Bruno T. Roseguini

Inspiratory muscle training improves blood flow to resting and exercising limbs in patients with chronic heart failure.

OBJECTIVES We tested the hypothesis that inspiratory muscle loading could result in exaggerated peripheral vasoconstriction in resting and exercising limbs and that inspiratory muscle training (IMT) could attenuate this effect in patients with chronic heart failure (CHF) and inspiratory muscle weakness. BACKGROUND Inspiratory muscle training improves functional capacity of patients with CHF, but the mechanisms of this effect are unknown. METHODS Eighteen patients with CHF and inspiratory muscle weakness (maximal inspiratory pressure <70% of predicted) and 10 healthy volunteers participated in the study. Inspiratory muscle loading was induced by the addition of inspiratory resistance of 60% of maximal inspiratory pressure, while blood flow to the resting calf (CBF) and exercising forearm (FBF) were measured by venous occlusion plethysmography. For the patients with CHF, blood flow measurements as well as ultrasound determination of diaphragm thickness were made before and after a 4-week program of IMT. RESULTS With inspiratory muscle loading, CHF patients demonstrated a more marked reduction in resting CBF and showed an attenuated rise in exercising FBF when compared with control subjects. After 4 weeks of IMT, CHF patients presented hypertrophy of the diaphragm and improved resting CBF and exercise FBF with inspiratory muscle loading. CONCLUSIONS In patients with CHF and inspiratory muscle weakness, inspiratory muscle loading results in marked reduction of blood flow to resting and exercising limbs. Inspiratory muscle training improves limb blood flow under inspiratory loading in these patients.

Voluntary Wheel Running Selectively Augments Insulin-Stimulated Vasodilation in Arterioles from White Skeletal Muscle of Insulin-Resistant Rats

Exercise (RUN) prevents declines in insulin‐mediated vasodilation, an important component of insulin‐mediated glucose disposal, in rats prone to obesity and insulin resistance.

Rapid vasodilation in isolated skeletal muscle arterioles: impact of branch order.

Microcirculation (2010) 17, 1–11. doi: 10.1111/j.1549‐8719.2009.00005.x

Muscle metaboreflex contribution to resting limb haemodynamic control is preserved in older subjects

Ageing is associated with tonic elevations in basal sympathetic vasoconstrictor outflow to skeletal muscle and a parallel decline in vascular function. The purpose of this study was to test the hypothesis that older individuals exhibit attenuated calf vascular resistance (CVR) responses to muscle metaboreflex activation in comparison with young subjects. Fourteen young (mean ± SD age 23 ± 3 years) and 13 older (62 ± 7 years) sedentary subjects participated in the study. To evaluate muscle metaboreflex, we measured heart rate, mean blood pressure (MBP), calf blood flow (CBF) (venous occlusion plethysmography) and CVR responses to static handgrip exercise at 30% of maximal voluntary contraction, followed by recovery with [postexercise circulatory occlusion, (PECO+)] or without (PECO−) circulatory occlusion. Mean BP and CVR increased significantly (ANOVA P<0·05) throughout exercise and remained elevated during PECO+ when compared with PECO− in both groups. There were no significant differences between the two groups in BP and CVR relative changes from baseline during the entire protocol in both trials. CBF responses were also similar in the young and older subjects, except for the first minute of exercise, where young subjects had higher CBF responses. Our results demonstrate that older subjects have similar BP and calf haemodynamic responses to static handgrip exercise and selective action of the muscle metaboreflex when compared with young subjects, compatible with preserved muscle metaboreflex contribution to resting limb haemodynamic control with ageing in humans.

Intermittent pneumatic leg compressions acutely upregulate VEGF and MCP-1 expression in skeletal muscle

Application of intermittent pneumatic compressions (IPC) is an extensively used therapeutic strategy in vascular medicine, but the mechanisms by which this method works are unclear. We tested the hypothesis that acute application (150 min) of cyclic leg compressions in a rat model signals upregulation of angiogenic factors in skeletal muscle. To explore the impact of different pressures and frequency of compressions, we divided rats into four groups as follows: 120 mmHg (2 s inflation/2 s deflation), 200 mmHg (2 s/2 s), 120 mmHg (4 s/16 s), and control (no intervention). Blood flow and leg oxygenation (study 1) and the mRNA expression of angiogenic mediators in the rat tibialis anterior muscle (study 2) were assessed after a single session of IPC. In all three groups exposed to the intervention, a modest hyperemia (approximately 37% above baseline) between compressions and a slight, nonsignificant increase in leg oxygen consumption (approximately 30%) were observed during IPC. Compared with values in the control group, vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) mRNA increased significantly (P < 0.05) only in rats exposed to the higher frequency of compressions (2 s on/2 s off). Endothelial nitric oxide synthase, matrix metalloproteinase-2, and hypoxia-inducible factor-1alpha mRNA did not change significantly following the intervention. These findings show that IPC application augments the mRNA content of key angiogenic factors in skeletal muscle. Importantly, the magnitude of changes in mRNA expression appeared to be modulated by the frequency of compressions such that a higher frequency (15 cycles/min) evoked more robust changes in VEGF and MCP-1 compared with a lower frequency (3 cycles/min).

