Microvascular Function In Women Research Articles

Microvascular dysfunction in women with a history of hypertensive disorders of pregnancy: A population-based retrospective cohort study.

To evaluate microvascular function in women with previous hypertensive disorders of pregnancy (HDP). Retrospective population-based cohort study. Linköping, Sweden. Women aged 50-65 years, participating in the Swedish CArdioPulmonary bioImage Study (SCAPIS) at one site (Linköping) 2016-18, who underwent microcirculatory assessment (N = 1222). Forearm skin comprehensive microcirculatory assessment was performed with a PeriFlux PF6000 EPOS (Enhanced Perfusion and Oxygen Saturation) system measuring oxygen saturation and total speed resolved perfusion. Obstetric records were reviewed to identify women with previous HDP. Data on cardiovascular risk factors, comorbidities, medication, lifestyle, anthropometric data, and biochemical analyses were obtained from SCAPIS. The microcirculatory data were compared between women with and without previous HDP. Skin microcirculatory oxygen saturation and total speed resolved perfusion at baseline and post-ischaemic peak. Women with previous pre-eclampsia displayed impaired post-ischaemic peak oxygen saturation compared with women with normotensive pregnancies (88%, interquartile range [IQR] 84-89% vs 91%, IQR 87-94%, p = 0.001) 6-30 years after pregnancy. The difference remained after multivariable adjustment (β -2.69, 95% CI -4.93 to -0.45). The findings reveal microvascular dysfunction at long-term follow up in women with previous pre-eclampsia and strengthen the possible role of endothelial dysfunction as a link to the increased risk of cardiovascular disease in women with HDP.

Metabolic and microvascular function assessed using near-infrared spectroscopy with vascular occlusion in women: age differences and reliability.

What is the central question of this study? Can the near-infrared spectroscopy with vascular occlusion test (NIRS-VOT) reliably measure skeletal muscle metabolic and microvascular function in women? What is the main finding and its importance? The NIRS-VOT can be used as a reliable technique for the assessment of skeletal muscle metabolism and microvascular function in women, with reliability being generally greater in younger women. These findings have important implications for the planning and development of future studies employing the NIRS-VOT in women, and provide insights into the effects of age on these parameters in women specifically. We investigated the test-retest reliability of, and age-related differences in, markers of skeletal muscle metabolism and microvascular function derived from the near-infrared spectroscopy with vascular occlusion test (NIRS-VOT) in younger women (YW) and middle-aged and older women (MAOW). Seventeen YW (age 23±4years) and 17 MAOW (age 59±8years) completed this study. Participants completed identical experimental visits separated by ∼4weeks during which the NIRS-VOT was used to quantify the occlusion slope, minimum and maximum tissue saturation, ischaemic index, reperfusion magnitude, the reperfusion and 10-s reperfusion slopes (slope 2 and slope 210-s ), time to max tissue saturation, and area under the reperfusion curve using the local tissue oxygen saturation signal. Except for slope 210-s (intraclass correlation coefficient (ICC)=0.37; coefficient of variation (CV)=31%), time to max tissue saturation (ICC=0.21), and ischaemic index (ICC=0.37) for MAOW, all of the NIRS variables demonstrated good to excellent relative reliability for the YW (ICCs=0.74-0.86) and the MAOW (ICCs=0.51-0.87), with CVs of 2-21% and 2-22%, respectively. The occlusion slope was significantly lower, indicating accelerated deoxygenation, while maximum tissue saturation, reperfusion magnitude, and ischaemic index were significantly higher in YW versus MAOW. No other group differences were found. In conclusion, our data support the use of the NIRS-VOT as a simple, reliable, non-invasive technique for the assessment of peripheral skeletal muscle metabolism and microvascular function in women, with the reliability being generally greater in YW versus MAOW. Further, our data suggest that ageing is associated with lower skeletal muscle metabolism and microvascular hyperaemic responsiveness in women.

Seven days of statin treatment improves nitric-oxide mediated endothelial-dependent cutaneous microvascular function in women with endometriosis.

