Anti-tumour necrosis factor-alpha therapy over conventional therapy improves endothelial function in adults with rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with cardiovascular morbidity and mortality and inflammation contributes to related endothelial dysfunction. We aimed to investigate the effect of anti-TNFalpha therapy on endothelial function in subjects with rheumatoid arthritis. We measured flow-mediated (FMD) and GTN-mediated dilation of the brachial artery before and following 36 weeks of anti-TNFalpha therapy in nine RA patients and in a group of RA patients on conventional therapy. Thirty-six weeks of anti-TNFalpha therapy improved FMD relative to those on conventional therapy (8.65 +/- 1.50 vs. 1.70 +/- 1.36%, P = 0.02). No significant changes in GTN responses were evident. Significant improvements in tender (P = 0.03) and swollen (P = 0.02) joint counts, patients' global self-assessment (P = 0.01) and DAS-28 scores (P = 0.04) were observed in the anti-TNFalpha treated group. The addition of anti-TNFalpha treatment to conventional therapy, in those with severe RA, reduces inflammatory symptoms and improves endothelial function, potentially lowering future atherosclerotic risk.

Effects of training resumption on conduit arterial diameter in elite rowers.

BACKGROUND: Exercise training is a known stimulus for arteriogenesis, but it is unclear whether elite athletes, who exhibit increased conduit vessel diameter at rest, experience further structural vascular adaptations as a result of intense exercise training. METHODS: Cross-sectional comparisons were performed between elite rowers (N = 17), following a respite from training, and eight untrained age- and gender-matched controls to assess the effects of long-term exercise on vessel structure. To determine the impact of the resumption of intensive exercise training on conduit artery structure, measures were repeated following 3 and 6 months of training in the athletes; the controls remained inactive. Conduit vessel structure was assessed, using high-resolution B-mode ultrasound, as brachial artery diameter at rest (BADr) and in response to 5-min (BAD5) and 10-min (BAD10) periods of forearm cuff ischemia. Shear rate profiles were also analyzed following cuff deflation at all time points. RESULTS: At entry, all measures of BAD were greater (all P < 0.05) in the athletes relative to controls (athletes vs controls; BADr 4.47 +/- 0.10 vs 3.84 +/- 0.22 mm; BAD5 4.70 +/- 0.10 vs 4.05 +/- 0.36 mm, and BAD10 4.93 +/- 0.10 vs 4.07 +/- 0.25 mm). Resumption of exercise training caused a further increase in brachial artery diameters in the athletes at 3 months (BADr, 4.71 +/- 0.10 mm, P < 0.01; BAD5 4.94 +/- 0.10 mm, P < 0.05; BAD10 5.12 +/- 0.10 mm, P < 0.001), which were maintained, but not further increased, after 6 months of training. CONCLUSIONS: Athletes exhibit enhanced conduit artery diameters at rest and in response to vasodilator stimuli. Despite this long-term training effect on arterial structure, resumption of training further enhances diameter, an effect that occurs within 3 months.

The 6-minute walk test does not reliably detect changes in functional capacity of patients awaiting cardiac transplantation.

BACKGROUND: Peak oxygen consumption (Vo(2)peak) is a strong independent predictor of prognosis in patients with severe chronic heart failure (CHF) and is used to guide optimal timing of transplantation. However, its assessment is relatively expensive and time-consuming and requires sophisticated equipment and highly trained personnel. The purpose of this study was to determine whether changes in 6-minute walk test (6WT) distance, a simple, inexpensive potential alternative measure of functional capacity, can predict changes in Vo(2)peak in patients with severe CHF. METHODS: Sixteen subjects (ejection fraction 23+/-2%, Vo(2)peak 16.2+/-1.1 ml kg (-1)min(-1)) underwent repeated 6WT and Vo(2)peak assessments that included familiarization and 4 serial measures, 6 weeks apart (baseline and at Weeks 6, 12 and 18). Analysis compared baseline performance with each subsequent testing occasion. RESULTS: At baseline, mean (+/-SE) VO(2)peak was 16.3+/-1.1 ml kg(-1) min(-1) and 6WT distance was 458+/-21 m. 6WT and Vo(2)peak were strongly correlated at all timepoints (average r=0.82; all p<0.05). However, mixed model analysis, assessing the capacity of the changes seen in 6WT to predict changes in Vo(2)peak, showed no statistical significance (F=0.11; p=0.74). CONCLUSIONS: The 6WT is commonly used to assess functional capacity in patients with heart failure. This study demonstrates that, despite a strong cross-sectional correlation with Vo(2)peak, changes in the 6WT are not a reliable predictor of changes in Vo(2)peak within patients. Therefore, the 6WT has limited utility as a serial measure to assess changes in the clinical status of patients with severe heart failure.

