Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction.

AIMS: Neutrophil extracellular traps (NETs) are chromatin filaments released by activated polymorphonuclear neutrophils (PMNs) and decorated with granule proteins with various properties. Several lines of evidence implicate NETs in thrombosis. The functional significance and the in vivo relevance of NETs during atherothrombosis in humans have not been addressed until now. METHODS AND RESULTS: Selective sampling of thrombotic material and surrounding blood from the infarct-related coronary artery (IRA) and the non-IRA was performed during primary percutaneous revascularization in 18 patients with ST-segment elevation acute myocardial infarction (STEMI). Thrombi isolated from IRA contained PMNs and NETs decorated with tissue factor (TF). Although TF was expressed intracellularly in circulating PMNs of STEMI patients, active TF was specifically exposed by NETs obtained from the site of plaque rupture. Treatment of NET structures with DNase I abolished TF functionality measurement. In vitro treatment of control PMNs with plasma obtained from IRA and non-IRA was further shown to induce intracellular up-regulation of TF but not NET formation. A second step consisting of the interaction between PMNs and thrombin-activated platelets was required for NET generation and subsequent TF exposure. CONCLUSION: The interaction of thrombin-activated platelets with PMNs at the site of plaque rupture during acute STEMI results in local NET formation and delivery of active TF. The notion that NETs represent a mechanism by which PMNs release thrombogenic signals during atherothrombosis may offer novel therapeutic targets.

Platelet microRNAs: From platelet biology to possible disease biomarkers and therapeutic targets.

Although anucleated, platelets contain megakaryocyte-derived messenger ribonucleic acid (mRNA) which can be translated to produce protein molecules. Recently, platelets have been found to contain small (∼23 base pair) non-coding microRNAs (miRNAs) derived from hairpin-like precursors. MiRNAs can specifically silence their mRNA targets regulating mRNA translation. Platelet miRNAs are reported to bind to important platelet target mRNAs involved in platelet reactivity including P2Y12 ADP receptor, GPIIb receptor, and cyclic AMP-dependent protein kinase A. They also regulate important functions such as platelet shape change, granules secretion, and platelet activation. Platelet miRNAs were also proposed as biomarkers of arteriosclerosis, although their role in vascular inflammation needs to be elucidated. Further, the possibility of using miRNAs as therapeutic tools has emerged. Using synthetic oligo-nucleotides that antagonize miRNAs binding to their mRNAs-targets or synthetic miRNAs mimics that enhance endogenous miRNAs function potentially will ultimately lead to the manipulation of platelet miRNAs expression and function with significant effects on specific protein levels and overall platelet reactivity.

Statin-induced immunomodulation alters peripheral invariant natural killer T-cell prevalence in hyperlipidemic patients.

PURPOSE: To assess the difference in the prevalence of invariant Natural Killer T (iNKT) lymphocytes between hyperlipidemic and control individuals and to evaluate changes in iNKT cell levels after 6 months lipid lowering therapy. METHODS: A total of 77 hyperlipidemic individuals (54 ± 5 years) were assigned to simvastatin 40 mg or ezetimibe 10 mg daily for 6 months. Fifty individuals with normal cholesterol levels were used as control. iNKT cells were measured by flow cytometry in peripheral blood. RESULTS: Patients with hypercholesterolemia had significantly lower iNKT cell levels (percentage on the lymphocyte population) compared to control group (0.16 ± 0.04% vs 0.39 ± 0.08%, p = 0.03). iNKT cells significantly increased after 6 months treatment with simvastatin (from 0.15 ± 0.04% to 0.28 ± 0.11%, p = 0.03) but not with ezetimibe (from 0.16 ± 0.05% to 0.17 ± 0.06%, p = 0.55). Simvastatin treatment did not alter the activation status of iNKT cells as measured by HLA-DR expression. Changes of iNKT cells were independent from changes in total (r(2) = 0.009, p = 0.76) or LDL cholesterol (r(2) = 0.008, p = 0.78) reached by simvastatin. CONCLUSIONS: Hyperlipidemic patients have reduced numbers of iNKT in peripheral circulation compared to individuals with normal cholesterol levels. Their number is increasing after long term administration of simvastatin 40 mg but not after ezetimibe.

