months following resolution of acute COVID-19 infection and was observed in a cohort comprising predominantly young patients (median age 47 years) who mostly (64%) recovered without hospitalization. Interestingly, the increase in convalescent D-dimers remained despite normalization of inflammatory markers and other coagulation parameters in most patients.”
Hypertension
Maestre-Muñiz et al38 investigated individuals who had recovered from acute COVID-19 infection and found that at the 1-year follow-up, new-onset hypertension and de novo heart failure were present in 2% of patients. Furthermore, they noted an increased need for readmission for heart failure medication augmentation.
Inflammatory Heart Disease
Inflammatory heart disease includes pericarditis, myocarditis, and myopericarditis. Carubbi et al39 stated that “pericarditis appears to be common in the acute infection but rare in the post-acute period, while small pericardial effusions may be relatively common in the post-acute period of COVID-19.” Khasnavis et al40 stated that pericarditis and pericardial effusions occur between a few days to a few months after infection. However, they reported on one patient who developed acute pericarditis 1 year or more following his acute COVID-19 infection. In that case, clinical issues were recurring pericardial symptoms, persistent elevations in the D-dimer, and persistent elevations in the C-reactive protein (CRP). Cardiac tamponade was reported in one individual 1 month following the patient's acute COVID-19 presentation.41
Marazzato et al23 stated:
As reported by a large body of evidence, besides interstitial pneumonia, SARSCoV-2 may be responsible for a cardiac phenotype of the syndrome, potentially leading to new-onset atrial fibrillation, pulmonary embolism and non-ST elevation myocardial infarction. However, the virus may elicit a far less dramatic clinical presentation with unremarkable electrocardiographic abnormalities, such as mild ST-T changes. Of note, most of these new-onset ECG findings are recorded in patients with negative nasopharyngeal swabs and several weeks after recovery from COVID-19 pneumonia. In keeping with these observations, ECG abnormalities were commonly reported in the population investigated in this study as persistent manifestations of previous COVID-19 pneumonia and reflected the high prevalence of the pericardial involvement observed on TTE.
It is indeed well known that SARS-CoV-2 infection may elicit a powerful multiorgan inflammatory response causing pleural and pericardial inflammation in the affected cases. If the postmortem analysis of these patients showed that mild pericardial effusion was extremely common immediately after the acute phase of the disease, mounting evidence has recently reported how pericardial involvement may be identified on cardiac magnetic resonance (CMR), even in fully recovered cases. Likewise, ongoing myocardial inflammation and residual fibrosis may still be detectable on CMR as areas of myocardial oedema and/or late gadolinium enhancement. However, as demonstrated in this study, LUS [lung ultrasound] and TTE can be useful in the detection of pleural and pericardial abnormalities, such as pleuro-pericardial thickening, hyper echogenicity and effusion.
Ischemic Heart Disease and Cardiac Injury
Khetpal et al32 stated:
Several mechanisms of myocardial injury in the setting of COVID-19 have been hypothesized, including a proinflammatory state from cytokine storm, direct viral invasion of myocytes, hypercoagulable state with thromboembolic phenomenon, coronary plaque instability, demand-supply mismatch with increased demand from systemic inflammation, and accelerated atherosclerosis and plaque rupture. In the post-acute phase of COVID-19, the cytokine-mediated damage can cause thrombogenesis, decreased oxygen supply, coronary plaque destabilization, progression of chronic cardiovascular disease (CVD) into unstable disease, increased metabolic demand, and reduced cardiac reserve. One study found that patients with COVID-19 had a three times higher likelihood of a major adverse cardiac event at a median of five months post-discharge compared to controls matched by age, sex, and risk factors. The one-year incidence rates of ischemic heart disease, including acute coronary disease (HR 1.72; 95% CI 1.56-1.90), myocardial infarction (HR 1.63; 95% CI 1.51-1.75), and ischemic cardio-myopathy (HR 1.75; 95% CI 1.44-2.13) are all increased when compared to a control cohort without COVID-19.
Oronsky et al13 stated:
COVID-19 patients commonly present with signs of myocardial injury including heart failure and myocarditis and/or exacerbation of existing cardiovascular disease as determined by elevated levels of troponin T (TnT) and brain natriuretic peptide (BNP). Potential mechanisms of injury include the following:
increased pulmonary vascular resistance with subsequent pulmonary hypertension and right heart failure
overstimulation of the renin-angiotensin system (RAS), which mediates deleterious effects on the cardiovascular system including secondary hyperaldosteronism, leading to hypokalemia and cardiac arrhythmias
atherosclerotic plaque rupture via the action of proinflammatory cytokines, precipitating infarction, especially in the context of pre-existing coronary artery diseases
ACE-2-mediated viral invasion of cardiomyocytes, resulting in myocarditis
myocardial oxygen supply/demand mismatch from the combination of decreased venous return and severe hypoxemia due to ARDS, leading to myocardial ischemia/necrosis
possible cardiotoxicity of potential anti-COVID agents including the macrolide antibiotic, azithromycin, associated with a prolonged QT interval, chloroquine/hydroxychloroquine, which may produce conduction defects in the heart, tocilizumab, which increases cholesterol levels], and lopinavir/ritonavir, the protease inhibitors that may prolong PR and QT intervals and also inhibit YP3A4 activity, which influences the metabolism of other cardiac medications including statins.
