key: cord-0970577-zvja7np1
authors: De Michieli, Laura; Jaffe, Allan S.; Sandoval, Yader
title: Use and Prognostic Implications of Cardiac Troponin in COVID-19
date: 2022-03-31
journal: Cardiol Clin
DOI: 10.1016/j.ccl.2022.03.005
sha: fa65b544291b593f1f5da1ee7471af2312706951
doc_id: 970577
cord_uid: zvja7np1

Myocardial injury is common in patients with COVID-19 and is associated with an adverse prognosis. Cardiac troponin (cTn) is used to detect myocardial injury and assist with risk stratification in this population. SARS-CoV-2 infection can play a role in the pathogenesis of acute myocardial injury due to both direct and indirect damage of the cardiovascular system. Despite the initial concerns for an increased incidence of acute myocardial infarction, most cTn increases are related to chronic myocardial injury due to comorbidities and/or acute non-ischemic myocardial injury. This review will discuss the latest findings on this topic.

The coronavirus disease 2019 pandemic caused by the SARS-CoV-2 infection continues to have a severe global impact. Since the earliest reports from China 1,2,3 , 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 4 . 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.

Per the Fourth Universal Definition of Myocardial Infarction (4UDMI) 5 , cTn is the biomarker of choice for detection of myocardial injury and in the proper clinical situation, the diagnosis of myocardial infarction (MI). If available, high-sensitivity assays (hs-cTn) cardiac troponin assays are preferred 6 . An assay is defined as high sensitivity if a) the 99 th 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 7 .

Myocardial injury is defined as any cTn increase above the assay-specific 99 th 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 99 th 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 5 . 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 J o u r n a l P r e -p r o o f and contribute to ischemia but are also associated with pulmonary embolism, 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.

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 8 . While clinicians often associate cTn increases in COVID-19 to direct effects, many patients often have clear antecedent causes for chronic injury such as chronic cardiovascular disease that explain such elevations. In this section, we will analyze potential mechanisms of cardiac involvement that can lead to myocardial injury.

One possible mechanism for direct damage are the cytotoxic effects of SARS-CoV-2 on the endothelium which can cause diffuse microthrombosis 9, 10 . At postmortem evaluation, non-occlusive fibrin microthrombi (without ischemic injury) are common (12/15 COVID-19 patients) 11 .

Another potential mechanism is direct virus-induced myocardial injury and the potential for myocarditis. SARS-CoV-2 has been detected in the myocardium 12 and, in a multicenter autopsy study 13 increased interstitial myocardial macrophages were identified in a majority of the cases but lymphocytic myocarditis in only a small fraction. Clinical studies suggest that myocarditis caused by SARS-CoV-2 is uncommon 14 .

Other hypotheses for direct damage include the possibility of infection and replication of virus within non-contractile cells in the heart such as endothelial cells, fibroblasts, and J o u r n a l P r e -p r o o f pericytes with matrix inflammation and fibrosis. There also are other speculative hypotheses 9 .

Non-direct effects of SARS-CoV-2 could be related to angiotensin-converting enzyme 2 (ACE2) downregulation/shedding with a subsequent hyperactive renin-angiotensinaldosterone system (RAAS). Moreover, SARS-CoV-2 infection induces activation of the innate immune system, leading to elevated levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1, interleukin-2, tumor necrosis factor alpha, and interferonc 9 .

Furthermore, SARS-CoV-2 can activate a cascade of thrombotic mechanisms through hyperactivated monocytes, platelets, and neutrophils generating neutrophil extracellular traps (NETs). 9 Indeed, hypercoagulation with diffuse microthrombi is considered the main cause of organ failure in severe cases 13, 11 .

There may be a relationship between viral load and myocardial injury. In one study 15 , 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 99 th percentile indicative of myocardial injury. While those without viremia also had quantifiable hs-cTnT concentrations (59% of cases) and myocardial injury (38%) 15 , these abnormalities were significantly more common in those with viremia. Another report 16 evaluating both groups, however, concluded that there was no significant difference in the incidence of myocardial injury in patients with low compared to elevated viral load. Nonetheless, both myocardial injury and an elevated viral load were independent predictors of in-hospital mortality 16 .

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 17 .

As suggested previously, 4 , each cTn increase >99 th percentile URL should be classified as: chronic myocardial injury, acute nonischemic myocardial injury, or acute myocardial infarction (MI). Figure 1 summarizes this classification and some of the possible mechanisms of myocardial injury in COVID-19 patients.

Chronic myocardial injury is defined as stable increases (<20% variation) above the 99 th percentile of cTn concentrations 5 . Patients with COVID-19 are frequently affected by chronic cardiovascular comorbidities, such as hypertension, diabetes, coronary artery disease, heart failure, and chronic kidney disease (CKD) 3,18,1 , all of which can be associated with cTn increases above the 99 th percentile. Structural heart disease and heart failure, are also often associated with chronic cTn increases which portend an adverse prognosis 5, 19, 20, 21 . Similarly, an elevated cTn in patients with diabetes and CKD identifies patients at higher risk of cardiovascular events 22, 23 .

