|Year : 2020 | Volume
| Issue : 2 | Page : 111-115
Myocarditis in Coronavirus disease 2019: Not an equivalent to troponinitis
Saikrishna Reddy, Bharath Kidambi, Sampath Madapati
Department of Cardiology, AIIMS, New Delhi, India
|Date of Submission||21-May-2020|
|Date of Decision||13-Jul-2020|
|Date of Acceptance||14-Jul-2020|
|Date of Web Publication||27-Aug-2020|
Dr. Saikrishna Reddy
Department of Cardiology, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
Coronavirus disease 2019 (COVID-19) has affected around 5 million people and is on raising trend. It has overwhelmed the health-care systems of all specialties including cardiology. Cardiac involvement has been seen based on the early reports from China showing elevation of troponin and especially in the critical cases varying form 7%–28%. Speculations were made about the possibilities of myocarditis based on those reports. This short review attempted to methodologically look at available clinical evidence on the true incidence of myocarditis in COVID-19. The data suggest that troponin elevation is not equal to either ischemic heart disease or myocarditis and is some form of nonischemic myocardial injury and a marker of higher morbidity. It is related to the cytokine storm, but more information is needed on its pathogenesis.
Keywords: COVID-19, myocardial injury, myocarditis, troponinitis
|How to cite this article:|
Reddy S, Kidambi B, Madapati S. Myocarditis in Coronavirus disease 2019: Not an equivalent to troponinitis. J Pract Cardiovasc Sci 2020;6:111-5
|How to cite this URL:|
Reddy S, Kidambi B, Madapati S. Myocarditis in Coronavirus disease 2019: Not an equivalent to troponinitis. J Pract Cardiovasc Sci [serial online] 2020 [cited 2022 Aug 16];6:111-5. Available from: https://www.j-pcs.org/text.asp?2020/6/2/111/293591
| Introduction|| |
The coronavirus disease of 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has emerged as a global pandemic within a short span of time and is a major public health crisis. Although COVID-19 primarily affects the lungs, it also involves multiple organs and especially cardiovascular system. As with many diseases, the mortality increases with increasing age, presence of multiple comorbidities, and pre-existing cardiovascular disease. The common cardiovascular complications include cardiac injury, heart failure, and arrhythmia. Most of the studies documented cardiac involvement up to 28%, but no evidence is available regarding the etiology of cardiac injury. Although the initial reports of fulminant myocarditis reported from China, no biopsy evidence was available. Evidence from the previous SARS epidemics showed variable involvement of the cardiovascular system.
| Data Search|| |
We have tried to collect all available information on possible myocardial injury on COVID and myocardial injury using the keywords: myocardial injury, COVID, Corona, COVID-19, troponins and searching Google, Google Scholar, PubMed, and also going through all webinars on this topic to search for unpublished data. Data presented in webinars, published or prepublished have been presented and cited.
| Pathogenesis|| |
SARS-CoV-2 has 80% molecular similarity with SARS-CoV (2002 SARS epidemic) and studies documented cardiac involvement during that epidemic. Hence, intuitively, there is an assumption of cardiac involvement with probably similar pathomechanism and early studies form China showed cardiac injury in the hospitalized patients. Multiple mechanisms of cardiac involvement have been proposed ranging from demand-supply mismatch to direct cardiac involvement, manifesting clinically as myocardial infarction, myocarditis, and heart failure. The various possible mechanisms have been discussed below.
| Mechanism of Direct Cardiac Injury|| |
Angiotensin converting enzyme 2 (ACE 2) expression is maximal in respiratory tract, and then myocardium, gastrointestinal tract, and liver. SARS–CoV-2 uses ACE2 receptor for entry into human cells and increases RAS activity.
| Cytokine Mediated Cardiac Damage|| |
“Interleukin-6 (IL-6) mediated cytokine storm.”
Other mechanisms of cardiac injury are listed in Figure below.
| Epidemiology and Prevalence of Cardiac Injury|| |
The evidence of myocardial injury in the form of elevation of troponin has been documented in the number of studies from China. However, the mechanism of myocardial injury remained elusive and was not elaborated further. The incidence varied from 7% to 28% among hospitalized patients, although the data are lacking on mild symptomatic patients. Major studies on myocardial injury in COVID-19 are summarized in [Table 1].
