Authors

• Ana Reschner Planinc — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska — ORCID: 0000-0002-6723-6822
• Maja Strozzi — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska — ORCID: 0000-0003-4596-8261
• Zoran Miovski — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska — ORCID: 0000-0002-3850-8905
• Kristina Marić Bešić — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska — ORCID: 0000-0002-4004-7271
• Joško Bulum — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska — ORCID: 0000-0002-1482-6503

Abstract

Troponin elevation usually indicates myocardial cell injury. However, elevated values of troponin are not always a consequence of infarction or ischemia. The aim of this study was to elucidate the diverse etiologies of elevated troponin in patients with normal coronary angiography. There were 947 patients at the Zagreb University Hospital Centre identified from the catheterization database who underwent coronary angiography in 2014 due to suspected acute coronary syndrome. We identified 32 (3.38%) patients who had an alternative cause for myocyte injury other than coronary artery disease, defined as coronary artery lumen stenosis above 30%. The elevation of cardiac troponin T (cTnT) in patients with normal coronary angiography was found to be the consequence of diverse etiologies, including hypertensive heart disease, Takotsubo syndrome, supraventricular tachycardia, myocarditis, and dilated cardiomyopathy, to name a few. Apart from acute coronary syndrome, cTnT can be elevated in a number of different conditions, which should be considered according to clinical presentation, and that could still reflect myocardial necrosis even in the absence of significant coronary artery disease.

Keywords

cardiac troponin, coronary artery disease, normal coronary angiography, myocardial cell injury

