Michelle L. Harrison

Endothelial ischemia-reperfusion injury in humans: association with age and habitual exercise

Advancing age is a major risk factor for coronary artery disease. Endothelial dysfunction accompanied by increased oxidative stress and inflammation with aging may predispose older arteries to greater ischemia-reperfusion (I/R) injury. Because coronary artery ischemia cannot be induced safely, the effects of age and habitual endurance exercise on endothelial I/R injury have not been determined in humans. Using the brachial artery as a surrogate model of the coronary arteries, endothelial function, assessed by brachial artery flow-mediated dilation (FMD), was measured before and after 20 min of continuous forearm occlusion in young sedentary (n = 10, 24 ± 2 yr) and middle-aged (n = 9, 48 ± 2 yr) sedentary adults to gain insight into the effects of primary aging on endothelial I/R injury. Young (n = 9, 25 ± 1 yr) and middle-aged endurance-trained (n = 9, 50 ± 2 yr) adults were also studied to determine whether habitual exercise provides protection from I/R injury. Fifteen minutes after ischemic injury, FMD decreased significantly by 37% in young sedentary, 35% in young endurance-trained, 68% in middle-aged sedentary, and 50% in middle-aged endurance-trained subjects. FMD returned to baseline levels within 30 min in young sedentary and endurance-trained subjects but remained depressed in middle-aged sedentary and endurance-trained subjects. Circulating markers of antioxidant capacity and inflammation were not related to FMD. In conclusion, advancing age is associated with a greater magnitude and delayed recovery from endothelial I/R injury in humans. Habitual endurance exercise may provide partial protection to the endothelium against this form of I/R injury with advancing age.

Low flow-mediated constriction: prevalence, impact and physiological determinant

Flow‐mediated dilation (FMD) is a surrogate marker for endothelial function. In the FMD procedure, arterial response during cuff inflation is not taken into consideration yet studies have demonstrated vasoconstriction, vasodilation and no change in the brachial artery during cuff inflation. The term low flow‐mediated constriction (L‐FMC) has been introduced to describe the vasoconstriction that occurs in some individuals during inflation of the cuff. The aims of this study were to examine (i) whether brachial artery response during cuff inflation differed in a population with varied coronary artery disease (CAD) risk factor profiles, (ii) the impact of this response on the subsequent calculation of FMD and (iii) the role of arterial stiffness in this variable response. L‐FMC, ‘traditional’ FMD and ‘modified’ FMD, which accounts for brachial artery response during cuff inflation, were studied in a total of 46 subjects varying in risk factor profiles for coronary artery disease. During cuff inflation, brachial artery responses varied widely from −5·6% (vasoconstriction) to 5·0% (vasodilation). When subjects were divided into healthy versus multiple risk factors (n = 34), L‐FMC and FMD were not different between the groups but modified FMD was significantly different (P = 0·02). L‐FMC was modestly but significantly associated with FMD (r = 0·41) and positively correlated with brachial artery pulse wave velocity (r = 0·30). Our results indicate that brachial artery responses to inflation of the cuff are very variable and are associated with arterial stiffness and that accounting for so‐called L‐FMC may provide a more comprehensive assessment of endothelial vasodilatory function.

Preliminary assessment of an automatic screening device for peripheral arterial disease using ankle-brachial and toe-brachial indices.

Background and objectivesAnkle–brachial index (ABI) is currently recommended for the screening of peripheral arterial disease. However, this method becomes less reliable in the presence of calcified, incompressible arteries, as they result in an erroneously elevated ABI, and an additional measure termed the toe–brachial index (TBI) is recommended. The evaluation of ABI, and in particular TBI, typically requires significant technical skill and often involves referral to a vascular laboratory. This present situation reveals the need for a valid and reliable, automatic, noninvasive device that will provide both ABI and TBI at the level of the primary care physician. The aim of this study was to evaluate the accuracy and reliability of such a device, the Vasera VS-1500AT, in the assessment of toe, ankle, and brachial systolic blood pressures. Materials and methodsThis study involved the assessment of 80 limbs from 40 normotensive and hypertensive individuals (17 men and 23 women) with a mean age of 45±18 years. ResultsThere was a statistically significant correlation (r=0.92) between toe systolic blood pressures obtained manually with photoplethysmography compared with those obtained through the automated device. The same significant correlation was also seen between the two with ankle (r=0.87) and brachial (r=0.88) systolic blood pressures. ConclusionThese strong correlations demonstrate that further investigation of this device is warranted regarding its use as a screening tool for the assessment of peripheral arterial disease. The automation provided by this device could potentially eliminate variability in these measurements thereby allowing for screening and diagnosis to be done without referral to a vascular laboratory.

