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 (V̇o2) remained significant ( P < 0.001). In PAD subjects, capillary density correlated with peak V̇o2, peak walking time (PWT), and claudication onset time (COT). Peak hyperemic blood flow related to peak V̇o2 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 V̇o2, PWT, and COT. These findings suggest that alterations in microcirculation may contribute to functional impairment capacity in PAD.

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

Vascular Medicine ◽

10.1177/1358863x20945794 ◽

2020 ◽

Vol 25 (5) ◽

pp. 411-418

Author(s):

Brian D Duscha ◽

William E Kraus ◽

William S Jones ◽

Jennifer L Robbins ◽

Lucy W Piner ◽

...

Keyword(s):

Skeletal Muscle ◽

Peripheral Artery Disease ◽

Anaerobic Threshold ◽

Cardiopulmonary Exercise Testing ◽

Capillary Density ◽

Exercise Intolerance ◽

Peripheral Artery ◽

Cross Sectional ◽

Control Subjects ◽

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.

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Loss of Id3 (Inhibitor of Differentiation 3) Increases the Number of IgM-Producing B-1b Cells in Ischemic Skeletal Muscle Impairing Blood Flow Recovery During Hindlimb Ischemia

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315501 ◽

2021 ◽

Author(s):

Victoria Osinski ◽

Prasad Srikakulapu ◽

Young Min Haider ◽

Melissa A. Marshall ◽

Vijay C. Ganta ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

B Cell ◽

Peripheral Artery Disease ◽

Myeloid Cell ◽

Hindlimb Ischemia ◽

Peripheral Artery ◽

Artery Ligation ◽

Artery Disease

Objective: Neovascularization can maintain and even improve tissue perfusion in the setting of limb ischemia during peripheral artery disease. The molecular and cellular mechanisms mediating this process are incompletely understood. We investigate the potential role(s) for Id3 (inhibitor of differentiation 3) in regulating blood flow in a murine model of hindlimb ischemia (HLI). Approach and Results: HLI was modeled through femoral artery ligation and resection and blood flow recovery was quantified by laser Doppler perfusion imaging. Mice with global Id3 deletion had significantly impaired perfusion recovery at 14 and 21 days of HLI. Endothelial- or myeloid cell-specific deletion of Id3 revealed no effect on perfusion recovery while B-cell–specific knockout of Id3 (Id3 BKO ) revealed a significant attenuation of perfusion recovery. Flow cytometry revealed no differences in ischemia-induced T cells or myeloid cell numbers at 7 days of HLI, yet there was a significant increase in B-1b cells in Id3 BKO . Consistent with these findings, ELISA demonstrated increases in skeletal muscle and plasma IgM. In vitro experiments demonstrated reduced proliferation and increased cell death when endothelial cells were treated with conditioned media from IgM-producing B-1b cells and tibialis anterior muscles in Id3 BKO mice showed reduced density of total CD31 + and αSMA + CD31 + vessels. Conclusions: This study is the first to demonstrate a role for B-cell–specific Id3 in maintaining blood flow recovery during HLI. Results suggest a role for Id3 in promoting blood flow during HLI and limiting IgM-expressing B-1b cell expansion. These findings present new mechanisms to investigate in peripheral artery disease pathogenesis.

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Abstract 11605: Proteinase-Activated Receptor-2 is Responsible for Amplified Function of Transient Receptor Potential Channel A1 in Skeletal Muscle Sensory Neurons of Rats With Peripheral Artery Disease

Circulation ◽

10.1161/circ.130.suppl_2.11605 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Jihong Xing ◽

Jian Lu ◽

Jianhua Li

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Peripheral Artery Disease ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Channel ◽

Peripheral Artery ◽

Drg Neurons ◽

Artery Disease ◽

Transient Receptor

Background: Limb ischemia occurs in peripheral artery disease (PAD). Sympathetic nerve activity that regulates blood flow directed to the limbs is augmented during exercise in this disease and transient receptor potential channel A1 (TRPA1) in thin-fiber muscle afferents contributes to the amplified sympathetic responses. The objective of this study was to determine the role played by proteinase-activated receptor-2 (PAR2) in regulating abnormal TRPA1 function. Methods: A rat model of femoral artery ligation was employed to study PAD. Dorsal root ganglion (DRG) tissues of control limbs and limbs with 24 hours of femoral occlusion were obtained to examine the protein levels of PAR2 using western blot analysis. Also, current responses induced by activation of TRPA1 in skeletal muscle DRG neurons of control limbs and ligated limbs were characterized using whole-cell patch clamp methods. All data are presented as mean ± SE. Results: Femoral occlusion significantly increased expression of PAR2 in DRG (optical density: 1.06±0.03 in control vs. 1.45±0.04 after occlusion, P< 0.05; n = 6 in each group). In addition, femoral occlusion amplified the amplitude of DRG current responses evoked by stimulation of TRPA1 with AITC (a TRPA1 agonist, 100 μM). The peak amplitude of TRPA1 currents was 0.28±0.03 nA in control and 0.41±0.04 nA ( P< 0.05 vs. control; n = 12 in each group) after occlusion, respectively. Activation of PAR2 with SL-NH2 (a PAR2 agonist, 100 μM) increased the TRPA1 currents by 78±10% in DRG neurons of control limb and by 125±10% in DRG neurons of ligated limb ( P< 0.05 vs. control; n = 8 in each group). Moreover, the potentiating effects of PAR2 activation were significantly inhibited by application of phospholipase C (PLC) inhibitors or phosphatidylinositol-4,5-bisphosphate (PIP2). Conclusions: A functional interaction in PAR2 and TRPA1 in muscle sensory nerves likely contributes to the amplified sympathetic responsiveness observed in PAD and that the PLC/PIP2 is engaged in sensitization mechanism of TRPA1. These findings provide a pathophysiological basis for autonomic responses during exercise activity in this disease, which may further help to aim at a potential therapeutic approach for improvement of blood flow in PAD patients.

