Jill N. Barnes

Interrelationships among noninvasive measures of postischemic macro- and microvascular reactivity

The clinical importance of vascular reactivity as an early marker of atherosclerosis has been well established, and a number of established and emerging techniques have been employed to provide measurements of peripheral vascular reactivity. However, relations between these methodologies are unclear as each technique evaluates different physiological aspects related to micro- and macrovascular reactive hyperemia. To address this question, a total of 40 apparently healthy normotensive adults, 19-68 yr old, underwent 5 min of forearm suprasystolic cuff-induced ischemia followed by postischemic measurements. Measurements of vascular reactivity included 1) flow-mediated dilatation (FMD), 2) changes in pulse wave velocity between the brachial and radial artery (DeltaPWV), 3) hyperemic shear stress, 4) reactive hyperemic flow, 5) reactive hyperemia index (RHI) assessed by fingertip arterial tonometry, 6) fingertip temperature rebound (TR), and 7) skin reactive hyperemia. FMD was significantly and positively associated with RHI (r=0.47) and TR (r=0.45) (both P<0.01) but not with reactive hyperemic flow or hyperemic shear stress. There was no correlation between two measures of macrovascular reactivity (FMD and DeltaPWV). Skin reactive hyperemia was significantly associated with RHI (r=0.55) and reactive hyperemic flow (r=0.35) (both P<0.05). There was a significant association between reactive hyperemia and RHI (r=0.30; P<0.05). In more than 75% of cases, vascular reactivity measures were not significantly associated. We concluded that associations among different measures of peripheral micro- and macrovascular reactivity were modest at best. These results suggest that different physiological mechanisms may be involved in changing different measures of vascular reactivity.

Ellagitannin Consumption Improves Strength Recovery 2-3 d after Eccentric Exercise

PURPOSE Dietary supplementation with polyphenols,particularly ellagitannins, may attenuate the muscular damage experienced after eccentric exercise, producing delayed-onset muscle soreness. The purpose of this study was to determine whether ellagitannin supplementation from Wonderful variety pomegranate extract (POMx) improved recovery of skeletal muscle strength after eccentric exercise. METHODS Recreationally active males were randomized into a crossover design with either pomegranate extract (POMx) or placebo (PLA), each given during a period of 9 d.To produce delayed-onset muscle soreness, subjects performed two sets of 20 maximal eccentric elbow flexion exercises with one arm.Maximal isometric elbow flexion strength and muscle soreness as well as serum measures of creatine kinase, myoglobin, interleukin 6, and C-reactive protein were made at baseline and 2, 24, 48, 72, and 96 h after exercise. RESULTS With both treatments, strength was similarly reduced 2 h after exercise (i.e., 72% of baseline), and recovery of strength was incomplete after 96 h (i.e., 91% of baseline).However, strength was significantly higher in POMx compared with that in PLA at 48 h (85.4% +/- 2.5% and 78.3% +/- 2.6%, P = 0.01) and 72 h (88.9% +/- 2.0% and 84.0% +/- 2.0%, P = 0.009) after exercise. Serum markers of inflammation and muscle damage did not provide insight regarding possible mechanisms. CONCLUSIONS Supplementation with ellagitannins from pomegranate extract significantly improves recovery of isometric strength 2-3 d after a damaging eccentric exercise.