Shi et al. evaluated 416 hospitalized patients with COVID-19 for cardiac injury and mortality. A total of 82 patients (19.7%) had cardiac injury. Cardiac injury has been defined as the elevation of high-sensitivity assay for troponin I (hs-cTnI) >99th percentile. They demonstrated a statistically significant association between cardiac involvement and mortality. Patients with cardiac injury were older (median age, 74 years vs. 64 years) had more comorbidities (hypertension in 60% vs. 23%), elevated total leukocyte count (9400 vs. 5500), higher C-reactive protein (CRP) (10% vs. 3.7%), higher procalcitonin (0.3 vs. 0.06), high-sensitivity troponin (0.2 vs. <0.006), N-terminal pro-brain natriuretic peptide (NT proBNP) (1689 vs. 139), serum creatinine (1.15 vs. 0.6), and higher ground-glass opacities on chest imaging (65% vs. 4.5%). Furthermore, these group patients required more invasive mechanical ventilation (22% vs. 4%), higher incidence of acute respiratory distress syndrome (ARDS) (58% vs. 15%), and acute kidney injury (8.5% vs. 0.3%). Patients with cardiac injury also had higher mortality than those without cardiac injury (51% vs. 4.5%). All patients were grouped into the single category of cardiac injury; however, substratification based on etiology was not done.
Guo et al. analyzed 187 patients with COVID-19 positivity, and the cardiovascular implications on fatal outcomes. Nearly 28.7% had myocardial injury as assessed by elevated troponin. Thirty-five percent had underlying hypertension, coronary artery disease, and cardiomyopathy. Patients with elevated troponin have more frequent complications such as ARDS (58% vs. 12%), acute kidney injury (37% vs. 4.7%), and coagulopathy (66% vs. 20%); most significant of all these is mortality (59.6% vs. 9%).
Huang et al. analyzed 41 patients, of which 5 had myocardial injury, again defined as elevations in hs-cTnI levels (>28 pg/mL).
Wang et al. analyzed 138 hospitalized COVID-19 patients, of which 16.7% had arrhythmias and 7.2% had acute myocardial injury.
| Myocardial Infarction|| |
Although no data exist on the interaction between COVID-19 and myocardial infarction, many putative mechanisms have been proposed based on the experience from the previous similar epidemics. COVID 19 can cause MI either by plaque destabilization (type 1 MI) or by supply demand mismatch (type 2 MI). Bangalore et al. analyzed 18 COVID-19-positive patients with ST elevation suggesting probable myocardial infarction. Fifty-percent patients underwent coronary angiography, only 67% had obstructive stenosis, and significant portion of patients had nonobstructive myocardial injury, despite presenting with ST elevation.
| Heart Failure|| |
The incidence of heart failure was higher in COVID-19 patients and especially those with elevated troponin. Chen et al. analyzed 113 diseased patients of a cohort of 799 hospitalized with the diagnosis of COIVD-19. Acute cardiac injury was documented in 77% and heat failure was in 49%. Shi et al. group, the largest to look at cardiac injury in COVID-19. They documented the higher incidence of heart failure around 20% as assessed by elevated NT-proBNP levels in those with cardiac injury (1689 pg/ml vs. 139 pg/ml).
