Cardiorespiratory Fitness and Bone Turnover Markers in Adults With Metabolic Syndrome: The Mediator Role of Inflammation.

The relationship between inflammatory markers and bone turnover in adults is well known, and a negative association between cardiorespiratory fitness (CRF) and inflammatory markers has also been described. Hence, we tested whether the association between CRF and bone turnover markers is mediated by inflammatory markers in adults with metabolic syndrome. A total of 81 adults (58.5 ± 5.0 years, 62.7% women) were included in the analysis. CRF was measured by the 6-min walking test. Serum interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor alpha, high-sensitivity c-reactive protein (hsCRP) and vascular endothelial growth factor, collagen type I cross-linked C-telopeptide, procollagen type I N-terminal propeptide (P1NP), and total osteocalcin were assessed using a sensitive ELISA kit. Body composition was assessed by dual-energy X-ray absorptiometry. Partial correlation was used to test the relationship between CRF, inflammatory markers, and bone turnover markers, controlling for sex, lean mass, and fat mass. Boot-strapped mediation procedures were performed, and indirect effects with confidence intervals not including zero were interpreted as statistically significant. CRF was positively correlated with P1NP levels (r = .228, p = .044) and osteocalcin levels (r = .296, p = .009). Furthermore, CRF was positively correlated with IL-1ß levels (r = .340, p = .002) and negatively correlated with hsCRP levels (r = -.335, p = .003), whereas IL-1ß levels were positively correlated with P1NP levels (r = .245, p = .030), and hsCRP levels were negatively correlated with P1NP levels (r = -.319, p = .004). Finally, the association between CRF and P1NP levels was totally mediated by hsCRP (percentage of mediation = 39.9). Therefore, CRF benefits on bone formation could be dependent on hsCRP concentrations in this population.

Cerebral haemodynamics and oxygenation during whole-body exercise over 5 days at high altitude.

NEW FINDINGS: What is the central question of this study? Impairment and subsequent improvement in cerebral oxygenation during acute and prolonged exposure to high altitude affect exercise performance. This study innovates by investigating the effect of acute and prolonged high-altitude exposure on cerebral haemodynamics during submaximal endurance exercise performed at the same relative intensity. What is the main finding and its importance? Despite exercising at the same relative intensity at sea level and high altitude, participants showed a sustained impairment in cerebral oxygenation after prolonged exposure to high altitude, which might contribute to the absence of improvement in exercise tolerance. ABSTRACT: Deterioration and subsequent improvement in cerebral oxygenation during acute and prolonged hypoxic exposure may affect whole-body exercise performance at high altitude. In this study, we investigated the effect of hypoxic exposure on cerebral haemodynamics at different cortical locations during exercise at the same relative intensity after 1 (D1) and 5 days (D5) at 4350 m. Eleven male subjects performed a submaximal bout of cycling exercise (6 min at 35% + 6 min at 55% + time-to-exhaustion at 75% of peak work rate achieved in the same conditions, i.e. normoxia or hypoxia at sea level) on D1 and D5. Transcranial Doppler and near-infrared spectroscopy were used to assess middle cerebral artery blood velocity and prefrontal and motor cortex oxygenation, respectively. Despite using the same relative intensity, the duration of exercise was reduced on D1 (22.7 ± 5.1 min) compared with sea level (32.2 ± 9.0 min; P < 0.001), with no improvement on D5 (20.9 ± 6.3 min; P > 0.05). Middle cerebral artery blood velocity during exercise was elevated on D1 (+18.2%) and D5 (+15.0%) compared with sea level (P < 0.001). However, prefrontal and motor cortex oxygenation was reduced on D1 and D5 compared with sea level (P < 0.001). This pattern was of similar magnitude between cortical locations, whereas the total haemoglobin concentration increased to a greater extent in the prefrontal versus motor cortex at exhaustion on D1 and D5. In contrast to our primary hypothesis, prefrontal and motor cortex oxygenation and exercise performance did not improve over 5 days at 4350 m. The sustained impairment in cerebral oxygenation might contribute to the absence of improvement in exercise performance after partial acclimatization to high altitude.

Changes in the profile of circulating HDL subfractions in severe obese adolescents following a weight reduction program.