Endometriosis is associated with systemic inflammation and increased risk of cardiovascular disease (CVD). Endothelial dysfunction is one of the first manifestations of CVD but is unexplored in women with endometriosis. HMG-CoA-reductase inhibitors (statins) exert potent anti-inflammatory effects, and have been proposed as an adjunctive therapy in women with endometriosis. We hypothesized that microvascular endothelial function would be impaired in otherwise healthy women with endometriosis mediated by reduced nitric oxide (NO)-dependent dilation and that short term statin administration would improve endothelial function. In 8 healthy control (HC: 33±9yr) and 8 women with endometriosis (EN: 34±9yr), laser-Doppler flux (LDF) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (Ach: 10-10-10-1M) alone and in combination with the NO synthase inhibitor (L-NAME: 0.015M). 6 EN repeated the microdialysis experiment following 7days of oral atorvastatin treatment (10mg). Cutaneous vascular conductance was calculated (CVC=LDF*mmHg-1) and normalized to site-specific maximum (28mM sodium nitroprusside, 43°C). The NO-dependent dilation was calculated as the difference between the areas under the dose response curves. Ach-induced vasodilation was blunted in women with endometriosis (main effect p<0.01), indicating impaired endothelial function. NO-dependent vasodilation was also reduced in women with endometriosis (HC: 217±120.3 AUC vs. EN: 88±97 AUC, p=0.03). Oral atorvastatin improved Ach-induced (main effect p<0.01) and NO-dependent (295±153 AUC; p=0.05) vasodilation in women with endometriosis. Microcirculatory endothelium-dependent vasodilation is impaired in women with endometriosis, mediated in part by reductions in NO. Short-term oral atorvastatin improved endothelium-dependent vasodilation, suggesting that statin therapy may be a viable intervention strategy to mitigate accelerated CVD risk in women with endometriosis.

Role of different echocardiographic modalities in the assessment of microvascular function in women with ischemia and no obstructive coronary arteries.

This review summarizes current knowledge about echocardiographic modalities used to assess microvascular function and left ventricular (LV) systolic function in women with ischemia and no obstructive coronary arteries (INOCA). Although the entire pathophysiological background of this clinical entity still remains elusive, it is primarily linked to microvascular dysfunction which can be assessed by coronary flow velocity reserve. Subtle impairments of LV systolic function in women with INOCA are difficult to assess by interpretation of wall motion abnormalities. LV longitudinal function impairment is considered to be an early marker of subclinical systolic dysfunction and can be assessed by global longitudinal strain quantification.

Effect of Oral Contraceptive Phase on Mechanisms of Cutaneous Microvascular Function

While the effect of oral contraceptive (OC) use on endothelial function has been previously studied, precise mechanisms of endothelial function in this group of women remains unclear. The purpose of this study was to investigate the contribution of cyclooxygenase (COX), endothelial‐derived hyperpolarizing factors (EDHF), and nitric oxide (NO) to cutaneous microvascular function in women during the low hormone (LH) and high hormone (HH) phases of OC. Five young, healthy women taking monophasic, combined OC of any generation visited the lab twice: once during the LH (d 1‐2 of placebo pills) and once during the HH phase (d 3‐6+ of active pills). Participants were instrumented with three microdialysis fibers, and each site was randomized as control (lactated Ringer's), COX inhibition (10 mM ketorolac), or EDHF inhibition (50 mM tetraethylammonium, TEA). Laser‐Doppler flowmetry and local heaters were used to measure skin blood flow and induce local thermal hyperemia, respectively. Each site was heated from 33°C to 39°C at a rate of 0.1°C/sec. Once a plateau to local heating was established, 20 mM L‐NAME, a NO synthase inhibitor, was infused at each site to quantify NO‐dependent vasodilation. Maximal vasodilation was induced by heating the skin to 43°C and infusing 28 mM sodium nitroprusside. Data are mean ± SD. For baseline, there was a main effect of OC phase (p = 0.03) and treatment (p &lt; 0.001) but no interaction effect (p = 0.21) such that baseline was increased at COX‐inhibited sites (23 ± 3 %CVCmax) compared with control (14 ± 6 %CVCmax; p = 0.03) during the HH phase. For initial peak, there was a main effect of treatment (p &lt; 0.001) but no effect of OC phase (p = 0.99) or interaction effect (p = 0.59) such that initial peak was decreased at EDHF‐inhibited sites during the HH phase (17 ± 6 %CVCmax) compared with control (51 ± 23 %CVCmax; p = 0.02). For local heating plateau, there was a main effect of treatment (p &lt; 0.001) but no effect of OC phase (p = 0.28) or interaction effect (p = 0.21) such that plateau was decreased at EDHF‐inhibited sites during both phases (LH: 18 ± 12 %CVCmax; HH: 20 ± 9 %CVCmax) compared with respective control (LH: 63 ± 13 %CVCmax; HH: 67 ± 23 %CVCmax) and ketorolac sites (LH: 58 ± 21 %CVCmax; HH: 71 ± 12 %CVCmax; all comparisons: p &lt; 0.01). For %NO, there was no observed effect of OC phase (p = 0.77), treatment (p = 0.21), or interaction (p = 0.09). While not statistically significant, there was a large effect size for %NO between LH and HH phases at control sites (LH: 72 ± 15 %NO; HH: 50 ± 23 %NO; Cohen’s d = 1.05). During the LH phase, large effect sizes were observed between control and TEA (48 ± 14 %NO; d = 1.65) sites and control and ketorolac (54 ± 22 %NO; d = 0.96) sites. During the HH phase, a large effect size was observed between control and ketorolac (69 ± 17 %NO; d = 0.94) sites. These preliminary data suggest mechanisms underlying endothelial function vary across OC phase in women. While overall endothelial function (i.e., magnitude of local heating plateau) is similar between OC phases, there may be basal constriction (i.e., increased baseline with COX inhibition) and reduced NO‐dependent dilation during the HH phase. This shift in mechanisms underlying endothelial function in women using OC may contribute to cardiovascular health outcomes.

