Effects of ß-Blockers on Maximal Heart Rate Prediction Equations in a Cardiac Population.

PURPOSE: To derive specific maximal heart rate (HRmax) prediction equations for a coronary artery disease (CAD) population based upon status of ß-blocker (BB) therapy and to compare these to prior HRmax equations (Fox and Brawner-specific for CAD). METHODS: We retrospectively reviewed stress echocardiogram treadmill tests in patients with CAD, dividing subjects into 3 groups based upon BB use on test day: not prescribed BB therapy (no BB group; n = 110); held for 12 to 24 hr prior (held BB group; n = 155); and continued taking (took BB group; n = 72). RESULTS: Derived HRmax equations for our CAD population were no BB = 200 - 0.79 × age; held BB = 193 - 0.71 × age; and took BB = 168 - 0.51 × age. Achieved HRmax mean was not significantly different between held BB and no BB groups; however, HRmax in the took BB group was significantly lower. Fox and Brawner (no BB)-HRmax equations significantly overestimated (+6 and +9 mean bias) and underestimated (-8 and -6 mean bias) achieved HRmax in no BB and held BB groups, respectively. The Brawner (no BB) equation intercept and slope were not significantly different from our CAD-held BB and no BB equations. The Brawner (on BB) equation intercept and slope were similar to our took BB equation, but greatly underestimated achieved HRmax (-17 mean bias). CONCLUSION: For patients holding BB therapy on test day, a similar CAD HRmax estimation equation to those patients never on BB can be used, comparable to the Brawner (no BB) equation. Further research is needed to determine when patients should take their BB therapy in conjunction with exercise testing.

High-dose vitamin D supplementation and measures of insulin sensitivity in polycystic ovary syndrome: a randomized, controlled pilot trial.

OBJECTIVE: To determine the effects of high-dose vitamin D on insulin sensitivity in polycystic ovary syndrome (PCOS). DESIGN: Randomized, placebo-controlled trial. SETTING: Academic medical center. PATIENT(S): Twenty-eight women with PCOS. INTERVENTION(S): Vitamin D3, 12,000 IU, or placebo daily for 12 weeks. MAIN OUTCOME MEASURE(S): The primary outcome was quantitative insulin sensitivity check index. Secondary outcomes included glucose and insulin levels during a 75-g oral glucose tolerance test and blood pressure. RESULT(S): Twenty-two women completed the study. Compared with placebo, vitamin D significantly increased 25-hydroxyvitamin D (mean [95% confidence interval] in vitamin D group 20.1 [15.7 to 24.5] ng/mL at baseline and 65.7 [52.3 to 79.2] ng/mL at 12 weeks; placebo 22.5 [18.1 to 26.8] ng/mL at baseline and 23.8 [10.4 to 37.2] ng/mL at 12 weeks). There were no significant differences in quantitative insulin sensitivity check index and other measures of insulin sensitivity; however, we observed trends toward lower 2-hour insulin and lower 2-hour glucose. We also observed a protective effect of vitamin D on blood pressure. CONCLUSION(S): In women with PCOS, insulin sensitivity was unchanged with high-dose vitamin D, but there was a trend toward decreased 2-hour insulin and a protective effect on blood pressure. CLINICAL TRIAL REGISTRATION NUMBER: NCT00907153.

Impaired retinal vasodilator responses in prediabetes and type 2 diabetes.

PURPOSE: In diabetes, endothelial dysfunction and subsequent structural damage to blood vessels can lead to heart attacks, retinopathy and strokes. However, it is unclear whether prediabetic subjects exhibit microvascular dysfunction indicating early stages of arteriosclerosis and vascular risk. The purpose of this study was to examine whether retinal reactivity may be impaired early in the hyperglycaemic continuum and may be associated with markers of inflammation. METHODS: Individuals with prediabetes (n = 22), type 2 diabetes (n = 25) and healthy age and body composition matched controls (n = 19) were studied. We used the Dynamic Vessel Analyzer to assess retinal vasoreactivity (percentage change in vessel diameter) during a flickering light stimulation. Fasting highly sensitive c-reactive protein (hs-CRP), a marker of inflammation, was measured in blood plasma. RESULTS: Prediabetic and diabetic individuals had attenuated peak vasodilator and relative amplitude changes in retinal vein diameters to the flickering light stimulus compared with healthy controls (peak dilation: prediabetic subjects 3.3 ± 1.8%, diabetic subjects 3.3 ± 2.1% and controls 5.6 ± 2.6%, p = 0.001; relative amplitude: prediabetic subjects 4.3 ± 2.2%, diabetic subjects 5.0 ± 2.6% and control subjects 7.2 ± 3.2%, p = 0.003). Similar findings were observed in retinal arteries. Levels of hs-CRP were not associated with either retinal vessel response parameters. CONCLUSION: Retinal reactivity was impaired in prediabetic and type 2 diabetic individuals in parallel with reduced insulin sensitivity but not associated with levels of hs-CRP. Retinal vasoreactivity measurements may be a sensitive tool to assess early vascular risk.

