Differences In Microvascular Function Research Articles

Racial Disparities in Cardio-Oncology: Contributions of Anti-Cancer Therapy Induced Endothelial Dysfunction

Background: Major adverse cardiovascular (CV) events (MACE) related to anti-cancer therapy (CTx) represent the leading cause of non-cancer related mortality among breast cancer (BC) survivors. Most preclinical studies have focused on the heart, but increasing evidence suggests decreased endothelial function is predictive of CTx induced cardiac events. To date, the role of microvascular endothelial (dys)function, a well-established predictor of MACE, has been mostly ignored and few mechanistic studies exist in human subjects. CV disease in general, and CTx induced adverse events specifically, are significantly more prevalent in Black (B) relative to non-Hispanic White (NHW) patients. Despite the overwhelming clinical evidence supporting these health disparities, the underlying causes are poorly understood. Our lab and others have demonstrated that isolated vessels from human tissue samples can be used to understand the mechanisms contributing to CV disease. The overall goal of this study is to determine the effect of anti-cancer therapy on microvascular function and identify possible racial disparities. Hypothesis: Ex vivo treatment with CTx leads to impaired endothelial function, which is augmented in healthy donor vessels from B compared to NHW patients. Methods: Human adipose arterioles obtained from de-identified surgical discarded specimens of healthy B and NWH patients were used for video-microscopy. Vessels were incubated ex vivo 16–20 h with CTx (trastuzumab-TZM, doxorubicin-Dox, or paclitaxel-PTX). Response to endothelial dependent flow mediated dilation (FMD 5-100 cmH2O pressure gradient), acetylcholine (ACh; 10−9 to 10−5 M), and the endothelial independent dilator papaverine (Pap 10-4 M) were evaluated. Data are presented as %Max diameter ± SEM, N. Statistical significance was established with 2-way ANOVA RM *p<0.05. Results: Exposure to Dox decreased FMD equally in vessels from B (19±3, n=8) vs. NHW patients (29±5 n=8). The TZM induced endothelial dysfunction in vessels from B patients (37±8*, n=11) was augmented compared to NHW patients (57±15, n=6). PTX did not impair FMD in NHW patients (93±0.9, n=7) but showed a significant reduction in vessels from B patients (49±10*, n=10). Similar results were observed with ACh dilation, but Max dilator capacity to papaverine was unchanged in either group (not shown). Conclusion: Our findings suggest that racial disparities may contribute to differences in microvascular function and clinical outcomes of BC patients. Since dysfunction of the microcirculation is a common predecessor to heart failure and other MACE, novel strategies designed to predict, manage, and treat these adverse effects are needed and should be tailored to individual patient populations. To date, we cannot differentiate between biological/genetic vs. social/environmental contributors to the observed microvascular responses to CTx; that will be the focus of future studies. This work was supported by the American Heart Association Scientific Focused Research Network grant (SFRN.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Reproducibility and sex differences in muscle oxygenation during brachial artery occlusion in healthy participants.

Near-infrared spectroscopy (NIRS) measurement is a widely used technique to measure muscle oxygenation. A knowledge of the reproducibility of NIRS measurements is essential for the correct interpretation of data. Our aim was to test the reproducibility and sex differences of NIRS measurements during brachial artery occlusion in healthy participants. An NIRS device was used to measure muscle oxygenation and microvascular function during a 5 min brachial occlusion. Muscle oxygen consumption (mVO2) and tissue saturation index (TSI%) were used. The occlusion test was performed three times on separate days for males (n = 13, 28 ± 8 years) and females (n = 13, 29 ± 7 years). During the occlusion phase, the reproducibility of mVO2 was excellent (intraclass correlation; ICC = 0.90). During the reperfusion phase, the maximal change in TSI% revealed the best reproducibility (ICC = 0.77). There were no sex differences in reproducibility. Male participants had higher muscle oxygenation during occlusion (mVO2, 0.054 ± 0.010 vs. 0.038 ± 0.012 mLO2/min/100 g, p = 0.001, male and female, respectively). There were no sex differences during the reperfusion phase. The reproducibility of NIRS to measure muscle oxygenation and microvascular function during circulation occlusion and reperfusion is good to excellent. Muscle oxygen capacity measured during occlusion is higher in males compared to females, and there are no sex differences in microvascular function during the reperfusion phase.

