If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Cardiovascular Diseases, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USADepartment of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Via Giustiniani 2, Padova 35128, Italy
Department of Cardiovascular Diseases, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA
For patients with COVID-19 infection, myocardial injury is diagnosed when cardiac troponin (cTn) concentrations exceed the 99th percentile upper-reference limit.
•
Although myocardial injury is common, cTn increases are usually modest and criteria for myocardial infarction (MI) are infrequently met.
•
While both direct and indirect mechanisms of myocardial damage play a role in acute myocardial injury during COVID-19, chronic myocardial injury related to comorbidities is frequently present.
•
Myocardial injury has adverse short-term prognostic implications, with more data needed on long-term outcomes. The magnitude of cTn increases is also prognostic.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 infection continues to have a severe global impact. Since the earliest reports from China,
it has been clear that cardiac involvement is frequent in patients with COVID-19, especially in those with concomitant cardiovascular comorbidities. The early studies had limitations due in part to arbitrary definitions for cardiac involvement.
Numerous studies have documented the value of cardiac troponin (cTn) to detect myocardial injury and for risk stratification. This review will discuss the latest information about cardiac involvement with an emphasis on the use of cTn.
Definition of myocardial injury
Per the Fourth Universal Definition of Myocardial Infarction (4UDMI),
cTn is the biomarker of choice for the detection of myocardial injury and, in the proper clinical situation, the diagnosis of myocardial infarction (MI). If available, high-sensitivity (hs-cTn) cTn assays are preferred.
An assay is defined as high sensitivity if (a) the 99th percentile can be measured with analytical imprecision ≤10% and (b) the assay measures cTn concentrations above the limit of detection (LOD) in ≥50% of both healthy men and women.
Myocardial injury is defined as any cTn increase above the assay-specific 99th percentile upper reference limit (URL) of a healthy population. When acute myocardial injury occurs, defined as a dynamic rising and/or falling pattern of cTn concentrations with at least one cTn concentration above the 99th percentile, and there are signs and/or symptoms of acute myocardial ischemia, a diagnosis of MI is made. Due to the increased sensitivity of hs-cTn assays, myocardial injury is detected far more frequently in a variety of clinical situations not related to myocardial ischemia than in those with MI.
It is often challenging for clinicians to identify the specific reason for hs-cTn elevations, as it can often occur in the critically ill. COVID-19 infections can induce alterations in myocardial oxygen consumption and contribute to ischemia but are also associated with pulmonary embolism (PE), critical illness, myocarditis, as well as the direct effects of SARS-CoV-2 on the myocardium and perhaps the microvasculature, making it challenging for clinicians to determine a discrete etiology.
Etiologies myocardial injury in COVID-19
There are multiple mechanisms that link COVID-19 disease to myocardial injury but also with other forms of cardiac involvement like heart failure (HF) with reduced ejection fraction and arrhythmias.
While clinicians often associate cTn increases in COVID-19 to direct effects, many patients often have clear antecedent causes for chronic injury like chronic cardiovascular disease that explain such elevations. In this section, we will analyze potential mechanisms of cardiac involvement that can lead to myocardial injury in this setting.
Direct Damage of SARS-CoV-2 in the Cardiovascular System
One possible mechanism for direct damage is the cytotoxic effect of SARS-CoV-2 on the endothelium which can cause diffuse microthrombosis.
COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.
Another potential mechanism is direct virus-induced myocardial injury and the potential for myocarditis. SARS-CoV-2 has been detected in the myocardium
increased interstitial myocardial macrophages were identified in most of the cases but lymphocytic myocarditis in only a small fraction. Clinical studies suggest that myocarditis caused by SARS-CoV-2 is uncommon.
Other hypotheses for direct damage include the possibility of infection and replication of virus within noncontractile cells in the heart such as endothelial cells, fibroblasts, and pericytes with matrix inflammation and fibrosis. There also are other speculative hypotheses.
COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.
