Repetitive transcranial magnetic stimulation improves cardiovascular autonomic nervous system control: A meta-analysis.

BACKGROUND: Cardiovascular autonomic system (ANS) may be affected by altered neural activations in the brain. This systematic review and meta-analysis investigated potential effects of repetitive transcranial magnetic stimulation (rTMS) protocols on cardiovascular ANS control. METHODS: Through 19 qualified studies, we acquired 70 comparisons for data synthesis. Individual effect sizes were estimated by comparing changes in following cardiovascular ANS control variables between active and sham stimulation conditions: (a) blood pressure (BP), (b) heart rate (HR), and (c) heart rate variability (HRV). Moreover, two moderator variable analyses determined whether changes in cardiovascular ANS control were different based on (a) rTMS protocols (excitatory rTMS versus inhibitory rTMS) and (b) specific targeted cortical regions, respectively. RESULTS: The random-effects model meta-analysis revealed significant improvements in cardiovascular ANS control after the rTMS protocols. Specifically, applying excitatory and inhibitory rTMS protocols significantly decreased values of BP and HR variables. For HRV variables, excitatory rTMS protocols showed significant positive effects. These improvements in cardiovascular ANS control were observed while applying either excitatory rTMS protocols to the left dorsolateral prefrontal cortex or inhibitory rTMS protocols to the right dorsolateral prefrontal cortex. LIMITATIONS: Relatively small number of studies for inhibitory rTMS on the right dorsolateral prefrontal cortex were included in this meta-analysis. CONCLUSION: These findings suggest that applying excitatory and inhibitory rTMS protocols on prefrontal cortical regions may be effective to improve cardiovascular ANS control.

Voluntary exercise training improves body weight of leptin-deficient ob/ob mice by altering hepatic stearoyl-CoA desaturase 1 and deleted in breast cancer 1 protein levels.

PURPOSE: Deleted in breast cancer 1 (DBC1) ablation causes obesity, and stearoyl-CoA desaturase 1 (SCD1) induces the biosynthesis of monounsaturated fatty acids. This study examined whether voluntary wheel running (VWR) alters SCD-1 and DBC1 protein levels in the liver of leptin-deficient ob/ob mice. METHODS: Twenty-five Ob/Ob mice were divided into two groups (ob/ob-Sed and ob/ob-Ex). The expression of DBC1 and SCD1 in the mouse liver was determined using western blotting. RESULTS: After 10 weeks, VWR significantly reduced body weight without affecting the fatty acid synthase and CD36 protein levels. The average daily running distance was 4.0±1.0 km/day. This improvement was associated with changes in the hepatic SCD1 and DBC1 levels. Hepatic SCD-1 protein levels increased significantly, and DBC1 protein levels decreased in ob/ob-Sed animals. On the other hand, VWR inhibited the obesity-induced increase in SCD1 expression and impaired the obesity-induced decrease in DBC1 expression in the liver of leptin-deficient ob/ob mice. CONCLUSION: This is the first study showing that VWR has strong effects on hepatic SCD1 and DBC1 in ob/ob mice, and provides key insights into the effects of exercise on obesity.

Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition.

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague-Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5-ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.

Functional Balance and Postural Control Improvements in Patients With Stroke After Noninvasive Brain Stimulation: A Meta-analysis.

OBJECTIVES: The postural imbalance poststroke limits individuals' walking abilities as well as increase the risk of falling. We investigated the short-term treatment effects of noninvasive brain stimulation (NIBS) on functional balance and postural control in patients with stroke. DATA SOURCES: We started the search via PubMed and the Institute for Scientific Information's Web of Science on March 1, 2019 and concluded the search on April 30, 2019. STUDY SELECTION: The meta-analysis included studies that used either repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) for the recovery of functional balance and postural control poststroke. All included studies used either randomized controlled trial or crossover designs with a sham control group. DATA EXTRACTION: Three researchers independently performed data extraction and assessing methodological quality and publication bias. We calculated overall and individual effect sizes using random effects meta-analysis models. DATA SYNTHESIS: The random effects meta-analysis model on the 18 qualified studies identified the significant positive effects relating to NIBS in terms of functional balance and postural control poststroke. The moderator-variable analyses revealed that these treatment effects were only significant in rTMS across patients with acute, subacute, and chronic stroke whereas tDCS did not show any significant therapeutic effects. The meta-regression analysis showed that a higher number of rTMS sessions was significantly associated with more improvements in functional balance and postural control poststroke. CONCLUSIONS: Our systematic review and meta-analysis confirmed that NIBS may be an effective option for restoring functional balance and postural control for patients with stroke.

