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Use and Prognostic Implications of Cardiac Troponin in COVID-19

Published:March 30, 2022DOI:https://doi.org/10.1016/j.ccl.2022.03.005

      Key Words

      Key Points

      • For patients with COVID-19 infection, myocardial injury is diagnosed when cardiac troponin concentrations exceed the 99th percentile upper-reference limit.
      • Although myocardial injury is common, cardiac troponin increases are usually modest and criteria for myocardial infarction 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 cardiac troponin 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 China1,2,3, 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
      • Sandoval Y.
      • Januzzi J.L.
      • Jaffe A.S.
      Cardiac Troponin for Assessment of Myocardial Injury in COVID-19.
      . 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)
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Fourth Universal Definition of Myocardial Infarction (2018).
      , 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
      • Sandoval Y.
      • Jaffe A.S.
      Using High-Sensitivity Cardiac Troponin T for Acute Cardiac Care.
      . 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
      • Apple F.S.
      • Jaffe A.S.
      • Collinson P.
      • et al.
      IFCC educational materials on selected analytical and clinical applications of high sensitivity cardiac troponin assays.
      .
      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
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Fourth Universal Definition of Myocardial Infarction (2018).
      . 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, 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
      • Jaffe A.S.
      • Cleland J.G.F.
      • Katus H.A.
      Myocardial injury in severe COVID-19 infection.
      . 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.

       Direct damage of SARS-CoV-2 in the cardiovascular system

      One possible mechanism for direct damage are the cytotoxic effects of SARS-CoV-2 on the endothelium which can cause diffuse microthrombosis
      • Pesce M.
      • Agostoni P.
      • Bøtker H.E.
      • et al.
      COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.
      ,
      • Libby P.
      • Lüscher T.
      COVID-19 is, in the end, an endothelial disease.
      . At postmortem evaluation, non-occlusive fibrin microthrombi (without ischemic injury) are common (12/15 COVID-19 patients)
      • Bois M.C.
      • Boire N.A.
      • Layman A.J.
      • et al.
      COVID-19–Associated Nonocclusive Fibrin Microthrombi in 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
      • Tavazzi G.
      • Pellegrini C.
      • Maurelli M.
      • et al.
      Myocardial localization of coronavirus in COVID‐19 cardiogenic shock.
      and, in a multicenter autopsy study
      • Basso C.
      • Leone O.
      • Rizzo S.
      • et al.
      Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.
      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
      • Ozieranski K.
      • Tyminska A.
      • Jonik S.
      • et al.
      Clinically Suspected Myocarditis in the Course of Severe Acute Respiratory Syndrome Novel Coronavirus-2 Infection: Fact or Fiction?.
      .
      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 pericytes with matrix inflammation and fibrosis. There also are other speculative hypotheses
      • Pesce M.
      • Agostoni P.
      • Bøtker H.E.
      • et al.
      COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.
      .

       Non-direct effects of SARS-CoV-2 in the cardiovascular system

      Non-direct 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 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 interferon-c
      • Pesce M.
      • Agostoni P.
      • Bøtker H.E.
      • et al.
      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).
      • Pesce M.
      • Agostoni P.
      • Bøtker H.E.
      • et al.
      COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.
      Indeed, hypercoagulation with diffuse microthrombi is considered the main cause of organ failure in severe cases
      • Basso C.
      • Leone O.
      • Rizzo S.
      • et al.
      Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.
      ,
      • Bois M.C.
      • Boire N.A.
      • Layman A.J.
      • et al.
      COVID-19–Associated Nonocclusive Fibrin Microthrombi in the Heart.
      .

