Cardiac troponin T in clinical and experimental studies

The cardiac troponin T (cTnT) assay became commercially available in the 1990’s, and together with cardiac troponin I (cTnI), cTnT is today the marker of choice for the detection of myocardial infarction. However, when the cTnT assay was introduced it was insufficiently evaluated in two important fields: in patients with renal disease and in experimental cardiovascular research. Therefore, the aims of this thesis were to evaluate cTnT in end-stage renal disease (ESRD) patients and in rat and mouse isolated heart preparations. cTnT in clinical studies Serum cTnT was elevated ( 0.10 μg/L) in a high proportion of both haemodialysis (HD) and peritoneal dialysis (PD) patients without symptoms of acute myocardial ischaemia. In HD + PD patients, chronic ischaemic heart disease was associated with higher levels of cTnT. In HD patients, concentrations of serum cTnT, creatine kinase MB (CKMB) and post-dialysis plasma big endothelin-1 were higher in patients with left ventricular hypertrophy (LVH). Furthermore there was a positive correlation between cTnT levels and left ventricular mass index. Also ESRD patients shortly before the onset of dialysis therapy had a high proportion (30%) of elevated serum cTnT, which correlated positively with CKMB, interleukin-6, C-reactive protein and was associated with the presence of cardiovascular disease. Elevated cTnT was a strong predictor of all-cause mortality in clinical outcomes studies. In summary, these findings suggest that circulating cTnT may reflect LVH and/or subclinical myocardial cell damage in dialysis patients and suggest that cTnT in serum from dialysis patients originates from the heart. The present data support the hypothesis that cTnT is associated with inflammation and poor outcome in ESRD. Further, elevated cTnT levels seem to be associated to the uraemic syndrome rather than the dialysis treatment per se. cTnT in experimental studies The kinetics of cTnT release after 30 min of ischaemia, and importance of preanalytical sample handling in buffer perfused isolated rat hearts were studied. After start of reperfusion there was a short-lasting peak of cTnT release followed by a plateau phase. There was no consistent correlation between cTnT release and post-ischaemic dysfunction. cTnT concentrations in coronary effluent declined rapidly in room temperature. The cTnT loss was attenuated by adding bovine albumin to the samples. Studies on mice revealed no difference in cTnT content (μg cTnT/g heart) in hearts from wild type C57BL/6J and ApoE/LDLr knock out (KO) mice. Baseline serum cTnT was considerably higher in samples from the thoracic cavity than in those from the jugular vein. The cTnT content in skeletal muscle was <0.1% of the cTnT content in heart muscle for both C57BL/6J and ApoE/LDLr KO mice. In summary, effluent cTnT after 20 min of reperfusion is complementary to haemodynamics in the evaluation of cardiac damage in the rat Langendorff preparation. Albumin should be added to coronary effluent to prevent cTnT loss and to increase precision of the assay. Hearts of C57BL/6J and ApoE/LDLr KO mice have similar cTnT content. Elevated baseline levels of serum cTnT in mice are not caused by troponin T from skeletal muscle. LIST OF PUBLICATIONS I. Lowbeer C, Ottosson-Seeberger A, Norrman R, Gutierrez A, Hulting J, Gustafsson SA. Increased cardiac troponin T and endothelin-1 in dialysis patients may indicate heart disease. Nephrol Dial Transplant 1999;14:1948-55. II. Lowbeer C, Gutierrez A, Gustafsson SA, Norrman R, Hulting J, Seeberger A. Elevated cardiac troponin T in peritoneal dialysis patients is associated with CRP and predicts all-cause mortality and cardiac death. Nephrol Dial Transplant 2002;17:2178-83. III. Lowbeer C, Stenvinkel P, Pecoits-Filho R, Heimburger O, Lindholm B, Gustafsson SA, Seeberger A. Elevated cardiac troponin T in predialysis patients is associated with inflammation and predicts mortality. J Intern Med 2003;253:153-60. IV. Kawakami T, Lowbeer C, Valen G, Vaage J. Post-ischaemic dysfunction does not correlate with release of cardiac troponin T in isolated rat hearts. Acta Physiol Scand 1999;167:23-7. V. Lowbeer C, Kawakami T, Tahepold P, Gustafsson SA, Vaage J, Valen G. Importance of preanalytical handling of samples for measurement of cardiac troponin T in coronary effluent from isolated rat hearts. Scand J Clin Lab Invest 2002;62:255-62. VI. Lowbeer C, Forsberg AM, Tokuno S, Hemdahl AL, Gustafsson SA, Valen G. Cardiac troponin T content in heart and skeletal muscle and in blood samples from ApoE/LDL receptor double knockout mice. Clin Chim Acta 2004;344:73-8.