Pain-free Distance Research Articles

Cardiac autonomic associations on exercise and ambulatory capacity in individuals with lower-extremity artery disease

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was in part supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2019/19596-7), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq #303399/2018-0). OnBehalf Exercise and Chronic Disease Research Laboratory - Bauru, Brazil; Research Group for Cardiovascular Rehabilitation - Leuven, Belgium. INTRODUCTION Lower-extremity artery disease (LEAD) characterized by progressive atherosclerotic build-up in leg arteries is becoming increasingly prevalent, affecting more than 200 million people worldwide. In line with other atherosclerotic disorders, LEAD is often associated with autonomic dysfunction as evidenced by a reduced heart rate variability (HRV). To date, little is known on the impact of cardiac autonomic function on exercise and ambulatory capacity. PURPOSE We aimed to investigate whether autonomic function is associated with ambulatory capacity and exercise capacity in patients with LEAD. METHODS Thirty-four patients (age≥17 years) diagnosed with LEAD (ankle brachial index: ABI ≤ 0.9 and/or 20% decrease after a maximal treadmill test) suffering from intermittent claudication (Rutherford I-III) were recruited in the PROSECO-IC trial. Patients were grouped based on beta-blocker medication (β-blocker and non β-blocker). Intervals between R waves (i-RR) obtained by heart rate (HR) signal were acquired beat-to-beat via a digital telemetry system (Polar®️ H10) during 15 min of supine rest and were used for 5-minute HRV analysis. Time domain indexes (mean i-RR, SNDD, pNN50%), and frequency domains (high frequency band (HF), low frequency (LF, very LF (VLF)) and the ratio (LF/HF). HRV was analyzed in absolute (abs), normalized (nu) and log units (log). Ambulatory capacity was assessed by means of a submaximal treadmill test, graded maximal treadmill test using Gardner protocol (GTM) and 6 minutes walking test (6MWT); exercise capacity was assessed by means of a graded maximal cardiopulmonary exercise test (HR, blood pressure (BP) and peak oxygen uptake (VO2peak)) at resting, 2 minutes, and peak of exercise. RESULTS Pearson test showed that sympathetic modulation indexes were moderate associated with pain free distance in GTM (LF/HF: r = 0.52, p = 0.04), and pain free time in 6MWT (LFlog: r=-0.62, p = 0.01; VLF: r=-0.52, p = 0.04), respectively, in patients without β-blocker. Similar HR associations with HRV (time and frequency domain) were observed during submaximal treadmill test and cardiopulmonary exercise test (p ≤ 0.05). Test-t demonstrated a significantly increased response intra-groups in HR and BP during both tests (p ≤ 0.05). Average BP were positive associated with the earlier stages of the cardiopulmonary test (resting to 2 min) with LFlog (r = 0.70, p= <0.001) in β-blocker while non-β-blocker were associated from 2 min to peak with LFabs (r = 0.67, p= <0.001) and LF/HF (r = 0.52, p = 0.03). CONCLUSION Sympathetic modulation was correlated with a longer pain free walking capacity in non-β-blockers. Yet, individuals treated by -β-blockers showed an earlier sympathetic modulation through exercise pressor response during the first stages of cardiopulmonary exercise compared to non-β-blockers with LEAD.

EXPLORING ASSOCIATIONS BETWEEN HEART RATE VARIABILITY AND EXERCISE TOLERANCE IN INDIVIDUALS WITH PERIPHERAL ARTERY DISEASE

