Passive Leg Movement Technique for Assessing Vascular Function: Further Defining the Distribution of Blood Flow

Continuous passive leg movement (PLM) is a promising clinical assessment of the age-related decline in peripheral vascular function. To further refine PLM, this study evaluated the efficacy of a single PLM (sPLM), a simplified variant of the more established continuous movement approach, to delineate between healthy young and old men based on vascular function. Twelve young (26 ± 5 yr) and 12 old (70 ± 7 yr) subjects underwent sPLM (a single passive flexion and extension of the knee joint through 90°), with leg blood flow (LBF, common femoral artery with Doppler ultrasound), blood pressure (finger photoplethysmography), and leg vascular conductance (LVC) assessed. A receiver operator characteristic curve analysis was used to determine an age-specific cut score, and a factor analysis was performed to assess covariance. Baseline LBF and LVC were not different between groups ( P = 0.6). The high level of covariance and similar predictive value for all PLM-induced LBF and LVC responses indicates LBF, alone, can act as a surrogate variable in this paradigm. The peak sPLM-induced increase in LBF from baseline was attenuated in the old (Young: 717 ± 227, Old: 260 ± 97 ml/min, P < 0.001; cut score: 372 ml/min), as was the total LBF response (Young: 155 ± 67, Old: 26 ± 17 ml, P < 0.001; cut score: 58 ml). sPLM, a simplified version of PLM, exhibits the prerequisite qualities of a valid screening test for peripheral vascular dysfunction, as evidenced by an age-related attenuation in the peripheral hyperemic response and a clearly delineated age-specific cut score. NEW & NOTEWORTHY Single passive leg movement (sPLM) exhibits the prerequisite qualities of a valid screening test for peripheral vascular dysfunction. sPLM displayed an age-related reduction in the peripheral hemodynamic response for amplitude, duration, initial rate of change, and total change with clearly delineated age-specific cut scores. sPLM has a strong candidate variable that is a simple single numeric value, for which to appraise peripheral vascular function, the 45-s hyperemic response (leg blood flow area under the curve: 45 s).

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The role of the endothelium in the hyperemic response to passive leg movement: looking beyond nitric oxide

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00784.2020 ◽

2020 ◽

Author(s):

Joel D. Trinity ◽

Oh Sung Kwon ◽

Ryan M. Broxterman ◽

Jayson R. Gifford ◽

Andrew C. Kithas ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Vascular Function ◽

No Synthase ◽

Ketorolac Tromethamine ◽

Arterial Infusion ◽

Healthy Men ◽

Leg Movement ◽

Hyperemic Response

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite NO synthase (NOS) inhibition. Therefore, in 9 young healthy men (25±4 yrs), this investigation aimed to determine if the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement) when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl L-arginine (L-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P450 (CYP450) by L-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF (LBFAUC) response to both PLM (control: 456±194, L-NMMA: 168±127 ml, p<0.01) and sPLM (control: 185±171, L-NMMA: 62±31 ml, p=0.03). The combined inhibition of NOS, COX, and CYP450 (i.e. L-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271±97 ml, p>0.05) or sPLM (LBFAUC: 72±45 ml, p>0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent, hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests.

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Aerobic training status does not attenuate prolonged sitting-induced lower limb vascular dysfunction

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2018-0420 ◽

2019 ◽

Vol 44 (4) ◽

pp. 425-433 ◽

Cited By ~ 5

Author(s):

Ryan S. Garten ◽

Austin C. Hogwood ◽

Jennifer B. Weggen ◽

R. Carson Fralin ◽

Kathryn LaRosa ◽

...

Keyword(s):