DOI

Full Text

## Introduction Troponin is a structural component of sarcomere and consists of three proteins: troponin C (cTnC), troponin I (cTnI), and troponin T (cTnT), which control skeletal and cardiac muscle contraction in response to intracellular calcium. Approximately 6-8% of cTnT and 2.8-8.3% of cTnI are found floating free in the cytosol (1). Most commonly they are released as a result of proteolytic degradation. After cardiomyocyte injury, troponin is initially released from the cytoplasmic pool, followed by release from quantities bound to deteriorating myofilaments (2). The measurement of serum cTnI and cTnT is superior in comparison with the measurement of cTnC in the identification of cardiac muscle damage in terms of sensitivity and specificity to cardiac muscle enzyme measurements (1). In peripheral blood, it takes 3-4 hours for cTnT to begin to rise after the onset of myocardial injury, and its concentration remains increased for 10-14 days (3). Troponins are markers which indicate presence of myocardial cell injury and necrosis but do not indicate the mechanism causing it (4-7). In 2019, the European Society of Cardiology published the Fourth Universal Definition of Myocardial infarction that defines 5 types of myocardial infarction. The term myocardial infarction (MI) should be used when there is acute myocardial injury with clinical evidence of acute myocardial ischemia with detection of a rise and/or fall of cTnT values, and at least one of the following: symptoms of myocardial ischemia, new ischemic ECG changes, development of pathological Q waves, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology, or identification of a coronary thrombus by angiography or autopsy (not for types 2 or 3 MIs). Classical MI as a consequence of obstructive coronary artery disease (CAD) is classified as type 1 MI. Type 2 MI fulfils the abovementioned criteria besides obstructive CAD, and is evidenced by an imbalance between myocardial oxygen supply and demand (8). Therefore, MI should be diagnosed in conjunction with other supportive evidence, such as corresponding clinical presentation, electrocardiographic changes, etc. In the last years, the term MINOCA (Myocardial Infarction with NON-obstructive coronary arteries), has received much attention, and it is thought that up to 8% of patients with MI actually have MINOCA. Evidence of elevated cTnT without the abovementioned additional criteria for MI should just be classified as myocardial injury. Myocardial injury can be the result of a number of other clinical scenarios with cardiac and non-cardiac etiologies (9-11), listed in **Table 1** and explained later. ### TABLE 1: Possible etiologies of elevated troponin in patients with normal coronary angiography ( 13 - 27 ). | **Direct damage to myocardium** | **Diminished oxygen** **supply to myocardium** | **Increased oxygen** **demand** | **Increased demand and diminished supply** | **Other causes** | | --- | --- | --- | --- | --- | | Inflammation (myopericarditis) | Coronary embolus | Left ventricular hypertrophy | Tachycardia, severe AS | Infiltrative disease of myocardium | | Electrical discharge | Shock of various etiologies | Cardiomyopathy | Tachycardia associated with bleeding | Renal failure | | Mechanical damage | Gastrointestinal bleeding | COPD | Sepsis | Hypothyroidism | | Chemical damage | Anemia | Valvular lesions (regurgitant or stenotic) | Severe CHF | False positive (RA, liver cirrhosis) | | | Coronary spasm | SVT | | Diabetic ketoacidosis | | | Hypercoagulable state | Extreme exercise | | Scorpion toxin | | | Aortic dissection | Increased sympathetic activity | | | | | Coronary dissection | Right ventricular failure (PE, ASD) | | | [†] AS=aortic stenosis, COPD=chronic obstructive pulmonary disease, CHF=chronic heart failure, RA=rheumatic arthritis, SVT=supraventricular tachycardia, PE=pulmonary embolism, ASD=atrial septal defect. ## Patients and Methods Data were assessed retrospectively from medical files and databases collected in 2014 at the Zagreb University Hospital Centre (UHC). Patients included in this study were those who underwent coronary angiography in 2014 due to suspected acute coronary syndrome (ACS) and who had troponin-positive chest pain. We excluded all patients that had coronary arterial luminal stenosis greater than 30% as well as patients with missing data on troponin concentrations. The patients underwent the usual routine procedures of Zagreb UHC for assessment of patients with chest pain that usually included clinical history to also establish risk factors for atherosclerotic CAD, laboratory examination, physical examination, ECG, echocardiography, and coronary angiography. We also collected data on laboratory parameters such as troponin T, C-reactive protein, renal parameters (creatinine), and creatine kinase (CK). Troponin T was determined immediately and serially after the onset of pain, but peak Troponin T values were used for the purpose of this study. A high-sensitive cTnT (hs-cTnT) assay was used to detect the presence of troponin in serum. This assay is a modification of the fourth-generation cTnT assay and is significantly improved to further