Shane A. Phillips

Benefit of Low-Fat Over Low-Carbohydrate Diet on Endothelial Health in Obesity

Obesity is associated with impaired endothelial-dependent flow-mediated dilation, a precursor to hypertension and atherosclerosis. Although dieting generally improves cardiovascular risk factors, the direct effect of different dietary strategies on vascular endothelial function is not known. The purpose of this study was to test the hypothesis that a low-fat (LF) diet improves endothelial function compared with an isocaloric low-carbohydrate (LC) diet. Obese (n=20; body mass index: 29 to 39; mean systolic blood pressure: 107 to 125 mm Hg) and otherwise healthy volunteers were randomly assigned to either the American Heart Association modeled LF (30% fat calories) diet or an isocaloric LC Atkins’ style diet (20 g of carbohydrates) for 6 weeks (4-week weight loss and 2-week maintenance phase). Brachial flow-mediated dilation and dilation to nitroglycerin were measured with ultrasound using automated edge detection technology (baseline, week 2, and week 6). Blood pressure, weight loss, and cholesterol profiles were measured throughout the study. Weight loss was similar in LF (100±4 to 96.1±4 kg; P<0.001) and LC (95.4±4 to 89.7±4 kg; P<0.001) diets. Blood pressure decreased similarly in both groups (LF: 8/5 mm Hg; LC: 12/6 mm Hg) at 6 weeks. After 6 weeks, the percentage of flow-mediated dilation improved (1.9±0.8; P<0.05) in the LF diet but was reduced in the LC diet (−1.4±0.6; P<0.05) versus baseline. Dilation to nitroglycerin and lipid panels was similar at 0, 2, and 6 weeks. Despite similar degrees of weight loss and changes blood pressure, LF diets improved brachial artery flow-mediated dilation over LC diets. LF diets may confer greater cardiovascular protection than LC diets.

Alcoholic cardiomyopathy: pathophysiologic insights.

Alcoholic cardiomyopathy (ACM) is a specific heart muscle disease found in individuals with a history of long-term heavy alcohol consumption. ACM is associated with a number of adverse histological, cellular, and structural changes within the myocardium. Several mechanisms are implicated in mediating the adverse effects of ethanol, including the generation of oxidative stress, apoptotic cell death, impaired mitochondrial bioenergetics/stress, derangements in fatty acid metabolism and transport, and accelerated protein catabolism. In this review, we discuss the evidence for such mechanisms and present the potential importance of drinking patterns, genetic susceptibility, nutritional factors, race, and sex. The purpose of this review is to provide a mechanistic paradigm for future research in the area of ACM.

Resistance and aerobic exercise protects against acute endothelial impairment induced by a single exposure to hypertension during exertion

Resistance and aerobic exercise is recommended for cardiovascular health and disease prevention. However, the accompanying increase in arterial pressure during resistance exercise may be detrimental to vascular health. This study tests the vascular benefits of aerobic compared with resistance exercise on preventing impaired vascular function induced by a single weight lifting session that is associated with acute hypertension. Healthy, lean sedentary (SED) subjects, weight lifters, runners (>15 miles/wk), and cross trainers (chronic aerobic and resistance exercisers), underwent a single progressive leg press weight lifting session with blood pressure measurements. Brachial artery flow-mediated vasodilation (FMD; an index of arterial endothelial function) was determined using ultrasonography immediately before and after weight lifting. Sublingual nitroglycerin (0.4 mg) was used to determine endothelium-independent dilation after weight lifting. All subjects were normotensive with similar blood pressure responses during exercise. Baseline FMD was lower in runners (5.4 ± 0.5%; n = 13) and cross trainers (4.44 ± 0.3%; n = 13) vs. SED (8.5 ± 0.8%; n = 13; P = 0.037). Brachial FMD improved in conditioned weight lifters (to 8.8 ± 0.9%; P = 0.007) and runners (to 7.6 ± 0.6%; P < 0.001) but not cross trainers (to 5.3 ± 0.6%; P = NS) after acute hypertension. FMD was decreased in SED (to 5.7 ± 0.4%; P = 0.019). Dilation to nitroglycerin was similar among groups. These data suggest that endothelial responses are maintained after exposure to a single bout of weight lifting in resistance and aerobic athletes. Resistance and aerobic exercise may confer similar protection against acute vascular insults such as exertional hypertension.