Abstract 15676: Sex Differences in Leg Microvascular Arteriolar Function in Patients With Limb Ischemia

Introduction: There are known sex differences in peripheral artery disease (PAD) symptom presentation with women manifesting atypical symptoms and a higher vascular burden. Women are also more prone to periprocedural complications possibly due to sex-specific endothelial dysfunction and microvascular impairment. There is a critical need to understand sex specific differences in microvascular function to improve outcomes for women with PAD. Hypothesis: Lower limb arteriolar flow induced dilation (FID) will be significantly reduced in women, compared to men. Methods: Combined muscle and fat tissue were obtained from the affected leg in patients undergoing revascularization due to PAD. Arterioles were dissected, cannulated, and suspended in a physiological chamber at a stable intraluminal pressure. FID was assessed at increasing intraluminal pressure gradients. A subsample of vessels underwent arteriolar dilation with ACh with and without L-NAME, and SNP. Results: We quantified arteriolar FID in 24 arterioles (7=not viable) from 18 patients undergoing revascularization due to PAD (age 60.2 + 7.4, 44%=F, 61%=Black). Heterogeneity was observed in FID with significantly reduced response observed in women. FID in women at 60 cmH 2 O was 24.7 + 20.5%, compared to 52.6 + 28.0% in men, p=.05, and AUC was 69.0 + 66.8 in women, compared to 147.6 + 82.0 in men (p=.07). Findings were similar in both muscle and adipose arterioles. Vessels treated with Ach responded similar to FID. Vessels treated with L-NAME and SNP showed variable blunted response. Conclusions: Women had more impairment in arteriolar function compared to men, providing insight into sex dimorphism in the PAD population. Findings indicated that FID in arterioles is mostly nitric oxide dependent, although patient and sex specific changes in vascular smooth muscle signaling/function are present. This study support the need to develop microvascular and sex specific interventions for patients with PAD.

Sex differences in microvascular function and arterial hemodynamics in nondialysis chronic kidney disease.

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). Abnormal arterial hemodynamics contribute to CVD, a relationship that can be mediated by microvascular dysfunction. The purpose of this study was to investigate potential sex differences in arterial hemodynamics and microvascular dysfunction in patients with stages 3 to 4 CKD. Vascular function was assessed in 22 male (mean ± SD; age, 56 ± 13 yr) and 10 female (age, 63 ± 9 yr) patients. Arterial hemodynamics were acquired with combined tonometry and oscillometry. Skin blood flow was used as a model of microvascular function. Participants were instrumented with three microdialysis fibers for the delivery of 1) Ringer's solution; 2) superoxide dismutase mimetic, Tempol; and 3) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin. Blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). Central pulse pressure (mean ± SE; 62 ± 9 vs. 46 ± 3 mmHg; P = 0.01) and augmentation index (36 ± 3 vs. 26 ± 3%; P = 0.03) were higher in females. There was a trend for higher central systolic pressures in females (146 ± 9 vs. 131 ± 3 mmHg; P = 0.06). Females reported higher forward (39 ± 4 vs. 29 ± 2 mmHg; P = 0.004) and reflected (27 ± 3 vs. 19 ± 1 mmHg; P < 0.001) wave amplitudes. Cutaneous vascular function was impaired in females compared with males (77 ± 3 vs. 89 ± 1%, P = 0.001). Microvascular function was improved following the delivery of Tempol and apocynin in females but not in males. Female patients with CKD had poorer central hemodynamics and reduced microvascular function compared with their male counterparts. Oxidative stress may contribute to lower microvascular function observed in females.NEW & NOTEWORTHY There are limited data regarding the physiological mechanisms of potential sex differences in central hemodynamics and vascular function in chronic kidney disease (CKD). We report that older female patients with nondialysis CKD have higher central pulse pressures compared with male patients with CKD. In addition, older females with CKD have lower microvascular function compared with their male counterparts, and oxidative stress contributes to the lower microvascular function in older female patients with CKD.

Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women.

Observed sex differences in the epidemiology of cardiovascular disease incidence and the efficacy of clinical intervention strategies, coupled with recent mandates from the National Institutes of Health (NIH), and its international counterparts to consider sex as a biological variable in all preclinical and clinical work (15), have led to increased enrollment of women in human physiology studies of vascular function with the goal of improving external validity and clinical applicability of the findings. However, standard practice in these studies is to test women during the early follicular phase (~days 1-5) of the menstrual cycle, during which estrogen and progesterone concentrations are lowest, and either exclude or limit testing of women who use hormonal contraceptives to the placebo phase. This approach seeks to control for, or limit, differences in circulating hormone concentrations between men and women and is based on the dogmatic theory that cyclic changes in estrogen and progesterone concentrations lead to greater variability in study outcomes and uninterpretable datasets. Contrary to this common approach, we propose that limiting testing of women to this single phase 1) decreases external validity of the findings, 2) obfuscates potential physiological differences contributable to differences in sex hormone concentrations between men and women, and 3) is, in many instances, contradicted by literature that demonstrates limited or no variability in vascular measurements across the menstrual cycle.