Reliability of the hyperaemic response to passive leg movement in young, healthy women.

What is the central question of this study? This is the first study to assess the day-to-day reliability of passive leg movement-induced hyperaemia (PLM-H), an index of lower-limb microvascular function, in young, healthy women. What is the main finding and its importance? Passive leg movement-induced hyperaemia demonstrated good day-to-day reliability, comparable to other common indices of endothelial function, supporting the use of PLM-H to assess lower-limb microvascular function in women. Passive leg movement-elicited hyperaemia (PLM-H) provides an index of lower-limb microvascular function. However, there is currently limited information regarding the reliability of PLM-H and no reliability information specific to women. The purpose of this study was to determine the reliability of PLM-H in women on two separate days. Seventeen young, healthy women [22±3 years old (mean±SD)] participated in two identical visits including three trials of PLM. Using duplex ultrasound, PLM-H was characterized by six indices: peak leg blood flow (LBF) and vascular conductance (LVC), peak change above baseline (Δpeak) for LBF and LVC, and area under the curve above baseline (AUC) during the first 60s of PLM for LBF and LVC. The results demonstrated good day-to-day reliability of PLM-H characterized as peak LBF [r=0.84, P<0.001; intraclass correlation coefficient (ICC)=0.84; coefficient of variation (CV)=13.2%], peak LVC (r=0.82, P<0.001; ICC=0.79; CV=14.4%), Δpeak LBF (r=0.83, P<0.001; ICC=0.82; CV=17.8%) and Δpeak LVC (r=0.83, P<0.001; ICC=0.80; CV=16.5%). Characterization of PLM as AUC demonstrated moderate day-to-day reliability: AUC LBF (r=0.71, P<0.05; ICC=0.70; CV=31.2%) and AUC LVC (r=0.78, P<0.001; ICC=0.74; CV=27.1%). In conclusion, this study demonstrates that PLM-H has good reliability as an index of microvascular function; however, characterization of PLM-H as peak, Δpeak LBF and LVC is more reliable than AUC.

Comprehensive treatment of microvascular angina in overweight women - a randomized controlled pilot trial.

