H. Jonathan Groot

Nitric oxide and passive limb movement: a new approach to assess vascular function

•  Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC) without a concomitant increase in skeletal muscle metabolism. •  The peripheral vascular mechanisms associated with the increase in LBF and LVC are unknown. •  Using an intra‐arterial infusion of NG‐monomethyl‐l‐arginine (l‐NMMA) to inhibit nitric oxide synthase (NOS) the hyperaemic and vasodilatory response to passive limb movement was attenuated by nearly 80%. •  This finding demonstrates that the increases in LBF and LVC during passive limb movement are primarily NO dependent. •  Passive limb movement appears to have significant promise as a new approach to assess NO‐mediated vascular function, an important predictor of cardiovascular disease risk.

Group III/IV muscle afferents impair limb blood in patients with chronic heart failure☆ , ☆☆

OBJECTIVE To better understand the hemodynamic and autonomic reflex abnormalities in heart-failure patients (HF), we investigated the influence of group III/IV muscle afferents on their cardiovascular response to rhythmic exercise. METHODS Nine HF-patients (NYHA class-II, mean left ventricular ejection-fraction: 27 ± 3%) performed single leg knee-extensor exercise (25/50/80% peak-workload) under control conditions and with lumbar intrathecal fentanyl impairing μ-opioid receptor-sensitive muscle afferents. RESULTS Cardiac-output (Q) and femoral blood-flow (QL) were determined, and arterial/venous blood samples collected at each workload. Exercise-induced fatigue was estimated via pre/post-exercise changes in quadriceps strength. There were no hemodynamic differences between conditions at rest. During exercise, Q was 8-13% lower with Fentanyl-blockade, secondary to significant reductions in stroke volume and heart rate. Lower norepinephrine spillover during exercise with Fentanyl revealed an attenuated sympathetic outflow that likely contributed to the 25% increase in leg vascular conductance (p<0.05). Despite a concomitant 4% reduction in blood pressure, QL was 10-14% higher and end-exercise fatigue attenuated by 30% with Fentanyl-blockade (p<0.05). CONCLUSION/PRACTICE/IMPLICATIONS Although group III/IV muscle afferents play a critical role for central hemodynamics in HF-patients, it also appears that these sensory neurons cause excessive sympatho-excitation impairing QL which likely contributes to the exercise intolerance in this population.

Passive leg movement and nitric oxide-mediated vascular function: the impact of age

UNLABELLED In young healthy men, passive leg movement (PLM) elicits a robust nitric oxide (NO)-dependent increase in leg blood flow (LBF), thus providing a novel approach to assess NO-mediated vascular function. While the magnitude of the LBF response to PLM is markedly reduced with age, the role of NO in this attenuated response in the elderly is unknown. Therefore, this study sought to determine the contribution of NO in the PLM-induced LBF with age. Fourteen male subjects (7 young, 24 ± 1 yr; and 7 old, 75 ± 3 yr) underwent PLM with and without NO synthase (NOS) inhibition achieved by intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central hemodynamics were measured by finger photoplethysmography. NOS inhibition blunted the PLM-induced peak increase in LBF in the young (control: 668 ± 106; L-NMMA 431 ± 95 Δml/min; P = 0.03) but had no effect in the old (control: 266 ± 98; L-NMMA 251 ± 92 Δml/min; P = 0.59). Likewise, the magnitude of the reduction in the overall (i.e., area under the curve) PLM-induced LBF response to NOS inhibition was less in the old (LBF: -31 ± 18 ml) than the young (LBF: -129 ± 21 ml; P < 0.01). These findings suggest that the age-associated reduction in PLM-induced LBF in the elderly is primarily due to a reduced contribution to vasodilation from NO and therefore support the use of PLM as a novel approach to assess NO-mediated vascular function across the lifespan.

