Cardiac troponins: from myocardial infarction to chronic disease

Abstract

Elucidation of the physiologically distinct subunits of troponin in 1973 greatly facilitated our understanding of cardiac contraction. Although troponins are expressed in both skeletal and cardiac muscle, there are isoforms of troponin I/T expressed selectively in the heart. By exploiting cardiac-restricted epitopes within these proteins, one of the most successful diagnostic tests to date has been developed: cardiac troponin (cTn) assays. For the past decade, cTn has been regarded as the gold-standard marker for acute myocardial necrosis: the pathological hallmark of acute myocardial infarction (AMI). Whilst cTn is the cornerstone for ruling-out AMI in patients presenting with a suspected acute coronary syndrome (ACS), elevated cTn is frequently observed in those without clinical signs indicative of AMI, often reflecting myocardial injury of 'unknown origin'. cTn is commonly elevated in acute non-ACS conditions, as well as in chronic diseases. It is unclear why these elevations occur; yet they cannot be ignored as cTn levels in chronically unwell patients are directly correlated to prognosis. Paradoxically, improvements in assay sensitivity have meant more differential diagnoses have to be considered due to decreased specificity, since cTn is now more easily detected in these non-ACS conditions. It is important to be aware cTn is highly specific for myocardial injury, which could be attributable to a myriad of underlying causes, emphasizing the notion that cTn is an organ-specific, not disease-specific biomarker. Furthermore, the ability to detect increased cTn using high-sensitivity assays following extreme exercise is disconcerting. It has been suggested troponin release can occur without cardiomyocyte necrosis, contradicting conventional dogma, emphasizing a need to understand the mechanisms of such release. This review discusses basic troponin biology, the physiology behind its detection in serum, its use in the diagnosis of AMI, and some key concepts and experimental evidence as to why cTn can be elevated in chronic diseases.

Keywords: Biomarker; Cardiac troponin; Chronic disease; Prognosis; Release mechanism.

Figure 1

Illustration of the detection ranges of different cardiac troponin (cTn) assays. cTn can be detected in healthy individuals using high-sensitivity assays, possibly due to physiological turnover of cardiac myocytes (green line). Subsequent to an acute myocardial infarction (AMI), there is a slight rise in cTn which may reflect either ischaemia-induced release of the ‘early-release pool’ or micronecrosis (orange line). After ∼2–6 h there is a precipitous rise in cTn reflecting extensive myocardial necrosis and degradation of myofibrillar cTn (red line). With the evolution of assay technology, the 99th percentile value of cTn which serves as a cut-off value for the diagnosis of AMI has been accordingly reduced. Edited from Hochholzer et al. with permission.

Figure 2

 Structure of the cardiac troponin-tropomyosin complex and the forms of troponin released following myocardial necrosis. Whilst most cardiac troponin (cTn) is bound to the myofibril, there is different subcellular localization of some cTn. ∼2–4% and ∼6–8% of cTnI and cTnT respectively exist either unbound in the cytosol, or loosely bound to the sarcomere. Following myocardial ischaemia, the ensuing necrosis of cardiac myocytes results in different forms of cTn being detectable in serum. After ischaemic insult, the free forms of cTnI and cTnT from the cytosol are soon detected in serum prior to detection of the complexed forms. There are several complexed forms that exist: non-covalent ternary complexed cTnT-I-C (T:I:C complex) and binary complexed cTnI-T (I:T complex). Edited from Gaze and Collinson with permission.

Figure 3

 The 99th percentile diagnostic cut-off for cardiac troponin (cTn) assays. A hypothetical case of an acute coronary syndrome is shown to illustrate the evolution of cTn assay precision and sensitivity. The diagnostic cut-off for cTnI assays in 1995 was ≥ 1.5 ng/mL, in 2003 > 0.10 ng/mL and in 2007 > 0.04 ng/mL. The increasing sensitivity of the assays meant that very small concentrations of cTn could be detected, thus the 99th percentile decision limit had to be lowered. The 99th percentile quantitatively represents a value at which 1 person in 100 will have a false positive result. Any concentration of cTn detected within the 99th percentile decision limit suggests a ‘normal’ result. Any concentration value which falls outside this decision limit indicates a ‘positive’ cTn and substantiates a possible AMI. Edited from Mahajan and Jarolim with permission.

Figure 4

 Presumed mechanisms for elevated cardiac troponin (cTn) in chronic diseases. Elevated cTn has been documented in the conditions listed. AF, atrial fibrillation; CAD, coronary artery disease; CHF, chronic heart failure; CKD, chronic kidney disease; ESRD, end-stage renal disease; LV, left ventricle; MVO₂, myocardial oxygen consumption; PAH, pulmonary arterial hypertension; RAAS, renin-angiotensin-aldosterone system; RV, right ventricle. Adapted from Jeremias and Gibson.