Effect of all-extremity high-intensity interval training vs. moderate-intensity continuous training on aerobic fitness in middle-aged and older adults with type 2 diabetes: A randomized controlled trial.

Aging and diabetes are associated with decreased aerobic fitness, an independent predictor of mortality. Aerobic exercise is prescribed to improve aerobic fitness; however, middle-aged/older diabetic patients often suffer from mobility limitations which restrict walking. Non-weight-bearing/low-impact exercise is recommended but the optimal exercise prescription is uncertain. The goal of this randomized controlled trial was twofold: 1) to test if high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), implemented on a non-weight-bearing all-extremity ergometer, are feasible, well-tolerated and safe in middle-aged/older adults with type 2 diabetes; and 2) to test whether all-extremity HIIT is more effective in improving aerobic fitness than MICT. A total of 58 sedentary individuals with type 2 diabetes (46 to 78 years; 63 ±â€¯1) were randomized to all-extremity HIIT (n = 23), MICT (n = 19) or non-exercise control (CONT; n = 16). All-extremity HIIT and MICT, performed 4×/week for 8 weeks under supervision, resulted in no adverse events requiring hospitalization or medical treatment. Aerobic fitness (VO2peak) improved by 10% in HIIT and 8% in MICT and maximal exercise tolerance increased by 1.8 and 1.3 min, respectively (P ≤ 0.002 vs. baseline; P ≥ 0.9 for HIIT vs. MICT). In conclusion, all-extremity HIIT and MICT are feasible, well-tolerated and safe and result in similar improvements in aerobic fitness in middle-aged/older individuals with type 2 diabetes. These findings have important implications for exercise prescription for diabetic patients; they indicate that all-extremity exercise is a feasible alternative to weight-bearing exercise and those who are unable or unwilling to engage in HIIT may receive similar benefits from MICT.

Effect of combined circuit exercise on arterial stiffness in hypertensive postmenopausal women: a local public health center-based pilot study.

OBJECTIVE: Postmenopausal women have increased arterial stiffness compared with premenopausal women. Regular physical activity including aerobic and resistance exercises are recommended to lower cardiovascular disease risk and to enhance musculoskeletal health in these women. This study examined the effect of combined circuit exercise on arterial stiffness in hypertensive postmenopausal women. Furthermore, it ascertained whether performing this exercise program is feasible in local public health centers with better accessibility than research and commercial facilities. METHODS: Among 24 hypertensive postmenopausal women, 16 finished this study in either the control (n = 8) or exercise (n = 8) group. Except for one participant who withdrew from the study due to the difficulty of the exercise program, seven participants withdrew due to reasons unrelated to the study. Circuit-type exercise (aerobic- and resistance-combined) program was applied to the exercise group, 60 min/d and 3 d/wk for 12 weeks under supervision. Brachial-ankle pulse wave velocity was measured to assess arterial stiffness. RESULTS: In response to the combined exercise, brachial-ankle pulse wave velocity was significantly reduced in the hypertensive women (-0.7 m/s; P < 0.05). Weight, body mass index, and total cholesterol level were also significantly decreased after the exercise program (-2.1 kg, -0.8 kg/m, and -16 mg/dL, respectively; P < 0.05). In addition, changes in arterial stiffness were related to body adiposity, blood pressure, and blood lipid alterations (r = 0.61-0.70; P < 0.01). CONCLUSIONS: Circuit combined exercise is an effective intervention to improve arterial stiffness in hypertensive postmenopausal women, and is feasible in local public health centers.