Ascorbate infusion increases skeletal muscle fatigue resistance in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with systemic oxidative stress and skeletal muscle dysfunction. The purpose of this study was to examine the impact of intravenous ascorbate administration (AO) on biological markers of antioxidant capacity and oxidative stress, and subsequently skeletal muscle function during dynamic, small muscle mass exercise in patients with COPD. Ten patients with spirometric evidence of COPD performed single-leg knee extensor (KE) trials matched for intensity and time (isotime) following intravenous ascorbate (2 g) or saline infusion (PL). Quadriceps fatigue was quantified by changes in force elicited by maximal voluntary contraction (MVC) and magnetic femoral nerve stimulation (Qtw,pot). AO administration significantly increased antioxidant capacity, as measured by the ferric-reducing ability of plasma (PL: 1 ± 0.1 vs. AO: 5 ± 0.2 mM), and significantly reduced malondialdehyde levels (PL: 1.16 ± 0.1 vs. AO: 0.97 ± 0.1 mmol). Additionally, resting blood pressure was significantly reduced (PL: 104 ± 4 vs. AO: 93 ± 6 mmHg) and resting femoral vascular conductance was significantly elevated after AO (PL: 2.4 ± 0.2 vs. AO: 3.6 ± 0.4 ml·min(-1)·mmHg(-1)). During isotime exercise, the AO significantly attenuated both the ventilatory and metabolic responses, and patients accumulated significantly less peripheral quadriceps fatigue, as illustrated by less of a fall in MVC (PL: -11 ± 2% vs. AO: -5 ± 1%) and Qtw,pot (PL: -37 ± 1% vs. AO: -30 ± 2%). These data demonstrate a beneficial role of AO administration on skeletal muscle fatigue in patients with COPD and further implicate systemic oxidative stress as a causative factor in the skeletal muscle dysfunction observed in this population.

Perfusion pressure and movement-induced hyperemia: evidence of limited vascular function and vasodilatory reserve with age

To better understand the mechanisms contributing to reduced blood flow with age, this study sought to elucidate the impact of altered femoral perfusion pressure (FPP) on movement-induced hyperemia. Passive leg movement was performed in 10 young (22 ± 1 yr) and 12 old (72 ± 2 yr) healthy men for 2 min, with and without a posture-induced change in FPP (~7 ± 1 ΔmmHg). Second-by-second measurements of central and peripheral hemodynamic responses were acquired noninvasively (finger photoplethysmography and Doppler ultrasound, respectively), with FPP confirmed in a subset of four young and four old subjects with arterial and venous catheters. Central hemodynamic responses (heart rate, stroke volume, cardiac output, mean arterial pressure) were not affected by age or position. The young exhibited a ~70% greater movement-induced peak change in leg blood flow (ΔLBF(peak)) in the upright-seated posture (supine: 596±68 ml/min; upright: 1,026 ± 85 ml/min). However, in the old the posture change did not alter ΔLBF(peak) (supine: 417±42 ml/min; upright: 412±56 ml/min), despite the similar increases in FPP. Similarly, movement-induced peak change in leg vascular conductance was ~80% greater for the young in the upright-seated posture (supine: 7.1 ± 0.8 ml·min(-1)·mmHg(-1); upright: 12.8 ± 1.3 ml·min(-1)·mmHg(-1)), while the old again exhibited no difference between postures (supine: 4.7 ± 0.4 ml·min(-1)·mmHg(-1); upright: 4.8 ± 0.5 ml·min(-1)·mmHg(-1)). Thus this study reveals that, unlike the young, increased FPP does not elicit an increase in movement-induced hyperemia or vasodilation in the old. In light of recent evidence that the majority of the first minute of passive movement-induced hyperemia is predominantly nitric oxide (NO) dependent in the young, these findings in the elderly may be largely due to decreased NO bioavailability, but this remains to be definitively determined.

Further Peripheral Vascular Dysfunction in Heart Failure Patients With a Continuous-Flow Left Ventricular Assist Device: The Role of Pulsatility.