Measuring FMD in the brachial artery: how important is QRS gating?

Recommendations for the measurement of brachial flow-mediated dilation (FMD) typically suggest images be obtained at identical times in the cardiac cycle, usually end diastole (QRS complex onset). This recommendation presumes that inter-individual differences in arterial compliance are minimized. However, published evidence is conflicting. Furthermore, ECG gating is not available on many ultrasound systems; it requires an expensive software upgrade or increased image processing time. We tested whether analysis of images acquired with QRS gating or with the more simplified method of image averaging would yield similar results. We analyzed FMD and nitroglycerin-mediated dilation (NMD) in 29 adults with type 2 diabetes mellitus and in 31 older adults and 12 young adults without diabetes, yielding a range of brachial artery distensibility. FMD and NMD were measured using recommended QRS-gated brachial artery diameter measurements and, alternatively, the average brachial diameters over the entire R-R interval. We found strong agreement between both methods for FMD and NMD (intraclass correlation coefficients = 0.88-0.99). Measuring FMD and NMD using average diameter measurements significantly reduced post-image-processing time (658.9 ± 71.6 vs. 1,024.1 ± 167.6 s for QRS-gated analysis, P < 0.001). FMD and NMD measurements based on average diameter measurements can be performed without reducing accuracy. This finding may allow for simplification of FMD measurement and aid in the development of FMD as a potentially useful clinical tool.

Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins.

Light chain amyloidosis (AL) involves overproduction of amyloidogenic light chain proteins (LC) leading to heart failure, yet the mechanisms underlying tissue toxicity remain unknown. We hypothesized that LC induces endothelial dysfunction in non-AL human microvasculature and apoptotic injury in human coronary artery endothelial cells (HCAECs). Adipose arterioles (n = 34, 50 ± 3 yr) and atrial coronary arterioles (n = 19, 68 ± 2 yr) from non-AL subjects were cannulated. Adipose arteriole dilator responses to acetylcholine/papaverine were measured at baseline and 1 h exposure to LC (20 μg/ml) from biopsy-proven AL subjects (57 ± 11 yr) without and with antioxidant cotreatment. Coronary arteriole dilation to bradykinin/papaverine was measured post-LC exposure. HCAECs were exposed to 1 or 24 h of LC. LC reduced dilation to acetylcholine (10(-4) M: 41.6 ± 7 vs. 85.8 ± 2.2% control, P < 0.001) and papaverine (81.4 ± 4.6 vs. 94.8 ± 1.3% control, P < 0.01) in adipose arterioles and to bradykinin (10(-6) M: 68.6 ± 6.2 vs. 90.9 ± 1.6% control, P < 0.001) but not papaverine in coronary arterioles. There was an increase in superoxide and peroxynitrite in arterioles treated with LC. Adipose arteriole dilation was restored by cotreatment with polyethylene glycol-superoxide dismutase and tetrahydrobiopterin but only partially restored by mitoquinone (mitochondria-targeted antioxidant) and gp91ds-tat (NADPH oxidase inhibitor). HCAECs exposed to LC showed reduced NO and increased superoxide, peroxynitrite, annexin-V, and propidium iodide compared with control. Brief exposure to physiological amounts of LC induced endothelial dysfunction in human adipose and coronary arterioles and increased apoptotic injury in coronary artery endothelial cells likely as a result of oxidative stress, reduced NO bioavailability, and peroxynitrite production. Microvascular dysfunction and injury is a novel mechanism underlying AL pathobiology and is a potential target for therapy.

Adipokine responses to acute resistance exercise in trained and untrained men.