The effects of exercise on vascular endothelial function in type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Vascular endothelial dysfunction induced by hyperglycemia and elevated insulin resistance is a potent risk factor for cardiovascular disease and likely contributes to multiple chronic disease complications associated with aging. The aim of this study was to systematically review and quantify the effects of exercise on endothelial function (EF) in type 2 diabetes (T2D). METHODS: Five electronic databases were searched (until June 2017) for studies that met the following criteria: (i) randomized controlled trials; (ii) T2D aged ≥ 18 years; (iii) measured EF by brachial artery flow-mediated dilation (FMD); (iv) structured and supervised exercise intervention for ≥ 8 weeks. RESULTS: Thirteen cohorts, selected from eight studies (306 patients, average age 59 years), met the inclusion criteria. Exercise training significantly increased FMD (mean ES = 0.41, 95% CI 0.21-0.62, P < 0.001). Low to moderate intensity subgroups and aerobic exercise (AE) subgroups significantly increased FMD more than moderate to high intensity subgroups and combined AE and resistance exercise subgroups respectively (P < 0.01, P < 0.05). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments reported that quality of evidence for all outcomes was moderate except shear rate showing low. Egger's test showed no significant publication bias for all outcomes. CONCLUSION: Our results suggest that in patients with T2D, lower intensity exercise has physiological meaningful effects on EF, in support of the emerging concept that the lower efforts of exercise are not necessarily less cardioprotective than higher intensity training.

The relationship between arterial stiffness and maximal oxygen consumption in healthy young adults.

OBJECTIVE: Arterial stiffness is associated with an increased risk of cardiovascular diseases in various populations. There was little research on the relationship between arterial stiffness and maximal aerobic capacity (VO2max) in healthy young adults. The aim of this study was to investigate the relationship between VO2max and arterial stiffness in young adults. METHODS: The subjects were 13 men and 10 women with mean age of 22.9 ±â€¯0.7, 23.6 ±â€¯0.4 years, respectively. Height, weight, body mass index, body fat (%), waist to hip ratio, total/high density lipoprotein (HDL)/low density lipoprotein (LDL) cholesterol, triglycerides, fasting glucose, blood pressure, heart rate, glycated hemoglobin and blood lactate were measured. In addition, peripheral arterial stiffness was assessed by measuring brachial-ankle pulse wave velocity (baPWV) and VO2max was determined using graded exercise test. RESULTS: VO2max had no significant correlation with baPWV (r = 0.2, p = 0.2). Total cholesterol correlated significantly to variables such as HDL (r = 0.6, p = 0.0015) and LDL cholesterol (r = -0.6, p = 0.0018). VO2max had a significant association with triglyceride (r = -0.5, p = 0.0033). CONCLUSIONS: This study suggests that there is no relationship between arterial stiffness and aerobic capacity in healthy young adults.

All-Extremity Exercise Training Improves Arterial Stiffness in Older Adults.

Large elastic arteries stiffen with age, which predisposes older adults to increased risk for cardiovascular disease. Aerobic exercise training is known to reduce the risk for cardiovascular disease, but the optimal exercise prescription for attenuating large elastic arterial stiffening in older adults is not known. PURPOSE: The purpose of this randomized controlled trial was to compare the effect of all-extremity high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on aortic pulse wave velocity (PWV) and carotid artery compliance in older adults. METHODS: Forty-nine sedentary older adults (age = 64 ± 1 yr), free of overt major clinical disease, were randomized to HIIT (n = 17), MICT (n = 18), or nonexercise controls (CONT; n = 14). HIIT (4 × 4 min at 90% HRpeak interspersed with 3 × 3 min active recovery at 70% HRpeak) and isocaloric MICT (70% HRpeak) were performed on an all-extremity non-weight-bearing ergometer, 4 d·wk for 8 wk under supervision. Aortic (carotid to femoral PWV [cfPWV]) and common carotid artery compliance were assessed at pre- and postintervention. RESULTS: cfPWV improved by 0.5 m·s in MICT (P = 0.04) but did not significantly change in HIIT and CONT (P > 0.05). Carotid artery compliance improved by 0.03 mm·mm Hg in MICT (P = 0.001), but it remained unchanged in HIIT and CONT (P > 0.05). Improvements in arterial stiffness in response to MICT were not confounded by changes in aortic or brachial blood pressure, HR, body weight, total and abdominal adiposity, blood lipids, or aerobic fitness. CONCLUSION: All-extremity MICT, but not HIIT, improved central arterial stiffness in previously sedentary older adults free of major clinical disease. Our findings have important implications for aerobic exercise prescription in older adults.