Arterial stiffening following eccentric exercise-induced muscle damage

Acute inflammatory responses are linked to a transient increase in risk of a cardiovascular event, and this risk may be mediated by a concomitant reduction in vascular function. Humans experience an acute inflammatory response as a consequence of infection, injury, or muscle damage. We measured macrovascular function before and after eccentric exercise to determine whether muscle damage from unaccustomed exercise has an unfavorable effect on the large elastic arteries. A total of 27 healthy sedentary or recreationally active men (age 18-38 years) participated in either bilateral leg press eccentric exercise or unilateral elbow flexor eccentric exercise. Postexercise muscle damage was confirmed by significant reductions in isometric strength and increases in muscle soreness (P < 0.05). Carotid-femoral pulse-wave velocity was significantly elevated 48 h after leg exercise (808 ± 31 vs. 785 ± 30 cm/s; P < 0.05) and arm exercise (790 ± 28 vs. 755 ± 24 cm/s; P < 0.05). There were no changes in mean arterial pressure. C-reactive protein was elevated after leg exercise but not after arm exercise. The increase in carotid-femoral pulse wave velocity 48 h after arm exercise was associated with muscle strength (r = -0.47; P < 0.05) and creatine kinase concentrations (r = 0.70; P < 0.01). We concluded that eccentric exercise in both small and large muscle mass translates to transient, unfavorable changes in central macrovascular function and that the increase in central arterial stiffness after small muscle eccentric exercise is associated with indicators of muscle damage.

Comparison of Central Artery Elasticity in Swimmers, Runners, and the Sedentary

Although swimming is one of the most popular, most practiced, and most recommended forms of physical activity, little information is available regarding the influence of regular swimming on vascular disease risks. Using a cross-sectional study design, key measurements of vascular function were performed in middle-aged and older swimmers, runners, and sedentary controls. There were no group differences in age, height, dietary intake, and fasting plasma concentrations of glucose, total cholesterol, and low-density lipoprotein cholesterol. Runners and swimmers were not different in their weekly training volume. Brachial systolic blood pressure and pulse pressure were higher (p <0.05) in swimmers than in sedentary controls and runners. Runners and swimmers had lower (p <0.05) carotid systolic blood pressure and carotid pulse pressure than sedentary controls. Carotid arterial compliance was higher (p <0.05) and β-stiffness index was lower (p <0.05) in runners and swimmers than in sedentary controls. There were no significant group differences between runners and swimmers. Cardiovagal baroreflex sensitivity was greater (p <0.05) in runners than in sedentary controls and swimmers and baroreflex sensitivity tended to be higher in swimmers than in sedentary controls (p = 0.07). Brachial artery flow-mediated dilation was significant greater (p <0.05) in runners compared with sedentary controls and swimmers. In conclusion, our present findings are consistent with the notion that habitual swimming exercise may be an effective endurance exercise for preventing loss in central arterial compliance.

Cyclooxygenase inhibition abolishes age-related differences in cerebral vasodilator responses to hypercapnia.

Blood flow and vasodilatory responses are altered by age in a number of vascular beds, including the cerebral circulation. To test the role of prostaglandins as regulators of cerebral vascular function, we examined cerebral vasodilator responses to CO(2) (cerebrovascular reactivity) in young (26 ± 5 yr; 6 males/6 females) and older (65 ± 6 yr, 5 males/5 females) healthy humans before and after cyclooxygenase inhibition (using indomethacin). Middle cerebral artery velocity (MCAv) responses to stepped hypercapnia were measured before and 90 min after indomethacin. Changes in MCAv during the recovery from hypercapnia (vasoconstrictor responses) were also evaluated before and after indomethacin. Cerebrovascular reactivity was calculated using linear regression between MCAv and end-tidal CO(2). Young adults demonstrated greater MCAv (55 ± 6 vs. 39 ± 5 cm/s: P < 0.05) and MCAv reactivity (1.67 ± 0.20 vs. 1.09 ± 0.19 cm·s(-1)·mmHg(-1); P < 0.05) to hypercapnia compared with older adults (P < 0.05). In both groups MCAv and MCAv reactivity decreased between control and indomethacin. Furthermore, the age-related differences in these cerebrovascular variables were abolished by indomethacin. During the recovery from hypercapnia, there were no age-related differences in MCAv reactivity; however, indomethacin significantly reduced the MCAv reactivity in both groups. Taken together, these results suggest that cerebral blood flow velocity and cerebrovascular reactivity are attenuated in aging humans, and may be due to a loss of prostaglandin-mediated vasodilation.