       Viral load and myocardial injury

      There may be a relationship between viral load and myocardial injury. In one study
      • Siddiqi H.K.
      • Weber B.
      • Zhou G.
      • et al.
      Increased Prevalence of Myocardial Injury in Patients with SARS-CoV-2 Viremia.
      , 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%)
      • Siddiqi H.K.
      • Weber B.
      • Zhou G.
      • et al.
      Increased Prevalence of Myocardial Injury in Patients with SARS-CoV-2 Viremia.
      , these abnormalities were significantly more common in those with viremia. Another report
      • Chehab O.
      • El Zein S.
      • Kanj A.
      • et al.
      SARS-CoV-2 Viral Load and Myocardial Injury: Independent and Incremental Predictors of Adverse Outcome.
      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
      • Chehab O.
      • El Zein S.
      • Kanj A.
      • et al.
      SARS-CoV-2 Viral Load and Myocardial Injury: Independent and Incremental Predictors of Adverse Outcome.
      . 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
      • Myhre P.L.
      • Prebensen C.
      • Jonassen C.M.
      • Berdal J.E.
      • Omland T.
      SARS‐CoV‐2 Viremia is Associated With Inflammatory, But Not Cardiovascular Biomarkers, in Patients Hospitalized for COVID‐19.
      .

      CLASSIFICATION OF MYOCARDIAL INJURY IN COVID-19

      As suggested previously,
      • Sandoval Y.
      • Januzzi J.L.
      • Jaffe A.S.
      Cardiac Troponin for Assessment of Myocardial Injury in COVID-19.
      , each cTn increase >99th 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.
      Figure thumbnail gr1
      Figure 1Classification of myocardial injury and its possible pathogenetic mechanisms in COVID-19 patients.

      1. Chronic myocardial injury

      Chronic myocardial injury is defined as stable increases (<20% variation) above the 99th percentile of cTn concentrations
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Fourth Universal Definition of Myocardial Infarction (2018).
      . 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)
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Wu C.
      • Chen X.
      • Cai Y.
      • et al.
      Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China.
      ,
      • Guo T.
      • Fan Y.
      • Chen M.
      • et al.
      Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19).
      , all of which can be associated with cTn increases above the 99th percentile. Structural heart disease and heart failure, are also often associated with chronic cTn increases which portend an adverse prognosis
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Fourth Universal Definition of Myocardial Infarction (2018).
      ,
      • de Lemos J.A.
      • Drazner M.H.
      • Omland T.
      • et al.
      Association of Troponin T Detected With a Highly Sensitive Assay and Cardiac Structure and Mortality Risk in the General Population.
      ,
      • Takashio S.
      • Yamamuro M.
      • Izumiya Y.
      • et al.
      Coronary Microvascular Dysfunction and Diastolic Load Correlate With Cardiac Troponin T Release Measured by a Highly Sensitive Assay in Patients With Nonischemic Heart Failure.
      ,
      • Myhre P.L.
      • Claggett B.
      • Ballantyne C.M.
      • et al.
      Association Between Circulating Troponin Concentrations, Left Ventricular Systolic and Diastolic Functions, and Incident Heart Failure in Older Adults.
      . Similarly, an elevated cTn in patients with diabetes and CKD identifies patients at higher risk of cardiovascular events
      • Dillmann W.H.
      Diabetic Cardiomyopathy: What Is It and Can It Be Fixed?.
      ,
      • Patel P.C.
      • Ayers C.R.
      • Murphy S.A.
      • et al.
      Association of Cystatin C With Left Ventricular Structure and Function: The Dallas Heart Study.
      .
      Studies in COVID-19 patients with serial cTn measurements indicate that from 13% to 26% have stable and thus chronic increases in cTn24,25,26. In our multicenter Mayo Clinic health system study
      • De Michieli L.
      • Ola O.
      • Knott J.D.
      • et al.
      High-Sensitivity Cardiac Troponin T for the Detection of Myocardial Injury and Risk Stratification in COVID-19.
      , 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 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

      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 99th percentile without clinical signs and symptoms of acute myocardial ischemia
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Fourth Universal Definition of Myocardial Infarction (2018).
      . These occur often in critically ill patients
      • Sandoval Y.
      • Januzzi J.L.
      • Jaffe A.S.
      Cardiac Troponin for Assessment of Myocardial Injury in COVID-19.
      ,
      • Jaffe A.S.
      • Cleland J.G.F.
      • Katus H.A.
      Myocardial injury in severe COVID-19 infection.
      and are not specific to COVID-19. A recent study

      Biasco L, Klersy C, Beretta GS, et al. Comparative frequency and prognostic impact of myocardial injury in hospitalized patients with COVID-19 and Influenza. Bäck M, ed. European Heart Journal Open. Published online August 30, 2021:oeab025.

