Statin use is associated with a significant reduction in cholesterol content of erythrocyte membranes. A novel pleiotropic effect?

PURPOSE: High cholesterol content of erythrocyte membranes (CEM) levels is present in patients with acute coronary syndromes (ACS). Intraplaque hemorrhage and erythrocyte lysis contribute to the deposition of cholesterol on the atherosclerotic plaque and to plaque rupture. With the present study we assessed the effect of statin therapy on CEM levels, a novel marker of coronary artery disease (CAD) instability during a 1-year follow-up in CAD patients. METHODS: 212 consecutive eligible (158 men, 62 +/- 10 years) patients undergoing diagnostic coronary angiography for the assessment of angina pectoris were assessed. The study population comprised of 84 chronic stable angina (CSA) patients and 128 ACS patients. All study participants were commenced on statin treatment in equipotent doses and were followed for up to 1 year (at - 1, - 3, - 6 and - 12 months). RESULTS: Repeated measurements analysis of variance after appropriate adjustment showed a significant decrease (p < 0.001) in CEM content during follow up. CEM levels were decreasing at each time point (1 month : 100 microg/mg 95%CI 94.3-105.6, 3 months : 78.1 microg/mg 95%CI 73.2-83, 6 months : 67.2 microg/mg 95%CI 63.1-71.2, 1 year : 45.3 microg/mg 95%CI 42.2-48.3) compared to admission (112.1 microg/mg 95% CI 105.9-118.3) and to all previous measurements. CONCLUSIONS: The present study showed, that use of statins is associated with a reduction in CEM, an emerging marker of clinical instability and plaque vulnerability in CAD patients. The pleiotropic effects of statins at the cell membrane level represent a promising novel direction for research in CAD.

Interleukin-8 is increased in the membrane of circulating erythrocytes in patients with acute coronary syndrome.

AIMS: Studies have shown that erythrocyte membranes are present within necrotic cores in atherosclerotic plaques, and that circulating erythrocytes in patients with acute coronary syndrome (ACS) have increased total cholesterol content (CEM). Interleukin-8 (IL-8) binds to erythrocytes and during intraplaque haemorrhage it is released into the plaque and thus may contribute to inflammatory cascade and atherosclerotic plaque instability. The present study was undertaken to test the hypothesis that erythrocyte membrane IL-8 is elevated in patients with ACS compared with those with chronic stable angina (CSA). METHODS AND RESULTS: Consecutive patients who presented with CSA (n = 120, 92 men, 62 +/- 9 years), ACS (n = 118, 90 men, 62 +/- 10 years) or with chest pain who had normal coronary arteries (n = 36, 26 men, 60 +/- 7 years), were studied prospectively. IL-8 concentrations in erythrocyte membranes (rIL-8) and in plasma (pIL-8), C-reactive protein (CRP) and CEM were measured. rIL-8 levels [mean +/- 1 SD (standard deviation)] were higher in ACS (102.9 +/- 70.1 pg/mL) compared with CSA (44.7 +/- 22.8 pg/mL) (P < 0.001). No difference in pIL-8 levels between the two coronary artery disease groups was observed (P = 0.280). Serum CRP levels were correlated with rIL-8 levels (r = 0.294, P < 0.001); no association was found between CRP and pIL-8 levels (r = 0.025, P = 0.706). Further, rIL-8 had an independent association with ACS, when CRP and CEM were taken into consideration. CONCLUSION: This study shows for the first time that rIL-8 content was significantly higher in ACS, compared with CSA. These findings endorse results from our previous studies suggesting that erythrocytes may play an important role in the development of unstable atherosclerotic plaque.

Retrobulbar hemodynamics and aqueous humor levels of endothelin-1 in exfoliation syndrome and exfoliation glaucoma.

