What are the What are the Causes of Troponin Causes of Troponin

Elevation in non Elevation in non ACS? ACS?

Carma Karam, MDCarma Karam, MDCardiologistCardiologist

AIHP, ACCA, FACCAIHP, ACCA, FACCClinique Clinique Médicale du RingMédicale du Ring

June 2011

Rationale Rationale

Measurement of cardiac troponin Measurement of cardiac troponin (cTn) has revolutionized the (cTn) has revolutionized the

evaluation and management of pts evaluation and management of pts with suspected acute coronary with suspected acute coronary

syndrome (ACS). Recent consensus syndrome (ACS). Recent consensus statements endorse the use of cTnI or statements endorse the use of cTnI or cTnT as the biomarker of choice for cTnT as the biomarker of choice for

such application.such application.

The most widely-used conventional The most widely-used conventional cTn methods cannot deliver the best cTn methods cannot deliver the best

combination of sensitivity & combination of sensitivity & precision.precision.

Novel very high sensitivity cTn (hsTn) Novel very high sensitivity cTn (hsTn) assays have been developed with assays have been developed with

greatly improved detection limit (greatly improved detection limit (10- 10- to 100-times lower than that of to 100-times lower than that of currently available commercial currently available commercial

assaysassays) with improved precision.) with improved precision. Soon to be more widely used. Soon to be more widely used.

AccuraAccuracy cy

In a recent study examining 69,299 In a recent study examining 69,299 pts admitted through the emergency pts admitted through the emergency

department, 48% had their cTn department, 48% had their cTn measured. Of these, 2,344 pts (3.3% measured. Of these, 2,344 pts (3.3% overall, or 7.0% of those that had a overall, or 7.0% of those that had a cTn measured) had an elevated cTn cTn measured) had an elevated cTn

concentration. Of those with a concentration. Of those with a positive cTn, positive cTn, 42.7% of the patients did 42.7% of the patients did

not have ACSnot have ACS..

Non-ACS elevation Non-ACS elevation of troponinof troponin

Prognostic meaning of elevated troponin

cTn complex is found in the sarcomere cTn complex is found in the sarcomere (~95% of cTn in the heart) as well as in the (~95% of cTn in the heart) as well as in the cytosol of cardiomyocytes. In the setting of cytosol of cardiomyocytes. In the setting of irreversible myocardial cell injury, contents irreversible myocardial cell injury, contents

of cTn complex are released into of cTn complex are released into circulation. circulation.

cTnI or T is measurable as early as 3-4 hrs cTnI or T is measurable as early as 3-4 hrs following myocardial injury. When using following myocardial injury. When using hsTn assays, a rising (or falling) pattern hsTn assays, a rising (or falling) pattern may be seen as early as one hour aftermay be seen as early as one hour after. .

cTn release is cTn release is independent of mechanismindependent of mechanism : : ischemic, infectious, toxic, or otherwise.ischemic, infectious, toxic, or otherwise.

Biological Biological ConsiderationsConsiderations

Acutely decompensated and chronic HF are Acutely decompensated and chronic HF are associated with elevated cTn values. associated with elevated cTn values.

Elevation Elevation often occurs in the absence of often occurs in the absence of coronary ischemiacoronary ischemia, and , and frequently even in frequently even in

the absence of CADthe absence of CAD. Various mechanisms as . Various mechanisms as subendocardial ischemia from wall tension, subendocardial ischemia from wall tension,

apoptosis, spontaneous necrosis, apoptosis, spontaneous necrosis, inflammation. Linked to ventricular inflammation. Linked to ventricular

remodeling, elevated cTn in HF should not remodeling, elevated cTn in HF should not be discarded as ‘false positive’ as the be discarded as ‘false positive’ as the

prognosis associated with elevated cTn in prognosis associated with elevated cTn in

this setting is poor.this setting is poor.