| Coronavirus Disease 2019 and Myocarditis|| |
Problems with using troponin as a marker of myocarditis
High-sensitive troponin is a sensitive biomarker of myocardial injury, but the problem is it does not distinguish between the causes of myocardial injury. The reference upper limit normal for troponin is from the young normal population, not the hospitalized patients. An editorial in JACC, “avoiding the imminent plague of troponinitis,” addressed the same problem of using the 14 pg/ml (reference upper limit normal) can lead to false positivity in around 10% cases, especially with increasing age., The various causes of cardiac injury are enlisted in [Figure 1]. All those listed are the putative mechanisms of myocardial injury, but the contribution of each of these is not known in COVID-19. At present, no study focused on isolated myocarditis alone in COVID-19. Hence, the evidence is majorly drawn from the case series and case reports. Although some reports have described findings consistent with a diagnosis of “clinically suspected myocarditis,” majority had no definitive diagnosis of myocarditis. Only one case report had EM biopsy-proven evidence of myocarditis. All the case reports of COVID-19 myocarditis published in the literature are summarized in [Table 2]. As was discussed earlier, in almost all of the case reports, the diagnosis of myocarditis is based on elevated biomarkers with supportive evidence from cardiac magnetic resonance imaging (cardiovascular magnetic resonance [CMR]). Some interesting findings observed were the median age of these patients is higher than a routine myocarditis and majority had electrocardiogram (ECG) changes as focal or diffuse ST-T changes, elevated D dimer, CRP, CMR showed subepicardial late gadolinium enhancement. Almost all patients improved despite fulminant nature. Few limited number autopsy studies showed predominant involvement of the lung with lymphocytic infiltration, fibrin micro thrombi, desquamation, areas of hemorrhage and consolidation, while myocardium showed mild lymphocytic infiltration but no areas of necrosis, almost similar findings in another autopsy series from Chongqing. Most of the patients with clinically suspected myocarditis or with elevated troponin had multiple cardiovascular comorbidities preexisting. With the evidence from case series and retrospective studies, cardiac involvement in COVID-19 is noted, but definite evidence in the form of myocarditis is uncertain.
|Figure 1: Pathophysiology of cardiovascular manifestation due to COVID 19.|
Click here to view
| Temporal Changes in Laboratory Markers from Illness Onset in Coronavirus Disease 2019 Patients|| |
Troponin elevation is in parallel to the elevations in total leukocyte count, d-dimer, ferritin, IL-6, and lactate dehydrogenase. Zhou et al. showed these parameters were elevated in nonsurvivors and increased with worsening of the general condition.
| Cardiovascular Comorbidities in Coronavirus Disease 2019|| |
Two major studies from China showed that three common comorbidities associated with poor outcomes. These are age, hypertension, and previous history of cardiovascular disease. The studies are summarized in [Table 3].
|Table 3: Summary of studies assessing cardiovascular comorbidities in COVID-19|
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| Troponin Elevation! a Marker of Risk or a Contributor in Coronavirus Disease 2019 Pathogenesis|| |
Zhou et al.'s multivariate cox regression analysis showed hazard ratio for cardiac injury as 4.26 (1.92–9.49) (P < 0.001), which is next only to ARDS of 7.89 (3.73–16.66) (P < 0.001). Guo et al. stratified the risk of death according to troponin elevations and cardiovascular disease. The mortality increases linearly in those with preexisting cardiovascular disease (7.6% vs. 13.3%). The risk of death in those with elevated troponin is 37.5%, and the risk increases significantly if these patients had preexisting cardiovascular disease to 69.4% (elevated troponin plus preexisting cardiovascular disease) any patients in the above summarized studies despite showing elevations in troponin showed improvement very early if multisystem involvement is absent, suggesting most of the cardiac injury is probably due to hypoxia and demand supply mismatch [Figure 2].
Thus, with the available evidence, the interim conclusion is myocardial injury is probably an independent risk marker in COVID-19 rather than an evidence for myocarditis.
| Conclusion|| |
Respiratory involvement is well documented in Covid-19 and is the most important contributor to morbidity and mortality. Evidence for cardiovascular involvement, especially in the form of elevation of troponin, echocardiographic, and ECG changes is accumulating. Even though case series and individual cases reports of myocarditis have been reported in the literature, most of them are “clinically suspected myocarditis” and only one case report had definitive myocarditis. One should be careful not to mislabel any troponinitis as myocarditis. Close cardiac surveillance is advised, especially in critically ill patients as cardiac involvement has shown to be an independent predictor of mortality in COVID-19.
Myocardial injury is common in sick COVID-19 patients, but the cause has not been elucidated.
Heart failure can be precipitated in COVID-19 due preexisting comorbidities or due to the multiple causes discussed above.
Routine measurements of cardiac troponin or BNP may add more clinical confusion than aiding in the cardiac involvement.
Mild elevation (>99th percentile upper limit of normal) of troponin is commonly seen. Consider cardiac involvement only if the troponins increase progressively, along with ECG and echo evidence.
Routine evaluation for myocarditis is not recommended in COVID-19 unless clinical suspicion mandates.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]