Micro- and macrovascular function in patients suffering from primary adrenal insufficiency: a cross-sectional case\u2013control study

BackgroundDespite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, patients suffering from primary adrenal insufficiency (AI) have an increased mortality, mainly due to cardiovascular diseases. Only little knowledge exists on the contribution of MC substitution to the cardiovascular risk. Therefore, this study investigates the impact of plasma renin concentration on parameters of micro- and macrovascular function.Methods26 patients with primary AI [female = 18, age: 51 (28; 78) years; BMI: 24 (18; 40) kg/m2; disease duration: 18 (5; 36) years] were included in this cross-sectional analysis. Intima media thickness (IMT) and pulse wave velocity (PWV) were investigated to assess macrovascular remodeling and arterial stiffness. Microvascular function was estimated by post-occlusive reactive hyperemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded. Patients were grouped according to their median plasma renin concentration of previous visits (Reninhigh vs Reninlow) and were compared to a group of healthy women [age: 44 (43; 46) years; BMI: 24.2 (21.8; 27.5)].ResultsPWV was significantly higher in AI patients compared to controls [9.9 (5; 18.5) vs 7.3 (6.8; 7.7) m/s; p < .01], whereas no differences in microvascular function could be found. In Reninlow time to peak perfusion was significantly longer [6.0 (3; 15) vs 3.5 (1.5; 11) s; p < .05], whereas no differences in IMT and PWV were observed between Reninhigh and Reninlow. No impact of GC dose was observed.ConclusionsMicrovascular function is not impaired in patients with primary AI under adequate replacement therapy, although higher renin concentrations are associated with subclinical improvements. No relation between RAAS activity and macrovascular function is observed, while arterial stiffness might be increased in primary AI.

Comparison of Indices Used to Assess Microvascular Function During Post‐Occlusion Reactive Hyperemia in Humans

Numerous studies have used reactive hyperemia in response to cuff occlusion to assess microvascular function/reactivity. However, there are inconsistencies amongst these studies in regard to the indices used to quantify microvascular function/reactivity. Some studies do not provide accurate details of their analysis, while others report different indices such as peak velocity post occlusion or reactive hyperemic velocity area under the curve (AUC) from cuff release up to varying durations (i.e., 1 min, 2 min or back to baseline). As such, the lack of consistency in the reported indices makes it challenging to compare microvascular function between studies. Moreover, it remains unclear as to which index better characterizes microvascular function. Therefore, to elucidate the marker(s) that better detect differences in microvascular function, we compared young healthy subjects (YH) with normal vascular function (n = 10, age = 21 ± 1 yrs, BMI = 24.4 ± 0.7 kg/m2, mean ± SEM), to patients with type 2 diabetes (T2D), a population known to have impaired vascular function (n = 9, age = 58 ± 11 yrs, BMI = 38.3 ± 8.2 kg/m2). Heart rate (ECG) and brachial artery diameter and blood velocity (duplex Doppler Ultrasound) were measured continuously while subjects laid in supine position. Baseline measures were recorded for 2 min, following which a cuff placed just distal to the antecubital fossa was rapidly inflated to 220 mmHg for 5 min. Measurements were recorded for 30 s prior to and 3 min after cuff release. Microvascular function was quantified using the following indices of mean blood velocity after cuff release: peak velocity, percent change in peak velocity from baseline, and reactive hyperemic velocity AUC to: peak velocity, 10 s, 30 s, 1 min, 2 min and back to baseline. Peak velocity following cuff release was not different between groups (p = 0.70), however, baseline mean blood velocity was higher in T2D patients (T2D: 13.9 ± 1.8 cm/s vs. YH: 9.1 ± 1.7 cm/s; p = 0.04). Thus, we compared the percent change in peak velocity from baseline, which was significantly lower in T2D patients (T2D: 414.9 ± 63.5% vs. YH: 680.1 ± 107.8%; p = 0.03). AUC to peak blood velocity was also significantly lower in T2D (T2D: 289.6 ± 24.4 a.u. vs. YH: 453.73 ± 52.9 a.u.; p = 0.02); however, a shorter time to peak velocity in the T2D group likely contributed (T2D: 6.4 ± 0.8 s vs. YH: 10.2 ± 0.9 s; p = 0.007). To compare a similar duration between the groups, AUC up to 10 s, 30 s, 1 min, 2 min and back to baseline were calculated and these indices were not different between groups (e.g., AUC up to 30 s, T2D: 951.5 ± 84.9 a.u. vs. YH: 1141.0 ± 101.0; p = 0.13). Collectively, these preliminary results suggest that percent increase in peak velocity was able to discern the difference in microvascular function between the healthy and T2D groups whereas other indices were less consistent.Support or Funding InformationSupported by UTA College of Nursing and Health InnovationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex Differences in Microvascular Function and Circulating Biomarkers in Patients with Type 2 Diabetes Mellitus