Acute impact of intermittent pneumatic leg compression frequency on limb hemodynamics, vascular function, and skeletal muscle gene expression in humans

The mechanisms by which intermittent pneumatic leg compression (IPC) treatment effectively treats symptoms associated with peripheral artery disease remain speculative. With the aim of gaining mechanistic insight into IPC treatment, the purpose of this study was to investigate the effect of IPC frequency on limb hemodynamics, vascular function, and skeletal muscle gene expression. In this two study investigation, healthy male subjects underwent an hour of either high-frequency (HF; 2-s inflation/3-s deflation) or low-frequency (LF; 4-s inflation/16-s deflation) IPC treatment of the foot and calf. In study 1 (n = 11; 23.5 ± 4.7 yr), subjects underwent both HF and LF treatment on separate days. Doppler/ultrasonography was used to measure popliteal artery diameter and blood velocity at baseline and during IPC treatment. Flow-mediated dilation (FMD) and peak reactive hyperemia blood flow (RHBF) were determined before and after IPC treatment. In study 2 (n = 19; 22.0 ± 4.6 yr), skeletal muscle biopsies were taken from the lateral gastrocnemius of the treated and control limb at baseline and at 30- and 150-min posttreatment. Quantitative PCR was used to assess mRNA concentrations of genes associated with inflammation and vascular remodeling. No treatment effect on vascular function was observed. Cuff deflation resulted in increased blood flow (BF) and shear rate (SR) in both treatments at the onset of treatment compared with baseline (P < 0.01). BF and SR significantly diminished by 45 min of HF treatment only (P < 0.01). Both treatments reduced BF and SR and elevated oscillatory shear index compared with baseline (P < 0.01) during cuff inflation. IPC decreased the mRNA expression of cysteine-rich protein 61 from baseline and controls (P <0 .01) and connective tissue growth factor from baseline (P < 0.05) in a frequency-dependent manner. In conclusion, a single session of IPC acutely impacts limb hemodynamics and skeletal muscle gene expression in a frequency-dependent manner but does not impact vascular function.

Sildenafil improves skeletal muscle oxygenation during exercise in men with intermittent claudication

Endothelial dysfunction caused by defective nitric oxide (NO) signaling plays a pivotal role in the pathogenesis of intermittent claudication (IC). In the present study, we evaluated the acute effects of sildenafil, a phosphodiesterase type 5 inhibitor that acts by prolonging NO-mediated cGMP signaling in vascular smooth muscle, on blood pressure (BP), skeletal muscle oxygenation, and walking tolerance in patients with IC. A randomized, double-blind, crossover study was conducted in which 12 men with stable IC received two consecutive doses of 50 mg of sildenafil or matching placebo and underwent a symptom-limited exercise test on the treadmill. Changes in gastrocnemius deoxy-hemoglobin by near-infrared spectroscopy estimated peripheral muscle O2 delivery-to-utilization matching. Systolic BP was significantly lower during the sildenafil trial relative to placebo during supine rest (∼15 mmHg), submaximal exercise (∼14 mmHg), and throughout recovery (∼18 mmHg) (P < 0.05). Diastolic BP was also lower after sildenafil during upright rest (∼6 mmHg) and during recovery from exercise (∼7 mmHg) (P < 0.05). Gastrocnemius deoxygenation was consistently reduced during submaximal exercise (∼41%) and at peak exercise (∼34%) following sildenafil compared with placebo (P < 0.05). However, pain-free walking time (placebo: 335 ± 42 s vs. sildenafil: 294 ± 35 s) and maximal walking time (placebo: 701 ± 58 s vs. sildenafil: 716 ± 62 s) did not differ between trials. Acute administration of sildenafil lowers BP and improves skeletal muscle oxygenation during exercise but does not enhance walking tolerance in patients with IC. Whether the beneficial effects of sildenafil on muscle oxygenation can be sustained over time and translated into positive clinical outcomes deserve further consideration in this patient population.