Nondirect Effects of SARS-CoV-2 in the Cardiovascular System
Nondirect effects of SARS-CoV-2 could be related to angiotensin-converting enzyme 2 (ACE2) downregulation/shedding with a subsequent hyperactive renin–angiotensin–aldosterone system (RAAS). Moreover, SARS-CoV-2 infection induces the activation of the innate immune system, leading to elevated levels of proinflammatory cytokines, including interleukin-6 (IL-6), interleukin-1, interleukin-2, tumor necrosis factor alpha, and interferon-c.
COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.
Furthermore, SARS-CoV-2 can activate a cascade of thrombotic mechanisms through hyperactivated monocytes, platelets, and neutrophils generating neutrophil extracellular traps (NETs).
COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.
all patients with detectable SARS-CoV-2 viral load had quantifiable (≥6 ng/L) hs-cTnT concentrations, and 76% of them had concentrations above the assay-specific 99th percentile indicative of myocardial injury. While those without viremia also had quantifiable hs-cTnT concentrations (59% of cases) and myocardial injury (38%),
evaluating both groups, however, concluded that there was no significant difference in the incidence of myocardial injury in patients with low compared with elevated viral load. Nonetheless, both myocardial injury and an elevated viral load were independent predictors of in-hospital mortality.
Finally, a study of symptomatic hospitalized patients suggest that patients with COVID-19 and viremia have higher concentrations of inflammatory markers (such as IL-6, C-reactive protein, procalcitonin, and ferritin), but similar levels of cTnT and NT-proBNP to patients without viremia.
each cTn increase greater than the 99th percentile URL should be classified as chronic myocardial injury, acute nonischemic myocardial injury, or acute MI. Fig. 1 summarizes this classification and some of the possible mechanisms of myocardial injury in patients with COVID-19.
Fig. 1Classification of myocardial injury and its possible pathogenetic mechanisms in patients with COVID-19.
Patients with COVID-19 are frequently affected by chronic cardiovascular comorbidities, such as hypertension, diabetes, coronary artery disease, HF, and chronic kidney disease (CKD),
all of which can be associated with cTn increases above the 99th percentile. Structural heart disease and HF are often associated with chronic cTn increases which portend an adverse prognosis.
Coronary microvascular dysfunction and diastolic load correlate with cardiac troponin T Release measured by a highly sensitive assay in patients with nonischemic heart failure.
Association between Circulating troponin concentrations, left ventricular systolic and diastolic functions, and incident heart failure in Older Adults.
we adjudicated every hs-cTnT increase above the sex-specific 99th percentile among patients with COVID-19. Most hs-cTnT elevations were modest, with a median value of 12 ng/L, and significantly higher in men than in women (15 vs 9 ng/L). About half of the increases were associated with conditions such as HF, cardiomyopathy, or CKD. These data support the hypothesis that, in significant proportions of patients with COVID-19, myocardial injury is chronic and not due to effects directly related to COVID-19.
Acute Nonischemic Myocardial Injury
Acute nonischemic myocardial injury is defined as a significant rise and/or fall in cTn concentrations with at least one cTn concentration above the 99th percentile without clinical signs and symptoms of acute myocardial ischemia.
Bäck M. Comparative frequency and prognostic impact of myocardial injury in hospitalized patients with COVID-19 and Influenza. European heart Journal Open. 2021
comparing COVID-19 with influenza patients showed that, despite a higher absolute risk of death in patients with COVID-19, myocardial injury was frequent and increased the risk of death in both diseases. Moreover, acute myocardial injury is common in critically ill patients,
compared the frequency of myocardial injury in intubated patients with COVID-19 with patients with other causes of acute respiratory distress syndrome (ARDS) and reported that the rate of myocardial injury was similar (51% in COVID-19 compared with 49.6% in ARDS). They concluded that myocardial injury in severe COVID-19 is related to baseline comorbidities, advanced age, and multisystem organ dysfunction, like what happens in traditional ARDS. In addition to the multiorgan dysfunction and hemodynamic impairment that can lead to cTn increases, patients with severe sepsis and septic shock may manifest abnormal systolic function and impaired myocardial relaxation.
An echocardiography study in patients with COVID-19 reported that those with myocardial injury more frequently manifested left ventricular (LV) dysfunction detected by global longitudinal strain (GLS) and right ventricular (RV) dysfunction, which only partially resolved during follow-up.