INTRODUCTION Adipose tissue-derived hormones act as key mediators that may link active lifestyles to improved cardiovascular function. This study tested the hypothesis that a single weight training session would beneficially modulate adipokine profile in a way that would exert protection against endothelial dysfunction, in trained but not sedentary subjects. METHODS Male subjects (n = 43) were categorized into four separate groups based on exercise history: 1) sedentary, 2) weight trainers, 3) runners, or 4) weight trainer + runners. All subjects underwent a single progressive leg press weight training session (low weight for two sets of 8-12 repetitions each and then near-maximal exertion for three sets of 8-12 repetitions each). RESULTS There were no differences between groups for age, body weight, BMI, waist circumference, or percent body fat. Adiponectin increased (P < 0.05) by 30% and 37%, whereas resistin decreased (P < 0.05) by 35% and 34% in the weight trainers and weight trainer + runners, respectively, after training. Flow-mediated dilation (FMD) was impaired (P < 0.05) in sedentary subjects (-1.1 +/- 0.3%) but not in the athletic groups (1.7 +/- 0.4%). Improvements in FMD were associated with increased adiponectin (r = 0.61, P = 0.01), and decreased resistin (r = -0.56, P = 0.01) in weight trainers only. Leptin was not altered by acute resistance training in any group. There were no differences after training for total, LDL, HDL cholesterol, triglycerides, C-reactive protein levels, and systolic or diastolic blood pressure. Increased adiponectin was related to higher levels of HDL cholesterol after intervention (r = 0.71, P = 0.001). CONCLUSIONS These findings suggest that habitual resistance training may modulate adipokine profiles in a way that is protective against endothelial dysfunction.

Binge Drinking Impairs Vascular Function in Young Adults

OBJECTIVES The aim of this study was to assess whether young binge drinkers (BD) have impaired macrovascular and microvascular function and cardiovascular disease risk factors compared with age-matched alcohol abstainers (A). BACKGROUND Binge drinking rates are highest on college campuses and among those age 18 to 25 years; however, macrovascular and microvascular endothelial function in young adults with histories of repeated binge drinking (≥ 5 standard drinks in 2 h in men, ≥ 4 standard drinks in 2 h in women) has not been investigated. METHODS Cardiovascular profiles, brachial artery endothelial-dependent flow-mediated dilation (FMD), and flow-independent nitroglycerin (NTG)-mediated dilation and vasoreactivity of resistance arteries (isolated from gluteal fat biopsies) were evaluated in A and BD. RESULTS Men and women (18 to 25 years of age; A, n = 17; BD, n = 19) were enrolled. In the BD group, past-month mean number of binge episodes was 6 ± 1, and the mean duration of binge drinking behavior was 4 ± 0.6 years. FMD and NTG-mediated dilation were significantly lower in the BD group (FMD: 8.4 ± 0.7%, p = 0.022; NTG-mediated dilation: 19.6 ± 2%, p = 0.009) than in the A group (FMD: 11 ± 0.7%; NTG-mediated dilation: 28.6 ± 2%). Acetylcholine-induced and sodium nitroprusside-induced dilation in resistance arteries was not significantly different between the A and BD groups. However, endothelin-1-induced constriction was significantly enhanced in the BD group compared with the A group (p = 0.032). No differences between groups were found in blood pressure, lipoproteins, and C-reactive protein. CONCLUSIONS Alterations in the macrocirculation and microcirculation may represent early clinical manifestations of cardiovascular risk in otherwise healthy young BD. This study has important clinical implications for screening young adults for a repeated history of binge drinking.

Thrombin increases inflammatory cytokine and angiogenic growth factor secretion in human adipose cells in vitro