AimsCoronary microvascular dysfunction (CMD) carries a poor cardiovascular prognosis and may explain angina in women without obstructive coronary artery disease (CAD). Currently, no evidence-based treatment for CMD exists. We investigated whether reducing cardiovascular risk factors improves symptoms and microvascular function in women with non-endothelial dependent CMD and no obstructive CAD.MethodsWe randomized 62 women aged 40–75, with body mass index (BMI) >25 kg/m2, angina ≥monthly, and coronary flow velocity reserve (CFVR) ≤2.5 to a 24-week intervention comprising low energy diet, exercise training, and optimized treatment of hypertension, dyslipidemia and diabetes or to control. Patients were assessed before randomization and after 24 weeks. Primary outcomes were CFVR assessed by transthoracic Doppler stress-echocardiography and angina burden by Seattle Angina Questionnaire (SAQ). Secondary outcomes were exercise capacity, body composition, glycemic control, myocardial function, and anxiety and depression symptoms.ResultsFifty-six participants (90%) completed the study. Median (IQR) age was 65.2 (57.1;70.7) years, BMI was 30.1 (28.4;32.7) kg/m2. The intervention resulted in relevant improvement in angina symptoms (9-21-point increase on SAQ-scales (all p<0.01)) but had no effect on CFVR (p = 0.468). Mean (CI) weight loss was 9.6 (7.80;11.48) kg, (p<0.0001). There was a significant mean (CI) decrease in depression symptoms = 1.16 (0.22;2.12), triglycerides = 0.52 (0.25;0.78) mmol/L, total cholesterol = 0.55 (0.12;0.98) mmol/L, and HbA1c in diabetics = 27.1 (1.60;52.6) mmol/mol but no effect on other secondary outcomes.ConclusionA major weight loss and intensified risk factor control resulted in significantly improved angina burden but no improvement of coronary microvascular function among women with microvascular angina.

Effect of weight loss, exercise and risk factor control in microvascular angina. A randomized controlled pilot trial

Abstract Background Coronary microvascular dysfunction (CMD) is a common cause of angina in women and associated with adverse cardiovascular prognosis. Currently, no evidence-based treatment for CMD exists. Purpose To examine whether an intervention targeting cardiovascular risk factors is feasible and improves angina symptoms and microvascular function in women with CMD and no obstructive coronary artery disease. Methods We randomized 62 women aged 40–75, with body mass index &amp;gt;25 kg/m2, angina symptoms monthly or more and coronary flow velocity reserve (CFVR) &amp;lt;2.5 to a 24-week intervention comprising low energy diet, exercise training, and optimized medical treatment of hypertension, dyslipidemia and diabetes or to usual care. Patients were assessed before randomization and after 24 weeks. The primary outcomes were CFVR assessed by transthoracic Doppler stress-echocardiography and angina burden measured by the Seattle Angina Questionnaire (SAQ). Secondary endpoints were exercise capacity (VO2max), body composition and glycemic control, anxiety and depression symptoms measured by the Hospital Anxiety and Depression Scale (HADS). Results Fifty-six participants (90%) completed the study. Median age was 65 years. The intervention group obtained a mean weight loss of 10 kg, mainly (9 kg) from fat tissue (all p&amp;lt;0.0001), increased work load (p&amp;lt;0.01), decreased triglycerides, low density lipoprotein and low plasma cholesterol (all p&amp;lt;0.006). HbA1c in non-diabetes participants also decreased (p&amp;lt;0.05). There was a clinically relevant improvement in all angina symptoms (9–21-point increase on all SAQ scales (all p&amp;lt;0.01)) as well as in depression score (p=0.008). There was no effect on CFVR or other secondary outcomes. Conclusion A major weight loss and intensified risk factor control resulted in significant improvement in angina burden but no improvement of coronary microvascular function among women with microvascular angina. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Unlimited research funding sources from the Capital region of Denmark and Bispebjerg-Frederiksberg Hospital internal funding sources.

Local angiotensin-(1-7) administration improves microvascular endothelial function in women who have had preeclampsia.