Comparison of retinal vasodilator and constrictor responses in type 2 diabetes.

PURPOSE: The retinal blood vessels provide a unique way to directly examine the human microvasculature, which is frequently damaged in individuals with diabetes. Previous studies have demonstrated that retinal flickering light-induced vasodilation and hyperoxia-induced vasoconstriction may operate by enhancing or reducing similar vasoregulatory factor(s), but a comparison between these two provocative stimuli in individuals with diabetes has not been studied. The purpose of the study was to examine the association between retinal flickering light-induced vasodilation and retinal hyperoxia-induced vasoconstriction in type 2 diabetic subjects and in healthy controls. METHODS: Twenty men and women with type 2 diabetes and 10 men and women without diabetes between 21 and 75 years of age were recruited. Changes in retinal artery and vein diameters to flickering light and during hyperoxia (100% oxygen) stimuli were measured on the same visit using a noninvasive retinal imaging device (Dynamic Vessel Analyzer, Imedos Inc., Germany). RESULTS: Compared with controls, diabetic subjects had impaired arterial vasodilator and vasoconstrictor responses to both flickering light and hyperoxia, respectively (both p<0.001). Merging both groups, an inverse correlation (r=-0.56; p=0.003) between the retinal artery's responses to flickering light-induced vasodilation and hyperoxia-induced vasoconstriction was demonstrated independent of glucose or insulin levels. CONCLUSION: This suggests that both responses are attenuated to a similar degree in diabetic subjects and that the attenuation to both stimuli can be observed in retinal arteries and veins. This would suggest that similar vasoregulatory factor(s) might in part help to explain the retinal diameter responses between the two stimuli. One suggested common vasoregulator of vascular tone is nitric oxide; however, other factor(s) may be involved, which contribute to this association and require further research.

Retinal vasoreactivity as a marker for chronic ischemic white matter disease?

UNLABELLED: The cerebral microvasculature cannot be easily studied non-invasively. Because the retina and brain share embryological, anatomical and physiological similarities, studies of retinal blood vessels may prove to be useful as a surrogate marker for cerebrovascular disease. In epidemiological studies abnormal retinal arteriovenous ratios (AVRs) predict the risk of stroke and vascular dementia. However, the association between retinal vasoreactivity, cerebral small vessel ischemic disease, and cerebral blood vessel function remains unknown. STUDY GOALS: To examine (1) the association between cerebral ischemic white matter disease (WMD) and retinal microvessel behavior and (2) the relationship between retinal blood vessel reactivity and measures of cerebrovascular function. METHODS: Cohort study of 12 patients with ischemic WMD and 14 healthy controls. Retinal vasoreactivity was measured following high frequency flicker light stimulation. Middle cerebral artery (MCA) vasoreactivity was measured using transcranial Doppler ultrasound (TCD). Magnetic resonance imaging scans (MRIs) were reviewed for evidence of ischemic WMD. RESULTS: Patients with ischemic WMD had attenuated retinal venous (2.2% ± 0.27 SD, vs. controls 6% ± 0.7 SD, p=0.002, CI 95%) and arterial (1.9% ± 0.8 SD, vs. controls 4.9% ± 0.8 SD, p=0.004, CI 95%) vasoreactivity compared to controls. An attenuated retinal venous light flicker response was associated with a significant decrease of MCA vasoreactivity (r=0.45, p=0.05, CI 95%). Decreased AVRs, an indicator for altered retinal vessel architecture in patients with cerebral chronic ischemic WMD, were also significantly correlated with dysfunction of cerebral vasoreactivity (r=0.69, p=0.001, CI 95%). CONCLUSION: In this study functional and structural impairment of the retinal microvasculature were associated with ischemic WMD and measures of cerebral vascular function. Microvascular dysfunction in the eye may predict cerebral small vessel disease, but validation by larger studies is needed.

Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults.

An inverse relation exists between intake of flavonoid-rich foods, such as cocoa, and cardiovascular-related mortality. Favorable effects of flavonoids on the endothelium may underlie these associations. We performed a randomized, double-blind, placebo-controlled study to test the hypothesis that acute cocoa ingestion dose dependently increases endothelium-dependent vasodilation, as measured by an increase in brachial artery flow-mediated dilation (FMD), in healthy older adults. Measurements were obtained before (preingestion) and after (1- and 2-h postingestion) ingestion of 0 (placebo), 2, 5, 13, and 26 g of cocoa in 23 adults (63 ± 2 yr old, mean ± SE). Changes in brachial artery FMD 1- and 2-h postingestion compared with preingestion were used to determine the effects of cocoa. FMD was unchanged 1 (Δ-0.3 ± 0.2%)- and 2-h (Δ0.1 ± 0.1%) after placebo (0 g cocoa). In contrast, FMD increased both 1-h postingestion (2 g cocoa Δ0.0 ± 0.2%, 5 g cocoa Δ0.8 ± 0.3%, 13 g cocoa Δ1.0 ± 0.3%, and 26 g cocoa Δ1.6 ± 0.3%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) and 2-h postingestion (2 g cocoa Δ0.5 ± 0.3%, 5 g cocoa Δ1.0 ± 0.3%, 13 g cocoa Δ1.4 ± 0.2%, and 26 g cocoa Δ2.5 ± 0.4%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) on the other study days. A serum marker of cocoa ingestion (total epicatechin) correlated with increased FMD 1- and 2-h postingestion (r = 0.44-0.48; both P < 0.05). Collectively, these results indicate that acute cocoa ingestion dose dependently increases brachial artery FMD in healthy older humans. These responses may help to explain associations between flavonoid intake and cardiovascular-related mortality in humans.

Vasoconstrictor responses in the upper and lower limbs to increases in transmural pressure.

The purpose of this study was to examine upper and lower limb vasoconstrictor responses to changes in transmural pressure in humans. Brachial and femoral blood mean blood velocity (MBV) and vessel diameter (Doppler ultrasound) were measured in 20 supine healthy subjects (10 men and 10 women; 27 +/- 1 yr; mean +/- SE) during four levels of limb suction at -25, -50, -75, and -100 mmHg, respectively. Limb suction led to an initial rise in MBV followed by a rapid fall in flow velocity to a level below MBV baseline, indicating a vasoconstriction effect. Femoral compared with brachial vessels exhibited a greater fall in flow velocity at all levels of suction (-89 +/- 17 vs. -10 +/- 2, -142 +/- 11 vs. -14 +/- 2, -156 +/- 22 vs. -13 +/- 2, and -162 +/- 29 vs. -12 +/- 2 ml/min for -25, -50, -75, and -100 mmHg, respectively; interaction effect, P < 0.05). Even at low tank suction levels (i.e., -10 and -20 mmHg), significant brachial flow velocity vasoconstriction from baseline values was demonstrated, reflecting downstream resistance vessel changes (n = 14). Brachial and femoral diameters did not change during changes in negative tank pressure. During suction, changes in limb volumes were significantly greater in the forearm (1.4 +/- 0.5%, 2.4 +/- 0.8%, 3.5 +/- 1.0%, and 4.3 +/- 1.1%) compared with the calf (0.9 +/- 0.5%, 1.4 +/- 0.7%, 2.0 +/- 0.8%, and 2.8 +/- 1.1%) at all levels of negative tank pressures (-25, -50, -75, and -100 mmHg, respectively). Simultaneous measurements of both upper limbs and both lower limbs suggested that the majority of the reduction in flow was due to myogenic influences except when -100 mmHg of suction was applied to the lower limb. The greater vasoconstriction responses in the leg compared with the arm with suction appear to be influenced by both myogenic and sympathetic mechanisms.

Sex differences in limb vasoconstriction responses to increases in transmural pressures.

