Elevated troponin level is not synonymous with myocardial infarction

International Journal of Cardiology 111 (2006) 442 – 449 www.elsevier.com/locate/ijcard

Elevated troponin level is not synonymous with myocardial infarction i,ii Nitin Mahajan a,*, Yatin Mehta a, Malcolm Rose a, Jacob Shani b, Edgar Lichstein a a b

Department of Medicine, Maimonides Medical Center, Brooklyn, NY 11219, USA Department of Cardiology, Maimonides Medical Center, Brooklyn, NY 11219, USA

Received 9 May 2005; received in revised form 6 August 2005; accepted 29 August 2005 Available online 10 November 2005

Abstract Background: Elevated troponin I in the absence of angiographically visible coronary lesions is seen in up to 10 – 15% of those undergoing angiography for suspected coronary artery disease. This study aims to elucidate the etiology of elevated cardiac troponin I in patients with normal coronary arteries on angiography. Methods: We identified 1551 (8.6%) patients with normal coronary arteries from our catheterization database of 17,950 patients from Jan 2000 to Jun 2004. Elevated troponin I levels were found in 217 (14%) of 1551 patients with normal coronary arteries. Of these 217 patients, 73 surgical patients were excluded, and the remaining 144 patients formed the study population. The study population was compared with age and gender matched patients with myocardial infarction and coronary artery disease (Group II). Results: The patients with elevated cardiac troponin I (cTnI) with normal coronary arteries had significantly lower prevalence of atherosclerotic risk factors and significantly higher left ventricular ejection fractions. The cTnI in patients with normal coronary arteries was elevated due to a number of causes including tachycardia, myocarditis, pericarditis, severe aortic stenosis, gastrointestinal bleeding, sepsis, left ventricular hypertrophy, severe congestive heart failure, cerebrovascular accident, electrical trauma, myocardial contusion, hypertensive emergency, myocardial bridging, pulmonary embolism, diabetic ketoacidosis, chronic obstructive pulmonary disease exacerbation and coronary spasm. Conclusions: Cardiac troponin I could be elevated in a number of conditions, apart from acute myocardial infarction, and could reflect myonecrosis. Acute myocardial infarction is a clinical diagnosis as the laboratory is an aide to, not a replacement for, informed decision making. D 2005 Published by Elsevier Ireland Ltd. Keywords: False-positive; Elevated troponin; Normal coronary arteries; Atherosclerosis; Non-ischemic; Myocardial infarction

1. Introduction i

Supported in part by Maimonides Research Grant. ii This is the largest series on retrospective analysis of patients with elevated troponin levels. We believe that this study elucidates the etiology and pathophysiology of elevated cardiac troponin I in patients with normal coronary arteries on angiography. Elevated troponins reflect myonecrosis as a result of imbalance between myocardial oxygen supply and consumption. Acute myocardial infarction is a clinical diagnosis. Elevated troponin levels should be interpreted appropriately based on underlying clinical setting. This study is a retrospective study, and hence did not involve any patient contact. Also, it had the approval of the Internal Review Board. * Corresponding author. Tel.: +1 347 277 6497. E-mail address: [email protected] (N. Mahajan). 0167-5273/$ - see front matter D 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.ijcard.2005.08.029

The World Health Organization definition requires two of the following three features to diagnose acute myocardial infarction (AMI): chest pain suggestive of cardiac disease, an ECG with characteristic changes suggesting myocardial infarction, and cardiac-specific biochemical markers exceeding the standard reference ranges in a pattern consistent with AMI [1]. Conventional cardiac enzymes have evolved from measurements of aspartate transaminase and lactate dehydrogenase to CK-MB to cardiac troponins. The latest American College of Cardiology/European Society of Cardiology (ACC/ESC) definition of MI (published in

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2000) emphasizes the use of cardiac markers in diagnosing MI [2], and has increased the number of patients diagnosed with MI especially non-ST-elevation MI [3]. The use of biomarkers in the definition of acute MI may not allow for proper analysis of other factors leading to ischemic myonecrosis. Cardiac troponin I (cTnI) is a marker of myonecrosis. Elevated levels of cTnI are not synonymous with coronary artery disease. Patients with normal angiograms despite elevated troponin are believed to constitute about 3% of patients with myocardial infarction and up to 10 –15% of those undergoing angiography for suspected coronary artery disease [4,5]. The number tends to be higher for women as compared to men [6]. This study seeks to elucidate the etiology of elevated troponins in patients with normal coronary angiogram.

