Microvascular dysfunction and neurovascular uncoupling are exacerbated in peripheral artery disease, increasing the risk of cognitive decline in older adults.

Peripheral artery disease (PAD) is a vascular pathology with high prevalence among the aging population. PAD is associated with decreased cognitive performance, but the underlying mechanisms remain obscure. Normal brain function critically depends on an adequate adjustment of cerebral blood supply to match the needs of active brain regions via neurovascular coupling (NVC). NVC responses depend on healthy microvascular endothelial function. PAD is associated with significant endothelial dysfunction in peripheral arteries, but its effect on NVC responses has not been investigated. This study was designed to test the hypothesis that NVC and peripheral microvascular endothelial function are impaired in PAD. We enrolled 11 symptomatic patients with PAD and 11 age- and sex-matched controls. Participants were evaluated for cognitive performance using the Cambridge Neuropsychological Test Automated Battery and functional near-infrared spectroscopy to assess NVC responses during the cognitive n-back task. Peripheral microvascular endothelial function was evaluated using laser speckle contrast imaging. We found that cognitive performance was compromised in patients with PAD, evidenced by reduced visual memory, short-term memory, and sustained attention. We found that NVC responses and peripheral microvascular endothelial function were significantly impaired in patients with PAD. A positive correlation was observed between microvascular endothelial function, NVC responses, and cognitive performance in the study participants. Our findings support the concept that microvascular endothelial dysfunction and neurovascular uncoupling contribute to the genesis of cognitive impairment in older PAD patients with claudication. Longitudinal studies are warranted to test whether the targeted improvement of NVC responses can prevent or delay the onset of PAD-associated cognitive decline.NEW & NOTEWORTHY Peripheral artery disease (PAD) was associated with significantly decreased cognitive performance, impaired neurovascular coupling (NVC) responses in the prefrontal cortex (PFC), left and right dorsolateral prefrontal cortices (LDLPFC and RDLPFC), and impaired peripheral microvascular endothelial function. A positive correlation between microvascular endothelial function, NVC responses, and cognitive performance may suggest that PAD-related cognitive decrement is mechanistically linked, at least in part, to generalized microvascular endothelial dysfunction and subsequent impairment of NVC responses.

Cognitive decrement in older adults with symptomatic peripheral artery disease.

Peripheral artery disease (PAD) is highly prevalent, affecting up to 20% of people over 70 years of age. To test the hypothesis that PAD promotes the pathogenesis of vascular cognitive impairment (VCI), we compared cognitive function in older adults with symptomatic PAD and in participants without PAD who had a burden of comorbid conditions. Furthermore, we compared the cognitive function of these groups after adjusting for demographic and clinical characteristics, comorbid conditions, and cardiovascular risk factors. Participants with PAD (age: 69 ± 8 years; n = 58) and those without PAD (age: 62 ± 8 years; n = 30) were assessed on a battery of eight neuropsychological tests. The tests assessed attention and working memory, verbal memory, non-verbal memory, perceptuo-motor speed, and executive function. Participants were further characterized on demographic and clinical characteristics, comorbid conditions, cardiovascular risk factors, and ankle-brachial index. The PAD group had significantly lower neuropsychological scores than the non-PAD control group on all eight tests (P < .01). After adjusting for covariates, significantly worse scores in the PAD group persisted for verbal memory, measured by tests on logical memory-immediate recall (P = .022), and logical memory-delayed recall (P < .001), and for attention and working memory, measured by tests on digits forward (P < .001), and digits backward (P = .003). Participants with symptomatic PAD have substantially lower levels of performance on tests of attention, working memory, and verbal memory than participants without PAD independent of demographic characteristics and comorbid health burdens. These findings provide additional evidence in support of the concept that generalized accelerated vascular aging manifesting as symptomatic PAD in the peripheral circulation also affects the brain promoting the pathogenesis of VCI. These cognitive difficulties may also negatively impact symptomatic patient's ability to understand and adhere to behavioral and medical therapies, creating a vicious cycle. We speculate that more intensive follow-up may be needed to promote adherence to therapies and monitor cognitive decline that may affect care.