Symptoms of Long COVID
Common symptoms of long COVID (and their risk factors) include:
fatigue (older age),
dyspnea (higher body mass index [BMI]),
chest pain (female gender),
palpitations (pre-COVID cardiovascular disease such as coronary disease, heart failure, and arrhythmias),
dizziness (pre-COVID comorbidities such as diabetes, hypertension, chronic kidney disease, and chronic lung disease),
tachycardia (initial symptomatic COVID-19 illness), and
exercise intolerance (limited baseline functional status).11
A systematic review and meta-analysis performed by Lopez-Leon et al42 in 2021 reviewed 18,251 publications, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated. Twenty-one meta-analyses were performed, and 47,910 patients were included in this review. The follow-up time ranged from 14 to 110 days following acute COVID-19 infection. The range of ages was 17 to 87 years with no mean value given. Half of the studies reviewed were for hospitalized patients only; the rest included individuals with mild to severe symptoms and hospitalized and nonhospitalized patients. It was estimated that 80% of the patients developed one or more long-term symptoms. The five most common symptoms were fatigue (50%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Abnormalities on chest radiography and CT were observed in 34%. D-dimer levels were elevated in 20%, NT–proBNP were elevated in 11%, CRP levels were elevated in 8%, serum ferritin levels were abnormal in 8%, serum procalcitonin levels were abnormal in 4%, and interleukin-6 levels were abnormal in 3%. Also of importance for this review was an increase in the resting heart rate in 11% of individuals, palpitations in 11%, chest pain and discomfort in 16%, limb edema in 3%, myocarditis in 1%, and arrhythmias in 0.4%.
A similar study published by in 2022 by Healey et al43 reviewed 19 studies with a total sample size of 10,643 patients in a follow-up time ranging between 30 and 340 days. The most common symptoms were fatigue (37%), shortness of breath (21%), olfactory dysfunction (70%), myalgia (12%), cough (11%), and gustatory dysfunction (10%). Again, of importance for this review was the presence of chest pain in 3%. No other cardiac symptom was discussed in this review.
Ramadan et al11 stated that chest pain or tightness is found in 12% to 44% of patients. As a rule, the chest discomfort lasts approximately 2 to 3 months after an acute COVID-19 infection and rarely longer. Less common persistent physical symptoms include dizziness from orthostasis, postural tachycardia, and vertigo. Pela et al33 reported on 160 consecutive patients. At an average of 5 months, 29% had palpitations and 28% had chest pain.
Of importance in the evaluation of long COVID patients is the ability to correctly identify the underlying causes of the individual's symptoms of shortness of breath, fatigue, and exercise intolerance. Equally important is the ability to provide objective proof for those causes. A study was undertaken of 231 patients (mean age, 47.8 years; 57.1% female). Acute COVID occurred, on average, 121 days previously. CMR and a cardiopulmonary exercise stress test were performed in 36 patients based on clinical concerns. Of those individuals, 16 (44.4%) had pathological findings. The remainder had subjective complaints without objective abnormalities. These abnormalities occurred in individuals with asymptomatic disease, as well as those whose acute COVID-19 infection was of sufficient severity necessitating hospitalization.44
Fatigue, shortness of breath, and exercise intolerance are frequent symptoms in long COVID patients. Tleyjeh et al45 interviewed 222 post-COVID patients who were hospitalized with COVID-19. The median timing was 122 days following discharge from the hospital. Of those, 56.3% experienced unresolved symptoms 1-month after discharge, and 28.8% failed to return to pre-COVID baseline status at a median of 4 months following discharge. Individuals with a higher Medical Research Council dyspnea scale were more likely to be female, have pre-existing lung disease, have a headache at presentation, and had been admitted to the intensive care unit. Lower exercise tolerance scores were also found to be more frequent in females but also in individuals older than 67 years with a history of hypertension and a history of an emergency room visit. Chronic fatigue symptoms were more likely in individuals who were female, had preexisting lung disease, had an emergency room visit, and had lower cardiopulmonary exercise testing (CPET) scores.
