Circulating level of microparticles and their correlation with arterial elasticity and endothelium-dependent dilation in patients with type 2 diabetes mellitus

ObjectiveThis study was designed to measure the circulating level of microparticles (MP) in patients with type 2 diabetes mellitus versus healthy volunteers and to evaluate their correlation with arterial elasticity and endothelium-dependent dilation.MethodsFlow cytometry was used to measure the circulating levels of MP, including annexinV+MP, platelet-derived microparticles (PMP), leukocyte-derived microparticles (LMP) and endothelial microparticles (EMP), in 63 patients with type 2 diabetes mellitus and 29 healthy volunteers. Brachial ankle pulse wave velocity (baPWV) and endothelium-dependent flow-mediated dilation (FMD) of the brachial artery were also measured.ResultsThe levels of annexinV+MP, PMP, LMP, CD31+/CD42?EMP and CD51+EMP increased significantly in diabetic patients compared with healthy controls (P < 0.001). Correlation analysis showed that HbA_1c was positively correlated to CD31+/CD42?EMP (r_s = 0.337, P = 0.008) and CD51+EMP (r_s = 0.266, P = 0.038). FMD in diabetic patients was significantly lower than that in healthy individuals (P = 0.007). FMD was negatively correlated to CD31+/CD42?EMP (r_s = ?0.441, P = 0.008) and CD51+EMP (r_s = ?0.405, P = 0.016). baPWV level in diabetic patients was significantly higher than that in healthy individuals (P < 0.001). baPWV was positively correlated to CD31+/CD42?EMP (r_s = 0.497, P < 0.001) and CD51+EMP (r_s = 0.428, P = 0.001). Multiple regression analysis indicated that EMP was an independent risk factor of FMD and baPWV.ConclusionsThe circulating level of microparticles increases in patients with type 2 diabetes. The level of endothelial microparticles is closely associated with vascular dysfunction.     

CD31+ T cells represent a functionally distinct vascular T cell phenotype

In contrast to CD3⁺/CD31^? cells, CD3⁺/CD31⁺ cells aid in endothelial repair and revascularization. There are limited data regarding the functional differences between circulating CD3⁺/CD31⁺ and CD3⁺/CD31^? cells that may contribute to their divergent cardiovascular effects. The aim of the present study was to characterize functional differences between CD3⁺/CD31⁺ and CD3⁺/CD31^? cells. To address this aim, migratory capacity, proangiogenic cytokine release and apoptotic susceptibility of CD3⁺/CD31⁺ and CD3⁺/CD31^? cells were determined. Human CD3⁺/CD31⁺ and CD3⁺/CD31^?cells from peripheral blood were isolated using magnetic-activated cell sorting. CD3⁺/CD31⁺ cells demonstrated significantly higher (～60%) migratory capacity to the chemokines SDF-1α (655 ± 99 vs. 273 ± 54 AU) and VEGF (618 ± 99 vs. 259 ± 57 AU) vs. CD3⁺/CD31^? cells. Release of angiogenic cytokines G-CSF, interleukin-8 and matrix metallopeptidase-9 were all ～100% higher (P < 0.05) in CD3⁺/CD31⁺ than CD3⁺/CD31^? cells. CD3⁺/CD31⁺ cells exhibited significantly higher intracellular concentrations of active caspase-3 (2.61 ± 0.60 vs. 0.34 ± 0.09 ng/mL) and cytochrome-c (21.8 ± 1.4 vs. 13.7 ± 1.0 ng/mL). In summary, CD3⁺/CD31⁺ cells have greater migratory and angiogenic cytokine release capacity, but are more susceptible to apoptosis compared with CD3⁺/CD31^? cells. Enhanced migratory capacity and angiogenic cytokine release may contribute to the vasculogenic properties of this unique T cell subpopulation.     

Differential expression of Toll-like receptor 4 and human monocyte subsets in acute myocardial infarction

