Physiology of the Troponin Complex and Characterisation of Clinical Assays

↳ This is a section part of Moment: Role of Cardiac Troponin Levels in Acute Heart Failure

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Summary

Physiology of the Troponin Complex and Characterisation of Clinical Assays

The troponin complex plays a critical role in regulating myocyte contraction.6 This complex consists of three subunits that regulate actin–myosin interaction: C, T and I. Troponin T binds the complex to tropomyosin, which is wrapped around actin. Troponin I inhibits the actin–myosin interaction. Troponin C binds calcium thereby regulating actin–myosin inhibition. In the presence of an action potential, intracellular calcium concentration increases and calcium binds troponin C leading to a conformational change in troponin I and tropomyosin, thus removing the inhibition of the actin–myosin interaction. This process occurs in skeletal and cardiac muscle, but not in smooth muscle.Image title

Troponin C is expressed as one isoform that is the same in skeletal and cardiac muscle. The isoforms for troponin T and I are different between skeletal and cardiac muscle; this difference is exploited in clinical assays. One notable aspect of cTn physiology is that not all cardiac troponin T or I (cTnT or cTnI) is bound to the contractile apparatus. Less than 10 % is free in the cytosol, with cTnI consisting of a larger proportion than cTnT.7 This cytosolic pool may play an important role in cTn release in heart failure.

As the isoforms of troponin T and I are specific to cardiac muscle, this has allowed the development of clinical assays for the quantitative assessment of cTnT and cTnI. While several companies make cTnI assays, the cTnT assay is strictly owned by Roche Diagnostics (Indianapolis, IN, USA). Most studies evaluating troponin in heart failure involved the use of early conventional assays. These assays are able to detect troponin at microgram levels. However, assays for both these subunits have gone through multiple generations, with each generation increasing the sensitivity to detect cTn at lower levels. This has led to the latest generation of hsTn assays, with the ability to detect troponin at nanogram and picogram levels. These assays by definition should be able to detect cTn in >50 % of healthy subjects and ideally >95 %.8 Both conventional and hsTn assays have demonstrated important prognostic value in AHF.

Pathophysiology of Troponin in Heart Failure

The exact mechanism for increased cTn levels in acute and chronic heart failure is unknown, but many mechanisms are believed to play a role (Figure 1).9 ACS is always a consideration and a Type I MI should be evaluated for in a patient presenting with AHF.3,9 Another possibility is a Type II MI from supply–demand mismatch. This can occur in patients both with and without ischaemic cardiomyopathy. While the primary mechanism is believed to be subendocardial ischaemia, other potential drivers could contribute, including elevated filling pressures, increased wall stress, endothelial dysfunction, tachycardia, arrhythmias, anaemia, and hypotension.5,9 Increased cardiomyocyte stretch and plasma membrane permeability can lead to release of cTn from the cytosolic pool.10,11 In addition, increased wall stress can lead to cardiomyocyte apoptosis, autophagy, and breakdown of the contractile apparatus releasing cTn.12,13 Inflammatory cytokines and neurohormones may be directly toxic to cardiomyocytes as proposed in stress-induced cardiomyopathy.14 Toxic substances such as alcohol, cocaine, methamphetamine or chemotherapy may lead to cTn release by various mechanisms. The exact mechanisms leading to cTn elevation in AHF are unknown, but multiple process including both ischaemic and non-ischaemic mechanisms may contribute.

Troponin and Acute Heart Failure

While troponin level elevation is clearly not diagnostic of acute heart failure, there is overwhelming evidence demonstrating increased morbidity and mortality rates in patients presenting with AHF and an elevated cTn level. Studies have varied in the type of troponin assay used (I or T) as well as the cut-off values used to define a positive test. In addition, as discussed above, as cTn assays have been further refined, they are able to detect cTn at smaller quantities in the blood. Through all of these iterations of troponin assays, cTn has retained its prognostic ability.

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