Troponin in Troponin in Heart FailureHeart Failure

An important diagnosis to consider in An important diagnosis to consider in a pt with chest pain and elevated cTn a pt with chest pain and elevated cTn

is acute aortic dissection . cTn is is acute aortic dissection . cTn is elevated in elevated in up to 18% up to 18% of pts with AAD, of pts with AAD, indicative of the high acuity of illness indicative of the high acuity of illness

than specific to aortic dissection than specific to aortic dissection itself, although coronary artery itself, although coronary artery

occlusion is well-described. occlusion is well-described. Misdiagnosis of AAD may result in Misdiagnosis of AAD may result in

incorrect administration of incorrect administration of anticoagulation therapy, or lead to a anticoagulation therapy, or lead to a

risky delay in the correct diagnosisrisky delay in the correct diagnosis..

Troponin in AADTroponin in AAD

Another cause is pulmonary Another cause is pulmonary embolism. Frequency of elevated cTn embolism. Frequency of elevated cTn

is 10-50% in such pts, and may be is 10-50% in such pts, and may be related to a combination of acute related to a combination of acute right ventricular strain and injury, right ventricular strain and injury,

hypoxia and tachycardia. Elevated cTn hypoxia and tachycardia. Elevated cTn is strongly associated with mortality is strongly associated with mortality in acute PE; in a meta-analysis of 20 in acute PE; in a meta-analysis of 20

acute PE studies, acute PE studies, pts with an elevated pts with an elevated cTn had more than 5-fold increase in cTn had more than 5-fold increase in

mortality (19.7% vs. 3.7%).mortality (19.7% vs. 3.7%).

Elevated Troponin Elevated Troponin in PEin PE

System Causes of Troponin Elevation

Cardiovascular Acute aortic dissection Arrhythmia Medical ICU patients Hypotension Heart failure Apical ballooning syndrome Cardiac inflammation   • Endocarditis, myocarditis, pericarditisHypertension Infiltrative disease   • Amyloidosis, sarcoidosis, hemochromatosis, sclerodermiaLeft ventricular hypertrophy

Myocardial Injury

Blunt chest trauma Cardiac surgeries Cardiac procedures  • Ablation, cardioversion, percutaneous interventionChemotherapy Hypersensitivity drug reactions

RespiratoryAcute PE ARDS

Infectious/Immune SepsisViral illness Thrombotic thrombocytopenic purpura

Gastrointestinal Severe GI bleeding

Nervous system

Acute stroke  • Ischemic stroke  • Hemorrhagic stroke Head trauma

Renal Chronic kidney disease

EndocrineDiabetes Hypothyroidism

Musculoskeletal Rhabdomyolysis

Integumentary Extensive skin burns

InheritedNeurofibromatosis Duchenne muscular dystrophy Klippel-feil syndrome

OthersEndurance exercise Environmental exposure  • Carbon monoxide, hydrogen sulfide

Causes of Troponin Elevation

In the context of life-threatening In the context of life-threatening illness, the prevalence of elevated cTn illness, the prevalence of elevated cTn

is considerable . In 1130 patients is considerable . In 1130 patients presenting to an emergency presenting to an emergency

department without chest pain, the department without chest pain, the frequency of elevated cTn was 3.6% frequency of elevated cTn was 3.6%

and was associated with an increased and was associated with an increased mortality. This prevalence increases mortality. This prevalence increases

further in population presenting with further in population presenting with chest pain to 4.5%, chest pain to 4.5%, whilewhile in critically in critically

ill pts without ACS, the frequency ill pts without ACS, the frequency ranges from 27% to 55%ranges from 27% to 55%..

Acute Illness

Elevated cTn may in fact have an Elevated cTn may in fact have an ischemic origin: a recent study ischemic origin: a recent study

demonstrated that an elevated hsTnT demonstrated that an elevated hsTnT in patients without ACS was strongly in patients without ACS was strongly

associated with the presence and associated with the presence and severity of CAD and heart muscle severity of CAD and heart muscle

disease, disease, implying that non-ACS cTn implying that non-ACS cTn elevation may result from coronary elevation may result from coronary ischemia in the absence of plaque ischemia in the absence of plaque

rupture or coronary thrombosisrupture or coronary thrombosis; this ; this situation of supply-demand mismatch situation of supply-demand mismatch

is known as a is known as a Type II MIType II MI..