ObjectiveTo investigate the involvement of Toll-like receptor 4 (TLR4) expression on two monocyte subsets in the pathologic processes related to acute coronary syndrome. How monocytes, which have recently been shown to comprise two distinct subsets, mediate the process of coronary plaque rupture remains to be fully elucidated. Recent studies have shown that TLR4 is involved in monocyte activation of patients with accelerated forms of atherosclerosis.MethodsWe enrolled 65 patients with acute myocardial infarction (AMI, n = 22), unstable angina pectoris (UAP, n = 16), and stable angina pectoris (SAP, n = 27) who underwent coronary angiography and 15 healthy controls. The expression of TLR4 on two monocyte subsets (CD14⁺CD16^? and CD14⁺CD16⁺) was measured by flow cytometry.ResultsIn patients with AMI, TLR4 was more expressed on circulating CD14⁺CD16⁺ monocytes than on CD14⁺CD16^? monocytes (p < 0.001). The expression levels of TLR4 on CD14⁺CD16⁺ monocytes were significantly elevated in patients with AMI compared with other 3 groups. TLR4 expression levels on CD14⁺CD16⁺ monocytes were significantly elevated at the culprit site compared with the systemic level (p = 0.044). The up-regulation of TLR4 on admission was remarkably decreased 12 days after AMI (p < 0.001). In addition, plasma levels of tumor necrosis factor-α were positively correlated with TLR4 expression levels on monocytes in patients with AMI (r = 0.47, p = 0.027).ConclusionTLR overexpression on CD14⁺CD16⁺ monocytes in AMI, as demonstrated both in the circulation and at the coronary culprit site, might be associated with the pathogenesis of AMI.     

Unstable shoes increase energy expenditure of obese patients

BackgroundErgonomic unstable shoes, which are widely available to the general population, could increase daily non-exercise activity thermogenesis as the result of increased muscular involvement. We compared the energy expenditure of obese patients during standing and walking with conventional flat-bottomed shoes versus unstable shoes.MethodsTwenty-nine obese patients were asked to stand quietly and to walk at their preferred walking speed while wearing unstable or conventional shoes. The main outcome measures were metabolic rate of standing and gross and net energy cost of walking, as assessed with indirect calorimetry.ResultsMetabolic rate of standing was higher while wearing unstable shoes compared with conventional shoes (1.11 ± 0.20 W/kg^?1vs 1.06 ± 0.23 W/kg^?1, P = .0098). Gross and net energy cost of walking were higher while wearing unstable shoes compared with conventional shoes (gross: 4.20 ± 0.42 J/kg^?1/m^?1vs 4.01 ± 0.39 J/kg^?1/m^?1, P = .0035; net: 3.37 ± 0.41 J/kg^?1/m^?1vs 3.21 ± 0.37 J/kg^?1/m^?1; P = .032).ConclusionIn obese patients, it is possible to increase energy expenditure of standing and walking by means of ergonomic unstable footwear. Long-term use of unstable shoes may eventually prevent a positive energy balance.     

Coptisine exert cardioprotective effect through anti-oxidative and inhibition of RhoA/Rho kinase pathway on isoproterenol-induced myocardial infarction in rats

ObjectiveBecause myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischemia is the focus of intense research. Coptisine is an isoquinoline alkaloid extracted form Coptidis Rhizoma. This study aims to elucidate if coptisine is responsible for cardioprotection using myocardial infarction (MI) rat models and investigate its potential mechanism of action.MethodsMyocardial infarction was produced in rats with 85 mg kg^?1 isoproterenol administered subcutaneously twice at an interval of 24 h. The rats were randomized into 7 groups: (I) Normal; (II) ISO; (III) ISO + fasudil; (IV) ISO + isosorbide dinitrate (ISDN) and (V–VII) ISO + coptisine (25, 50 and 100 mg kg^?1). Cardiac function and markers of cardiac ischemic were assessed after MI.ResultsRats pretreated with coptisine (25, 50 and 100 mg kg^?1) for 21 days and received subcutaneously injected with ISO (85 mg kg^?1) on the 20th and 21st day at an interval of 24 h. The results suggested that coptisine has strong antioxidant activity, and it can maintain cell membrane integrity, ameliorate mitochondrial respiratory dysfunction, reduce myocardial cells apoptosis, inhibit RhoA/ROCK expression induced by high-dose isoproterenol administration.ConclusionsCoptisine provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage.     

Can crossover and maximal fat oxidation rate points be used equally for ergocycling and walking/running on a track?