Despite remission of clinical symptoms postpartum, women who have had preeclampsia demonstrate microvascular endothelial dysfunction, mediated in part by increased sensitivity to angiotensin II (ANG II). Angiotensin-(1-7) [Ang-(1-7)] is an endogenous inhibitor of the actions of ANG II and plausible druggable target in women who had preeclampsia. We therefore examined the therapeutic potential of Ang-(1-7) in the microvasculature of women with a history of preeclampsia (PrEC; n = 13) and parity-matched healthy control women (HC; n = 13) hypothesizing that administration of Ang-(1-7) would increase endothelium-dependent dilation and nitric oxide (NO)-dependent dilation and decrease ANG II-mediated constriction in PrEC. Using the cutaneous microcirculation, we assessed endothelium-dependent vasodilator function in response to graded infusion of acetylcholine (ACh; 10-7 to 102 mmol/L) in control sites and sites treated with 15 mmol/L NG-nitro-l-arginine methyl ester (l-NAME; NO-synthase inhibitor), 100 µmol/L Ang-(1-7), or 15 mmol/L l-NAME + 100 µmol/L Ang-(1-7). Vasoconstrictor function was measured in response to ANG II (10-20-10-4 mol/L) in control sites and sites treated with 100 µmol/L Ang-(1-7). PrEC had reduced endothelium-dependent dilation (P < 0.001) and NO-dependent dilation (P = 0.04 vs. HC). Ang-(1-7) coinfusion augmented endothelium-dependent dilation (P < 0.01) and NO-dependent dilation (P = 0.03) in PrEC but had no effect in HC. PrEC demonstrated augmented vasoconstrictor responses to ANG II (P < 0.01 vs. HC), which was attenuated by coinfusion of Ang-(1-7) (P < 0.001). Ang-(1-7) increased endothelium-dependent vasodilation via NO synthase-mediated pathways and attenuated ANG II-mediated constriction in women who have had preeclampsia, suggesting that Ang-(1-7) may be a viable therapeutic target for improved microvascular function in women who have had a preeclamptic pregnancy.

Index of microvascular resistance to assess the effect of rosuvastatin on microvascular function in women with chest pain and no obstructive coronary artery disease: A double-blind randomized study.

Many women undergoing coronary angiography for chest pain have no or only minimal coronary artery disease (CAD). However, despite the lack of obstructive CAD, they still have an increased risk of major adverse cardiovascular events. Pleiotropic effects of statins may influence microvascular function, but if statins improve microvascular function in unselected chest pain patients is not well studied. This study assessed microvascular function by using the thermodilution-derived test "the index of microvascular resistance" (IMR) with the aim of determining the (i) IMR level in women with chest pain and non-obstructive CAD and if (ii) IMR is modified by high-dose statin treatment in these patients. Additional objectives were to identify the influence of statins on the health status as assessed with generic health questionnaires and on biomarkers of endothelial activation. The study was a randomized, double-blind, single-center trial comparing 6 months of rosuvastatin treatment with placebo. In total, 66 women without obstructive CAD were included. Mean age was 52.7 years and 55.5 years in the placebo and rosuvastatin group, respectively. Microvascular function was assessed using the IMR, health status was assessed using the SF-36 and EQ-5D questionnaires, and biochemical values were assessed at baseline and 6 months later. In the placebo group IMR was 14.6 (SD 5.7) at baseline and 14.4 (SD 6.5) at follow-up. In the rosuvastatin group IMR was 16.5 (SD 7.5) at baseline and 14.2 (SD 5.8) at follow-up. IMR did not differ significantly between the two study groups at follow-up controlled for preintervention values. C-reactive protein (CRP) was comparable between the groups at baseline, while at follow-up CRP was significantly lower in the rosuvastatin group compared to placebo [0.6 (±0.5) mg/L vs. 2.6 (±3.0) mg/L; p = 0.002]. Whereas rosuvastatin treatment for 6 months attenuated CRP levels, it did not improve microvascular function as assessed by IMR (Clinical Trials.gov NCT01582165, EUDRACT 2011-002630-39.3tcAZ).

Coronary artery microvascular dysfunction: Role of sex and arterial load

BackgroundThe prognosis of cardiovascular disease is worse in women than men, and coronary microvascular dysfunction explains the excess cardiovascular risk in women. In addition, age-related increases in pulsatile arterial load are greater in women than men; and lower arterial compliance has been shown to independently predict cardiovascular events. However, whether arterial load differentially affects the coronary microvasculature in men and women remains unknown. We hypothesized that lower arterial compliance would be associated with coronary artery microvascular dysfunction in women. Methods and results285 subjects (60% women, age: 61.2 ± 11.0 yrs) undergoing cardiac 82Rb positron-emission tomography between 2010 and 2013, with ejection fraction ≥50%, no heart failure, dyspnea, coronary artery disease or regional perfusion defects were included. Left ventricular microvascular function was assessed by myocardial flow reserve (MFR). Pulsatile arterial load was estimated by indexed arterial compliance [ACi: (stroke volume/pulse pressure)/BSA]. Multivariable linear regression evaluated associations of arterial compliance with myocardial flow reserve after adjustment for confounders. ACi was lower in women than men [0.39 ± 0.15 vs. 0.52 ± 0.28 (mL/mm Hg)/m2, P < 0.0001]. We found that the effect of ACi on MFR differs by sex: lower ACi was associated with lower MFR in women (β ± SE: 0.20 ± 0.07, P = 0.004) but not in men (0.03 ± 0.11, P = 0.75). ConclusionsLower ACi was associated with altered coronary microvascular function in women, but not in men. Our findings highlight low arterial compliance as a potential link between hypertension, coronary microvascular dysfunction and adverse cardiovascular events in women.