Reduced ventricular flow propagation velocity in elite athletes is augmented with the resumption of exercise training.

Chronic exercise induces physiological enlargement of the left ventricle ('athlete's heart'), but the effects of current and long-term exercise training on diastolic function have not been investigated. Echocardiography and Doppler imaging were used to assess left ventricular (LV) dimensions and indices of diastolic filling in 22 elite athletes at the end of their 'off-season' (baseline) and, subsequently, following 3 and 6 months of training. Twelve matched controls were also studied at baseline, 3 and 6 months. Compared to controls at baseline, athletes exhibited significantly higher LV mass (235.7 +/- 7.1 g versus 178.1 +/- 14.5 g, P < 0.01) and reduced flow propagation velocity (V(P): 50.21 +/- 1.7 versus 72.2 +/- 3.6 cm s(-1), P < 0.01), a measure of diastolic function. Three months of training further increased LV mass in athletes (253.2 +/- 7.1 g; P < 0.01 versus baseline), and significantly increased their V(P) (66.7 +/- 2.5 cm s(-1); P < 0.05 versus baseline). These trends for increased mass and diastolic filling persisted following 6 months of training (LV mass 249.0 +/- 8.7 g P < 0.05 versus baseline; V(P) 75.7 +/- 3.0 cm s(-1); P < 0.01 versus baseline, and P = 0.01 versus 3 months). This study suggests that following a period of relative inactivity the rate of ventricular relaxation during early diastole may be slowed in athletes who exhibit ventricular hypertrophy, whilst resumption of training increases the speed of ventricular relaxation in the presence of further hypertrophy of the left ventricle.

Vasomotor responses to decreased venous return: effects of cardiac deafferentation in humans.

We compared haemodynamic and peripheral vasomotor responses to lower body negative pressure (LBNP) in cardiac transplant recipients who had undergone bicaval anastomoses, involving right atrial deafferentation (-RA), and the conventional procedure in which some atrial baroreceptor afferents remain intact (+RA). We measured mean forearm blood flow (FBF) responses using Doppler/ultrasound during three randomised trials involving 0 (baseline), -20 and -40 mmHg LBNP in 15 transplant recipients (9 -RA, 6 +RA) and in eight healthy matched controls. A significant effect of LBNP on FBF existed between control and transplant groups (P < 0.05; two-way ANOVA). Mild LBNP (-20 mmHg), significantly decreased FBF by 29.7 +/- 10.0% relative to baseline in +RA subjects (P < 0.05), whereas the 17.7 +/- 10.3% decrease in -RA subjects was not significant. In response to -40 mmHg LBNP, FBF significantly decreased in control (42.4 +/- 4.6%, P < 0.05) and +RA subjects (33.3 +/- 11.4%, P < 0.05) with no significant change in the -RA group. The response of systolic blood pressure (SBP) to -40 mmHg significantly differed between groups (P < 0.05): -RA subjects decreased significantly (P < 0.05) whilst the decrease in SBP in +RA subjects did not achieve significance and control subjects exhibited an increase. The heart rate increase from baseline to -40 mmHg was significantly attenuated in -RA relative to controls and the +RA group (P < 0.05). The present study demonstrates that atrial deafferentation impairs reflex vasomotor control of the circulation in response to low- and high-level LBNP, indicating that atrial deafferentation may contribute to abnormal arterial pressure regulation.

Vasomotor responses to hypoxia in type 2 diabetes.