A study by Wood et al46 looked at 22 individuals with persistent cardiac symptoms. Of those, 13 were healthcare professionals. The 22 participants were reviewed in the cardiology clinic a mean of 401 days after their acute illness. They were investigated using echocardiography, CMR, a 6-minute walking test, electrocardiography, and CPET. The authors stated that “among a cohort of 22 patients with self-reported persistent cardiac symptoms, we identified no underlying cardiac disease or reduced cardiopulmonary exercise fitness one year following COVID-19.”
Baranauskas and Carter47 studied 29 women approximately 3 months after mild-to-moderate acute COVID-19 infection using a complete pulmonary function test and a 6-minute walk. The results are outlined in Table 2.
Pulmonary Function Data for Individuals With Abnormal Heart Rates in Response to Exertion
| Total Lung Capacity (TLC) % | Vital Capacity (VC) % | Functional Residual Capacity (FRC) % | Residual Volume (RV) % | Increased Heart Rate With Exertion | |
|---|---|---|---|---|---|
| Cases (n = 29) | 84 ± 8 | 87 ± 10 | 75 ± 16 | 76 ± 18 | + 52 ± 20 |
| Controls (n = 16) | 93 ± 13 | 93 ± 10 | 88 ± 16 | 93 ± 22 | + 65 ± 18 |
In addition, there was no between-group difference in the 6-minute walk distance (P = 0.19). However, there was also a delay in the decrease in the heart rate between minutes 1 through 5 of the recovery period (P < 0.05). The differences in the TLC, VC, FRC, and RV all had P values of at least 0.04. As such, the differences were statistically significant. The ages, BMI, and comorbidities were comparable between both groups. There were no differences in the oxygen saturations. In the case-cohort, five individuals were symptomatic, and 23 were asymptomatic. Greater impairment was found in the symptomatic individuals compared to those who were asymptomatic. Lastly, the diffusion capacity for carbon monoxide (DLCO) was measured in these individuals. The DLCO was below the lower limit of normal in only two of the 28 cases. However, a lower DLCO was associated with a lower 6-minute walk distance and heart rate recovery. These results suggest that pulmonary function abnormalities and dysautonomia probably contribute to a long COVID patient's shortness of breath and exercise intolerance.
In one of the few studies that reviewed individuals 1 year following acute COVID-19 infection, Maestre-Muñiz et al38 studied 587 patients (266 following hospital admission and 321 following emergency room visits). Clinical symptoms possibly associated with long-COVID were found in 56.9% of patients and were more common in hospitalized individuals (66.8%) than in those who were not hospitalized (49.5%). The most common symptoms were shortness of breath (41.6%), fatigue (35.4%), abnormalities with the sense of taste (30.2%), and abnormalities with the sense of smell (26.3%). Overall, 46.5% had shortness of breath at some point after discharge, and this symptom was more common in individuals who were hospitalized. In the year following acute COVID-19 infection, 13 individuals presented with deep venous thrombosis, and nine had a pulmonary embolus. Among those who survived, eight (1.5%) presented with acute myocardial infarction, and seven (1.3%) had a stroke. There were no differences between the in-hospital and out-of-hospital individuals. Heart failure was reported in all 11 individuals (2%) and another seven patients who had a history of heart failure required treatment augmentation. Lastly, “2% of patients developed de novo arterial hypertension during the study year, which can be explained by the interference SARS-CoV-2 has over the rennin angiotensin system (RAS), with angiotensin-converting enzyme 2 (ACE2) being the major counter-regulatory mechanism for the main axis of the RAS, and critical for the control of blood pressure and electrolyte balance. SARS-CoV-2 binds with ACE2 and enhances its degradation, thus decreasing the counteraction of ACE2 on the RAS, with increased reabsorption of sodium and water, leading to increased blood pressure and excretion of potassium.”38
Regarding exercise intolerance, Singh et al48 studied 10 individuals “nearly 1 year after recovery for mild disease” who recovered from COVID-19 and compared them with “normal” individuals. They stated48:
The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO2]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4 ± 2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation.
In the current study, we demonstrate that nearly 1 year after recovery from mild disease, patients who experienced COVID-19 with decreased exercise tolerance, but no long-term cardiopulmonary disease sequelae, exhibited a peripheral, rather than a central, cardiac limit to aerobic exercise characterized by impaired systemic EO2 with resulting increased peak exercise mixed venous oxygen saturation and peak VO2 content. Additionally, they also demonstrated an exaggerated hyperventilatory response during exercise.
In other words, Singh et al48 stated that long COVID patients can show significant abnormalities on CPET such as reduced peak exercise aerobic capacity, impaired systemic oxygen extraction, and greater ventilatory insufficiency.