Sex-specific risk of cardiovascular disease and cognitive decline: pregnancy and menopause

Understanding the biology of sex differences is integral to personalized medicine. Cardiovascular disease and cognitive decline are two related conditions, with distinct sex differences in morbidity and clinical manifestations, response to treatments, and mortality. Although mortality from all-cause cardiovascular diseases has declined in women over the past five years, due in part to increased educational campaigns regarding the recognition of symptoms and application of treatment guidelines, the mortality in women still exceeds that of men. The physiological basis for these differences requires further research, with particular attention to two physiological conditions which are unique to women and associated with hormonal changes: pregnancy and menopause. Both conditions have the potential to impact life-long cardiovascular risk, including cerebrovascular function and cognition in women. This review draws on epidemiological, translational, clinical, and basic science studies to assess the impact of hypertensive pregnancy disorders on cardiovascular disease and cognitive function later in life, and examines the effects of post-menopausal hormone treatments on cardiovascular risk and cognition in midlife women. We suggest that hypertensive pregnancy disorders and menopause activate vascular components, i.e., vascular endothelium and blood elements, including platelets and leukocytes, to release cell-membrane derived microvesicles that are potential mediators of changes in cerebral blood flow, and may ultimately affect cognition in women as they age. Research into specific sex differences for these disease processes with attention to an individual’s sex chromosomal complement and hormonal status is important and timely.

Arterial Stiffening, Wave Reflection, and Inflammation in Habitually Exercising Systemic Lupus Erythematosus Patients

BACKGROUND Chronic systemic inflammation has been implicated in the pathogenesis of hypertension and cardiovascular disease. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation and an increased risk for cardiovascular disease. Currently few studies have evaluated the potential cardiovascular benefits of exercise in SLE. It is unknown whether the favorable effect of habitual exercise on arterial stiffness observed in healthy adults can be extended to SLE. Therefore, as an initial step, we determined the association between habitual exercise, inflammatory markers, central arterial compliance, and aortic wave reflection in healthy adults and SLE patients. METHODS We studied 41 adults, aged 33 ± 11 years (15 healthy controls, 12 sedentary SLE, and 14 physically active SLE patients). RESULTS Age, body mass index, and metabolic risk factors were not different between the three groups. Carotid arterial compliance was lower whereas augmentation index (AI) and inflammatory markers (C-reactive protein (CRP), interleukin (IL)-12, tumor necrosis factor-α (TNF-α)) were higher in sedentary SLE patients compared with healthy controls, but were not different between physically active SLE patients and healthy controls. Cardiac ejection fraction was lower in sedentary SLE than physically active SLE or healthy controls. In the pooled population, carotid arterial compliance was inversely associated with TNF-α (r = -0.38; P < 0.01), and AI was positively associated with both CRP (r = 0.33; P < 0.05) and intercellular adhesion molecule-1 (r = 0.28; P < 0.05). CONCLUSIONS SLE-associated stiffening of the central artery and wave reflection were not observed in habitually exercising adults with SLE. Furthermore, greater arterial stiffness was associated with higher inflammatory markers, suggesting that need for studies on inflammation and SLE-associated arterial stiffening.

Contribution of blood viscosity in the assessment of flow-mediated dilation and arterial stiffness

Flow-mediated dilation (FMD) is a non-invasive index of endothelial function. In an attempt to standardize FMD for shear stimulus, shear rate (velocity/diameter), rather than shear stress (viscosity*velocity/diameter), is commonly used as a surrogate measure, although it is limited by individual differences in blood viscosity. The purpose of this study was to determine the contribution of whole blood viscosity to FMD and other key measures of vascular function. Blood viscosity, FMD, carotid artery compliance, and carotid–femoral pulse wave velocity (cfPWV) were measured in 98 apparently healthy adults varying widely in age (18–63 years). Whole blood viscosity was not significantly correlated with FMD, cfPWV, or carotid artery compliance. Shear rate was a stronger correlate with FMD than shear stress that takes blood viscosity into account (r = 0.43 vs 0.28). No significant differences were observed between whole blood viscosity and traditional risk factors for cardiovascular disease. Age was positively correlated with cfPWV (r = 0.65, p < 0.001) and negatively correlated with FMD (r = −0.24, p < 0.05) and carotid artery compliance (r = −0.45, p < 0.01). Controlling for viscosity did not reduce the strength of these relations. These results indicate that whole blood viscosity does not significantly impact measures of vascular function and suggests that the common practice to use shear rate, rather than shear stress, in the adjustment of FMD is valid.