      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
      • Babuin L.
      • Vasile V.C.
      • Rio Perez J.A.
      • et al.
      Elevated cardiac troponin is an independent risk factor for short- and long-term mortality in medical intensive care unit patients.
      , in those with acute respiratory distress
      • Vasile V.C.
      • Chai H.S.
      • Khambatta S.
      • Afessa B.
      • Jaffe A.S.
      Significance of Elevated Cardiac Troponin T Levels in Critically Ill Patients with Acute Respiratory Disease.
      , and sepsis
      • Vasile V.C.
      • Chai H.S.
      • Abdeldayem D.
      • Afessa B.
      • Jaffe A.S.
      Elevated Cardiac Troponin T Levels in Critically Ill Patients with Sepsis.
      . In our COVID-19 study
      • De Michieli L.
      • Ola O.
      • Knott J.D.
      • et al.
      High-Sensitivity Cardiac Troponin T for the Detection of Myocardial Injury and Risk Stratification in COVID-19.
      , we found that critical illness and sepsis could be identified as drivers of cTn increases in about 40% of patients. Metkus et al.
      • Metkus T.S.
      • Sokoll L.J.
      • Barth A.S.
      • et al.
      Myocardial Injury in Severe COVID-19 Compared With Non–COVID-19 Acute Respiratory Distress Syndrome.
      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
      • Landesberg G.
      • Jaffe A.S.
      • Gilon D.
      • et al.
      Troponin Elevation in Severe Sepsis and Septic Shock: The Role of Left Ventricular Diastolic Dysfunction and Right Ventricular Dilatation.
      . An echocardiography study in COVID-19 patients 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
      • Bieber S.
      • Kraechan A.
      • Hellmuth J.C.
      • et al.
      Left and right ventricular dysfunction in patients with COVID-19-associated myocardial injury.
      . 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
      • Giustino G.
      • Croft L.B.
      • Stefanini G.G.
      • et al.
      Characterization of Myocardial Injury in Patients With COVID-19.
      .
      Other causes of acute non ischemic myocardial injury include RV pressure overload related to pulmonary embolism (PE)
      • Roncon L.
      • Zuin M.
      • Barco S.
      • et al.
      Incidence of acute pulmonary embolism in COVID-19 patients: Systematic review and meta-analysis.
      ,
      • Fauvel C.
      • Weizman O.
      • Trimaille A.
      • et al.
      Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.
      and/or microthrombi in the pulmonary circulation
      • Basso C.
      • Leone O.
      • Rizzo S.
      • et al.
      Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.
      . In a retrospective study
      • Fauvel C.
      • Weizman O.
      • Trimaille A.
      • et al.
      Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.
      of 1240 COVID-19 patients , 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
      • Roncon L.
      • Zuin M.
      • Barco S.
      • et al.
      Incidence of acute pulmonary embolism in COVID-19 patients: Systematic review and meta-analysis.
      of 7178 COVID-19 patients reported a pooled incidence of acute PE in 15% of patients hospitalized in general wards and in 23% of ICU patients.
      Data on endomyocardial biopsy (EMB)/autopsy tissue characterization in suspected COVID-19 are scarce
      • Caforio A.L.P.
      • Baritussio A.
      • Basso C.
      • Marcolongo R.
      Clinically Suspected and Biopsy-Proven Myocarditis Temporally Associated with SARS-CoV-2 Infection.
      but myocardial inflammation (without necrosis) caused by macrophages and T cells is common in non-infectious and in COVID-19 related deaths but usually without histological criteria for myocarditis
      • Kawakami R.
      • Sakamoto A.
      • Kawai K.
      • et al.
      Pathological Evidence for SARS-CoV-2 as a Cause of Myocarditis.
      . There are however a few cases of EMB/autopsy-proven histological 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
      • Caforio A.L.P.
      • Baritussio A.
      • Basso C.
      • Marcolongo R.
      Clinically Suspected and Biopsy-Proven Myocarditis Temporally Associated with SARS-CoV-2 Infection.
      . In our report
      • De Michieli L.
      • Ola O.
      • Knott J.D.
      • et al.
      High-Sensitivity Cardiac Troponin T for the Detection of Myocardial Injury and Risk Stratification in COVID-19.
      , myocarditis was rare. There was clinical suspicion in 3 patients, but none had confirmatory testing performed.
      Finally, features compatible with Takotsubo cardiomyopathy have been identified in 2-4%
      • Dweck M.R.
      • Bularga A.
      • Hahn R.T.
      • et al.
      Global evaluation of echocardiography in patients with COVID-19.
      ,
      • Giustino G.
      • Croft L.B.
      • Oates C.P.
      • et al.
      Takotsubo Cardiomyopathy in COVID-19.
      of COVID-19 patients undergoing transthoracic echocardiogram. It could develop from catecholamine-induced microvascular dysfunction or secondary to the metabolic, inflammatory, and emotional impairment associated with COVID-19
      • Giustino G.
      • Croft L.B.
      • Oates C.P.
      • et al.
      Takotsubo Cardiomyopathy in COVID-19.
      .

