Cardiac Troponin in Patients With Light Chain and Transthyretin Cardiac Amyloidosis: JACC: CardioOncology State-of-the-Art Review

Abstract

Cardiac amyloidosis (CA) is an infiltrative disease caused by amyloid fibril deposition in the myocardium; the 2 forms that most frequently involve the heart are amyloid light chain (AL) and amyloid transthyretin (ATTR) amyloidosis. Cardiac troponin (cTn) is the biomarker of choice for the detection of myocardial injury and is frequently found to be elevated in patients with CA, particularly with high-sensitivity assays. Multiple mechanisms of myocardial injury in CA have been proposed, including cytotoxic effect of amyloid precursors, interstitial amyloid fibril infiltration, coronary microvascular dysfunction, amyloid- and non-amyloid-related coronary artery disease, diastolic dysfunction, and heart failure. Regardless of the mechanisms, cTn values have relevant prognostic (and potentially diagnostic) implications in both AL and ATTR amyloidosis. In this review, the authors discuss the significant aspects of cTn biology and measurement methods, potential mechanisms of myocardial injury in CA, and the clinical application of cTn in the management of both AL and ATTR amyloidosis.

Keywords: amyloidosis; diagnosis; myocardial injury; prognosis; troponin.

Graphical abstract

Figure 1

Cardiac Troponin Structure, Release in Bloodstream, and Methodologies of Measurement After a myocardial infarction, cardiac troponin I (cTnI) circulates in the blood mainly as a binary complex with cardiac troponin C, but also as free cTnI and a ternary complex, cTnI-C-T. Various molecular modifications and protein fragmentations have been described. cTnT circulates mainly in a free form, but cardiac troponin T (cTnT) fragments as well as the cTnI-C-T complex are also present. The high-sensitivity cTnT (hs-cTnT) assay uses fragment antigen binding portions of 2 cTnT-specific mouse monoclonal antibodies. For the fifth-generation assay, the original antibody has been re-engineered to produce a mouse-human chimeric detection antibody. Several high-sensitivity cTnI (hs-cTnI) assays are approved for clinical use, with a lack of harmonization related to different aspects, starting with the difference in epitope specificity of antibodies produced by different companies. Indeed, immunoassays that use anti-cTnI monoclonal antibodies are dependent on the epitope regions recognized by the antibodies incorporated into each assay. Moreover, cTnI-related characteristics such as biochemical modifications (eg, degradation, phosphorylation, oxide reduction) and different circulating complexes can lead to altered signal generation of sandwich-type cTnI immunoassays that use antibodies directed against these modified regions. Reproduced with permission from Brush et al.

Central Illustration

Myocardial Injury and Applications of Troponin Measurement in Cardiac Amyloidosis Several mechanisms are potentially involved in the development of myocardial injury (defined as an increase in cardiac troponin values greater than the 99th percentile sex-specific and assay-specific reference limits) in patients with cardiac amyloidosis. These mechanisms include amyloid-related causes, such as amyloid precursor toxicity, amyloid interstitial infiltration, and amyloid vascular involvement, but also non-amyloid-related causes such as diastolic and systolic dysfunction, heart failure, atherosclerotic coronary artery disease, and other causes of supply-demand imbalance such as tachyarrhythmias and hypotension. Regardless of the cause, measurement of cardiac troponin is important in the management of patients with cardiac amyloidosis for diagnostic, prognostic, and monitoring purposes. hs-cTn = high-sensitivity cardiac troponin; LV = left ventricular; RV = right ventricular.