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.

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.

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.

Regional and overall aortic function in nondiabetic individuals with insulin resistance and normal glucose tolerance.

CONTEXT: Insulin resistance is associated with altered vascular function in diabetes. OBJECTIVE: The objective of the study was to define the overall and regional aortic function as well as the changes of aortic function over time in nondiabetic individuals with insulin resistance and a normal oral glucose tolerance test (OGTT). DESIGN: This was a cross-sectional and longitudinal analysis with 12 months follow-up. SETTING: The setting of the study was in primary care. PATIENTS: Nondiabetic individuals (n = 181, mean age 42 ± 8 y) with a normal OGTT and insulin resistance as defined by the insulin sensitivity index (ISI) participated in the study. INTERVENTIONS: ISI was estimated from serial measurements of plasma insulin and glucose during an iv glucose tolerance test. Ascending and abdominal aortic distensibility (AoD) and stiffness index-ß (AoSI) were assessed using echocardiography. Carotid-to-femoral artery pulse wave velocity (PWVc-f; an index of overall aortic function) was measured from carotid and femoral arteries Doppler flow velocities recorded simultaneously with an electrocardiogram. Associations between ISI, AoD, AoSI, and PWVc-f were assessed using linear regression analyses and ANOVA. Differences between baseline and 12 months were compared using a paired t test. MAIN OUTCOME MEASURES: AoD and AoSI associations as well as changes over a 12-month period in relation to ISI were measured. RESULTS: Ascending AoD (P = .01) and ascending AoSI (P = .025) were significantly associated with ISI; in contrast, abdominal AoD and AoSI and PWVc-f did not. Changes in AoD, AoSI, and PWVc-f over time were more prominent in individuals with low ISI compared with those with high ISI. CONCLUSIONS: The significant associations between ISI and aortic function suggest that insulin resistance may affect the cardiovascular system, even when OGTT is normal.

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.

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.

Mechanisms of platelet activation in acute coronary syndromes.

Platelets are known to play a fundamental role in acute coronary syndromes. After atherosclerotic plaque rupture, platelets can form pathogenic, occlusive thrombi leading to acute ischemic events. Today there are promising results from recently developed antiplatelet agents. However, morbidity and mortality from acute coronary syndromes remain significant despite the administration of combination therapies (aspirin, thienopyridines). Sharing similar mechanisms, platelets may also form a thin monolayer in areas of damaged endothelium contributing to primary hemostasis. For this reason, administration of antiplatelet drugs is often associated with increased bleeding risk. As a result, currently available antiplatelet therapy cannot be characterized as optimal. The precise mechanisms of platelet activation in acute coronary syndromes are still under investigation. The study of basic mechanisms of platelet adhesion, activation and aggregation after atherosclerotic plaque rupture may help to define new targets for their inhibition. In the future, newer antiplatelet agents may offer more comprehensive platelet inhibition without interfering with primary hemostasis, thus offering greater protection with lower hemorrhagic risk.

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.

Associations between collagen synthesis and degradation and aortic function in arterial hypertension.

BACKGROUND: Studies have suggested that collagen accumulation in the aortic wall may contribute to the stiff aorta in arterial hypertension. However, data in human hypertension are limited. In this investigation, relations between markers of collagen metabolism and aortic function in patients with arterial hypertension were evaluated. METHODS: We studied 72 hypertensive patients (age 53 +/- 5 years) and 27 age- and gender-matched normotensive individuals. Elastic properties of the aorta were assessed by aortic pulse wave velocity (carotid-to-femoral pulse wave velocity (PWVc-f)). Free amino-terminal propeptides of precollagen type I (PINP, reflecting collagen I synthesis), serum telopeptides of collagen type I (CITP, an index of collagen I degradation), free amino-terminal propeptides on precollagen type III (PIIINP, reflecting collagen III metabolism), prometalloproteinase-1 (proMMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined by commercially available immunoassays. RESULTS: Patients with arterial hypertension had greater PWVc-f (P = 0.01); and higher levels of PINP/CITP compared to control (P = 0.04). PWVc-f was significantly associated with PINP/CITP ratio (analysis of variance (ANOVA), P = 0.03). Hypertensive patients had significantly higher levels of proMMP-1/TIMP-1 (P = 0.04); PWVc-f was significantly associated with proMMP-1 (ANOVA, P = 0.03) and proMMP-1/TIMP-1 (ANOVA, P = 0.04). Associations between PWVc-f and proMMP-1 and between PWVc-f and PINP/CITP ratio remained significant after adjustment for PWVc-f confounders and antihypertensive treatment. CONCLUSIONS: Alterations in collagen turnover that favor collagen type I synthesis; as well as proMMP-1 expression are related to increased aortic stiffness in treated hypertensive individuals without left ventricular (LV) hypertrophy.