Similarly, another study reported that patients with myocardial injury more frequently manifest global LV dysfunction, regional wall motion abnormalities, diastolic dysfunction, RV dysfunction, and pericardial effusions.
of 1240 patients with COVID-19, PE was identified in 8.3% by computed tomography. Male gender, higher C-reactive protein levels, and longer hospitalization were associated with higher risk of PE while anticoagulation (both at prophylactic and therapeutic dose) were protective. A meta-analysis
but myocardial inflammation (without necrosis) caused by macrophages and T cells is common in noninfectious and in COVID-19 related deaths but usually without histologic criteria for myocarditis.
There are, however, a few cases of EMB/autopsy-proven histologic and immuno-histological active myocarditis but only 3 tested positive for SARS-CoV-2 by polymerase chain reaction on heart tissue suggesting the hypothesis that a virus-negative form, possibly triggered by the infection, might be etiologic.
of patients with COVID-19 undergoing transthoracic echocardiogram. It could develop from catecholamine-induced microvascular dysfunction or secondary to the metabolic, inflammatory, and emotional impairment associated with COVID-19.
When reports demonstrated a high incidence of myocardial injury in patients with COVID-19, there were concerns about a possible high incidence of type 1 MI related to the prothrombotic state or, in those critically ill, type 2 MI. In our study
of all hs-cTnT increases, only a minority (5%) met MI criteria. Among those with type 2 MI, the most frequent triggers were hypoxia, hypotension, and/or tachyarrhythmias. Salbach and colleagues
reported a similarly low incidence. Differences in the frequency of type 2 MI in nonadjudicated studies are likely related to patient selection and less rigor in applying criteria establishing the presence of acute myocardial ischemia. One potential difference is that
in patients with COVID-19, oxygen demand-supply imbalance is often secondary to hypoxemia, increased heart rate, inflammatory status, and/or decompensated HF, whereas in most type 2 MIs, tachyarrhythmias and anemia are often prevalent mechanisms. Conventional treatment strategies seem appropriate but individualized care is warranted given the heterogeneous presentations and mechanisms. It is worth noting that in those with STEMI,
Table 1 tabulates the frequency of myocardial injury based on hs-cTn concentrations above the 99th percentile URL or above specified thresholds. As shown in Fig. 2, the frequency of myocardial injury varies widely probably in relation to patient selection. In studies of patients admitted to intensive care units (ICU), the frequency of myocardial injury is as high as or greater than 50%.
Admission high-sensitive cardiac troponin T level increase is independently associated with higher mortality in critically ill patients with COVID-19: a multicenter study.
This variation is likely related to the specific assay and/or threshold used, patient selection, and the population baseline characteristics. Only a small number of studies (see Table 1) applied sex-specific 99th percentiles as recommended.
Myocardial injury and COVID-19: Serum hs-cTnI level in risk stratification and the prediction of 30-day fatality in COVID-19 patients with no prior cardiovascular disease.
Admission high-sensitive cardiac troponin T level increase is independently associated with higher mortality in critically ill patients with COVID-19: a multicenter study.
Fig. 2Frequency of myocardial injury in multiple studies based on hs-cTn values. Details about different studies’ population, the assays used, and a complete list of references are available on Table 1.
The use of uniform criteria will allow reporting in a comparable way between studies. Moreover, the prognostic significance of myocardial injury as defined by cTn concentrations greater than 99th percentile URL has been demonstrated repeatedly in the COVID-19 population. Irrespective of etiology, myocardial injury is associated with adverse events and increased mortality in patients with COVID-19.