Attenuated cerebral vasodilatory capacity in response to hypercapnia in college-aged African Americans.

What is the central question of this study? The main purpose of this investigation is to determine whether there is a difference in cerebral vasodilatory capacity in response to rebreathing‐induced hypercapnia between African Americans and Caucasian Americans. What is the main finding and its importance? College‐aged African Americans have reduced cerebral vasodilatory capacity during hypercapnia when compared with Caucasian counterparts, a finding that suggests cerebral vascular dysfunction in this population. These findings may contribute to the understanding of the greater prevalence of cerebral vascular disease in this population.African Americans (AAs) have increased risk for cardiovascular, cerebral vascular and metabolic disease, including hypertension, stroke, coronary artery disease, metabolic syndrome and type II diabetes, relative to Caucasian Americans (CAs). While it is accepted that endothelial function is impaired in AAs, less is known regarding their cerebral vasodilatory capacity in response to hypercapnia. We hypothesized that AAs have a reduction in the total range of change in cerebral blood flow velocity (CBFV) measured in the middle cerebral artery and an index of cerebral vascular conductance (CVCI) in response to changes in the partial pressure of end-tidal carbon dioxide () during rebreathing-induced hypercapnia when compared with CAs. Twenty-one healthy, college-aged AA (10 male) and 21 age- and sex-matched CA (10 male) subjects participated in this study. A four-parameter logistic regression was used for curve fitting the responses of CBFV and CVCI relative to changes in . The total ranges of change in CBFV (101 ± 18 versus 69 ± 23%; P < 0.001) and CVCI (83 ± 21 versus 58 ± 21%; P < 0.001) as well as the maximal increase in CBFV (205 ± 24 versus 169 ± 24%; P < 0.001) and CVCI (188 ± 30 versus 154 ± 19%; P < 0.001) were reduced during hypercapnia in AAs relative to CAs despite a similar increase in (change, 15 ± 3 versus 15 ± 3 mmHg; P = 0.65). In conclusion, these data indicate that AAs have attenuated cerebral vascular capacity to respond to hypercapnia when compared with CAs.

The magnitude of heat stress-induced reductions in cerebral perfusion does not predict heat stress-induced reductions in tolerance to a simulated hemorrhage

The mechanisms responsible for heat stress-induced reductions in tolerance to a simulated hemorrhage are unclear. Although a high degree of variability exists in the level of reduction in tolerance amongst individuals, syncope will always occur when cerebral perfusion is inadequate. This study tested the hypothesis that the magnitude of reduction in cerebral perfusion during heat stress is related to the reduction in tolerance to a lower body negative pressure (LBNP) challenge. On different days (one during normothermia and the other after a 1.5°C rise in internal temperature), 20 individuals were exposed to a LBNP challenge to presyncope. Tolerance was quantified as a cumulative stress index, and the difference in cumulative stress index between thermal conditions was used to categorize individuals most (large difference) and least (small difference) affected by the heat stress. Cerebral perfusion, as indexed by middle cerebral artery blood velocity, was reduced during heat stress compared with normothermia (P < 0.001); however, the magnitude of reduction did not differ between groups (P = 0.51). In the initial stage of LBNP during heat stress (LBNP 20 mmHg), middle cerebral artery blood velocity and end-tidal PCO(2) were lower; whereas, heart rate was higher in the large difference group compared with small difference group (P < 0.05 for all). These data indicate that variability in heat stress-induced reductions in tolerance to a simulated hemorrhage is not related to reductions in cerebral perfusion in this thermal condition. However, responses affecting cerebral perfusion during LBNP may explain the interindividual variability in tolerance to a simulated hemorrhage when heat stressed.

Acute flavanol consumption improves the cerebral vasodilatory capacity in college‐aged African Americans

What is the central question of this study? The purpose was to determine whether acute flavanol consumption improves cerebral vasodilatory capacity during rebreathing‐induced hypercapnia in African Americans. What is the main finding and its importance? The reduced cerebral vasodilatory response to hypercapnia in young healthy African Americans was improved acutely following consumption of a flavanol‐rich beverage. This may have important clinical implications regarding racial differences in cerebrovascular disease risk and possible interventional approaches to offset this risk.

Variability in orthostatic tolerance during heat stress: cerebrovascular reactivity to arterial carbon dioxide.

