Akutes Koronarsyndrom und Entzündung Trepels, Thomas; Zeiher, Andreas M; Fichtlscherer, Stephan
Herz,
12/2004, Letnik:
29, Številka:
8
Journal Article
Recenzirano
Die Inflammation spielt eine zentrale Rolle in der Pathophysiologie der Atherosklerose und der koronaren Herzerkrankung (KHK): Inflammatorische Prozesse führen zur Plaqueentstehung, -progression und ...schließlich -instabilität, welche sich in den jeweiligen klinischen Manifestationen der stabilen KHK oder des akuten Koronarsyndroms (ACS; instabile Angina pectoris, Nicht-ST-Hebungsinfarkt und ST-Hebungsinfarkt) präsentieren. Das pathomorphologische Korrelat des ACS stellt die rupturierte oder erodierte Plaque mit konsekutiver Thrombusbildung dar, die zur Ischämie und Nekrose von Myozyten führt, begleitet von einer diffusen multifokalen myokardialen und vaskulären Entzündung. Entsprechend haben hierbei zirkulierende Nekrosemarker, z. B. in Form der kardialen Troponine, entscheidende diagnostische und prognostische Bedeutung. Nekrosemarker können jedoch definitionsgemäß innerhalb der heterogenen Gruppe der "troponinnegativen ACS" nicht zur Risikostratifizierung herangezogen werden. Verschiedene inflammatorische Marker deuten aber hier mittlerweile ihren prognostischen Nutzen an: Als Standard gilt bislang das C-reaktive Protein, das einen wertvollen Prädiktor des Risikos für kardiovaskuläre Ereignisse nach ACS darstellt. Das Potential anderer pro- (z. B. löslicher CD40-Ligand, "placental growth factor", Interleukin-6, "pregnancy-associated plasma protein A", Myeloperoxidase, "monocyte chemoattractant protein-1") und antiinflammatorischer Marker (Interleukin-10, Activin A) ist zwar bereits erkannt, bedarf jedoch noch der breiten klinischen Validierung. Inflammation plays a pivotal role in atherosclerosis and coronary heart disease. Inflammatory processes of the coronary arterial wall are involved in plaque formation, progression and, finally, plaque instability consecutively leading to the clinical manifestations of stable coronary artery disease or acute coronary syndromes (unstable angina, non-ST elevation and ST elevation myocardial infarction). Acute coronary syndromes result from plaque rupture or erosion leading to local thrombus formation with consecutive necrosis of myocytes due to ischemia, which is associated with widespread and diffuse pancoronary and panmyocardial inflammation. Accordingly, markers of myocardial necrosis (e. g., cardiac troponins) do have crucial diagnostic and prognostic value. In case of troponin-negative acute coronary syndromes, however, markers of inflammation emerged as potentially useful tools for risk stratification. C-reactive protein has been shown to serve as a powerful predictor of future cardiovascular events following acute coronary syndromes, even if troponins are not (yet) positive. Moreover, a variety of pro- (soluble CD40 ligand, placental growth factor, interleukin-6, pregnancy-associated plasma protein A, myeloperoxidase, monocyte chemoattractant protein-1) and anti-inflammatory markers (interleukin-10, activin A) have been suggested to provide relevant prognostic information in patients with acute coronary syndrome. However, the clinical utility of these novel markers has not been established so far.
Akutes Koronarsyndrom und Entz ndung Trepels, Thomas; Zeiher, Andreas M.; Fichtlscherer, Stephan
Herz,
12/2004, Letnik:
29, Številka:
8
Journal Article
The goal of this study was to determine the predictive value of pregnancy-associated plasma protein-A (PAPP-A) in patients with acute coronary syndromes (ACS).
Pregnancy-associated plasma protein-A ...is a zinc-binding matrix metalloproteinase abundantly expressed in eroded and ruptured plaques and may serve as a marker of plaque destabilization.
In 547 patients with angiographically validated ACS and in a heterogeneous emergency room population of 644 patients with acute chest pain, respectively, PAPP-A as well as markers of myocardial necrosis (troponin T TnT), ischemia (vascular endothelial growth factor VEGF), inflammation (high-sensitivity C-reactive protein hsCRP), anti-inflammatory activity (interleukin IL-10), and platelet activation (soluble CD40 ligand sCD40L) were determined. Patients were followed for the occurrence of death or myocardial infarction.