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.

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.

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.

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.

Effect of angiotensin-converting enzyme insertion/deletion genotype on collagen type I synthesis and degradation in patients with atrial fibrillation and arterial hypertension.

OBJECTIVE: The present study was undertaken to assess the impact of the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphisms on circulating markers of collagen type I synthesis and degradation, and also to study the effect of therapy with ACE inhibitors on these markers in hypertensive patients with atrial fibrillation (AF). RESEARCH DESIGN AND METHODS: ACE I/D genotypes were assessed in 158 hypertensive patients (71 +/- 9 years; 72 male) with AF and 174 patients with arterial hypertension in sinus rhythm (SR) (71 +/- 9 years; 88 male). Serum concentrations of amino-terminal propeptide of pro-collagen type I (PINP) and of carboxy-terminal telopeptide of collagen type I (CITP), indices of collagen type I synthesis and degradation, respectively, were measured. RESULTS: Of the 332 study participants, 74 (22.3%) were I/I, 158 (47.6%) were I/D and 100 (30.1%) were D/D carriers. Genetic variation in ACE significantly influenced serum CITP levels in AF patients (p = 0.011). CITP levels were lower in D allele carriers (DD and ID) compared with I/I carriers. There was no difference in PINP levels between the different ACE genotype groups (p = 0.302). Patients treated with ACE inhibitors had higher CITP levels compared with those not treated (p = 0.036). CONCLUSIONS: This study suggests that the presence of the D allele in hypertensive patients with AF is associated with attenuation of type-I collagen degradation, and that therapy with ACE inhibitors increases degradation of collagen type I. The data indicate a subgroup of patients with AF and arterial hypertension who may benefit to a greater extent from therapy with ACE inhibitors, thus, providing a basis for pharmacogenetics.

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.

Circulating levels of collagen type I degradation marker depend on the type of atrial fibrillation.

AIMS: To investigate the hypothesis that circulating levels of collagen type I degradation or synthesis markers are associated with the presence and pattern of atrial fibrillation (AF). METHODS AND RESULTS: We assessed the serum concentrations of amino-terminal propeptide of procollagen type I (PINP) and of carboxy-terminal telopeptide of collagen type I (CITP), indexes of collagen type I synthesis and degradation, respectively, in 98 paroxysmal AF (PAF) patients (65 +/- 14 years, 62 men), in 80 persistent AF (PsAF) patients (73 +/- 8 years, 32 men), in 114 permanent AF (PmAF) patients (73 +/- 10 years, 54 men), and in 180 patients in sinus rhythm (SR) (66 +/- 13 years, 88 men) who represented a control group. Serum CITP levels were higher (P < 0.001) in AF patients [0.41 ng/mL, 95% confidence interval (CI) 0.38-0.44] when compared with SR patients (0.29 ng/mL, 95% CI 0.26-0.33) and were significantly different between the three AF pattern groups (P < 0.001). Patients with PAF (0.31 ng/mL, 95% CI 0.26-0.36) had lower CITP levels when compared with patients with PsAF (0.41 ng/mL, 95% CI 0.34-0.47) (P = 0.006), as well as with PmAF patients (0.49 ng/mL 95% CI, 0.43-0.56) (P < 0.001). Levels of CITP tended to be lower (P = 0.219) in PsAF patients when compared with sustained AF patients. No differences were found in PINP levels between AF and SR study groups (P = 0.637) as well as between the three AF pattern groups (P = 0.301). CONCLUSION: In the clinical setting, circulating levels of collagen type I degradation marker are associated with both type and duration of AF. Further studies are needed to evaluate the clinical use of serum concentrations of CITP as a potential diagnostic, prognostic, and therapeutic target in patients with AF.

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.