Plasma leptin and adiponectin concentrations in healthy, non-obese children.

BACKGROUND: Alterations in plasma leptin and adiponectin concentrations are associated with an adverse metabolic profile in obese children. OBJECTIVE: To simultaneously assess multiple factors with possible effects on plasma leptin and adiponectin concentrations in healthy, non-obese children. SUBJECTS: We studied 170 healthy non-obese children (86 males, age 10+1.5 years), with available medical records from birth. METHODS: Plasma leptin and adiponectin concentrations were assessed by immunoassay. The ratio of current weight/birth weight (WBWR) was used as an index of children growth from birth. Children's intensity of physical activity and parental characteristics were also assessed. RESULTS: Leptin was positively associated with WBWR (p<0.0001); parental smoking (analysis of variance, ANOVA; p-=0.03) and parental obesity (ANOVA; p<0.001) were negatively associated with breastfeeding (p<0.01) and children's access to exercise (p<0.0001). Adiponectin was negatively associated with WBWR (p<0.0001) and parental smoking (p=0.04), with an additive negative effect of parental smoking status and parental obesity on children's adiponectin levels (ANOVA; p=0.02). CONCLUSIONS: Children's and parental factors are related and could possibly influence leptin and adiponectin concentrations in healthy non-obese children. Early preventive strategies that target both children and parents could improve the profile of adipocytokine in these children.

Relation of tricuspid annular displacement and tissue Doppler imaging velocities with duration of weaning in mechanically ventilated patients with acute pulmonary edema.

BACKGROUND: Liberation from the ventilator is a difficult task, whereas early echocardiographic indices of weaning readiness are still lacking. The aim of this study was to test whether tricuspid annular plane systolic excursion (TAPSE) and right ventricular (RV) systolic (Sm) and diastolic (Em & Am) tissue Doppler imaging (TDI) velocities are related with duration of weaning in mechanically ventilated patients with acute respiratory failure due to acute pulmonary edema (APE). METHODS: Detailed quantification of left and right ventricular systolic and diastolic function was performed at admission to the Intensive Care Unit by Doppler echocardiography, in a cohort of 32 mechanically ventilated patients with APE. TAPSE and RV TDI velocities were compared between patients with and without prolonged weaning (> or = or < 7 days from the first weaning trial respectively), whereas their association with duration of ventilation and left ventricular (LV) echo-derived indices was tested with multivariate linear and logistic regression analysis. RESULTS: Patients with prolonged weaning (n = 12) had decreased TAPSE (14.59 +/- 1.56 vs 19.13 +/- 2.59 mm), Sm (8.68 +/- 0.94 vs 11.62 +/- 1.77 cm/sec) and Em/Am ratio (0.98 +/- 0.80 vs 2.62 +/- 0.67, p <0.001 for all comparisons) and increased Epsilon/e' (11.31 +/- 1.02 vs 8.98 +/- 1.70, p <0.001) compared with subjects without prolonged weaning (n = 20). Logistic regression analysis revealed that TAPSE (R2 = 0.53, beta slope = 0.76, p < 0.001), Sm (R2 = 0.52, beta = 0.75, p < 0.001) and Em/Am (R2 = 0.57, beta = 0.32, p < 0.001) can predict length of weaning > or = 7 days. The above measures were also proven to correlate significantly with Epsilon/e' (r = -0.83 for TAPSE, r = -0.87 for Sm and r = -0.79 for Em/Am, p < 0.001 for all comparisons). CONCLUSIONS: We suggest that in mechanically ventilated patients with APE, low TAPSE and RV TDI velocities upon admission are associated with delayed liberation from mechanical ventilation, probably due to more severe LV heart failure.