2. Methods 2.1. Study population We reviewed the database of cardiac catheterizations done at our Cardiac Institute from January 2000 to June 2004. This involved a review of a total of 17,950 cardiac catheterizations performed at our catheterization center. It led to the identification of a total of 1551 patients with normal coronary arteries, defined by smooth contours and no focal reduction on the coronary angiogram, accounting for 8.6% of patients who underwent cardiac catheterization over this period. Patients with elevated cTnI levels (N = 217) were further selected from this population. These patients accounted for 14% of patients with normal angiograms on cardiac catheterization. Surgical patients with elevated troponins and normal coronaries (n = 73/217, 34%) were excluded from further analysis. This led to identification of 144 patients with elevated TnI and normal coronaries who were admitted to medical floors. These patients formed Group I. The diagnosis of myocarditis was established by a combination of criteria, such as a preceding infection of the upper respiratory tract, thoracic pain, diffuse STsegment elevations in different precordial leads without classic evolutionary changes followed by T wave inversions, elevation of cardiac enzymes (following a ‘‘plateau’’ rather than usual cyclic trend on serial blood tests), reversible hypokinesia by echocardiography, and normal coronary arteries. At least 3 of 5 criteria were needed for diagnosis. Acute pericarditis was defined as patients with an audible pericardial friction rub or chest pain with typical electrocardiographic findings, most notably widespread ST-segment elevation and PR depression. Left ventricular hypertrophy was defined as the sum of R wave in lead aVL and S wave in lead V3 being greater than 2 mV in females and greater than 2.8 mV in males [7]. Shock was defined as acute hypotension (systolic

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blood pressure <80 mmHg) or low cardiac index (< 2.0 l/ min/m2) despite pharmacologic or mechanical support. Coronary spasm was documented if the narrowing of the epicardial coronary vessel was reversed with nitroglycerin resulting in increased luminal diameter and restoration to thrombolysis in myocardial infarction flow grade III. Systemic sepsis was defined as fever and bacteremia that was treated with broad-spectrum antibiotics. Tachycardia was defined by ventricular response in excess of 100/min. Pulmonary embolism was defined by the presence of dyspnea or pleuritic chest pain and high probability V/Q scan or by documented pulmonary vessel clot on spiral CT scan. Diabetic ketoacidosis was defined by the demonstration of hyperglycemia, hyperketonemia, and increased anion-gap acidosis. Cerebral vascular accidents were identified by an embolic, thrombotic, or hemorrhagic stroke with motor, sensory, or cognitive dysfunction that persisted for 24 h. Hypertensive emergencies included accelerated or malignant hypertension, hypertensive encephalopathy, acute aortic dissection, and pheochromocytoma crisis. Diagnosis of myocardial contusion was based on history of chest wall injury with echocardiographic documentation of segmental wall motion abnormally that resolved on a subsequent echocardiogram or a fixed segmental defect with Q wave on ECG that could be documented as new [8]. The mean time from symptom onset to angiogram was 12 T 4 h, with the exception of patients who presented with gastrointestinal bleeding, septic shock and diabetic ketoacidosis. The precipitating event for TnI elevation was decided on the temporal relationship with regard to conditions suspected to be associated with troponin release [9 –21]. Patients admitted for acute myocardial infarction and documented coronary artery disease (defined by  50% reduction of at least one major epicardial coronary vessel at the angiogram performed 8 T 4 h after the index myocardial infarction) formed Group II. Patients in Group I were matched for age and gender with a group of 144 patients who presented with acute myocardial infarction and elevated troponins during the same period. The diagnosis of acute myocardial infarction was based on the triad of chest pain, ECG changes and elevated cardiac enzymes [1]. The enzymes were measured at 6 –8 h intervals during the first 24 h. The atherosclerotic risk factor profile and echocardiographic parameters (where available) were compared for the study groups. Troponin I was measured using the Bayer Diagnostic’s ADVIA CentaurR assays. This assay is a two-site sandwich immunoassay using direct chemoluminometric technology. The first antibody is a polyclonal goat antitroponin I antibody labeled with acridinium ester. The second antibody is a combination of monoclonal mouse anti-troponin antibodies coupled to paramagnetic particles. A direct relationship exists between the amount of troponin I present in the patient sample and the amount

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Table 1 Baseline characteristics of study population

3. Results

Variables

Group I (N = 134)

Group II (N = 134)