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Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease

Circulation Research ◽

10.1161/circresaha.121.318242 ◽

2021 ◽

Vol 128 (12) ◽

pp. 1851-1867 ◽

Cited By ~ 1

Author(s):

Mary M. McDermott ◽

Sudarshan Dayanidhi ◽

Kate Kosmac ◽

Sunil Saini ◽

Joshua Slysz ◽

...

Keyword(s):

Skeletal Muscle ◽

Lower Extremity ◽

Peripheral Artery Disease ◽

Capillary Density ◽

Mitochondrial Activity ◽

Peripheral Artery ◽

Supervised Exercise ◽

Walking Exercise ◽

Artery Disease ◽

Response To Exercise

Walking exercise is the most effective noninvasive therapy that improves walking ability in peripheral artery disease (PAD). Biologic mechanisms by which exercise improves walking in PAD are unclear. This review summarizes evidence regarding effects of walking exercise on lower extremity skeletal muscle in PAD. In older people without PAD, aerobic exercise improves mitochondrial activity, muscle mass, capillary density, and insulin sensitivity in skeletal muscle. However, walking exercise increases lower extremity ischemia in people with PAD, and therefore, mechanisms by which this exercise improves walking may differ between people with and without PAD. Compared with people without PAD, gastrocnemius muscle in people with PAD has greater mitochondrial impairment, increased reactive oxygen species, and increased fibrosis. In multiple small trials, walking exercise therapy did not consistently improve mitochondrial activity in people with PAD. In one 12-week randomized trial of people with PAD randomized to supervised exercise or control, supervised treadmill exercise increased treadmill walking time from 9.3 to 15.1 minutes, but simultaneously increased the proportion of angular muscle fibers, consistent with muscle denervation (from 7.6% to 15.6%), while angular myofibers did not change in the control group (from 9.1% to 9.1%). These findings suggest an adaptive response to exercise in PAD that includes denervation and reinnervation, an adaptive process observed in skeletal muscle of people without PAD during aging. Small studies have not shown significant effects of exercise on increased capillary density in lower extremity skeletal muscle of participants with PAD, and there are no data showing that exercise improves microcirculatory delivery of oxygen and nutrients in patients with PAD. However, the effects of supervised exercise on increased plasma nitrite abundance after a treadmill walking test in people with PAD may be associated with improved lower extremity skeletal muscle perfusion and may contribute to improved walking performance in response to exercise in people with PAD. Randomized trials with serial, comprehensive measures of muscle biology, and physiology are needed to clarify mechanisms by which walking exercise interventions improve mobility in PAD.

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Supervised exercise therapy, blood pressure and heart rate during exercise, and functional impairment in Peripheral Artery Disease: results of a randomized clinical trial

Journal of Vascular Surgery ◽

10.1016/j.jvs.2021.05.033 ◽

2021 ◽

Author(s):

Joshua T. Slysz ◽

Lu Tian ◽

Lihui Zhao ◽

Dongxue Zhang ◽

Mary M. McDermott

Keyword(s):

Blood Pressure ◽

Clinical Trial ◽

Heart Rate ◽

Randomized Clinical Trial ◽

Peripheral Artery Disease ◽

Exercise Therapy ◽

Functional Impairment ◽

Peripheral Artery ◽

Supervised Exercise ◽

Artery Disease

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Heat treatment attenuates activities of ET‐1 signaling pathway and enhances the protective HSP72‐SOD2 in ischemic skeletal muscle of rats with peripheral artery disease

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.02623 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Lu Qin ◽

Jianhua Li

Keyword(s):

Heat Treatment ◽

Skeletal Muscle ◽

Signaling Pathway ◽

Peripheral Artery Disease ◽

Peripheral Artery ◽

Artery Disease

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Eight weeks of nitrate supplementation improves blood flow and reduces the exaggerated pressor response during forearm exercise in peripheral artery disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00015.2018 ◽

2018 ◽

Vol 315 (1) ◽

pp. H101-H108 ◽

Cited By ~ 9

Author(s):

Nicholas T. Kruse ◽

Kenichi Ueda ◽

William E. Hughes ◽

Darren P. Casey

Keyword(s):

