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

Robbins, Jennifer L.; Jones, W. Schuyler; Duscha, Brian D.; Allen, Jason D.; Kraus, William E.; Regensteiner, Judith G.; Hiatt, William R.; Annex, Brian H.

doi:10.1152/japplphysiol.00141.2011

Cited by 104 publications

(108 citation statements)

References 43 publications

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“…Previous findings of reduced muscle vascular endothelial growth factor protein content (26) and elevated thrombospondin-1 in the muscle (16) and muscle extracellular fluid (26) also provides some indication that the angiogenic potential of PAD-affected muscle may be impaired. However, the capillary-to-fiber ratio differed only nonsignificantly between the two groups, which is in contrast to other studies (16,45). This discrepancy may be a result of the presence of comorbidities or the age and physical activity levels of study participants and low group sample sizes but also of the muscle sampling site where the ischemic insult of PAD is likely to be less severe, and perhaps more variable, at the vastus lateralis than at the distal muscle groups, which have been sampled (3,16,45).…”

Section: Discussioncontrasting

confidence: 99%

“…However, the capillary-to-fiber ratio differed only nonsignificantly between the two groups, which is in contrast to other studies (16,45). This discrepancy may be a result of the presence of comorbidities or the age and physical activity levels of study participants and low group sample sizes but also of the muscle sampling site where the ischemic insult of PAD is likely to be less severe, and perhaps more variable, at the vastus lateralis than at the distal muscle groups, which have been sampled (3,16,45). It should be noted that some studies have likewise failed to demonstrate such capillary rarefaction in IC patients compared with controls (21,30).…”

Section: Discussioncontrasting

confidence: 99%

“…In accordance with our previous findings (3), the capillary density was significantly lower in the IC group than the control group, concordant with previous studies in which either capillary density or capillary-to-fiber ratio was reduced, and significantly related to walking capacity and cardiorespiratory fitness (3,11,45). Previous findings of reduced muscle vascular endothelial growth factor protein content (26) and elevated thrombospondin-1 in the muscle (16) and muscle extracellular fluid (26) also provides some indication that the angiogenic potential of PAD-affected muscle may be impaired.…”

Section: Discussionsupporting

confidence: 92%

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Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication

Baum

Torchetti

Malik

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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(PAD). Impaired limb blood flow is a major casual factor of lower exercise tolerance in PAD but cannot entirely explain it. We hypothesized that IC is associated with structural changes of the capillary-mitochondria interface that could contribute to the reduction of exercise tolerance in IC patients. Capillary and mitochondrial morphometry were performed after light and transmission electron microscopy using vastus lateralis muscle biopsies of 14 IC patients and 10 age-matched controls, and peak power output (PPO) was determined for all participants using an incremental single-leg kneeextension protocol. Capillary density was lower (411 Ϯ 90 mm Ϫ2 vs. 506 Ϯ 95 mm Ϫ2 ; P Յ 0.05) in the biopsies of the IC patients than in those of the controls. The basement membrane (BM) around capillaries was thicker (543 Ϯ 82 nm vs. 423 Ϯ 97 nm; P Յ 0.01) and the volume density of mitochondria was lower (3.51 Ϯ 0.56% vs. 4.60 Ϯ 0.74%; P Յ 0.01) in the IC patients than the controls. In the IC patients, a higher proportion of capillaries appeared with collapsed slit-like lumen and/or swollen endothelium. PPO was lower (18.5 Ϯ 9.9 W vs. 33.5 Ϯ 9.4 W; P Յ 0.01) in the IC patients than the controls. We suggest that several structural alterations in skeletal muscle, either collectively or separately, contribute to the reduction of exercise tolerance in IC patients. capillary; morphometry; peripheral arterial disease; skeletal muscle; transmission electron microscopy PERIPHERAL ARTERIAL DISEASE (PAD) is an atherosclerotic disease characterized by stenosis or occlusion of the conduit arteries of the lower limbs (20,36). Risk factors associated with PAD include advancing age, cigarette smoking, diabetes mellitus, arterial hypertension, and disturbances in lipid metabolism (12). While many PAD patients are asymptomatic, the arterial narrowing leads to ischemia and hypoxia of the supplied tissues and in severe cases, this manifests as critical limb ischemia (CLI), usually requiring surgical interventions. Intermittent claudication (IC), which is typically described as a cramp-like muscle pain during exercise, is the most commonly reported symptom of PAD and is usually the first noted symptom of the disease.Patients with IC have limited muscular strength and endurance capacities (35), reduced cardiorespiratory fitness (V O 2 peak ), and demonstrate reduced oxygen uptake kinetics at the onset of exercise (6). They also exhibit a significantly reduced tolerance for physical activities such as walking and cycling (2, 13). This reduction in exercise tolerance leads to functional impairments that are similar to those observed in patients with heart failure (31) and contributes to their impaired mobility, reduced quality of life, and elevated risk for the development of cardiovascular complications (17).Impaired limb blood flow is commonly assumed to be the main casual factor of the reduction in exercise tolerance in PAD but cannot entirely explain it. For example, restoration of blood flow capacity with percutaneous endovascular revascularizat...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 92%