Type 2 diabetes is associated with vascular dysfunction, accelerated atherosclerotic morbidity, and mortality. Abnormal vasomotor responses to chemoreflex activation may contribute to the acceleration of atherosclerotic diabetes complications, but these responses have not previously been investigated. We measured forearm mean blood flow (MBF) and mean vascular conductance (MVC) responses to isocapnic hypoxia in seven healthy and eight type 2 diabetic subjects during local intra-arterial saline infusion and alpha-adrenergic blockade (phentolamine). The effects of hypoxia on saline and phentolamine responses significantly differed between groups; relative to normoxia, the %DeltaMVC with hypoxia during saline was -3.3 +/- 11.2% in control and 24.8 +/- 13.3% in diabetic subjects, whereas phentolamine increased hypoxic %DeltaMVC to similar levels (39.4 +/- 9.7% in control subjects and 48.0 +/- 11.8% in diabetic subjects, P < 0.05, two-way ANOVA). Absolute normoxic MBF responses during saline infusion were 91.9 +/- 21.1 and 77.9 +/- 15.3 in control and diabetic subjects, respectively, and phentolamine increased normoxic MBF to similar levels (165.2 +/- 40.1 ml/min in control subjects and 175.9 +/- 32.0 ml/min in diabetic subjects; both P < 0.05). These data indicate that diabetic and control subjects exhibit similar responses to hypoxia in the presence of alpha-adrenergic blockade despite evidence of exaggerated alpha-mediated vasoconstriction at rest.

Effects of exercise training on vascular function in obese children.

OBJECTIVES: Atherosclerosis is a disease that begins in childhood; endothelial dysfunction is its earliest detectable manifestation, and primary prevention strategies are likely to be most effective if instituted early. The aim of this study was to characterize the impact of obesity on vascular function in young children and to determine whether an exercise program improves abnormalities in vascular function. STUDY DESIGN: The influence of 8 weeks of exercise training was examined in 14 obese subjects, 8.9 +/- 0.4 years of age, with the use of a randomized crossover protocol. Conduit vessel endothelial function was assessed by means of high-resolution ultrasound and flow-mediated dilation of the brachial artery (FMD). RESULTS: Exercise training did not change subcutaneous fat mass, body weight, or body mass index. FMD in the obese group was significantly impaired relative to matched control subjects at entry (6.00% +/- 0.69% to 12.32% +/- 3.14%, P <.0001). FMD significantly improved with exercise training (7.35% +/- 0.99%, P <.05) in the obese group. CONCLUSIONS: Conduit vessel FMD, a validated surrogate measure of early atherosclerosis, was impaired in obese children but improved as a result of exercise training. This study supports the value of an exercise program in the treatment of obese children in a primary prevention setting.

Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents.

OBJECTIVES: We sought to characterize the impact of obesity on vascular function in adolescents and to determine whether an exercise program reverses abnormalities in endothelial function. BACKGROUND: Obesity, a major modifiable risk factor for cardiovascular disease, is epidemic in Western societies, with rapid rates of increase in the young. Atherosclerosis begins in childhood, and endothelial dysfunction is its earliest detectable manifestation. METHODS: The influence of eight weeks of circuit training (CT) was examined in 19 obese subjects (14.3 +/- 1.5 years), using a randomized, crossover protocol. Functional capacity and muscular strength were assessed by standard techniques. Body composition was examined using anthropometric measures and dual-energy X-ray absorptiometry. Conduit vessel endothelial function was assessed using high-resolution ultrasound and flow-mediated dilation (FMD) of the brachial artery. RESULTS: Circuit training decreased abdominal and trunk fat and significantly improved fitness and muscular strength (p < 0.05). In the obese group, FMD was significantly impaired relative to control subjects (n = 20) at entry (5.3 +/- 0.9% vs. 8.9 +/- 1.5%, p < 0.05) and was normalized after CT (8.8 +/- 0.8%, p < 0.05). CONCLUSIONS: Circuit training improved functional capacity, muscular strength, and body composition in obese adolescents. Furthermore, conduit vessel function was normalized after exercise training. If vascular dysfunction is an integral component of the pathogenesis of vascular disease, this study supports the value of an exercise program in the management of obese adolescents.

Exercise and the nitric oxide vasodilator system.