evaluated hs-cTnI measurements between 72h before and 48h after the COVID19 diagnosis and classified patients as suffering from chronic myocardial injury or acute myocardial injury (>20% or >50% delta with elevated or normal baseline cTn, respectively). They found that both types of myocardial injury were associated with increased mortality at 30 days and 6 months even after multivariable adjustment. However, among patients less than 65 years and those without known coronary artery disease, acute myocardial injury was associated with a worse prognosis at 6 months. It was associated with a more pronounced inflammatory status, more ischemic risk factors such as intracoronary thrombosis and more oxygen supply–demand imbalance due to sepsis, but also more nonischemic conditions, like myocarditis, PE, and Takotsubo syndrome. In contrast, patients with chronic myocardial injury had more chronic comorbidities, including CKD and HF. Nuzzi and colleagues
evaluated hs-cTn measurements (either T or I) within 24 h of admission and, subsequently, again between 24 and 48 h. They categorized patients in 4 groups: normal (troponin <99th URL at both assessments), normal-elevated (normal cTn at admission and elevated thereafter), elevated-normal or elevated (ie, cTn>99th URL at both measurements). Patients with incident myocardial injury, with persistent elevated cTn, and with elevated cTn only at admission had a higher risk of death compared with those with normal cTn at both evaluations. By multivariable analysis, patients that developed myocardial injury had the highest mortality risk. A smaller study
showed that patients with significant variation in concentrations of hs-cTnI (delta ≥ 20%), and at least one value ≥ 99th sex-specific URLs had longer hospital stays, more aggressive disease, and more often needed admission to ICU. Therefore, the data seem to indicate an adjunctive prognostic role for serial sampling although the populations that benefit most from this monitoring are a matter of debate.
Adjunctive Role of Cardiac Troponin in Risk Stratification
The role of very low hs-cTn concentrations to facilitate the identification of low-risk patients with a favorable prognosis has been demonstrated for both hs-cTnT
Patients with very low values at presentation (<6 ng/L for Roche hs-cTnT and < 5 ng/L for Abbott hs-cTnI) are at low risk for mortality and adverse events. Particularly, a single hs-cTnT less than 6 ng/L identified 26% of patients with COVID-19 without mortality and a low risk of major adverse events among patients presenting to the ED.
Similarly, an initial hs-cTnI less than 5 ng/L identified 33% of patients at low risk with 97.8% sensitivity and 99.2% negative predictive value in a hospitalized cohort.
These findings are similar to what is suggested for ruling-out MI, and likely occur because very low hs-cTn concentrations represent an objective measure to identify younger patients with fewer comorbidities.
Conversely, whether cTn increases enhance risk stratification in patients with COVID-19 remains a matter of debate. Omland and colleagues
reported that in multivariable models adjusting for clinical variables and a severity of illness score, only ferritin and lactate dehydrogenase (but not cTn) were significant predictors of a composite outcome of hospital mortality and admission to the ICU for mechanical ventilation and lasting greater than 24 hours in consecutive unselected COVID-19 patients. In our Padova study,
in patients with COVID-19 presenting through the ED, hs-cTnI was a significant predictor of mortality for patients with lower Acute Physiology and Chronic Health Evaluation II (APACHE II) score but not in those with higher (>13) APACE score. One could argue that in those that are more critically ill, the adjunctive role of cTn in predicting outcomes is more limited. However, hs-cTn can help to identify those who are less severely ill but are also at risk. Moreover, its use may be more clinically convenient than a more complex multivariable model. It may also be the case that many studies were based on cTn concentrations obtained for clinical reasons, potentially biasing the analysis.
When to Measure Cardiac Troponin and What to Do if It Is Elevated?
The European Society of Cardiology Study Group on Biomarkers in Cardiology of the Acute Cardiovascular Care Association developed a document discussing the significance and the proper use of cTn in COVID-19.
There is a paucity of evidence regarding the appropriate response to finding an increased hs-cTn concentration. If a type 1 MI is suspected, established diagnostic algorithms for rule-out and/or rule-in of MI should be deployed according to current guidelines.
However, given that in most patients with COVID-19 a type 1 MI is not present, these individuals rarely undergo coronary angiography. Indeed, in critically ill patients with septic shock and/or ARDS, cTn increases are more likely due to critical illness with or without hemodynamic impairment, resulting in myocardial injury or, if ischemia is present, type 2 MI.
Data on the appropriate therapy for type 2 MI in the critically ill are scarce and this is even more true for patients with COVID-19, constituting an important research gap.
Most studies have correlated myocardial injury with a poor in hospital outcome and short term mortality, regardless of the presence of known concomitant cardiovascular disease.
