Skeletal muscle capillary density is related to anaerobic threshold and claudication in peripheral artery disease.

Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, causing claudication and exercise intolerance. Exercise intolerance may result from reduced skeletal muscle capillary density and impaired muscle oxygen delivery. This cross-sectional study tested the hypothesis that capillary density is related to claudication times and anaerobic threshold (AT) in patients with PAD. A total of 37 patients with PAD and 29 control subjects performed cardiopulmonary exercise testing on a treadmill for AT and gastrocnemius muscle biopsies. Skeletal muscle capillary density was measured using immunofluorescence staining. PAD had decreased capillary density (278 ± 87 vs 331 ± 86 endothelial cells/mm2, p = 0.05), peak VO2 (15.7 ± 3.9 vs 24.3 ± 5.2 mL/kg/min, p ⩽ 0.001), and VO2 at AT (11.5 ± 2.6 vs 16.1 ± 2.8 mL/kg/min, p ⩽ 0.001) compared to control subjects. In patients with PAD, but not control subjects, capillary density was related to VO2 at AT (r = 0.343; p = 0.038), time to AT (r = 0.381; p = 0.020), and time after AT to test termination (r = 0.610; p ⩽ 0.001). Capillary density was also related to time to claudication (r = 0.332; p = 0.038) and time after claudication to test termination (r = 0.584; p ⩽ 0.001). In conclusion, relationships between capillary density, AT, and claudication symptoms indicate that, in PAD, exercise limitations are likely partially dependent on limited skeletal muscle capillary density and oxidative metabolism.

Angiogenesis in skeletal muscle precede improvements in peak oxygen uptake in peripheral artery disease patients.

OBJECTIVE: Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, causing claudication and exercise intolerance. The mechanism(s) by which exercise training improves functional capacity is not understood. This study tested the hypothesis that in PAD patients who undergo supervised exercise training, increases in capillary density (CD) in calf muscle take place before improvements in peak oxygen uptake (VO(2)). METHODS AND RESULTS: Thirty-five PAD patients were randomly assigned to 12 weeks of directly supervised or home-based exercise training. Peak VO(2) testing and gastrocnemius muscle biopsies were performed at baseline and after training. CD (endothelial cells/mm(2)) was measured using immunofluorescence staining. After 3 weeks of directly supervised training, patients had an increase in CD (216±66 versus 284±77, P<0.01) but no increase in peak VO(2). However, after 12 weeks, peak VO(2) increased (15.3±2.8 versus 16.8±3.8, P<0.01), whereas in muscle, CD remained increased over baseline, but there were no changes in markers of oxidative capacity. Within subjects, CD was related to peak VO(2) before and after directly supervised training. CONCLUSION: Changes in CD in ischemic muscle with training may modulate the response to training, and those changes precede the increase in VO(2).

Alteration in angiogenic and anti-angiogenic forms of vascular endothelial growth factor-A in skeletal muscle of patients with intermittent claudication following exercise training.

The aims of this study were twofold: (1) to identify whether peripheral artery disease (PAD) patients had increased muscle concentration of angiogenic VEGF-A, anti-angiogenic VEGF165b or VEGF receptor 1 (VEGF-R1) when compared with control subjects, and (2) to evaluate whether exercise training in PAD patients was associated with changes in muscle concentration of VEGF-A, VEGF165b or VEGF-R1. At baseline, 22 PAD and 30 control subjects underwent gastrocnemius muscle biopsy. Twelve PAD patients were treated with supervised exercise training (SET) and underwent muscle biopsy after 3 weeks and 12 weeks of training and had sufficient tissue to measure VEGF-A, VEGF165b and VEGF-R1 concentrations in skeletal muscle lysates by ELISA. Muscle concentrations of VEGF-A and VEGF165b were similar in PAD patients versus controls at baseline. At both time points after the start of SET, VEGF-A levels decreased and there was a trend towards increased VEGF165b concentrations. At baseline, VEGF-R1 concentrations were lower in PAD patients when compared with controls but did not change after SET. Skeletal muscle concentrations of VEGF-A are not different in PAD patients when compared with controls at baseline. SET is associated with a significant reduction in VEGF-A levels and a trend towards increased VEGF165b levels. These somewhat unexpected findings suggest that further investigation into the mechanism of vascular responses to exercise training in PAD patients is warranted.