INTRODUCTION A high degree of interindividual variability exists in the magnitude of heat stress (HS)-induced reductions in orthostatic tolerance relative to normothermia (NT). This variability may be associated with HS-mediated reductions in cerebral perfusion (indexed as middle cerebral artery blood velocity; MCAV(mean)) and altered cerebrovascular regulation. METHODS We tested the hypothesis that cerebrovascular reactivity to hypocapnia would be positively correlated with differences in tolerance to lower body negative pressure (LBNP) [assessed with a cumulative stress index (CSI)] between HS and NT (CSI(diff)). Subjects (N = 13) underwent LBNP twice (NT and HS) separated by > 72 h to assess CSI. On a third day, cerebrovascular reactivity [changes in cerebral vascular conductance (CVCi) during hyperventilation-induced hypocapnia (indexed by end tidal carbon dioxide; P(ET)CO2)] was assessed during NT, HS, and HS+LBNP (-20 mmHg; HS(LBNP)). RESULTS Tolerance to LBNP was reduced after a 1.5 +/- 0.1 degrees C increase in internal temperature and a high degree of variability was observed for CSI(diff) (range: 122 to 1826 mmHg x min(-1)). The magnitude of reduction in CVCi during voluntary hyperventilation-induced hypocapnia (-16 +/- 5 Torr) was attenuated during HS and HS(LBNP) VS. NT (NT: -0.20 +/- 0.09 cm x s(-1) x mmHg(-1); HS: -0.12 +/- 0.09 cm x s(-1) x mmHg(-1); HS(LBNP): -0.11 +/- 0.11 cm x s(-1). mmHg(-1)); however, no relationship existed between deltaCVCi/ P(ET)CO2 and CSI(diff) in any condition. CONCLUSIONS Cerebrovascular reactivity to hyperventilation-induced hypocapnia is attenuated when internal temperature is elevated, perhaps as a protective mechanism to protect against further reductions in the already diminished cerebral perfusion in this thermal state. However, individual differences in these responses do not appear to predict orthostatic tolerance during HS.

Identifying cytokine predictors of cognitive functioning in breast cancer survivors up to 10 years post chemotherapy using machine learning

INTRODUCTION The purpose of this study is to explore 13 cytokine predictors of chemotherapy-related cognitive impairment (CRCI) in breast cancer survivors (BCS) 6 months to 10 years after chemotherapy completion using a multivariate, non-parametric approach. METHODS Cross sectional data collection included completion of a survey, cognitive testing, and non-fasting blood from 66 participants. Data were analyzed using random forest regression to identify the most significant predictors for each of the cognitive test scores. RESULTS A different cytokine profile predicted each cognitive test. Adjusted R2 for each model ranged from 0.71-0.77 (ps < 9.50-10). The relationships between all the cytokine predictors and cognitive test scores were non-linear. CONCLUSIONS Our findings are unique to the field of CRCI and suggest non-linear cytokine specificity to neural networks underlying cognitive functions assessed in this study.

Health Indices and Cognitive Performance in Emerging Adults

Purpose: The purpose of this study was to examine the relationship of health indices with cognition in emerging adults. Methods: Methods included collecting measures of C-Reactive Protein (CRP), arterial stiffness, cardiorespiratory fitness, blood pressure, Body Mass Index (BMI), and cognitive performance from fourteen participants. Cognitive performance was assessed through the administration of Kaufman Brief Intelligence Test, Stroop Color-Word Test, and Trail Making Test A & B. CRP was commercially measured using the hsCRP Enzyme Immunoassay kit. Cardiorespiratory fitness was determined by the VO2 maximal testing using incremental stages on a cycle ergometer, while arterial stiffness and pulse wave velocity were measured using two identical transcutaneous Doppler flowmeters. Results: ANOVA calculations revealed gender differences in cardiorespiratory fitness and BMI. Pearson correlations Surprisingly, in this sample, CRP was not significantly related to BMI. Multiple regression analyses, using Stroop tests as the dependent variable while controlling for IQ and BMI, evidenced that CRP negatively and cardiorespiratory fitness positively contributed to cognitive performance for multiple conditions of the Stroop conditions. No single factor significantly predicted cognitive performance on the Trail Making test. Conclusions: Despite being at the developmental peak, CRP and cardiorespiratory fitness were associated with cognitive performance in emerging adults. On the Stroop task, CRP level significantly predicted cognitive performance reaction time tasks. These findings are valuable because identifying how health risks are related to cognition at this stage of lifespan may help us to better understanding how to maintain cognitive health and minimize premature cognitive decline as we age.