BackgroundAbdominal obesity is associated with pro-thrombotic and inflammatory states. Therefore, the purpose of this study was to examine the expression of thrombin receptors (PAR1 and PAR4) human adipose tissue and whether thrombin stimulates an inflammatory cytokine and growth factor profile in human adipose tissue.MethodsHuman adipose tissue, isolated preadipocytes and differentiated adipocytes were used in this study. PAR1 and PAR4 mRNA and protein were detected by RT-PCR and immunoblot analysis in both adipose tissue and adipose microvessels. In separate studies, IL-1β, IL-6, MCP-1, TNF-α, IL-10, FGF-2, VEGF, and PDGF production were measured from adipose tissue (n = 5), adipocytes (n = 5), and preadipocytes (n = 3) supernatants with and without thrombin (1 or 10 U/ml; 24 hrs) treatment.ResultsThrombin increased cytokine secretion of IL-1β, IL-6, MCP-1 and TNF-α and growth factor secretion of VEGF from adipocytes along with MCP-1 and VEGF from preadipocytes. The direct thrombin inhibitor lepirudin given in conjunction with thrombin prevented the thrombin-mediated increase in cytokine and growth factor secretion.ConclusionHere we show that thrombin PAR1 and PAR4 receptors are present and that thrombin stimulates inflammatory cytokine generation and growth factor release in human adipose tissue and cells in vitro. These data suggest that thrombin may represent a molecular link between obesity and associated inflammation.

Exercise interventions and peripheral arterial function: implications for cardio-metabolic disease.

Physical inactivity is a major risk factor for the development of obesity and other cardiovascular (CV) disease (CVD). Vascular endothelial dysfunction is a key event in the development of CVD and is associated with a sedentary lifestyle in otherwise healthy adults. In addition, vascular endothelial dysfunction may be exacerbated in sedentary individuals who are obese and insulin resistant, since excess body fat is associated with elevated levels of pro-atherogenic inflammatory adipokines and cytokines that reduce the nitric oxide (NO) and other upstream paracrine signaling substances which reduces vascular health. Since blood flow-related shear stress is a major stimulus to NO release from the endothelium, disturbed flow or low shear stress is the likely mechanism by which vascular endothelial function is altered with inactivity. Evidence shows that regular physical exercise has beneficial effects on CVD and the risk factors that promote peripheral arterial function and health. Both aerobic and resistance exercise training are generally believed to improve endothelial function and are commonly recommended for CV health, including the management of obesity, hypertension, and insulin resistance. However, many factors including age, disease status, and race appear to influence these outcomes. Although evidence supporting the health benefits of exercise is compelling, the optimum prescription (volume and intensity) and the exact mechanism underlying the effects of exercise training on arterial function and cardiometabolic risk has yet to be identified. The focus of this review will be on the evidence supporting exercise interventions for peripheral arterial function.

An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles.

Endothelial nitric oxide (NO) is the primary mediator of flow-mediated dilation (FMD) in human adipose microvessels. Impaired NO-mediated vasodilation occurs after acute and chronic hypertension, possibly due to excess generation of reactive oxygen species (ROS). The direct role of pressure elevation in this impairment of human arteriolar dilation is not known. We tested the hypothesis that elevation in pressure is sufficient to impair FMD. Arterioles were isolated from human adipose tissue and cannulated, and vasodilation to graded flow gradients was measured before and after exposure to increased intraluminal pressure (IILP; 150 mmHg, 30 min). The mediator of FMD was determined using pharmacological agents to reduce NO [N(G)-nitro-l-arginine methyl ester (l-NAME), 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO)], or H2O2 [polyethylene glycol (PEG)-catalase], and mitochondrial (mt) ROS was quantified using fluorescence microscopy. Exposure to IILP decreased overall FMD (max %dilation: 82.7 ± 4.9 vs. 62 ± 5.6; P < 0.05). This dilation was abolished by treatment with l-NAME prepressure and PEG-catalase after IILP (max %dilation: l-NAME: 23.8 ± 6.1 vs. 74.8 ± 8.6; PEG-catalase: 71.8 ± 5.9 vs. 24.6 ± 10.6). To examine if this change was mediated by mtROS, FMD responses were measured in the presence of the complex I inhibitor rotenone or the mitochondrial antioxidant mitoTempol. Before IILP, FMD was unaffected by either compound; however, both inhibited dilation after IILP. The fluorescence intensity of mitochondria peroxy yellow 1 (MitoPY1), a mitochondria-specific fluorescent probe for H2O2, increased during flow after IILP (%change from static: 12.3 ± 14.5 vs. 127.9 ± 57.7). These results demonstrate a novel compensatory dilator mechanism in humans that is triggered by IILP, inducing a change in the mediator of FMD from NO to mitochondria-derived H2O2.