Effects of acute hyperoxia on autonomic function and coronary tone in patients with peripheral artery disease.

Numerous studies have shown that oxidative stress plays an important role in peripheral artery disease (PAD). Prior reports suggested autonomic dysfunction in PAD. We hypothesized that responses of the autonomic nervous system and coronary tone would be impaired in patients with PAD during exposure to acute hyperoxia, an oxidative stressor. In 20 patients with PAD and 16 healthy, sex- and age-matched controls, beat-by-beat heart rate (HR, from ECG) and blood pressure (BP, with Finometer) were recorded for 10 min during room air breathing and 5 min of hyperoxia. Cardiovagal baroreflex sensitivity and HR variability (HRV) were evaluated as measures of autonomic function. Transthoracic coronary echocardiography was used to assess peak coronary blood flow velocity (CBV) in the left anterior descending coronary artery. Cardiovagal baroreflex sensitivity at rest was lower in PAD than in healthy controls. Hyperoxia raised BP solely in the patients with PAD, with no change observed in healthy controls. Hyperoxia induced an increase in cardiac parasympathetic activity assessed by the high-frequency component of HRV in healthy controls but not in PAD. Indices of parasympathetic activity were lower in PAD than in healthy controls throughout the trial as well as during hyperoxia. Hyperoxia induced coronary vasoconstriction in both groups, while the coronary perfusion time fraction was lower in PAD than in healthy controls. These results suggest that the response in parasympathetic activity to hyperoxia (i.e., oxidative stress) is blunted and the coronary perfusion time is shorter in patients with PAD.NEW & NOTEWORTHY Patients with peripheral artery disease (PAD) showed consistently lower parasympathetic activity and blunted cardiovagal baroreflex sensitivity compared with healthy individuals. Notably, hyperoxia, which normally boosts parasympathetic activity in healthy individuals, failed to induce this response in patients with PAD. These data suggest altered autonomic responses during hyperoxia in PAD.

Aortic blood pressure and pulse wave indices responses to exercise in peripheral artery disease.

Peripheral artery disease (PAD) refers to obstructed blood flow in peripheral arteries typically due to atherosclerotic plaques. How PAD alters aortic blood pressure and pressure wave propagation during exercise is unclear. Thus, this study examined central blood pressure responses to plantar flexion exercise by investigating aortic pulse wave properties in PAD. Thirteen subjects with PAD and 13 healthy [age-, sex-, body mass index (BMI) matched] subjects performed rhythmic plantar flexion for 14 min or until fatigue (20 contractions/min; started at 2 kg with 1 kg/min increment up to 12 kg). Brachial (oscillometric cuff) and radial (SphygmoCor) blood pressure and derived-aortic waveforms were analyzed during supine rest and plantar flexion exercise. At rest, baseline augmentation index (P = 0.0263) and cardiac wasted energy (P = 0.0321) were greater in PAD due to earlier arrival of the reflected wave (P = 0.0289). During exercise, aortic blood pressure (aMAP) and aortic pulse pressure showed significant interaction effects (P = 0.0041 and P = 0.0109, respectively). In particular, PAD had a greater aMAP increase at peak exercise (P = 0.0147). Moreover, the tension time index was greater during exercise in PAD (P = 0.0173), especially at peak exercise (P = 0.0173), whereas the diastolic time index (P = 0.0685) was not different between the two groups. Hence, during exercise, the subendocardial viability ratio was lower in PAD (P = 0.0164), especially at peak exercise (P = 0.0164). The results suggest that in PAD, the aortic blood pressure responses and myocardial oxygen demand during exercise are increased compared with healthy controls.

Renal medullary oxygenation decreases with lower body negative pressure in healthy young adults.