BACKGROUND AND AIMS: Epidemiological studies show that obese adolescents are candidates to suffer cardiovascular pathologies in adulthood. In order to detect subfractions with a diagnostic value for future cardiovascular disorders, we analyzed the complete lipoprotein profile of severely obese adolescents. METHODS AND RESULTS: Twenty-eight obese adolescents free from comorbidities were admitted into a weight reduction program. Anthropometric parameters were monitored. The circulating lipoproteins and glycemia were measured at the beginning and at the end of the study by conventional blood analysis as well as by using lipoprotein electrophoresis. Twenty-one puberty-matched normal-weight adolescents were recruited as controls. After 4 months, participants improved anthropometric parameters. Blood analysis indicated that circulating lipoproteins were in the healthy range during intervention. Nevertheless, results obtained from lipoprotein electrophoresis showed a significant increase in the large high-density lipoprotein subfraction in the obese population at the end of intervention, but significantly lower than normal-weight counterparts. In addition, intermediate- and low-density lipoprotein subfractions were in the healthy range in controls and in obese adolescents during intervention. CONCLUSIONS: Altogether, it seems that the obese adolescents with no comorbidities do not develop a clear dyslipidemia. However, low values of large high-density lipoprotein subfractions could be considered as candidate predictors to develop cardiovascular disease in the future. For this reason, diet and exercise are key tools to fight against this pathology. REGISTRATION NUMBER FOR CLINICAL TRIALS: ISRCTN99414527.

Artificial sweeteners impair endothelial vascular reactivity: Preliminary results in rodents.

BACKGROUND AND AIMS: Prospective epidemiological studies highlighted recently the link between artificial sweeteners (AS) consumption and the risk of developing cardiometabolic diseases. However, underlying mechanisms remain unknown. Thus, the aim of this preliminary study was to characterize, in a healthy rat population, the effect of chronic AS consumption on body composition and vascular function, an early marker for cardiovascular disease. METHODS AND RESULTS: Healthy Wistar rats followed a 10-week standard diet including the consumption of water sweetened or not with a sucralose/acesulfame potassium solution at different concentrations: for moderate consumption at 1 and 2 mg.kg-1.day-1, respectively or high intake at 15 and 15 mg.kg-1.day-1 for both molecules (acceptable daily intake). Body fat composition has been evaluated and ex vivo aortic vasomotor function has been investigated with a pharmacological approach. CONCLUSION: Both groups of AS-treated rats showed a significant increase in subcutaneous and perirenal adipose tissue mass storage, without changes in total body mass. However, rats that have consumed AS at Acceptable Daily Intake (ADI) concentration revealed a significant vascular endothelial dysfunction compared to other groups. These results are interesting because they will help to better explain the observed increase in cardiometabolic risk.

Medex 2015: The key role of cardiac mechanics to maintain biventricular function at high altitude.

NEW FINDINGS: What is the central question of this study? This study is the first to investigate the effects of high-altitude trekking on biventricular mechanics, including measurements of left ventricular subendocardial and subepicardial function. What is the main finding and its importance? We provide new evidence that an increased contractility and untwisting efficiency, a key element of diastolic function, probably plays a key role in preservation of cardiac function during high-altitude trekking. Persistent increased loading conditions during several weeks at high altitude might have a key role in the appearance of left or right ventricular dysfunction. ABSTRACT: Cardiac responses to acute hypoxic exposure have been thoroughly investigated. We analysed the effects of high-altitude trekking (i.e. prolonged hypoxic exposure) on biventricular function, including the evaluation of subendocardial and subepicardial function in the left ventricle (LV). Resting evaluations of LV and right ventricular (RV) function and mechanics were assessed by speckle tracking echocardiography on 20 subjects at sea level and at high altitude (5085 m, after a 10 day ascent). Pulmonary artery systolic pressure was increased at high altitude (sea level, 13.1 ± 5.9 mmHg; high altitude, 26.6 ± 10.8 mmHg; P < 0.001). Left ventricular volumes were decreased, whereas RV volumes were increased at high altitude. Alterations in pulmonary artery systolic pressure and cardiac volumes were correlated with hypoxaemia. We observed neither RV nor LV systolic dysfunction, including analysis of LV subendocardial and subepicardial function. Left ventricular systolic strain rates were enhanced at high altitude. Transmitral and transtricuspid diastolic filling ratios were decreased at high altitude. Diastolic apical rotational rate, untwisting rate and untwisting rate/peak twist ratio (i.e. untwisting efficiency) were enhanced at high altitude. We observed no echocardiographic signs of LV and RV pathological dysfunction at rest at high altitude. In contrast, our data highlighted major changes in the LV mechanics, with an increased LV contractility and a higher untwisting efficiency at high altitude. Biventricular interaction, alterations in loading conditions and an increase in plasma catecholamine concentration might partly explain these modifications. Thus, we demonstrated that LV mechanics (i.e. increased strain rates and untwisting efficiency) have a key role in preservation of cardiac function during high-altitude trekking.