BACKGROUND: Endothelin-1 (ET-1) is the most potent vasoconstrictor in the body. There are reports in the literature correlating plasma levels of ET-1 and its impact on retrobulbar hemodynamics. This study evaluates aqueous humor levels of ET-1 and retrobulbar hemodynamics in patients with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). PATIENTS AND METHODS: Patients scheduled for cataract surgery were included. Patients were allocated to non-exfoliation non-glaucoma group (controls), XFG and XFS groups. Peak systolic velocity (PSV), end diastolic velocity, and resistivity index of the ophthalmic artery (OA), short posterior ciliary arteries, and central retinal artery (CRA) were determined preoperatively using color Doppler imaging. Aqueous humor samples obtained at the beginning of cataract surgery were analyzed with enzyme-linked immunosorbent assay. RESULTS: Sixty-nine participants of similar age were included (controls: n=24, XFG: n=22, XFS: n=23). Multiple regression analysis showed that ET-1, OA-PSV, OA-resistivity index, CRA-PSV, and CRA-end diastolic velocity were influenced by group but not by sex or age. ET-1 for the XFG group (15.93±2.8 pg/mL) was significantly higher than for the XFS (8.92±2.7 pg/mL) and control (8.44±2.6 pg/mL) groups. The difference in ET-1 titers between the control and XFS groups was not statistically significant. All four hemodynamic parameters affected by group status significantly correlated with ET-1 levels in eyes with XFS. In eyes with XFG, two of the four hemodynamic parameters significantly correlated with ET-1 levels. In control eyes, no correlation between ET-1 and hemodynamic parameters affected by group status was detected. CONCLUSION: ET-1 aqueous levels in eyes with XFG were significantly higher than those of age-matched controls. Reduced blood flow and increased vascular resistivity were detected in the OA and the CRA in eyes with XFG/XFS. ET-1 levels in eyes with XFG/XFS exhibit a significant correlation with hemodynamic parameters that indicate reduced perfusion.

Inflammatory and anti-inflammatory variable clusters and risk prediction in acute coronary syndrome patients: a factor analysis approach.

BACKGROUND: Numerous inflammatory mediators such as C-reactive protein (CRP), fibrinogen, interleukin-18 (IL-18), and inter-cellular adhesion molecule-1 (ICAM-1) have been proposed for risk stratification in acute coronary syndrome (ACS) patients. However, interactions between these markers have made it difficult to assess their true role in risk prediction. Factor analysis is a multivariable statistical technique that reduces a large number of intercorrelated variables to a smaller set of independent clusters, underlining physiological relationships. The aim of this study was to investigate, using factor analysis, a clustering of pro-inflammatory markers, anti-inflammatory cytokines such as interleukin-10 (IL-10) and HDL cholesterol, and to determine their role in prediction of risk of recurrent coronary events in ACS patients. METHODS: We assessed 320 consecutive patients (236 men; 67 years; IQ 58-74 years) admitted with ACS. The composite of cardiac death and re-hospitalization with non-fatal myocardial infarction, or unstable angina, was the pre-specified study end-point. Serum CRP, fibrinogen, HDL cholesterol, IL-10, IL-18 and ICAM-1 levels were measured at study entry. We assessed independent predictors of the combined end-point during a 1-year follow-up using multiple logistic regression analysis. RESULTS: Factor analysis identified three clusters which were arbitrarily interpreted as (1) a "systemic inflammation" cluster with positive loadings of CRP and fibrinogen, (2) a "local inflammation-endothelial dysfunction" cluster with positive loadings of IL-18 and ICAM-1 and (3) an "anti-inflammation" cluster comprising IL-10 and HDL cholesterol. Only the "anti-inflammation" cluster was a significant predictor (OR 0.66, 95% CI: 0.49-0.89) of adverse cardiac events during a 1-year follow-up and remained significant (OR 0.65, 95% CI: 0.48-0.88) in a multivariate model that included all three factors. CONCLUSIONS: Although inflammatory markers such as CRP predict future cardiovascular events in ACS patients, when all inflammatory mediators are taken into account in a prospective analysis of risk, markers reflecting anti-inflammatory mechanisms are better prognostic markers.

Prepartum Psychosis and Neonaticide: Rare Case Study and Forensic-Psychiatric Synthesis of Literature.