P value

3.1. Study population

Age (years) Diabetes mellitus (%) Hypertension (%) Hypercholesterolemia (%) Smoking (%) History of congestive heart failure (%) Family history (%) Males (%) Peripheral vascular disease (%) History of PTCA/CABG (%) History of myocardial infarction (%) History of cerebrovascular events (%) Left ventricular hypertrophy (%) Left ventricular ejection fraction

60 T 17 19 47 30 28 13

59 T 16 35 69 66 31 13

NS <0.01 <0.001 <0.001 NS NS

8 49 2

50 52 18

<0.001 NS <0.001

0

23

<0.001

5

18

0.001

0

4

0.045

32

35

NS

48.4 T 14.5

40.2 T 12.6

<0.001

The comparison of demographic characteristics and atherosclerotic risk factor profiles of patients belonging to Group I and Group II are given in Table 1. Mean age and gender distribution is similar in both study groups. Mean age of females (64 T 12) is greater than males (49 T 19). Statistically significant higher prevalence rates of atherosclerotic risk factors including hypertension, hypercholesterolemia, obesity, diabetes mellitus and family history of premature coronary artery disease is seen in Group II. However, no significant difference in smoking prevalence is seen. Also, there is a significantly higher prevalence of peripheral vascular disease, history of prior myocardial infarction, history of CABG or PTCA and history of cerebrovascular events in Group II. The clinical presentations of Group I are given in Table 2. Chest pain was the most common complaint followed by dyspnea on exertion and palpitations. 3.2. Etiology of myonecrosis with normal coronaries

of relative light units detected by the system. Reference interval is 0.00 – 0.09 ng/ml. It has a coefficient of variation of 18% at the reference limit of 0.20 Ag/L. The 99th percentile for normal controls is 0.16 Ag/L [22]. This study was approved by the IRB of the participating hospital. 2.2. Data collection A detailed review of the medical records, echocardiograms, stress test results and angiogram records was performed. The medical records were reviewed for historical details at time of admission as well as established risk factors for atherosclerotic coronary artery disease. These variables included age, diabetes mellitus, hypertension, smoking, hypercholesterolemia, family history of premature coronary artery disease, gender, history of percutaneous transluminal angioplasty (PTCA) /coronary artery bypass grafting (CABG), history of myocardial infarction, peripheral vascular disease, and history of stroke. We evaluated for causes of elevated troponins in Group I as described in prior published reports [9 –21]. Left ventricular regional wall motion abnormalities were assessed by right anterior oblique angiography in all the study patients. 2.3. Statistical analysis Unless otherwise indicated, data are expressed as the mean value T S.D. Statistical analyses were conducted with SPSS Version 11.5. Differences among groups were assessed by v 2 test for categorical variable and one way ANOVA for continuous variables. A p-value < 0.05 was considered significant.

The proposed etiological factors for elevated cTnI in Group I are summarized in Table 3. The commonest cause of elevated cTnI was tachycardia followed by myocarditis in Group I. Other causes included pericarditis, severe aortic stenosis, gastrointestinal bleeding, sepsis, left ventricular hypertrophy, severe congestive heart failure, cerebrovascular accident, electrical trauma (automatic implantable cardioverter defibrillator/cardioversion), myocardial contusion, hypertensive emergency, myocardial bridging, pulmonary embolism, diabetic ketoacidosis, chronic obstructive pulmonary disease (COPD) exacerbation and coronary spasm. In 10 patients, no precipitant for cTnI release was identified. Of these 10 patients, 5

Table 2 The clinical presentations of the patients in study groups Proportion of patients [% (n)]

Chest pain Abdominal pain Shortness of breath Palpitations Automated implantable cardioverter defibrillator discharge Complication of stress Syncope Stroke Gastrointestinal bleeding Altered mental status Cardiac arrest

Group I (N = 144)

Group II (N = 144)

50 7 22 10 1

(72) (10) (31) (14) (1)

90 (130) 0 (0) 8 (11) 0 0

1 2 1 6 1 1

(1) (3) (1) (9) (1) (1)

0 0 2 (3) 0 0 0

P value

<0.001 0.004 0.006 0.003 NS

NS NS NS 0.008 NS NS

N. Mahajan et al. / International Journal of Cardiology 111 (2006) 442 – 449 Table 3 The cause of elevated troponin in group I Event

Number of events, proportion of patients [% (n)]

