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.

Protective Role of Chronic Exercise Training in Modulating the Impact of Hyperglycemia on Vascular Sensitivity to Ischemia-Reperfusion.

Hyperglycemia (HG) is associated with increased mortality and morbidity in acute ischemic events. Regardless of the tissue or organs involved, the vascular endothelium is a key target of ischemia-reperfusion (I/R) injury severity. Among endothelium-protective strategies, exercise has been widely described as useful. However, whether this strategy is able to impact the deleterious effect of HG on endothelial function during I/R has never been challenged. For this, 48 male Wistar rats were randomized into 4 groups: sedentary (Sed) or exercised (Ex, 45 min/day, 5 days/week for 5 weeks) rats, treated (hyperglycemic, HG) or not (normoglycemic, NG) with streptozotocin (40 mg/kg, 48 h before procedure). Vascular I/R (120/15 min) was performed by clamping the femoral artery. Arterial and downstream muscular perfusions were assessed using laser speckle contrast imaging. Vascular endothelial function was assessed in vivo 15 min after reperfusion. HG was responsible for impairment of reperfusion blood flow as well as endothelial function. Interestingly exercise was able to prevent those impairments in the HG group. In agreement with the previous results, HG increased reactive oxygen species production and decreased nitric oxide bioavailability whereas exercise training normalized these parameters. It, therefore, appears that exercise may be an effective prevention strategy against the exacerbation of vascular and muscular damage by hyperglycemia during I/R.

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.

Non-invasive biomarkers of non-alcoholic fatty liver disease in patients with Metabolic Syndrome: insights from the RESOLVE study.

BACKGROUND: The aim of the present study was to evaluate i) the presence of liver steatosis using Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI) and Liver Fat Score (LFS) in patients suffering from MS and ii) the association of FLI, HSI and LFS with the cardiometabolic risks. METHODS: A total of 91 patients with MS (MS; 39 men, 52 women) and 44 age matched healthy subjects (Control; 23 men and 21 women) were enrolled in the study. A continuous cardiometabolic score (MetsScore) and the noninvasive tests of hepatic steatosis were calculated for comparison and association analysis. RESULTS: Liver steatosis was detected in 86%, 84% and 80% of people diagnosed with MS using FLI, HSI and LFS respectively and MetsScore increases with FLI severity (p<0,05). Also, FLI and LFS were positively associated with MetsScore (p<0.01 and p<0.05 respectively) but not HSI. Multivariate linear regression models revealed that FLI has a stronger association with MetsScore compared with HSI and LFS (p<0,001). CONCLUSIONS: FLI is associated with the severity of MS and represent a good indicator to assess the relation between liver steatosis and a cardiometabolic disorders in clinical routine.

MEDEX 2015: Prophylactic Effects of Positive Expiratory Pressure in Trekkers at Very High Altitude.

Purpose: Positive expiratory pressure (PEP) breathing has been shown to increase arterial oxygenation during acute hypoxic exposure but the underlying mechanisms and consequences on symptoms during prolonged high-altitude exposure remain to be elucidated. Methods: Twenty-four males (41 ± 16 years) were investigated, at sea level and at 5,085 m after 18 days of trekking from 570 m. Participants breathed through a face-mask with PEP = 0 cmH2O (PEP0, 0-45th min) and with PEP = 10 cmH2O (PEP10, 46-90th min). Arterial (SpO2), quadriceps and prefrontal (near infrared spectroscopy) oxygenation was measured continuously. Middle cerebral artery blood velocity (MCAv, transcranial Doppler), cardiac function (2D-echocardiography), extravascular lung water accumulation (UsLC, thoracic ultrasound lung comets) and acute mountain sickness (Lake Louise score, LLS) were assessed during PEP0 and PEP10. Results: At 5,085 m with PEP0, SpO2 was 78 ± 4%, UsLC was 8 ± 5 (a.u.) and the LLS was 2.3 ± 1.7 (all P < 0.05 versus sea level). At 5,085 m, PEP10 increased significantly SpO2 (+9 ± 5%), quadriceps (+2 ± 2%) and prefrontal cortex (+2 ± 2%) oxygenation (P < 0.05), and decreased significantly MCAv (-16 ± 14 cm.s-1) and cardiac output (-0.7 ± 1.2 L.min-1) together with a reduced stroke volume (-9 ± 15 mL, all P < 0.05) and no systemic hypotension. PEP10 decreased slightly the number of UsLC (-1.4 ± 2.7, P = 0.04) while the incidence of acute mountain sickness (LLS ≥ 3) fell from 42% with PEP0 to 25% after PEP10 (P = 0.043). Conclusion: PEP10 breathing improved arterial and tissue oxygenation and symptoms of acute mountain sickness after trekking to very high altitude, despite reduced cerebral perfusion and cardiac output. Further studies are required to establish whether PEP-breathing prophylactic mechanisms also occur in participants with more severe acute mountain sickness.