Effects of Low-Level Tragus Stimulation on Endothelial Function in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation. METHODS AND RESULTS: We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 µs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement. CONCLUSIONS: Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.

Daily Step Counts in Participants With and Without Peripheral Artery Disease.

PURPOSE: We compared the prevalence of participants with and without symptomatic peripheral artery disease (PAD) who met the goals of attaining >7000 and 10 000 steps/d, and we determined whether PAD status was significantly associated with meeting the daily step count goals before and after adjusting for demographic variables, comorbid conditions, and cardiovascular risk factors. METHODS: Participants with PAD (n = 396) and without PAD (n = 396) were assessed on their walking for 7 consecutive days with a step activity monitor. RESULTS: The PAD group took significantly fewer steps/d than the non-PAD control group (6722 ± 3393 vs. 9475 ± 4110 steps/d; P < .001). Only 37.6% and 15.7% of the PAD group attained the goals of walking >7000 and 10 000 steps/d, respectively, whereas 67.9% and 37.4% of the control group attained these goals (P < .001 for each goal). Having PAD was associated with a 62% lower chance of attaining 7000 steps/d than compared with the control group (OR = 0.383; 95% CI, 0.259-0.565; P < .001), and a 55% lower chance of attaining 10 000 steps/d (OR = 0.449; 95% CI, 0.282-0.709; P < .001). Significant covariates (P < .01) included age, current smoking, diabetes, and body mass index. CONCLUSIONS: Participants with symptomatic PAD had a 29% lower daily step count compared with age- and sex-matched controls, and were less likely to attain the 7000 and 10 000 steps/d goals. Additionally, participants who were least likely to meet the 7000 and 10 000 daily step count recommendations included those who were older, currently smoked, had diabetes, and had higher body mass index.

Diet is associated with ankle-brachial index, inflammation, and ambulation in patients with intermittent claudication.

OBJECTIVE: The aims of this investigation were to determine whether the daily dietary intake of nutrients by patients with peripheral artery disease (PAD) and intermittent claudication (IC) met recommended levels for adults older than 50 years and to determine whether meeting recommended levels of nutrients was associated with ankle-brachial index (ABI), inflammation, and ambulation of patients with PAD and IC. METHODS: A total of 48 patients were assessed on their dietary intake of 20 nutrients during a 3-day period. Patients were further characterized on demographic variables, comorbid conditions, cardiovascular risk factors, ABI, 6-minute walk distance (6MWD), and high-sensitivity C-reactive protein (hsCRP) concentration. RESULTS: Few patients met the daily recommended intakes for calcium (4%), fiber (6%), vitamin E (6%), trans fatty acids (13%), vitamin A (15%), total sugars (19%), potassium (23%), sodium (29%), saturated fat (29%), and vitamin C (31%), and none of the patients met the daily recommended intake of vitamin D (0%). Overall, patients met few of the 20 dietary recommendations as the median score was seven recommendations. Only 17 of 48 patients met more than seven of the recommendations. For the ABI regression model adjusted for age, sex, race, smoking, hypertension, dyslipidemia, body mass index, and percentage body fat, the only significant predictor was total sugars (P < .001); patients who did not meet the recommendation had lower ABI values. For the hsCRP-adjusted regression model, the strongest significant predictor was omega-3 polyunsaturated fatty acids (P = .001), indicating that those who did not meet the recommendation had higher hsCRP values. Finally, for the 6MWD-adjusted regression model, folate (P = .011) and dietary score index (P = .014) were significant predictors; those who did not meet the recommendation for folate and those who met 5 or fewer of the 20 recommendations had shorter 6MWD. CONCLUSIONS: Patients with PAD and IC consume a low-nutrient-dense diet that is deficient in many vitamins, calcium, fruits, and vegetables and contains too much added sugar, saturated and trans fats, and processed foods. In addition, more severe PAD, greater inflammation, and ambulatory dysfunction are independently associated with aspects of a low-nutrient-dense diet, such as too much intake of added sugars, low intake of omega-3 polyunsaturated fatty acids and folate, and meeting the recommended intakes of only five or fewer nutrients.