AimTo verify whether exercise intensities at the crossover point (COP) and maximal lipid oxidation (Lipox_max) can be used interchangeably regardless of exercise mode, this study compared COP, Lipox_max and maximal fat oxidation rate (MFO) obtained during two modes of submaximal metabolic exercise tests: stationary cycling under laboratory conditions and walking/running on a track.MethodsAfter preliminary indirect maximal progressive tests, 15 healthy subjects randomly performed submaximal exercise tests on a stationary cycle ergometer (E) and on a track (T), during which gas exchanges and substrate oxidation rates were measured.ResultsThere were no significant mean differences in COP [heart rate (HR): 149 ± 23 beats.min^?1 (T), 145 ± 28 beats.min^?1 (E); VO₂: 2168 ± 896 mL.min^?1 (T), 2052 ± 714 mL.min^?1 (E)], Lipox_max [HR: 127 ± 27 beats.min^?1 (T), 126 ± 23 beats.min^?1 (E); VO₂: 1638 ± 839 mL.min^?1 (T), 1696 ± 656 mL.min^?1 (E)] or MFO [498.3 ± 192.0 mg.min^?1 (T), 477.7 ± 221.5 mg.min^?1 (E)] between the two modes of exercise. However, Bland–Altman analysis showed a clear disagreement between the two exercise modes and, in particular, a large random error [bias ± random error: for COP, ?3.5 ± 53.2 beats.min^?1 (HR), ?116.8 ± 1556.4 mL.min^?1 (VO₂); for Lipox_max, ?0.4 ± 43.3 beats.min^?1 (HR), ?5.7 ± 1286.4 mL.min^?1 (VO₂); and for MFO, ?20.6 ± 384.9 mg.min^?1].ConclusionThis study showed that, in young, healthy, reasonably fit subjects, exercise mode can affect intensities at the COP and the Lipox_max. These results, which now have to be confirmed in patients with metabolic defects, suggest the need to perform specific tests to make individualized adaptations to physical activity outside of clinical settings.     

Deficient or abundant but unable to fight? Estimation of circulating FoxP3+ T regulatory cells and their counteracting FoxP3− in rheumatoid arthritis and correlation with disease activity

Aim of the workPersistent inflammation and recurring activity in rheumatoid arthritis (RA) daring a quarterback of T regulatory cells (Tregs) intrigued rheumatologists. Tregs’ most specific marker is the forkhead box P3 (FoxP3) denoting FoxP3⁺ cells as suppressors whereas FoxP3^? as effectors. This study evaluates subset distribution of peripheral blood (PB) CD4⁺CD25⁺ Tregs according to FoxP3 expression in RA to better understand its role in pathogenesis.Patients and methodsIn our observational cross-sectional study PB Tregs from 40 RA patients and 20 age and sex matched healthy controls (HC) were characterized and quantified by flow cytometry. Disease activity was evaluated by DAS28. Patients were divided into: active RA group (ARA) and remission RA group (RRA).ResultsSignificantly higher CD4⁺CD25⁺FoxP3⁺ Tregs were found on comparing RRA, ARA patients and HC (mean 153.25 ± 6.29, 136.3 ± 3.27 and 97.25 ± 6.25, respectively) with a statistically highly significant difference (F = 553.13, p < 0.001). CD4⁺CD25⁺FoxP3^? increased 3-folds in RRA and 4-folds in ARA compared to HC and CD4⁺CD25⁺FoxP3⁺ increased 1.6-folds in RRA and 1.5-folds in ARA. Thus the ratio of FoxP3^?/FoxP3⁺ cells is altered from 1:3 in HC to 2:3 in RRA and 1:1 in ARA. CD4⁺CD25⁺FoxP3⁺ had a highly significant negative correlation with disease activity score DAS28 (r = ?0.86, p < 0.001).ConclusionThough CD4⁺CD25⁺FoxP3⁺ and CD4⁺CD25⁺FoxP3^? are both increased in RA, their balance is more important; abundant FoxP3^? cells with effector function have the upper hand over suppressive FoxP3⁺ cells. This imbalance relates to RA presence and activity. Reinforcing FoxP3 expression might be a good potential therapeutic target in RA.     

Endothelin-1 levels predict endothelial progenitor cell mobilization after acute myocardial infarction

IntroductionEndothelin-1 (ET-1), circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) are well-known modulators of endothelial function with important cardiac effects after an acute myocardial infarction. However, the relationship between them has never been assessed.The objective of the present study was to establish the relationship between ET-1, CEC, and EPC concentrations after ST-elevation myocardial infarction (STEMI).MethodsEndothelin-1, CEC, and EPC levels were measured in 61 patients presenting with a first STEMI. Samples were withdrawn acutely 6–24 h and 1 week after admission. Assessments included reperfusion outcomes (angiography), left ventricular ejection fraction (echocardiography), and 30-day mortality.ResultsMean age was 60.6 ± 12.6 years and 45 (74%) were males. Higher ET-1 plasma levels were associated with lower EPC count after 1 week (7.45 ± 2.53 pg/ml if EPCs in the first quartile vs 5.72 ± 1.49 pg/ml if EPCs in the fourth quartile; P = 0.04).In contrast with CEC and EPC count, higher ET-1 concentrations on admission were associated with Killip ≥ 2 (9.92 ± 2.01 pg/ml vs 7.32 ± 2.13 pg/ml; P < 0.001), post-reperfusion thrombolysis in myocardial infarction (TIMI) < 3 (8.65 ± 2.86 pg/ml vs 5.87 ± 1.93 pg/ml; P = 0.002), myocardial blush grade (MBG) < 3 (7.46 ± 2.48 pg/ml vs 5.99 ± 2.01 pg/ml; P = 0.004) and higher 30-day mortality (10.29 ± 2.02 pg/ml vs 6.57 ± 2.20 pg/ml; P = 0.005).ConclusionsIn STEMI patients, high ET-1 levels on admission predict a lower EPC mobilization after 1 week. Endothelin-1 provides better clinical, angiographic and echocardiographic information for prognosis than do CEC and EPC concentrations.     