Peripartum psychosis is a rare but serious psychiatric disorder characterized by the presence of a mood episode with psychotic features. Although controversy surrounds the nosological status of peripartum mental disorders, these conditions continue to be of exceptional interest to the medical and forensic mental health communities. The aim of this study was to report a rare case of prepartum psychosis which escalated to the endpoint of neonaticide and summarize literature on peripartum mental disorders and infanticide. A 30-year-old mother murdered her newborn with the spike of her serum delivery system and planned to commit suicide while in hospital after hallucinating due to an acute puerperal psychotic disorder with a prepartum onset and postpartum deterioration. Her disorder was not managed until neonaticide. Throughout this paper, the significance of a multidisciplinary approach for the optimal management of these incidents is highlighted and diagnostic as well as therapeutic issues are addressed.

Alteplase treatment affects circulating matrix metalloproteinase concentrations in patients with ST segment elevation acute myocardial infarction.

INTRODUCTION: Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques. Acute coronary syndromes may be precipitated by MMPs through degradation of the fibrous cap and subsequent plaque disruption. Serine proteases such as plasmin activate MMPs and may contribute to plaque events. Thrombolysis with recombinant tissue plasminogen activator (rtPA) is widely used for treatment of acute ST segment elevation myocardial infarction (STEMI). In the present study we assessed whether thrombolytic therapy with rtPA in patients with STEMI influences serum levels of MMP-2 and MMP-9. METHODS: We recruited 108 patients (92 men, mean age 64 +/- 12 years) with STEMI, of whom 84 (78%) received thrombolytic treatment with rtPA and 24 (22%) did not. MMP-2 and MMP-9 levels were assessed at hospital admission (baseline), and at 24 and 72 h after admission, using a commercially available ELISA. RESULTS: Overall, MMP-9 levels were higher in the thrombolysis group compared to patients without thrombolysis (p < 0.001). Thrombolysis treatment significantly affected the change in MMP-9 levels during the 72-h study period (p < 0.001). CONCLUSIONS: The present study showed that thrombolysis could affect circulating levels of MMP-9 in STEMI patients. Whether this effect may lead to plaque instability deserves further investigation.

Interleukin-18: interleukin-10 ratio and in-hospital adverse events in patients with acute coronary syndrome.

INTRODUCTION: Inflammatory mechanisms contribute to the development of acute coronary syndromes (ACS), and it has been suggested that an imbalance between pro- and anti-inflammatory responses may be an important determinant of recurrent cardiac events in this setting. Both increased serum levels of interleukin (IL)-18 and reduced concentrations of IL-10 have been shown to have prognostic significance in ACS. We sought to assess whether the ratio of serum IL-18/IL-10 levels has higher positive predictive value than the individual measurement of IL-10 and IL-18 in patients admitted to hospital with ACS. METHODS: We recruited 107 consecutive patients (79 men, mean age 65+/-12 years) with ACS (41 STEMI, 39 NSTEMI and 27 UA). The composite of cardiac death, recurrence of unstable angina, re-infarction, life threatening arrhythmias, and urgent revascularization during hospitalization was the pre-specified study end-point. We assessed independent predictors of the combined end-point using multiple logistic regression analysis. Serum IL-10 and IL-18 levels were measured at study entry using commercially available ELISAs. RESULTS: During hospitalization 44 patients (41%) had events and 63 (59%) had no events. Significantly higher odd ratios were found for IL-18/IL-10 ratio (1.74 95% CI 1.09-2.78) compared to individual IL-18 (1.46 95% CI 0.93-2.27) and 1/IL-10 (1.63 95% CI 1.04-2.56) measurements. CONCLUSION: Serum IL-18/IL-10 ratio is an independent predictor of in-hospital adverse events in patients with ACS. Our study strongly endorses the notion that an imbalance between pro and anti-inflammatory forces predisposes to plaque disruption and recurrent cardiovascular events.

Comparison of levels of matrix metalloproteinase-2 and -3 in patients with ischemic cardiomyopathy versus nonischemic cardiomyopathy.