One in three Americans suffer from kidney diseases such as chronic kidney disease, and one of the etiologies is suggested to be long-term renal hypoxia. Interestingly, sympathetic nervous system activation evokes a renal vasoconstrictor effect that may limit oxygen delivery to the kidney. In this report, we sought to determine if sympathetic activation evoked by lower body negative pressure (LBNP) would decrease cortical and medullary oxygenation in humans. LBNP was activated in a graded fashion (LBNP; -10, -20, and -30 mmHg), as renal oxygenation was measured (T2*, blood oxygen level dependent, BOLD MRI; n = 8). At a separate time, renal blood flow velocity (RBV) to the kidney was measured (n = 13) as LBNP was instituted. LBNP significantly reduced RBV (P = 0.041) at -30 mmHg of LBNP (Δ-8.17 ± 3.75 cm/s). Moreover, both renal medullary and cortical T2* were reduced with the graded LBNP application (main effect for the level of LBNP P = 0.0008). During recovery, RBV rapidly returned to baseline, whereas medullary T2* remained depressed into the first minute of recovery. In conclusion, sympathetic activation reduces renal blood flow and leads to a significant decrease in oxygenation in the renal cortex and medulla.NEW & NOTEWORTHY In healthy young adults, increased sympathetic activation induced by lower body negative pressure, led to a decrease in renal cortical and medullary oxygenation measured by T2*, a noninvasive magnetic resonance derived index of deoxyhemoglobin levels. In this study, we observed a significant decrease in renal cortical and medullary oxygenation with LBNP as well as an increase in renal vasoconstriction. We speculate that sympathetic renal vasoconstriction led to a significant reduction in tissue oxygenation by limiting oxygen delivery to the renal medulla.

Patients With Peripheral Arterial Disease With Exaggerated Pressor Response Have Greater Ambulatory Dysfunction Than Patients With Lower Pressor Response.

We determined whether patients with peripheral arterial disease (PAD) who have either an exaggerated or a negative pressor response during treadmill walking have shorter peak walking time (PWT) and claudication onset time (COT) than patients with a normal pressor response, independent of comorbid conditions. A total of 249 patients were categorized to 1 of 3 groups based on systolic blood pressure (SBP) responses at 2 minutes of treadmill walking (speed = 2 mph, grade = 0%): group 1 (negative pressor response, SBP < 0 mm Hg), group 2 (normal pressor response, SBP 18 mm Hg), and group 3 (exaggerated pressor response, SBP > 18 mm Hg). After adjusting for comorbid conditions, group 3 (exaggerated) had significantly reduced COT (P = .011) and PWT (P = .002) compared to group 2 (normal), while group 1 (negative) and group 2 (normal) were not different. Patients with symptomatic PAD with an increase in SBP > 18 mm Hg after 2 minutes of treadmill walking experience claudication earlier and thus have greater ambulatory dysfunction, compared to patients with PAD with a normal pressor response, whereas patients with PAD with negative pressor response had a similar walking performance. The implication is that the magnitude of pressor response to only 2 minutes of treadmill walking can partially explain the degree of ambulatory dysfunction in patients with PAD.

Systemic and regional hemodynamic response to activation of the exercise pressor reflex in patients with peripheral 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 (SmO2) 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, SmO2 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.

Vascular Inflammation, Calf Muscle Oxygen Saturation, and Blood Glucose are Associated With Exercise Pressor Response in Symptomatic Peripheral Artery Disease.

We determined whether calf muscle oxygen saturation (StO2) and vascular biomarkers of inflammation and oxidative stress were associated with an exercise pressor response during treadmill walking in 179 patients with symptomatic peripheral artery disease (PAD). The exercise pressor response was measured as the change in blood pressure from rest to the end of the first 2-minute treadmill stage (2 mph, 0% grade). There was a wide range in the change in systolic blood pressure (-46 to 50 mm Hg) and in diastolic blood pressure (-23 to 38 mm Hg), with mean increases of 4.3 and 1.4 mm Hg, respectively. In multiple regression analyses, significant predictors of systolic pressure included glucose (P < .001) and insulin (P = .039). Significant predictors of diastolic pressure included cultured endothelial cell apoptosis (P = .019), the percentage drop in exercise calf muscle (StO2; P = .023), high-sensitivity C-reactive protein (P = .032), and glucose (P = .033). Higher levels in pro-inflammatory vascular biomarkers, impaired calf muscle StO2 during exercise, and elevated blood glucose were independently associated with greater exercise pressor response in patients with symptomatic PAD. The clinical implication is that exercise and nutritional interventions designed to improve inflammation, microcirculation, and glucose metabolism may also lower blood pressure during exercise in patients with symptomatic PAD.

Effects of acute dietary nitrate supplementation on aortic blood pressures and pulse wave characteristics in post-menopausal women.

