The continuing evolution of cardiac troponin I biomarker analysis: from protein to proteoform

The troponin complex consists of three proteins that fundamentally couple excitation with contraction. Circulating cardiac-specific Troponin I (cTnI) serves as diagnostic biomarker tools for risk stratification of acute coronary syndromes and acute myocardial infarction (MI). Within the heart, cTnI oscillates between inactive and active conformations to either block or disinhibit actinomyosin formation. This molecular mechanism is fine-tuned through extensive protein modifications whose profiles are maladaptively altered with co-morbidities including hypertrophic cardiomyopathy, diabetes, and heart failure. Technological advances in analytical platforms over the last decade enable routine baseline cTnI analysis in patients without cardiovascular complications, and hold potential to expand cTnI readouts that include modified cTnI proteoforms. Areas covered: This review covers the current state, advances, and prospects of analytical platforms that now enable routine baseline cTnI analysis in patients. In parallel, improved mass spectrometry instrumentation and workflows already reveal an array of modified cTnI proteoforms with promising diagnostic implications. Expert commentary: New analytical capabilities provide clinicians and researchers with an opportunity to address important questions surrounding circulating cTnI in the improved diagnosis of specific patient cohorts. These techniques also hold considerable promise for new predictive and prescriptive applications for individualized profiling and improve patient care.