It has been reported that circulating matrix metalloproteinase (MMP) levels are upregulated in patients with chronic heart failure. However, experimental studies indicate that differences in the profiles of MMPs and tissue inhibitors of metalloproteinase (TIMPs) may exist in ischemic compared with nonischemic cardiomyopathy. This study examined whether circulating levels of MMPs and TIMP-1 are related to the pathogenesis of heart failure. Circulating levels of MMP-2, MMP-3, and TIMP-1 were assessed in 52 patients with compensated end-stage chronic heart failure, including 26 patients (mean 64 +/- 7 years; 10 men) with ischemic cardiomyopathy (IC) and 26 (mean age 66 +/- 6 years; 14 men) with idiopathic dilated cardiomyopathy (IDC). Serum MMP-2 (p <0.001) and MMP-3 (p <0.001) levels were higher in patients with IDC than in those with IC. Serum TIMP-1 levels were lower in patients with IDC (p = 0.011) than in those with IC. This study shows that in patients with compensated end-stage chronic heart failure, circulating levels of MMP-2, MMP-3, and TIMP-1 are associated with the pathogenesis of heart failure.

N-terminal pro-B-type natriuretic peptide and matrix metalloproteinases in early and late left ventricular remodeling after acute myocardial infarction.

N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) is a predictor of left ventricular remodeling. Matrix metalloproteinases (MMPs) contribute to collagen breakdown that is associated with ventricular remodeling after acute myocardial infarction (AMI). We assessed the association between circulating levels of NT-pro-BNP, MMP-2, and MMP-9 and their inhibitor (tissue inhibitor of metalloproteinase-1) early (24 and 72 hours) and late (7 and 30 days) after AMI in 108 patients who had ST-elevation AMI (90 men; mean age 60 years). Serum MMP-2 levels measured 24 and 72 hours after AMI were inversely associated with NT-pro-BNP levels, whereas MMP-9 serum levels were positively related. During late-stage remodeling after AMI, circulating concentrations of tissue inhibitor of metalloproteinase-1 were independently associated with NT-pro-BNP levels 7 and 30 days after AMI. This study shows that, in patients who have ST-elevation AMI, circulating levels of NT-pro-BNP are associated with MMPs in a species-specific and time-dependent manner.

Serum profiles of matrix metalloproteinases and their tissue inhibitor in patients with acute coronary syndromes. The effects of short-term atorvastatin administration.

There is increasing evidence that abnormal cytokine expression and increased metalloproteinase activity are implicated in the pathophysiology of acute coronary syndromes. This study investigates the serum profiles of representative metalloproteinases (MMP-1, -2, -9) and their tissue inhibitor (TIMP-1) in patients with myocardial infarction (MI) and unstable angina (UA) in relation to circulating proinflammatory cytokine (TNF-alpha and IL-6) activity. Furthermore, we examined the effects of a 30-day treatment with atorvastatin on serum levels of these inflammatory factors. Serum concentrations of MMP-1, -2, -9, TIMP-1, IL-6 and TNF-alpha were measured (enzyme-linked immunosorbent assay (ELISA) method) in 23 acute myocardial infarction patients and 20 unstable angina patients on 0 day, 1st, 3rd, 7th and 30th day after admission. Sixteen normal volunteers were used as healthy controls. Additionally, 12 patients of myocardial infarction group and 11 patients of unstable angina group were treated with atorvastatin (20 mg/day) for 30 days in a randomized design. In patients with myocardial infarction and unstable angina, serum levels of MMP-2, -9, TIMP-1, TNF-alpha and IL-6 were significantly higher than those of healthy controls in all time frames (p<0.05). In the group of unstable angina patients, we observed a statistically significant reduction in the levels of MMP-9, TIMP-1 and IL-6 after the 30-day atorvastatin administration. Our results suggest that serum MMPs, TIMP-1 and proinflammatory cytokines play an important role in the pathophysiology of the acute coronary syndromes. The reduction of these factors by short-term atorvastatin administration may provide a new insight into the pleiotropic effects of statins on unstable coronary artery disease.

Anti-inflammatory cytokine profile in acute coronary syndromes: behavior of interleukin-10 in association with serum metalloproteinases and proinflammatory cytokines.

