Question 10

College Answer

Greater specificity to cardiac damage than CK-MB / AST which can also be found in skeletal muscle

• Useful marker in acute coronary syndromes, where a higher level is indicative of a greater mortality and morbidity

• There has been recent discussion regarding the use of troponin and the diagnosis of myocardial infarction, and the definition has been standardised by the ECS / AHA. Myocardial infarction is defined as demonstration of myocardial ischaemia plus the addition of a significant plasma troponin rise (Circulation 2007)

• Numerous studies that show plasma troponin can be raised in other cardiac conditions, e.g. pericarditis, atrial fibrillation cardioversion, and non cardiac conditions e.g. renal failure, PE, sepsis.

• Plasma troponin levels should be used as a risk stratification tool in conjunction with other tests e.g. ecg and echo, depending on the presenting medical condition

• This has significance in critically ill patients in the non ACS-AMI setting. Medications used for a troponin rise in the setting of ACS / AMI, e.g. anti-coagulants and anti-platelet therapy are not benign, and can have detrimental effects in critically ill patients who have troponin rises due to non ACS / AMI

• Monitoring for ischaemia in the ICU patient

Discussion

Though the college answer is different, this question closely resembles Question 8  from the second paper of 2006. One is tempted to point out that these questions do not ask specifically about troponin use in the acute coronary syndromes.

In general, the college seems to have wanted to observe several key points in the answer:

• Awareness regarding the origins and physiological role of troponin in the myocyte
• Knowledge that it is specific to the myocardium
• Understanding of its high specificity and sensitivity for cardiac damage
• Relationship between high levels and poorer prognosis in acute coronary sydnrome
• Awareness that troponins can rise in other conditions.

Rationale for the use of troponin in the critically ill:

• Troponin is an enzyme involved in the excitation-contraction coupling of the myocardium.
• Troponin T serves to attach the troponin complex to actin and tropomyosin.
• Myocardiac damage (for example infarction) causes the release of troponin.
• There is a cytosolic pool (which is released early in the infarct) and a structural pool (which is slowly released over days as the damaged myocardium decomposes).

Advantages of using troponin in critically ill patients

• Its a sensitive and specific marker of myocardial ischaemia.
• It is more sensitive and specific than AST, CK and CK-MB (which are also found is skeletal muscle)
• It is an independent predictor of 30-day mortality in STEMI 
• It is associated with a poorer outcome in the critically ill patients.
• Troponin levels can be used to monitor for myocardial ischaemia in critically ill patients when history and examination are unreliable.

Advantages of using troponin in acute coronary syndromes

• Troponin forms a part of the ECS and AHA universal definition of acute coronary syndrome (it consists of a troponin rise as well as a demonstration of ischaemic symptoms,  echocardiographic evidence, or ECG changes.)
• The troponin levels are not diagnostic, but are a risk stratification tool to be used together with echocardiography, ECG, history and examination.
• Troponin levels can be used for the late diagnosis of MI and to monitor for reinfarction
•  The use of troponin as a part of a risk stratification strategy is important in selecting patients for anticoagulation and anti-platelet therapy, so as to prevent the exposure of patients to unnecessary bleeding risk.

Disadvantages for the use of troponin in critical illness

• A reliance on biomarkers may become unhealthy if it takes focus off clinical examination and history.
• It is not quantitatively validated outside the setting of ACS / AMI, but only qualitatively: i.e. a "positive" troponin is associated with worse outcomes in noncardiac critical illness, but we don't know whether a higher troponin is associated with a proportionally higher mortality.
• As with all biomarkers, inappropriately low threshold levels or testing out of appropriate clinical context could give rise to unnecessary treatments (eg. loading doses of antiplatelet drugs) or investigations (eg. angiography, with needless contrast exposure)
• Troponin levels can be raised for a variety of non-cardiac reasons.In their 2006 article, Korff et al offer an excellent table of things which cause troponin elevation, together with the mechanism of troponin release or assay confusion. Their Table 1 is reinterpreted here. 
  • Myocarditis 
  • Renal failure - its cleared renally
  • Sepsis
  • Atrial fibrillation
  • Post-cardioversion 
  • Cardiac trauma 
  • Pulmonary embolism 
  • Acute stroke
  • Intracranial haemorrhage
  • Severe burns
  • Rhabdomyolysis (particularly during recovery)
  • Skeletal muscle damage in glycogen storage disease
  • Defective assay (cross-reactivity with skeletal troponin isoforms)