In patients with ACS, elevated PAPP-A levels (>12.6 mIU/l) indicated an increased risk (odds ratio 2.44 95% confidence interval (CI) 1.43 to 4.15; p = 0.001). When the analysis was restricted to TnT-negative patients, PAPP-A still identified a subgroup of high-risk patients (odds ratio OR 2.72 95% confidence interval (CI) 1.25 to 5.89; p = 0.009). In a multivariable model, PAPP-A (OR 2.01; p = 0.015), sCD40L (OR 2.37; p = 0.003), IL-10 (OR 0.43; p = 0.003), and VEGF (OR 2.19; p = 0.018) were independent predictors. Prospective validation in patients with chest pain confirmed that PAPP-A levels reliably identify high-risk patients (adjusted OR 2.32 95% CI 1.32 to 4.26; p = 0.008). Patients negative for all three markers (TnT, sCD40L, and PAPP-A) were at very low cardiac risk (30 days: 3.0% event rate; no death).
The PAPP-A level as a marker of plaque instability is a strong independent predictor of cardiovascular events in patients with ACS. Simultaneous determination of biomarkers with distinct pathophysiological profiles appears to remarkably improve risk stratification in patients with ACS.
In cultured human endothelial cells, physiological levels of NO prevent apoptosis and interfere with the activation of the caspase cascade. In vitro data have demonstrated that NO inhibits the ...activity of caspase-3 byS-nitrosation of the enzyme. Here we present evidence for the in vivo occurrence and functional relevance of this novel antiapoptotic mechanism. To demonstrate that the cysteine residue Cys-163 of caspase-3 is S-nitrosated, cells were transfected with the Myc-tagged p17 subunit of caspase-3. After incubation of the transfected cells with different NO donors, Myc-tagged p17 was immunoprecipitated with anti-Myc antibody.S-Nitrosothiol was detected in the immunoprecipitate by electron spin resonance spectroscopy after liberation and spin trapping of NO byN-methyl-d-glucamine-dithiocarbamate-iron complex. Transfection of cells with a p17 mutant, where the essential Cys-163 was mutated into alanine, completely preventedS-nitrosation of the enzyme. As a functional correlate, in human umbilical vein endothelial cells the NO donors sodium nitroprusside or PAPA NONOate (50 μm) significantly reduced the increase in caspase-3-like activity induced by overexpressing caspase-3 by 75 and 70%, respectively. When human umbilical vein endothelial cells were cotransfected with β-galactosidase, morphological analysis of stained cells revealed that cell death induction by overexpression of caspase-3 was completely suppressed in the presence of sodium nitroprusside, PAPA NONOate, or S-nitroso-l-cysteine (50 μm). Thus, NO supplied by exogenous NO donors serves in vivo as an antiapoptotic regulator of caspase activity viaS-nitrosation of the Cys-163 residue of caspase-3.
Impulse response analysis of digital coronary angiographic images calculates a parameter known as the mean transit time of the microcirculation (Tmicro). This has been shown to accurately assess the ...regional microcirculatory response to proximal stenosis in relation to flow. Our goal was to apply impulse response analysis to patients undergoing successful angioplasty and to quantify the induced physiological changes with respect to quantitative angiographic measurements of stenosis dimensions.
We studied 24 patients before and after successful single-vessel percutaneous transluminal coronary angioplasty (PTCA). Minimal luminal stenosis area was increased from 0.9 +/- 0.6 before PTCA to 4.1 +/- 1.3 mm2 after PTCA (P < .0001). In all patients this was accompanied by an increase in the inverse of Tmicro (Tmicro-1), from 8.5 +/- 3.0 to 26.5 +/- 9.0 min-1 (P < .0001) with a linear correlation between Tmicro-1 and minimal luminal stenosis area (r = .73; SEE = 7.74). Stenosis flow reserve, estimated by integration of stenosis dimensions, increased in all patients from 1.8 +/- 1.0 to 4.5 +/- 0.4 after PTCA (P < .01). A comparison of Tmicro-1 with stenosis flow reserve revealed a nonlinear relation. In 16 patients undergoing PTCA of the left anterior descending or circumflex artery, contrast injections into the left main stem allowed simultaneous measurements of Tmicro-1 in the adjacent, nonstenotic artery. Adjacent artery Tmicro-1 did not change after PTCA (25.8 +/- 6.2 compared with 25.6 +/- 6.8 min-1 before PTCA; P = NS); moreover, Tmicro-1 of the dilated artery measured after PTCA was equivalent to the nonstenotic adjacent artery, indicating normalization of microcirculatory responses.
These data suggest that Tmicro-1 determined by digital angiographic impulse response analysis of a single contrast injection under resting flow conditions may be a practical method to assess the regional microcirculatory response to changes in stenosis severity effected by coronary angioplasty.
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