PURPOSE: Consumption of nitrate-rich beetroot juice can lower blood pressure in peripheral as well as central arteries and may exert additional hemodynamic benefits (e.g. reduced aortic wave reflections). The specific influence of nitrate supplementation on arterial pressures and aortic wave properties in postmenopausal women, a group that experiences accelerated increases in these variables with age, is unknown. Accordingly, the primary aim of this study was to determine the effect of consuming nitrate-rich beetroot juice on resting brachial and aortic blood pressures (BP) and pulse wave characteristics in a group of healthy postmenopausal women, in comparison to a true (nitrate-free beetroot juice) placebo. METHODS: Brachial (oscillometric cuff) and radial (SphygmoCor) pressures and derived-aortic waveforms were measured during supine rest in thirteen healthy postmenopausal women (63 ±â€¯1 yr) before and 100 min after consumption of 140 ml of either nitrate-rich (9.7 mmol, 0.6 gm NO3-) or nitrate-depleted beetroot juice on randomized visits approximately 10 days apart (cross-over design). Ten young premenopausal women (22 ±â€¯1 yr) served as a reference (non-supplemented) cohort. RESULTS: Brachial and derived-aortic variables showed the expected age-associated differences in these women (all p < 0.05). In post-menopausal women, nitrate supplementation reduced (p < 0.05 vs. placebo visit) brachial systolic BP (BRnitrate -4.9 ±â€¯2.1 mmHg vs BRplacebo +1.1 ± 1.8 mmHg), brachial mean BP (BRnitrate -4.1 ±â€¯1.7 mmHg vs BRplacebo +0.9 ± 1.3 mmHg), aortic systolic BP (BRnitrate -6.3 ±â€¯2.0 mmHg vs BRplacebo +0.5 ± 1.7 mmHg) and aortic mean BP (BRnitrate -4.1 ±â€¯1.7 mmHg vs BRplacebo +0.9 ± 1.3 mmHg), and increased pulse pressure amplification (BRnitrate +4.6 ± 2.0% vs BRplacebo +0.7 ± 2.5%, p = 0.04), but did not alter aortic pulse wave velocity or any other derived-aortic variables (e.g., augmentation pressure or index). CONCLUSIONS: Dietary nitrate supplementation favorably modifies aortic systolic and mean blood pressure under resting conditions in healthy postmenopausal women. Acute supplementation of nitrate does not, however, appear to restore indices of aortic stiffness in this group. Future work should evaluate chronic, long-term effects of this non-pharmacological supplement.

Retrograde and oscillatory shear increase across the menopause transition.

Declines in endothelial function can take place rapidly across the menopause transition, placing women at heightened risk for atherosclerosis. Disturbed patterns of conduit artery shear, characterized by greater oscillatory and retrograde shear, are associated with endothelial dysfunction but have yet to be described across menopause. Healthy women, who were not on hormone therapy or contraceptives, were classified into early perimenopausal, late perimenopausal, and early postmenopausal stage. Resting antegrade, retrograde, and oscillatory shear were calculated from blood velocity and diameter measured in the brachial and common femoral artery using Doppler ultrasound. Serum was collected for measurements of estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone. After adjusting for age, brachial artery oscillatory shear was significantly higher in early postmenopausal women (n = 15, 0.17 ± 0.08 a.u.) than both early (n = 12, 0.08 ± 0.05 a.u., P < 0.05) and late (n = 8, 0.08 ± 0.04 a.u) perimenopausal women, and retrograde shear was significantly greater in early postmenopausal versus early perimenopausal women (-19.47 ± 12.97 vs. -9.62 ± 6.11 sec-1 , both P < 0.05). Femoral artery oscillatory and retrograde shear were greater, respectively, in early postmenopausal women (n = 15, 0.19 ± 0.08 a.u.; -13.57 ± 5.82 sec-1 ) than early perimenopausal women (n = 14, 0.11 ± 0.08 a.u.; -8.13 ± 4.43 sec-1 , P < 0.05). Further, Pearson correlation analyses revealed significant associations between FSH and both retrograde and oscillatory shear, respectively, in the brachial (r = -0.40, P = 0.03; r = 0.43, P = 0.02) and common femoral artery (r = -0.45, P = 0.01; r = 0.56, P = 0.001). These results suggest menopause, and its associated changes in reproductive hormones, adversely influences conduit arterial shear rate patterns to greater oscillatory and retrograde shear rates.

Greater Exercise Pressor Response Is Associated With Impaired Claudication Outcomes in Symptomatic Peripheral Artery Disease.