This article has a nice graph of cardiac biomarker concentrations over time after an infarct:
Wu et al; National Academy of Clinical Biochemistry Standards of Laboratory Practice: Recommendations for the Use of Cardiac Markers in Coronary Artery Diseases. Clinical Chemistry 45:7 1104 –1121 (1999)

There is a CICM fellowship question regarding the critical appraisal of troponin in the ICU population.

The ECS and AHA statement referred to in the college answer is this article published in Circulation in 2007:

(Kristian Thygesen et al; Universal Definition of Myocardial Infarction. Circulation 2007, 116:2634-2653

This article from Current Opinion in Critical care (2004) discusses the various causes of raised troponin among ICU patients:

Ammann et al,Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. Journal of the American College of Cardiology Volume 41, Issue 11, 4 June 2003, Pages 2004–2009

The fact that troponin rise among the critically ill population is associated with a poorer prognosis is supported by this study:

Gunnewiek et al. Cardiac troponin elevations among critically ill patients. Current Opinion in Critical Care: October 2004 - Volume 10 - Issue 5 - pp 342-346

Liu, Michael, et al. "Prognostic Value of Initial Elevation in Cardiac Troponin I Level in Critically Ill Patients Without Acute Coronary Syndrome." Critical care nurse 35.2 (2015): e1-e10.

Ahmed, Amna N., et al. "Prognostic significance of elevated troponin in non-cardiac hospitalized patients: A systematic review and meta-analysis." Annals of medicine 46.8 (2014): 653-663.

Ammann, P., et al. "Elevation of troponin I in sepsis and septic shock." Intensive care medicine 27.6 (2001): 965-969.

Landesberg, Giora, et al. "Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation." Critical care medicine 42.4 (2014): 790-800.

Smith, Andria, et al. "Elevated cardiac troponins in sepsis: what do they signify?." West Virginia Medical Journal 105.4 (2009): 29-33.

Tiruvoipati, Ravindranath, Nasreen Sultana, and David Lewis. "Cardiac troponin I does not independently predict mortality in critically ill patients with severe sepsis." Emergency Medicine Australasia 24.2 (2012): 151-158.

Suarez, Keith, et al. "TROPONIN TESTING IN PATIENTS HOSPITALIZED FOR SEPSIS IS ASSOCIATED WITH INCREASED CARDIOVASCULAR TESTING AND LENGTH OF STAY." Journal of the American College of Cardiology 67.13 (2016): 451.

Sheyin, Olusegun, et al. "The prognostic significance of troponin elevation in patients with sepsis: a meta-analysis." Heart & Lung: The Journal of Acute and Critical Care 44.1 (2015): 75-81.

Hunter, J. D., and M. Doddi. "Sepsis and the heart." British journal of anaesthesia 104.1 (2009): 3-11.

Vieillard-Baron, Antoine, et al. "Actual incidence of global left ventricular hypokinesia in adult septic shock." Critical care medicine 36.6 (2008): 1701-1706.

Donzé, Jacques D., et al. "Impact of sepsis on risk of postoperative arterial and venous thromboses: large prospective cohort study." BMJ 349 (2014): g5334.

Korff, Susanne, Hugo A. Katus, and Evangelos Giannitsis. "Differential diagnosis of elevated troponins." Heart 92.7 (2006): 987-993.

Wens, Stephan CA, et al. "Elevated Plasma Cardiac Troponin T Levels due to Skeletal Muscle Damage in Pompe Disease." Circulation: Genomic and Precision Medicine (2016): CIRCGENETICS-115.

Sribhen, Kosit, Rewat Phankingthongkum, and Nilrat Wannasilp. "Skeletal muscle disease as noncardiac cause of cardiac troponin T elevation." Journal of the American College of Cardiology 59.14 (2012): 1334-1335.