Use of temperature alterations to characterize vascular reactivity.

Monitoring alterations in fingertip temperature during ischaemia and the subsequent hyperaemia provides a novel way of studying microvascular reactivity. The relations between parameters characterizing blood perfusion and the thermal response of fingertips were studied using experimental and theoretical approaches. During the experimental protocol, two brachial artery occlusion tests were conducted in 12 healthy volunteers, and fingertip temperature, heat flux and skin perfusion using laser Doppler flowmetry (LDF) were measured. The temperature curves provide a smooth and robust response that is able to capture occlusion and reperfusion. The temperature fall during occlusion as well as the maximum temperature recorded depended linearly on the initial temperature. The magnitude of the LDF signal was associated with local tissue temperature and followed an exponential response. Heat flux measurements demonstrated rapid changes and followed variations in blood perfusion closely. The time points at which the heat flux reached its maximum corresponded to the time at which the fingertip temperature curves showed an inflection point after cuff release. The time required for the fingertip temperature to arrive at the maximum temperature was greater than the time to peak for the heat flux signal, which was greater than the LDF signal to reach a maximum. The time lag between these signals was a function of the finger size and finger temperature at the moment reperfusion restarted. Our present results indicate that finger temperature, heat flux and perfusion display varying rates of recovery following ischaemic stimuli and that differential responses are associated with the initial finger temperature.

Cerebrovascular Reactivity and Central Arterial Stiffness in Habitually Exercising Healthy Adults

Reduced cerebrovascular reactivity to a vasoactive stimulus is associated with age-related diseases such as stroke and cognitive decline. Habitual exercise is protective against cognitive decline and is associated with reduced stiffness of the large central arteries that perfuse the brain. In this context, we evaluated the age-related differences in cerebrovascular reactivity in healthy adults who habitually exercise. In addition, we sought to determine the association between central arterial stiffness and cerebrovascular reactivity. We recruited 22 young (YA: age = 27 ± 5 years, range 18–35 years) and 21 older (OA: age = 60 ± 4 years, range 56–68 years) habitual exercisers who partake in at least 150 min of structured aerobic exercise each week. Middle cerebral artery velocity (MCAv) was recorded using transcranial Doppler ultrasound. In order to assess cerebrovascular reactivity, MCAv, end-tidal carbon dioxide (ETCO2), and mean arterial pressure (MAP) were continuously recorded at rest and during stepwise elevations of 2, 4, and 6% inhaled CO2. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. Central arterial stiffness was assessed using carotid–femoral pulse wave velocity (PWV). Older adults had higher PWV (YA: 6.2 ± 1.2 m/s; OA: 7.5 ± 1.3 m/s; p < 0.05) compared with young adults. MCAv and CVCi reactivity to hypercapnia were not different between young and older adults (MCAv reactivity, YA: 2.0 ± 0.2 cm/s/mmHg; OA: 2.0 ± 0.2 cm/s/mmHg; p = 0.77, CVCi reactivity, YA: 0.018 ± 0.002 cm/s/mmHg2; OA: 0.015 ± 0.001 cm/s/mmHg2; p = 0.27); however, older adults demonstrated higher MAP reactivity to hypercapnia (YA: 0.4 ± 0.1 mmHg/mmHg; OA: 0.7 ± 0.1 mmHg/mmHg; p < 0.05). There were no associations between PWV and cerebrovascular reactivity (range: r = 0.00–0.39; p = 0.07–0.99). Our results demonstrate that cerebrovascular reactivity was not different between young and older adults who habitually exercise; however, MAP reactivity was augmented in older adults. This suggests an age-associated difference in the reliance on MAP to increase cerebral blood flow during hypercapnia.