New York Heart Association functional class predicts exercise parameters in the current era.

BACKGROUND: The New York Heart Association (NYHA) functional class is a subjective estimate of a patient's functional ability based on symptoms that do not always correlate with the objective estimate of functional capacity, peak oxygen consumption (peak V(O2)). In addition, relationships between these 2 measurements have not been examined in the current medical era when patients are using beta-blockers, aldosterone antagonists, and cardiac resynchronization therapy (CRT). Using baseline data from the HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing) study, we examined this relationship. METHODS: One thousand seven hundred fifty-eight patients underwent a symptom-limited metabolic stress test and stopped exercise due to dyspnea or fatigue. The relationship between NYHA functional class and peak V(O2) was examined. In addition, the effects of beta-blockers, aldosterone antagonists, and CRT therapy on these relationships were compared. RESULTS: The NYHA II patients have a significantly higher peak Vo(2) (16.1 +/- 4.6 vs 13.0 +/- 4.2 mL/kg per minute), a lower ventilation (Ve)/V(CO2) slope (32.8 +/- 7.7 vs 36.8 +/- 10.4), and a longer duration of exercise (11.0 +/- 3.9 vs 8.0 +/- 3.4 minutes) than NYHA III/IV patients. Within each functional class, there was no difference in any of the exercise parameters between patients on or off of beta-blockers, aldosterone antagonists, or CRT therapy. Finally, with increasing age, a significant difference in peak Vo(2), Ve/V(CO2) slope, and exercise time was found. CONCLUSION: For patients being treated with current medical therapy, there still is a difference in true functional capacity between NYHA functional class II and III/IV patients. However, within each NYHA functional class, the presence or absence or contemporary heart failure therapies does not alter exercise parameters.

A sex-specific relationship between capillary density and anaerobic threshold.

Although both capillary density and peak oxygen consumption (Vo(2)) improve with exercise training, it is difficult to find a relationship between these two measures. It has been suggested that peak Vo(2) may be more related to central hemodynamics than to the oxidative potential of skeletal muscle, which may account for this observation. We hypothesized that change in a measure of submaximal performance, anaerobic threshold, might be related to change in skeletal muscle capillary density, a marker of oxidative potential in muscle, with training. Due to baseline differences among these variables, we also hypothesized that relationships might be sex specific. A group of 21 subjects completed an inactive control period, whereas 28 subjects (17 men and 11 women) participated in a 6-mo high-intensity exercise program. All subjects were sedentary, overweight, and dyslipidemic. Potential relationships were assessed between change in capillary density with both change in Vo(2) at peak and at anaerobic threshold with exercise training. All variables and relationships were assessed for sex-specific effects. Change in peak Vo(2) was not related to change in capillary density after exercise training in either sex. Men had a positive correlation between change in Vo(2) at anaerobic threshold and change in capillary density with exercise training (r = 0.635; P < 0.01), whereas women had an inverse relationship (r = -0.636; P < 0.05) between the change in these variables. These findings suggest that, although enhanced capillary density is associated with training-induced improvements in submaximal performance in men, this relationship is different in women.

Plasma nitrite response and arterial reactivity differentiate vascular health and performance.

NO is crucial for endothelial function and vascular health. Plasma nitrite (NO(2)(-)) is the main oxidation product of NO and has been shown to reflect changes in eNOS activity. We hypothesized that plasma NO(2)(-) response to physical exercise stress along with physiological endothelial function would be reduced with increasing severity of vascular disease. Subject groups were: (a) risk factors but no vascular disease (RF); (b) Type 2 diabetes with no vascular disease (DM); (c) diagnosed peripheral arterial disease (PAD); and (d) DM+PAD. Venous blood was drawn at rest and 10min following maximal exercise. Plasma samples were analyzed by reductive chemiluminescence. Brachial diameters were imaged prior to, during and following 5min of forearm occlusion (BAFMD). There were no differences in resting plasma NO(2)(-) or BA diameters between groups. The PAD groups had lower age adjusted BAFMD responses (p0.05). Within group analysis revealed an increase in NO(2)(-) in the RF group (+39.3%), no change in the DM (-15.51%), and a decrease in the PAD (-44.20%) and PAD+DM (-39.95%). This was maintained after adjusting for age and VO(2peak) (p0.05). DeltaNO(2)(-) and BAFMD were the strongest independent predictors of VO(2peak) in multivariate linear regression. These findings suggest DeltaNO(2)(-) discriminates severity of cardiovascular disease risk, is related to endothelial function and predicts exercise capacity.