In the past two decades, normal endothelial function has been identified as integral to vascular health. The endothelium produces numerous vasodilator and vasoconstrictor compounds that regulate vascular tone; the vasodilator, nitric oxide (NO), has additional antiatherogenic properties, is probably the most important and best characterised mediator, and its intrinsic vasodilator function is commonly used as a surrogate index of endothelial function. Many conditions, including atherosclerosis, diabetes mellitus and even vascular risk factors, are associated with endothelial dysfunction, which, in turn, correlates with cardiovascular mortality. Furthermore, clinical benefit and improved endothelial function tend to be associated in response to interventions. Shear stress on endothelial cells is a potent stimulus for NO production. Although the role of endothelium-derived NO in acute exercise has not been fully resolved, exercise training involving repetitive bouts of exercise over weeks or months up-regulates endothelial NO bioactivity. Animal studies have found improved endothelium-dependent vasodilation after as few as 7 days of exercise. Consequent changes in vasodilator function appear to persist for several weeks but may regress with long-term training, perhaps reflecting progression to structural adaptation which may, however, have been partly endothelium-dependent. The increase in blood flow, and change in haemodynamics that occur during acute exercise may, therefore, provide a stimulus for both acute and chronic changes in vascular function. Substantial differences within species and within the vasculature appear to exist. In humans, exercise training improves endothelium-dependent vasodilator function, not only as a localised phenomenon in the active muscle group, but also as a systemic response when a relatively large mass of muscle is activated regularly during an exercise training programme. Individuals with initially impaired endothelial function at baseline appear to be more responsive to exercise training than healthy individuals; that is, it is more difficult to improve already normal vascular function. While improvement is reflected in increased NO bioactivity, the detail of mechanisms, for example the relative importance of up-regulation of mediators and antioxidant effects, is unclear. Optimum training schedules, possible sequential changes and the duration of benefit under various conditions also remain largely unresolved. In summary, epidemiological evidence strongly suggests that regular exercise confers beneficial effects on cardiovascular health. Shear stress-mediated improvement in endothelial function provides one plausible explanation for the cardioprotective benefits of exercise training.

Effects of exercise training on conduit and resistance vessel function in treated and untreated hypercholesterolaemic subjects.

AIMS: Despite the importance of both lipid metabolism and physical activity to cardiovascular health, few studies have examined the effect of exercise training on vascular function in hypercholesterolaemic humans. METHODS AND RESULTS: A randomized, cross-over design investigated the effect of 8 weeks of combined aerobic and resistance exercise training on conduit and resistance vessel function in 11 untreated subjects with hypercholesterolaemia and 11 subjects taking lipid-lowering medication. High-resolution vascular ultrasonography following forearm ischaemia and glyceryl trinitrate administration determined conduit vessel endothelium-dependent and independent function. Strain-gauge plethysmography, with intra-aerial infusions of acetylcholine, sodium nitroprusside and N(G)-monomethyl-L-arginine, determined resistance vessel function. Flow-mediated dilation and the forearm blood flow response to acetylcholine improved significantly following training in the treated subgroup (both P<0.05) but not the untreated, although the blood flow response to N(G)-monomethyl-L-arginine was augmented following training in the untreated subjects (P<0.05), indicating greater basal nitric oxide bioactivity. Training did not alter responsiveness to glyceryl trinitrate or sodium nitroprusside. CONCLUSIONS: Combined aerobic and resistance training improves endothelium-dependent conduit and resistance vessel function in hypercholesterolaemic subjects taking lipid-lowering medications and basal nitric oxide bioactivity in untreated hypercholesterolaemic subjects. Exercise training may provide additional cardiovascular benefits for hypercholesterolaemic patients including those taking lipid-lowering medication.

Endothelial nitric oxide synthase gene polymorphism, homocysteine, cholesterol and vascular endothelial function.

Nitric oxide-dependent vasodilation is impaired early in the pathogenesis of vascular disease. Both the 4ab polymorphism of endothelial nitric oxide synthase (eNOS) and elevated plasma homocysteine are putatively associated with coronary artery disease (CAD). Few studies have investigated the influence of either on endothelial function in normal subjects. We aimed to examine any effect of three eNOS gene polymorphisms and plasma levels of homocysteine, folate and lipids on vascular endothelial function in normal healthy subjects. Community subjects (n=60) were selected for their eNOS genotype. Largely NOz.-dependent, flow-mediated dilation (FMD) of the brachial artery and the response to glyceryl trinitrate (GTN) were measured. Neither FMD nor response to GTN in 4a allele carriers was significantly different from that of 4b homozygotes, (7.1+/-0.5 S.E.M. vs. 7.1+/-0.6%) and (18.9+/-1.2 vs. 18.9+/-0.9%), respectively. Responses were also independent of the other polymorphisms. FMD was significantly correlated with HDL-cholesterol (P=0.02). After accounting for serum folate, there was a significant inverse correlation between FMD and plasma homocysteine (P=0.03). In these normal community subjects, plasma homocysteine and HDL-cholesterol were predictors of FMD despite subjects being recruited without regard to these variables and despite normal plasma levels.