Fernández-de-las-Peñas et al49 conducted telephone interviews with 1,950 patients (mean age, 61 ± 16 years; 53% male) 11.2 months following hospital discharge. While this study was primarily addressing respiratory problems, chest pain was found in 6.5%, shortness of breath in 23.3%, and fatigue in 61.2%.
Implications for an Impairment Evaluation on a Long-COVID Examinee
Individuals who perform impairment assessments should be well acquainted, conversant in, and concerned about issues that can be supported by medical science. Our understanding of COVID-19 and its impact is evolving.
The SARS-CoV-2 infection began in late 2019 and was declared a pandemic in 2020. Case numbers of individuals infected remain high in both 2020 and 2021. Fortunately, by mid-2022, these case numbers have diminished, most likely due to vaccinations and herd immunity. Reviews of residual effects of COVID-19 began to appear in the world's medical literature in 2021. This review focused on studies published in 2022, although with incomplete success. When addressing the short- and long-term effects of any disease, the longer the period between the acute infection and the study, the greater the reliance can be made upon the results. Unfortunately, this is not the case with COVID-19 based on the time of the onset of the pandemic.
This article focused on the following seven studies that showed residual signs, symptoms, or laboratory abnormalities 1 year following the acute infection:
When addressing ischemic heart disease and cardiac injury, Khetpal et al32 found that patients with COVID-19 had a three times higher likelihood of a major adverse cardiac event at a median of 5 months postdischarge compared with controls matched by age, sex, and risk factors. The 1-year incidence rates of ischemic heart disease, including acute coronary disease (HR 1.72; 95% CI 1.56-1.90), myocardial infarction (HR 1.63; 95% CI 1.51-1.75), and ischemic cardiomyopathy (HR 1.75; 95% CI 1.44-2.13) are all increased when compared with a control cohort without COVID-19.
When addressing the issue of inflammatory heart disease, the article by Carubbi et al39 stated that one patient, 1 year or more following his acute COVID-19 infection, developed pericarditis.
Maestre-Muñiz et al38 found that 2% of individuals developed de novo arterial hypertension. In addition, they found 13 individuals presented with deep venous thrombosis, nine of whom had a pulmonary embolus. In their series of 587 COVID-19 patients and of those who survived, eight (1.5%) presented with acute myocardial infarction, and seven (1.3%) had a stroke. Heart failure was reported in all 11 individuals (2%), and another seven patients who had a history of heart failure required treatment augmentation.
Xie et al18 found that the risk of cardiovascular disease in survivors of acute COVID-19 “were substantial.”
Singh et al48 found a peripheral, rather than a central, cardiac limitation to aerobic exercise characterized by impaired systemic EO2 with increased peak exercise mixed venous oxygen saturation and peak VO2 content. There was also an exaggerated hyperventilatory response during exercise.
Fernández-de-Las-Peñas et al49 found symptoms of chest pain in 6.5% of patients, shortness of breath in 23.3%, and fatigue in 61.2%.
Wood et al46 stated: “Among a cohort of 22 patients with self-reported persistent cardiac symptoms, we identified no underlying cardiac disease or reduced cardiopulmonary exercise fitness one year following COVID-19.”
The remaining studies reviewed in this article document residual signs, symptoms, or laboratory abnormalities at only 3 to 6 months. More time is necessary for more data inclusion and review. It will take another 12 to 24 months to make more definitive statements. However, based on current knowledge, the following can be concluded and used during impairment assessments and individuals claiming cardiovascular damage caused by long COVID:
Symptoms of long COVID are frequent. The most frequent cardiovascular symptoms include shortness of breath, chest pain and pressure, palpitations, fatigue, and exercise intolerance.
There is a low possibility of persistent and new onset of:
arrhythmias,
chest pain,
inflammatory conditions (pericarditis, myocarditis, myopericarditis),
myocardial ischemia,
cerebrovascular disease,
heart failure,
hypertension,
thromboembolic disease,
dysautonomia, and
exercise intolerance.
While symptoms are frequent, objective abnormalities are much less frequent—generally less than 10% or more. The most critical issues regarding an impairment assessment are objective documentation of persistent or new-onset signs or symptoms, an opinion based on reasonable medical probability and a review of the medical literature to support that opinion. Lastly, the issue of maximum medical improvement (MMI) is of paramount importance, especially considering the time frame of long COVID-19. In other words, are the reported studies that generally reference the signs, symptoms, and laboratory abnormalities at 3 to 6 months post-acute COVID-19 infection representative of those issues that occur later (see the references regarding the 12-month issues)? And do the 12 months post-acute COVID-19 studies actually represent MMI concerning an individual's claim of impairment? Methods for assessing impairment can be found in many of the studies reviewed in this article and especially in the article written by Talmage et al.4
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