PKA-mediated eNOS phosphorylation in the protection of ischemic preconditioning against no-reflow

ObjectiveTo investigate whether ischemic preconditioning (IP) can reduce myocardial no-reflow by activating endothelial (e-) nitric oxide synthase (NOS) via the protein kinase A (PKA) pathway.Methods and ResultsIn a 90-min ischemia and 3-h reperfusion model, minipigs were assigned into sham, ischemia–reperfusion (IR), IR + IP, IR + IP + L-NNA (an eNOS inhibitor, 10 mg·kg^? 1), IR + IP + H-89 (a PKA inhibitor, 1.0 μg·kg^? 1·min^? 1), IR + L-NNA, and IR + H-89 groups. IP pretreatment improved cardiac function and coronary blood flow, decreased the activities of creatine kinase by 36.6% after 90 min of ischemia and by 32.8% after 3 h of reperfusion (P < 0.05), reduced the no-reflow areas from 49.9% to 11.0% (P < 0.01), and attenuated the infarct size from 78.2% to 35.4% (P < 0.01). IP stimulated myocardial PKA activities and the expression of PKA and Ser¹³³ phosphorylated (p-) cAMP response element-binding protein (CREB) in the reflow and no-reflow myocardium, and enhanced the activities of constitutive NOS and the phosphorylation of eNOS at Ser¹¹⁷⁹ and Ser⁶³⁵ in the no-reflow myocardium. IP suppressed the expression of tumor necrosis factor-α and P-selectin, and attenuated cardiomyocytes apoptosis by regulating the expression of Bcl-2 and caspase-3 in the reflow and no-reflow myocardium. The eNOS inhibitor L-NNA completely canceled these beneficial effects of IP without any influence on PKA activity, whereas the PKA inhibitor H-89 partially blocked the IP cardioprotective effects and eNOS phosphorylation at the same time.ConclusionIP attenuates myocardial no-reflow and infarction after ischemia and reperfusion by activating the phosphorylation of eNOS at Ser¹¹⁷⁹ and Ser⁶³⁵ in a partly PKA-dependent manner.     

Circulating angiogenic cell populations, vascular function, and arterial stiffness

ObjectiveSeveral bone marrow-derived cell populations have been identified that may possess angiogenic activity and contribute to vascular homeostasis in experimental studies. We examined the extent to which lower quantities of these circulating angiogenic cell phenotypes may be related to impaired vascular function and greater arterial stiffness.MethodsWe studied 1948 Framingham Heart Study participants (mean age, 66 ± 9 years; 54% women) who were phenotyped for circulating angiogenic cells: CD34+, CD34+/KDR+, and early outgrowth colony forming units (CFU). Participants underwent non-invasive assessments of vascular function including peripheral arterial tone (PAT), arterial tonometry, and brachial reactivity testing.ResultsIn unadjusted analyses, higher CD34+ and CD34+/KDR+ concentrations were modestly associated with lower PAT ratio (β = ?0.052 ± 0.011, P < 0.001 and β = ?0.030 ± 0.011, P = 0.008, respectively) and with higher carotid-brachial pulse wave velocity (β = 0.144 ± 0.043, P = 0.001 and β = 0.112 ± 0.043, P = 0.009), but not with flow-mediated dilation; higher CD34+ was also associated with lower carotid-femoral pulse wave velocity (β = ?0.229 ± 0.094, P = 0.015). However, only the association of lower CD34+ concentration with higher PAT ratio persisted in multivariable analyses that adjusted for standard cardiovascular risk factors. In all analyses, CFU was not associated with measures of vascular function or arterial stiffness.ConclusionsIn our large, community-based sample of men and women, circulating angiogenic cell phenotypes largely were not associated with measures of vascular function or arterial stiffness in analyses adjusting for traditional risk factors.     

