1. What are the Causes of Troponin Elevation in non ACS? Carma Karam, MD Cardiologist AIHP, ACCA, FACC Clinique Médicale du Ring June 2011

2. Rationale Measurement of cardiac troponin (cTn) has revolutionized the evaluation and management of pts with suspected acute coronary syndrome (ACS). Recent consensus statements endorse the use of cTnI or cTnT as the biomarker of choice for such application.

3. The most widely-used conventional cTn methods cannot deliver the best combination of sensitivity & precision. Novel very high sensitivity cTn (hsTn) assays have been developed with greatly improved detection limit (10- to 100-times lower than that of currently available commercial assays) with improved precision. Soon to be more widely used. The most widely-used conventional cTn methods cannot deliver the best combination of sensitivity & precision. Novel very high sensitivity cTn (hsTn) assays have been developed with greatly improved detection limit (10- to 100-times lower than that of currently available commercial assays) with improved precision. Soon to be more widely used. Accuracy

4. In a recent study examining 69,299 pts admitted through the emergency department, 48% had their cTn measured. Of these, 2,344 pts (3.3% overall, or 7.0% of those that had a cTn measured) had an elevated cTn concentration. Of those with a positive cTn, 42.7% of the patients did not have ACS. In a recent study examining 69,299 pts admitted through the emergency department, 48% had their cTn measured. Of these, 2,344 pts (3.3% overall, or 7.0% of those that had a cTn measured) had an elevated cTn concentration. Of those with a positive cTn, 42.7% of the patients did not have ACS. Non-ACS elevation of troponin

5. Prognostic meaning of elevated troponin

6. cTn complex is found in the sarcomere (~95% of cTn in the heart) as well as in the cytosol of cardiomyocytes. In the setting of irreversible myocardial cell injury, contents of cTn complex are released into circulation. cTnI or T is measurable as early as 3-4 hrs following myocardial injury. When using hsTn assays, a rising (or falling) pattern may be seen as early as one hour after. cTn release is independent of mechanism : ischemic, infectious, toxic, or otherwise. cTn complex is found in the sarcomere (~95% of cTn in the heart) as well as in the cytosol of cardiomyocytes. In the setting of irreversible myocardial cell injury, contents of cTn complex are released into circulation. cTnI or T is measurable as early as 3-4 hrs following myocardial injury. When using hsTn assays, a rising (or falling) pattern may be seen as early as one hour after. cTn release is independent of mechanism : ischemic, infectious, toxic, or otherwise. BiologicalConsiderations

7. Acutely decompensated and chronic HF are associated with elevated cTn values. Elevation often occurs in the absence of coronary ischemia, and frequently even in the absence of CAD. Various mechanisms as subendocardial ischemia from wall tension, apoptosis, spontaneous necrosis, inflammation. Linked to ventricular remodeling, elevated cTn in HF should not be discarded as ‘false positive’ as the prognosis associated with elevated cTn in this setting is poor. Acutely decompensated and chronic HF are associated with elevated cTn values. Elevation often occurs in the absence of coronary ischemia, and frequently even in the absence of CAD. Various mechanisms as subendocardial ischemia from wall tension, apoptosis, spontaneous necrosis, inflammation. Linked to ventricular remodeling, elevated cTn in HF should not be discarded as ‘false positive’ as the prognosis associated with elevated cTn in this setting is poor. Troponin in Heart Failure

8. An important diagnosis to consider in a pt with chest pain and elevated cTn is acute aortic dissection. cTn is elevated in up to 18% of pts with AAD, indicative of the high acuity of illness than specific to aortic dissection itself, although coronary artery occlusion is well-described. Misdiagnosis of AAD may result in incorrect administration of anticoagulation therapy, or lead to a risky delay in the correct diagnosis. Troponin in AAD

9. Another cause is pulmonary embolism. Frequency of elevated cTn is 10-50% in such pts, and may be related to a combination of acute right ventricular strain and injury, hypoxia and tachycardia. Elevated cTn is strongly associated with mortality in acute PE; in a meta-analysis of 20 acute PE studies, pts with an elevated cTn had more than 5- fold increase in mortality (19.7% vs. 3.7%). Elevated Troponin in PE