Exercise training restores eNOS activation in the perivascular adipose tissue of obese rats: Impact on vascular function.

OBJECTIVE: This study evaluated in obese rats the effect of exercise training on eNOS expressed in perivascular adipose tissue (PVAT) and its consequences on vascular function. METHODS: Wistar rats were divided in 3 groups: control (standard diet), obese (high fat/high sucrose diet, HFS for 15 weeks), and exercised obese (HFS diet and exercise from week 6 to week 15, HFS-Ex) rats. The eNOS-adiponectin pathway and reactive oxygen species (ROS) were evaluated. Vascular reactivity was assessed on isolated aortic rings with or without PVAT and/or endothelium and exposed or not to the conditioned media of PVAT. RESULTS: Obesity reduced eNOS level and phosphorylation on its activation site in the PVAT and had no impact on the vascular wall. Exercise training was able to increase eNOS and P-eNOS both in the vascular wall and in the PVAT. Interestingly, this was associated with increased level of adiponectin in the PVAT and to lower ROS in the vascular wall. Finally, PVAT of HFS-Ex aorta has eNOS-dependent anticontractile effects on endothelium denuded aortic rings and has beneficial effects on the endothelium-dependent vasorelaxation to ACh. CONCLUSION: Exercise training in obese rats is able to impact PVAT eNOS with subsequent beneficial impact on vascular function.

Transient endothelial dysfunction induced by sugar-sweetened beverage consumption may be attenuated by a single bout of aerobic exercise.

BACKGROUND: This study assessed whether aerobic exercise would attenuate microvascular endothelial dysfunction induced by commercial sugar-sweetened beverage (SSB) consumption. METHODS: Eleven healthy males participated in this randomized, single-blind crossover study. Cutaneous microvascular endothelial function was assessed using laser speckle contrast imaging coupled with post-occlusive reactive hyperemia before and after a) consumption of water; b) consumption of a commercial SSB; c) 30min of aerobic exercise followed by water consumption; and d) 30 minutes of aerobic exercise followed by SSB consumption. Blood glucose and arterial pressure responses were also monitored. Volumes of water and SSB consumed (637.39±29.15 mL) were individualized for each participant, ensuring SSB consumption delivered 1 g of sucrose per kg of body weight. Exercise was performed at 75% of the maximal oxygen uptake heart rate. RESULTS: Compared to water consumption, the commercial SSB elevated blood glucose concentrations in both sedentary (4.69±0.11 vs. 7.47±0.28 mmol/L, P<0.05) and exercised states (4.95±0.13 vs. 7.93±0.15 mmol/L, P<0.05). However, the decrease in microvascular endothelial function observed following sedentary SSB consumption, expressed as the percentage increase from baseline (208.60±22.40 vs. 179.83±15.80%, P=0.01) and the change in peak hyperemic blood flux from basal to post-intervention assessments (-0.04±0.03 vs. -0.12±0.02 ΔCVC, P=0.01), was attenuated following 30min of aerobic exercise. CONCLUSIONS: To our knowledge, this is the first study to provide evidence that a single bout of aerobic exercise may prevent transient SSB-mediated microvascular endothelial dysfunction.

Effects of Sugar-Sweetened Beverage Consumption on Microvascular and Macrovascular Function in a Healthy Population.

