Microvascular Dysfunction In Women Research Articles

Heterogeneity of Coronary Vascular Function and Myocardial Oxygenation in Women with Angina and Non-obstructive Coronary Artery Disease.

Women with angina and non-obstructive coronary artery disease (ANOCA) have a heightened risk for cardiovascular events, and the pathophysiology for ischemic symptoms may be related to alterations in microvascular structure and function. We examined the use of breathing-enhanced oxygenation-sensitive cardiac magnetic resonance imaging (OS-CMR) using vasoactive breathing maneuvers to assess myocardial oxygenation in women with ANOCA. We recruited women (aged 40-65 years) from two sites in Canada who presented to healthcare with persistent retrosternal chest pain and found to have ANOCA, or without a history of cardiovascular disease. All participants were scanned using a clinical 3T MRI scanner, OS-CMR images were acquired over a breath hold following paced hyperventilation to measure global and regional measurements of heterogeneity.Fifty-four women with ANOCA (age: 55 +/- 6.2 years) and 48 healthy controls (age: (51.2+/- 4.8 years) were recruited. There was no significant difference in volume, function, mass, or global myocardial oxygenation between the two groups (mean % Δ in SI: 4.9 (+/- 7.3) vs. 4.5 (+/- 10.1), p = 0.82). Women with ANOCA had higher regional variations in myocardial oxygenation in circumferential (median % Δ in SI: 5.1 (2.0-7.6) vs. 2.2 (1.4-3.5), p = 0.0004) and longitudinal directions (median % Δ in SI: 11.4 (5.4-16.7) vs. 6.0 (3.0-7.0), p = 0.001), which remained present in a multivariate model. Heterogeneous myocardial oxygenation may explain ischemic symptoms without any associated epicardial obstructive coronary artery disease. Regional variations in myocardial oxygenation on OS-CMR could serve as an important diagnostic marker for microvascular dysfunction in women with ANOCA.

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.

Biomarkers and Coronary Microvascular Dysfunction in Women With Angina and No Obstructive Coronary Artery Disease

BackgroundCoronary microvascular dysfunction (CMD) is a major cause of ischemia with no obstructed coronary arteries. ObjectivesThe authors sought to assess protein biomarker signature for CMD. MethodsWe quantified 184 unique cardiovascular proteins with proximity extension assay in 1,471 women with angina and no obstructive coronary artery disease characterized for CMD by coronary flow velocity reserve (CFVR) by transthoracic echo Doppler. We performed Pearson’s correlations of CFVR and each of the 184 biomarkers, and principal component analyses and weighted correlation network analysis to identify clusters linked to CMD. For prediction of CMD (CFVR < 2.25), we applied logistic regression and machine learning algorithms (least absolute shrinkage and selection operator, random forest, extreme gradient boosting, and adaptive boosting) in discovery and validation cohorts. ResultsSixty-one biomarkers were correlated with CFVR with strongest correlations for renin (REN), growth differentiation factor 15, brain natriuretic protein (BNP), N-terminal-proBNP (NT-proBNP), and adrenomedullin (ADM) (all P < 1e-06). Two principal components with highest loading on BNP/NTproBNP and interleukin 6, respectively, were strongly associated with low CFVR. Weighted correlation network analysis identified 2 clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. The best prediction model for CFVR <2.25 using clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI: 0.56-0.66). ROC-AUC was 0.66 (95% CI: 0.62-0.71) with addition of biomarkers (P for model improvement = 0.01). Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66; the most predictive biomarkers were REN, BNP, NT-proBNP, growth differentiation factor 15, and ADM. ConclusionsCMD was associated with pathways particularly involving inflammation (interleukin 6), blood pressure (REN, ADM), and ventricular remodeling (BNP/NT-proBNP) independently of clinical risk factors. Model prediction improved with biomarkers, but prediction remained moderate.

Proteomics to identify biological pathways and develop prediction models of coronary microvascular dysfunction in women with angina and no obstructive coronary artery disease

