Toward a Better Understanding of Muscle Microvascular Perfusion During Exercise in Patients With Peripheral Artery Disease: The Effect of Lower-Limb Revascularization

Purpose: Leg muscle microvascular blood flow (perfusion) is impaired in response to maximal exercise in patients with peripheral artery disease (PAD); however, during submaximal exercise, microvascular perfusion is maintained due to a greater increase in microvascular blood volume compared with that seen in healthy adults. It is unclear whether this submaximal exercise response reflects a microvascular impairment, or whether it is a compensatory response for the limited conduit artery flow in PAD. Therefore, to clarify the role of conduit artery blood flow, we compared whole-limb blood flow and skeletal muscle microvascular perfusion responses with exercise in patients with PAD (n=9; 60±7 years) prior to, and following, lower-limb endovascular revascularization. Materials and Methods: Microvascular perfusion (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after a 5 minute bout of submaximal intermittent isometric plantar-flexion exercise using contrast-enhanced ultrasound imaging. Exercise contraction-by-contraction whole-leg blood flow and vascular conductance were measured using strain-gauge plethysmography. Results: With revascularization there was a significant increase in whole-leg blood flow and conductance during exercise (p<0.05). Exercise-induced muscle microvascular perfusion response did not change with revascularization (pre-revascularization: 3.19±2.32; post-revascularization: 3.89±1.67 aU.s−1; p=0.38). However, the parameters that determine microvascular perfusion changed, with a reduction in the microvascular volume response to exercise (pre-revascularization: 6.76±3.56; post-revascularization: 2.42±0.69 aU; p<0.01) and an increase in microvascular flow velocity (pre-revascularization: 0.25±0.13; post-revascularization: 0.59±0.25 s−1; p=0.02). Conclusion: These findings suggest that patients with PAD compensate for the conduit artery blood flow impairment with an increase in microvascular blood volume to maintain muscle perfusion during submaximal exercise. Clinical Impact The findings from this study support the notion that the impairment in conduit artery blood flow in patients with PAD leads to compensatory changes in microvascular blood volume and flow velocity to maintain muscle microvascular perfusion during submaximal leg exercise. Moreover, this study demonstrates that these microvascular changes are reversed and become normalized with successful lower-limb endovascular revascularization.

[1]  J. Sharman,et al.  Impaired postprandial skeletal muscle vascular responses to a mixed meal challenge in normoglycaemic people with a parent with type 2 diabetes , 2021, Diabetologia.

[2]  James R. Broatch,et al.  Reduced post‐exercise muscle microvascular perfusion with compression is offset by increased muscle oxygen extraction: Assessment by contrast‐enhanced ultrasound , 2021, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  J. Golledge,et al.  Skeletal muscle microvascular perfusion responses to cuff occlusion and submaximal exercise assessed by contrast‐enhanced ultrasound: The effect of age , 2020, Physiological reports.

[4]  N. Basaglia,et al.  Biomarkers of Muscle Metabolism in Peripheral Artery Disease: A Dynamic NIRS-Assisted Study to Detect Adaptations Following Revascularization and Exercise Training , 2020, Diagnostics.

[5]  Y. Hellsten,et al.  Leg blood flow and skeletal muscle microvascular perfusion responses to submaximal exercise in peripheral arterial disease. , 2018, American journal of physiology. Heart and circulatory physiology.

[6]  A. Gardner,et al.  Minimal clinically important differences in treadmill, 6-minute walk, and patient-based outcomes following supervised and home-based exercise in peripheral artery disease , 2018, Vascular medicine.

[7]  B. Annex,et al.  Therapeutic Angiogenesis for Peripheral Artery Disease , 2017, JACC. Basic to translational science.

[8]  D. Proctor,et al.  Blood pressure and calf muscle oxygen extraction during plantar flexion exercise in peripheral artery disease. , 2017, Journal of applied physiology.

[9]  J. Linden,et al.  Exercise versus vasodilator stress limb perfusion imaging for the assessment of peripheral artery disease , 2017, Echocardiography.

[10]  R. Ritti-Dias,et al.  Combined Lower Limb Revascularisation and Supervised Exercise Training for Patients with Peripheral Arterial Disease: A Systematic Review of Randomised Controlled Trials , 2017, Sports Medicine.

[11]  R. Kinscherf,et al.  Age-related differences in skeletal muscle microvascular response to exercise as detected by contrast-enhanced ultrasound (CEUS) , 2017, PloS one.

[12]  B. Lal,et al.  Contrast-Enhanced Ultrasound Reveals Exercise-Induced Perfusion Deficits in Claudicants , 2017, Journal of vascular and endovascular surgery.

[13]  Y. Hellsten,et al.  Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication. , 2016, American journal of physiology. Regulatory, integrative and comparative physiology.

[14]  J. Sacre,et al.  Association of Exercise Intolerance in Type 2 Diabetes With Skeletal Muscle Blood Flow Reserve. , 2015, JACC. Cardiovascular imaging.