      Type 1 and type 2 myocardial infarction

      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
      • De Michieli L.
      • Ola O.
      • Knott J.D.
      • et al.
      High-Sensitivity Cardiac Troponin T for the Detection of Myocardial Injury and Risk Stratification in COVID-19.
      which employed systematic adjudication
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Fourth Universal Definition of Myocardial Infarction (2018).
      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.
      • Salbach C.
      • Mueller-Hennessen M.
      • Biener M.
      • et al.
      Interpretation of myocardial injury subtypes in COVID-19 disease per fourth version of Universal Definition of Myocardial Infarction.
      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
      • Talanas G.
      • Dossi F.
      • Parodi G.
      Type 2 myocardial infarction in patients with coronavirus disease 2019.
      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
      • Choudry F.A.
      • Hamshere S.M.
      • Rathod K.S.
      • et al.
      High Thrombus Burden in Patients With COVID-19 Presenting With ST-Segment Elevation Myocardial Infarction.
      , there appears to be a higher thrombus burden, and these patients can have worse outcomes.

      FREQUENCY OF MYOCARDIAL INJURY IN COVID-19 PATIENTS

      Many studies in this area have used arbitrary definitions and cutoffs to define myocardial injury

      Shi S, Qin M, Shen B, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. Published online March 25, 2020.