Blood Flow ◽

Lower Limb ◽

Vascular Function ◽

Aerobic Training ◽

Vascular Dysfunction ◽

Area Under The Curve ◽

Training Status ◽

Prolonged Sitting ◽

Leg Movement ◽

The Relationship

This study examined if the degree of aerobic training protects against the lower limb vascular dysfunction associated with a prolonged sitting bout. Ten young, aerobically trained (AT) and 10 young, untrained (UT) individuals completed a prolonged (3 h) sitting bout. Leg vascular function was measured prior to and at 1.5 and 3 h into the prolonged sitting bout using the passive leg movement (PLM) technique. PLM-induced hyperemia was significantly reduced from baseline at 1.5 and 3 h into the prolonged sitting bout in both groups when evaluated as peak change in leg blood flow from baseline (Δ LBF) (UT: 956 ± 140, 586 ± 80, and 599 ± 96 mL·min−1 at baseline, 1.5 h, and 3 h, respectively; AT: 955 ± 183, 789 ± 193, and 712 ± 131 mL·min−1 at baseline, 1.5 h, and 3 h, respectively) and LBF area under the curve (UT: 283 ± 73, 134 ± 31, and 164 ± 42 mL·min−1 at baseline, 1.5 h, and 3 h, respectively; AT: 336 ± 86, 242 ± 86, and 245 ± 73 mL·min−1 at baseline, 1.5 h, and 3 h, respectively), but no significant differences between groups were revealed. No significant correlations were observed when examining the relationship between maximal oxygen uptake (relative and absolute) and reductions in leg vascular function at 1.5 and 3 h into the prolonged sitting bout. This study revealed that aerobic training did not provide a protective effect against prolonged sitting-induced lower limb vascular dysfunction and further highlights the importance of reducing excessive sitting in all populations.

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Confocal Blood Flow Videomicroscopy of Thrombus Formation over Human Arteries and Local Targeting of P2X7

International Journal of Molecular Sciences ◽

10.3390/ijms22084066 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4066

Author(s):

Patrizia Marchese ◽

Maria Lombardi ◽

Maria Elena Mantione ◽

Domenico Baccellieri ◽

David Ferrara ◽

...

Keyword(s):

Blood Flow ◽

Vascular Function ◽

Collagen Type ◽

Thrombus Formation ◽

Collagen Type I ◽

Type I ◽

Prevention Therapy ◽

Healthy Donors ◽

Internal Mammary ◽

Human Arteries

Atherothrombosis exposes vascular components to blood. Currently, new antithrombotic therapies are emerging. Herein we investigated thrombogenesis of human arteries with/without atherosclerosis, and the interaction of coagulation and vascular components, we and explored the anti-thrombogenic efficacy of blockade of the P2X purinoceptor 7 (P2X7). A confocal blood flow videomicroscopy system was performed on cryosections of internal mammary artery (IMA) or carotid plaque (CPL) determining/localizing platelets and fibrin. Blood from healthy donors elicited thrombi over arterial layers. Confocal microscopy associated thrombus with tissue presence of collagen type I, laminin, fibrin(ogen) and tissue factor (TF). The addition of antibodies blocking TF (aTF) or factor XI (aFXI) to blood significantly reduced fibrin deposition, variable platelet aggregation and aTF + aFXI almost abolished thrombus formation, showing synergy between coagulation pathways. A scarce effect of aTF over sub-endothelial regions, more abundant in tissue TF and bundles of laminin and collagen type I than deep intima, may suggest tissue thrombogenicity as molecular structure-related. Consistently with TF-related vascular function and expression of P2X7, the sections from CPL but not IMA tissue cultures pre-treated with the P2X7 antagonist A740003 demonstrated poor thrombogenesis in flow experiments. These data hint to local targeting studies on P2X7 modulation for atherothrombosis prevention/therapy.

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Activation of angiotensin type 2 receptor attenuates testosterone-induced hypertension and uterine vascular resistance in pregnant rats

Biology of Reproduction ◽

10.1093/biolre/ioab051 ◽

2021 ◽

Author(s):

Jay S Mishra ◽

Sathish Kumar

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Vascular Function ◽

Uterine Artery ◽

Artery Blood Flow ◽

Protein Levels ◽

Angiotensin Type 2 Receptor ◽

Enos Protein ◽

Angiotensin Type

Abstract Preeclampsia is a pregnancy-related hypertensive disorder with unclear mechanisms. While hypersensitivity to angiotensin II via vasoconstrictive angiotensin type-1 receptor (AT1R) is observed in preeclampsia, the importance of vasodilatory angiotensin type-2 receptor (AT2R) in the control of vascular dysfunction is less clear. We assessed whether AT1R, AT2R and eNOS expression is altered in placental vessels of preeclamptic women and tested if ex vivo incubation with AT2R agonist Compound 21 (C21; 1 μM) could restore AT1R, AT2R and eNOS balance. Further, using a rat model of gestational hypertension induced by elevated testosterone, we examined whether C21 (1 μg·kg−1·day−1, oral) could preserve AT1R and AT2R balance and improve blood pressure, uterine artery blood flow, and vascular function. Western blots revealed that AT1R protein level was higher while AT2R and eNOS protein were reduced in preeclamptic placental vessels, and AT2R agonist C21 decreased AT1R and increased AT2R and eNOS protein levels in preeclamptic vessels. In testosterone-dams, blood pressure was higher, and uterine artery blood flow was reduced, and C21 treatment reversed these levels similar to those in controls dams. C21 attenuated the exaggerated Ang II contraction and improved endothelium-dependent vasorelaxation in uterine arteries of testosterone-dams. These C21-mediated vascular effects were associated with decreased AT1R and increased AT2R and eNOS protein levels. C21 also increased serum nitrate/nitrite and bradykinin production in testosterone-dams and attenuated the feto-placental growth restriction. Thus, AT1R upregulation and AT2R downregulation is observed in preeclampsia and testosterone-model, and increasing AT2R activity could help restore AT1R and AT2R balance and improve gestational vascular function.