OBJECTIVES Using flow-mediated vasodilation (FMD) and reactive hyperemia (RH), this study aimed to provide greater insight into left ventricular assist device (LVAD)-induced changes in peripheral vascular function. BACKGROUND Peripheral endothelial function is recognized to be impaired in patients with heart failure with reduced ejection fraction (HFrEF), but the peripheral vascular effects of continuous-flow LVAD implantation, now used as either a bridge to transplantation or as a destination therapy, remain unclear. METHODS Sixty-eight subjects (13 New York Heart Association [NYHA] functional class II HFrEF patients, 19 NYHA functional class III/IV HFrEF patients, 20 NYHA functional class III/IV HFrEF patients post-LVAD implantation, and 16 healthy age-matched control subjects) underwent FMD and RH testing in the brachial artery with blood flow velocity, artery diameters, and pulsatility index (PI) assessed by ultrasound Doppler. RESULTS PI was significantly lower in the LVAD group (2.0 ± 0.4) compared with both the HFrEF II (8.6 ± 0.8) and HFrEF III/IV (8.1 ± 0.9) patients, who, in turn, had significantly lower PI than the control subjects (12.8 ± 0.9). Likewise, LVAD %FMD/shear rate (0.09 ± 0.01 %Δ/s(-1)) was significantly reduced compared with all other groups (control subjects, 0.24 ± 0.03; HFrEF II, 0.17 ± 0.02; and HFrEF III/IV, 0.13 ± 0.02 %Δ/s(-1)), and %FMD/shear rate significantly correlated with PI (r = 0.45). RH was unremarkable across groups. CONCLUSIONS Although central hemodynamics are improved in patients with HFrEF by a continuous-flow LVAD, peripheral vascular function is further compromised, which is likely due, at least in part, to the reduction in pulsatility that is a characteristic of such a mechanical assist device.

Oxidative stress and COPD: the effect of oral antioxidants on skeletal muscle fatigue.

PURPOSE Oxidative stress may contribute to exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). This study sought to determine the effect of an acute oral antioxidant cocktail (AOC, vitamins C and E, and alpha-lipoic acid) on skeletal muscle function during dynamic quadriceps exercise in COPD. METHODS Ten patients with COPD performed knee extensor exercise to exhaustion and isotime trials after either the AOC or placebo (PL). Pre- to postexercise changes in quadriceps maximal voluntary contractions and potentiated twitch forces (Q(tw,pot)) quantified quadriceps fatigue. RESULTS Under PL conditions, the plasma electron paramagnetic resonance (EPR) spectroscopy signal was inversely correlated with the forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC), an index of lung dysfunction (r = -0.61, P = 0.02), and maximal voluntary contraction force (r = -0.56, P = 0.04). AOC consumption increased plasma ascorbate levels (10.1 ± 2.2 to 24.1 ± 3.8 μg · mL(-1), P < 0.05) and attenuated the area under the curve of the EPR spectroscopy free radical signal (11.6 ± 3.7 to 4.8 ± 2.2 AU, P < 0.05), but it did not alter the endurance time or quadriceps fatigue. The ability of the AOC to decrease the EPR spectroscopy signal, however, was prominent in those with high basal free radicals (n = 5, PL, 19.7 ± 5.8, to AOC, 5.8 ± 4.5 AU; P < 0.05) with minimal effects in those with low levels (n = 5, PL, 1.6 ± 0.5, to AOC, 3.4 ± 1.1 AU). DISCUSSION These data document a relation between directly measured free radicals and lung dysfunction and the ability of the AOC to decrease oxidative stress in COPD. Acute amelioration of free radicals, however, does not appear to affect dynamic quadriceps exercise performance.