The Alzheimer's Disease Amyloid-Beta Hypothesis in Cardiovascular Aging and Disease: JACC Focus Seminar.

Aging-related cellular and molecular processes including low-grade inflammation are major players in the pathogenesis of cardiovascular disease (CVD) and Alzheimer's disease (AD). Epidemiological studies report an independent interaction between the development of dementia and the incidence of CVD in several populations, suggesting the presence of overlapping molecular mechanisms. Accumulating experimental and clinical evidence suggests that amyloid-beta (Aß) peptides may function as a link among aging, CVD, and AD. Aging-related vascular and cardiac deposition of Αß induces tissue inflammation and organ dysfunction, both important components of the Alzheimer's disease amyloid hypothesis. In this review, the authors describe the determinants of Aß metabolism, summarize the effects of Aß on atherothrombosis and cardiac dysfunction, discuss the clinical value of Αß1-40 in CVD prognosis and patient risk stratification, and present the therapeutic interventions that may alter Aß metabolism in humans.

Oxidised low-density lipoprotein and arterial function in beta-thalassemia major.

OBJECTIVES: Vascular abnormalities such as endothelial dysfunction and arterial stiffness have been described in patients with beta-thalassemia major (beta-TM). Increased concentrations of oxidised low-density lipoprotein cholesterol (oxLDL) have been observed in those patients, but possible associations between oxLDL and arterial function in beta-TM have not been defined. METHODS: Twenty-six patients (11 males) with beta-TM (age 23 +/- 4 yr) and 30 age and gender-matched healthy subjects were studied. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (PWVc-f) using applanation tonometry; brachio-radial artery stiffness was assessed by carotid-radial PWV (PWVc-r). Flow-mediated dilatation (FMD) of the brachial artery and oxLDL (ELISA) were also measured. RESULTS: Patients with beta-TM had higher oxLDL levels (68.6 +/- 13.7 mU/mg vs. 50.0 +/- 12.6 mU/mg, P = 0.005), decreased FMD (3.6 +/- 2.5% vs. 7.3 +/- 3.5%, P = 0.001) and higher PWVc-f compared with controls (8.4 +/- 1.7 vs. 7.2 +/- 1.1. P < 0.002). FMD of the brachial artery was negatively associated with OxLDL concentrations in simple linear (r(2) = -0.25, P = 0.001) and multiple linear regression analysis (beta = -0.242, P = 0.03, R(2) = 0.43, P = 0.0002). PWVc-r was positively associated with OxLDL (r(2) = 0.23, P = 0.003) and showed a tendency in multiple regression analysis (beta = 0.18, P = 0.05). PWVc-r and FMD were also significantly correlated (beta = -0.213, P = 0.04) in beta-TM patients. There was no association between oxLDL and PWVc-f. CONCLUSION: An association between oxLDL, arterial elastic properties and endothelial dysfunction of muscular arteries was found. OxLDL may represent a contributing factor for the vascular manifestations described in beta-TM patients.

Resolution of symptoms and serum peptides of collagen type I turnover in acute heart failure patients.

OBJECTIVES: Myocardial collagen content as a fundamental component of extracellular matrix, is altered in pathological states including heart failure (HF). Serum peptides related to myocardial collagen synthesis and degregation can be measured and may be used as indices of myocardial collagen turnover. The present study was undertaken to assess the hypothesis that resolution of acute decompensation of chronic HF is associated with changes in serum peptides related to collagen synthesis and degregation. METHODS AND RESULTS: Serum concentrations of the amino-terminal propetide of procollagen type I (PINP) and the carboxy-terminal telopeptide of collagen type I (CITP), indices of collagen type I synthesis and degradation, respectively, were determined at the time of admission and discharge in 156 patients (100 men, 68 +/- 10 years) with acute decompensation of chronic HF. A significant decrease (-3.5 ng/ml 95% CI -5.3/-1.6 ng/ml, P < 0.001) of PINP was observed whereas CITP levels were significantly increased (+ 0.04 ng/ml 95% CI 0.01-0.08 ng/ml, P = 0.031) at discharge compared to admission. CONCLUSIONS: Findings of the present study showed that serum indices of myocardial collagen turnover were changed significantly in a short period of time during the improvement of acute decompensation of chronic HF.

