Suppressed MMP-9 Activity in Myocardial Infarction-Related Cardiogenic Shock Implies Diminished Rage Degradation.

BACKGROUND: Receptor for advanced glycation end products (RAGE) and its cleavage fragment soluble RAGE (sRAGE) are opposite players in inflammation. Enhanced monocytic RAGE expression and decreased plasma sRAGE levels are associated with higher mortality in infarction-related cardiogenic shock. Active matrix metalloproteinase-9 (MMP-9) has been implied in RAGE ectodomain cleavage and subsequently sRAGE shedding in vitro. We investigated MMP-9 activity in myocardial infarction-induced cardiogenic shock with regard to RAGE/sRAGE regulation. METHODS AND RESULTS: We determined MMP-9 serum activity by zymography and tissue inhibitor of matrix metalloproteinases (TIMP-1) expression by Western blot and correlated it to RAGE/sRAGE data in patients with cardiogenic shock after acute myocardial infarction (CS, n = 30), in patients with acute myocardial infarction without shock (AMI, n = 20) and in healthy volunteers (n = 20).MMP-9 activity is increased in AMI (P = 0.02 versus controls), but significantly decreased in CS with lowest levels in non-survivors (n = 13, P = 0.02 versus AMI). In all patients, MMP-9 activity correlated inversely with RAGE expression on circulating monocytes (r = -0.57; P = 0.0001; n = 50).TIMP-1 levels showed an inverse regulation in comparison to active MMP-9 with significantly decreased levels in AMI as compared with controls (P = 0.02 versus controls) and highest levels in non-survivors of CS (P <0.001 versus AMI). CONCLUSIONS: Serum MMP-9 activity is increased in acute myocardial infarction, but markedly suppressed in cardiogenic shock. Maintaining MMP-9 activity could be a therapeutic target to limit RAGE-induced deleterious inflammation in cardiogenic shock.

Role of receptor for advanced glycation end products in cardiogenic shock.

OBJECTIVES: Activation of the receptor for advanced glycation end products by its ligands promotes inflammatory processes and tissue injury. The available evidence suggests that soluble forms of receptor for advanced glycation end products circulating in the plasma may neutralize the ligand-mediated damage by acting as a decoy. Thus, it is hypothesized that receptor for advanced glycation end products expression might be deleterious, whereas soluble receptor for advanced glycation end products might be beneficial in cardiogenic shock. However, until now, no data exist regarding the role of soluble receptor for advanced glycation end products and receptor for advanced glycation end products in humans with cardiogenic shock complicating myocardial infarction. DESIGN: Prospective observational cohort study. SETTING: Intensive critical care unit of a university hospital. PATIENTS: Forty patients with cardiogenic shock complicating acute myocardial infarction, 20 age-matched patients with acute uncomplicated myocardial infarction and, 20 age-matched healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Monocytic receptor for advanced glycation end products expression assessed by flow cytometry was significantly increased in cardiogenic shock nonsurvivors (137.02±7.48 mean fluorescence intensity; n=13) compared to survivors (67.80±8.33 mean fluorescence intensity; n=17; p<.001). Conversely, nonsurvivors had significantly decreased plasma soluble receptor for advanced glycation end products levels (79.87±10.62 arbitrary units; n=13; p=.004) compared to survivors (127.65±10.52 arbitrary units; n=17) as assessed by Western blotting. Receptor for advanced glycation end products expression and soluble receptor for advanced glycation end products levels were determined as independent predictors for 28-day mortality in cardiogenic shock confirmed by receiver-operator characteristics and multivariate analysis (receptor for advanced glycation end products: area under the curve, 0.943±0.05; p<.001; soluble receptor for advanced glycation end products: area under the curve, 0.815±0.08; p<.01). Both receptor for advanced glycation end products>103.6 mean fluorescence intensity or soluble receptor for advanced glycation end products<76.88 arbitrary units independently predicted a 27.87-fold (p<.001) and a 3.97-fold (p=.019) increase in 28-day mortality in cardiogenic shock. CONCLUSIONS: Enhanced monocytic receptor for advanced glycation end products expression and decreased plasma soluble receptor for advanced glycation end products levels play a central role in patients with cardiogenic shock associated with proinflammatory and destroying pathways, resulting in an enhanced 28-day mortality-rate. Receptor for advanced glycation end products and soluble receptor for advanced glycation end products may be prognostic biomarkers for survival in cardiogenic shock and might represent a novel therapeutic target in cardiogenic shock.

Rosuvastatin induces apoptosis in CD4(+)CD28 (null) T cells in patients with acute coronary syndromes.

AIMS: CD4(+)CD28(null) cells represent an aggressive and long-living T cell subpopulation, capable of infiltrating atheromatous plaque, leading to destabilisation and resulting in acute coronary syndromes (ACS). The aim of this study was to evaluate whether statins decrease the number of circulating CD4(+)CD28(null) T cells by apoptosis in patients with ACS. METHODS AND RESULTS: Patients with troponin-positive ACS (n = 35) without cholesterol lowering drugs were randomised to placebo (n = 17) or rosuvastatin 20 mg (n = 18) once daily for 6 weeks. CD4(+)CD28(null) T cell abundance (>1%) was distributed equally among the two groups at entry (n = 10 per group). Within 72 h rosuvastatin treatment significantly reduced mean CD4(+)CD28(null) T cell numbers (37 × 106/L vs. placebo 122 × 106/L, n = 20, P = 0.041), IFN-γ production (62.6 vs. 101.5%, P = 0.049) and increased apoptosis of these T cells (63.4 vs. 12.3%, P < 0.001). The intrinsic mitochondria-dependent pathway measured by the anti-apoptotic protein expression of B cell lymphoma 2 (BCL-2) was significantly down-regulated (mean fluorescence intensity 16.08 vs. placebo 43.34, P < 0.001). CONCLUSIONS: The down-regulation of anti-apoptotic BCL-2 expression by statins induces apoptosis in CD4(+)CD28(null) T cells. Targeting CD4(+)CD28(null) T cells in ACS statins could provide one further therapeutic strategy to prevent acute life-threatening coronary events.