Maximal Fat Oxidation During Exercise Is Already Impaired in Pre-pubescent Children With Type 1 Diabetes Mellitus.

Objective: We evaluated substrate utilization during submaximal exercise, together with glycemic responses and hormonal counter-regulation to exercise, in children with type 1 diabetes mellitus (T1DM). Methods: Twelve pre-pubescent children with T1DM and 12 healthy children were matched by sex and age. Participants completed a submaximal incremental exercise test to determine their fat and carbohydrate oxidation rates by indirect calorimetry. Levels of glycemia, glucagon, cortisol, growth hormone, noradrenaline, adrenaline, and insulin were monitored until 120 min post-exercise. Results: Absolute peak oxygen uptake (VO2 peak) was significantly lower in the children with T1DM than in the healthy controls (1131.4 ± 102.5 vs. 1383.0 ± 316.6 ml.min-1, p = 0.03). Overall carbohydrate and lipid oxidation rates were the same in the two groups, but for exercise intensities, higher than 50% of VO2 peak, fat oxidation rate was significantly lower in the children with T1DM. The absolute maximal lipid oxidation rate was significantly lower in the T1DM children (158.1 ± 31.6 vs. 205.4 ± 42.1 mg.min-1, p = 0.005), and they reached a significantly lower exercise power than the healthy controls (26.4 ± 1.2 vs. 35.4 ± 3.3 W, p = 0.03). Blood glucose responses to exercise were negatively correlated with pre-exercise blood glucose concentrations (r = -0.67; p = 0.03). Conclusion: Metabolic and hormonal responses during sub-maximal exercise are impaired in young children with T1DM.

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.

Sucralose and Cardiometabolic Health: Current Understanding from Receptors to Clinical Investigations.

The excess consumption of added sugar is consistently found to be associated with weight gain, and a higher risk of type 2 diabetes mellitus, coronary heart disease, and stroke. In an effort to reduce the risk of cardiometabolic disease, sugar is frequently replaced by low- and null-calorie sweeteners (LCSs). Alarmingly, though, emerging evidence indicates that the consumption of LCSs is associated with an increase in cardiovascular mortality risk that is amplified in those who are overweight or obese. Sucralose, a null-caloric high-intensity sweetener, is the most commonly used LCS worldwide, which is regularly consumed by healthy individuals and patients with metabolic disease. To explore a potential causal role for sucralose in increased cardiovascular risk, this present review summarizes the preclinical and clinical data from current research detailing the effects of sucralose on systems controlling food intake, glucose homeostasis, and gut microbiota.

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.

Dietary Fibres and the Management of Obesity and Metabolic Syndrome: The RESOLVE Study.

OBJECTIVES: This study was performed to evaluate the long-term maintenance of nutritional changes promoted during an intensive initial intervention to induce body weight loss. The ability of these changes to predict long-term health outcomes was also examined. METHODS: Nutritional variables, body composition, and metabolic markers collected in the RESOLVE project were analyzed before and after a 3-week intensive diet-exercise intervention (Phase 1), and during a subsequent supervision under free living conditions, of 12 months (Phase 2). RESULTS: As expected, the macronutrient composition of the diet was modified to promote a negative energy balance during Phase 1. The decrease in carbohydrates imposed during this phase was maintained during Phase 2 whereas the increase in protein intake returned to baseline values at the end of the program. Dietary fiber intake was almost doubled during Phase 1 and remained significantly greater than baseline values throughout Phase 2. Moreover, fiber intake was the only nutritional variable that systematically and significantly predicted variations of health outcomes in the study. CONCLUSION: The adequacy of dietary fiber intake should be a matter of primary consideration in diet-based weight reduction programs.

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.

Glutathione-dependent enzyme activities of peripheral blood mononuclear cells decrease during the winter season compared with the summer in normal-weight and severely obese adolescents.

Oxidative stress-related inflammation is known to play a vital role in obesity-associated cardiovascular disease, contributing to the early stages of the pathology as well as during its development. Therefore, it is of great interest to understand how obesity-induced stress modulates antioxidant enzyme activity during puberty. To this end, 27 severely obese adolescents (body mass index > 30, z-score > 3.7) were recruited from a paediatric weight management centre. Eighteen were recruited during the summer and nine in the winter. All underwent a 4-month weight loss programme consisting in diet and physical activity. Twenty normal-weight age-matched adolescents were recruited from the same geographical area to serve as controls. Blood samples were extracted, and antioxidant enzyme activities were determined in peripheral blood mononuclear cells (PBMCs) and erythrocytes. The enzymes studied included catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase. Severely obese adolescents presented lower PBMC-glutathione reductase activity than their corresponding normal-weight counterparts. In addition, glutathione-dependent activities tended to be lower in both groups during the winter compared with summer. These changes coincided with differences in circulating vitamin D levels. Results may suggest that season-dependent factors such as vitamin D could affect glutathione-dependent activities in severely obese as well as in normal-weight adolescents.