Decreased fat oxidation during exercise in severe obstructive sleep apnoea syndrome

AimTo assess whether the severity of obstructive sleep apnoea syndrome (OSAS) is associated with altered fat oxidation (FO) during physical exercise in men with type 2 diabetes (T2DM) and/or the metabolic syndrome (MetS).MethodsA total of 105 consecutive overweight or/and T2DM male patients were hospitalized for metabolic check-ups including bioimpedancemetry to measure lean body mass (LBM), standardized exercise calorimetry to assess FO, maximum fat oxidation (MFO) and carbohydrate oxidation (CHO), and OSAS screening using respiratory polygraphy. Twenty patients were classified as having severe OSAS, according to the apnoea/hypopnoea index (AHI), with greater than 30 events/h (mean AHI: 45.2 ± 14.3 events/h). They were group-matched for age, BMI, and the presence of T2DM and/or MetS with two other OSAS groups: mild (AHI < 15 events/h [n = 20]; mean AHI: 8.8 ± 4.5 events/h); and moderate (AHI > 15 events/h and < 30 events/h [n = 20]; mean AHI: 23.7 ± 4.2 events/h).ResultsMFO adjusted for LBM was severely decreased in the severe OSAS group (1.6 ± 1.0 mg.min^?1.kgLM^?1) compared with the moderate (2.5 ± 0.9 mg.min^?1.kgLM^?1; P = 0.008) and mild (2.9 ± 0.8 mg.min^?1.kgLM^?1; P = 0.003) groups. All exercise-intensity levels (20%, 30%, 40% and 60% of the theoretical maximum aerobic power) showed reduced FO levels between the severe and mild-to-moderate OSAS groups. However, no differences in CHO were seen at any level of exercise between groups. Pearson's correlation analysis showed that AHI and the oxygen desaturation index were negatively associated with MFO corrected for LBM (r = 0.41 and r = 0.37, respectively; P < 0.005).ConclusionOSAS severity is associated with altered FO during exercise.     

Salt and the metabolic syndrome

Background and aimsHigh blood pressure in subjects with the metabolic syndrome (MS) is largely related to dietary salt. We investigated in free-living men and women whether increase in dietary salt intake is associated with the presence and severity of the MS.Methods and resultsA total of 766 subjects (251M, 515F) of 44.9 ± 0.5 years/age and SBP/DBP of 120 ± 0.6/77 ± 0.4 mmHg were studied. Twenty-four hour urinary sodium (UNa⁺) and potassium (UK⁺) excretions were 143±2.5 mmol (median: 131.5) and 48 ± 0.9 mmol (median: 44). UNa⁺ was higher in men than in women (median: 155.5 vs. 119.8 mmol/day; P < 0.0001). UK⁺ (r = 0.34; P < 0.0001), measures of obesity (r = 0.26; P < 0.0001) and BP (r = 0.15; P < 0.0001) were significantly associated with UNa⁺. The association with BP was lost after adjusting for weight.Of the 766 subjects, 256 (33.4%) met the NCEP-ATPIII criteria for the MS. Median UNa⁺ in men and women with no traits of the MS was 140 and 116.7 mmol/day, respectively (P < 0.001), increasing to 176 in men and 135 mmol/day in women with 4–5 components of the syndrome (P < 0.001). Weight, BMI and waist increased significantly across the quartiles of UNa⁺ both in men and women; whereas, age, lipids and fasting glucose did not. SBP and DBP were associated with UNa⁺ in men but not in women. UK⁺ correlated with age in men and women (r = 023; P < 0.0001) and with obesity in women (r = 0.14; P = 0.001).ConclusionsUNa⁺ a measure of dietary sodium intake in free-living subjects was markedly increased in subjects with the MS. Higher UNa⁺ was associated with obesity and higher BP, but not with age, dyslipidemia or fasting glucose.     