OBJECTIVE: To assess vascular function during acute hyperglycemia induced by commercial sugar-sweetened beverage (SSB) consumption and its effect on underlying mechanisms of the nitric oxide pathway. APPROACH AND RESULTS: In a randomized, single-blind, crossover trial, 12 healthy male participants consumed 600 mL (20 oz.) of water or a commercial SSB across 2 visits. Endothelial and vascular smooth muscle functions were assessed in the microcirculation using laser speckle contrast imaging coupled with iontophoresis and in the macrocirculation using brachial artery ultrasound with flow- and nitrate-mediated dilation. Compared with water, SSB consumption impaired microvascular and macrovascular endothelial function as indicated by a decrease in the vascular response to acetylcholine iontophoresis (208.3±24.3 versus 144.2±15.7%, P<0.01) and reduced flow-mediated dilation (0.019±0.002 versus 0.014±0.002%/s, P<0.01), respectively. Systemic vascular smooth muscle remained preserved. Similar decreases in endothelial function were observed during acute hyperglycemia in an in vivo rat model. However, function was fully restored by treatment with the antioxidants, N-acetylcysteine and apocynin. In addition, ex vivo experiments revealed that although the production of reactive oxygen species was increased during acute hyperglycemia, the bioavailability of nitric oxide in the endothelium was decreased, despite no change in the activation state of endothelial nitric oxide synthase. CONCLUSIONS: To our knowledge, this is the first study to assess the vascular effects of acute hyperglycemia induced by commercial SSB consumption alone. These findings suggest that SSB-mediated endothelial dysfunction is partly due to increased oxidative stress that decreases nitric oxide bioavailability. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366442&isReview=true. Australian New Zealand Clinical Trials Registry Number: ACTRN12614000614695.

Regional myocardial function abnormalities are associated with macro- and microcirculation dysfunction in the metabolic syndrome: the RESOLVE study.

Abnormalities in myocardial and vascular function have been reported in the metabolic syndrome (MetS), but whether these alterations are related remains poorly documented. Our aim was accordingly to investigate interrelationships between macro- and microcirculatory vasoreactivity and left ventricular (LV) myocardial function in MetS patients. Eighty-eight MetS individuals and 44 age- and gender-matched healthy controls were enrolled. LV global longitudinal strain (GLS) was measured using Vector Velocity Imaging. Endothelial-dependent and independent reactivity in macro- and microcirculatory territories was established using flow-mediated dilation and nitrate-mediated dilation of the brachial artery and cutaneous blood flow measured with laser Doppler flowmetry in response to iontophoresis of acetylcholine and sodium nitroprusside, respectively. Carotid intima-media thickness (cIMT) was measured according to the Mannheim consensus. Compared to controls, MetS patients presented with reduced GLS (p < 0.001) increased cIMT and impaired (p < 0.001) endothelial and smooth muscle function of the brachial artery and the forearm skin microcirculation. Highly significant relationships (p < 0.01) were noticed between GLS and vascular outcomes. In addition, cIMT (ß = 0.21, p = 0.024) and microcirculatory endothelium-dependent reactivity (ß = - 0.20, p = 0.035) were identified as independent predictors of GLS. In MetS, abnormalities in myocardial function and endothelial as well as smooth muscle function of small and large arteries co-exist and are closely associated. This study supports a role for microvascular dysfunction in the pathogenesis of LV myocardial dysfunction.

Assessing cutaneous microvascular function with iontophoresis: Avoiding non-specific vasodilation.

AIM: Iontophoresis of vasoactive agents is commonly used to assess cutaneous microvascular reactivity. However, it is known that iontophoresis can be limited by confounding non-specific vasodilatory effects. Despite this, there is still no standardization of protocols or data expression. Therefore, this study evaluated commonly used protocols of iontophoresis by assessing each for evidence of non-specific vasodilatory effects and examined the reproducibility of those protocols that are free of non-specific responses. METHODS: Twelve healthy participants were administered doses of acetylcholine (ACh) 1-2% and sodium nitroprusside (SNP) 1%, diluted in sodium chloride 0.9% or deionized water, and insulin 100U/mL in a sterile diluent using iontophoresis coupled with laser speckle contrast imaging (LSCI). Increases in blood flux at a control electrode, containing the diluent only, indicated a non-specific response. Reproducibility of iontophoresis protocols that were free of non-specific vasodilatory effects were subsequently compared to that of post-occlusive reactive hyperemia (PORH), used as a standard, in 20 healthy participants. RESULTS: Iontophoresis of ACh or SNP in sodium choloride (0.02mA for 200 and 400s, respectively) and ACh in deionized water (0.1mA for 30s) mediated the least non-specific vasodilatory effects. Microvascular responses to insulin were mediated mainly by non-specific effects. Compared to PORH, the intraday and interday reproducibility for iontophoresis of ACh and SNP (0.02mA for 200 and 400s, respectively) with LSCI was weaker, but still deemed good to excellent when data was expressed, in perfusion units or cutaneous vascular conductance, as the absolute peak blood flux response to the vascular reactivity test or as the change in blood flux between peak and baseline values. CONCLUSION: This study provides updated recommendations for assessing cutaneous microvascular function with iontophoresis.

