Georgios K. Chalikias

Development of an easily applicable risk score model for contrast-induced nephropathy prediction after percutaneous coronary intervention: A novel approach tailored to current practice

BACKGROUND Several risk factors for contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) have been identified. The cumulative effect of these risk factors on renal function has been assessed with the development of risk score models in a number of studies. However, concerns were raised that estimates of the risk attributable to individual factors may be unreliable. We sought to develop a simple risk score for developing CIN after PCI irrespective of use of prophylactic measures and also capturing the effect of pre-intervention medication and presence of various co-morbidities. METHODS Consecutive patients treated with elective or urgent PCI at our cardiac catheterization laboratory were enrolled (derivation cohort n = 488, validation cohort n = 200). CIN was defined as increase ≥ 25% and/or ≥ 0.5 mg/dl in serum creatinine at 48 h after PCI vs baseline. Multivariable logistic regression analysis was then performed to identify independent predictors of CIN (pre-existing renal disease, metformin use, history of previous PCI, peripheral arterial disease and ≥ 300 ml of contrast volume). RESULTS The incidence of CIN in the development cohort was 10.2% with a significant trend across increasing score values (p < 0.001). The model demonstrated good discriminating power (c-statistic 0.759) and excellent calibration (calibration slope 0.91). The model was validated internally by bootstrapping in 1000 samples (c-statistic 0.753) and in a cohort of 200 patients (c-statistic 0.864) demonstrating stable performance. CONCLUSIONS The proposed risk score is easily applicable and allows for practically simple risk assessment compared to other published scores while at the same time overcomes drawbacks of previous model designs.

Red blood cell distribution width: a strong prognostic marker in cardiovascular disease: is associated with cholesterol content of erythrocyte membrane.

OBJECTIVES Red blood cell distribution width (RDW), a measure of the variability in size of circulating erythrocytes, has recently been shown to be a strong predictor of adverse outcomes in patients with a great spectrum of cardiovascular disease. Recently, cholesterol content of erythrocytes membranes (CEM) has been associated with clinical instability in coronary artery disease whilst it has been linked with red blood cells (RBC) size and shape. Since the biological mechanisms underlying the association of higher RDW with cardiovascular mortality risk are currently unclear, we studied the association of CEM with RDW. METHODS 296 consecutive angina patients (236 men, mean age 69 ± 2 years) were prospectively assessed; 160 had chronic stable angina (CSA) and 136 had an acute coronary syndrome (ACS). RESULTS Patients presenting with ACS had increased CEM levels (121.6 μg/mg (40.1) vs 74.4 μg/mg (26.6), p < 0.001) as well as exhibited greater anisocytosis (13.9% (0.9) vs 13.3% (0.7), p < 0.001) compared to patients with CSA. Simple correlation analysis showed that CEM levels were positively associated with RDW values (r = 0.320, p < 0.001). Multivariable linear regression showed that CEM levels were associated with RDW values independently from possible confounders (inflammatory, nutritional renal or hematological). CONCLUSIONS Data from the present study showed an independent association between cholesterol content of erythrocyte membranes and anisocytosis. Increased CEM levels -a novel biomarker of clinical instability in CAD - may facilitate our understanding why RDW is associated with increased morbidity and mortality in cardiovascular 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.

The role of red blood cells in the progression and instability of atherosclerotic plaque

This review attempts to present a focused summary of selected areas of the rapidly growing knowledge regarding the red blood cells role in atherosclerotic plaque progression and instability. A summary of the characteristics of the erythrocyte membranes is provided, followed by a brief review of the in vitro and in vivo work that has helped clarify their role in atherosclerosis. Mechanisms by which erythrocytes enter the atherosclerotic plaque and contribute to its progression and instability are presented. Finally, some elements that may be clinically important regarding erythrocytes in coronary artery disease are discussed.

Leptin-Dependent and Leptin-Independent Paracrine Effects of Perivascular Adipose Tissue on Neointima Formation