Age-related decline in peripheral vascular health predicts cognitive impairment.

Preclinical studies demonstrate that generalized endothelial cell dysfunction and microvascular impairment are potentially reversible causes of age-related vascular cognitive impairment and dementia (VCID). The present study was designed to test the hypothesis that severity of age-related macro- and microvascular dysfunction measured in the peripheral circulation is an independent predictor of cognitive performance in older adults. In this study, we enrolled 63 healthy individuals into young (< 45 years old) and aged (> 65 years old) groups. We used principal component analysis (PCA) to construct a comprehensive peripheral vascular health index (VHI) encompassing peripheral microvascular reactivity, arterial endothelial function, and vascular stiffness, as a marker of aging-induced generalized vascular dysfunction. Peripheral macrovascular and microvascular endothelial function were assessed using flow-mediated dilation (FMD) and laser speckle contrast imaging tests. Pulse waveform analysis was used to evaluate the augmentation index (AIx), a measure of arterial stiffness. Cognitive function was measured using a panel of CANTAB cognitive tests, and PCA was then applied to generate a cognitive impairment index (CII) for each participant. Aged subjects exhibited significantly impaired macrovascular endothelial function (FMD, 5.6 ± 0.7% vs. 8.3 ± 0.6% in young, p = 0.0061), increased arterial stiffness (AIx 29.3 ± 1.8% vs 4.5 ± 2.6% in young, p < 0.0001), and microvascular dysfunction (2.8 ± 0.2 vs 3.4 ± 0.1-fold change of perfusion in young, p = 0.032). VHI showed a significant negative correlation with age (r = - 0.54, p < 0.0001) and CII significantly correlated with age (r = 0.79, p < 0.0001). VHI significantly correlated with the CII (r = - 0.46, p = 0.0003). A decline in peripheral vascular health may reflect generalized vascular dysfunction and predict cognitive impairment in older adults.

Prediction of 6-minute walk performance in patients with peripheral artery disease.

BACKGROUND: Peripheral artery disease (PAD) is a highly prevalent disease that impairs walking ability. Walking tests, such as the 6-minute walk test (6MWT) and 4-meter walk test, are commonly used to assess exercise endurance and ambulatory function over a short distance, respectively. The 6MWT performance is predictive of PAD severity and disease outcomes, but it is not feasible in many clinical settings because it requires a long walkway to serve as the test route and lengthens clinic visits. As an alternative, the 4-meter walk test is convenient, inexpensive, and repeatable, but whether it accurately predicts endurance performance in the long-distance 6MWT is not known. The goal of this study was to develop a statistical model to predict 6MWT gait speed from 4-meter walk test results and clinical characteristics among patients with PAD. METHODS: Measures of 6MWT gait speed were derived from 183 patients with symptomatic PAD who were evaluated at the University of Oklahoma Health Sciences Center (2004-2012). The testing procedures and research personnel remained constant throughout the duration of the study. Independent variables included demographic and clinical information and 4-meter walk test gait speed. Fivefold cross validation and manual backward selection were used for model selection. Adjusted R2 and corrected Akaike information criterion were applied to quantify the predictive performance of the regression models. RESULTS: A total of 183 people (54% male; mean age, 65 [standard deviation (SD), 10] years) with moderate PAD severity (ankle-brachial index [ABI]; mean, 0.72 [SD, 0.24]) performed the walking tests. Participants covered an average distance of 335 (SD, 97) m distance in the 6MWT. The 4-meter walk gait speed, ABI, and dyspnea were independent predictors of 6MWT speed in the multivariate model (adjusted R2 = 0.55). The model resulted in 95% prediction interval widths of 30 m for mean and 260 m for individual predicted 6MWT distance measures. CONCLUSIONS: Slower 4-meter walking speed, lower ABI, and presence of dyspnea all predict slower 6MWT gait speed, which corresponds to shorter 6MWT distance. Prediction of group means is reasonably precise; however, prediction of individual patient 6MWT performance is imprecise relative to between-group differences that are clinically important.