Cardiovascular diseases are the major cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Evidence has shown that women have a greater risk for cardiovascular complications than men with T2DM, indicating a sex‐gender specific difference. Further studies regarding the mechanisms of sex differences are required for better prevention and treatment of diabetes complications in women. The aim of this study was to examine the microvascular endothelial function and circulating biomarkers in postmenopausal women (50–67 years) and age‐matched men with T2DM, without a history of cardiovascular events or complications. Participants without T2DM were also evaluated as control groups. This study was approved by the Ethical Committee of UNESP and UNICAMP (Number: 1.548.242). The eligible participants composed 4 groups: postmenopausal women (W) (n=16); postmenopausal women with T2DM (DW) (n=15); middle‐aged men (M) (n=15); middle‐aged men with T2DM (DM) (n=14). All participants were physically inactive, non‐smokers and not taking hormonal replacement or on insulin therapy. Both diabetic groups were on oral hypoglycemic therapy. After resting blood pressure measurement, the microvascular endothelial function was performed using EndoPAT 2000 and expressed as the reactive hyperemic index (RHI). Fasting blood samples were collected for biochemical analyses. All groups were age‐matched and the time of T2DM diagnosis was similar between the groups (DW: 7.5±1.3 DM: 9.6±2.3 yrs). Anthropometric parameters, systolic and diastolic blood pressure, lipid profile, HbA1c and insulin levels were not different between women and men with diabetes. On the other hand, DM showed a higher blood glucose level and HOMA‐IR compared with DW. Regarding microvascular endothelial function, RHI was similar between DW (1.97±0.14) and DM (1.93±0.12) without alterations in circulating biomarkers: adiponectin, N‐ɛ‐(carboxymethyl) lysine (CML), nitrite/nitrate (NOx−), transforming growth factor‐β (TGF‐β), tumor necrosis factor‐α (TNF‐α) and C‐reactive protein (CRP). Nevertheless, when diabetic groups were compared with the control groups, we observed a higher body mass index (BMI) and abdominal circumference in DW compared with its respective control group. Besides that, DW also presented impaired RHI and a lower adiponectin level associated with increased CML and NOx− concentrations compared with W group (RHI: 2.51±0.13). All these alterations were not found in DM compared with its respective control group. Our findings show that circulatory biomarkers disturbance and microvascular dysfunction are present in diabetic women showing that this population is more affected by the deleterious effects of T2DM than men.Support or Funding InformationCNPq and FAPESPThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

This hyperoxia mouse model using the wavelet transform analysis of flowmotion signals helps to look further into microvascular dysfunction

The use of animal models still presents many difficulties mostly because (a) no single model accurately recreates one disease, (b) the use of so many models impair comparison of results and (c) extrapolation to human is very limited. We have been dedicated to develop the potential use of oxygen as a challenger to study microcirculatory function and regulatory mechanisms. In the present study we show how this hyperoxia mouse model helps to identify different events associated to angiogenesis, following an hindlimb ischemia procedure, and test its discriminative capacities in detecting relevant differences in microvascular function between healthy and non‐healthy mice. Animals (n=66) were divided in three groups ‐ Control (C) with 33 C57/BL6 non‐transgenic male mice, part of which (9) submitted to a hindlimb ischemia (HLI) procedure, a genetically modified diabetic group (DB) including 8 transgenic C57BLKsJ‐db/db obese diabetic mice and the corresponding internal control of 8 age‐matched C57BLKsJ‐db/+ mice, and a transgenic cardiac hypertrophy group (CH) with 9 BALB/c mice prone to develop cardiac failure and 8corresponding age‐matched internal controls. Animals were anesthetized with a ketamine ‐ xylazine mixture and perfusion data collect by Laser Doppler Flowmetry during baseline rest (Phase 1), while breathing a 100% oxygen atmosphere (Phase2) and during recovery (Phase 3) and compared. Laser Doppler (LD) imaging and flowmetry were used as assessment instruments allowing to follow up all the processes regarding the HLI recovery. The wavelet transform (WT) component's analysis was allowed to further distinct between groups. Hyperoxia by itself revealled that new vessels are not functionally equivalent to those in the non‐operated limb but that recovery, also involves this limb, suggesting a cooperation mechanism probably centrally mediated. The WT analysis suggests that cardiorespiratory, myogenic and endothelial components act as main markers. In DB group db/+ animals behave as the Control group, as expected, but WT analysis shown significant differences for myogenic and the endothelial components. Noteworthy was the increase of the sympathetic components in the db/db set, as in the NHE1‐OE animals, in both cases reported as a main component of these pathophysiological processes. In conclusion, this hyperoxia‐mouse model, including the WT component analysis of LDF signal, seems to be reproducible, robust and discriminative, providing a deeper look into these different expressions of microcirculatoru pathophysiology in different experimental conditionsSupport or Funding InformationThis work was supported by national funds from FCT I.P, within the project UID/DTP/04567/2016.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Evidence of Racial Differences in Microvascular Function Among College-Aged Women