Exercise training improves conduit vessel function in patients with coronary artery disease.

It is well established that endothelial dysfunction is present in coronary artery disease (CAD), although few studies have determined the effect of training on peripheral conduit vessel function in patients with CAD. A randomized, crossover design determined the effect of 8 wk of predominantly lower limb, combined aerobic and resistance training, in 10 patients with treated CAD. Endothelium-dependent dilation of the brachial artery was determined, by using high-resolution vascular ultrasonography, from flow-mediated vasodilation (FMD) after ischemia. Endothelium-independent vasodilation was measured after administration of glyceryl trinitrate (GTN). Baseline function was compared with that of 10 control subjects. Compared with matched healthy control subjects, FMD and GTN responses were significantly impaired in the untrained CAD patients [3.0 +/- 0.8 (SE) vs. 5.8 +/- 0.8% and 14.5 +/- 1.9 vs. 20.4 +/- 1.5%, respectively; both P < 0.05]. Training significantly improved FMD in the CAD patients (from 3.0 +/- 0.8 to 5.7 +/- 1.1%; P < 0.05) but not responsiveness to GTN (14.5 +/- 1.9 vs. 12.1 +/- 1.4%; P = not significant). Exercise training improves endothelium-dependent conduit vessel dilation in subjects with CAD, and the effect, evident in the brachial artery, appears to be generalized rather than limited to vessels of exercising muscle beds. These results provide evidence for the benefit of exercise training, as an adjunct to routine therapy, in patients with a history of CAD.

Effect of cardiac pacing on forearm vascular responses and nitric oxide function.

We examined the hypothesis that changes in heart rate at rest influence bioactivity of nitric oxide (NO) in humans by examining forearm blood flow responses during cardiac pacing in six subjects. Peak forearm and mean forearm blood flows across the cardiac cycle were continuously recorded at baseline and during pacing, with the use of high-resolution brachial artery ultrasound and Doppler flow velocity measurement. The brachial artery was cannulated to allow continuous infusion of saline or N(G)-monomethyl-L-arginine (L-NMMA). As heart rate increased, no changes in pulse pressure and mean or peak blood flow were evident. L-NMMA had no effect on brachial artery diameter, velocity, or flows compared with saline infusion. These results contrast with our recent findings that exercise involving the lower body, associated with increases in heart rate and pulse pressure, also increased forearm blood flow, the latter response being diminished by L-NMMA. These data suggest that changes in blood pressure, rather than pulse frequency, may be the stimulus for shear stress-mediated NO release in vivo.

Effect of lowering tumour necrosis factor-alpha on vascular endothelial function in Type II diabetes.

Tumour necrosis factor-alpha (TNF alpha) is a mediator of reactive oxygen species, which are implicated in endothelial dysfunction and atherosclerosis. Type II diabetes is associated with endothelial dysfunction and elevated circulating TNF alpha. We hypothesized that reducing serum levels of TNFalpha, using pentoxifylline, would improve endothelial function. Thirteen subjects [age 58+/-2 (S.E.M.) years] with Type II diabetes (disease duration 74+/-13 months) undertook a randomized, crossover study of 8 weeks pentoxifylline and 8 weeks placebo. Endothelium-dependent and-independent vasodilation in resistance arteries was assessed via bilateral forearm venous occlusion plethysmography during intra-brachial infusions of acetylcholine (ACh), sodium nitroprusside (SNP) and N(G)-monomethyl-L-arginine (L-NMMA). High-resolution ultrasound of the brachial artery in response to ischaemia was used to determine endothelium-dependent conduit vessel flow-mediated dilation (FMD), and endothelium-independent conduit function was assessed by sublingual administration of glyceryl trinitrate (GTN). Serum concentrations of TNF alpha were also determined. Pentoxifylline lowered serum TNF alpha from 4.1+/-0.7 to 2.9+/-0.6 pg x ml(-1) (P=0.001). Forearm blood flow (FBF) responses at each dose of ACh did not differ with treatment (P=0.4). Similarly, FBF responses to SNP (P=0.8) and L-NMMA (P=0.2) did not differ. There was also no significant difference in brachial artery diameter during FMD (P=0.2) or GTN administration (P=0.06). Despite lowering serum TNF alpha concentration, pentoxifylline at a dose of 400 mg three times a day for 8 weeks did not improve vascular function in either conduit or resistance vessels in this group of Type II diabetic subjects.