Objective—Clinical and experimental evidence suggests that periadventitial adipose tissue may modulate vascular lesion formation. The aim of this study was to determine the role of perivascular leptin expression on neointima formation and to differentiate it from local inflammation and systemically elevated leptin levels. Approach and Results—Increased neointima formation after carotid artery injury was observed in hyperleptinemic, diet–induced obese wild-type mice, but not in leptin-deficient ob/ob mice. High-fat diet was associated with increased leptin expression in visceral adipose tissue (VAT) as well as in perivascular adipose tissue. Perivascular leptin overexpression achieved by adenoviral vectors enhanced intimal cell proliferation and neointima formation in wild-type mice, but not in leptin receptor–deficient mice. Perivascular transplantation of VAT from high-fat diet–induced obese wild-type mice around the carotid artery of immunodeficient mice also promoted neointima formation, without affecting body weight or systemic leptin levels, and this effect was absent, if VAT from ob/ob mice was used. On the contrary, perivascular transplantation of VAT from ob/ob mice fed high-fat diet, characterized by marked immune cell accumulation, promoted neointimal hyperplasia also in the absence of leptin. In vitro, recombinant leptin and VAT-conditioned medium increased human arterial smooth muscle cell proliferation in a (partly) leptin-dependent manner. Conclusions—Our findings suggest that locally elevated leptin levels may promote neointima formation, independent of obesity and systemic hyperleptinemia, but also underline the importance of perivascular inflammation in mediating the increased cardiovascular risk in obesity.

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.

Epidemiology of the diabetic heart.

Diabetes mellitus is a worldwide epidemic. Cardiovascular disease remains the major cause of morbidity and mortality in people with diabetes. Studies have suggested that increased risk of cardiovascular disease is not restricted to type II or type I diabetes mellitus, but extends to prediabetic stages such as impaired fasting glucose, impaired glucose tolerance, metabolic syndrome, and obesity. Insulin resistance, impaired fasting glucose, impaired glucose tolerance, and diabetes mellitus form a continuous sequence of risk for cardiovascular disease. Therefore, cardiovascular disease mortality and morbidity within the diabetes epidemic grow into vast proportions. Evidence also exists that diabetic patients have a high prevalence of heart failure or impaired diastolic and systolic cardiac function subsequent to the combination of coronary artery disease, hypertension, and diabetic cardiomyopathy. In view of the proportions of this new epidemic, prevention of diabetes and its prediabetic states is likely to be the most effective strategy to prevent serious cardiovascular events.

Biomarkers of the extracellular matrix and of collagen fragments

A great body of evidence has shown that extracellular matrix (ECM) alterations are present in the major types of cardiac diseases: ischemic heart disease, heart disease associated with pressure overload, heart disease associated with volume overload, and intrinsic myocardial disease or cardiomyopathy. Collagen, type I and III, is the principal structural protein found in the myocardium and its pro- or telopeptides are released into the circulation during the course of cardiovascular diseases. Therefore, these peptides may reflect collagen synthesis and break-down and also represent a much more useful tool to address ECM changes from a distance. Clinical trials have been performed during recent years to examine the usage of these peptides as diagnostic or prognostic biomarkers in heart failure (HF) patients. This review aims to summarize published data concerning cardiac ECM and its circulating biomarkers. Studies that focused on collagen metabolism related biomarkers in patients with HF are analyzed. Finally, limitations associated with the clinical use of the aforementioned biomarkers are also discussed.

Independent and additive prognostic ability of serum carboxy-terminal telopeptide of collagen type-I in heart failure patients: a multi-marker approach with high-negative predictive value to rule out long-term adverse events

BACKGROUND Altered myocardial extracellular matrix turnover has been proposed as a major determinant of myocardial remodelling. Carboxy-terminal telopeptide of collagen type-I (CITP) represents a collagen type-I degradation-derived serum peptide. In this study we examined the independent and additive prognostic value of serum concentrations of CITP compared with well-known mortality predictors such as the N-terminal pro-brain natriuretic peptide (NT-proBNP) in chronic heart failure (CHF) patients. METHODS We studied 196 consecutive patients (126 male, mean age 69 ± 10 years), who were admitted for acute decompensation of the CHF syndrome. The study entry point was determined at the discharge of the patients after achieving a stable compensated status. The primary endpoint was cardiac mortality during a 12-month follow-up. RESULTS In the multivariate Cox proportional hazard model the levels of CITP remained a predictor of survival (hazards ratio 0.4 95% confidence interval 0.21-0.76, P = 0.005), independent of NT-proBNP levels. The stratified log-rank test (P < 0.001) showed that CHF patients characterized by low levels of both biomarkers had better survival (hazards ratio 0.12 95% confidence interval 0.04-0.35, P < 0.001) compared with patients characterized by high levels of both biomarkers. The negative predictive value of the combined measure for long-term adverse events was 94%. CONCLUSION Serum levels of CITP were shown to be an independent and strong prognostic marker regarding survival in CHF patients. Furthermore, CITP levels had an additive prognostic value compared with NT-proBNP levels. These findings underline the detrimental role of myocardial fibrosis in the progression of heart failure and suggest a novel multi-marker approach for risk stratification in the CHF syndrome.

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.