Exercise does not activate the ß3 adrenergic receptor-eNOS pathway, but reduces inducible NOS expression to protect the heart of obese diabetic mice.

Obesity and diabetes are associated with higher cardiac vulnerability to ischemia-reperfusion (IR). The cardioprotective effect of regular exercise has been attributed to ß3-adrenergic receptor (ß3AR) stimulation and increased endothelial nitric oxide synthase (eNOS) activation. Here, we evaluated the role of the ß3AR-eNOS pathway and NOS isoforms in exercise-induced cardioprotection of C57Bl6 mice fed with high fat and sucrose diet (HFS) for 12 weeks and subjected or not to exercise training during the last 4 weeks (HFS-Ex). HFS animals were more sensitive to in vivo and ex vivo IR injuries than control (normal diet) and HFS-Ex mice. Cardioprotection in HFS-Ex mice was not associated with increased myocardial eNOS activation and NO metabolites storage, possibly due to the ß3AR-eNOS pathway functional loss in their heart. Indeed, a selective ß3AR agonist (BRL37344) increased eNOS activation and had a protective effect against IR in control, but not in HFS hearts. Moreover, iNOS expression, nitro-oxidative stress (protein s-nitrosylation and nitrotyrosination) and ROS production during early reperfusion were increased in HFS, but not in control mice. Exercise normalized iNOS level and reduced protein s-nitrosylation, nitrotyrosination and ROS production in HFS-Ex hearts during early reperfusion. The iNOS inhibitor 1400 W reduced in vivo infarct size in HFS mice to control levels, supporting the potential role of iNOS normalization in the cardioprotective effects of exercise training in HFS-Ex mice. Although the ß3AR-eNOS pathway is defective in the heart of HFS mice, regular exercise can protect their heart against IR by reducing iNOS expression and nitro-oxidative stress.

Divalent Amino-Acid-Based Amphiphilic Antioxidants: Synthesis, Self-Assembling Properties, and Biological Evaluation.

We report herein the synthesis of a divalent amphiphilic carrier onto which α-phenyl-N-tert-butyl nitrone (PBN) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) antioxidants were grafted to give the divalent derivative called FATxPBN. The divalent carrier consists of two lysine amino acids as a scaffold upon which the antioxidant moieties are grafted, a perfluorinated chain that supplies hydrophobicity, and a sugar-based polar headgroup that ensures water solubility. For the sake of comparison, a divalent PBN derivative called FADiPBN was also synthesized. The self-aggregation properties of FATxPBN and FADiPBN were studied by means of surface tension, dynamic light scattering, and transmission electron microscopy methods, and showed they form small micelles (i.e., 12 and 6 nm diameter, respectively) at submillimolar concentrations (i.e., 0.01 and 0.05 mM, respectively), in agreement with partition coefficient values. The superior antioxidant properties of FATxPBN over FADiPBN and the parent compounds PBN and Trolox were demonstrated using in vitro ABTS(•+) reduction (98%) and soybean lipoxygenase inhibition (94%) assays. Finally, FATxPBN was found to significantly inhibit hyperglycemia-induced toxicity on an ex-vivo rat model, demonstrating its potency as a bioactive antioxidant against oxidative stress-induced damage.

Acute Hyperglycemia Impairs Vascular Function in Healthy and Cardiometabolic Diseased Subjects: Systematic Review and Meta-Analysis.