Novel all-extremity high-intensity interval training improves aerobic fitness, cardiac function and insulin resistance in healthy older adults.

Aging is associated with decreased aerobic fitness and cardiac remodeling leading to increased risk for cardiovascular disease. High-intensity interval training (HIIT) on the treadmill has been reported to be more effective in ameliorating these risk factors compared with moderate-intensity continuous training (MICT) in patients with cardiometabolic disease. In older adults, however, weight-bearing activities are frequently limited due to musculoskeletal and balance problems. The purpose of this study was to examine the feasibility and safety of non-weight-bearing all-extremity HIIT in older adults. In addition, we tested the hypothesis that all-extremity HIIT will be more effective in improving aerobic fitness, cardiac function, and metabolic risk factors compared with all-extremity MICT. Fifty-one healthy sedentary older adults (age: 65±1years) were randomized to HIIT (n=17), MICT (n=18) or non-exercise control (CONT; n=16). HIIT (4×4min 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on a non-weight-bearing all-extremity ergometer, 4×/week for 8weeks under supervision. All-extremity HIIT was feasible in older adults and resulted in no adverse events. Aerobic fitness (peak oxygen consumption; VO2peak) and ejection fraction (echocardiography) improved by 11% (P<0.0001) and 4% (P=0.001), respectively in HIIT, while no changes were observed in MICT and CONT (P≥0.1). Greater improvements in ejection fraction were associated with greater improvements in VO2peak (r=0.57; P<0.0001). Insulin resistance (homeostatic model assessment) decreased only in HIIT by 26% (P=0.016). Diastolic function, body composition, glucose and lipids were unaffected (P≥0.1). In conclusion, all-extremity HIIT is feasible and safe in older adults. HIIT, but not MICT, improved aerobic fitness, ejection fraction, and insulin resistance.

Insulin resistance: vascular function and exercise.

Insulin resistance associated with metabolic syndrome and Type 2 diabetes mellitus is an epidemic metabolic disorder, which increases the risk of cardiovascular complications. Impaired vascular endothelial function is an early marker for atherosclerosis, which causes cardiovascular complications. Both experimental and clinical studies indicate that endothelial dysfunction in vasculatures occurs with insulin resistance. The associated physiological mechanisms are not fully appreciated yet, however, it seems that augmented oxidative stress, a physiological imbalance between oxidants and antioxidants, in vascular cells is a possible mechanism involved in various vascular beds with insulin resistance and hyperglycemia. Regardless of the inclusion of resistance exercise, aerobic exercise seems to be beneficial for vascular endothelial function in both large conduit and small resistance vessels in both clinical and experimental studies with insulin resistance. In clinical cases, aerobic exercise over 8 weeks with higher intensity seems more beneficial than the cases with shorter duration and lower intensity. However, more studies are needed in the future to elucidate the physiological mechanisms by which vascular endothelial function is impaired in insulin resistance and improved with aerobic exercise.

Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults.