Effect of statins on collagen type I degradation in patients with coronary artery disease and atrial fibrillation.

The present study was undertaken to assess the effect of statins on collagen type I degradation and C-reactive protein in patients with coronary artery disease and atrial fibrillation. One hundred six patients with coronary artery disease and atrial fibrillation were studied: 40 (36 men, mean age 72 +/- 8 years) treated with a statin and 66 (48 men, mean age 74 +/- 9 years) not treated with a statin. Serum concentrations of carboxy-terminal telopeptide of collagen type I, an index of collagen type I degradation, and high-sensitivity C-reactive protein were measured in all patients. Carboxy-terminal telopeptide of collagen type I levels were significantly higher (p <0.001) in statin-treated patients (0.64 ng/ml, 95% confidence interval [CI] 0.57 to 0.71) compared with nonstatin-treated patients (0.38 ng/ml, 95% CI 0.31 to 0.44). These changes were independent of cholesterol levels (before or after therapy). Statin-treated patients had significantly lower (p <0.001) C-reactive protein levels (0.25 mg/dl, 95% CI 0.23 to 0.28) compared to statin nonusers (1.1 mg/dl, 95% CI 0.92 to 1.25). In conclusion, this study suggests that therapy with statins in patients with coronary artery disease and atrial fibrillation is associated with an increase in collagen degradation and an attenuation of inflammation, independently of cholesterol lowering.

Serum levels of collagen type-I degradation markers are associated with vascular stiffness in chronic heart failure patients.

BACKGROUND: Chronic heart failure (CHF) induces peripheral vasoconstriction, endothelial dysfunction and arterial stiffness by activation of various neurohormonal pathways. The abnormal collagen turnover observed in CHF may be attributed not only to myocardial remodelling, but also to vascular remodelling. However, the effect of collagen metabolism on progressive large artery stiffening in the setting of CHF is understudied. AIMS: The present study was undertaken to investigate the association between circulating markers of collagen turnover and vascular stiffness in patients with CHF. METHODS: Eighty patients (mean age 65+/-11 years, 68 men) with stable CHF and in sinus rhythm, were studied. Serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) and amino-terminal propetide of procollagen type I (PINP), markers of collagen type I degregation and synthesis respectively, were measured in all patients. Pulse wave velocity (PWV) and augmentation index (AIx) of aortic pulse wave form, markers of arterial stiffness, were also determined by applanation tonometry. RESULTS: Peripheral PWV was inversely associated with serum CITP levels (r=-0.585, p<0.001). AIx although weakly was negatively correlated with serum CITP levels (r=-0.285, p=0.01). Multiple regression analysis showed that peripheral PWV remained independently associated with serum CITP levels after adjustment for all confounding variables. CONCLUSIONS: Findings from the present study imply a possible link between altered collagen metabolism and peripheral vascular stiffness in CHF.

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.

Association between glycosylated hemoglobin, left ventricular mass and aortic function in nondiabetic individuals with insulin resistance.