Increased platelet,leukocyte and endothelial microparticles predict enhanced coagulation and vascular inflammation in pulmonary hypertension

Pulmonary hypertension (PH) is associated with platelet activation, vascular inflammation and endothelial dysfunction leading to often life threatening thrombo-embolic complications. Microparticles (MPs) are cell vesicles with strong coagulatory and inflammatory effects being released during cell activation and apoptosis. As there are currently no established surrogate markers predicting platelet activation and pro-coagulation in PH patients, the aim of the study was to analyze different pro-coagulatory MP populations that might be related to thrombo-embolic complications in PH patients. Circulating MPs from platelet- (PMP, CD31⁺/61⁺), leukocyte- (LMP, CD11b⁺) and endothelial- (EMP, CD62E⁺) origin were measured by flow cytometry in 19 PH patients and were compared to 16 controls. PH patients had increased levels of PMP (PH vs. control 1,016 ± 201 vs. 527 ± 59 counts per min [cpm], P = 0.032), LMP (PH vs. control 31 ± 3 cpm vs. 18 ± 2 cpm, P = 0.001) and EMP (PH vs. control 99 ± 14 cpm vs. 46 ± 6 cpm, P = 0.001). Furthermore, PMP correlated to LMP (PMP vs. LMP: r = 0.75, P < 0.001) and LMP correlated to EMP levels (LMP vs. EMP, r = 0.74, P < 0.001) indicating a functional interaction between the different types of MP. In comparison to non-embolic PH patients, patients with a thrombo-embolic PH suffered from enhanced endothelial cell dysfunction as represented by significantly increased EMP levels (thrombo-embolic PH vs. non-embolic PH 137 ± 27 vs. 72 ± 10, P = 0.02). PH patients have increased levels of platelet-, leukocyte- and endothelial MP indicating an increased vascular pro-coagulation and inflammation which might be related to thrombo-embolic complications as well as PH progression.     

Normalization of visceral adiposity is required to normalize plasma apolipoprotein B levels in response to a healthy eating/physical activity lifestyle modification program in viscerally obese men

ObjectiveLittle is known about how visceral adipose tissue (VAT) influences circulating apolipoprotein B (apoB) levels, which reflect atherogenic risk. We have examined the effects of a 1-year lifestyle modification program on plasma apoB levels in viscerally obese men and compared post-intervention levels to those of a reference group of lean healthy men.MethodsFasting plasma apoB levels were measured in 107 non-diabetic, viscerally obese men, before and after a 1-year lifestyle intervention program aiming at improving nutritional and physical activity/exercise habits.ResultsAfter the intervention, subjects significantly decreased their volume of VAT (Δ = ?26 ± 18%, p < 0.0001) measured by computed tomography and significantly, but modestly reduced their fasting apoB levels (Δ = ?3 ± 14%, p = 0.04). When compared to the reference group, men in the intervention group still had higher apoB levels suggesting that they did not “normalize” their apoB concentrations to the level of the healthy non-obese reference men. To further explore the relationship between VAT and apoB, men in the intervention group were stratified according to quartiles of VAT achieved after the intervention. Only men of the lowest quartile of VAT (corresponding to 844 ± 42 cm³, similar to the value of the reference group; 809 ± 52 cm³ of VAT) showed plasma apoB levels which were similar to those of the reference group (0.98 ± 0.21 vs. 0.99 ± 0.24 g/L, NS, for lowest VAT quartile and reference group, respectively).ConclusionThese results suggest that, in order to “normalize” apoB levels in response to a lifestyle modification program, viscerally obese dyslipidemic men need to achieve levels of VAT similar to healthy non-obese men.     

Plasma levels of antibodies against oxidized LDL are inherited but not associated with HDL-cholesterol level in families with early coronary heart disease

AimsThus far, the prognostic value of reverse left ventricular (LV) remodeling after ST-elevation acute myocardial infarction (STEMI) has not been fully evaluated. We sought to investigate the incidence, major determinants, and long-term clinical significance of reverse LV remodeling in a large series of STEMI patients successfully treated with primary percutaneous coronary intervention (P-PCI).Methods and resultsSerial complete 2D-echocardiograms were obtained within 24 h after P-PCI, and at 1 and 6 months in 512 consecutive reperfused STEMI patients. Reverse remodeling was defined as a reduction >10% in LV end-systolic volume (LVESV) at 6 month follow-up. Reverse LV remodeling occurred in 49% of study population. At follow-up (41.6 ± 23 months), late heart failure (HF) rate was significantly higher among patients without reverse LV remodeling as compared with those with it (32% vs. 11%, P < 0.0001). At multivariate analysis, independent predictors of reverse LV remodeling were a small infarct size measured as peak creatine kinase value (P < 0.0001), a small functional myocardial damage measured as wall motion score index within the infarct zone (P = 0.018) and baseline LVESV (P < 0.0001). After adjustment for several clinical, echographic and angiographic variables, Cox analysis identified reverse LV remodeling as the only beneficial independent predictor of long-term heart failure-free survival (HR: 0.44, 95% CI: 0.275–0.722).ConclusionsReverse LV remodeling occurred in half of successfully reperfused STEMI patients. Small structural and functional myocardial damages within the infarct zone are the major determinants of reverse LV remodeling. As expression of effective myocardial salvage by P-PCI, the reverse remodeling is an important predictor of favorable long-term outcome.     