Mineralocorticoid receptor (MR) activation by aldosterone may regulate vascular function in health or contribute to vascular dysfunction in cardiovascular disease. Whether the effects are beneficial or detrimental to vascular function appear to be dependent on the integrity of the vascular endothelium and whether the responses are short-term or chronic. Acute modulation of MR activation has resulted in conflicting outcomes on vascular function in young healthy adults. Little is known about the vascular role of aldosterone and MR activation in healthy human aging. The primary objective of this study was to examine whether acute inhibition of MR by the selective antagonist eplerenone, influences vascular function in healthy older adults. We performed a randomized, double-blind, placebo-controlled crossover study in 22 adults (61±1 years; mean±SE, 53-79 years) who were free from overt clinical cardiovascular disease. We measured brachial artery flow-mediated endothelium-dependent dilation and endothelium-independent dilation to sublingual nitroglycerin (0.4 mg) following eplerenone (100 mg/dose, 2 doses, 24h between doses) or placebo. In response to acute MR antagonism, flow-mediated dilation decreased by 19% (from 6.9±0.5 to 5.6±0.6%, P=0.02; placebo vs. eplerenone). Endothelial nitric oxide synthase (eNOS) activity also decreased following MR antagonism based on the ratio of phosphorylated eNOS(Ser1177) to total eNOS (1.53±0.08 vs. 1.29±0.06, P=0.02). Nitroglycerin-induced dilation and blood pressure were unaffected (nitroglycerin-induced dilation: 21.9±1.9 vs. 21.0±1.5%, P=0.5 and systolic/diastolic blood pressure: 135/77±4/2 vs. 134/77±4/2 mmHg, P≥0.6). In conclusion, acute MR antagonism impairs vascular endothelial function in healthy older adults without influencing vascular smooth muscle responsiveness to exogenous nitric oxide or blood pressure.

Effect of Selective Mineralocorticoid Receptor Blockade on Flow-Mediated Dilation and Insulin Resistance in Older Adults with Metabolic Syndrome.

BACKGROUND: The prevalence of metabolic syndrome is especially high in older adults. Metabolic syndrome is associated with impaired vascular endothelial function, insulin resistance, and increased risk for cardiovascular disease but the underlying mechanisms are not fully elucidated. Plasma aldosterone is independently associated with metabolic syndrome and is linked to endothelial dysfunction and insulin resistance. Thus, we hypothesized that mineralocorticoid receptor (MR) blockade would improve flow-mediated dilation and insulin resistance in older adults with metabolic syndrome. METHODS: To test this hypothesis, we conducted a balanced, randomized, double-blind, placebo-controlled, crossover study using selective MR blockade (eplerenone; 100 mg/day) for 1 month with 1 month washout in older adults with metabolic syndrome (62.6 ± 3.2 yrs; mean ± standard error). We evaluated brachial artery flow-mediated dilation (ultrasonography), oxidative stress (oxidized low-density lipoproteins and F2-isoprostanes) and insulin resistance (homeostatic model assessment). RESULTS: In response to MR blockade, flow-mediated dilation (5.37 ± 0.85 vs. 5.98 ± 1.29%; placebo vs. eplerenone; P = 0.4), oxidized low-density lipoproteins (51.6 ± 11.5 vs. 56.1 ± 10.9 U/L; P = 0.6), and F2-isoprostanes (0.07 ± 0.02 vs. 0.06 ± 0.01 pg/mL; P = 0.3) did not improve. Insulin resistance also did not change following MR blockade (1.04 ± 0.26 vs. 1.38 ± 0.50; P = 0.6). However, MR blockade resulted in a large reduction (10 mmHg) in systolic blood pressure (140 ± 6 vs. 130 ± 6 mmHg; P = 0.02), with no significant change in diastolic blood pressure (81 ± 3 vs. 75 ± 2 mmHg; P = 0.2). CONCLUSIONS: Our data do not support a contributing role for MRs in endothelial dysfunction and insulin resistance in older adults with metabolic syndrome. However, our findings suggest MR activation is an important contributor to systolic hypertension in this patient group.

Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy.

Although doxorubicin (DOX) is a highly effective anti-tumour agent used to treat a variety of cancers, DOX administration is associated with significant side effects, including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted anti-oxidant to prevent DOX-induced increases in mitochondrial ROS emission, whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibres and the prevention of DOX-induced increases in mitochondrial ROS emission protects against fibre atrophy and contractile dysfunction in both cardiac and skeletal muscles. Furthermore, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and, importantly, calpain activation is a major contributor to DOX-induced myopathy. Taken together, these findings show that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibres.

Higher levels of adiponectin in vascular endothelial cells are associated with greater brachial artery flow-mediated dilation in older adults.