Kotecha T, Knight DS, Razvi Y, et al. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance. Eur Heart J 2021;42(19):1866-1878. doi:10.1093/eurheartj/ehab075.
performed cardiac magnetic resonance (CMR) in 148 patients with such injury who recovered from severe COVID-19 after a median of 68 days. They found late gadolinium enhancement and/or ischemia in 54% of patients. This included myocarditis-like scar in 26%, infarction and/or ischemia in 22%, and dual pathology in 6%. Myocarditis-like injury was limited in extent and had minimal functional consequences; however, in 30% signs of active myocarditis persisted. Of the patients with an ischemic injury pattern, 66% had no history of coronary disease suggesting pre-existing silent disease or de novo COVID-19-related changes. Puntmann and colleagues
performed CMR after a median of 71 days in 100 recovered patients with COVID-19 (including two-thirds of patients that recovered at home). hs-TnT was detectable in 71 patients and elevated (>13.9 pg/mL) in 5 patients. CMR revealed cardiac involvement in 78 patients and ongoing myocardial inflammation in 60. Hs-cTnT was significantly correlated with native T1 mapping, native T2 mapping, and LV mass.
Data regarding long-term consequences of myocardial injury in those who survived COVID-19 are scarce. A prospective exercise echocardiographic evaluation of 48 patients 6 months after COVID-19 disease (some of whom had experienced myocardial injury
) revealed that exercise induced a significant increase in the average E/e′ ratio and systolic pulmonary artery pressure in those who had suffered myocardial injury.
Summary
Myocardial injury, defined as cTn increases above the assay-specific 99th percentile, is frequent in patients with COVID-19. It correlates with adverse events and short-term mortality. Most increases seem related to chronic cardiovascular conditions and acute nonischemic myocardial injury, similarly to that reported in severely ill patients. However, some studies with advanced cardiac imaging and long-term follow-up indicate that myocardial injury might be associated with long-term structural abnormalities and worse cardiac performance. Except for patients suffering from type 1 MI, the appropriate treatment of patients with COVID-19 with myocardial injury remains case-specific and further investigations are necessary to understand how to improve outcomes in this population.
Clinics care points
•
Myocardial injury is common in patients with COVID-19 infection, but its frequency varies widely based on the population studied and the cTn assay and threshold used.
•
Even though COVID-19 patients can present with type 1 or type 2 MI, acute and chronic myocardial injury (cTn increases above the 99th percentile without clinical evidence of acute myocardial ischemia) are the most common reasons for cTn increases.
•
Regardless of the mechanism, myocardial injury, and the magnitude of cTn increases have prognostic significance.
Disclosure
Dr Y. Sandoval has previously served on the Advisory Boards for Roche Diagnostics and Abbott Diagnostics without personal compensation. He has also been a speaker without personal financial compensation for Abbott Diagnostics. Dr A.S. Jaffe has consulted or presently consults for most of the major diagnostics companies, including Beckman-Coulter, Abbott, Siemens, Ortho Diagnostics, ET Healthcare, Roche, Radiometer, Sphingotec, RCE, and Amgen and Novartis. Dr L. De Michieli has nothing to disclose.
References
Guo T.
Fan Y.
Chen M.
et al.
Cardiovascular implications of Fatal outcomes of patients with coronavirus disease 2019 (COVID-19).
COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.
Coronary microvascular dysfunction and diastolic load correlate with cardiac troponin T Release measured by a highly sensitive assay in patients with nonischemic heart failure.
Association between Circulating troponin concentrations, left ventricular systolic and diastolic functions, and incident heart failure in Older Adults.
Bäck M. Comparative frequency and prognostic impact of myocardial injury in hospitalized patients with COVID-19 and Influenza. European heart Journal Open. 2021 (oeab025)
Admission high-sensitive cardiac troponin T level increase is independently associated with higher mortality in critically ill patients with COVID-19: a multicenter study.
Kotecha T, Knight DS, Razvi Y, et al. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance. Eur Heart J 2021;42(19):1866-1878. doi:10.1093/eurheartj/ehab075.
Myocardial injury and COVID-19: Serum hs-cTnI level in risk stratification and the prediction of 30-day fatality in COVID-19 patients with no prior cardiovascular disease.
00057-5&id=gr1.jpg){kind=link}
00057-5&id=gr2.jpg){kind=link}