      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      and others have been based on non-high sensitivity cTn assays
      • Lala A.
      • Johnson K.W.
      • Januzzi J.L.
      • et al.
      Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection.
      . Supplemental 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 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%
      • Metkus T.S.
      • Sokoll L.J.
      • Barth A.S.
      • et al.
      Myocardial Injury in Severe COVID-19 Compared With Non–COVID-19 Acute Respiratory Distress Syndrome.
      ,
      • Demir O.M.
      • Ryan M.
      • Cirillo C.
      • et al.
      Impact and Determinants of High-Sensitivity Cardiac Troponin-T Concentration in Patients With COVID-19 Admitted to Critical Care.
      ,
      • Larcher R.
      • Besnard N.
      • Akouz A.
      • et al.
      Admission High-Sensitive Cardiac Troponin T Level Increase Is Independently Associated with Higher Mortality in Critically Ill Patients with COVID-19: A Multicenter Study.
      . Studies that include a broader spectrum of patients suggest a frequency that ranges from 10%
      • Li C.
      • Jiang J.
      • Wang F.
      • et al.
      Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients.
      ,
      • de Falco R.
      • Vargas M.
      • Palma D.
      • et al.
      B-Type Natriuretic Peptides and High-Sensitive Troponin I as COVID-19 Survival Factors: Which One Is the Best Performer?.
      to more than 45%
      • Salbach C.
      • Mueller-Hennessen M.
      • Biener M.
      • et al.
      Interpretation of myocardial injury subtypes in COVID-19 disease per fourth version of Universal Definition of Myocardial Infarction.
      ,
      • De Michieli L.
      • Ola O.
      • Knott J.D.
      • et al.
      High-Sensitivity Cardiac Troponin T for the Detection of Myocardial Injury and Risk Stratification in COVID-19.
      ,
      • Inciardi R.M.
      • Adamo M.
      • Lupi L.
      • et al.
      Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy.
      ,
      • Lombardi C.M.
      • Carubelli V.
      • Iorio A.
      • et al.
      Association of Troponin Levels With Mortality in Italian Patients Hospitalized With Coronavirus Disease 2019: Results of a Multicenter Study.
      ,
      • Singh N.
      • Anchan R.K.
      • Besser S.A.
      • et al.
      High sensitivity Troponin-T for prediction of adverse events in patients with COVID-19.
      . 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
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Fourth Universal Definition of Myocardial Infarction (2018).
      .
      Figure thumbnail gr2
      Figure 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 1Frequency of myocardial injury based on hs-cTn concentrations above the 99th percentile URL or above specified thresholds
      StudyLocationPopulationCardiac troponin assayCutoffs usedFrequency of myocardial injury
      Cao et al.1Wuhan, China244 COVID-19 admitted patients w/o CV disease or CKDADVIA Centaur XP, Siemens Healthcare Diagnostics,

      Erlangen, Germany).
      >40 ng/L11%
      Li et al.2Wuhan, China2068 COVID-19 admitted patientsHs-cTnI, other details NR>34.2 pg/mL8.8% total,

      2.3% in non-critically ill

      30% in critically ill
      Lorente-Ros et al.3Spain707 COVID-19 admitted patientsAbbott hs-cTnI> 14 ng/L20.9%
      Huang et al.4Wuhan, China.41 COVID-19 admitted patientsHs-cTnI, other details NR.>28 ng/LAll: 12%

      ICU: 31%

      Non-ICU: 4%
      Zhou F. et al.5Wuhan, China.191 COVID-19 admitted patientsHs-cTnI, other details NR>28 pg/mLAll: 17%

      Non-survivor: 46%

      Survivor: 1%
      Inciardi et al.6Brescia, Italy99 COVID-19 admitted patientsHs-TnT>14 ng/L71% of patients with cardiac disease,

      47% without cardiac disease
      Cecconi et al.7Milano, Italy239 COVID-19 admitted patientsTroponin I, other details NR>19.8 ng/L27.7% overall
      Nie et al.8Huazhong, China311 COVID-19 admitted patientshs-cTnI, ARCHITECT STAT, Abbott>99th URL33.1%
      Wei et al.9China101 COVID-19 admitted patientshs-TnT>14 ng/L15.8%
      Wang et al.10Wuhan, China22 COVID-19 admitted patients with severe pneumoniahs-TnI, other details NR>34.2 pg/mL13%
      Heberto et al.11Mexico254 COVID-19 admitted patientshs-cTnI Beckman Coulter>17.5 ng/L28.7%
      Raad et al.12Southeast