Objective: Lower-extremity artery disease (LEAD) characterized by a progressive atherosclerotic build-up in leg arteries affects more than 200 million people worldwide. LEAD is often associated with autonomic dysfunction as evidenced by a reduced heart rate variability (HRV). We aimed to investigate whether the autonomic function is associated with ambulatory capacity and exercise capacity in patients with LEAD. Design and method: Thirty-four patients (age > 17 years) diagnosed with LEAD (ABI < 0.9 and/or 20% decrease after a maximal treadmill test) suffering from intermittent claudication (Rutherford I-III) were recruited in the PROSECO-IC trial. Patients were grouped based on beta-blocker medication (B-blocker and non-B-blocker). Intervals between R waves (i-RR) obtained by heart rate (HR) signal were acquired beat-to-beat (Polar®H10) during 15 min of supine rest and were used for 5-minute HRV analysis. Time-domain indexes (mean i-RR, SDDD)and frequency domains (high-frequency band (HF), low frequency (LF, very LF (VLF)), and the ratio (LF/HF). Ambulatory capacity was assessed by a submaximal treadmill test, graded maximal treadmill test using Gardner protocol (GTM), and 6 minutes walking test (6MWT); exercise capacity was assessed by graded maximal cardiopulmonary exercise test (HR, blood pressure (BP) and peak oxygen uptake (VO2peak)) at resting, 2 minutes and the peak of exercise. Results: Pearson test showed that sympathetic modulation indexes were moderately associated with pain-free distance in GTM (LF/HF: r = 0.52, p = 0.04) and pain-free time in 6MWT (LFlog: r = -0.62, p = 0.01; VLF: r = -0.52, p = 0.04), respectively, in patients without B-blocker. Similar HR associations with HRV (time and frequency domain) were observed during the submaximal treadmill test and cardiopulmonary exercise test (p < 0.05). Test-t demonstrated a significantly increased response intra-groups in HR and BP during both tests (p < 0.05). Average BP was positive associated with the earlier stages of the cardiopulmonary test (resting to 2 min) with LFlog (r = 0.70, p = < 0.001) in B-blocker while non-B-blocker were associated from 2 min to peak with LFabs (r = 0.67, p = < 0.001) and LF/HF (r = 0.52, p = 0.03). Conclusions: Sympathetic modulation was correlated with a longer pain-free walking capacity in non-B-blockers. Yet, individuals treated by -B-blockers showed an earlier sympathetic modulation through exercise pressor response during the first stages of cardiopulmonary exercise compared to non-B-blockers.

The Unusual Improvement of Intermittent Claudication Distance in Patient with Peripheral Arterial Disease Utilizing “2/3 Claudication Distance” Protocol of Exercise Training

Peripheral arterial disease (PAD) affects 12% - 20% of the population over 65 years. PAD is a component of systemic atherosclerosis and is associated with increased rate of all-cause mortality and cardiovascular events, compared with those without PAD. The strongest risk factors for PAD are older age and cigarette smoking. PAD accelerates functional decline leading to physical disability. Many randomized clinical trials demonstrated that treadmill walking training increases pain-free and maximal walking distances in patients with PAD. Exercise intervention is strongly recommended for patients with PAD and symptoms of intermittent claudication (IC). The need to provide an exercise training program to patients with peripheral arterial disease is essential, as almost half of these patients will eventually develop coronary artery disease. There are many existing treadmill walking protocols for patients with PAD. Most of these are based on claudication severity. We present a case of significant improvement of pain-free distance and maximum treadmill walking distance in a patient with PAD after 12 weeks of walking training program utilizing the “2/3 claudication distance” formula.

Abstract 20913: Endothelial Cell Inflammation and Antioxidant Capacity Are Associated With 6-Minute Walk Performance in Patients With Symptomatic Peripheral Artery Disease

Introduction: The aim of the study was to determine whether 6-minute walk total distance and pain-free distance were associated with circulating biomarkers of antioxidant capacity and inflammation, and with endothelial cell inflammation, oxidative stress, and apoptosis in patients with symptomatic peripheral artery disease (PAD). Methods: Exercise performance in 251 patients was assessed by pain-free distance and total distance covered during a 6-minute walk test. Patients were further characterized on clinical characteristics, on circulating biomarkers of antioxidant capacity and inflammation, and on the endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells. Results: In a multivariate regression model, pain-free distance during the 6-minute walk test was negatively associated with dyslipidemia (p<0.001), chronic kidney disease (p=0.004), and NF-κB (p=0.007), and was positively associated with height (p=0.008). In multivariate analyses, total distance walked during the 6-minute walk test was negatively associated with NF-κB (p< 0.001), coronary artery disease (p=0.009), and BMI (p=0.022), and was positively associated with ABI (p<0.001), male sex (p<0.001), and hydroxyl radical antioxidant capacity (p<0.001). Conclusions: 6-minute walk performance in symptomatic patients with PAD was associated with vascular biomarkers, as walking distances were negatively associated with endothelial cell inflammation and positively associated with circulating antioxidant capacity. The clinical implication is that behavioral interventions designed to alleviate endothelial cell inflammation and increase circulating antioxidant capacity, such as exercise and antioxidant intake, may improve ambulatory ability in patients with PAD during submaximal exercise that is typically performed during daily activities.

Endothelial Cell Inflammation and Antioxidant Capacity are Associated With 6-Minute Walk Performance in Patients With Symptomatic Peripheral Artery Disease.