OBJECTIVES: Controversy exists over the effect of acute hyperglycemia on vascular function. In this systematic review, we compared the effect of acute hyperglycemia on endothelial and vascular smooth muscle functions across healthy and cardiometabolic diseased subjects. APPROACH AND RESULTS: A systematic search of MEDLINE, EMBASE, and Web of Science from inception until July 2014 identified articles evaluating endothelial or vascular smooth muscle function during acute hyperglycemia and normoglycemia. Meta-analyses compared the standardized mean difference (SMD) in endothelial and vascular smooth muscle functions between acute hyperglycemia and normoglycemia. Subgroup analyses and metaregression identified sources of heterogeneity. Thirty-nine articles (525 healthy and 540 cardiometabolic subjects) were analyzed. Endothelial function was decreased (39 studies; n=1065; SMD, -1.25; 95% confidence interval, -1.52 to -0.98; P<0.01), whereas vascular smooth muscle function was preserved (6 studies; n=144; SMD, -0.07; 95% confidence interval, -0.30 to 0.16; P=0.55) during acute hyperglycemia compared with normoglycemia. Significant heterogeneity was detected among endothelial function studies (P<0.01). A subgroup analysis revealed that endothelial function was decreased in the macrocirculation (30 studies; n=884; SMD, -1.40; 95% confidence interval, -1.68 to -1.12; P<0.01) but not in the microcirculation (9 studies; n=181; SMD, -0.63; 95% confidence interval, -1.36 to 0.11; P=0.09). Similar results were observed according to health status. Macrovascular endothelial function was inversely associated with age, blood pressure, and low-density lipoprotein cholesterol and was positively associated with the postocclusion interval of vascular assessment. CONCLUSIONS: To our knowledge, this is the first systematic review and meta-analysis of its kind. In healthy and diseased subjects, we found evidence for macrovascular but not microvascular endothelial dysfunction during acute hyperglycemia.

Metabolic syndrome individuals with and without type 2 diabetes mellitus present generalized vascular dysfunction: cross-sectional study.

OBJECTIVES: The first objective of this study was to demonstrate differences within endothelial-dependent and endothelial-independent vasoreactivity in macro- and microcirculation beds among patients with metabolic syndrome (MetS) with and without type 2 diabetes mellitus (T2D) compared with healthy counterparts. The second objective was to determine relationships among the function of macro- and microvascular systems and abdominal adiposity, as well as inflammatory markers in the 3 groups. APPROACH AND RESULTS: Cross-sectional analyses of 53 patients with MetS without T2D and 25 with T2D, as well as aged 40 years and sex-matched healthy controls included microvascular (cutaneous blood flow measured with laser Doppler flowmetry in response to iontophoresis of acetylcholine and sodium nitroprusside), and macrovascular reactivity (flow-mediated dilation and nitrate-mediated dilation) along with anthropometric measures, plasma glucose, and insulin and inflammatory markers. Compared with controls, MetS participants showed depressed endothelial function of both micro- and macrocirculation beds. T2D in patients with MetS revealed an exacerbated vascular smooth muscle dysfunction in micro- and macrocirculation compared with MetS without T2D. Indices of micro- and macrocirculation were predominantly inversely related to abdominal fat and inflammatory markers. CONCLUSIONS: MetS was associated with endothelial-dependent and endothelial-independent dysfunction, affecting both the macro- and the microvascular systems. Participants with diabetes mellitus demonstrated the most severe smooth muscle dysfunction. The presence of central abdominal fat and systemic inflammation seems implicated in the pathogenesis of vascular dysfunctions in MetS.

Phlebotomy eliminates the maximal cardiac output response to six weeks of exercise training.

With this study we tested the hypothesis that 6 wk of endurance training increases maximal cardiac output (Qmax) relatively more by elevating blood volume (BV) than by inducing structural and functional changes within the heart. Nine healthy but untrained volunteers (Vo2max 47 ± 5 ml·min(-1)·kg(-1)) underwent supervised training (60 min; 4 times weekly at 65% Vo2max for 6 wk), and Qmax was determined by inert gas rebreathing during cycle ergometer exercise before and after the training period. After the training period, blood volume (determined in duplicates by CO rebreathing) was reestablished to pretraining values by phlebotomy and Qmax was quantified again. Resting echography revealed no structural heart adaptations as a consequence of the training intervention. After the training period, plasma volume (PV), red blood cell volume (RBCV), and BV increased (P < 0.05) by 147 ± 168 (5 ± 5%), 235 ± 64 (10 ± 3%), and 382 ± 204 ml (7 ± 4%), respectively. Vo2max was augmented (P < 0.05) by 10 ± 7% after the training period and decreased (P < 0.05) by 8 ± 7% with phlebotomy. Concomitantly, Qmax was increased (P < 0.05) from 18.9 ± 2.1 to 20.4 ± 2.3 l/min (9 ± 6%) as a consequence of the training intervention, and after normalization of BV by phlebotomy Qmax returned to pretraining values (18.1 ± 2.5 l/min; 12 ± 5% reversal). Thus the exercise training-induced increase in BV is the main mechanism increasing Qmax after 6 wk of endurance training in previously untrained subjects.