Adiponectin, an adipocyte-derived protein, exerts anti-atherosclerotic effects on the vascular endothelium. Recently adiponectin protein has been reported in murine vascular endothelial cells, however, whether adiponectin is present in human vascular endothelial cells remains unexplored. We sought to examine 1) adiponectin protein in vascular endothelial cells collected from older adults free of overt cardiovascular disease; 2) the relation between endothelial cell adiponectin and in vivo vascular endothelial function; and 3) the relation between endothelial cell adiponectin, circulating (plasma) adiponectin and related factors. We measured vascular endothelial function (brachial artery flow-mediated dilation using ultrasonography), vascular endothelial cell adiponectin (biopsy coupled with quantitative immunofluorescence) and circulating adiponectin (Mercodia, ELISA) in older, sedentary, non-smoking, men and women (55-79 years). We found that higher endothelial cell adiponectin was related with greater flow-mediated dilation (r = 0.43, P < 0.05) and greater flow-mediated dilation normalized for shear stress (r = 0.56, P < 0.01), but was not related with vascular smooth muscle responsiveness to nitric oxide (r = 0.04, P = 0.9). Vascular endothelial cell adiponectin was not related with circulating adiponectin (r = -0.14, P = 0.6). Endothelial cell and circulating adiponectin were differentially associated with adiposity, metabolic and other factors, but both were inversely associated with renal function (r = 0.44 to 0.62, P ≤ 0.04). In conclusion, higher endothelial cell adiponectin levels are associated with higher vascular endothelial function, independent of circulating adiponectin levels in older adults.

Type 2 Diabetes: Endothelial dysfunction and Exercise.

PURPOSE: Vascular endothelial dysfunction is an early marker of atherosclerosis characterized by decreased nitric oxide bioavailability in the vascular endothelium and smooth muscle cells. Recently, some animal models and in vitro trials demonstrated that excessive superoxide production from mitochondria within vascular endothelial cells played a role in the pathogenesis of atherosclerosis in type 2 diabetes. This review provides a systematic assessment of the effectiveness of exercise to identify effective approaches to recognize diabetes risk and prevent progression to heart disease. METHODS: A systematic literature search was conducted to retrieve articles from 1979 to 2013 using the following databases: the MEDLINE, PubMed. Articles had to describe an intervention that physical activity and exercise to identify effective approaches to heart and vascular endothelium. RESULTS: Currently, physical activity and exercise guidelines aimed to improve cardiovascular health in patients with type 2 diabetes are nonspecific. Benefit of aerobic exercise training on vascular endothelial function in type 2 diabetic patients is still controversial. CONCLUSION: it is necessary to demonstrate the mechanism of endothelial dysfunction from live human tissues so that we can provide more specific exercise training regimens to enhance cardiovascular health in type 2 diabetic patients.

Mineralocorticoid receptors modulate vascular endothelial function in human obesity.

Obesity increases linearly with age and is associated with impaired vascular endothelial function and increased risk of cardiovascular disease. MRs (mineralocorticoid receptors) contribute to impaired vascular endothelial function in cardiovascular disease; however, their role in uncomplicated human obesity is unknown. Because plasma aldosterone levels are elevated in obesity and adipocytes may be a source of aldosterone, we hypothesized that MRs modulate vascular endothelial function in older adults in an adiposity-dependent manner. To test this hypothesis, we administered MR blockade (eplerenone; 100 mg/day) for 1 month in a balanced randomized double-blind placebo-controlled cross-over study to 22 older adults (ten men, 55-79 years) varying widely in adiposity [BMI (body mass index): 20-45 kg/m²], but who were free from overt cardiovascular disease. We evaluated vascular endothelial function [brachial artery FMD (flow-mediated dilation)] via ultrasonography) and oxidative stress (plasma F2-isoprostanes and vascular endothelial cell protein expression of nitrotyrosine and NADPH oxidase p47phox) during placebo and MR blockade. In the whole group, oxidative stress (P>0.05) and FMD did not change with MR blockade (6.39 ± 0.67 compared with 6.23 ± 0.73%; P=0.7). However, individual improvements in FMD in response to eplerenone were associated with higher total body fat (BMI: r=0.45, P=0.02; and dual-energy X-ray absorptiometry-derived percentage body fat: r=0.50, P=0.009) and abdominal fat (total: r=0.61, P=0.005; visceral: r=0.67, P=0.002; and subcutaneous: r=0.48, P=0.03). In addition, greater improvements in FMD with eplerenone were related to higher baseline fasting glucose (r=0.53, P=0.01). MRs influence vascular endothelial function in an adiposity-dependent manner in healthy older adults.