Association between daily walking and antioxidant capacity in patients with symptomatic peripheral artery disease.

OBJECTIVE: The primary aim of the study was to assess whether both the amount and pace of daily walking were associated with circulating antioxidant capacity in symptomatic patients with peripheral artery disease (PAD). METHODS: Community-based walking was measured in 244 men and women who were limited by symptomatic PAD during a 1-week period in which they wore an ankle-mounted step activity monitor. Patients were further characterized by circulating antioxidant capacity with the OxiSelect (Cell Biolabs Inc, San Diego, Calif) hydroxyl radical antioxidant capacity (HORAC) activity assay. RESULTS: To assess the amount of walking, patients were grouped into low (≤2440 strides/d), middle (2441-3835 strides/d), and high (>3835 strides/d) stride tertiles. HORAC was higher in the middle (P = .03) and high (P = .01) stride tertiles than in the low tertile, but there was no difference between middle and high tertiles (P = .44). To assess the pace of walking, patients were grouped into slow (<25.0 strides/min), middle (25.0-31.6 strides/min), and fast (>31.6 strides/min) cadence tertiles. HORAC was higher in the high cadence tertile than in the low (P < .01) and middle (P < .01) tertiles, but there was no difference between low and middle tertiles (P = .48). Similar findings were obtained on group differences in HORAC after adjusting for age, sex, race, and ankle-brachial index for both the amount and pace of daily walking. CONCLUSIONS: Walking >2440 strides each day and walking at a cadence faster than 31.6 strides/min for 30 minutes each day are both associated with greater circulating antioxidant capacity in symptomatic patients with PAD. The clinical significance is that a home-based walking program may be one approach to increase endogenous antioxidant capacity.

Association between gait characteristics and endothelial oxidative stress and inflammation in patients with symptomatic peripheral artery disease.

The aim of the study was to determine whether gait characteristics were associated with endothelial cell inflammation, oxidative stress, and apoptosis and with circulating biomarkers of inflammation and antioxidant capacity in older patients with symptomatic peripheral artery disease (PAD). Gait measurements of 231 symptomatic men and women with PAD were assessed during a 4-m walk test. Patients were further characterized on endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells and on circulating inflammatory and vascular biomarkers. In a multivariate regression model for gait speed, the significant independent variables were age (p < 0.001), intercellular cell adhesion molecule-1 (ICAM-1) (p < 0.001), diabetes (p = 0.003), sex (p = 0.003), and history of cerebrovascular accidents (p = 0.021). In multivariate analyses for gait cadence, the significant independent predictors included high-sensitivity C-reactive protein (HsCRP) (p < 0.001), diabetes (p = 0.001), and hypertension (p = 0.001). In a multivariate regression model for gait stride length, the significant independent variables were HsCRP (p < 0.001), age (p < 0.001), ICAM-1 (p < 0.001), hypertension (p = 0.002), cellular reactive oxygen species production (p = 0.007), and sex (p = 0.008). Higher levels of circulating biomarkers of inflammation and endothelial cell oxidative stress were associated with slower gait speed, slower cadence, and shorter stride length in older symptomatic patients with PAD. Additionally, this profile of impaired gait was more evident in older patients, in women, and in those with diabetes, hypertension, and history of cerebrovascular accidents.

Sedentary behavior is associated with impaired biomarkers in claudicants.