Sidestream Dark Field Imaging of the Microcirculation to Assess Preeclampsia Microvascular Dysfunction.

BackgroundDevelopment of predictive models of preeclampsia has only yielded modest results. We hypothesized that impaired indices of microcirculatory function could be detected using sidestream dark field imaging. The objective of this study was to examine microvascular function in women at high risk for preeclampsia at mid-gestation.MethodsWomen between 16 and 22 weeks of gestation were screened for eligibility. Patients were recruited if they met eligibility criteria indicating high risk for preeclampsia. Investigators performed non-invasive sidestream dark field imaging of the sublingual microcirculation. Images were analyzed to determine microcirculatory parameters (microvascular flow index, perfused vessel density, total vessel density, and proportion of perfused vessels). After delivery, charts were reviewed to determine if they developed gestational hypertension, preeclampsia or severe preeclampsia.ResultsTwelve of 66 participants (18.2%) developed preeclampsia or severe preeclampsia during the course of their pregnancy. Microvascular flow index was not significantly different between participants with normal pregnancies and participants with preeclampsia or severe preeclampsia (2.75 ± 0.38 vs. 2.80 ± 0.34, respectively; P = 0.459). Similarly, there were no significant differences between groups in the remaining microcirculatory parameters.ConclusionsSidestream dark field imaging of the sublingual microcirculation may remain an appropriate tool to identify women at risk for preeclampsia, albeit later in pregnancy.

Microvascular function in women with former gestational diabetes: A cohort study.

In the long term, diabetes mellitus is potentially associated with the occurrence of microvascular damage. This study sought to assess whether a history of prior gestational diabetes mellitus is associated with long-term effects on the women's microcirculation. Within the scope of a long-term follow-up of the 'Viennese Post-Gestational Diabetes Project', women with prior gestational diabetes mellitus as well as women with previous pregnancy but with no history of gestational diabetes mellitus (controls) were enrolled in this cross-sectional study. Microvascular function was assessed by post-occlusive reactive hyperaemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded and compared between both groups. Microvascular function was assessed in 55 women with prior gestational diabetes mellitus (46.1 ± 4.6 years) and 32 women with previous pregnancy but without prior gestational diabetes mellitus (42.9 ± 5.3 years). The mean period of time between delivery and the assessment of microvascular function was 16.2 ± 5.2 years in women with prior gestational diabetes mellitus group and 14.2 ± 4.8 years in controls. Regarding microvascular function, baseline perfusion, biological zero, peak perfusion, time to peak and recovery time did not differ between women with prior gestational diabetes mellitus and controls (all p > 0.05). In the long term, microvascular function appears not to be impaired in women with prior gestational diabetes mellitus.

Effect of Sex Differences on Invasive Measures of Coronary Microvascular Dysfunction in Patients With Angina in the Absence of Obstructive Coronary Artery Disease

This study investigated sex differences in coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients with angina in the absence of obstructive coronary artery disease. Coronary microvascular dysfunction is associated with worse long-term outcomes, especially in women. Coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) are 2 methods of assessing the coronary microcirculation. We prospectively enrolled 117 women and 40 men with angina in the absence of obstructive coronary artery disease. We performed CFR, IMR, fractional flow reserve, and quantitative coronary angiography in the left anterior descending artery. Coronary flow was assessed with a thermodilution method by obtaining mean transit time (Tmn) (an inverse correlate to absolute flow) at rest and hyperemia. All patients had minimal atherosclerosis by quantitative coronary angiography (% diameter stenosis: 23.2 ± 12.3%), and epicardial disease was milder in women (fractional flow reserve: 0.88 ± 0.04 vs. 0.87 ± 0.04; p = 0.04). IMR was similar between the sexes (20.7 ± 9.8 vs. 19.1 ± 8.0; p = 0.45), but CFR was lower in women (3.8 ± 1.6 vs. 4.8 ± 1.9; p = 0.004). This was primarily due to a shorter resting Tmn in women (p = 0.005), suggesting increased resting coronary flow, whereas hyperemic Tmn was identical (p = 0.79). In multivariable analysis, female sex was an independent predictor of lower CFR and shorter resting Tmn. Despite similar microvascular function in women and men by IMR, CFR is lower in women. This discrepancy appears to be due to differences in resting coronary flow between the sexes. The effect of sex differences should be considered in interpretation of physiological indexes using resting coronary flow.