Role of mineralocorticoid receptors in arterial stiffness in human aging.

Arterial stiffness, an independent predictor of cardiovascular disease, is increased in aging, but the underlying mechanisms are not completely understood. Mineralocorticoid receptors (MR) may contribute to oxidative stress and arterial stiffness in healthy older adults. To test the hypothesis that short-term MR blockade may reduce oxidative stress and improve arterial stiffness, we conducted a randomized, double blind, crossover study using the selective MR blocker Eplerenone or placebo in 23 older adults (age, 64±1 years; mean±SE) free from overt cardiovascular and other clinical disease (e.g, diabetes, renal and liver disease). In response to MR blockade, brachial and carotid blood pressure decreased (P≤0.01). However, MR blockade had no effect on oxidative stress (oxidized LDL, 61.2±6.8 vs. 62.4±7.4 U/L, P=0.9; placebo vs. Eplerenone) and arterial stiffness (aortic pulse wave velocity (PWV), 9.17±1.19 vs. 8.92±1.19 m/s, P=0.5; leg PWV, 13.45±0.45 vs. 12.81±0.47 m/s, P=0.3; arm PWV, 11.43±0.62 vs. 11.73±0.68 m/s, P=0.7; carotid artery compliance, 0.150±0.013 vs. 0.149±0.014 mm(2)/mmHg, P=0.8; distensibility, 23.1±1.8 vs. 23.3±1.7 10(-3)/kPa, P=0.8; ß stiffness index, 3.5±0.3 vs. 3.6±0.3, P=0.6; and augmentation index, 16.0±2.2 vs. 15.6±2.8%, P=0.8). These results provide the first evidence that MR do not appear to contribute to oxidative stress in human aging and that short-term MR blockade does not result in reduced oxidative stress and improved arterial stiffness.

Vascular smooth muscle responsiveness to nitric oxide is reduced in healthy adults with increased adiposity.

Vascular smooth muscle responsiveness to nitric oxide, as assessed by nitroglycerin-induced dilation (NID), is impaired in clinical cardiovascular disease, but its relation to adiposity is unknown. We determined the relation of NID to total and abdominal adiposity in healthy adults varying widely in adiposity. In 224 men and women [age, 18-79 years; body mass index (BMI), 16.4-42.2 kg/m(2)], we measured NID (brachial artery dilation to 0.4 mg sublingual nitroglycerin), total body adiposity [BMI and percent body fat (percent BF via dual-energy X-ray absorptiometry)], and indexes of abdominal adiposity [waist circumference (WC) and waist-to-hip ratio (WHR)]. In a subgroup (n = 74), we also measured total abdominal fat (TAF), abdominal visceral fat (AVF), and subcutaneous fat (ASF) using computed tomography. Based on multiple linear regression, NID was negatively related to BMI [part correlation coefficient (r(part)) = -0.19, P = 0.004] and abdominal adiposity (WC, r(part) = -0.22; WHR, r(part) = -0.19; TAF, r(part) = -0.36; AVF, r(part) = -0.36; and ASF, r(part) = -0.30; all P ≤ 0.009) independent of sex, but only tended to be related to total percent BF (r(part) = -0.12, P = 0.07). In a subgroup of subjects with the highest compared with the lowest amount of AVF, NID was 35% lower (P = 0.003). Accounting for systolic blood pressure, HDL cholesterol, glucose, insulin resistance, adiponectin, and brachial artery diameter reduced or abolished some of the relations between NID and adiposity. In conclusion, NID is or tends to be negatively associated with measures of total adiposity (BMI and percent BF, respectively) but is consistently and more strongly negatively associated with abdominal adiposity. Adiposity may influence NID in part via other cardiovascular risk factors.