Long-term effects of high-intensity resistance and endurance exercise on plasma leptin and ghrelin in overweight individuals: the RESOLVE Study.

The objective of this study was to evaluate the effects of high-intensity resistance and endurance exercise on body composition and plasma leptin and ghrelin concentrations in overweight individuals. One hundred participants were randomly assigned to 3 exercise interventions: high-resistance-low-aerobic exercise (Re), low-resistance-high-aerobic exercise (rE), low-resistance-low-aerobic exercise (re). Interventions began with 3 weeks of residential supervision (phase 1) after which participants had to manage the physical activity programs individually (phase 2). Body composition and plasma variables were measured at baseline and after phase 1 as well as after 3, 6, and 12 months. Significant decreases in body weight and fat were observed after phase 1 (p < 0.001) and continued at a lower rate for up to 3 months and then remained stable for the rest of the protocol. Once a body weight plateau was reached, body fat loss after the Re and rE conditions exceeded the fat loss observed in the re condition by 1.5-2 kg (p < 0.05). Leptin was significantly decreased after day 21 and month 3 (p < 0.001) and remained stable for the rest of the study. Ghrelin was significantly increased after day 21 and month 3 (p < 0.001) and returned to a level comparable to baseline between month 6 and 12 when body weight and fat had reached a plateau. In conclusion, this study reinforces the idea that an increase in exercise intensity may accentuate body fat loss before the occurrence of a body weight plateau. Resistance to further fat loss was accompanied by a decrease in plasma leptin and an increase in plasma ghrelin.

The continuums of impairment in vascular reactivity across the spectrum of cardiometabolic health: A systematic review and network meta-analysis.

This study aimed to assess, for the first time, the change in vascular reactivity across the full spectrum of cardiometabolic health. Systematic searches were conducted in MEDLINE and EMBASE databases from their inception to March 13, 2017, including studies that assessed basal vascular reactivity in two or more of the following health groups (aged ≥18 years old): healthy, overweight, obesity, impaired glucose tolerance, metabolic syndrome, or type 2 diabetes with or without complications. Direct and indirect comparisons of vascular reactivity were combined using a network meta-analysis. Comparing data from 193 articles (7226 healthy subjects and 19344 patients), the network meta-analyses revealed a progressive impairment in vascular reactivity (flow-mediated dilation data) from the clinical onset of an overweight status (-0.41%, 95% CI, -0.98 to 0.15) through to the development of vascular complications in those with type 2 diabetes (-4.26%, 95% CI, -4.97 to -3.54). Meta-regressions revealed that for every 1 mmol/l increase in fasting blood glucose concentration, flow-mediated dilation decreased by 0.52%. Acknowledging that the time course of disease may vary between patients, this study demonstrates multiple continuums of vascular dysfunction where the severity of impairment in vascular reactivity progressively increases throughout the pathogenesis of obesity and/or insulin resistance, providing information that is important to enhancing the timing and effectiveness of strategies that aim to improve cardiovascular outcomes.

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.

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.

Different modalities of exercise improve macrovascular function but not microvascular function in metabolic syndrome: The RESOLVE randomized trial.

OBJECTIVE: To determine which modality of exercise program (endurance and/or resistance dominance) is the most effective for improving vascular function in the micro- and macrocirculation in metabolic syndrome (MetS). METHODS: Sixty-two MetS patients were enrolled in a 6-month lifestyle intervention program based on diet and exercise training. Each participant was randomly assigned to one of 3 groups categorized by exercise modality (e.g. high-intensity resistance or endurance training, or combined moderate-intensity). Measurements of anthropometrics, biological blood markers, physical fitness and vascular function were performed at baseline, at the end of the 3-week residential program, and at 3 and 6 months after baseline. Brachial artery flow-mediated dilation (FMD) and the response to sublingual nitrate were assessed by high-resolution ultrasound. Microvascular reactivity was evaluated using laser Doppler flowmetry in conjunction with iontophoresis of acetylcholine and sodium nitroprusside. RESULTS: Regardless of the training program, FMD significantly increased from baseline to 3 weeks in all groups with no further changes at 3 and 6 months. Changes in central fat, diastolic blood pressure, triglycerides, interleukin-6 and physical fitness were independent predictors of increased FMD. Nitrate-mediated dilation increased from baseline to 3 months and then remained unchanged up to 6 months. Endothelium-dependent and endothelium-independent function of the skin microcirculation did not change significantly in all groups. CONCLUSIONS: In MetS patients, exercise training, regardless of its endurance or resistance dominance, is able to improve vascular function in large vessels only. Lifestyle intervention programs including exercise training must be encouraged in those with MetS. NCT00917917.

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.