10. SystemCauses of Troponin Elevation Cardiovascular Acute aortic dissection Arrhythmia Medical ICU patients Hypotension Heart failure Apical ballooning syndrome Cardiac inflammation Endocarditis, myocarditis, pericarditis Hypertension Infiltrative disease Amyloidosis, sarcoidosis, hemochromatosis, sclerodermia Left ventricular hypertrophy Myocardial Injury Blunt chest trauma Cardiac surgeries Cardiac procedures Ablation, cardioversion, percutaneous intervention Chemotherapy Hypersensitivity drug reactions

11. Respiratory Acute PE ARDS Infectious/Immune Sepsis Viral illness Thrombotic thrombocytopenic purpura GastrointestinalSevere GI bleeding Nervous system Acute stroke Ischemic stroke Hemorrhagic stroke Head trauma RenalChronic kidney disease Endocrine Diabetes Hypothyroidism MusculoskeletalRhabdomyolysis IntegumentaryExtensive skin burns

12. Inherited Neurofibromatosis Duchenne muscular dystrophy Klippel-feil syndrome Others Endurance exercise Environmental exposure Carbon monoxide, hydrogen sulfide Causes of Troponin Elevation

13. In the context of life-threatening illness, the prevalence of elevated cTn is considerable. In 1130 patients presenting to an emergency department without chest pain, the frequency of elevated cTn was 3.6% and was associated with an increased mortality. This prevalence increases further in population presenting with chest pain to 4.5%, while in critically ill pts without ACS, the frequency ranges from 27% to 55%. Acute Illness

14. Elevated cTn may in fact have an ischemic origin: a recent study demonstrated that an elevated hsTnT in patients without ACS was strongly associated with the presence and severity of CAD and heart muscle disease, implying that non-ACS cTn elevation may result from coronary ischemia in the absence of plaque rupture or coronary thrombosis; this situation of supply-demand mismatch is known as a Type II MI. Acute Illness (2)

15. Elevated cTn in asymptomatic CKD is common, the frequency which is dependent on the assay (cTnT > cTnI) and cut-off value used. Specificity of cTn for ACS is lower compared with pts without renal disease. This is problematic, as the incidence and prevalence of coronary artery disease and ACS is high in this population. Troponin & kidney disease

16. A true positive cTn related to ACS in pts with CKD is associated with a heightened risk for mortality compared to non CKD pts, while an asymptomatic elevation in cTn in severe CKD is associated with an increased incidence of ACS and a 2- to 5-fold increase in mortality. Serial measurements, for a rise and/or fall of an elevated cTn value in a pt with CKD is recommended to differentiate ACS from non-ACS causes of cTn elevations. Troponin in CKD

17. Cardiac Tn elevations have been reported in pts with snake or scorpion bites, and thought to be in part due to myocardial injury by biologic toxins, vasospasm and coagulation abnormalities. Elevated cTn levels have been reported to be frequently elevated in asymptomatic athletes who complete endurance exercise. The exact mechanism by which cTn release occurs in this setting remains unknown but may be due to right ventricular injury. Other Causes

18. Troponin increases were relatively common among marathon finishers and can reach levels typically diagnostic for acute MI. Less marathon experience and younger age appeared to be associated with troponin increases, whereas race duration and the presence of traditional cardiovascular risk factors were not. Ann Emerg Med. 2007 Feb;49(2):137-43 Cardiac troponin increases among runners in the Boston Marathon

19. Elevated cTn values outside of ACS are not uncommon and reflect cardiomyocyte necrosis from a wide array of cardiac, pulmonary and systemic diseases. -hsTn assays are expected to detect more pts. Importantly, an elevated cTn in the absence of ACS is most often associated with a worse prognosis and should not be disregarded as a ‘false positive’ result. Conclusion Carma Karam, MD Cardiologist AIHP, ACCA, FACC