Failure to increase postprandial blood flow in subcutaneous adipose tissue is associated with tissue resistance to adrenergic stimulation

AimsAdequate adipose tissue blood flow (ATBF) is essential for its metabolic and endocrine functions. From a metabolic point of view, sufficient increases in ATBF after meals permits full storage of excess energy into fat, thus protecting other tissues against the toxic effects of fatty acids and glucose spillover. It was previously shown that postprandial increases in ATBF are blunted in obese and insulin-resistant subjects, and that much of the postprandial ATBF response is the result of β-adrenergic activation. Examination of previously recorded data on postprandial ATBF responses revealed an underlying heterogeneity, with postprandial ATBF being largely unresponsive to food stimuli in a substantial proportion of normal weight healthy people (low responders). Our study tests the hypothesis that this unresponsive pattern is due to resistance to β-adrenergic stimulation in adipose tissue.MethodsFive responders and five low responders were selected from a previously studied cohort and matched for BMI (20.5 ± 0.7 vs 22 ± 1 kg/m², respectively), gender (male/female: 2/3) and age (30 ± 3 vs 37 ± 6 years). Subcutaneous adipose tissue microinfusions of stepwise increasing doses of isoproterenol were performed with concomitant monitoring of blood flow, using the ¹³³Xenon washout technique.ResultsAlthough BMI was similar between responders and low responders, there were significant differences in fat mass (9.9 ± 1.6 vs 14.4 ± 1.6 kg; P < 0.05) and four-point skinfold thickness (33 ± 4 vs 52 ± 16 mm; P < 0.05). Lack of ATBF response to oral glucose was confirmed in the low responder group. In responders, ATBF was higher at baseline (5.4 ± 1 vs 3.4 ± 1 mL/min/100 g of tissue) and responded more distinctly to increasing isoproterenol doses (10^?8 M: 7.6 ± 1.4 vs 4.9 ± 1; 10^?6 M: 12.5 ± 1.7 vs 7.5 ± 1.6; and 10^?4 M: 20 ±1.7 vs 9 ± 0.9 mL/min/100 g of tissue).ConclusionThese data suggest that the lack of glucose-stimulated ATBF is associated with resistance to sympathetic activation in adipose tissue.     

Altered monocyte CD44 expression in peripheral arterial disease is corrected by fish oil supplementation

Background and aimsCD44 and its splice variants can be expressed on all leukocytes, conferring adhesive properties and enhancing cellular recruitment to the endothelium during inflammation. CD44 expression is increased in inflammatory conditions such as rheumatoid arthritis and CD44 variant 3 (CD44v3) expression may be associated with inflammation. We have examined CD44 and CD44v3 expression on peripheral blood monocytes from patients with peripheral arterial disease (PAD) and healthy controls. We have also examined the effect of fish oil supplementation on these markers.Methods and resultsCD44 and CD44v3 were assessed at baseline and following dietary supplementation with fish oil for 12 weeks in both PAD and control groups. Monocytes from PAD patients had higher CD44 expression than those from controls (median intensity fluorescence (MIF): 480 ± 278 vs 336 ± 251 (mean ± SD); p < 0.001). Following 12 weeks dietary supplementation with fish oil, CD44 expression was reduced in PAD patients (MIF: 480 ± 278 vs 427 ± 262; p = 0.05) but not in controls (336 ± 251 vs 355 ± 280; ns). Monocyte CD44v3 expression was lower in cultured monocytes from PAD patients compared to those from controls (0.15 ± 0.15 vs 0.22 ± 0.14 OD units; p < 0.02). This was increased in the PAD group following fish oil supplementation (0.15 ± 0.14 to 0.27 ± 0.23 OD units; p < 0.001).ConclusionMonocyte CD44 and CD44v3 expression are altered in arterial disease but are returned towards levels seen in control subjects by dietary fish oil supplementation.     