Microvascular dysfunction contributes to the development of hypertension and insulin resistance. The black population is at an elevated risk of both conditions relative to other racial groups. Previous studies indicate that college-aged black men, compared to their white counterparts, exhibit impaired microvascular function as assessed by post- occlusion reactive hyperemia (RH). It is unknown whether this racial disparity is present in healthy, young adult black (BW) and white women (WW). Furthermore, whether nitric oxide-mediated cutaneous microvascular hyperemia during local heating (LH) is different in these populations has not been determined. PURPOSE: The purpose of this study was to test the hypothesis that college-aged BW exhibit blunted RH and attenuated LH induced cutaneous hyperemia compared to age-matched WW. METHODS: College-aged BW (n=7) and WW (n=7) were studied during the early follicular phase of the menstrual cycle. For RH, brachial artery diameter and blood velocity were measured via Doppler ultrasound before and after 5 min of forearm occlusion. For LH, a microdialysis membrane was inserted in the dermis of the forearm and perfused with Ringer’s solution. Red blood cell flux was assessed with laser Doppler after ~40 min of continuous 39°C LH. Maximal flux was established with 28 mM sodium nitroprusside infusion and 43°C LH. Brachial BP was measured throughout the protocol and cutaneous vascular conductance (CVC) was calculated as flux / MAP and reported as % of max CVC. RESULTS: WW and BW were matched for age (21 ± 3 vs 20 ± 1 y, P = 0.58) and BMI (23 ± 2 vs 23 ± 3 kg/m2, P = 0.94). There were no differences between WW and BW in baseline blood velocity (23.1 ± 5.7 vs 24.4 ± 11.6 cm/s, P = 0.79) or blood flow (98.9 ± 38.3 vs 114.5 ± 80.7 ml/min, P = 0.65). WW and BW also had similar peak blood velocity (109.2 ± 13.8 vs 109.7 ± 28 cm/s, P = 0.97), peak blood flow (453.7 ± 164.7 vs 482.5 ± 187.7 ml/min, P = 0.77), and total blood flow AUC during the 120 s after cuff release (487.4 ± 178.5 vs 486.8 ± 190.1 ml, P = 0.99). However, compared to WW, BW had a significantly blunted CVC during 39°C LH (66 ± 17 vs 45 ± 10 %max, P = 0.02). CONCLUSIONS: BW had blunted blood flow responses to LH compared to WW despite similar blood velocity and flow responses during RH. This suggests that LH is more sensitive than RH to early impairments in microvascular function.

The influence of sex on microvascular function.

A number of studies consistently report higher rates of all clinical outcomes including postinfarction mortality, need for repeat revascularization, and reinfarction in women with cardiovascular diseases than in men. As well, the gender gap in the prevalence of cardiovascular diseases decreases progressively with increasing age. Yet, the diagnosis and treatment of these diseases differ between genders and women remain underdiagnosed for coronary heart disease. In a recent retrospective analysis we showed that, along with vessel under study and age, gender is a determinant of adenosine responses during studies of fractional flow reserve, an effect that was probably due to differences in microvascular function and that influenced the interpretation of fractional flow reserve data. These data demonstrate that not only the clinical presentation is different, but also the diagnostic approach to coronary artery disease might differ between sexes.A gap still exists in the understanding of the mechanisms, awareness, and treatment of coronary artery disease in women, but also, as we show, in the application of diagnostic modalities that are well established in men.