Effect of lower limb exercise on forearm vascular function: contribution of nitric oxide.

We examined vascular function in an inactive muscle bed, the forearm, during lower limb exercise and determined the contribution of endothelium-derived nitric oxide (NO) to the hyperemic response. Eight young males were randomized to participate in two studies, each consisting of two bouts of lower limb exercise, separated by a 30-min recovery. Peak forearm blood flow (PFBF) and mean blood flow (MFBF) were continuously recorded at baseline and during exercise using continuous high-resolution vascular ultrasound and Doppler flow velocity measurement. During one session, the brachial artery was cannulated to allow continuous infusion of saline or N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase. The alternate session was performed to control for possible effects of repeated exercise. At 60, 100, and 160 W, L-NMMA significantly decreased both PFBF and MFBF compared with the saline infusion. These results suggest that systemic production of NO occurs during exercise in resting vessel beds, which do not feed metabolically active tissue. This finding provides a plausible explanation for the antiatherogenic benefits of exercise.

Effect of aerobic and resistance exercise on central hemodynamic responses in severe chronic heart failure.

Exercise is now considered an important component of management in chronic heart failure (CHF), but little is known about central hemodynamic changes that occur during different exercise modalities in these patients. Seventeen patients (ejection fraction 25 +/- 2%) undertook brachial artery and right heart catheterization and oxygen consumption assessment at rest, during submaximal and peak cycling (Cyc), and during submaximal upper and lower limb resistance exercise. Cardiac output (CO) increased relative to baseline during peak Cyc (P < 0.05) but did not change during submaximal Cyc or upper or lower limb exercise. Heart rate (HR) was lowest during upper limb exercise and progressively increased during lower limb exercise, submaximal Cyc, and peak Cyc, with significant differences between each of these (P < 0.01). Conversely, stroke volume (SV) decreased during submaximal Cyc and lower limb exercise and was lower during peak and submaximal Cyc and lower limb exercise than during upper limb exercise (P < 0.05). CHF patients are dependent on increases in HR to increase CO during exercise when SV may decline. Resistance exercise, performed at appropriate intensity, induces a similar hemodynamic burden to aerobic exercise in patients with CHF.

Combined aerobic and resistance exercise improves glycemic control and fitness in type 2 diabetes.

We investigated the effect of an 8 week circuit training (CT) program, combining aerobic and resistance exercise, on indices of glycemic control, cardiorespiratory fitness, muscular strength and body composition in 16 subjects (age 52 +/- 2 years) with type 2 diabetes using a prospective randomised crossover protocol. Submaximal exercise heart rate and rate pressure product were significantly lower after training (P<0.05), whilst ventilatory threshold increased (11.8 +/- 0.7 vs 13.8 +/- 0.6 ml kg(-1)min(-1), P<0.001). Muscular strength also increased with training (403 +/- 30 to 456 +/- 31 kg, P<0.001), whilst skinfolds (148.7 +/- 11.5 vs 141.1 +/- 10.7 mm, P<0.05), % body fat (29.5 +/- 1.0 vs 28.7 +/- 1.1%, P<0.05) and waist:hip ratio (99.2 +/- 1.5 vs 97.9 +/- 1.4%, P<0.05) significantly decreased. Concurrently, peak oxygen uptake (P<0.05) and exercise test duration (P<0.001) increased following training, whilst glycated hemoglobin (P<0.05) and fasting blood glucose (P<0.05) decreased. CT is an effective method of training that improved functional capacity, lean body mass, strength and glycemic control in subjects with type 2 diabetes.