Endothelin B receptor contribution to peripheral microvascular function in women with polycystic ovary syndrome

Endothelin-1 is elevated in women with polycystic ovary syndrome (PCOS), and may play a role in the endothelial dysfunction associated with PCOS. Endothelin-1 binds two receptor subtypes, endothelin A (ET-A) and endothelin B (ET-B). We hypothesized that ET-A mediates vasoconstriction in the cutaneous microvasculature in women with and without PCOS. We further hypothesized that while the ET-B receptors mediate vasodilatation in both groups of women, this response would be blunted in women with PCOS. During local skin warming, we used laser Doppler flowmetry combined with intradermal microdialysis to measure skin blood flow (SkBF) during graded ET-A (BQ-123) and ET-B (BQ-788) antagonist infusions in women with (n = 6) and without (n = 8) PCOS. In both groups, SkBF increased during local heating. The percentage of maximal SkBF-[BQ123] sigmoidal dose-response curve indicated a vasodilatory response as the concentration of the antagonist increased (Hill slope 4.96 ± 4.77, 4.74 ± 5.01; logED(50) 2.53 ± 0.09, 2.49 ± 0.09 nm, for PCOS and Control, respectively). In contrast, the % max SkBF-[BQ788] curve indicated a vasoconstrictive response (Hill slope -4.69 ± 3.85, -4.03 ± 3.85; logED(50), 2.56 ± 0.09, 2.41 ± 0.12 nm, in PCOS and Control). Moreover, the SkBF-[BQ788] curve shifted to the right in women with PCOS, suggesting attenuated ET-B receptor mediated vasodilatation during local skin warming compared to Controls. Thus, the endothelium located ET-B receptors function similarly in women with and without PCOS, although with blunted responsiveness in women with PCOS. Our studies suggest that the lower ET-B receptor responsiveness associated with PCOS may reflect lower endothelial-mediated vasodilatation independent of generally lower vascular reactivity.

Noninvasive assessment of coronary microvascular function in women at risk for ischaemic heart disease

The primary objective of the current review is to describe the assessment of coronary microvascular function by noninvasive imaging techniques in women at risk for and with ischaemic heart disease (IHD). The search criteria were the analyses of the related bibliography published in PUBMED database. Normal or minimal obstructive coronary artery disease (CAD) at angiography is a common finding in women with signs of ischaemia. Up to 50% of them will have coronary microvascular dysfunction, suggesting that the mechanism of ischaemia may be localised at coronary microcirculation level. Noninvasive measurements of coronary microvascular function can be performed by radionuclide techniques. In particular, positron emission tomography (PET) measures myocardial blood flow (MBF) not only relatively but also in absolute units. Thus, PET offers the possibility to uncover microvascular dysfunction even in patients without obstructive CAD. PET-derived estimates of MBF showed an abnormal coronary microvascular function in women with chest pain and non-obstructive CAD and in women with high-risk conditions for CAD. Interestingly, there is a relationship between an abnormal coronary vascular function and adverse cardiovascular outcomes. In particular, this significant relationship was observed with measurements related to endothelial function. Recent evidence suggests that vascular dysfunction plays a central role as an estimator of outcomes in women at risk for or with IHD. Therefore, assessment of coronary vascular function in these women appears to be of clinical relevance. Whether such evaluation may have an impact to reduce cardiac events needs further investigation.