Index of microvascular resistance after early conversion from calcineurin inhibitor to everolimus in heart transplantation: A sub-study to a 1-year randomized trial

Microvascular function in transplanted hearts can be evaluated by methods used in routine left heart catheterization follow-up after heart transplantation (HTx). This sub-study of a randomized study compared the effects of everolimus (EVR) and calcineurin inhibitor (CNI) treatment on microvascular function as expressed by the index of microvascular resistance (IMR) at 1 year after HTx. A secondary objective was to compare the change in IMR from 7-11 weeks to 1 year after HTx between randomized groups. There were 70 HTx recipients included and randomly assigned to combination therapy (EVR and CNI with early CNI withdrawal) vs conventional CNI treatment. Coronary physiologic assessment was performed 7-11 weeks and 1 year after HTx. A linear mixed model was used to assess the group difference at 1 year and the difference in IMR change between 7-11 weeks and 1 year after HTx. At 1 year, there was no significant difference in IMR between the EVR group (17.5 mm Hg∙sec ± 8.9) (mean ± SD) and the CNI group (14.9 mm Hg∙sec ± 6.6, p = 0.17). The difference in IMR change between the 2 treatment arms was 1.6 mm Hg∙sec (95% confidence interval, -2.8 to 5.9; p = 0.49). Spearman's rank correlation coefficient at 1 year after HTx between IMR and maximal intimal thickness as assessed with intravascular ultrasound in the left anterior descending artery was -0.13 (p = 0.28). In this prospective, open, randomized study comparing early CNI withdrawal with mammalian target of rapamycin inhibitors immunosuppression during the first year after HTx, early transition from CNI-based immunosuppression to EVR-based treatment did not result in differences in microvascular function as assessed by the IMR.

Ethnic differences in microvascular function in apparently healthy South African men and women.

Microvascular dysfunction precedes the clinical manifestations of cardiovascular disease. Given the ethnic disparities in cardiovascular disease, we aimed to investigate ethnic differences in microvascular endothelial function in a group of young (18-33years old), apparently healthy individuals (n=33, nine Black African, 12 mixed ancestry and 12 Caucasian). Microvascular endothelium-dependent and -independent function was assessed by laser Doppler imagery and iontophoresis of ACh and sodium nitroprusside (SNP), respectively, adjusting for skin resistance. Microvascular reactivity was expressed as maximum absolute perfusion, percentage change from baseline and area under the curve (AUC). Skin resistance was significantly lower in the Caucasian group in response to ACh (Caucasian, mean 0.16±0.03Ω versus Black, 0.21±0.04Ω and mixed ancestry, 0.20±0.02Ω, P<0.01) and SNP (Caucasian, 0.08±0.01Ω versus Black, 0.11±0.02Ω and mixed ancestry, 0.12±0.01Ω, P<0.01). Microvascular function in response to ACh was significantly higher in the Caucasian group compared with the other two groups; however, after adjusting for skin resistance these differences were no longer significant. Conversely, the microvascular SNP response remained significantly higher in the Caucasian group, even after adjusting for skin resistance (P<0.01). Diastolic blood pressure was inversely associated with the AUC of ACh (r=-0.4) and all SNP responses (r=-0.3 to -0.6). Skin resistance was inversely associated with AUC and maximum absolute ACh response (r=-0.59 and -0.64, respectively) and all SNP responses (r=-0.37 to -0.79). Ethnic differences in endothelium-independent microvascular function may contribute to ethnic disparities in cardiovascular disease. Moreover, skin resistance plays a significant role in the interpretation of the microvascular response to outcomes of iontophoresis in a multiethnic group.

The influence of sex and antenatal betamethasone exposure on vasoconstrictors and the preterm microvasculature

Objective. Dysregulated vascular resistance contributes to hypotension following preterm birth with sex-specific differences in microvascular function conferring a male disadvantage. We hypothesized that glucocorticoid mediated, sex-specific differences in the endogenous catecholamine norepinephrine and endothelially derived endothelin-1 (ET-1) contribute to microvascular dysfunction in preterm neonates in the immediate newborn period.Methods. Umbilical and plasma ET-1 and normetanephrine, in 24 h urine samples, were determined at 24, 72, and 120 h of age in 24–34 week infants (n = 60). Microvascular blood flow was determined by laser Doppler flowmetry.Results. In infants born within 72 h of antenatal glucocorticoid exposure, normetanephrine was higher in females than males (p = 0.048). Normetanephrine was inversely correlated with both microvascular blood flow at 24 h (p = 0.025) and CRIB II (p = 0.001). While umbilical arterial ET-1 was higher in females delivered <72 h after antenatal betamethasone (p = 0.006), plasma ET-1 did not correlate with microvascular blood flow or illness severity. Only sex and normetanephrine contributed significantly to both microvascular blood flow and endothelium dependant vasodilatation.Conclusions. These data support glucocorticoid mediated, sex-specific differences in mediators of vascular tone that may contribute to the impaired mechanisms compromising successful hemodynamic adaption to neonatal life and resulting in excess male morbidity and mortality.