BACKGROUND: The anti-inflammatory cytokine interleukin-10 (IL-10) downregulates the production of metalloproteinases (MMPs) and upregulates the production of their tissue inhibitors (TIMPs). The aim of this study was to assess the levels of IL-10 in patients with acute myocardial infarction (AMI) and unstable angina (UA), as well as to investigate the relationship of circulating IL-10 with the levels of MMPs (MMP-1, -2, -9), their tissue inhibitor (TIMP-1), pro-inflammatory cytokines (IL-6, tumor necrosis factor (TNF)-alpha) and serum lipids in the same patient population. METHODS: Serum MMP-1, -2, -9, TIMP-1, IL-6, TNF-alpha and IL-10 were measured by ELISA assays in 23 patients with AMI and 20 patients with UA after their hospital admission, as well as in 16 healthy controls subjects. The lipid profile was assessed by measuring the serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides. RESULTS: AMI patients exhibited significantly higher serum levels of IL-10 as compared with those of UA patients and healthy controls (both P=0.005). In contrast, there was no significant difference in IL-10 levels between UA patients and healthy controls. In AMI patients there was a statistically significant positive correlation of serum IL-10 with the levels of MMP-9 (rho=0.588, P=0.003), IL-6 (rho=0.502, P=0.015) and HDL-cholesterol (rho=0.697, P<0.001), as well as a significant negative correlation with the levels of triglycerides (rho=-0.417, P=0.048). CONCLUSIONS: Our results suggest that UA is associated with low serum activity of IL-10, while a significant elevation of this anti-inflammatory cytokine accompanies the peripheral immune responses of AMI. This observation indicates that different patterns of inflammatory reactions are implicated in the pathophysiology of two clinical conditions.

Matrix metalloproteinase imbalance in inguinal hernia formation.

BACKGROUND: Emerging evidence supports the role of matrix metalloproteinases (MMPs) in hernia formation. However, the imbalance between the proteolytic activity of MMPs and their endogenous inhibitors (TIMPs) has not been investigated. The aim of the present study was to determine changes of MMP and TIMP levels in patients with inguinal hernia. METHODS: Two matrix metalloproteinases (MMP-9 and MMP-2) and their main inhibitors TIMP-1 and TIMP-2 were evaluated in consecutive patients undergoing inguinal hernia repair and control subjects. MMP/TIMP quantification was performed using ELISA in abdominal fascia tissue specimens and preoperative plasma samples. RESULTS: Tissue explants from hernia patients produced significantly higher levels of MMP-9 and MMP-2, and reduced TIMP-1 and TIMP-2 concentrations compared to those of controls. In plasma, a reverse correlation was found regarding the concentrations of MMPs; the circulating levels of MMP-9 and MMP-2 were significantly lower in patients with inguinal hernia than controls. Furthermore, hernia patients were found to have elevated plasma levels of TIMP-2 and reduced plasma levels of TIMP-1. CONCLUSIONS: The imbalance in MMP/TIMP activity indicates a dysregulation of the extracellular matrix degradation process in patients with inguinal hernia. The results of the present study suggest that impaired collagen metabolism may be an underlying pathophysiological mechanism of inguinal hernia formation.

Independent and additive predictive value of total cholesterol content of erythrocyte membranes with regard to coronary artery disease clinical presentation.

BACKGROUND: A new mechanism for clinical instability in coronary artery disease (CAD) has been proposed where erythrocytes could play an active role in atherosclerotic plaque growth and rupture. Clinical studies showed increased total cholesterol levels in the membrane of circulating erythrocytes (CEM) in acute coronary syndrome (ACS) patients compared to patients with chronic stable angina (CSA). We investigated the independent and incremental discriminating value of CEM along with N-terminal propeptide of BNP (NT-proBNP), high sensitivity C-reactive protein (hs CRP), myeloperoxidase (MPO) and apolipoprotein B (apoB) with regard to CAD clinical presentation. METHODS: 519 consecutive angina patients were assessed; 252 had CSA (195 men, 62 ± 9 years) and 267 had ACS (213 men, 62 ± 10 years).CEM levels and serum concentrations of NT-proBNP, hs CRP, MPO and apoB were measured upon study admission. RESULTS: Simple logistic regression models showed that all biomarkers could distinguish ACS, nevertheless CEM with greater potency (OR 9.26 95%CI 6.31-13.59, p<0.001). Multiple logistic regression models after adjustment for all the variables that were different between the 2 groups as well as for other biomarkers showed that CEM continued to be a significant and an independent predictor of ACS (OR 22.27 95%CI 10.63-46.67, p<0.001). An increment of the C-statistic was also shown when CEM levels were incorporated in the predictive model (including traditional vascular risk factors and new well established biomarkers i.e. hs CRP, MPO, apoB and NT-proBNP). CONCLUSIONS: The present study showed that CEM levels are associated with clinical instability in CAD patients in an independent and incremental manner.