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Abstract 032: Uninterrupted Sitting Induces Unfavorable Changes In Resting Hemodynamics And Inflammatory And Vascular Biomarkers In Physically Inactive And Active Adults

Circulation ◽

10.1161/circ.143.suppl_1.032 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Megan C Nelson ◽

Madeline P Casanova ◽

Jennavere R Ball ◽

Rachel D Midence ◽

Timothy R Johnson ◽

...

Keyword(s):

Physical Activity ◽

Blood Flow ◽

Mean Arterial Pressure ◽

Shear Rate ◽

Arterial Pressure ◽

Vascular Function ◽

Blood Velocity ◽

Inflammatory Biomarkers ◽

Active Adults ◽

Over Time

Introduction: A single bout of uninterrupted sitting impairs vascular function in the legs, which may be due to reductions in blood flow and shear stress. Participating in regular moderate-to-vigorous physical activity (MVPA) has been identified as an effective approach for improving vascular function, and recent evidence suggests meeting the physical activity (PA) guidelines may attenuate some of the negative health outcomes associated with excessive sedentary behavior; however, it is not well understood how meeting the PA guidelines may influence the acute response to sitting. Our aim was to investigate the effects of 3 h of uninterrupted sitting on hemodynamics and vascular and inflammatory biomarkers in physically inactive and active adults. Hypothesis: We hypothesized active adults would experience less detrimental physiological changes after sitting compared to inactive adults. Methods: Eleven inactive (mean±SD, age: 47.1±8.9 y, body fat: 33.1±8.5%; 78.5% women) and 16 active adults (age: 46.1±8.9 y, body fat: 25.2±7.2%; 31.1% women) completed 3 h of uninterrupted sitting. Adults self-reported their PA with the International PA Questionnaire. Adults engaging in ≥150 min·wk -1 were classified as active and <150 min·wk -1 , inactive. Hemodynamic variables, and superficial femoral artery (SFA) diameter and blood velocity were measured each hour over 3 h of sitting. Mean arterial pressure, blood flow and shear rate were calculated. Serum vascular and inflammatory biomarkers were measured pre and post sitting. Linear mixed-effects modeling was used to assess changes in dependent variables over time and between inactive and active adults, controlling for sex. Results: Inactive and active adults self-reported 7.3±7.1 and 93.3±64.8 min·d -1 of MVPA, respectively. Endothelin-1 (baseline: 8.3±13.4 pg/mL, post: 81.1±103.0 pg/mL; p<0.001) and interleukin-6 (baseline: 0.08±0.06 pg/mL, post: 0.11±0.11 pg/mL; p=0.03) increased post sitting compared to baseline in all adults, regardless of PA status. Systolic blood pressure, mean arterial pressure, calf circumference, and SFA diameter, blood velocity, and mean blood flow decreased over time in both groups (p<0.05 for all). There was an interaction effect for mean shear rate (p=0.008); inactive adults experienced a decline over 3 h of sitting (baseline: 76.1±48.2 s -1 ; 1 h: 55.0±27.4 s -1 ; 2 h: 45.3±24.2 s -1 ; 3 h: 40.8±25.5 s -1 ) while active participants demonstrated no change (baseline: 36.6±21.4 s -1 ; 1 h: 28.1±21.4 s -1 ; 2 h: 26.1±20.9 s -1 ; 3 h: 23.8±19.5 s -1 ). Inactive adults also had a higher oscillatory shear index compared to active adults (p<0.001). Conclusion: Uninterrupted sitting induced unfavorable changes regardless of PA status; however, active adults demonstrated a more favorable shear profile. Meeting PA guidelines may attenuate some unfavorable changes within the vasculature associated with prolonged sitting.