Congestive heart failure (E f < 25) AICD/resuscitation/defibrillator Myocarditis Pericarditis Cerebrovascular accident Sepsis Collagen vascular disease (rheumatoid arthritis, etc.) Severe aortic stenosis (aortic area <0.1) Left anterior descending artery bridging Documented coronary spasm Tachycardia (Themodynamic compromise) Hypertensive emergency (aortic dissection) Gastrointestinal bleeding Myocardial contusion Pulmonary embolism Diabetic ketoacidosis Chronic obstructive pulmonary disease exacerbation Left ventricular hypertrophy Septic shock Renal failure Unknown

8 (12) 3 (4) 16 (23) 5 (7) 2 (3) 3 (4) 1.4 (2) 6 (9) 3 (5) 1.4 (2) 24 (35) 0.7 (1) 7 0.7 1.4 1.4 3

(9) (1) (2) (2) (4)

1.4 3 1.4 7

(2) (5) (2) (10)

patients had significant ST-deviations and T wave changes suggestive of ischemia.

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response to intracellular calcium. The cTnI is considered the regulatory subunit of the troponin complex. The majority of cardiac troponin is found in the contractile apparatus, and is released as a result of proteolytic degradation. About 6 – 8% of cTnT and 2.8 –8.3% of cTnI are found free in cytosol [24]. Disruption of intracellular contractile proteins as a result of hypoxic injury (ischemic or non-ischemic) may increase the cytosolic pool [25]. The cytosolic pool tends to leak into the circulation when the membrane integrity of the sarcolemma is disrupted as a result of myonecrosis (Table 5). Elevated cTnI is a marker of myonecrosis and does not necessarily imply myocardial infarction. It may arise as a result of direct myocardial damage or as a result of mismatch between myocardial oxygen supply and consumption. It has been suggested that irreversible myocyte injury causes an initial release of cytosolic troponin followed by the gradual release of myofibril-bound troponin complexes, while reversible injury causes release of factors leading to increased permeability of the membrane to macromolecules and leakage of degraded free troponin without myocyte necrosis [9]. The cut-off level for the 99th percentile value for cardiac troponin I for this study was obtained from the literature of Bayer Diagnostic’s ADVIA CentaurR assays [22]. Although 50% of Group I patients presented with chest pain, and, in view of elevated troponins, would meet criteria for myocardial infarction [1,2], coronary angiograms were normal. Although lysis of coronary thrombosis is possible, most patients had early angiography (12 T 4 h), and other factors are more likely operative.

3.3. Electrocardiogram findings 4.1. Direct damage The electrocardiogram findings on presentation in Group I are given in Table 4. It was seen that the STsegment depressions were more common in patients with supraventricular tachycardia and resolved on slowing the ventricular response. ST-segment elevations were not uncommon in patients with myocarditis and pericarditis. None of the ST-segment elevations evolved to Q waves during the hospital stay.

Electrical damage (electrocution/AICD/cardioversion) is associated with structural damage or stunning of the cardiac muscle, and may manifest as significant ST-segment deviations in the ECG reflecting the myocardial insult. Myocyte necrosis in myocarditis is multifocal and associated with a diffuse, faint, and heterogeneous uptake of antimyosin antibody [10]. Smith et al. noted a direct relation

4. Discussion

Table 4 The 12-lead electrocardiogram findings on presentation in group I

Troponin I has three isoforms that are encoded by separate genes. Two isoforms are found in skeletal muscle: fast twitch and slow twitch skeletal muscle (skeletal TnI) that weigh around 19,800 Da, and the third larger cardiac isoform weighing around 24,000 Da. The cardiac isoform differs in amino acid sequence from the skeletal isoforms. The cTnI is not found in other tissues, and is not produced in response to regeneration of damaged muscle cells [23]. The cTnC, cTnI and cardiac troponin T (cTnT) are part of the sarcomeric apparatus of the myocardium, and control myocardial contraction in

Electrocardiogram findings Left bundle branch block (%) Right bundle branch block (%) ST depression (0.05 mV) (%) ST elevation (0.05 mV) (%) T inversion (%) Left ventricular hypertrophy (%)

Patients with chest pain (N = 72) [% (n)] 6 (4)

Patients without chest pain (N = 72) [% (n)] 8 (6)

10 (7)

6 (4)

19 (14)

56 (40)

18 (13)

19 (14)

29 (21) 7 (5)

28 (20) 17 (12)

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Table 5 Etiology of elevated troponin in patients with normal coronaries