Attenuation of microvascular function in those with cardiovascular disease is similar in patients of Indian Asian and European descent

BackgroundIndian Asians are at increased risk of cardiovascular death which does not appear to be explained by conventional risk factors. As microvascular disease is also more prevalent in Indian Asians, and as it is thought to play a role in the development of macrovascular disease, we decided to determine whether impaired microcirculation could contribute to this increased cardiovascular risk in Indian Asians.MethodsForearm skin laser Doppler fluximetry in response to heating and ischaemia was assessed in 83 Europeans (41 with angiographically confirmed atherosclerotic coronary artery disease (CAD) and 42 from the general population) and 84 Indian Asians (41 with CAD). Explanations for differences in microvascular function were sought using multivariate analysis including conventional cardiovascular risk factors.ResultsCompared to ethnically matched control populations both Europeans and Indian Asians with CAD had poorer microvascular responses to heating than those without (117(95% CI 105-131) vs. 142(130-162) arbitrary units, (au) for Europeans and 111(101-122) vs. 141(131-153)au for Indian Asians) and to ischaemia (44(38-50) vs. 57(49-67)au & 39(34-45) vs. 49(43-56)au respectively). These differences were not accounted for by conventional cardiovascular risk factors. There was no ethnic difference in the attenuation of microvascular function associated with CAD.ConclusionPatients of European and Indian Asian descent with symptomatic CAD have poorer microvascular maximal tissue perfusion and reactive hyperaemia in the skin compared to ethnically matched asymptomatic control populations. Despite the increased cardiovascular risk in Indian Asians, the attenuation of microvascular function associated with CAD was equivalent in the ethic groups. This suggests that in Indian Asians microcirculation does not explain the increased susceptibility to CAD.

Pulse wave amplitude is associated with brachial artery diameter: Implications for gender differences in microvascular function

The ratio of pulse wave amplitude (PWA) during reactive hyperemia compared to baseline as measured by peripheral arterial tonometry (PAT) is a non-invasive measure of microvascular endothelial function referred to as the pulse wave amplitude reactive hyperemia index (PWA-RHI). Whether upstream conduit vessel structure may affect downstream resistance vessel PWA has not been clearly examined. We tested the hypothesis that digital PWA is influenced by brachial artery diameter (BAD) and that this association would influence comparison of PWA-RHI between genders. Measures of vascular structure and microvascular function were carried out in 115 patients varying in cardiovascular risk profiles (average age 57 years, male n = 79, CAD n = 43). PWA was assessed using plethysmography at baseline and following 5 minutes of brachial artery occlusion. BAD was assessed using high-resolution ultrasonography. Results : There was a negative association between BAD and PWA-RHI ( r = -0.34, p < 0.05). Women had greater PWA-RHI and smaller BAD compared with men (p < 0.05). When co-varying for BAD, there were no longer gender differences in PWA-RHI. Moreover, when a sub-group of men and women without CAD (n = 40), matched for BAD, were examined, there were no gender differences in PWA-RHI. In conclusion, PWA-RHI obtained from PAT is associated with BAD. Studies examining gender differences in microvascular endothelial function with PAT may need to correct for BAD as a potential confounder.

Effects of Black Race on Forearm Resistance Vessel Function

Presentation, response to therapy, and clinical outcome in hypertension differ according to race, and these observations could relate to differences in microvascular function. We examined forearm microvascular function in age-matched black (n=56) and white subjects (n=62) using intra-arterial agonist infusion and venous occlusion plethysmography. In normotensive subjects (n=70; 34 black and 36 white normotensives), methacholine-, sodium nitroprusside-, and verapamil-induced vasodilation was equivalent in black and white subjects. In hypertensive subjects (n=48; 22 black and 26 white hypertensives), the vasodilator response to methacholine was markedly lower in black subjects compared with white subjects (P<0.001). The vasodilator responses to sodium nitroprusside and verapamil, however, were equivalent in black and white hypertensive subjects. Acute ascorbic acid infusion improved the methacholine response equally in black and white hypertensive patients, suggesting that a difference in a rapidly reversible form of oxidative stress does not explain these findings. Thus, the present study demonstrates important racial differences in vascular function and a marked impairment in endothelial vasomotor function in black patients with hypertension. Further studies will be required to elucidate the mechanisms and determine whether these insights will lead to more appropriately tailored management of hypertension and its complications.