[15]  S. Peirce,et al.  Computational Network Model Prediction of Hemodynamic Alterations Due to Arteriolar Rarefaction and Estimation of Skeletal Muscle Perfusion in Peripheral Arterial Disease , 2015, Microcirculation.

[16]  Daniel P. Credeur,et al.  Characterizing rapid-onset vasodilation to single muscle contractions in the human leg. , 2015, Journal of applied physiology.

[17]  D. Poole,et al.  Skeletal muscle capillary function: contemporary observations and novel hypotheses , 2013, Experimental physiology.

[18]  J. Teijink,et al.  Endovascular revascularisation versus conservative management for intermittent claudication. , 2013, The Cochrane database of systematic reviews.

[19]  H. Kauczor,et al.  Dynamic contrast-enhanced ultrasound for assessment of therapy effects on skeletal muscle microcirculation in peripheral arterial disease: pilot study. , 2013, European journal of radiology.

[20]  Jason D. Allen,et al.  Relationship between leg muscle capillary density and peak hyperemic blood flow with endurance capacity in peripheral artery disease. , 2011, Journal of applied physiology.

[21]  J. Lindholt,et al.  Quality of Life and Functional Status After Revascularization or Conservative Treatment in Patients With Intermittent Claudication , 2011, Vascular and endovascular surgery.

[22]  Y. Hellsten,et al.  Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition. , 2011, American journal of physiology. Heart and circulatory physiology.

[23]  M. Olschewski,et al.  Success of arterial revascularization determined by contrast ultrasound muscle perfusion imaging. , 2010, Journal of vascular surgery.

[24]  S. Kaul,et al.  Limb stress-rest perfusion imaging with contrast ultrasound for the assessment of peripheral arterial disease severity. , 2008, JACC. Cardiovascular imaging.

[25]  A. Seifalian,et al.  Statins and Peripheral Arterial Disease: Potential Mechanisms and Clinical Benefits , 2006, Annals of vascular surgery.

[26]  B. Parker,et al.  Vasodilation and Vascular Control in Contracting Muscle of the Aging Human , 2006, Microcirculation.

[27]  H. Kauczor,et al.  Relationship of Skeletal Muscle Perfusion Measured by Contrast‐Enhanced Ultrasonography to Histologic Microvascular Density , 2006, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[28]  S. Meeson,et al.  Measuring the rate of change of haemodynamic response at the onset of exercise in normal limbs and those with intermittent claudication , 2005, Physiological measurement.

[29]  Sun-hee Ahn,et al.  Quality of life and exercise performance after aortoiliac stent placement for claudication. , 2005, Journal of vascular and interventional radiology : JVIR.

[30]  Andrew D. Williams,et al.  Skeletal muscle phenotype is associated with exercise tolerance in patients with peripheral arterial disease. , 2005, Journal of vascular surgery.

[31]  S. Kaul,et al.  Detection of peripheral vascular stenosis by assessing skeletal muscle flow reserve. , 2005, Journal of the American College of Cardiology.

[32]  W. Hiatt,et al.  Impaired muscle oxygen use at onset of exercise in peripheral arterial disease. , 2004, Journal of vascular surgery.

[33]  S. Green Haemodynamic limitations and exercise performance in peripheral arterial disease , 2002, Clinical physiology and functional imaging.

[34]  R. Newton,et al.  Muscle fiber characteristics in patients with peripheral arterial disease. , 2001, Medicine and science in sports and exercise.

[35]  A R Jayaweera,et al.  Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. , 1998, Circulation.

[36]  M. Clark,et al.  Vascular and endocrine control of muscle metabolism. , 1995, The American journal of physiology.

[37]  G. Guyatt,et al.  The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. , 1985, Canadian Medical Association journal.

[38]  S. Lucas,et al.  Reliability of contrast-enhanced ultrasound for the assessment of muscle perfusion in health and peripheral arterial disease. , 2015, Ultrasound in medicine & biology.

[39]  Christian Greis,et al.  Quantitative evaluation of microvascular blood flow by contrast-enhanced ultrasound (CEUS). , 2011, Clinical hemorheology and microcirculation.

[40]  M. Prins,et al.  Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery. , 2003, The Cochrane database of systematic reviews.

[41]  S. Kaul,et al.  Changes in myocardial blood volume with graded coronary stenosis. , 1997, The American journal of physiology.

[42]  J P Clarys,et al.  Anatomical segmentation in humans and the prediction of segmental masses from intra-segmental anthropometry. , 1986, Human biology.

[43]  G. Borg Psychophysical bases of perceived exertion. , 1982, Medicine and science in sports and exercise.

[44]  J. Holm,et al.  Capillary supply and muscle fibre types in patients with intermittent claudication: relationships between morphology and metabolism. , 1980, European journal of clinical investigation.

[45]  K. Myhre,et al.  Exercise-and post-exercise metabolism of the lower leg in patients with peripheral arterial insufficiency. , 1978, Scandinavian journal of clinical and laboratory investigation.