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Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication

Baum

Torchetti

Malik

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Impairment of the hyperemic blood flow response is associated with functional impairment in PAD. 53 There is evidence connecting greater brachial flowmediated dilation to greater physical activity in daily life in patients with PAD. 54 Recent studies related impaired brachial flow-mediated dilation with reduced self-reported walking ability and 6-minute walk test.…”

Section: Smoking Cessationmentioning

confidence: 99%

Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

Hamburg

Creager

2017

Circ J

151

124

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estimates a more than 30% increase in deaths and disability attributable to PAD between 2005 and 2015, which is largely determined by population aging. 3,12 PAD prevalence escalates with advancing age, affecting 1 in 10 adults older than 70 years. In addition to age, smoking and diabetes are the strongest risk factors for PAD across the world. A comprehensive global evaluation of PAD found that its prevalence and risk factors are similar in high-income countries to low-and middle-income countries. 2,13 Lower socioeconomic status is a newly recognized risk factor for PAD. 14 Importantly, there has been a greater increase in PAD prevalence in low-and middle-income countries, rising by 28.7% from 2000 to 2010 as compared with 13.1% in high-income countries. 2, 15 The changing burden of PAD is also greater in women as compared with men.The health implications of PAD derive from both its limb and cardiovascular manifestations. Consistent with the systemic nature of atherosclerosis, polyvascular disease is common in patients with PAD. 16 In the REACH registry, 61% of PAD patients had concomitant coronary artery disease (CAD) and/or cerebrovascular disease. 16 Thus, the presence of PAD portends a high risk for subsequent cardiovascular events. A meta-analysis of over 48,000 participants in population-based cohort studies demonstrated that a low ankle-brachial index (ABI) predicted a 2-fold risk of death, cardiovascular death, and major coronary events at all ranges of the Framingham Risk Score. 4 Further, the elevated risk of cardiovascular events is present in both symptomatic and asymptomatic patients. 17 Patients with atherosclerotic disease in more than 1 vascular territory have particularly poor outcomes. 6 In the over 5,000 Japanese T here is growing recognition of the effect of peripheral artery disease (PAD) on cardiovascular health. 1 Recent studies indicate that, globally, over 200 million adults have PAD, 2,3 which is an expression of systemic atherosclerosis and well-established as heightening the risk for cardiovascular events. 4-6 The limb manifestations of PAD induce considerable suffering. Patients with PAD experience intermittent claudication, characterized as exertional leg pain that limits walking ability, and often times, disability. 7-9 Current medical therapies to reduce the burden of lower extremity symptoms in patients with PAD are limited. Revascularization by endovascular intervention or surgical reconstruction is used to treat lifestyle-limiting claudication if patients do not respond adequately to medical therapy including exercise training. Indeed, lower extremity revascularization with endovascular approaches has undergone a dramatic increase in use. 10 Though endovascular therapy improves blood flow and function, there are significant associated risks, and durability may be limited, especially in infrainguinal disease. Abundant evidence demonstrates the benefits of exercise therapy in claudication, yet the mechanisms underlying the beneficial effects remain incompletely defined. 11 Thus, ...

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“…These exercise improvements are not correlated with changes in limb hemodynamics but may be associated with changes in skeletal muscle metabolism and capillary density. 22,23 In contrast, revascularization results in substantial improvements in limb blood flow and oxygen delivery, but these improvements in limb flow are not well correlated with the change in exercise performance. 24 The recognition that a limitation in maximal exercise performance is a direct result of a complex pathophysiology and that both endurance and submaximal exercise performance are inherently impaired when maximal performance is limited has important implications for considering how to assess function and response to treatment in these patients.…”

Section: Pathophysiology Of the Exercise Limitation In Padmentioning

confidence: 99%

The Treadmill Is a Better Functional Test Than the 6-Minute Walk Test in Therapeutic Trials of Patients With Peripheral Artery Disease

2014

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

Cited by 104 publications

References 43 publications

Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication

Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication

Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

The Treadmill Is a Better Functional Test Than the 6-Minute Walk Test in Therapeutic Trials of Patients With Peripheral Artery Disease

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