Blood Flow ◽

Peripheral Artery Disease ◽

Pressor Response ◽

Treated Group ◽

Moderate Intensity ◽

Peripheral Artery ◽

Pressor Responses ◽

Nitrate Supplementation ◽

Artery Disease ◽

Forearm Exercise

Peripheral artery disease (PAD) is characterized by a reduced blood flow (BF) and an elevated blood pressure (pressor) response during lower extremity exercise. Although PAD is evident in the upper extremities, no studies have determined BF and pressor responses during upper extremity exercise in PAD. Emerging evidence suggests that inorganic nitrate supplementation may serve as an alternative dietary strategy to boost nitric oxide bioavailability, improving exercising BF and pressor responses during exercise. The present study investigated 1) BF and pressor responses to forearm exercise in patients with PAD ( n = 21) relative to healthy age-matched control subjects ( n = 16) and 2) whether 8 wk of NaNO3 supplementation influenced BF and pressor responses to forearm exercise in patients with PAD. Patients with moderate to severe PAD were randomly assigned to a NaNO3 (1 g/day, n = 13)-treated group or a placebo (microcrystalline cellulose, n = 8)-treated group. Brachial artery forearm BF (FBF; via Doppler) and blood pressure (via finger plethysmography) were measured during mild-intensity (~3.5-kg) and moderate-intensity (~7-kg) handgrip exercise. The absolute change (from baseline) in FBF was reduced (except in the 3.5-kg condition) and BP responses were increased in patients with PAD compared with healthy control subjects in 3.5- and 7-kg conditions (all P < 0.05). Plasma nitrate and nitrite were elevated, exercising (7-kg) ΔFBF was improved (from 141 ± 17 to 172 ± 20 ml/min), and mean arterial pressure response was reduced (from 13 ± 1 to 9 ± 1 mmHg, P < 0.05) in patients with PAD that received NaNO3 supplementation for 8 wk relative to those that received placebo. These results suggest that the BF limitation and exaggerated pressor response to moderate-intensity forearm exercise in patients with PAD are improved with 8 wk of NaNO3 supplementation. NEW & NOTEWORTHY Peripheral artery disease (PAD) results in an exaggerated pressor response and reduced blood flow during lower limb exercise; however, the effect of PAD in the upper limbs has remained unknown. These results suggest that 8 wk of inorganic nitrate supplementation improves the blood flow limitation and exaggerated pressor response to moderate-intensity forearm exercise in PAD.

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Systemic and regional hemodynamic response to activation of the exercise pressor reflex in patients with peripheral artery disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00493.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. H916-H924 ◽

Cited By ~ 1

Author(s):

Danielle Jin-Kwang Kim ◽

Marcos Kuroki ◽

Jian Cui ◽

Zhaohui Gao ◽

J. Carter Luck ◽

...

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Peripheral Artery Disease ◽

Plantar Flexion ◽

Peripheral Artery ◽

Exercise Pressor Reflex ◽

Femoral Blood Flow ◽

Femoral Blood ◽

Pressor Reflex ◽

Artery Disease

Patients with peripheral artery disease (PAD) have an accentuated exercise pressor reflex (EPR) during exercise of the affected limb. The underlying hemodynamic changes responsible for this, and its effect on blood flow to the exercising extremity, are unclear. We tested the hypothesis that the exaggerated EPR in PAD is mediated by an increase in total peripheral resistance (TPR), which augments redistribution of blood flow to the exercising limb. Twelve patients with PAD and 12 age- and sex-matched subjects without PAD performed dynamic plantar flexion (PF) using the most symptomatic leg at progressive workloads of 2–12 kg (increased by 1 kg/min until onset of fatigue). We measured heart rate, beat-by-beat blood pressure, femoral blood flow velocity (FBV), and muscle oxygen saturation ([Formula: see text]) continuously during the exercise. Femoral blood flow (FBF) was calculated from FBV and baseline femoral artery diameter. Stroke volume (SV), cardiac output (CO), and TPR were derived from the blood pressure tracings. Mean arterial blood pressure and TPR were significantly augmented in PAD compared with control during PF. FBF increased during exercise to an equal extent in both groups. However, [Formula: see text] of the exercising limb remained significantly lower in PAD compared with control. We conclude that the exaggerated pressor response in PAD is mediated by an abnormal TPR response, which augments redistribution of blood flow to the exercising extremity, leading to an equal rise in FBF compared with controls. However, this increase in FBF is not sufficient to normalize the SmO2 response during exercise in patients with PAD. NEW & NOTEWORTHY In this study, peripheral artery disease (PAD) patients and healthy control subjects performed graded, dynamic plantar flexion exercise. Data from this study suggest that previously reported exaggerated exercise pressor reflex in patients with PAD is driven by greater vasoconstriction in nonexercising vascular territories which also results in a redistribution of blood flow to the exercising extremity. However, this rise in femoral blood flow does not fully correct the oxygen deficit due to changes in other mechanisms that require further investigation.

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