      Michigan, USA
      1020 COVID-19 admitted patientshs-cTnI Beckman-Coulter>18 ng/L38%
      Stefanini et al.13Milan, Italy397 COVID-19 admitted patientshs-TnI Beckman Coulter≥19.6 ng/L25%
      Schiavone et al.14Italy674 COVID-19 admitted patientsHs-cTn, other details NR>99th URL43.8% in CCS 14.4% without CCS
      Arcari et al.15Rome, Italy111 COVID-19 admitted patientsHs-Troponin T

      Hs-Troponin I (other details NR)
      < 14 pg/ml

      < 35 pg/ml
      38%
      Ghio et al.16Pavia, Italy405 COVID-19 admitted patientsHs-cTnI (other details NR)99th URL74/340 (22%)
      Karbalai Saleh et al.17Tehran, Iran386 COVID-19 admitted patientshs-cTnI, other details NR>26 ng/mL for men

      >11 ng/L for women
      29.8%
      Lombardi et al.18Italy, multicentric614 COVID-19 patients admitted to Cardiology UnitsHs-cTnI or hs-cTnT, other details NR>99th URL45%
      Salvatici et al.19Milan, Italy523 COVID-19 admitted patientshs-TnI Beckman Coulter11.6 ng/L for women 19.8 ng/L for men37.3 %
      Singh et al.20Chicago USA276 COVID-19 admitted patientsHs-TnT17 ng/L (median in their population)48%
      Fan et al.21Wuhan china353 COVID-19 admitted patientsHs-cTnI STAT High Sensitive Troponin‐I Abbott>34.2 pg/mL for men

      >15.6 pg/mL for women
      22.4%
      He et al.22Wuhan china1031 COVID-19 admitted patientsHs-cTnI, other details NR>99th URL20.7%
      Zaninotto el al.23Padova, Italy113 COVID-19 admitted patientsHs-cTnI Architect i2000, Abbott Diagnostics16 ng/L for women

      34 ng/L for men
      45%
      Ferrante et al.24Milano. Italy332 COVID-19 admitted patients with chest CTHs-cTnI, other details NR>20 ng/L37%
      Chen et al.25Wuhan china726 COVID-19 admitted patients severe or critically illHs-cTnI Architect i2000, Abbott Diagnostics>28 ng/L37.4% in critical patients

      10.4% in severe patients
      Poterucha et al.26New York, USA887 COVID-19 admitted patients with ECGHs-cTnT≥20 ng/L43%
      Perrone et al.27Italy, multicentric543 COVID-19 admitted patientshs-cTnT>14 ng/L47%
      Metkus et al.28Baltimore, USA243 COVID-19 admitted patients intubated.Hs-cTnI and hs-cTnT>99th URL51%
      Peirò et al.29Tarragona, Spain196 COVID-19 patients ED/hospitalHs-cTn I Assay, Advia Centaur, Siemens>21 ng/L39.3%
      Efros et al.30Tel-Aviv, Israel559 COVID-19 admitted patientshs-TnT>99th URL28.4%
      Cipriani et al.31Padova, Italy109 COVID-19 admitted patientsHs-cTnI Architect i2000, Abbott Diagnostics16 ng/L for women

      34 ng/L for men
      38%
      Qian et al.32Wuhan china77 ICU COVID-19 patientsHs-cTnI, other details NR>28 ng/L53%
      De Michieli et al.33Padova, Italy426 ED COVID-19 patientsHs-cTnI Architect i2000, Abbott Diagnostics16 ng/L for women

      34 ng/L for men
      27.2%
      Siddiqi et al.34Boston, USA70 COVID-19 admitted patientsHs-cTnT>14 ng/L16/21 (76%)

      Pts with viremia 18/49 (38%) w/o viremia
      Larcher et al.35France111 ICU COVID-19 patientsHs-cTnT>14 ng/L55%
      Demir et al.36London, UK176 ICU COVID-19 pts with cTnHs-cTnT>14 ng/L56%
      Myhre et al.37Akershus

      University Hospital Norway
      123 COVID-19 admitted patientsHs-cTnT>10 ng/L for women