PRIME: A Novel Low-Mass, High-Repetition Approach to Improve Function in Older Adults.

INTRODUCTION: The ability to maintain functional independence in a rapidly aging population results in an increased life expectancy without corresponding increases in health care costs. The accelerated decline in V˙O2peak after the age of 65 yr is primarily due to peripheral tissue changes rather than centrally mediated factors. The purpose of this study was to determine whether the Peripheral Remodeling through Intermittent Muscular Exercise (PRIME) approach, consisting of a low-mass, high-repetition/duration skeletal muscle focused training regimen would provide superior functional benefits in participants older than 70 yr old and at risk for losing functional independence. METHODS: In this clinical trial, 107 participants were randomized to 4 wk of either standard aerobic training (AT) or PRIME (phase 1). This was followed by 8 wk of a progressive whole-body aerobic and resistance training (AT + RT) for all participants (phase 2). The major outcome measures were cardiorespiratory fitness (peak oxygen consumption [V˙O2peak]), muscular fitness (1 repetition maximal strength [1RM]), and physical function (Senior Fitness Test [SFT] scores). Results were analyzed under a per-protocol criterion. RESULTS: Thirty-eight PRIME and 38 AT participants completed the 3-month protocols. V˙O2peak, 1RM, and SFT scores all increased significantly after 12 wk for both treatment groups (P < 0.05). However, relative to AT, participants randomized to PRIME demonstrated a greater increase in V˙O2peak (2.37 + 1.83 vs 1.50 + 1.82 mL·kg·min, P < 0.05), 1RM (48.52 + 27.03 vs 28.01 + 26.15 kg, P < 0.01) and SFT (22.50 + 9.98 vs 18.66 + 9.60 percentile, P < 0.05). CONCLUSIONS: Participants experienced greater increases in cardiorespiratory and muscular fitness and physical function when PRIME training was initiated before a combined AT + RT program. This novel exercise approach may be advantageous to individuals with other chronic disease conditions characterized by low functional capacity.

Physiological and psychological correlates of sleep in HIV infection.

Insomnia, a common problem associated with HIV disease, is most likely caused by a multitude of factors. This study investigated the correlations between a selected group of physiological and psychological factors and sleep quality in an HIV-infected population. A convenience sample of 79 ethnically diverse HIV-positive adults, ages 24 to 63, completed a number of questionnaires and released their laboratory records for CD4+ cell count and viral load information. Variables significantly related to sleep quality were HIV-related symptoms, total pain, fatigue, depression, state anxiety, and the number of adults in the household. Findings support the need for health care providers to consider factors that contribute to impaired sleep when developing effective care for HIV-infected individuals with sleep disturbance.

Diabetes status differentiates endothelial function and plasma nitrite response to exercise stress in peripheral arterial disease following supervised training.

AIMS: To determine if type 2 diabetes mellitus (T2D) differentiates endothelial function and plasma nitrite response (a marker of nitric oxide bioavailability) during exercise in peripheral arterial disease (PAD) subjects prior to and following 3 months supervised exercise training (SET). METHODS: In subjects with T2D+PAD (n = 13) and PAD-only (n = 14), endothelial function was measured using brachial artery flow-mediated dilation. On a separate day, venous blood draws were performed at rest and 10 min following a symptom-limited graded treadmill test (SL-GXT). Plasma samples were snap-frozen for analysis of nitrite by reductive chemiluminescence. All testing was repeated following 3 months of SET. RESULTS: Prior to training both groups demonstrated endothelial dysfunction, which was correlated with a net decrease in plasma nitrite following a SL-GXT (p ≤ 0.05). Following SET, the PAD-only group demonstrated an improvement in endothelial function (p ≤ 0.05) and COT (p ≤ 0.05), which was related to a net increase in plasma nitrite following the SL-GXT (both p ≤ 0.05). The T2D+PAD group had none of these increases. CONCLUSIONS: T2D in the presence of PAD attenuated improvements in endothelial function, net plasma nitrite, and COT following SET. This suggests that T2D maybe associated with an inability to endogenously increase vascular NO bioavailability to SET.