We determined whether a greater exercise pressor response during a constant-load treadmill test was associated with lower peak walking time (PWT) and claudication onset time (COT) measured during a graded maximal treadmill test in 304 patients with symptomatic peripheral artery disease (PAD). The exercise pressor response was assessed by measuring heart rate and blood pressure (BP) at rest and during a constant-load treadmill test (speed = 2 mph, grade = 0%). After only 2 minutes of walking, mean heart rate increased by 26 beats/min from rest and mean systolic BP increased by 16 mm Hg. In adjusted analyses, increases in systolic BP (P = .021), heart rate (P = .002), mean arterial pressure (P = .034), and rate-pressure product (P < .001) from rest to 2 minutes of constant-load exercise were negatively associated with COT. Similarly, increases in heart rate (P = .012) and rate-pressure product (P = .018) from rest to 2 minutes of constant-load exercise were negatively associated with PWT. A greater exercise pressor response observed after only 2 minutes of walking at no incline was independently associated with impaired claudication outcomes in patients with symptomatic PAD. The implication is that the exercise pressor response is an important and easily obtained clinical measurement that partially explains differences in PWT and COT.

Peripheral revascularization attenuates the exercise pressor reflex and increases coronary exercise hyperemia in peripheral arterial disease.

Peripheral arterial disease (PAD) is associated with augmented blood pressure (BP) and impaired coronary blood flow responses to exercise, which may increase cardiovascular risk. We investigated the effects of leg revascularization on the BP and coronary blood flow responses to exercise in PAD. Seventeen PAD patients (11 men, 66 ± 2 yr) performed single-leg plantar flexion exercise 24 h before and 1 mo following leg revascularization. BP and heart rate (HR) were measured continuously, and rate pressure product (systolic BP × HR) was calculated as an index of myocardial oxygen demand. Coronary blood velocity was obtained by transthoracic Doppler echocardiography in 8/17 subjects. The mean BP response to plantar flexion exercise was attenuated by leg revascularization (pre-revascularization: 15 ± 4 vs. post-revascularization: 7 ± 3 mmHg, P = 0.025). The HR response to plantar flexion was also attenuated following leg revascularization (pre-revascularization: 9 ± 1 vs. post-revascularization: 6 ± 1 beats/min, P = 0.006). The change in coronary blood velocity with exercise was greater at the post-revascularization visit: 4 ± 1 vs. pre-revascularization: -1 ± 2 cm/s ( P = 0.038), even though the change in rate pressure product was not greater following revascularization in these subjects (pre-revascularization: 2,796 ± 871 vs. post-revascularization: 1,766 ± 378 mmHg·beats/min, P = 0.082). These data suggest that leg revascularization alters reflex control of BP, HR, and coronary blood flow in response to exercise in patients with PAD. NEW & NOTEWORTHY We found that peripheral revascularization procedures lowered exercise blood pressure and improved coronary blood flow in patients with peripheral arterial disease.

Blood pressure and leg deoxygenation are exaggerated during treadmill walking in patients with peripheral artery disease.

The purpose of this study was to investigate blood pressure (BP) and leg skeletal muscle oxygen saturation (Smo2) during treadmill walking in patients with peripheral artery disease (PAD) and healthy subjects. Eight PAD patients (66 ± 8 yr, 1 woman) and eight healthy subjects (65 ± 7 yr, 1 woman) walked on a treadmill at 2 mph (0.89 m/s). The incline increased by 2% every 2 min, from 0 to 15% or until maximal discomfort. BP was measured every 2 min with an auscultatory cuff. Heart rate (HR) was recorded continuously with an ECG. Smo2 in the gastrocnemius muscle was measured on each leg using near-infrared spectroscopy. The change in systolic BP from seated to peak walking time (PWT) was greater in PAD (healthy: 23 ± 9 vs. PAD: 44 ± 19 mmHg, P = 0.007). HR was greater in PAD patients compared with controls at PWT (P = 0.011). The reduction in Smo2 (PWT - seated) was greater in PAD (healthy: 15 ± 12 vs. PAD: 49 ± 5%, P < 0.001) in the most affected leg and in the least affected leg (healthy: 12 ± 11 vs. PAD: 32 ± 18%, P = 0.003). PAD patients have an exaggerated decline in leg Smo2 during walking compared with healthy subjects, which may elicit the exaggerated rise in BP and HR during walking in PAD.NEW & NOTEWORTHY This is the first study to simultaneously measure skeletal muscle oxygen saturation and blood pressure (BP) during treadmill exercise in patients with peripheral arterial disease. We found that BP and leg deoxygenation responses to slow-paced, graded treadmill walking are greater in patients with peripheral arterial disease compared with healthy subjects. These data may help explain the high cardiovascular risk in patients with peripheral arterial disease.