4.2. Diminished myocardial oxygen supply

1) Direct damage a) Inflammation Myocarditis [26] – Infection — bacterial, post-viral – Inflammation – Auto-immune-polymyositis, scleroderma, sarcoid – Drugs — alcohol, chemotherapy Pericarditis b) Electrical discharge Electrocution AICD/cardioversion/atrioventricular ablation c) Mechanical damage Myocardial contusion [8] CABG/valve surgery d) Chemical damage Cardiotoxic chemotherapy 2) Diminished oxygen supply Coronary embolus — PTCA/CABG, atrial myxoma Shock GI bleeding (Tshock) Anemia Coronary spasm Myocardial bridging (Ttachycardia) Coronary artery inflammation with microvascular occlusion — hypercoagulable state (SLE, cancer, others), vasculitides Aortic dissection Coronary dissection 3) Increased oxygen demand Left ventricular hypertrophy [25] (THOCM) Cardiomyopathy [31] PE-associated RV dysfunction [32] Cor pulmonale (COPD) Non-cardiac surgery [44] Valvular lesions (severe aortic stenosis and others) Congestive heart failure [30] (myocardial necrosis caused by neurohumoral changes) Supraventricular/ventricular tachycardia [20] Extreme endurance exercise — extreme marathons, strenuous exercise [36] Increased sympathetic activity — cocaine, catecholamine storm (pheochromocytoma, stroke, head injury, TIA, seizure, subarachnoid hemorrhage) [34] RV dilatation and failure associated with ASD 4) Diminished supply and increased demand Tachycardia and severe aortic stenosis Bleeding (associated with tachycardia) Myocardial bridging and tachycardia Sepsis Severe CHF (may be associated with tachycardia in decompensated phase) 5) Other causes Infiltrative diseases of the myocardium — amyloidosis, sarcoidosis Renal failure [18,42] Hypothyroidism False positive troponins: collagen vascular disease, cirrhosis, rheumatoid arthritis [41] Diabetic ketoacidosis (extreme oxygen debt producing necrosis) [43] Acute graft failure in cardiac transplant patients Scorpion envenomation

4.2.1. Coronary spasm It is typically characterized by chest pain at rest, especially in the morning, due to transient vasospasm. Coronary spasm may also be associated with sudden death in patients with structurally normal hearts. h-Blockers can have deleterious effects in such patients by unmasking aadrenergic vasoconstriction.

between the size of myocardial inflammation and cTnI levels [26]. Myonecrosis may also be seen in patients with pericarditis as a result of epicardial damage from pericardial inflammation.

4.2.2. Myocardial bridging It includes LAD artery traversing from sub epicardial surface into myocardium before returning to sub epicardium. Transient vasoconstriction during systole and infrequently during diastole diminishes blood supply especially during periods of increased demand (like tachycardia) and leads to myonecrosis [11]. 4.2.3. Shock It can produce cardiac injury as a result of tachycardia and hemodynamic compromise. Treatment with pressor medications may also contribute to elevated cTnI concentrations. 4.2.4. Anemia It is commonly seen following gastrointestinal bleeding (e.g., duodenal ulcers, arteriovenous malformations, angiodysplasia, diverticulosis, Paget disease) in elderly patients, and is associated with decreased myocardial oxygen supply leading to myonecrosis. 4.2.5. Dissections Aortic and coronary dissection is associated with myocardial micro infarction resulting in elevated troponin levels. Coronary dissection is associated with impaired blood flow and oxygen delivery to myocardium resulting in hypoxic injury and elevated troponin levels. Angiography may reveal a thin streak of radiolucent contrast separating true and false channels. However, in the absence of blood flow into false lumen, angiographic findings may mimic coronary obstruction. 4.3. Increased myocardial oxygen demand 4.3.1. Tachycardia Increased demand during the period of tachycardia is associated with reduced oxygen supply to the myocardium resulting from shortened diastole. Troponin may be elevated during supraventricular or ventricular tachycardia [20]. ST alterations during tachycardia are not evidence for the presence of ischemia. They are seen in patients without other evidence of ischemia and with normal ECG after conversion to sinus rhythm. 4.3.2. Left ventricular hypertrophy It is associated with increased risk of angina pectoris, myocardial infarction, cardiac failure, lethal dysrhythmias

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and sudden cardiac deaths. Increased mechanical stress induced by in vivo h-adrenergic stimulation or in vitro by the pacing of cultured myocytes, may alter plasma membrane permeability and cause leakage of troponins [27]. The elevated cTnI may be reflective of ongoing sub clinical myonecrosis [28].

4.3.8. Extreme endurance exercise Extreme marathons and heavy-resistance exercise may raise levels of cTnI [36]. Ostium secundum type-atrial septal defect with left-to-right shunt may cause right ventricular dilatation and dysfunction leading to elevated troponin levels [16].