Total cholesterol content of erythrocyte membranes and coronary atherosclerosis: an intravascular ultrasound pilot study.

BACKGROUND: Increasing evidence suggests that erythrocytes may participate in atherogenesis. We sought to investigate the relationship between total cholesterol content in erythrocyte membranes (CEM) and coronary atheroma burden in patients with coronary artery disease (CAD). METHODS: We prospectively enrolled 28 participants: 11 patients with angiographically significant CAD and 17 controls. Intravascular ultrasound (IVUS) and 3-dimensional reconstruction of coronary arteries was performed in the patient subgroup. RESULTS: Cholesterol content of erythrocyte membranes was higher in patients compared to controls (P < .01). Cholesterol content of erythrocyte membranes correlated with total atheroma volume (r = .82, P < .01) and with percentage plaque area at the vessel site with minimal lumen area (r = .75, P < .05). On multivariate analysis, CEM was the only variable independently predicting total atheroma volume (P = .05). CONCLUSIONS: This pilot study is the first to demonstrate a significant relation between CEM and coronary atherosclerotic burden, suggesting a possible role of erythrocyte membrane-derived lipids in the expansion of atheromata. The results merit validation in larger studies.

Cholesterol composition of erythrocyte membranes and its association with clinical presentation of coronary artery disease.

OBJECTIVES: Presence of free cholesterol in atherosclerotic plaques is a major determinant of plaque instability. It is hypothesized that extravasated erythrocytes may contribute to free cholesterol accumulation in atherosclerotic plaques through their rich in cholesterol membrane. In this study we assessed whether cholesterol in erythrocyte membranes (CEMs), that is, free (FCEM) versus esterified (ECEM), differs in patients with chronic stable angina (CSA) compared with patients presenting with acute coronary syndromes (ACSs). METHODS: Consecutive angina patients were prospectively assessed; 154 had CSA (118 men, 63 years, 56-69 years) and 164 ACS (124 men, 63 years, 55-71 years). FCEM and ECEM were measured using an enzymatic assay, and protein content was assessed by the Bradford method. RESULTS: FCEM was significantly higher (P<0.001) in the ACS patients group (94.1 microg/mg, IQ 71-116.5 microg/mg) compared with patients with CSA (61.9 microg/mg, IQ 49.3-73.1 microg/mg). ECEM levels were also significantly higher (P<0.001) in ACS patients (23.3 microg/mg, IQ 14.9-47.7 microg/mg) compared with CSA patients (10.8 microg/mg, IQ 8-22.3 microg/mg). In contrast, ratio of free-to-esterified cholesterol (P=0.110) as well as ratio of free-to-total CEM (P=0.109) were not different among CSA and ACS patients. CONCLUSION: Findings of this study show that although free cholesterol is the prevailing form of CEMs, both FCEM and ECEM levels are increased in patients with ACS compared with CSA patients. These findings suggest that it is the quantity of CEM rather than the type of cholesterol present in the erythrocyte membrane that determines plaque progression.

Interleukin-18/interleukin-10 ratio is an independent predictor of recurrent coronary events during a 1-year follow-up in patients with acute coronary syndrome.

