The Liver and Kidneys mediate clearance of cardiac troponin in the rat

Abstract

Cardiac-specific troponins (cTn), troponin T (cTnT) and troponin I (cTnI) are diagnostic biomarkers when myocardial infarction is suspected. Despite its clinical importance it is still not known how cTn is cleared once it is released from damaged cardiac cells. The aim of this study was to examine the clearance of cTn in the rat. A cTn preparation from pig heart was labeled with fluorescent dye or fluorine 18 (18 F). The accumulation of the fluorescence signal using organ extracts, or the 18 F signal using positron emission tomography (PET) was examined after a tail vein injection. The endocytosis of fluorescently labeled cTn was studied using a mouse hepatoma cell line. Close to 99% of the cTnT and cTnI measured with clinical immunoassays were cleared from the circulation two hours after a tail vein injection. The fluorescence signal from the fluorescently labeled cTn preparation and the radioactivity from the 18F-labeled cTn preparation mainly accumulated in the liver and kidneys. The fluorescently labeled cTn preparation was efficiently endocytosed by mouse hepatoma cells. In conclusion, we find that the liver and the kidneys are responsible for the clearance of cTn from plasma in the rat. Cardiac troponin (cTn) is a ternary complex consisting of three distinct subunits: cardiac troponin T (cTnT), cardiac troponin I (cTnI) and cardiac troponin C (cTnC). cTn binds thin filaments within the cardiomyocyte sarcomere and, with tropomyosin, makes muscular contraction dependent on calcium ions 1. Both cTnT and cTnI are released into the circulation following cardiac damage 2 and are the preferred cardiac biomarkers when myocardial infarction (MI) is suspected 3. The use of cTn assays with low diagnostic cutoffs improve diagnostic accuracy for MI on the emergency departments 4,5 and reduce hospital spending 6. However, low diagnostic cutoffs have been accompanied by an accumulation of patients presenting with stable cTn levels above the accepted cutoff point without MI 7,8. A third of older emergency department patients without MI on emergency departments have stable cTn elevations 7 , often for unknown reasons 9 , and are generally admitted to have their workup done 6,10. Even if MI can be excluded during the hospital stay, patients with stable cTn elevations still constitute a significant health care problem, as a stable cTn elevation is a strong risk factor for the development of heart disease and death 11-14. The reason behind stable cTn elevations, where sample-to-sample variation is often 10% 7 but can be as large as 40-50% 15 , is still unclear but is typically found at old age, in patients with decreased renal function or with comorbidities 10. It is possible that, in addition to necrosis, cTnT and cTnI are also released from living cardiomyocytes under ischemic stress 16 and possibly from normal cardiomyocytes as well 17. To understand the possible mechanisms that link stable cTn elevations to mortality, we need to know how cTn is released and cleared from the circulation 10,18,19. Surprisingly little is know...

The Main Causes and Mechanisms of Increase in Cardiac Troponin Concentrations Other Than Acute Myocardial Infarction (Part 1): Physical Exertion, Inflammatory Heart Disease, Pulmonary Embolism, Renal Failure, Sepsis

“…1) In cells of the reticuloendothelial system (intracellular cleavage by specific proteases); 93 , 94 …”

Diagnosis, Investigation and Management of Patients with Acute and Chronic Myocardial Injury

“…They observed an increase in prevalence of participants with troponin concentrations over the 99th percentile from 1 to 9% after walking. During an average of 43 [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ] months of follow up, patients with acute myocardial injury had a significantly increased risk of all-cause mortality or...…”

“…This can likely be explained by scavenger receptors having reduced affinity for troponin at such low concentrations and smaller degradation products of troponin readily passing through the glomerular membrane. A further study using radiolabelled cardiac troponin in rats revealed uptake in both the kidneys and liver, with liver uptake inhibited through inhibition of endocytosis, suggesting both renal and extra-renal systems of clearance [ 74 ]. These studies may explain the correlation between those with reduced renal function and slightly elevated concentrations of circulating cardiac troponin.…”

Myocardial, renal and intestinal injury in liver resection surgery—A prospective observational pilot study

“…Similarly, Brown et al showed that the use of hs‐TnT compared to conventional TnT increased the detection rate of MINS by a factor of 2 24 . One could argue that the increase in hs‐TnT post‐operatively could to some extent be caused by an impairment of renal function, as there was a positive correlation between serum creatinine and hs‐TnT and as circulating hs‐TnT is cleared from plasma by renal filtration and hepatic clearance 25 . The role of perioperative kidney dysfunction to explain the perioperative release of hs‐TnT in major surgery has, to our knowledge, not been addressed previously, which should be done in larger cohorts of patients undergoing high‐risk surgery.…”