We determined whether 6-minute walk total distance and pain-free distance were associated with circulating biomarkers of antioxidant capacity and inflammation and with cultured endothelial cell inflammation, oxidative stress, and apoptosis in 251 patients with symptomatic peripheral artery disease (PAD). In multivariate analyses, pain-free distance during the 6-minute walk test was negatively associated with dyslipidemia ( P < .001), chronic kidney disease ( P = .004), and transient transfection, nuclear factor κ-Light-Chain-Enhancer of activated B (NF-κB) cultured endothelial cells ( P = .007) and was positively associated with height ( P = .008). Furthermore, total distance walked during the 6-minute walk test was negatively associated with cultured endothelial cell NF-κB ( P < .001), coronary artery disease ( P = .009), and body mass index ( P = .022) and was positively associated with ankle-brachial index ( P < .001), male sex ( P < .001), and hydroxyl radical antioxidant capacity ( P < .001). The 6-minute walk performance in symptomatic patients with PAD was associated with vascular biomarkers, as walking distances were negatively associated with cultured endothelial cell inflammation and positively associated with circulating antioxidant capacity. The clinical implication is that behavioral interventions designed to alleviate endothelial cell inflammation and increase circulating antioxidant capacity, such as exercise and antioxidant intake, may improve ambulation of patients with PAD during submaximal exercise that is typically performed during daily activities.

Abstract 11: Effects of Canakinumab in Patients With Peripheral Artery Disease

Background: Peripheral artery disease (PAD) affects 8.5 million people in the US. PAD patients are at high risk for cardiovascular events, and their quality of life is often significantly impaired by decreased mobility. Interleukin-1β (IL-1β) may play an important role in this disease by promoting inflammatory responses that drive atherosclerotic plaque progression and impair vascular function. We sought to test whether interruption of IL-1β signaling would improve patient mobility and decrease plaque progression in the lower extremities. Methods: 38 patients (mean age 65; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive Canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. Plaque volume in the superficial femoral artery (SFA) was assessed serially using 3.0T MRI. Mobility was assessed serially using the 6-minute walk test (maximum and pain-free walking distance). Results: Canakinumab was safe and well-tolerated. 12 patients discontinued (8 placebo, 4 Canakinumab). MRI data (from 31 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA at either time point in placebo-treated patients; nor was there a change in plaque volume in the Canakinumab-treated group. There was a serial and significant improvement in placebo-adjusted maximum and pain-free walking distance observed as early as 3 months after treatment with Canakinumab (58-meter improvement over placebo in pain-free distance at 3 months, P=0.01). Two placebo-treated patients required peripheral vascular interventions due to progression of disease; however, no Canakinumab-treated patients required revascularization during the study. Canakinumab decreased markers of systemic inflammation (IL-6 and hsCRP). Conclusions: Treatment with Canakinumab may improve maximum and pain-free walk distance in patients with symptomatic PAD. In conjunction with results soon to be reported for the CANTOS trial of Canakinumab for secondary prevention of cardiovascular events, additional studies may provide support that inhibition of IL-1β signaling can improve symptoms and function in this patient population with high unmet need.

Lower functional capacity is associated with higher cardiovascular risk in Brazilian patients with intermittent claudication

The purpose of this study was to examine the association between cardiovascular risk estimated by the Framingham Risk Score and functional capacity in patients with peripheral artery disease using a 6-minute walk test. Fifty-six participants with intermittent claudication were recruited. The Framingham Risk Score was calculated and used to split the participants into two groups: Group A (mild and moderate risk) and group B (severe risk). The ankle-brachial index (ABI) was calculated for each leg using a handheld Doppler probe. Walking ability was verified by a 6-minute walk test. Descriptive statistics were used to describe the sample's demographic and clinical characteristics. To compare clinical data between the two groups, a t test or Mann-Whitney test was used as appropriate according to the type of variable being analyzed. The Pearson coefficient was used to verify the association between cardiovascular risk and functional capacity. Group A had 19 participants (60.5 ± 6.3 years; 36.8% male) and group B had 37 participants (63.4 ± 8.7 years; 73% male). No differences were observed when comparing the ABI between both groups. The total distances covered by the men in group A were shorter compared with those of group B (331.4 + 51.5 vs 257.9 + 84.0; P = .02). The cardiovascular risk score was negative and was significantly correlated with total distances for men (r = -0.53; P = .001) and with pain-free distances for women (r = -0.46; P = .03). Functional capacity, evaluated through a 6-minute walk test, seems to be associated with 10-year total mortality risk.

Vascular Reactivity is Impaired and Associated With Walking Ability in Patients With Intermittent Claudication.