BACKGROUND: The pro-inflammatory cytokine IL-18 has been suggested to play a role in atherogenesis and atheromatous plaque rupture leading to the acute coronary syndrome (ACS). Conversely, the anti-inflammatory cytokine IL-10 seems to have an atheroprotective role. Patients with unstable coronary artery disease show an imbalance between serum levels of pro- and anti-inflammatory cytokines, and studies have shown that IL-18/IL-10 ratio is an independent predictor of adverse in-hospital events in patients with ACS. We assessed the long-term prognostic significance of admission interleukin-18 (IL-18)/interleukin-10 (IL-10) ratio for recurrent coronary events during a 1-year follow-up in patients presenting with an ACS. METHODS: We assessed independent predictors of the combined end-point using multiple logistic regression analysis, in 186 patients (138 men, 65+/-12 years) with ACS (75 STEMI, 65 NSTEMI and 46 unstable angina). The composite of cardiac death and re-hospitalization with non-fatal myocardial infarction, or unstable angina, was the pre-specified study end-point. Serum IL-10 and IL-18 levels were measured at study entry using commercially available ELISAs. RESULTS: During the 1-year follow-up, 48 (26%) patients had recurrent cardiac events and 138 (74%) were event-free. IL-18/IL-10 ratio predicted the occurrence of adverse cardiac events (OR 1.91, 95% CI 1.37-2.65, p<0.001), and was found to be an independent predictor among other established biochemical and clinical risk markers (OR 2.31, 95% CI 1.55-3.42, p<0.001). CONCLUSIONS: Serum IL-18/IL-10 ratio is an independent predictor of recurrent coronary events during long-term follow-up in patients presenting with ACS. Our study further supports the hypothesis that the balance between pro-inflammatory and anti-inflammatory cytokines may be an important determinant of patient outcome, suggesting a pathogenic role in plaque progression and instability.

Total cholesterol content of erythrocyte membranes is increased in patients with acute coronary syndrome: a new marker of clinical instability?

OBJECTIVES: We hypothesized that cholesterol content is increased in the circulating erythrocytes of patients with acute coronary syndrome (ACS) and may be a marker of clinical instability. We therefore sought to investigate whether cholesterol content differs in erythrocyte membranes of patients presenting with ACS compared to patients with chronic stable angina (CSA). BACKGROUND: Plaque rupture in ACS depends at least partly on the volume of the necrotic lipid core. Histopathologic studies have suggested that cholesterol transported by erythrocytes and deposited into the necrotic core of atheromatous plaques contributes to lipid core growth. METHODS: Consecutive angina patients were prospectively assessed; 120 had CSA (83 men, age 64 +/- 11 years) and 92 ACS (67 men, 66 +/- 11 years). Total cholesterol content in erythrocyte membranes (CEM) was measured using an enzymatic assay, and protein content was assessed by the Bradford method. RESULTS: The CEM (median and interquartile range) was higher (p < 0.001) in ACS patients (184 microg/mg; range 130.4 to 260.4 microg/mg) compared with CSA patients (81.1 microg/mg; range 53.9 to 109.1 microg/mg) (analysis of covariance). Total plasma cholesterol concentrations did not correlate with CEM levels (r = -0.046, p = 0.628). CONCLUSIONS: This study shows, for the first time, that CEM is significantly higher in patients with ACS compared with CSA patients. These findings suggest a potential role of CEM as a marker of atheromatous plaque growth and vulnerability. Large ad hoc studies are required to establish the clinical importance and pathogenic significance of CEM measurement.

Intraarterial chemotherapy as an adjuvant treatment in locally advanced gastric cancer.

