High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease.

BACKGROUND: In stable patients with unknown coronary anatomy, higher levels of cardiac troponin are associated with an increased risk of cardiovascular events. It was supposed that this association might be explained by the ability of cardiac troponin to detect minor myocardial necrosis which might be caused by subclinical coronary atherosclerosis. Thus, this analysis tested if the predictive value of high-sensitivity troponin T (hsTnT) in stable patients is dependent of the presence or absence of angiographically documented coronary heart disease. METHODS: Stable patients undergoing elective coronary angiography were enrolled (n=2046). HsTnT was determined before diagnostic procedures. The patients were followed for up to seven years. Primary endpoint was all-cause mortality or non-fatal myocardial infarction. All endpoints were adjudicated by independent physicians. Results were adjusted to a clinical model including independent clinical predictors of the primary endpoint. RESULTS: Out of the 2046 patients enrolled, 1236 (60%) had a diagnosis of obstructive coronary heart disease. HsTnT predicted independently the primary endpoint (adjusted HR 1.33, 95%-CI 1.21-1.46, P<0.001). The use of hsTnT in addition to the clinical model significantly improved discrimination (c-statistic: 0.751 to 0.773, P<0.001) as well as reclassification of the primary endpoint (NRI=0.362, P<0.001). This significant improvement persisted across various subsets and was independent of the presence of clinically detectable coronary heart disease and other variables. CONCLUSION: The use of hsTnT in addition to clinical variables significantly improves discrimination and reclassification of patients with respect to all-cause mortality or non-fatal myocardial infarction irrespective of the presence of clinically detectable coronary heart disease. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT00457236).

Platelet activation and myocardial necrosis in patients undergoing radiofrequency and cryoablation of isthmus-dependent atrial flutter.

AIMS: Lower platelet activation by cryoenergy compared with radiofrequency (RF) energy was recently demonstrated immediately following ablation procedures of cardiac arrhythmias. Due to the delayed occurrence of cryolesions it is currently unknown, if cryoenergy and RF energy are associated with similar platelet activation and myocardial necrosis in the days after the procedure. METHODS AND RESULTS: We enrolled 38 patients with common atrial flutter undergoing cavotricuspid isthmus ablation with either RF energy (n = 23) or cryoenergy (n = 13). Ten patients undergoing RF ablation and receiving aspirin served as antiplatelet control group. Troponin T and platelet surface protein expression of P-selectin were determined before and immediately after ablation as well as on day 1 and 2 thereafter. Rise in troponin T was amplified after RF ablation (0.50 +/- 0.37 microg/L) when compared with cryoablation (0.24 +/- 0.20 microg/L; P = 0.024). In patients without aspirin, a significant increase in P-selectin expression was observed on day 1 after intervention in RF ablation compared with cryoablation (80 +/- 26 vs. 63 +/- 16 arbitrary units; P = 0.048). Platelet activation was attenuated in patients receiving aspirin. CONCLUSION: Successful ablation of atrial flutter with cryoenergy is associated with less myocardial necrosis and platelet activation compared with ablation with RF energy. Increased platelet activation following RF ablation can be attenuated by concomitant treatment with aspirin.

Colocalization of oxidized low-density lipoprotein, caspase-3, cyclooxygenase-2, and macrophage migration inhibitory factor in arteriosclerotic human carotid arteries.

Apoptotic and inflammatory processes occur in human arteriosclerotic lesions. We examined the hypothesis whether both processes are possibly associated by studying the colocalization of corresponding markers. In 11 human arteriosclerotic carotid arteries, proapoptotic markers (CPP32 (caspase-3), poly(ADP-ribose) polymerase, apoptosis-inducing factor, c-Jun/AP-1, and p53) and proinflammatory markers (macrophage migration inhibitory factor (MIF) and cyclooxygenase-2) were found in macrophages (MPhi) evaluated by computer-assisted immunohistomorphometry. Double-labeling studies demonstrated a colocalization of, both, proapoptotic and proinflammatory markers in these MPhi. Moreover, these MPhi also contained oxidized low-density lipoproteins (oxLDL). Exposure of cultured human MPhi to oxLDL, C6-ceramide, and tumor necrosis factor-alpha or H2O2 resulted in a significant increase of the apoptosis rate as well as of the MIF protein expression. Our study of MPhi in arteriosclerotic carotid arteries and in vitro experiments provide evidence that markers of apoptosis and inflammation are not only significantly increased but are also coexpressed. We conclude there are reciprocal modulatory interactions between apoptotic and inflammatory pathways in human plaque MPhi, which might importantly modify plaque progression or stability.

Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions.

Growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) is a new member of the transforming growth factor beta (TGF-beta) superfamily, which has most recently been found in activated macrophages (MPhi). We have now investigated GDF-15/MIC-1 in human MPhi after exposure to oxidized low-density lipoproteins (oxLDL) related mediators in vitro and in arteriosclerotic carotid arteries. Using RT-PCR and Western blotting a pronounced induction of GDF-15/MIC-1 expression by oxLDL, C6-ceramide, tumor necrosis factor (TNFalpha) and hydrogen peroxide (H2O2) was found in cultured human MPhi. In 11 human arteriosclerotic carotid arteries, immunohistochemical analyses supported by computer-assisted morphometry and regression analyses demonstrated a significant colocalization of GDF-15/MIC-1 immunoreactivity (IR) with oxLDL IR and manganese superoxide dismutase (MnSOD) IR in CD68 immunoreactive (ir) MPhi, which were also expressing AIF-IR (apoptosis-inducing factor), caspase-3-IR (CPP32), PARP-IR, c-Jun/AP-1-IR and p53-IR. Our data suggest that GDF-15/MIC-1 is inducible in human MPhi by oxLDL and its mediators in vitro and is supposed to contribute to oxidative stress dependent consequences in arteriosclerotic plaques, e.g. modulating apoptosis and inflammatory processes in activated MPhi.