Unlocking the barriers to improved functional capacity in the elderly: rationale and design for the "Fit for Life trial".

Advancing age is associated with an increase in physical impairment, functional limitations, disability, and loss of independence. Regular physical activity conveys health benefits, but the yield on physical function in the elderly, is less clear. Current exercise guidelines are focused predominantly on aerobic programs despite evidence that age-associated declines are mediated by peripheral tissue changes. The Fit for Life trial proposes a new paradigm of exercise training for the elderly that uses a low-mass high-repetition training regimen specifically focused on peripheral tissue beds or body regions (Regional Specific Training Stimulus - RSTS). RSTS is designed to deliver a localized stimulus to the peripheral vasculature, bone and muscle, without imposing a significant central cardiorespiratory strain. The purpose of this study is three-fold; 1) to derive effect sizes from the RSTS intervention by which to power a subsequent larger, confirmatory trial; 2) to assess fidelity of the RSTS intervention; and 3) to assess the interrelationship of the primary endpoints of physical impairment/fitness (VO(2peak), 1 repetition maximal contraction) and function (Senior Fitness Test scores) following two versions of a 4 + 8 week protocol. Men and women over 70 years, at risk for losing independence will be randomized to either 4 weeks of RSTS or "aerobic" exercise, followed by an identical 8 weeks of progressive whole-body training (aerobic plus resistance). The guiding hypothesis is that the magnitude of adaptation after 12 weeks will be greatest in those initially randomized to RSTS. Possible mediators of the intervention effect - physical impairment/fitness and function relationship, including vascular function, muscle mass, strength, and physiology will also be assessed.

Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease.

Peripheral arterial disease (PAD) results in a failure to adequately supply blood and oxygen (O(2)) to working tissues and presents as claudication pain during walking. Nitric oxide (NO) bioavailability is essential for vascular health and function. Plasma nitrite (NO(2)(-)) is a marker of vascular NO production but may also be a protected circulating "source" that can be converted to NO during hypoxic conditions, possibly aiding perfusion. We hypothesized that dietary supplementation of inorganic nitrate in the form of beetroot (BR) juice would increase plasma NO(2)(-) concentration, increase exercise tolerance, and decrease gastrocnemius fractional O(2) extraction, compared with placebo (PL). This was a randomized, open-label, crossover study. At each visit, subjects (n = 8) underwent resting blood draws, followed by consumption of 500 ml BR or PL and subsequent blood draws prior to, during, and following a maximal cardiopulmonary exercise (CPX) test. Gastrocnemius oxygenation during the CPX was measured by near-infrared spectroscopy. There were no changes from rest for [NO(2)(-)] (152 ± 72 nM) following PL. BR increased plasma [NO(2)(-)] after 3 h (943 ± 826 nM; P ≤ 0.01). Subjects walked 18% longer before the onset of claudication pain (183 ± 84 s vs. 215 ± 99 s; P ≤ 0.01) and had a 17% longer peak walking time (467 ± 223 s vs. 533 ± 233 s; P ≤ 0.05) following BR vs. PL. Gastrocnemius tissue fractional O(2) extraction was lower during exercise following BR (7.3 ± 6.2 vs. 10.4 ± 6.1 arbitrary units; P ≤ 0.01). Diastolic blood pressure was lower in the BR group at rest and during CPX testing (P ≤ 0.05). These findings support the hypothesis that NO(2)(-)-related NO signaling increases peripheral tissue oxygenation in areas of hypoxia and increases exercise tolerance in PAD.

Relationship between leg muscle capillary density and peak hyperemic blood flow with endurance capacity in peripheral artery disease.