      >15 ng/L for men
      42% in pts with viremia

      33% in pts w/o
      Bieber et al.38Munich, Germany32 COVID-19 admitted patients with 3D echoHs-cTnT>14 ng/L56%
      Garcia de Guadiana-Romualdo et al.39Spain, multicenter1280 ED COVID-19 patientsHs-cTnT cTnI Siemens Atellica

      cTnI Siemens Advia Centaur cTn I Siemens Dimension EXL cTnI Abbott Architect cTn I Beckman DxI 800/Access
      >99th URL26.9% w/o sex specific cutoffs

      30% with sex specific cutoffs
      de Falco et al.40Naples, Italy174 COVID-19 admitted patientsHs-cTnI Architect i2000, Abbott Diagnostics16 ng/L for women

      34 ng/L for men
      11.5%
      Barman et al.41Turkey607 COVID-19 admitted patientsHs-cTnI, other details NR>14 pg/ml24.7%
      De Michieli et al.42USA, multicenter367 COVID-19 admitted patients with cTn measuredHs-cTnT>10 ng/L for women,

      >15 ng/L for men
      46%
      Ozer et al.43Turkey73 COVID-19 admitted patients with Chest CTAbbott, ARCHITECT

      STAT High Sensitive Troponin-I
      >11.5 ng / l39.7%
      Caro-Codón et al.44Madrid, Spain918 COVID-19 ED patients with cTn measuredAtellica Solution IM1600, Siemens Healthineers hs-cTnI> 34.1 ng/l > 53.5 ng/L20.7%
      Maino et al.45Rome, Italy189 COVID-19 admitted patientshs-TnI Advia Centaur

      Siemens
      57 ng / L

      For men

      37 ng/L for women
      16% overall

      9.7% in mild

      29.0% in severe

      61.3% in critical
      Chehab et al.46Detroit, USA270 COVID-19 admitted patients with cTnHs-cTnI Beckman Coulter100 ng/L (not URL)32.6%
      Arcari et al.47Italy, multicenter252 COVID-19 admitted patients, 229 with cTnHs-Troponin T hs-Troponin I, other details NR14 pg/ml

      35 pg/ml
      36%
      Salbach et al.48Heildeberg, Germany104 COVID-19 admitted patientsHs-cTnT>14 ng/L44.2%
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      THE USE OF CARDIAC TROPONIN IN PATIENTS WITH COVID-19

      Using high-sensitivity cardiac troponin assays, following guideline recommendations, sex-specific 99th percentile URLs should be used to define myocardial injury
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Fourth Universal Definition of Myocardial Infarction (2018).
      . 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 >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 COVID-19 patients

      Shi S, Qin M, Shen B, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. Published online March 25, 2020.

      ,
      • Lala A.
      • Johnson K.W.
      • Januzzi J.L.
      • et al.
      Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection.
      ,
      • Lombardi C.M.
      • Carubelli V.
      • Iorio A.
      • et al.
      Association of Troponin Levels With Mortality in Italian Patients Hospitalized With Coronavirus Disease 2019: Results of a Multicenter Study.
      .

       Single sample versus serial samples

      Most studies only report values at baseline. Limited data exist addressing serial samples. Kini et al.
      • Kini A.
      • Cao D.
      • Nardin M.
      • et al.
      Types of myocardial injury and mid-term outcomes 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 <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 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.

      Nuzzi V, Merlo M, Specchia C, et al. The prognostic value of serial troponin measurements in patients admitted for COVID‐19. ESC Heart Failure. Published online July 8, 2021:ehf2.13462.

      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 <99th URL at both assessments), normal-elevated (normal cTn at admission and elevated thereafter), elevated-normal or elevated (i.e. 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
      • Zaninotto M.
      • Mion M.M.
      • Padoan A.
      • Babuin L.
      • Plebani M.
      Cardiac troponin I in SARS-CoV-2-patients: The additional prognostic value of serial monitoring.
      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.