Right ventricle free wall mechanics in metabolic syndrome without type-2 diabetes: effects of a 3-month lifestyle intervention program.

BACKGROUND: Growing evidence demonstrates subtle left ventricular myocardial dysfunction in patients with metabolic syndrome (MetS), with central obesity, glucose intolerance and inflammation emerging as important contributors. Whether these results can be translated to the right ventricle (RV) is not yet fully elucidated. Furthermore, although lifestyle intervention favorably impacts MetS components and inflammatory biomarkers, its effect on RV myocardial function remains unknown today. METHODS: Thirty-nine MetS adults free of diabetes were enrolled in a three month lifestyle intervention program including diet and physical exercise, and compared with forty healthy controls. Blood biochemistry, echocardiography including tissue Doppler imaging (TDI), and vector velocity imaging of the RV free wall to assess global longitudinal strain (GLS) and strain rates (SR) were obtained at baseline and after the intervention. RESULTS: Compared with controls, MetS patients presented similar right atrial and RV morphology but reduced systolic (P = 0.04) and early diastolic (P = 0.02) velocities of the tricuspid annulus. They showed attenuated RV GLS (-21.4 ± 4.5 vs -25.7 ± 4.9%, P < 0.001) as well as early diastolic (P = 0.003) and systolic (P < 0.001) SR. Multiple regression analyses revealed log PAI-1 active, (P < 0.001), log adiponectin, (P = 0.01), LV mass indexed (P = 0.004) and central fat (P = 0.03) as independent predictors of RV GLS (R2 = 0.46, P < 0.001). Biological markers of MetS and inflammation as well as RV GLS (-21.8 ± 3.8 vs -24.3 ± 3.0%, P = 0.009) and systolic (P = 0.003) and early diastolic (P = 0.01) SR, but not TDI indexes, significantly improved after diet and exercise training, and vector velocity imaging data in MetS following the lifestyle intervention no longer differed from controls. CONCLUSIONS: MetS is associated with subtle impairments in both RV free wall diastolic and systolic myocardial function which could be partly related to central-obesity induced changes in pro- and anti-inflammatory cytokines and left ventricular remodeling. The favorable impact of healthy dieting and physical activity on RV free wall mechanics indicates that cellular and sub-cellular alterations responsible for the RV myocardial abnormalities are probably not permanent and modifiable throughout adequate interventional strategies. TRIAL REGISTRATION: American National Institutes of Health database NCT00917917.

Atherogenic subfractions of lipoproteins in the treatment of metabolic syndrome by physical activity and diet - the RESOLVE trial.

BACKGROUND: We aimed to comprehensively evaluate lipoprotein profile including lipid particle size following a lifestyle intervention in metabolic syndrome (MetS) volunteers and to assess the associations between lipoprotein subfractions and carotid-intima-media-thickness (CIMT) - a surrogate indicator of atherogenesis. METHODS: 100 participants (50-70 years) from the RESOLVE trial, underwent a one-year follow-up beginning with a three-week residential program combining high exercise volume (15-20 h/week), restrictive diet (-500 kcal/day), and education. For baseline references, 40 aged-matched healthy controls were recruited. Independent associations between subfractions of lipoproteins and CIMT were evaluated using a generalized estimating equations model accounting for variation in correlations between repeated measures. The lipoprotein subfractions profile was assessed using Lipoprint® electrophoresis allowing to separate: the very low-density lipoprotein (VLDL) fraction, then the intermediate-density lipoprotein (IDL) C, B and A, the low-density lipoprotein (LDL) with subfractions 1 and 2 as large LDL and subfractions 3 to 7 as small dense LDL (sdLDL), and the high density lipoprotein (HDL) subfractions categorized into large, intermediate, and small HDL. Apolipoproteins A1 and B were also measured. RESULTS: 78 participants completed the program. At baseline, apolipoproteins B/A1, VLDL, sdLDL and small HDL were higher in MetS than in healthy controls; IDL, LDL size, large and intermediate HDL were lower. Despite time-related regains during the follow-up, lipoprotein subfractions traditionally involved in cardiovascular risk, such as sdLDL, improved immediately after the residential program with values closest to those of healthy controls. CIMT improved throughout the lifestyle intervention. Using a generalized estimating equations model, none of the subfractions of lipoproteins nor apolipoproteins were linked to CIMT. CONCLUSIONS: Lipoprotein subfractions traditionally involved in CVR, decreased after the 3-week residential program. During a 12 month follow-up, the time-related regains remained closer to the values of healthy controls than they were at baseline. CIMT improved throughout the lifestyle intervention. However, we failed to demonstrate a link between some lipoprotein subfractions and the atherogenicity directly measured from the wall thickness of arteries (CIMT). Further investigations are required to explore the atherogenicity of lipoprotein subfractions. TRIAL REGISTRATION: NCT00917917.

