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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 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.

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.

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.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.Overall, MMP-9 levels were higher in the thrombolysis group compared to patients without thrombolysis (p0.001). Thrombolysis treatment significantly affected the change in MMP-9 levels during the 72-h study period (p0.001).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.

Fibrin d-dimers levels have been advocated as a useful clinical marker of thrombogenesis. It is accepted that patients with atrial fibrillation (AF) are characterized by increased levels of plasmatic d-dimers. AF is a high risk factor for hypercoagulability, with a substantial risk of thromboembolism. The most effective way of minimizing the increased thromboembolic risk and treating patients’ symptoms is to return the heart rhythm to sinus rhythm by electrical or chemical cardioversion. However, cardioversion of AF itself leads to a further increased risk of thromboembolism. A marker of coagulation activation would be useful to identify patients at the highest thromboembolic risk after cardioversion in AF patients. Indicators of hypercoagulability, such as d-dimers, appear to be a useful parameter for assessing the degree of hypercoagulability of AF patients after cardioversion. Mean changes in plasma d-dimers levels could be used as a useful clinical marker of the clotting state after the return of atrial systole.

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.

Matrix metalloproteinases (MMPs) appear to play a central role in atherosclerotic plaque remodeling; however, the relationship of increased MMP levels in inducing carotid plaque instability remains controversial. We investigated whether gelatinases (MMP-2 and MMP-9) are implicated in carotid intraplaque hemorrhage and whether their serum levels may predict local carotid events. Nineteen carotid specimens obtained by endarterectomy of 18 patients were studied. The presence of gross intraplaque hemorrhage was recorded before plaque removal and quantification of MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) in extracts from (1) the more stenotic area of the plaque, (2) the periphery of the plaque, and (3) serum was performed by enzyme-linked immunosorbent assay. MMP-9 levels measured in extracts from the most stenotic area were significantly higher in patients with intraplaque hemorrhage (p = 0.007); however, serum levels showed no difference, while those taken from the periphery of the lesion were also increased but did not reach a statistically significant level (p = 0.06). An increase in MMP-2 values was observed in the periphery of the lesion (p = 0.04) in patients with intraplaque hemorrhage. TIMP-1 levels showed no difference between the two groups regardless of the presence or absence of intraplaque hemorrhage. No significant differences in MMP levels were observed between symptomatic and asymptomatic patients. Increased levels of MMPs, particularly MMP-9, have been implicated in carotid intraplaque hemorrhage without their serum levels being predictive of local events.

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.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.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, P0.001), as well as a significant negative correlation with the levels of triglycerides (rho=-0.417, P=0.048).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.

It is well known that atrial fibrillation is associated with high incidence of thromboembolic events, propably due to a prothrombotic or hypercoagulable state. However, it is unclear whether or not there is any difference of this prothrombotic state in the clinical subgroups of atrial fibrillation patients, that is, in those with paroxysmal, persistent or permanent atrial fibrillation. From the other side the role of the arrhythmia duration on the changes of coagulative variables in atrial fibrillation patients is not clearly enough.

Definitive diagnosis of tuberculous pericarditis requires identification of bacilli in pericardial fluid or tissue. Conventional diagnostic methods are time-consuming and have a low sensitivity making bacteriological confirmation of the disease very difficult. Hereby, we report the case of molecular detection of Mycobacterium tuberculosis in pericardial fluid, bone marrow and peripheral blood from a 63-year-old woman with pericardial tuberculosis, using a nested PCR assay specific for IS6110 insertion element of M. tuberculosis complex. The patient had an excellent response to a three-drug combination anti-tuberculous regimen and 1 year later was asymptomatic, without evidence of constrictive pericarditis.

The presence of systemic inflammation determined by elevations in high-sensitivity C-reactive protein (hs-CRP) has been associated with persistence of atrial fibrillation (AF). The influence of inflammation markers, such as hs-CRP, on the recurrences of lone AF, however, has not been clarified. We tested the hypothesis of whether, in patients with a first paroxysmal episode of lone AF, the hs-CRP levels were elevated, and whether elevated hs-CRP could predict the recurrence rate of lone AF in patients without antiarrhythmic drugs. Using a case-control study design, the hs-CRP levels in 125 patients with a documented symptomatic first paroxysmal episode of lone AF was compared with the hs-CRP levels in 65 control patients. hs-CRP levels are presented as median values with the interquartile range (25th to 75th percentiles). The hazard ratio compared the 75th percentile of hs-CRP with the 25th percentile. In the arrhythmia group, hs-CRP was higher than in the control patients (median 0.23 mg/dl, interquartile range 0.12 to 0.49, vs 0.087 mg/dl, interquartile range 0.058 to 0.098, p

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 (p0.001) and MMP-3 (p0.001) 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.

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).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.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.The CEM (median and interquartile range) was higher (p0.001) 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).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.

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.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.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, p0.001), 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, p0.001).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.

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.

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.

Cardiac resynchronization therapy (CRT) is a well-accepted therapy in patients with advanced, congestive heart failure (HF). In these patients, changes of mean heart rate (HR), heart rate variability (HRV) and physical performance after starting CRT have not been fully investigated. In this study we rewieved data stored on a CRT-D (Contak-Renewal II, Guidant, USA) implanted in 28 pts (mean age 60.6±3.8 years, QRS duration 149.6 ±6.8 msec, LVEF 19±0.9%) with symptomatic CHF (functional NYHA class >II) despite optimal pharmacological treatment. Sexteen pts have had ischemic dilated cardiomyopathy. Over a period of 16 weeks, weekly changes of minimum HR and mean HR, standard deviation of mean R-R intervals (SDANN) and degree of physical activity done by each patient, measured by Activity Log Index (AL) of the device, were analysed. Moreover, a cardiopulmonary exercise testing was performed before and 4 months after implantation. Results: after 16 weeks, CRT-D determined a significant decrease of minimum and mean HR (67.6 ±14 vs 57.4±2.6, and 79.4±15.2 vs 72.7±2.9 bpm, respectively, p

Background Fibrin D-dimer levels have been advocated as an useful clinical marker of thrombogenesis.

We evaluated the sensitivity and specificity of a diagnosis of peripheral arterial occlusive disease (PAOD) as a predictor of the severity of coronary artery disease (CAD) in patients with and without diabetes. A total of 302 patients were assigned to groups according to the angiographic severity of their CAD and their diabetes status. Both PAOD and severe PAOD were diagnosed by measuring the ankle-brachial index (ABI) and toe-brachial index (TBI). A diagnosis of PAOD had a low sensitivity (34.3%) but a high specificity (87.0%) for detecting patients with severe CAD. Sensitivity was higher in patients with diabetes (52.4%) than without (19.5%), whereas specificity was higher in patients without diabetes (95.4%) than those with diabetes (69.8%). A diagnosis of severe PAOD had a higher specificity (96.0%), but a very low sensitivity (16.4%). We conclude that a diagnosis of PAOD among patients with CAD had a low sensitivity but a high specificity for detecting those with severe CAD, particularly in patients without diabetes.