       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
      • De Michieli L.
      • Ola O.
      • Knott J.D.
      • et al.
      High-Sensitivity Cardiac Troponin T for the Detection of Myocardial Injury and Risk Stratification in COVID-19.
      and hs-cTnI
      • De Michieli L.
      • Babuin L.
      • Vigolo S.
      • et al.
      Using high sensitivity cardiac troponin values in patients with SARS-CoV-2 infection (COVID-19): The Padova experience.
      . 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
      • De Michieli L.
      • Ola O.
      • Knott J.D.
      • et al.
      High-Sensitivity Cardiac Troponin T for the Detection of Myocardial Injury and Risk Stratification in COVID-19.
      . 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.
      • De Michieli L.
      • Babuin L.
      • Vigolo S.
      • et al.
      Using high sensitivity cardiac troponin values in patients with SARS-CoV-2 infection (COVID-19): The Padova experience.
      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 enhances risk stratification in COVID-19 patients remains a matter of debate. Omland et al.
      • Omland T.
      • Prebensen C.
      • Røysland R.
      • et al.
      Established Cardiovascular Biomarkers Provide Limited Prognostic Information in Unselected Patients Hospitalized With COVID-19.
      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
      • De Michieli L.
      • Babuin L.
      • Vigolo S.
      • et al.
      Using high sensitivity cardiac troponin values in patients with SARS-CoV-2 infection (COVID-19): The Padova experience.
      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.

       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 COVID19
      • Mueller C.
      • Giannitsis E.
      • Jaffe A.S.
      • et al.
      Cardiovascular biomarkers in patients with COVID-19.
      . 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
      • Mueller C.
      • Giannitsis E.
      • Jaffe A.S.
      • et al.
      Cardiovascular biomarkers in patients with COVID-19.
      . 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 due to critical illness with or without hemodynamic impairment, resulting in myocardial injury or, if ischemia is present, type 2 MI
      • Mueller C.
      • Giannitsis E.
      • Jaffe A.S.
      • et al.
      Cardiovascular biomarkers in patients with COVID-19.
      . 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
      • Bularga A.
      • Chapman A.R.
      • Mills N.L.
      Mechanisms of Myocardial Injury in COVID-19.
      .

      PROGNOSTIC IMPLICATIONS

      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
      • Barman H.A.
      • Atici A.
      • Sahin I.
      • et al.
      Prognostic significance of cardiac injury in COVID-19 patients with and without coronary artery disease.
      ,
      • Çınar T.
      • Hayıroğlu M.İ.
      • Çiçek V.
      • et al.
      Prognostic significance of cardiac troponin level in Covid-19 patients without known cardiovascular risk factors.
      . Conversely, cTn concentrations remain within normal range in most survivors
      • Mueller C.
      • Giannitsis E.
      • Jaffe A.S.
      • et al.
      Cardiovascular biomarkers in patients with COVID-19.
      . The incidence of myocardial injury increases with a greater severity of illness and, with the development of ARDS
      • Mueller C.
      • Giannitsis E.
      • Jaffe A.S.
      • et al.
      Cardiovascular biomarkers in patients with COVID-19.
      . Regarding the consequences of myocardial injury in COVID-19, Kotecha et al. 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 et al.
      • Puntmann V.O.
      • Carerj M.L.
      • Wieters I.
      • et al.
      Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19).
      performed CMR after a median of 71 days in 100 recovered COVID19 patients (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 left ventricular mass.
      Data regarding long term consequences of myocardial injury in those who survived COVID19 are scarce. A prospective exercise echocardiographic evaluation of 48 patients 6 months after COVID19 disease (some of whom had experienced myocardial injury
      • Fayol A.
      • Livrozet M.
      • Boutouyrie P.
      • et al.
      Cardiac performance in patients hospitalized with COVID‐19: a 6 month follow‐up study.
      ) 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.

      CONCLUSIONS

      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 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.

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