OBJECTIVE: An association between glycosylated hemoglobin (GHb) and cardiovascular mortality in nondiabetic individuals has recently been reported. Prompt detection of nondiabetic individuals with high-normal GHb and early cardiovascular involvement may be of value for preventive strategies. In this investigation, a possible relationship between GHb, aortic function and left ventricular (LV) mass in nondiabetic individuals has been studied. METHODS: A total of 263 nondiabetic African-Americans, aged 22-63 (mean 42 +/- 8) years were studied. All individuals were first degree relatives of diabetic patients, had normal oral glucose tolerance test (2-h OGTT) and decreased peripheral action of insulin. LV diameters and mass (echocardiography); ascending and abdominal aortic distensibility (echocardiography, arterial pressure); pulse wave velocity (PWV; electrocardiography, Doppler); fasting glucose; GHb; insulin sensitivity index (S(I)) and 2-h OGTT were measured. Multiple linear and logistic regression analyses were used to identify significant independent associations of fasting glucose; GHb; S(I) and 2-h OGTT with aortic function and LV mass. RESULTS: In fully adjusted multivariate logistic regression analysis, GHb predicted lower values of aortic distensibility (odds ratio (OR) 1.67 95% CI (1.04-2.75), P=0.04); higher PWV (OR 1.79 95% CI (1.09-2.93), P=0.022); and higher values of LV mass (OR 1.56 95% CI (1.08-2.88), P=0.029). Fasting glucose, S(I), and 2 h OGTT were not associated with aortic function and LV mass. CONCLUSION: Higher GHb concentrations, even within 'normal' range, are independently associated with stiffer aorta and increased LV mass and thus may detect nondiabetic individuals at increased cardiovascular risk.

Leukocyte activation after coronary stenting in patients during the subacute phase of a previous ST-elevation myocardial infarction.

OBJECTIVE: To study leukocyte activation after percutaneous coronary intervention in patients with previous ST elevation myocardial infarction. METHODS: Neutrophil and monocyte activation (by flow cytometric assessment of the surface expression of CD11b and CD62L adhesion molecules) was assessed in 39 patients during the subacute period of a previous ST elevation myocardial infarction initially treated with fibrinolytic agents, before and after diagnostic coronary angiography (coronary angiography control phase) as well as before and after stent implantation (percutaneous coronary intervention phase). Simultaneous evaluation of C-reactive protein (C-reactive protein immonoturbidimetry) and plasma cytokine levels (interleukins-1, -6, -10 and tumor necrosis alpha by immunoassay) was also performed. To track the earliest detectable change in the first few minutes after stent deployment, all measurements were performed before and 60 min after the procedures. RESULTS: CD11b expression increased 1 h after stent deployment in neutrophils (P<0.0001) and monocytes (P<0.0001). A comparable increase, however, was also observed after coronary angiography (neutrophils, P=0.03; monocytes, P=0.01), although the increase of CD11b expression was greater after percutaneous coronary intervention on both neutrophils (90 vs. 40%, P=0.014) and monocytes (65 vs. 33%, P=0.04). CD62L expression decreased significantly after percutaneous coronary intervention (neutrophils, P=0.01; monocytes, P=0.006), but remained unchanged after coronary angiography. Plasma cytokine and C-reactive protein concentrations did not change after the procedures. CONCLUSION: CD62L appears to be a specific and reliable early cellular biomarker of leukocyte activation after percutaneous coronary intervention, when this procedure is performed in patients with previous ST elevation myocardial infarction. Whether this marker represents also a potential predictor of future events and/or restenosis in this group of patients remains to be defined.

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.

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.

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.

Cardiovascular effects of type 1 diabetes mellitus in children.

Previous studies have shown that type 1 diabetes mellitus (DM) is associated with cardiovascular abnormalities. Early detection and treatment of these abnormalities may help to prevent the natural progression of the disease. The present study was undertaken to define early cardiovascular abnormalities in children with type 1 DM. Simultaneous evaluation of multiple cardiovascular parameters was performed in 14 children with type 1 DM and 14 age-and gender-matched normal subjects. Measurements of carotid artery intima-media thickness (cIMT, echocardiography), carotid and aortic (ascending and abdominal) distensibility (echocardiography, brachial artery blood pressure), aortic pulse wave velocity (carotid to femoral artery, Doppler), and left ventricular dimensions, mass, and function (echocardiography) were performed. Diabetic children demonstrated a greater cIMT (0.36 +/- 0.04 mm vs 0.31 +/- 0.03 mm, p = 0.002) and decreased carotid artery distensibility (4.4 +/- 1.6 cm(2) . dynes(-1) . 10(-6) vs 6.0 +/- 1.9 cm(2) . dynes(-1) .10(-6), p < 0.01) compared to control. Aortic pulse wave velocity was increased in DM (6.70 +/- 0.39 vs 6.30 +/- 0.31, p = 0.02) compared to control. Left ventricular diameters, mass, and systolic and diastolic function did not differ between the 2 groups. Simultaneous assessment of multiple cardiovascular parameters in children with type 1 DM revealed impaired carotid artery structure and function, and decreased elastic properties of the aorta, before demonstrable changes in left ventricular structure and function could be detected.