Lung albumin accumulation is spatially heterogeneous but not correlated with regional pulmonary perfusion.

The contribution of pulmonary perfusion heterogeneity to the development of regional differences in lung injury and edema is unknown. To test whether regional differences in pulmonary perfusion are associated with regional differences in microvascular function during lung injury, pigs were mechanically ventilated in the prone position and infused with endotoxin (Escherichia coli 055:B5, 0.15 microg. kg(-1). h(-1); n = 8) or saline (n = 4) for 4 h. Extravascular albumin accumulation and perfusion were measured in multiple approximately 0.7-ml lung regions by injecting pigs with radiolabeled albumin and radioactive microspheres, respectively. Extravascular albumin accumulation was spatially heterogeneous but not correlated with regional perfusion. Extravascular albumin accumulation was greater in dorsal than ventral regions, and regions with similar albumin accumulation were spatially clustered. This spatial organization was less evident in endotoxemic than control pigs. We conclude that there are regional differences in lung albumin accumulation that are spatially organized but not mediated by regional differences in pulmonary perfusion. We speculate that regional differences in microvascular pressure or endothelial function may account for the observed distribution of extravascular albumin accumulation.

Spatial heterogeneity in striated muscle arteriolar tone, cell flow, and capillarity

Spatial variations in microvascular function are described at two tissue sites in hamster cremaster muscle (pentobarbital sodium, 70 mg/kg ip). Arterioles observed include terminal arterioles and their feeding vessels, termed capillary network controllers (CNC). Although terminal arterioles at both sites had similar maximum diameters and cell flows, those at site I were significantly more constricted at rest (2.7 +/- 0.3 vs. 5.1 +/- 0.3 microns at site II) and showed lower resting flows (19.0 +/- 5.5 vs. 174 +/- 34 cells/s at site II). There were no spatial differences in CNC maximal parameters or CNC resting tone, yet CNC resting flow at site II (798 +/- 118 cells/s) significantly exceeded the value at site I (460 +/- 85 cells/s). At rest, median capillary cell flow at site I (3.3 cells/s) was half that at site II (6.3 cells/s). During hyperemia, perfused capillary segment length per unit volume was 84% greater at site I and estimated tissue erythrocyte content nearly double that at site II. Thus significant spatial differences in microvascular function exist in cell flow and vessel tone among terminal arterioles, in cell flow among CNC, and in capillarity and indices of capillary exchange.

Lung Microvascular Transport Properties Measured by Multiple Indicator Dilution Methods in Patients with Adult Respiratory Distress Syndrome: A Comparison between Patients Reversing Respiratory Failure and Those Failing to Reverse

We conducted indicator dilution studies on the lungs of patients in the early phases of adult respiratory distress syndrome (ARDS) to test the hypothesis that capillary permeability was increased in patients with respiratory failure. Indicator dilution studies were performed using 51Cr-erythrocytes, 125I-albumin, 14C-urea, and 3H-water as tracers. The injectate was infused as a bolus into a central venous line. Peripheral arterial blood was collected and counted for radioactivity. Mathematical analysis of the indicator curves yielded cardiac output, measures of the product of capillary permeability and surface area for urea (PS and D1/2S), the intravascular lung volume (Vv), and the extravascular lung water volume (Ve). Permeability was separated from surface area by normalizing PS and D1/2S to Vv. Patients could be divided into 16 in whom blood gas determinations and radiologic criteria for ARDS were reversed and 23 in whom they were not. We examined indicator dilution and other measures of lung function in the two groups to determine whether significant differences in microvascular function existed. PS and PS/Vv were significantly higher in the nonreversal patients. Ve was above normal, but not different between groups. Linear regression analysis showed significant correlations for all of the following in the nonreversal group: Ve and all measures of permeability, pulmonary vascular resistance (PVR), and the inverse of permeability-surface area measures and AaDO2 and PVR. Only measures of Ve and PS correlated in the reversal group. These results support the hypothesis that capillary permeability is increased in patients with early ARDS and continuing respiratory failure.(ABSTRACT TRUNCATED AT 250 WORDS)