Hyperglycemia triggers RyR2-dependent alterations of mitochondrial calcium homeostasis in response to cardiac ischemia-reperfusion: Key role of DRP1 activation.

Hyperglycemia increases the heart sensitivity to ischemia-reperfusion (IR), but the underlying cellular mechanisms remain unclear. Mitochondrial dynamics (the processes that govern mitochondrial morphology and their interactions with other organelles, such as the reticulum), has emerged as a key factor in the heart vulnerability to IR. However, it is unknown whether mitochondrial dynamics contributes to hyperglycemia deleterious effect during IR. We hypothesized that (i) the higher heart vulnerability to IR in hyperglycemic conditions could be explained by hyperglycemia effect on the complex interplay between mitochondrial dynamics, Ca2+ homeostasis, and reactive oxygen species (ROS) production; and (ii) the activation of DRP1, a key regulator of mitochondrial dynamics, could play a central role. Using transmission electron microscopy and proteomic analysis, we showed that the interactions between sarcoplasmic reticulum and mitochondria and mitochondrial fission were increased during IR in isolated rat hearts perfused with a hyperglycemic buffer compared with hearts perfused with a normoglycemic buffer. In isolated mitochondria and cardiomyocytes, hyperglycemia increased mitochondrial ROS production and Ca2+ uptake. This was associated with higher RyR2 instability. These results could contribute to explain the early mPTP activation in mitochondria from isolated hearts perfused with a hyperglycemic buffer and in hearts from streptozotocin-treated rats (to increase the blood glucose). DRP1 inhibition by Mdivi-1 during the hyperglycemic phase and before IR induction, normalized Ca2+ homeostasis, ROS production, mPTP activation, and reduced the heart sensitivity to IR in streptozotocin-treated rats. In conclusion, hyperglycemia-dependent DRP1 activation results in higher reticulum-mitochondria calcium exchange that contribute to the higher heart vulnerability to IR.

Vascular smooth muscle function in type 2 diabetes mellitus: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: In type 2 diabetes, in contrast to the well-documented endothelial dysfunction, studies assessing vascular smooth muscle (VSM) function have yielded discrepant results over the last two decades. We therefore sought to determine whether or not VSM function is impaired in individuals with type 2 diabetes. METHODS: We conducted a systematic search of MEDLINE, Cochrane, Scopus and Web of Science databases, from their respective inceptions until December 2012, for articles evaluating VSM function in individuals with type 2 diabetes. A meta-analysis was performed to compare the standardised mean difference (SMD) in VSM function between individuals with type 2 diabetes and age-matched controls. Subgroup analyses and meta-regression were used to identify sources of heterogeneity. RESULTS: Twenty-seven articles (1,042 individuals with type 2 diabetes and 601 control subjects) were included in this analysis. VSM function was significantly impaired in diabetic compared with control subjects (SMD -0.68, 95% CI -0.84, -0.52; p < 0.001). Although moderate heterogeneity among studies was found (I (2) = 52%), no significant publication bias was detected. Subgroup analyses showed a further decline in VSM function assessed in the microcirculation compared with the macrocirculation of individuals with type 2 diabetes (p = 0.009). In meta-regression, VSM function in the microcirculation was inversely associated with BMI and triacylglycerols and was positively associated with HDL-cholesterol. CONCLUSIONS/INTERPRETATION: In addition to the endothelium, the VSM is a source of vascular dysfunction in type 2 diabetes. An exacerbation of VSM function in the microcirculation may be a distinctive feature in type 2 diabetes.