Women compared with men are more likely to have orthostatic intolerance. The purpose of this study was to examine whether sex affects limb vasoconstrictor response to increases in transmural pressure. Brachial and femoral mean blood velocity (MBV) and diameter (Doppler Ultrasound) were measured in 10 women and 10 men as transmural pressure was altered by applying local suction (-25, -50, -75, and -100 mmHg) via pressurized-limb tanks for 1 min to a single arm and leg. With the abrupt application of forearm suction (-75 and -100 mmHg), women compared with men had a greater initial rise in MBV (peak), followed by a quicker dynamic rate of velocity reduction. In the leg, women had a tendency for higher peak MBV but had similar dynamic velocity reductions compared with men. After 60 s of suction, women compared with men had attenuated reductions in brachial flow and conductance (-8.05 +/- 1.71 vs. -16.25 +/- 1.71 ml/min; -0.12 +/- 0.03 vs. -0.20 +/- 0.03 ml x min(-1) x mmHg(-1); main effect, P < 0.05), as well as attenuated femoral flow and conductance to sustained leg negative pressure at -100 mmHg (P < 0.05). When the data were expressed as percent change, women compared with men continued to have attenuated brachial flow responses (-24 +/- 2 vs. -36 +/- 2%, main effect, P < 0.05), with a trend toward attenuation at the highest leg pressure (-25 +/- 11 vs. -46 +/- 4%; P = 0.08). These sex differences remained after normalizing the flow responses by limb volume (percent change). Our findings suggest that young women compared with men have attenuated brachial and femoral vasoconstrictor responses to increases in transmural pressure, which may have implications for the greater incidence of orthostatic intolerance in women.

Effects of an oral glucose tolerance test on the myogenic response in healthy individuals.

The myogenic response, the inherent ability of blood vessels to rapidly respond to changes in transmural pressure, is involved in local blood flow autoregulation. Animal studies suggest that both acute hyperglycemia and hyperinsulinemia may impair myogenic vasoconstriction. The purpose of this study was to examine the effects of an oral glucose load on brachial mean blood velocity (MBV) during increases in forearm transmural pressure in humans. Eight healthy men and women (38 +/- 5 yr) underwent an oral glucose tolerance test (OGTT). MBV (in cm/s; Doppler ultrasound) responses to a rise in forearm transmural pressure (arm tank suction, -50 mmHg) were studied before and every 30 min for 120 min during the OGTT. Before the start of the OGTT, MBV was lower than baseline values 30 and 60 s after the application of negative pressure. This suggests that myogenic constriction was present. During the OGTT, blood glucose rose from 88 +/- 2 to 120 +/- 6 mg/dl (P < 0.05) and insulin rose from 14 +/- 1 to 101 +/- 32 microU/ml (P < 0.05). Glucose loading attenuated the reduction in MBV with arm suction (Delta-0.73 +/- 0.14 vs. Delta-1.67 +/- 0.43 cm/s and Delta-1.07 +/- 0.14 vs. Delta-2.38 +/- 0.54 cm/s, respectively, during 30 and 60 s of suction postglucose compared with preglucose values; all P < 0.05). We observed no such time effect for myogenic responses during a sham OGTT. In an additional 5 subjects, glucose loading had no effect on brachial diameters with the application of negative pressure. Oral glucose loading leads to attenuated myogenic vasoconstriction in healthy individuals. The role that this diminished postglucose reactivity plays in mediating postprandial hypotension and/or orthostasis needs to be further explored.

Extracellular calcium and vascular responses after forearm ischemia.

BACKGROUND: The myogenic response is a phenomenon in which blood vessels respond to increases and decreases in transmural pressure with constriction and dilation, respectively. Despite intense investigation into the signaling mechanisms underlying this response, the precise mechanisms remain unclear. It has been suggested that the myogenic response occurs when pressure or stretch evokes increases in vessel wall tension that results in vessel smooth muscle cell depolarization. This causes Ca2+ entry through voltage-gated Ca2+ channels. Of note, in vitro studies demonstrate that the magnitude of the myogenic response is dependent on the extracellular Ca2+. We tested the hypothesis that in conscious humans, physiological changes in extracellular Ca2+ concentrations would be an important determinant of the myogenic response. METHODS AND RESULTS: Venous blood ionized calcium was used as an index of interstitial calcium and was measured 5, 15, and then every 15 seconds for 75 seconds, then every 30 seconds for 90 seconds, then finally at the 300-second mark. Forearm blood pressure and flow velocity were determined after 10 minutes of forearm ischemia. We found that the rate of change in serum calcium levels varied as a function of transmural pressure (r=0.96). Moreover, the calcium concentration was inversely proportional to forearm blood velocity (r=0.99). CONCLUSIONS: We hypothesize that muscle stretch caused by a rise in transmural pressure raises interstitial calcium by unknown mechanisms and this in turn acts to lower limb flow velocity.