Phytoestrogens and Coronary Microvascular Function in Women with Suspected Myocardial Ischemia: A Report from the Women's Ischemia Syndrome Evaluation (WISE) Study

Soy phytoestrogens are popular, but information on their coronary effects in patients with suspected ischemic heart disease is limited. Accordingly, we investigated the relationship between blood phytoestrogen levels and coronary reactivity in women with suspected myocardial ischemia referred for coronary angiography. Coronary flow velocity reserve (CFVR) and volumetric flow reserve (VFR) to adenosine (ADO) and nitroglycerin (NTG) (nonendothelial-dependent responses) and acetylcholine (ACH) (endothelial-dependent response) were assessed in 106 women from the Women's Ischemia Syndrome Evaluation (WISE). Blood phytoestrogen (daidzein and genistein) and estrogen (estradiol) levels were correlated with coronary reactivity measures. Participants were mostly postmenopausal (79%), mean age 56 years, and 24% had obstructive coronary artery disease (CAD) at angiography. Genistein blood levels were negatively correlated with nonendothelial-dependent coronary flow responses. The highest genistein tertile (>6.1 ng/mL) had a CFVR of 2.1 +/- 0.5 (mean +/- SD) and VFRADO of 1.0 +/- 0.6, and both were significantly (p= 0.0001) lower compared with the other genistein tertiles combined. Similar associations were noted for CFVR(NTG) and VFR(NTG) (p = 0.03 and p = 0.01, respectively). The highest genistein tertile was associated with lower CFVR(ACH) compared with the other tertiles (p = 0.03). In multivariable modeling, blood genistein levels were significant independent predictors of coronary flow responses to ADO. There were no significant correlations between coronary reactivity variables and daidzein or endogenous estrogen. In women with suspected myocardial ischemia, higher genistein blood levels are associated with impaired nonendothelial-dependent and endothelial-dependent coronary microvascular function.

Microvascular dysfunction: a link between pre‐eclampsia and maternal coronary heart disease

Epidemiological studies have recently demonstrated a relationship between pre-eclampsia and coronary heart disease. Insulin resistance has been implicated as a common factor. We have demonstrated, for the first time, using laser Doppler imaging in vivo, impaired microvascular function in women 15-25 years following a pregnancy complicated by pre-eclampsia. Thus, microvascular dysfunction, which is associated with insulin resistance, may be a predisposing vascular mechanism for both coronary heart disease and pre-eclampsia. Pregnancies complicated by pre-eclampsia may identify women at risk of vascular disease in later life and may provide the opportunity for lifestyle and risk factor modification to alter maternal vascular disease risk.

Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease: Results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) Study

OBJECTIVESWe sought to develop and validate a definition of coronary microvascular dysfunction in women with chest pain and no significant epicardial obstruction based on adenosine-induced changes in coronary flow velocity (i.e., coronary velocity reserve).BACKGROUNDChest pain is frequently not caused by fixed obstructive coronary artery disease (CAD) of large vessels in women. Coronary microvascular dysfunction is an alternative mechanism of chest pain that is more prevalent in women and is associated with attenuated coronary volumetric flow augmentation in response to hyperemic stimuli (i.e., abnormal coronary flow reserve). However, traditional assessment of coronary volumetric flow reserve is time-consuming and not uniformly available.METHODSAs part of the Women’s Ischemia Syndrome Evaluation (WISE) study, 48 women with chest pain and normal coronary arteries or minimal coronary luminal irregularities (mean stenosis = 7%) underwent assessment of coronary blood flow reserve and coronary flow velocity reserve. Blood flow responses to intracoronary adenosine were measured using intracoronary Doppler ultrasonography and quantitative angiography.RESULTSCoronary volumetric flow reserve correlated with coronary velocity reserve (Pearson correlation = 0.87, p < 0.001). In 29 (60%) women with abnormal coronary microcirculation (mean coronary flow reserve = 1.84), adenosine increased coronary velocity by 89% (p < 0.001) but did not change coronary cross-sectional area. In 19 (40%) women with normal microcirculation (mean flow reserve = 3.24), adenosine increased coronary velocity and area by 179% (p < 0.001) and 17% (p < 0.001), respectively. A coronary velocity reserve threshold of 2.24 provided the best balance between sensitivity and specificity (90% and 89%, respectively) for the diagnosis of microvascular dysfunction. In addition, failure of the epicardial coronary to dilate at least 9% was found to be a sensitive (79%) and specific (79%) surrogate marker of microvascular dysfunction.CONCLUSIONSCoronary flow velocity response to intracoronary adenosine characterizes coronary microvascular function in women with chest pain in the absence of obstructive CAD. Attenuated epicardial coronary dilation response to adenosine may be a surrogate marker of microvascular dysfunction in women with chest pain and no obstructive CAD.