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CORP: Ultrasound assessment of vascular function with the passive leg movement technique

Journal of Applied Physiology ◽

10.1152/japplphysiol.00557.2017 ◽

2017 ◽

Vol 123 (6) ◽

pp. 1708-1720 ◽

Cited By ~ 22

Author(s):

Jayson R. Gifford ◽

Russell S. Richardson

Keyword(s):

Vascular Function ◽

Cardiovascular Health ◽

Vascular System ◽

The Elderly ◽

Passive Movement ◽

Flow Mediated Dilation ◽

Peripheral Vascular ◽

Ultrasound Assessment ◽

Leg Movement ◽

Hyperemic Response

As dysfunction of the vascular system is an early, modifiable step in the progression of many cardiovascular diseases, there is demand for methods to monitor the health of the vascular system noninvasively in clinical and research settings. Validated by very good agreement with more technical assessments of vascular function, like intra-arterial drug infusions and flow-mediated dilation, the passive leg movement (PLM) technique has emerged as a powerful, yet relatively simple, test of peripheral vascular function. In the PLM technique, the change in leg blood flow elicited by the passive movement of the leg through a 90° range of motion is quantified with Doppler ultrasound. This relatively easy-to-learn test has proven to be ≤80% dependent on nitric oxide bioavailability and is especially adept at determining peripheral vascular function across the spectrum of cardiovascular health. Indeed, multiple reports have documented that individuals with decreased cardiovascular health such as the elderly and those with heart failure tend to exhibit a substantially blunted PLM-induced hyperemic response (~50 and ~85% reduction, respectively) compared with populations with good cardiovascular health such as young individuals. As specific guidelines have not yet been put forth, the purpose of this Cores of Reproducibility in Physiology (CORP) article is to provide a comprehensive reference for the assessment and interpretation of vascular function with PLM with the aim to increase reproducibility and consistency among studies and facilitate the use of PLM as a research tool with clinical relevance.

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Effects of aging and exercise training on spinotrapezius muscle microvascular Po2 dynamics and vasomotor control

Journal of Applied Physiology ◽

10.1152/japplphysiol.01084.2010 ◽

2011 ◽

Vol 110 (3) ◽

pp. 695-704 ◽

Cited By ~ 19

Author(s):

Danielle J. McCullough ◽

Robert T. Davis ◽

James M. Dominguez ◽

John N. Stabley ◽

Christian S. Bruells ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Exercise Training ◽

Sodium Nitroprusside ◽

Vascular Function ◽

Treadmill Running ◽

Aged Rats ◽

Phosphorescence Quenching

With advancing age, there is a reduction in exercise tolerance, resulting, in part, from a perturbed ability to match O2 delivery to uptake within skeletal muscle. In the spinotrapezius muscle (which is not recruited during incline treadmill running) of aged rats, we tested the hypotheses that exercise training will 1) improve the matching of O2 delivery to O2 uptake, evidenced through improved microvascular Po2 (PmO2), at rest and throughout the contractions transient; and 2) enhance endothelium-dependent vasodilation in first-order arterioles. Young (Y, ∼6 mo) and aged (O, >24 mo) Fischer 344 rats were assigned to control sedentary (YSED; n = 16, and OSED; n = 15) or exercise-trained (YET; n = 14, and OET; n = 13) groups. Spinotrapezius blood flow (via radiolabeled microspheres) was measured at rest and during exercise. Phosphorescence quenching was used to quantify PmO2 in vivo at rest and across the rest-to-twitch contraction (1 Hz, 5 min) transition in the spinotrapezius muscle. In a follow-up study, vasomotor responses to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) stimuli were investigated in vitro. Blood flow to the spinotrapezius did not increase above resting values during exercise in either young or aged groups. Exercise training increased the precontraction baseline PmO2 (OET 37.5 ± 3.9 vs. OSED 24.7 ± 3.6 Torr, P < 0.05); the end-contracting PmO2 and the time-delay before PmO2 fell in the aged group but did not affect these values in the young. Exercise training improved maximal vasodilation in aged rats to acetylcholine (OET 62 ± 16 vs. OSED 27 ± 16%) and to sodium nitroprusside in both young and aged rats. Endurance training of aged rats enhances the PmO2 in a nonrecruited skeletal muscle and is associated with improved vascular smooth muscle function. These data support the notion that improvements in vascular function with exercise training are not isolated to the recruited muscle.

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