OBJECTIVE: Time spent in sedentary behavior has been associated with worse inflammation and cardiometabolic biomarkers in various populations. However, the association between time spent in sedentary behavior and biomarkers remains unknown in patients with intermittent claudication. The aim of the current study was to analyze the relationship between sedentary behavior and inflammatory and cardiometabolic biomarkers in patients with symptomatic peripheral arterial disease (PAD). METHODS: The sample included 297 patients with intermittent claudication. Sedentary behavior was assessed using a step activity monitor. Biomarkers of inflammation, oxidative stress, lipid profile, insulin resistance, and endogenous fibrinolysis were assessed. Demographic data, body mass index, physical activity status, and measures of severity of PAD (ankle-brachial index, peak walking time, and ischemic window) also were obtained. RESULTS: Time spent in sedentary behavior was related with high-sensitivity C-reactive protein (b = 0.187; P = .005), glucose (b = 0.238; P < .001), fibrinogen (b = 0.167; P = .017), plasminogen activator inhibitor 1 activity (b = 0.143; P = .036), and high-density lipoprotein cholesterol (b = -0.133; P = .029). After adjustment for sex, age, physical activity status, body mass index, and severity of PAD, sedentary behavior remained related with high-sensitivity C-reactive protein (b = 0.170; P = .015), glucose (b = 0.178; P = .004), fibrinogen (b = 0.189; P = .010), and high-density lipoprotein cholesterol (b = -0.128; P = .032). CONCLUSIONS: Time spent in sedentary activities was associated with worse inflammatory and cardiometabolic profile in patients with intermittent claudication.

Impact of tornadoes on hospital admissions for acute cardiovascular events.

BACKGROUND: There is a paucity of data describing cardiovascular events after tornado outbreaks. We proposed to study the effects of tornadoes on the incidence of cardiovascular events at a tertiary care institution. POPULATION AND METHODS: Hospital admission records from a single center situated in a tornado-prone area three months before and after a 2013 tornado outbreak were abstracted. To control for seasonal variation, we also abstracted data from the same period of the prior year (control). Hospital admissions for cardiovascular events (CVEs) including acute myocardial infarction, stroke and venous thromboembolism (VTE) were summated by zip codes, and compared by time period. RESULTS: There were 22,607 admissions analyzed, of which 6,705 (30%), 7,980 (35%), and 7,922 (35%) were during the pre-tornado, post-tornado, and control time frames, respectively. There were 344 CVE in the controls, 317 CVE in pre-tornado and 364 CVEs in post tornado periods. There was no difference in the prevalence of CVE during the post-tornado season compared with the control (PPR=1.05 95% CI: 0.91 to 1.21, p=0.50) or the pre-tornado season (PPR=0.96, 95% CI: 0.83 to 1.21, p=0.63). CONCLUSION: In conclusion, tornado outbreaks did not increase the prevalence of cardiovascular events. In contrast to the effect of hurricanes, implementation of a healthcare policy change directed toward the early treatment and prevention of cardiovascular events after tornadoes does not seem warranted.

Predicting fat percent by skinfolds in racial groups: Durnin and Womersley revisited.

PURPOSE: Despite their widespread use in research and fitness settings, Durnin and Womersley's (DW) 1974 prediction equations using skinfold thickness to estimate body fat percent by hydrodensitometry have not been systematically evaluated in racial or ethnic groups using body fat percent measured by dual-energy x-ray absorptiometry (%BF(DXA)) as the standard. METHODS: This cross-sectional, population-based study examined whether the DW skinfold equations predict %BF(DXA) in a large, multiracial sample. Four skinfold measures (biceps, triceps, subscapular, and suprailiac), other clinical anthropometrics, and %BF(DXA) were obtained from 1675 healthy adults, age 18-110 yr, who were classified into four racial or ethnic categories: Caucasian, African American, Hispanic, or Asian. Predicted body fat percent using DW equations was compared with %BF(DXA) and evaluated within race/ethnicity- and sex-specific groups. RESULTS: Mean body fat percent predicted by DW equations was significantly different from %BF(DXA) in four of eight race/ethnicity- and sex-specific groups, particularly in Asian women and African American men (3.3 and 2.4 percentage point overestimates, respectively, P < 0.0001). New linear regression equations were developed estimating %BF(DXA) specific to each race/ethnicity and sex group, using the original DW skinfold sites. Body weight, height, and waist circumference independently predicted fat percent and were also included in the new equations. CONCLUSIONS: The 1974 DW equations did not predict %BF(DXA) uniformly in all races or ethnicities. Using %BF(DXA) as the criterion measure, the original DW skinfold equations have been updated specific to sex and race/ethnicity while maintaining the DW options for a minimalistic model using fewer predictors.