The role of nitric oxide in passive leg movement-induced vasodilatation with age: insight from alterations in femoral perfusion pressure

The passive leg movement (PLM) model is a novel approach to assess vascular function. Increasing femoral perfusion pressure (FPP) by moving from the supine to the upright‐seated posture augments the vasodilatory response to PLM in the young, with no effect in the old, but whether this augmented vasodilatation is nitric oxide (NO) dependent is unknown. Using an intra‐arterial infusion of NG‐monomethyl‐L‐arginine (L‐NMMA) to inhibit nitric oxide synthase (NOS), the posture‐induced increases in the PLM responses in the young were nearly ablated, with no effect of NOS inhibition in the old. Therefore, PLM in combination with alterations in posture can be used to determine changes in NO‐mediated vasodilatation with age, and thus, may be a clinically useful tool for assessing NO bioavailability across the human lifespan.

Impact of Age and Body Position on the Contribution of Nitric Oxide to Femoral Artery Shear Rate: Implications for Atherosclerosis

Reduced shear stress and augmented oscillatory shear rate are associated with the proatherogenic phenotype observed with aging. To date, mechanisms contributing to the age-related alterations in shear rate in humans have only been examined in the conduit vessels of the arm. Therefore, this study sought to examine the contribution of nitric oxide (NO) bioavailability to age-related alterations in shear rate and the impact of common body positions (supine and seated) in the atherosclerotic-prone conduit artery of the leg. Inhibition of NO synthase (NOS) was accomplished by intra-arterial infusion of N G -monomethyl-L-arginine (L-NMMA), and common femoral artery diameter and blood velocity were measured by Doppler ultrasound in healthy young (n=8, 24±1 years) and old (n=8, 75±3 years) men. Old subjects exhibited reduced mean shear rate in the supine (18±3 s−1) and seated positions (17±3 s−1) compared with young subjects (supine: 42±6 s−1; seated: 32±4 s−1). This reduced mean shear in the old was driven by attenuated antegrade shear as there were no differences in retrograde shear. Inhibition of NOS reduced antegrade shear in the young such that age-related differences were abolished. In contrast, NOS-induced reductions in retrograde shear rate were similar between groups. The seated position reduced mean shear rate in the young to that normally observed in old. Overall, this study reveals that age-related reductions in mean shear rate, assessed in the atherosclerotic-prone vasculature of the leg, are largely explained by reductions in antegrade shear as a result of reduced NO bioavailability in the elderly.

Heart failure and movement-induced hemodynamics: partitioning the impact of central and peripheral dysfunction.

BACKGROUND The complex pathophysiology of heart failure (HF) creates a challenging paradigm to differentiate the role of central and peripheral hemodynamic dysfunction during conventional exercise. Adopting a novel reductionist approach with potential clinical relevance, we studied the central and peripheral contributors to both continuous and single passive leg movement (PLM)-induced hyperemia in 14 HF patients with reduced ejection fraction (HFrEF) and 13 controls. METHODS Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and femoral artery blood flow (FBF) were recorded during PLM. RESULTS The FBF response (area under the curve; AUC) to 60s of continuous PLM was attenuated in the HFrEF (25±15ml AUC) compared to controls (199±34ml AUC) as were peak changes from baseline for FBF, leg vascular conductance (LVC), CO, and HR. During single PLM, increases in CO and HR were smaller and no longer different between groups, supporting the use of this modality to assess groups with disparate central hemodynamics. Interestingly, single PLM-induced hyperemia, likely predominantly driven by flow-mediated vasodilation due to minimal vessel deformation, was essentially nonexistent in the HFrEF (-9±10ml AUC) in contrast to the controls (43±25ml AUC). CONCLUSIONS These data fail to support a HFrEF-associated exaggeration in the mechanoreceptor driven component of the exercise pressor response. In fact, by exhibiting limited central hemodynamic responses compared to the controls, the observed attenuation in movement-induced FBF in HFrEF appears largely due to peripheral vascular dysfunction, particularly flow-mediated vasodilation.