New insights into the physiologic basis for intermittent pneumatic limb compression as a therapeutic strategy for peripheral artery disease

The capability for externally applied rhythmic limb compressions to improve the outcomes of patients with peripheral artery disease has been recognized for nearly a century. Modern technology has permitted the development of portable and cost-effective intermittent pneumatic compression (IPC) systems to be made readily available for affordable at-home use. Mounting clinical evidence attests to the effectiveness of this strategy, with improvements in claudication distance rivaling those seen with exercise training or pharmacologic interventions, or both. However, owing to a lack of mechanistic knowledge, whether current application protocols are optimized for clinical outcomes is unknown. Traditional thinking has suggested that IPC transiently elevates blood flow, which is purported to relieve ischemia, improve vascular function, and promote vascular remodeling. Surprisingly, much ambiguity exists regarding the physiologic stimuli and adaptations that are responsible for the clinical effectiveness of IPC treatment. This review presents and critically discusses emerging evidence that sheds new light on the physiologic and molecular responses to IPC therapy. These novel findings highlight the importance of characterizing the phasic changes in the hemodynamic profile during IPC application. Further, these studies indicate that factors other than the elevation in blood flow during this therapy should be taken into account when designing an optimal IPC device. Lastly, we advance the hypothesis that manipulation of IPC stimulation characteristics could potentially magnify the documented clinical benefits associated with this therapy. In conclusion, recent evidence challenges the physiologic basis on which current IPC systems were designed, and further research to elucidate the basic and clinical outcomes of alternate stimulation characteristics is necessary.

Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication

Increased oxidative stress and inflammation contribute to impaired walking capacity and endothelial dysfunction in patients with intermittent claudication (IC). The goal of the study was to determine the effects of oral treatment with the antioxidant N-acetylcysteine (NAC) on walking capacity, leg postocclusive reactive hyperemia, circulating levels of inflammatory mediators, and whole blood expression of angiogenic mediators in patients with IC. Following a double-blinded randomized crossover design, 10 patients with IC received NAC (1,800 mg/day for 4 days plus 2,700 mg before the experimental session) and placebo (PLA) before undergoing a graded treadmill exercise test. Leg postocclusive reactive hyperemia was assessed before and after the test. Blood samples were taken before and after NAC or PLA ingestions and 5 and 30 min after the exercise test for the analysis of circulating inflammatory and angiogenic markers. Although NAC increased the plasma ratio of reduced to oxidized glutathione, there were no differences between experimental sessions for walking tolerance and postocclusive reactive hyperemia. Plasma concentrations of soluble vascular cell adhesion protein-1, monocyte chemotactic protein-1, and endothelin-1 increased similarly following maximal exercise after PLA and NAC (P < 0.001). Whole blood expression of pro-angiogenic microRNA-126 increased after maximal exercise in the PLA session, but treatment with NAC prevented this response. Similarly, exercise-induced changes in whole blood expression of VEGF, endothelial nitric oxide synthase and phosphatidylinositol 3-kinase R2 were blunted after NAC. In conclusion, oral NAC does not increase walking tolerance or leg blood flow in patients with IC. In addition, oral NAC prevents maximal exercise-induced increase in the expression of circulating microRNA-126 and other angiogenic mediators in patients with IC.

Intermittent pneumatic leg compressions enhance muscle performance and blood flow in a model of peripheral arterial insufficiency

Despite the escalating prevalence in the aging population, few therapeutic options exist to treat patients with peripheral arterial disease. Application of intermittent pneumatic leg compressions (IPC) is regarded as a promising noninvasive approach to treat this condition, but the clinical efficacy, as well the mechanistic basis of action of this therapy, remain poorly defined. We tested the hypothesis that 2 wk of daily application of IPC enhances exercise tolerance by improving blood flow and promoting angiogenesis in skeletal muscle in a model of peripheral arterial insufficiency. Male Sprague-Dawley rats were subjected to bilateral ligation of the femoral artery and randomly allocated to treatment or sham groups. Animals were anesthetized daily and exposed to 1-h sessions of bilateral IPC or sham treatment for 14-16 consecutive days. A third group of nonligated rats was also studied. Marked increases in treadmill exercise tolerance (∼33%, P < 0.05) and improved muscle performance in situ (∼10%, P < 0.05) were observed in IPC-treated animals. Compared with sham-treated controls, blood flow measured with isotope-labeled microspheres during in situ contractions tended to be higher in IPC-treated animals in muscles composed of predominantly fast-twitch white fibers, such as the plantaris (∼93%, P = 0.02). Capillary contacts per fiber and citrate synthase activity were not significantly altered by IPC treatment. Collectively, these data indicate that IPC improves exercise tolerance in a model of peripheral arterial insufficiency in part by enhancing blood flow to collateral-dependent tissues.