We verified whether vascular reactivity is impaired and whether there is any association between vascular reactivity, walking ability, and peripheral artery disease (PAD) severity in patients with intermittent claudication (IC). We studied 63 patients and 17 age- and sex-matched volunteers without PAD. Vascular reactivity was evaluated in the brachial artery during reactive hyperemia (flow-mediated dilation [FMD]) and after a sublingual single dose of nitroglycerin (nitroglycerin-induced vasodilation [NID]). Walking ability was verified by a 6-minute walk test. Vascular reactivity and walking ability were significantly worse in patients with IC compared with control participants. The ankle-brachial index correlated with FMD, NID, as well as total and pain-free distances. The NID and walking ability progressively decreased as PAD severity increased. Walking ability correlated with NID but not with FMD. In patients with IC, vascular reactivity is impaired and is related to the severity of PAD and to walking ability.

Gender and racial differences in endothelial oxidative stress and inflammation in patients with symptomatic peripheral artery disease

We compared (1) cellular reactive oxygen species (ROS) production, inflammation, and apoptosis of cultured endothelial cells treated with sera and (2) circulating inflammatory measures, antioxidant capacity, vascular biomarkers, and calf muscle hemoglobin oxygen saturation (StO2) in men and women with peripheral artery disease (PAD). A secondary aim was to compare exercise performance and daily ambulatory activity between men and women. We hypothesized that women would have more impaired endothelial cellular ROS, inflammation, and apoptosis than men as well as worse systemic inflammation, antioxidant capacity, vascular biomarkers, calf muscle StO2, exercise performance, and daily ambulatory activity. The 148 symptomatic men and women with PAD were characterized on the endothelial effects of circulating factors present in the sera by a cell culture-based bioassay on primary human arterial endothelial cells. Patients were further evaluated by circulating inflammatory and vascular biomarkers, physical examination and medical history, exercise performance, and calf muscle StO2 during exercise, and ambulatory activity was monitored during 1 week. Cellular ROS production was higher in African American women than in men (P = .021), but there was no gender difference in white individuals (P = .537). Men and women were not significantly different on endothelial cell apoptosis (P = .833) and nuclear factor κB activity (P = .465). For circulating factors, additional gender differences were found when comparisons were made within each race. In African Americans, women had higher intercellular adhesion molecule 1 (P = .022) and leptin (P < .001); whereas in white individuals, women had higher matrix metallopeptidase 9 (P = .047), higher vascular cell adhesion molecule 1 (P = .047), and lower hepatocyte growth factor (P = .046). Overall, women had higher apolipoprotein CIII (P = .035), lower pain-free distance (P = .048) and total distance (P < .001) during the 6-minute walk test, shorter time for calf muscle StO2 to reach the minimum value during exercise (P = .027), and slower average cadence (P = .004) during daily ambulation. African American women with symptomatic PAD have a heightened oxidative status, likely resulting in increased endothelial oxidative stress, compared with men. Furthermore, women exhibit a more pronounced proinflammatory profile of circulating biomarkers as well as more limited peripheral microcirculation, exercise performance, and ambulatory activity than men do. The clinical significance is that women with symptomatic PAD are in greater need than men of clinical intervention to improve oxidative stress, inflammation, and microcirculation, which may in turn have a favorable impact on their lower exercise performance and daily activity.

Use of a three-curved rocker sole shoe modification to improve intermittent claudication calf pain — A pilot study

This was a pilot study utilizing hospital-based walking trials to compare two footwear conditions. Two pairs of identical therapeutic shoes were ordered for volunteer claudicant subjects. One pair was adapted with a specifically designed three-curve rocker sole. Volunteer claudicant subjects (n = 8, mean age 66 +/- 9.9 years) with stable pain-free distances of 10-400 meters to calf claudication pain were recruited into the study. Walking trials were used to compare differences in both the pain-free distance to claudication and the intensity of the calf pain once claudicating exhibited by each subject while walking separately with the two footwear conditions during the same clinical session. The results demonstrated that claudicant pain-free walking distance was increased, and the intensity of claudication calf pain reduced when walking with the rocker-soled in comparison with baseline. A specifically designed rocker sole has the potential to offer a reduction in the intensity of calf pain experienced by claudicants. A more extensive study is planned to determine the efficacy of this new footwear adaptation when the footwear is worn for extended periods.