Studies in COVID-19 patients with serial cTn measurements indicate that from 13% to 26% have stable and thus chronic increases in cTn 24, 25, 26 . In our multicenter Mayo Clinic health system study 27 , we adjudicated every hs-cTnT increase above the sex-specific 99 th 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 heart failure, cardiomyopathy, or chronic kidney disease. 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 non ischemic myocardial injury is defined as a significant rise and/or fall in cTn concentrations with at least one cTn concentration above the 99 th percentile without clinical signs and symptoms of acute myocardial ischemia 5 . These occur often in critically ill patients 4, 8 and are not specific to COVID-19. A recent study 28 comparing COVID-19 with influenza patients showed that despite a higher absolute risk of death in COVID-19 patients, myocardial injury was frequent and increased the risk of death in both diseases. Moreover, acute myocardial injury is common in critically ill patients 29 , in those with acute respiratory distress 30 , and sepsis 31 . In our COVID-19 study 27 , we found that critical illness and sepsis could be identified as drivers of cTn increases in about 40% of patients. Metkus et al. 32 compared the frequency of myocardial injury in intubated patients with COVID-19 with patients with other causes for 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 33 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 35 .

Other causes of acute non ischemic myocardial injury include RV pressure overload related to pulmonary embolism (PE) 36, 37 and/or microthrombi in the pulmonary circulation 13 .

In a retrospective study 37 J o u r n a l P r e -p r o o f

When reports demonstrated a high incidence of myocardial injury in COVID-19 patients, there were concerns for a possible high incidence of type 1 MI related to the pro-thrombotic state or in those critically ill, type 2 MI. In our study 27 which employed systematic adjudication 5 of all hs-cTnT increases, only a minority (5%) met MI criteria. Among those with type 2 MI, the most frequent triggers of were hypoxia, hypotension, and/or tachyarrhythmias. Salbach et al. 26 reported a similarly low incidence. Differences in the frequency of type 2 MI in non-adjudicated 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 42 in COVID-19 patients, oxygen demand-supply imbalance is often secondary to hypoxemia, increased heart rate, inflammatory status and/or decompensated heart failure, whereas in most type 2 MIs, tachyarrhythmias and anemia are often prevalent mechanisms. Conventional treatment strategies appear appropriate but individualized care is warranted given the heterogeneous presentations and mechanisms. It is worth noting that in those with STEMI 43 , there appears to be a higher thrombus burden, and these patients can have worse outcomes.

Many studies in this area have used arbitrary definitions and cutoffs to define myocardial injury 2,44 and others have been based on non-high sensitivity cTn assays 45 . Supplemental Table 1 tabulates the frequency of myocardial injury based on hs-cTn concentrations above the 99 th percentile URL or above specified thresholds. As shown in Figure 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 >50% 32, 46, 47 . Studies that include a broader spectrum of patients suggest a frequency J o u r n a l P r e -p r o o f that ranges from 10% 48, 49 to more than 45% 26, 27, 50, 51, 52 . 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 99 th percentiles as recommended 5 .

Using high-sensitivity cardiac troponin assays, following guideline recommendations, sexspecific 99 th percentile URLs should be used to define myocardial injury 5 . 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 >99 th 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 COVID-19 patients 2,45,51 .

Most studies only report values at baseline. Limited data exist addressing serial samples.

Kini et al. 25 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 <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 non-ischemic conditions, like J o u r n a l P r e -p r o o f myocarditis, pulmonary embolism, and Takotsubo syndrome. In contrast, patients with chronic myocardial injury had more chronic comorbidities, including chronic kidney disease and heart failure. Nuzzi et al. 53 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 four groups: normal (troponin <99 th URL at both assessments), normal-elevated (normal cTn at admission and elevated thereafter), elevated-normal or elevated (i.e. cTn>99 th 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 24 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 is a matter of debate.

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 27 and hs-cTnI 54 . 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 <6 ng/L identified 26% of COVID-19 patients without mortality and a low risk of major adverse events among patients presenting to the ED 27 . Similarly, an initial hs-cTnI <5 ng/L identified 33% of patients at low risk with 97.8% sensitivity and 99.2% negative predictive value in a hospitalized cohort. 54 Conversely, whether cTn increases enhances risk stratification in COVID-19 patients remains a matter of debate. Omland et al. 55 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 the a composite outcome of hospital mortality and admission to the ICU for mechanical ventilation and lasting >24 hours in consecutive unselected patients. In our Padova study 54 in COVID-19 patients 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 that case that many studies were based on cTn concentrations obtained for clinical reasons, potentially biasing the analysis.

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 COVID19 56 . There is 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 in patients and patients should be deployed according to current guidelines 56 . However, given that in most COVID-19 patients 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 J o u r n a l P r e -p r o o f due to critical illness with or without hemodynamic impairment, resulting in myocardial injury or, if ischemia is present, type 2 MI 56 . Data on the appropriate therapy of type 2 MI in the critically ill are scarce and this is even more true for COVID-19 patients, constituting an important research gap 57 .

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 58, 59 .

Conversely, cTn concentrations remain within normal range in most survivors 56 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.

Myocardial injury, defined as cTn increases above the assay-specific 99 th 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 non ischemic 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 for COVID-19 patients with myocardial injury remains case-specific and further investigations are necessary to understand how to improve outcomes in this population. Table 1 . Table 1 . Frequency of myocardial injury based on hs-cTn concentrations above the 99 th percentile URL or above specified thresholds J o u r n a l P r e -p r o o f

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