Narrative review:alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded

1. Narrative review:alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded Ann intern med. 2005;142:786-791 Allen jeremlas, MD and C. Micheal Glbson, MS, MD

2. The Joint Euripan society of cardiology/american college of cardiology (ESC/ACC) • 2000,Sep:detection of the cardiopecific biomakers troponin T and troponin I in approriate clinical setting . • “any amount of myocardial damage …implies an impaired clinical outcome for the patient” • “no discernible threshold below which an elevated value of cardiac troponin would be deemed harmless”

3. ACC/American Heart association (AHA) • 2002: Myocardial necrosis signified by troponin elevation may not necessarily be due to CAD and that myocardial infarction should therefore be diagnosed in conjuction with other supportive evidence

4. Troponin and MI • Troponin level increased up to 195% as compared with CK/CKMB • Mortality at 30 days significantly higher among patient with elevated troponin • Troponin elevated had likewise been associated with poor prognosis • N Engl J Med. 1996 Oct 31;335(18):1342-9.

5. Troponin in nonthrombotic cardiac and systemic disease • Arise from demand ischemia or microcirculatory dysfunciton, rather “ supply-side” thrombotic ischemia • At ER ,45% patient of tropnoni I elevated had a final diagnosis other than acute coronary syndrome • Troponin is a high sensitivity but low specificity among low risk of CAD

6. Table. Nonthrombotic Causes and Presumed Mechanism for Elevated Cardiac Troponin Level Diagnosis Mechanism Demand ischemia Sepsis/systemic inflammatory Myocardial depression/supply– response syndrome demand mismatch Hypotension Decreased perfusion pressure Hypovolemia Decreased filling pressure/output Supraventricular tachycardia/ Supply–demand mismatch atrial fibrillation Left ventricular hypertrophy Subendocardial ischemia Myocardial ischemia Coronary vasospasm Prolonged ischemia with myonecrosis Intracranial hemorrhage or sroke Imbalance of autonomic nervous system Ingestion of Direct adrenergic effects sympathomimetic agents

7. Diagnosis Mechanism Direct myocardial damage Cardiac contusion Traumatic Direct current cardioversion Traumatic Cardiac infiltrative disorders Myocyte compression Chemotherapy Cardiac toxicity Myocarditis Inflammatory Pericarditis Inflammatory Cardiac transplantation Inflammatory/immune-mediated Myocardial strain Congestive heart failure Myocardial wall stretch Pulmonary embolism Right ventricular stretch Pulmonary hypertension or Right ventricular stretch emphysema Strenuous exercise Ventricular stretch Chronic renal insufficiency Unknown

8. Cardiac troponins • Troponin T:bind to troppomycin and faciliates contrsction • Troponin I :binds to actin and inhibits actin-myosin interaction • Troponin C :bind to calcium ions, both cardiac and smooth muscle share isoforms • Troponin increased after irreversible myocardial necrosis?? Increased membrane permeablity

9. NONTHROMBOTIC MECHANISMS OF TROPONIN ELEVATION-Demand Ischemia • mismatch between myocardial oxygen demand and supply in the absence of flow limiting epicardial stenosis • Sepsis,septic shock and SIRS, hypotension or hypovolemia, and atrial fibrillation or other tachyarrhythmias shortening diastolic time • Caridac depression: increased oxygen consumption, reduced perfusion pressure, and decreased oxygen delivery to the heart • left ventricular hypertrophy occult subendocardial ischemia + decreased flow reserve due to remodeled coronary microcirculation.

10. Guest and colleagues :elevated cardiac troponin level is a common finding among critically ill patients(15%) and is associated with a significant increase in mortality JAMA. 1995 Jun 28;273(24):1945- • Ammann and colleagues :55% of sepsis patients with elevated troponin levels,TNF, IL-6 and CRP • mortality was fourfold higher in the troponin-positive group • JAm Coll Cardiol. 2003;41:2004-9

11. Myocardial Ischemia in the Absence of FixedObstructive Coronary Artery Disease • myocardial ischemia can be caused by vasospasm(Prinzmetal angina) • Subsequent ergonovine provocation testing explained 74% of elevated troponin levels in these patient vasospasm may lead to prolonged ischemia and myonecrosis. • 27% of stroke and 20% SAH with troponin elevation:imbalance ofthe autonomic nervous system, with resulting excess of sympathetic activity and increased catecholamine effect on the myocardial cells

12. Direct Myocardial Damage • traumatic or inflammatory processes. • implantable cardioverter defibrillator shocks and infiltrative disorders such as amyloidosis • cardiotoxic effects of high-dose chemotherapy and predict the development of future left ventricular dysfunction • acute pericarditis, myocarditis, and an immune response after heart transplantation. • In fact, chronically elevated troponin levels after cardiac transplantation may be associated with a poorer prognosis

13. Myocardial Strain • CHF lead to the release of troponin in the absence of myocardial ischemia due to excessive wall tension or “myocardial strain,” with resulting myofibrillary damage • increased myocardial wall stress may lead to decreased subendocardial perfusion • Strain ,RAA system, sympathetic stimulation, and inflammatory mediator may be partially responsible for myocyte injury and cell death. myocyte loss progression of cardiac dysfunction • 238 patients with advanced heart failure who were referred for cardiac transplantation evaluation,49% have elevated troponin levels and had twofold mortality

14. Cardiopulmonary Disease and Right-Heart Strain • The reported incidence of troponin elevation among patients with acute pulmonary embolism varies from 16% to 50%,and elevated levels are associated with a significant increase in mortality • Am J Cardiol. 2004 Jan 15;93(2):263-4 • chronic pulmonary hypertension, troponin was detectable in 14%; higher heart rates, lower mixed venous oxygen saturation, and higher levels of B-type natriuretic peptide, as well as significantly worse cumulative survival at 2 years (81% vs. 29%) • Circulation. 2003;108:844-8

15. Cardiac Troponin in Chronic Renal Insufficiency • a higher troponin(0.75ng/ml) threshold was proposed for the diagnosis of myocardial ischemia in patients with chronic renal insufficiency J Am Coll Cardiol. 1999 Feb;33(2):471-8. • may be the result of small areas of clinically silent myocardial necrosis, but other causes, such as increased left ventricular mass and impaired renal troponin excretion • troponin was found to be an independent predictor of death or myocardial infarction across the entire spectrum of renal function in a recent analysis of 7033 patients with acute coronary syndrome in the GUSTO IV NEJM 2002;346:2047 • increased troponin values among patients with chronic renal failure in the absence of clinically suspected ischemia may be as high as 53%

16. SIGNIFICANCE OF TROPONIN ELEVATION IN THEABSENCE OF ACUTE CORONARY SYNDROMES ANDPOTENTIAL TREATMENT STRATEGIES • Ischemic electrocardiogram changes, chest pain, wall motion abnormalities on echocardiography, and the presence of atherosclerotic risk factors may be associated with a thrombotic origin of the troponin elevation • Patients with a low pretest probability of coronary artery disease will most likely not derive any benefit from a treatment strategy aimed at coronary thrombosis or early re vascularization • Unless aspirin is contraindicated, we frequently recommend the use of this drug, which appears to be relatively safe in most clinical circumstances.

17. CONCLUSIONS • Troponin is a highly sensitive biomarker that aids in the detection of myocardial cell damage • troponin is a sensitive biomarker to “rule out” non–ST-segment elevation myocardial infarction • troponin elevation in nonthrombotic syndrome. Treatment should be aimed at the underlying disorder. • troponin still retains prognostic value, and screening may be justified on this basis

18. Thanks your attention