Evan DeVallance

Aerobic exercise training reduces arterial stiffness in metabolic syndrome

The metabolic syndrome (MetS) is associated with a threefold increase risk of cardiovascular disease (CVD) mortality partly due to increased arterial stiffening. We compared the effects of aerobic exercise training on arterial stiffening/mechanics in MetS subjects without overt CVD or type 2 diabetes. MetS and healthy control (Con) subjects underwent 8 wk of exercise training (ExT; 11 MetS and 11 Con) or remained inactive (11 MetS and 10 Con). The following measures were performed pre- and postintervention: radial pulse wave analysis (applanation tonometry) was used to measure augmentation pressure and index, central pressures, and an estimate of myocardial efficiency; arterial stiffness was assessed from carotid-femoral pulse-wave velocity (cfPWV, applanation tonometry); carotid thickness was assessed from B-mode ultrasound; and peak aerobic capacity (gas exchange) was performed in the seated position. Plasma matrix metalloproteinases (MMP) and CVD risk (Framingham risk score) were also assessed. cfPWV was reduced (P < 0.05) in MetS-ExT subjects (7.9 ± 0.6 to 7.2 ± 0.4 m/s) and Con-ExT (6.6 ± 1.8 to 5.6 ± 1.6 m/s). Exercise training reduced (P < 0.05) central systolic pressure (116 ± 5 to 110 ± 4 mmHg), augmentation pressure (9 ± 1 to 7 ± 1 mmHg), augmentation index (19 ± 3 to 15 ± 4%), and improved myocardial efficiency (155 ± 8 to 168 ± 9), but only in the MetS group. Aerobic capacity increased (P < 0.05) in MetS-ExT (16.6 ± 1.0 to 19.9 ± 1.0) and Con-ExT subjects (23.8 ± 1.6 to 26.3 ± 1.6). MMP-1 and -7 were correlated with cfPWV, and both MMP-1 and -7 were reduced post-ExT in MetS subjects. These findings suggest that some of the pathophysiological changes associated with MetS can be improved after aerobic exercise training, thereby lowering their cardiovascular risk.

Is obesity predictive of cardiovascular dysfunction independent of cardiovascular risk factors

Introduction:Obesity is thought to exert detrimental effects on the cardiovascular (CV) system. However, this relationship is impacted by the co-occurrence of CV risk factors, type 2 diabetes (T2DM) and overt disease. We examined the relationships between obesity, assessed by body mass index (BMI) and waist circumference (WC), and CV function in 102 subjects without overt CV disease. We hypothesized that obesity would be independently predictive of CV remodeling and functional differences, especially at peak exercise.Methods:Brachial (bSBP) and central (cSBP) systolic pressure, carotid-to-femoral pulse wave velocity (PWVcf) augmentation index (AGI; by SphygmoCor), and carotid remodeling (B-mode ultrasound) were examined at rest. Further, peak exercise cardiac imaging (Doppler ultrasound) was performed to measure the coupling between the heart and arterial system.Results:In backward elimination regression models, accounting for CV risk factors, neither BMI nor WC were predictors of carotid thickness or PWVcf; rather age, triglycerides and hypertension were the main determinants. However, BMI and WC predicted carotid cross-sectional area and lumen diameter. When examining the relationship between body size and SBP, BMI (β=0.32) and WC (β=0.25) were predictors of bSBP (P<0.05), whereas, BMI was the only predictor of cSBP (β=0.22, P<0.05) indicating a differential relationship between cSBP, bSBP and body size. Further, BMI (β=−0.26) and WC (β=−0.27) were independent predictors of AGI (P<0.05). As for resting cardiac diastolic function, WC seemed to be a better predictor than BMI. However, both BMI and WC were inversely and independently related to arterial-elastance (net arterial load) and end-systolic elastance (cardiac contractility) at rest and peak exercise.Conclusion:These findings illustrate that obesity, without T2DM and overt CV disease, and after accounting for CV risk factors, is susceptible to pathophysiological adaptations that may predispose individuals to an increased risk of CV events.

Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats.