reduce the possibility of false “positive” findings (12). Troponin T increase was defined as >0.014 ng/mL (14 ng/L) (cut-off value). Routine CRP was measured within 24 h from admission. A concentration of >5 ng/mL was considered elevated. Creatinine was determined by enzymatic colorimetric assay. Cut-off value for men was 105 μmol/L and 85 μmol/L for women. Serum values of creatine kinase were measured using an enzymatic rate method of foregoing reaction catalyzed by creatine kinase. The normal reference range was 0-177 U/L. Creatine kinase activities are greatest in skeletal muscles, followed by the heart, brain, and other tissues (13). ## Results In Zagreb UHC in 2014, a total of 2433 coronary angiography procedures were performed due to different indications that are listed in **Table 2**. Indications correspond to possible entry options from the catheterization laboratory database (entered before the procedure), and although there is some overlap present, the table gives an overview of the spectrum of reasons for coronary angiography in 2014 in Zagreb UHC. ### TABLE 2: Indications for coronary angiography in 2014 at the Zagreb University Hospital Centre. | **Indications** | **% of patients (n=2433)** | **Indications** | **% of patients (n=2433)** | | --- | --- | --- | --- | | **Stable angina** | 564 (23.18) | **Cardiac arrest** | 25 (1.03) | | **STEMI** | 336 (13.81) | **Pre-transplantation evaluation** | 15 (0.62) | | **Unstable angina** | 314 (12.91) | **Hypertrophic cardiomyopathy** | 13 (0.53) | | **NSTEMI** | 297 (12.21) | **Aortic aneurysm** | 9 (0.37) | | **Elective PCI** | 280 (11.51) | **Myocarditis** | 5 (0.21) | | **Ischemic heart disease screening** | 146 (6.00) | **Cardiogenic shock** | 3 (0.12) | | **Valvular heart disease evaluation** | 103 (4.23) | **Congenital Heart Disease** | 3 (0.12) | | **Cardiomyopathy screening** | 95 (3.90) | **Endocarditis** | 3 (0.12) | | **Pre-operative evaluation** | 94 (3.86) | **Pericarditis** | 3 (0.12) | | **Post-transplant evaluation** | 57 (2.34) | **Pulmonary arterial hypertension** | 2 (0.08) | | **Rhythm abnormality** | 34 (1.40) | **Explant preparation** | 1 (0.04) | | **Subacute myocardial infarction** | 31 (1.27) | | | [†] STEMI=acute myocardial infarction with ST-segment elevation, NSTEMI=acute myocardial infarction without ST-segment elevation, PCI= percutaneous coronary intervention. Out of the total number of 2433 procedures, 947 (38.92%) patients had troponin-positive chest pain and were consequently suspected of having ACS. Of those 947 patients with suspected ACS, 32 (3.38%) had an alternative cause for myocyte injury. The average serum troponin T in patients without ACS or any other significant CAD was 0.372 ng/L (range 0.02-3.48ng/L). CRP was measured in 30/32 patients, and in 19 (63.33%) was found to be elevated (mean 26.1 mg/L, range 5.13-115.2 mg/L). CK was measured in 30/32 of patients with normal coronary angiography and was found to be elevated in 12 patients (40%) (mean 281.7 U/L, range 18-1921 U/L). Creatinine was measured in 29/32 of the patients with normal coronary angiography (mean 127.6, range 39-629 μmol/L). We have also analyszed the leading symptoms in the patient subgroup of increased troponin and normal coronary angiography. Chest pain can be further classified as typical, atypical, or non-anginal. Typical features of anginal chest pain are retrosternal location, provocation by activity or stress, and fast relief by rest or nitroglycerine administration. If two of these three features are present the chest pain is classified as atypical, while the chest pain is classified as non-anginal pain if only one of the features is present (12, 14). Classification of chest pain described in those patients is shown in **Table 3**. ### TABLE 3: Types of chest pain. | **Type of chest pain** | **Number of patients (n=32)** | | --- | --- | | **Atypical** | 14/32 | | **Typical** | 13/32 | | **Non-anginal pain** | 5/32 | Other clinical presentations found in patients with troponin-positive chest pain are shown in **Table 4**. The majority of patients with troponin-positive chest pain had cardiovascular risk factors and comorbidities that increase risk for further cardiovascular events (**Table 5**). The most common causes identified were hypertensive heart, Takotsubo syndrome, and myocarditis (**Table 6**). ### TABLE 4: Clinical presentations of patients with elevated troponin and normal coronary angiography. | **Clinical presentation** | **Number of patients (n=32)** | | --- | --- | | **Dyspnea** | 8/32 | | **None** | 5/32 | | **Fever** | 5/32 | | **Nausea** | 4/32 | | **Palpitations** | 3/32 | | **Headache** | 2/32 | | **Cough** | 2/32 | ### TABLE 5: Comorbidities and risk factors. | **Comorbidity** | **Number of patients (n=32)** | | --- | --- | | **Hypertension** | 23/32 | | **Dyslipidemia** | 10/32 | | **Smoking** | 10/32 | | **Diabetes type 2** | 7/32 | | **History of ACS** | 6/32 | | **Obesity** | 5/32 | | **Malignant disease** | 3/32 | | **COPD** | 3/32 | | **Permanent AF** | 2/32 | | **CHF** | 1/32 | [†] ACS=acute coronary syndrome, COPD=chronic obstructive pulmonary disease, AF=atrial fibrillation, CHF=chronic heart