Implications of the complex biology and micro-environment of cardiac sarcomeres in the use of high affinity troponin antibodies as serum biomarkers for cardiac disorders

Abstract

Cardiac troponin I (cTnI), the inhibitory-unit, and cardiac troponin T (cTnT), the tropomyosin-binding unit together with the Ca-binding unit (cTnC) of the hetero-trimeric troponin complex signal activation of the sarcomeres of the adult cardiac myocyte. The unique structure and heart myocyte restricted expression of cTnI and cTnT led to their worldwide use as biomarkers for acute myocardial infarction (AMI) beginning more than 30 years ago. Over these years, high sensitivity antibodies (hs-cTnI and hs-cTnT) have been developed. Together with careful determination of history, physical examination, and EKG, determination of serum levels using hs-cTnI and hs-cTnT permits risk stratification of patients presenting in the Emergency Department (ED) with chest pain. With the ability to determine serum levels of these troponins with high sensitivity came the question of whether such measurements may be of diagnostic and prognostic value in conditions beyond AMI. Moreover, the finding of elevated serum troponins in physiological states such as exercise and pathological states where cardiac myocytes may be affected requires understanding of how troponins may be released into the blood and whether such release may be benign. We consider these questions by relating membrane stability to the complex biology of troponin with emphasis on its sensitivity to the chemo-mechanical and micro-environment of the cardiac myocyte. We also consider the role determinations of serum troponins play in the precise phenotyping in personalized and precision medicine approaches to promote cardiac health.

Mechanisms of troponin release into serum in cardiac injury associated with COVID-19 patients

“…In the early phases of the pandemic caused by the SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus 2) the emphasis of diagnosis and treatment was on acute respiratory distress syndrome (ARDS). Moreover, early guidelines from the American Heart Association (AHA) advised against determinations of serum cardiac troponin I (cTnI) and cardiac troponin T (cTnT), which are universally accepted biomarkers of myocardial injury [ 1 ]. Cardiac troponin (cTn) is a regulatory protein complex consisting of three units located at the sarcomere thin filament [ 2 ].…”

“…In systole, there is a rise in intracellular Ca 2+ that binds to cardiac troponin C (cTnC) releasing inhibition and promoting contraction and ejection. cTnI and cTnT are unique in cardiac myocytes, whereas cTnC is also expressed in slow skeletal muscle [ 1 ]. We previously reviewed mechanisms related to the complex biology of cTn leading to release of cTnI and cTnT to serum in a variety of clinical conditions, in the broad population, and in strenuous exercise [ 1 ].…”

“…cTnI and cTnT are unique in cardiac myocytes, whereas cTnC is also expressed in slow skeletal muscle [ 1 ]. We previously reviewed mechanisms related to the complex biology of cTn leading to release of cTnI and cTnT to serum in a variety of clinical conditions, in the broad population, and in strenuous exercise [ 1 ]. In a paper responding to the AHA guidelines regarding use of these biomarkers in COVID-19 patients, Chapman et al [ 3 ] published a statement of strong support for the value of determinations of serum cTnI and cTnT as biomarkers for cardiac injury in SARS-CoV-2 infected patients, who are older with coronary syndromes, demand ischemia, and inflammation.…”

NH2-Terminal Cleavage of Cardiac Troponin I Signals Adaptive Response to Cardiac Stressors

“…Early evidence demonstrated a release of cardiac troponin I (cTnI) into serum in myocardial infarction (MI). This finding led to the development of specific high affinity antibodies for detection of serum cTnI, and led to a vast literature on their use as the preferred marker for MI as well as other cardiac related pathologies (see Solaro and Solaro [1]; Katrukha and Katrukha [2] for recent reviews). Adding to the complexity of its use as a biomarker is evidence that there is a proteolysis of cTnI occurring in the necrosis and necroptosis in these pathologies.…”

“…Adding to the complexity of its use as a biomarker is evidence that there is a proteolysis of cTnI occurring in the necrosis and necroptosis in these pathologies. Understanding the nature of these products of proteolysis in serum and correlating these data with clinical profiles has been proposed to be important in diagnosis, prognosis, and stratification of patients [1,2].…”