Acute Illness (2)

Elevated cTn in asymptomatic CKD is Elevated cTn in asymptomatic CKD is common, the frequency which is common, the frequency which is

dependent on the assay (cTnT > cTnI) dependent on the assay (cTnT > cTnI) and cut-off value used. and cut-off value used. Specificity of Specificity of cTn for ACS is lower compared with cTn for ACS is lower compared with

pts without renal diseasepts without renal disease. This is . This is problematic, as the incidence and problematic, as the incidence and

prevalence of coronary artery disease prevalence of coronary artery disease

and ACS is high in this population.and ACS is high in this population.

Troponin & kidney disease

A true positive cTn related to ACS in A true positive cTn related to ACS in pts with CKD is associated with a pts with CKD is associated with a

heightened risk for mortality heightened risk for mortality compared to non CKD pts, while an compared to non CKD pts, while an asymptomatic elevation in cTn in asymptomatic elevation in cTn in severe CKD is associated with an severe CKD is associated with an

increased incidence of ACS and a 2- to increased incidence of ACS and a 2- to 5-fold increase in mortality. 5-fold increase in mortality. Serial Serial

measurementsmeasurements, for a rise and/or fall of , for a rise and/or fall of an elevated cTn value in a pt with an elevated cTn value in a pt with

CKD is recommended CKD is recommended to differentiate to differentiate ACS from non-ACS causesACS from non-ACS causes of cTn of cTn

elevationselevations..

Troponin in CKD

Cardiac Tn elevations have been Cardiac Tn elevations have been reported in pts with reported in pts with snake or scorpion snake or scorpion bitesbites, and thought to be in part due to , and thought to be in part due to myocardial injury by myocardial injury by biologic toxins, biologic toxins,

vasospasm and coagulation vasospasm and coagulation abnormalitiesabnormalities. Elevated cTn levels . Elevated cTn levels

have been reported to be frequently have been reported to be frequently elevated in asymptomatic athletes elevated in asymptomatic athletes who complete endurance exercise. who complete endurance exercise. The exact mechanism by which cTn The exact mechanism by which cTn

release occurs in this setting remains release occurs in this setting remains unknown but may be due to right unknown but may be due to right

ventricular injury.ventricular injury.

Other Causes

Troponin increases were Troponin increases were relatively common among relatively common among marathon finishers and can marathon finishers and can reach levels typically reach levels typically diagnostic for acute MI. diagnostic for acute MI. Less marathon experience Less marathon experience and younger ageand younger age appeared appeared to be associated with to be associated with troponin increases, whereas troponin increases, whereas race duration and the race duration and the presence of traditional presence of traditional cardiovascular risk factors cardiovascular risk factors were not. were not.

Ann Emerg Med. 2007 Feb;49(2):137-43

Cardiac troponin increases among runners in the Boston Marathon

Elevated cTn values outside of ACS Elevated cTn values outside of ACS are not uncommon and reflect are not uncommon and reflect

cardiomyocyte necrosis from a wide cardiomyocyte necrosis from a wide array of cardiac, pulmonary and array of cardiac, pulmonary and

systemic diseases. systemic diseases. -hsTn assays are expected to detect -hsTn assays are expected to detect

more pts.more pts. Importantly, an Importantly, an elevated cTn in the elevated cTn in the

absence of ACS is most often absence of ACS is most often associated with a worse prognosis and associated with a worse prognosis and should not be disregarded as a ‘false should not be disregarded as a ‘false

positive’ resultpositive’ result..

Conclusion

Carma Karam, MDCardiologistAIHP, ACCA, FACC