Effects of age on brachial artery myogenic responses in humans.

The myogenic response, the inherent ability of blood vessels to rapidly respond to changes in transmural pressure, is involved in local blood flow autoregulation. Animal studies suggest that aging impairs the myogenic response. The purpose of this study was to compare the effects of changes in transmural pressure on mean blood velocity (MBV, cm/s) in young and older subjects. Twelve younger men and women (25 +/- 1 yr) were gender and body composition matched to twelve older men and women (65 +/- 1 yr). A specially designed tank raised or lowered forearm pressure by 50 mmHg within 0.2 s. Brachial artery MBV was measured directly above the site of forearm pressure change using Doppler methods. In response to increasing transmural pressure (i.e., release of +50 mmHg), older subjects compared with younger subjects had significantly lower peak MBV (Delta 12.43 +/- 1.16 vs. Delta 17.97 +/- 2.01 cm/s; P < 0.05), reduced rates in the dynamic fall of MBV after peak values were achieved (vasoconstriction) (-1.88 +/- 0.17 vs. -2.90 +/- 0.28 cm.s(-1).s(-1); P < 0.05), and lower MBV values with sustained suction. In response to decreasing transmural pressure (i.e., change to +50 mmHg), there was a significantly greater increase in MBV (Delta peak flow from trough 7.71 +/- 1.32 vs. 4.38 +/- 0.71 cm/s; P < 0.05) and a trend toward a greater rate of rise in MBV (vasodilation; 1.61 +/- 0.29 vs. 0.96 +/- 0.21 cm.s(-1).s(-1); P = 0.08) in the older subjects. Older subjects compared with the younger subjects exhibited decreased dynamic vasoconstriction, enhanced steady-state constriction, as well as evidence for enhanced dynamic vasodilation responses to sustained alterations in forearm transmural pressure.

What has microdialysis shown us about the metabolic milieu within exercising skeletal muscle?

Microdialysis provides insight to the metabolic changes in the interstitial space during muscle contractions. This review examines the contribution that interstitial muscle-derived compounds may play in exercise-induced hyperemia and the exercise pressor reflex.

Effects of transmural pressure on brachial artery mean blood velocity dynamics in humans.

The effects of changes in transmural pressure on brachial artery mean blood velocity (MBV) were examined in humans. Transmural pressure was altered by using a specially designed pressure tank that raised or lowered forearm pressure by 50 mmHg within 0.2 s. Brachial MBV was measured with Doppler directly above the site of forearm pressure change. Pressure changes were evoked during resting conditions and after a 5-s handgrip contraction at 25% maximal voluntary contraction. The handgrip protocol selected was sufficiently vigorous to limit flow and sufficiently brief to prevent autonomic engagement. Changes in transmural pressure evoked directionally similar changes in MBV within 2 s. This was followed by large and rapid adjustments [-2.14 +/- 0.24 cm/s (vasoconstriction) during negative pressure and +2.14 +/- 0.45 cm/s (vasodilatation) during positive pressure]. These adjustments served to return MBV to resting levels. This regulatory influence remained operative after 5-s static handgrip contractions. Of note, changes in transmural pressure were capable of altering the timing of the peak MBV response (5 +/- 0, 2 +/- 0, 6 +/- 1 s ambient, negative, and positive pressure, respectively) as well as the speed of MBV adjustment (-2.03 +/- 0.18, -2.48 +/- 0.15, -0.84 +/- 0.19 cm x s(-1) x s(-1) ambient, negative, and positive pressure, respectively) after handgrip contractions. Vascular responses, seen with changes in transmural pressure, provide evidence that the myogenic response is normally operative in the limb circulation of humans.