4.3.3. Chronic heart failure In patients with systolic dysfunction, sub clinical myocyte degeneration occurs during compensated heart failure. La Vecchia et al. found elevated cTnI levels in 23% of study patients [12]. The elevated cTnI levels reflect the ongoing loss of viable cardiac myocytes characteristic of progressive HF. The mechanisms include chronic ischemia, loss of cell membrane integrity, and apoptosis [10,29]. Elevated cTnI levels may be related to increased left ventricular wall strain and remodeling [30]. Elevated cTnI is an adverse prognostic marker in such patients [31].

4.3.9. Sepsis, septic shock and systemic inflammatory response syndrome In a study involving patients with sepsis, septic shock or systemic inflammatory response syndrome and controls, 85% of septic patients were found to have elevated cTnI levels [17]. Possible mechanisms include direct effects of bacterial micro organisms (bacterial myocarditis) and indirect effects of cytokine mediated inflammatory response (e.g., tumor necrosis factor-a, interleukin-1) affecting myocyte permeability to macromolecules, endotoxin effects, myocardial depressant substance and ischemic damage due to elevated oxygen consumption, prolonged hypotension or inotropic agents [17,37,38]. Elevated cTnI has been shown to be an independent adverse prognostic marker in septic shock and critically ill patients [39,40].

4.3.4. Pulmonary embolism (PE) Elevated troponin has been observed in patients with either moderate-to-large PE or massive PE [13]. The increase in right ventricular myocardial oxygen demand may lead to right ventricular dilation, ischemia, and resultant elevated serum troponin levels. Pruszczyk et al. found higher in-hospital mortality among patients with pulmonary embolism and elevated troponin levels [32]. 4.3.5. Valvular heart disease Valve diseases especially aortic stenosis and aortic regurgitation are associated with impaired coronary flow reserve [14], increased myocardial oxygen flow requirements, increased coronary impedance and higher left ventricular wall stress. All these factors may play a role in elevated cTnI in such patients. 4.3.6. COPD Serum troponins are commonly raised in acute exacerbations of COPD and reflect the severity of the exacerbation. Harvey et al. found that COPD patients with elevated troponins were older, had lower pulse oximetry saturations, were more acidotic and more hypercapnoeic [15]. Elevated cTnI is a strong and independent predictor of in-hospital death in patients admitted for COPD exacerbation [33]. 4.3.7. Increased sympathetic drive It is commonly seen with stroke, transient ischemic attacks, subarachnoid hemorrhage, pheochromocytoma and sympathomimetic drug ingestion (cocaine abuse). Increased sympathetic stimulation is associated with alpha receptor mediated vasoconstriction. Cocaine use is associated with impaired endothelial function, and platelet activation [34]. Furthermore, the use of sympathomimetic agents is associated with left ventricular hypertrophy as well as aortic dissection [35].

4.4. Other causes False positive troponin I levels may be seen in patients with heterophile antibodies including rheumatoid arthritis [18]. Infiltrative conditions like amyloidosis are associated with myocyte compression injury that precipitates the cTnI release [19,41]. Elevated cTnI is frequently seen in end stage renal failure patients, even in the absence of uremic perimyocarditis (pericardial effusion) or pulmonary congestion [42]. Elevated cTnI levels are not uncommon in states of anerobic debt like diabetic ketoacidosis [43]. Cardiac troponins have been shown to have prognostic value in certain non-ischemic causes of elevated troponin. These include pulmonary embolism [33], chronic obstructive pulmonary disease exacerbation [34], renal failure [42], congestive heart failure [32], perioperative [44], septic shock [39], critically ill patients [40], and primary systemic amyloidosis [45].

5. Conclusions Although the laboratory can provide a cardiac specific test, it cannot provide a diagnosis specific test. Among 17,950 patients who underwent angiogram, 14% of those with normal coronary arteries had increased levels of troponin. In this subgroup, the clinical profile and comorbidities suggest an extensive range of possible subjacent mechanism of myocardial injury. Notion that all cases of elevated cardiac troponin I reflect an underlying acute coronary syndrome can lead to inappropriate investigations, including coronary angiography and treatment. However, it must be stressed that although cardiac troponin I elevations

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are specific for cardiac damage, cardiac damage does not automatically equate to myocardial infarction, laboratory measurement is required for diagnosis of myocardial infarction but is not the only arbiter. The use of cardiac troponin assays as part of a Fbiochemical screen_ in patients presenting with conditions other than acute coronary syndrome should be discouraged.

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