Evolution of metabolic syndrome is associated with a progressive reduction in skeletal muscle microvessel density, known as rarefaction. Although contributing to impairments to mass transport and exchange, the temporal development of rarefaction and the contributing mechanisms that lead to microvessel loss are both unclear and critical areas for investigation. Although previous work suggests that rarefaction severity in obese Zucker rats (OZR) is predicted by the chronic loss of vascular nitric oxide (NO) bioavailability, we have determined that this hides a biphasic development of rarefaction, with both early and late components. Although the total extent of rarefaction was well predicted by the loss in NO bioavailability, the early pulse of rarefaction developed before a loss of NO bioavailability and was associated with altered venular function (increased leukocyte adhesion/rolling), and early elevation in oxidant stress, TNF-α levels, and the vascular production of thromboxane A2 (TxA2). Chronic inhibition of TNF-α blunted the severity of rarefaction and also reduced vascular oxidant stress and TxA2 production. Chronic blockade of the actions of TxA2 also blunted rarefaction, but did not impact oxidant stress or inflammation, suggesting that TxA2 is a downstream outcome of elevated reactive oxygen species and inflammation. If chronic blockade of TxA2 is terminated, microvascular rarefaction in OZR skeletal muscle resumes, but at a reduced rate despite low NO bioavailability. These results suggest that therapeutic interventions against inflammation and TxA2 under conditions where metabolic syndrome severity is moderate or mild may prevent the development of a condition of accelerated microvessel loss with metabolic syndrome.

Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7-8, 12-13, and 16-17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7-8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS.

Improved arterial-ventricular coupling in metabolic syndrome after exercise training: a pilot study.

PURPOSE The metabolic syndrome (MetS) is associated with threefold increased risk of cardiovascular (CV) morbidity and mortality, which is partly due to a blunted CV reserve capacity, reflected by a reduced peak exercise left ventricular (LV) contractility and aerobic capacity and a blunted peak arterial-ventricular coupling. To date, no study has examined whether aerobic exercise training in MetS can reverse peak exercise CV dysfunction. Furthermore, examining how exercise training alters CV function in a group of individuals with MetS before the development of diabetes and/or overt CV disease can provide insights into whether some of the pathophysiological CV changes can be delayed/reversed, lowering their CV risk. The objective of this study was to examine the effects of 8 wk of aerobic exercise training in individuals with MetS on resting and peak exercise CV function. METHODS Twenty participants with MetS underwent either 8 wk of aerobic exercise training (MetS-ExT, n = 10) or remained sedentary (MetS-NonT, n = 10) during this period. Resting and peak exercise CV function was characterized using Doppler echocardiography and gas exchange. RESULTS Exercise training did not alter resting LV diastolic or systolic function and arterial-ventricular coupling in MetS. In contrast, at peak exercise, an increase in LV contractility (40%, P < 0.01), cardiac output (28%, P < 0.05), and aerobic capacity (20%, P < 0.01), but a reduction in vascular resistance (30%, P < 0.05) and arterial-ventricular coupling (27%, P < 0.01), were noted in the MetS-ExT but not in the MetS-NonT group. Furthermore, an improvement in lifetime risk score was also noted in the MetS-ExT group. CONCLUSIONS These findings have clinical importance because they provide insight that some of the pathophysiological changes associated with MetS can be improved and can lower the risk of CV disease.

Chronic exposure to electronic cigarette (E-cig) results in impaired cardiovascular function in mice

Proponents for electronic cigarettes (E-cigs) claim that they are a safe alternative to tobacco-based cigarettes; however, little is known about the long-term effects of exposure to E-cig vapor on vascular function. The purpose of this study was to determine the cardiovascular consequences of chronic E-cig exposure. Female mice (C57BL/6 background strain) were randomly assigned to chronic daily exposure to E-cig vapor, standard (3R4F reference) cigarette smoke, or filtered air ( n = 15/group). Respective whole body exposures consisted of four 1-h-exposure time blocks, separated by 30-min intervals of fresh air breaks, resulting in intermittent daily exposure for a total of 4 h/day, 5 days/wk for 8 mo. Noninvasive ultrasonography was used to assess cardiac function and aortic arterial stiffness (AS), measured as pulse wave velocity, at three times points (before, during, and after chronic exposure). Upon completion of the 8-mo exposure, ex vivo wire tension myography and force transduction were used to measure changes in thoracic aortic tension in response to vasoactive-inducing compounds. AS increased 2.5- and 2.8-fold in E-cig- and 3R4F-exposed mice, respectively, compared with air-exposed control mice ( P < 0.05). The maximal aortic relaxation to methacholine was 24% and 33% lower in E-cig- and 3R4F-exposed mice, respectively, than in controls ( P < 0.05). No differences were noted in sodium nitroprusside dilation between the groups. 3R4F exposure altered cardiac function by reducing fractional shortening and ejection fraction after 8 mo ( P < 0.05). A similar, although not statistically significant, tendency was also observed with E-cig exposure ( P < 0.10). Histological and respiratory function data support emphysema-associated changes in 3R4F-exposed, but not E-cig-exposed, mice. Chronic exposure to E-cig vapor accelerates AS, significantly impairs aortic endothelial function, and may lead to impaired cardiac function. The clinical implication from this study is that chronic use of E-cigs, even at relatively low exposure levels, induces cardiovascular dysfunction. NEW & NOTEWORTHY Electronic cigarettes (E-cigs) are marketed as safe, but there has been insufficient long-term exposure to humans to justify these claims. This is the first study to report the long-term in vivo vascular consequences of 8 mo of exposure to E-cig vapor in mice (equivalent to ~25 yr of exposure in humans). We report that E-cig exposure increases arterial stiffness and impairs normal vascular reactivity responses, similar to other risk factors, including cigarette smoking, which contribute to the development of cardiovascular disease.