Plasma leptin and adiponectin concentrations correlate with cardiometabolic risk and systemic inflammation in healthy, non-obese children.

BACKGROUND: Plasma adipocytokines are associated with metabolic profile and cardiovascular risk in obese children. OBJECTIVE: To investigate the association of plasma leptin and adiponectin concentrations with cardiometabolic risk profile and systemic inflammation in non-obese children. SUBJECTS: We studied 170 healthy, non-obese children (86 males, mean age 10±2 years). METHODS: Children's current body mass index (BMI), plasma leptin and adiponectin concentrations, lipid profile, fasting plasma glucose and high sensitivity C reactive protein (hsCRP) were measured. RESULTS: After adjustment for age, gender and BMI, plasma leptin concentrations were positively associated with hsCRP (t=2.72, p=0.009) and fasting plasma glucose (t=4.27, p<0.0001); plasma adiponectin concentrations were negatively associated with hsCRP (t=-3.31, p=0.0016); and positively with high density lipoprotein cholesterol (t=2.32, p=0.02). Children in the highest quartile of leptin/adiponectin (L/A) ratio demonstrated significantly higher BMI, systolic blood pressure, hsCRP, triglycerides and fasting glucose and the lowest high density lipoprotein (HDL) compared to lower L/A ratio quartiles. CONCLUSIONS: Alterations in plasma leptin and adiponectin may help to reclassify non-obese children, detecting those with more unfavorable risk profiles independent of BMI status.

Chest pain in patients with arterial hypertension, angiographically normal coronary arteries and stiff aorta: the aortic pain syndrome.

INTRODUCTION: Arterial hypertension is often associated with a stiff aorta as a result of collagen accumulation in the aortic wall and may produce chest pain. In the present study, possible interrelationships between aortic function, collagen turnover and exercise-induced chest pain in patients with arterial hypertension and angiographically normal coronary arteries were investigated. METHODS: Ninety-seven patients with arterial hypertension, angiographically normal coronary arteries and no evidence of myocardial ischemia on nuclear cardiac imaging during exercise test were studied. Of these, 43 developed chest pain during exercise (chest pain group) while 54 did not (no chest pain group). Carotid femoral pulse-wave velocity (PWVc-f) was used to assess the elastic properties of the aorta. Amino-terminal pro-peptides of pro-collagen type I, (PINP, reflecting collagen synthesis), serum telopeptides of collagen type I (CITP, reflecting collagen degradation), pro-metalloproteinase 1 (ProMMP-1), and tissue inhibitor of metalloproteinase 1 (TIMP-1, related to collagen turnover) were measured in plasma by immunoassay. RESULTS: The chest pain group had higher PWVc-f, higher and /CITP ratio, and lower proMMP-1/ TIMP-1 ratio compared to the no chest pain group. PWVc-f (t=2.53, p=0.02) and PINP (t=2.42, p=0.02) were independently associated with the presence of chest pain in multiple regression analysis. CONCLUSIONS: Patients with arterial hypertension, exercise-induced chest pain and angiographically normal coronary arteries, without evidence of exercise-induced myocardial ischemia, had a stiffer aorta compared to those without chest pain. Alterations in collagen type I turnover that favor collagen accumulation in the aortic wall may contribute to aortic stiffening and chest pain in these patients.