Placenta growth factor expression in human atherosclerotic carotid plaques is related to plaque destabilization

Background and purposePlacenta growth factor (PlGF) mediates angiogenesis and inflammation, but its role in human atherosclerosis is unknown. This study was designed to test the hypothesis that PlGF-expression in human atherosclerotic carotid plaques is related to inflammation, vascularization and clinical plaque instability.MethodsThe expression of PlGF, C-reactive protein (CRP) and CD40L was analyzed with Western blots in carotid plaques of 60 patients. Cellular infiltration (CD68, CD3) and vascularization (von-Willebrand-factor) was assessed by immunohistochemistry.ResultsSymptomatic patients showed higher levels of PlGF than asymptomatic patients (115.4 ± 8.2 versus 83.6 ± 10.5 densitometric units (DU), p < 0.05) and higher grading for inflammatory cells and microvessels (CD3: 2.3 ± 0.1 versus 0.6 ± 0.1, p < 0.001, CD68: 2.4 ± 0.1 versus 0.8 ± 0.1, p < 0.001, microvessels: 2.3 ± 0.1 versus 1.5 ± 0.1, p < 0.01). PlGF-expression showed a positive correlation to the expression of CRP (r = 0.5, p < 0.001) and CD40L (r = 0.4, p < 0.01).ConclusionsPlGF-expression within human atherosclerotic lesions is associated with plaque inflammation and microvascular density, suggesting a role for PlGF in plaque destabilization and, thus, in clinical manifestation of the disease.     

Protein and glutamine kinetics during counter-regulatory failure in type 1 diabetes

Background and aimsHealthy individuals counteract insulin-induced hypoglycaemia by increasing glutamine utilization but not proteolysis. Glucagon is important to this response because it increases glutamine uptake. In type 1 diabetes (T1DM) glucagon and epinephrine responses to hypoglycaemia are defective. We investigated whether glutamine and amino acid utilization during hypoglycaemia is altered in T1DM with defective counter-regulatory responses.Methods and resultsEight T1DM patients (duration of diabetes 14 ± 4 years and therefore with presumed defective counter-regulatory response) and eight controls (CON) received a 3 h hypoglycaemic hyperinsulinaemic (0.65 mU/kg per min) clamp coupled to [6,6-²H₂]glucose, [1-¹³C]leucine and [2-¹⁵N]glutamine to trace the relative kinetics.Post-absorptive plasma glucose and glucose uptake were increased in T1DM (9.09 ± 0.99 vs 5.01 ± 0.22 mmol/l and 19.5 ± 0.9 vs 12.6 ± 0.8 μmol/kg per min, p < 0.01). During the clamp T1DM but not CON required exogenous glucose (4.4 ± 1.7 μmol/kg per min) to maintain the hypoglycaemic plateau because the endogenous glucose production was significantly suppressed (p < 0.01). In T1DM the leucine and phenylalanine concentrations were less suppressed from basal (p < 0.05) despite a similar insulin suppression of proteolysis (−16 ± 2 vs −20 ± 4%, p = ns) indicating a defective stimulation of leucine metabolic clearance from basal (+18 ± 3% vs +55 ± 9%, p < 0.01). Glutamine concentration remained unchanged from basal (−7 ± 3% vs −35 ± 3%, p < 0.01) and the clearance of glutamine was markedly defective in T1DM (+6 ± 2%) in comparison with controls (+22 ± 4%; p = 0.02).ConclusionsIn T1DM, the counter-regulatory failure to hypoglycaemia seems to be associated with a defective glutamine utilization. The failure to clear circulating amino acids, specifically glutamine, during hypoglycaemia may adversely affect gluconeogenesis.     

Metabolic syndrome is a predictor for an ECG sign of no-reflow after primary PCI in patients with acute ST-elevation myocardial infarction

Background and aimThe purpose of this study was to evaluate both the predictive value of metabolic syndrome (MS) on no-reflow phenomenon and 30-day clinical outcomes on patients undergoing primary percutaneous coronary intervention (PCI) for acute ST-elevation myocardial infarction (STEMI).Methods and resultsOne hundred and twelve consecutive patients (mean age 57 ± 11 years, 94 male) with acute STEMI treated with primary PCI were analysed prospectively. Sum of ST-segment elevation was obtained immediately before and 60 min after the restoration of TIMI-3 flow. The difference between two measurements was accepted as the amount of ST-segment resolution and was expressed as ∑STR. ∑STR < 50% was accepted as ECG sign of no-reflow phenomenon. Metabolic syndrome was defined based on Adult Treatment Panel-III criteria.The no-reflow was found in 22.3% of the entire group and was significantly higher in patients with MS than those without MS (43.7% vs. 13.7%, p < 0.001). There was no significant difference in no-reflow between patients who had both MS and diabetes mellitus (DM) and patients who had MS but not DM (42.5% vs. 50%, respectively; p > 0.05).ConclusionThe presence of MS may play an important role in the occurrence of no- reflow in STEMI treated with primary PCI.