Clinical and microcirculatory effects of transcutaneous CO2 therapy in intermittent claudication. Randomized double-blind clinical trial with a parallel design

This randomized, double blind trial determined the short and long-term clinical and hemodynamic vasodilator effects induced by percutaneous applications of natural CO2 gas in patients with moderate Fontaine stage II. 62 patients with intermittent claudication (100-500 meters) were randomized to 18 consecutive days of CO2 treatment or placebo (air). The gas fluids were applied at a constant temperature of 30 degrees C on pre-humidified skin. The effects of the treatment were evaluated by total distance walked (primary criterion) and hemodynamic and microcirculatory findings. Patients also answered a quality of life questionnaire. The Strandness test showed a significant increase in total distance walked (+ 131 meters, 66%; p = 0.001) and pain-free distance (+ 81 meters, 73%; p = 0.02) after 18 days of CO2 treatment. The improvement was maintained 3 and 12 months later. The systolic pressure index (ABI) increased by 37% (p = 0.001) 1 minute after treadmill walking and ABI recovery time decreased significantly by 38% (p = 0.002). Microcirculatory findings showed an increase in systolic pressure of the great toe (13%; p < 0.0001), in baseline pO2 (20%; p = 0.01) and in vasomotion (78%; p = 0.001) in the treatment group. The improvement in total walking distance was correlated with the increase in ABI and peripheral cutaneous oxygenation. Patients' subjective assessments corroborated the benefits. No significant change was observed in the placebo group. This study demonstrates that 18 consecutive days of percutaneous CO2 treatment significantly increases walking distance in patients with moderate intermittent claudication. This effect, which was associated with an increase in peripheral systolic pressure and pO2, is evidence of a better ability to withstand effort.

Experimental Model of Short-Time Exercise-Induced Preconditioning in POAD Patients

Regular physical exercise improves walking performance in patients affected with peripheral obliterative arterial disease (POAD). The mechanisms underlying the phenomenon are still controversial. In order to verify the hypothesis that physical conditioning of lower limbs on a treadmill and ischemic preconditioning of the heart could share some biological aspects, 14 POAD subjects underwent a training program on the treadmill consisting of five repeated submaximal exercises at five-minute and two-hour intervals preceding the maximal tolerance test. Moreover, a protocol with two daily submaximal walking exercises over one week was also performed. Pain-free and total walking distance were measured before and after they performed the program. Moreover, plasma levels of adenosine and adenosine triphosphate (ATP) were measured and polymorphonuclear (PMN) leukocyte activity was studied together with rheologic parameters. Pain-free distance was prolonged by 15.4% and 14.3%, and total distance was prolonged by 23.1% and 26.9%, in the exercises with five-minute and two-hour intervals, respectively. After one week of daily exercises, the onset of pain and the end of the test were delayed by 24% and 43.7%, respectively. An improvement in blood rheology and a reduced PMN reactivity were also observed with the three protocols, associated with an increase in plasma levels of adenosine and ATP. Similarly to ischemic preconditioning in the heart, the possibility is suggested that an adenosine-mediated mechanism may contribute to the development of physical conditioning in treadmill-trained POAD patients.

A multicenter study of doxazosin in the treatment of patients with mild or moderate essential hypertension and concomitant intermittent claudication

This study assessed the efficacy and safety of once-daily doxazosin in the treatment of patients ( n = 19) with mild or moderate essential hypertension (sitting diastolic blood pressure [DBP] 95 to 114 mm Hg) and concomitant intermittent claudication (Doppler ankle/arm ratio of <0.80 and walking tolerance of <700 m on the treadmill). After 14 weeks of treatment with doxazosin, a significant ( p < 0.05) reduction in systolic blood pressure and DBP was observed. Mean blood pressures were reduced from 170 100 mm Hg at baseline to 161 93 mm Hg at the end of treatment. Minor changes in heart rate occurred, which with continued treatment were not statistically significant from baseline. In 12 of 16 (75.0%) efficacy-evaluable patients blood pressure was normalized (DBP to ≤90 mm Hg with an ≥5 mm Hg reduction from baseline) with a mean daily dose of 7.6 mg/day. Doxazosin improved the hypertension severity category in 13 of 16 (81.3%) patients. The blood pressure ratios between both the thighs and arms and ankles and arms showed no statistically significant changes after treatment with doxazosin. Thigh blood flow at rest and the reactive hyperemia after 3 minutes of arterial occlusion did not change statistically. There was a tendency for pain-free distance to improve. Laboratory data were not significantly changed after treatment with doxazosin. Of the 19 patients studied, 5 reported mild or moderate side effects that were either tolerated or disappeared with continued treatment. No patient had therapy withdrawn and no patient required a dose reduction. The investigators' global assessment of patient tolerance was excellent or good for 16 of 19 (84.2%) patients.