Effect of chronic stress on running wheel activity in mice

Acute and chronic stress have been reported to have differing effects on physical activity in rodents, but no study has examined a chronic stress protocol that incorporates stressors often experienced by rodents throughout a day. To examine this, the effects of the Unpredictable Chronic Mild Stress (UCMS) protocol on voluntary running wheel activity at multiple time points, and/or in response to acute removal of chronic stress was determined. Twenty male Balb/c mice were given access and accustomed to running wheels for 4 weeks, after which they were randomized into 2 groups; exercise (EX, n = 10) and exercise with chronic stress using a modified UCMS protocol for 7 hours/day (8:00 a.m.-3:00p.m.), 5 days/week for 8 weeks (EXS, n = 10). All mice were given access to running wheels from approximately 3:30 p.m. to 7:30 a.m. during the weekday, however during weekends mice had full-time access to running wheels (a time period of no stress for the EXS group). Daily wheel running distance and time were recorded. The average running distance, running time, and work each weekday was significantly lower in EXS compared to EX mice, however, the largest effect was seen during week one. Voluntary wheel running deceased in all mice with increasing age; the pattern of decline appeared to be similar between groups. During the weekend (when no stress was applied), EXS maintained higher distance compared to EX, as well as higher daily distance, time, and work compared to their weekday values. These results indicate that mild chronic stress reduces total spontaneous wheel running in mice during the first week of the daily stress induction and maintains this reduced level for up to 8 consecutive weeks. However, following five days of UCMS, voluntary running wheel activity rebounds within 2–3 days.

Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα‐ and NOX2‐dependent pathway

What is the central question of this study? Tumour necrosis factor‐α (TNFα) has been shown to impair vascular function, but the impact of thoracic aorta perivascular adipose tissue (tPVAT)‐derived TNFα on tPVAT and aortic function in metabolic syndrome is unknown. What is the main finding and its importance? Release of TNFα by tPVAT causes production of reactive oxygen species in tPVAT through activation of an NADPH‐oxidase 2 (NOX2)‐dependent pathway, activates production of aortic reactive oxygen species and mediates aortic stiffness, potentially through matrix metalloproteinase 9 activity. Neutralization of TNFα and/or inhibition of NOX2 blocks the tPVAT‐induced impairment of aortic function. These data partly implicate tPVAT NOX2 and TNFα in mediating the vascular pathology of metabolic syndrome.

Psychological stress‐induced cerebrovascular dysfunction: the role of metabolic syndrome and exercise

What is the central question of this study? How does chronic stress impact cerebrovascular function and does metabolic syndrome accelerate the cerebrovascular adaptations to stress? What role does exercise training have in preventing cerebrovascular changes to stress and metabolic syndrome? What is the main finding and its importance? Stressful conditions lead to pathological adaptations of the cerebrovasculature via an oxidative nitric oxide pathway, and the presence of metabolic syndrome produces a greater susceptibility to stress‐induced cerebrovascular dysfunction. The results also provide insight into the mechanisms that may contribute to the influence of stress and the role of exercise in preventing the negative actions of stress on cerebrovascular function and structure.

Circulating leucocytes perpetuate stroke‐induced aortic dysfunction

What is the central question of this study? Does a stroke event influence aortic endothelial function; and what is the role of peripheral circulating leucocytes in stroke on the vascular reactivity of the aorta? What is the main finding and its importance? In vitro co‐culture experiments demonstrated that aortic endothelium‐dependent relaxation was impaired when rat aortic rings were co‐cultured with leucocytes stimulated with serum from stroke patients. Impaired vascular reactivity was not observed in aortic rings without leucocytes stimulated with serum from stroke patients or age‐matched control patients with or without leucocytes. These data suggest that leucocyte‐dependent altered aortic endothelium‐dependent relaxation with stroke and the systemic consequences of stroke on vascular inflammation may occur in the aorta.