The aim of this study was to determine if skeletal muscle capillary density is lower in patients with peripheral artery disease (PAD) and if capillary density relates to functional limitations. PAD patients with intermittent claudication (IC) have a decreased exercise tolerance due to exercise-induced muscle ischemia. Despite the apparent role diminished arterial flow has in this population, the degree of walking pain and functional limitation is not entirely explained by altered hemodynamics of the affected limbs. We hypothesized that skeletal muscle capillary density is lower in PAD and is related to the functional impairment observed in this population. Sixty-four patients with PAD and 56 controls underwent cardiopulmonary exercise testing and a gastrocnemius muscle biopsy. A subset of these patients (48 PAD and 47 controls) underwent peak hyperemic flow testing via plethysmography. Capillary density in PAD patients was lower compared with controls (P < 0.001). After adjustment for several baseline demographic imbalances the model relating capillary density to peak oxygen consumption (Vo(2)) remained significant (P < 0.001). In PAD subjects, capillary density correlated with peak Vo(2), peak walking time (PWT), and claudication onset time (COT). Peak hyperemic blood flow related to peak Vo(2) in both PAD and control subjects. PAD is associated with lower capillary density, and capillary density is related to the functional impairment as defined by a reduced peak Vo(2), PWT, and COT. These findings suggest that alterations in microcirculation may contribute to functional impairment capacity in PAD.

Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3months of exercise training.

Plasma nitrite is a major oxidation product of nitric oxide. It has also recently been suggested to perform an endocrine-like function as a nitric oxide donor in hypoxic tissues, allowing vasodilation. Exercise performance is limited in peripheral arterial disease because of an inadequate blood supply to working tissues. We hypothesized that exercise training in peripheral arterial disease subjects will improve "plasma nitrite flux" and endothelial function, to accompany increased exercise performance. Peripheral arterial disease subjects were tested at baseline and after 3 months supervised or home exercise training. Venous blood (arm) was drawn at rest and 10 min after a maximal graded treadmill test. Samples were added to heparin and centrifuged and plasma was snap-frozen for analysis by reductive chemiluminescence. Brachial artery endothelial function was measured in response to a hyperemic stimulus (flow-mediated dilation). At 3 months the peripheral arterial disease-supervised exercise group showed increases in claudication onset pain time (+138 s, p< or =0.05), peak walking time (+260 s, p< or =0.01), VO(2peak) (1.3 ml/kg/min, p< or =0.05), brachial artery flow-mediated dilation (+2%, p< or =0.05), and plasma nitrite flux (+33% p< or =0.05). There were no changes in the peripheral arterial disease-home exercise group. The change in plasma nitrite flux predicted the change in claudication onset pain (r(2)=0.59, p< or =0.01). These findings suggest that changes in plasma nitrite are related to endothelial function and predict exercise performance in peripheral arterial disease.

Implications of chronic heart failure on peripheral vasculature and skeletal muscle before and after exercise training.

The pathophysiology of chronic heart failure (CHF) is typically conceptualized in terms of cardiac dysfunction. However, alterations in peripheral blood flow and intrinsic skeletal muscle properties are also now recognized as mechanisms for exercise intolerance that can be modified by therapeutic exercise. This overview focuses on blood delivery, oxygen extraction and utilization that result from heart failure. Related features of inflammation, changes in skeletal muscle signaling pathways, and vulnerability to skeletal muscle atrophy are discussed. Specific focus is given to the ways in which perfusion and skeletal muscle properties affect exercise intolerance and how peripheral improvements following exercise training increase aerobic capacity. We also identify gaps in the literature that may constitute priorities for further investigation.

Increased levels of apoptosis in gastrocnemius skeletal muscle in patients with peripheral arterial disease.

Intermittent claudication (IC) is the major clinical manifestation of peripheral arterial disease (PAD). Apoptosis has been linked to skeletal muscle pathophysiology in other chronic diseases such as congestive heart failure. This study tested the hypothesis that there would be increased levels of apoptosis in the skeletal muscle of patients with PAD compared with control individuals. In total, 26 individuals with PAD and 28 age-appropriate controls underwent studies of peak oxygen consumption (peak VO2) and a gastrocnemius muscle biopsy in the most symptomatic leg. Muscle biopsies were analyzed for apoptosis and caspase-3 activity. Patients with PAD had a reduced peak VO2 compared with controls. Apoptosis was increased in those with PAD compared with age-appropriate controls (3.83% +/- 2.6 vs 1.53% +/- 0.96; p < 0.001). In conclusion, PAD is associated with increased levels of apoptosis in the peripheral skeletal muscle. Further study is required to ascertain whether apoptosis plays a role in decreased functional capacity.