BACKGROUND AND AIMS: D2 gastrectomy has improved survival in gastric cancer. Adjuvant intravenous chemotherapy, radiotherapy, or multimodal therapy has failed to demonstrate improved survival. The results of intraarterial chemotherapy (IARC) as an adjuvant have been encouraging in a few studies. A prospective randomized trial was designed to evaluate the toxicity and survival in locally advanced gastric cancer using IARC as an adjuvant after potentially curative gastrectomy. PATIENTS AND METHODS: Forty patients with locally advanced gastric cancer were randomly selected to undergo either potentially curative gastrectomy and receive IARC (study group) or gastrectomy only (control group). Clinical and histopathologic data were analyzed and the toxicity related to IARC was recorded. RESULTS: The groups were comparable (p>0.05). Three patients in the study group had minor toxicity. Five-year survival rate for the study and the control group was 52 and 54%, respectively (p>0.05). Mean survival for the study and the control group was 50+/-8 and 62+/-10 months, respectively (p>0.05). The number of recurrences and the failure sites were comparable (p>0.05). CONCLUSION: Intraarterial chemotherapy can be safely applied to gastric cancer patients. As proposed by the protocol, the method cannot be recommended as an adjuvant treatment for locally advanced tumors because it appears that there is no survival benefit compared to potentially curative gastrectomy alone.

Apolipoprotein E genotype and circulating interleukin-10 levels in patients with stable and unstable coronary artery disease.

OBJECTIVES: This study was designed to assess the relation between apolipoprotein E (apoE) genotype and serum interleukin (IL)-10 levels in patients with acute coronary syndrome (ACS) and chronic stable angina (CSA). BACKGROUND: Genetic variations in the apoE gene affect the risk for coronary artery disease (i.e., carriers of the e4 allele have an increased risk). Increased levels of C-reactive protein (CRP), an inflammatory marker, correlate with an increased risk of acute coronary events, whereas increased IL-10 concentrations have an atheroprotective role. Studies have reported a negative association between the apoE e4 allele and CRP levels. METHODS: Apolipoprotein E genotypes were assessed in 166 consecutive ACS patients (119 men, mean age 68 years, interquartile range [IQR] 60 to 74 years) and 70 CSA patients (54 men, mean age 65 years, IQR 62 to 68 years). Serum IL-10 and CRP were assessed at study entry. RESULTS: Analysis of covariance showed that genetic variation in the apoE gene locus significantly influences serum IL-10 levels in both ACS (p = 0.009) and CSA patients (p = 0.013). Among ACS patients, IL-10 levels were lower in E3/E4 carriers compared with E3/E3 carriers (p = 0.01) and marginally lower compared with E2/E3 carriers (p = 0.065). Among CSA patients, IL-10 levels were lower in E3/E4 carriers compared with E2/E3 carriers (p = 0.004) and marginally lower compared with E3/E3 carriers (p = 0.086). CONCLUSIONS: The IL-10 concentrations differ in ACS and in CSA patients with different apoE genotypes. The e4 allele was associated with a trend toward lower IL-10 serum levels. Our results may provide an explanation of findings in previous studies that cardiovascular risk is higher in e4 carriers despite the presence of low CRP levels.

Levosimendan use reduces matrix metalloproteinase-2 in patients with decompensated heart failure.

BACKGROUND: Extracellular matrix metabolism (ECM) has an important role in left ventricular (LV) remodeling in chronic heart failure (CHF). Matrix metalloproteinases (MMPs) are involved in the regulation of extracellular matrix (ECM) metabolism. We investigated the effect of levosimendan, a novel calcium sensitizer, on serum levels of MMP-2. METHODS: Our study population consisted of 60 consecutive patients with advanced heart failure who were admitted to hospital with an acute decompensation of their CHF. Patients were randomized to levosimendan (n = 30; 18 men, aged 65 +/- 3 years) or placebo (n = 30; 15 men, aged 67 +/- 4 years). Serum MMP-2 levels were assessed before and after treatment with levosimendan or placebo, using a commercially available ELISA. RESULTS: Serum levels of MMP-2 were reduced from 427 ng/ml 95%CI 372-484 to 371 ng/ml 95%CI 329-413 in the levosimendan treated group and from 433 ng/ml 95%CI 422-444 to 425 ng/ml 95%CI 414-436 in the placebo group. Repeated measurements ANOVA showed that treatment with levosimendan significantly affected levels of MMP-2 (p = 0.019). CONCLUSIONS: The present study showed that levosimendan may beneficially affect ECM remodeling in patients with acutely decompensated CHF. Whether these effects translate into added clinical benefits, as suggested by an improved ejection fraction in the levosimendan group, deserves further investigation.