failure. ### TABLE 6: The causes of elevated troponin in the study population. | **Diagnosis** | **Number of patients (n=32)** | | --- | --- | | **Myocarditis** | 6/32 | | **Hypertensive heart disease** | 6/32 | | **Hypertensive crisis** | 5/32 | | **Takotsubo syndrome** | 4/32 | | **Dilated cardiomyopathy** | 2/32 | | **SVT (including FA)** | 2/32 | | **COPD exacerbation** | 1/32 | | **Pancreatitis** | 1/32 | | **Pneumonia** | 1/32 | | **Acute pulmonary embolism** | 1/32 | | **Lung cancer** | 1/32 | | **Collagenosis** | 1/32 | | **Chronic kidney disease** | 1/32 | [†] SVT=supraventricular tachycardia, AF=atrial fibrillation, COPD=chronic obstructive pulmonary disease. All electrocardiogram findings in our subgroup of patients are shown in **Table 7**. ST-segment elevation was common in patients diagnosed with Takotsubo syndrome, while negative T waves were most commonly seen with hypertensive crisis (**Table 7**). ### Table 7: ECG findings. | **ECG findings** | **Number of patients (n=32)** | | --- | --- | | **Normal ECG** | 17 | | **ST-segment elelavation (more than 0.05 mV)** | 6 | | **T wave inversion** | 5 | | **Atrial fibrillation** | 2 | | **Sinus tachycardia** | 2 | | **ST denivelation** | 2 | | **Voltage criteria for LVH** | 1 | | **LBBB** | 1 | [†] LVH=left ventricle hypertrophy, LBBB=left bundle branch block. ## Discussion In this study, 32 (3.38%) patients in 2014 at Zagreb UHC with troponin-positive chest pain and suspected ACS had no angiographically significant CAD, therefore fulfilling criteria for neither myocardial injury or type 2 MI. Various cardiac and non-cardiac conditions have been described to cause the increase of troponin in the absence of criteria to clearly diagnose type 1 MI (5-7, 15-24). Mechanisms causing elevation of troponin are of major therapeutic importance. Coronary angiography may not be appropriate in some of these patients. Increased troponin and absence of typical presentation of ACS presents a diagnostic challenge, as shown by patients included in this study, who all underwent coronary angiography and were later shown to have an alternative etiology of elevated troponin. Troponin may rise as a result of mismatch between myocardial oxygen supply and demand or as a result of direct damage to the myocardium. Irreversible myocyte injury can cause an initial release of cytosolic troponin, in contrast to reversible injury which causes release of factors which lead to increased permeability of the membrane and leakage of degraded free troponin without myocyte necrosis (25). Both mechanisms may occur in different phases of myocarditis. For the diagnosis of acute myocarditis, the patient has to have elevated cTnT with varying severity of clinical presentation of acute heart failure (from no or mild symptoms to fulminant myocarditis causing cardiogenic shock). Some cases in our study involved true myocyte necrosis that was related to increased oxygen demand in the absence of an appropriate supply (10). A good example of mismatch are hypertrophied hearts such as in hypertensive heart disease, which was observed in most of the patients reviewed (26, 27). Strenuous exercise, catecholamine release, and stress-related neuropeptides (the latter two most commonly seen in Takotsubo syndrome) are also documented causes (23, 28). Tachycardia can also result in an increase of troponin because there is decreased time available for diastolic coronary perfusion (29). Alteration in the ST-segment during episodes of tachycardia is not necessarily an indication of the presence of ischemia (30). Troponin elevation and the rate and duration of tachycardia, however, showed no relationship in previous studies (29, 30). Toxic cytokines, ongoing apoptosis, chronic ischemia, and loss of cellular membrane integrity can all cause elevation of troponin in patients with heart failure (31, 32). In addition, ongoing loss of viable cardiac myocytes, which is characteristic for progressive heart failure, explains elevation of troponin (33). Elevation of troponin has been observed in patients with moderate-to-large pulmonary embolism or massive pulmonary embolism. It can be a result of an increase in right ventricular myocardial oxygen demand, which may lead to right ventricular dilation and ischemia (34). Exaggerated inflammatory response, as seen in patients with chronic obstructive pulmonary disease (COPD) exacerbation, can also predispose for myocardial injury (35). Elevated troponin is a strong predictor of in-hospital death in patients who are admitted for COPD exacerbation (36). Ischemia can also be the result of impaired coronary flow reserve caused by a combination of ventricular hypertrophy, tachycardia, and lower perfusion pressure, all which can occur in patients with significant aortic stenosis (37). ## Conclusion Absence of angiographically significant CAD in patients with criteria for MI warrants further investigation on the etiology of myocardial injury in those patients. Troponin is not so useful to “rule in” ACS due to its lack of specificity, but it is a sensitive biomarker to “rule out” non-ST-segment elevation myocardial infarction.

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