Abstract Aims Coronary microvascular dysfunction (CMD) is a major cause of angina and impaired outcome. Protein biomarkers could simplify patient selection for assessment and help uncover pathophysiologic pathways. Methods and results We quantified 184 protein biomarkers in 1471 women with angina and no obstructive coronary artery disease on angiography characterized for CMD by coronary flow velocity reserve (CFVR) by Doppler Echocardiography. Sixty-one biomarkers were significantly associated with CFVR (Figure 1). The strongest correlations were seen for renin, growth differentiation factor 15 (GDF15), brain natriuretic protein (BNP), NT-proBNP and adrenomedullin (ADM) (all p&amp;lt;1e-06). To identify pathophysiological patterns, we applied principal components (PC) analyses and weighted protein co-abundance network analyses. Two PCs with the highest loading on BNP/ NTproBNP and interleukin 6 (IL-6), respectively, were strongly associated with low CFVR. The weighted protein co-abundance network analyses identified two clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. For prediction of CMD (CFVR &amp;lt;2.25, n=646), data was split into model and validation cohorts. The best model using only clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI 0.56–0.66). ROC-AUC improved to 0.66 (95% CI: 0.62–0.71) with addition of biomarkers. Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66 (Figure 2); the most predictive biomarkers were renin, BNP, NT-proBNP, GDF15 and ADM. Conclusion CMD was associated with biological pathways, particularly involving inflammation (IL-6), blood pressure (renin, ADM) and ventricular remodelling (BNP/NTproBNP). The identified biomarker pathways may prove potential treatment targets for CMD. Diagnostic models improved significantly when adding protein biomarkers to clinical information. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Danish Heart Foundation

N-Terminal pro-B-type natriuretic peptide and coronary microvascular dysfunction in women with preserved ejection fraction: A report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

BackgroundWomen with symptoms and signs of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive coronary artery disease (CAD), often have coronary microvascular dysfunction (CMD), and are at risk of future heart failure with preserved ejection fraction (HFpEF). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used to evaluate HF and myocardial ischemia. Relationships between NT-proBNP and CMD are not well defined in this population.MethodsWe evaluated resting NT-proBNP levels in 208 women with symptoms and signs of ischemic heart disease, preserved LVEF and no obstructive CAD undergoing clinically indicated invasive coronary flow reserve (CFR) as a measure of CMD-related ischemia and resting left ventricular end-diastolic pressure (LVEDP). Chi-square testing was used for categorical variables and ANOVA or Kruskal-Wallis tests were used for continuous variables.ResultsOverall, 79% had an elevated resting LVEDP, and mean NT-proBNP was 115 ± 158 pg/mL. NT-proBNP levels correlated directly with age (r = 0.28, p = <0.0001), and indirectly with body mass index (r = -0.21, p = 0.0006), but did not independently associate with CFR. When stratified by NT-proBNP thresholds, higher NT-proBNP was initially associated with lower CFR, which did not persist with adjustment for multiple testing (p = 0.01 and 0.36, respectively).ConclusionAmong women with symptoms and signs of ischemia, preserved LVEF, no obstructive CAD, and undergoing clinically indicated functional coronary angiography (FCA) for suspected CMD, while a majority had elevated resting LVEDP, we failed to find an independent association between CFR and NT-proBNP, although stratified clinical thresholds may relate to lower CFR. Further work is needed to investigate if these findings support the hypothesis that CMD-related ischemia may be a precursor to HFpEF.

Phytoestrogen blood levels and adverse outcomes in women with suspected ischemic heart disease.

Prior studies linked higher blood phytoestrogen (phytoE) levels of daidzein to beneficial lipoprotein profiles, and higher genistein levels related to worse coronary microvascular dysfunction in women with suspected ischemic heart disease (IHD). However, relationships to adverse outcomes remain unclear. We investigated the associations between eight serum phytoE and major adverse cardiac events (MACE) including myocardial infarction, stroke, hospitalization for heart failure and angina, cardiovascular and all-cause mortality, in women undergoing functional coronary angiography (FCA) for suspected ischemia. We evaluated 143 women enrolled in the Women's Ischemia Syndrome Evaluation (1996-2001) for serum phytoE levels and 10-year outcomes. Median follow-up duration was 6.08 years (range 0.01-8.16) for time to MACE and 9.11 years (range 0.01-11.08 years) for time to death. Kaplan-Meier plots were analyzed and Cox regression models adjusted for age, body mass index, hypertension, diabetes, dyslipidemia and tobacco use. The median age was 54.7 (range 20.6-76.1) years and BMI was 29.3 (range 18.4-57.2). Of the cohort, 80.4% had nonobstructive coronary artery disease, 56% had hypertension, 22.4% had diabetes, 58.1% had dyslipidemia and 59.4% of the women used tobacco. Each unit decrease in log glycitin was associated with increased MACE hazard (HR 1.97, 95% [CI 1.23, 3.14], p = 0.005). Glycitin absence was associated with earlier angina hospitalization (log rank p = 0.05). After 6 years, MACE increased with each unit decrease in log genistein (HR 6.17, 95% [CI 1.81, 20.8], p = 0.0036). Other phytoE did not show statistically significant associations with outcomes. Among women with suspected IHD undergoing clinically indicated invasive FCA, low serum glycitin was associated with increased MACE and earlier angina hospitalization, while low genistein was associated with increased MACE after 6 years. Future studies are needed regarding phytoE, nutrition, outcomes and possibly supplementation.

State of the Art in Noninvasive Imaging of Ischemic Heart Disease and Coronary Microvascular Dysfunction in Women: Indications, Performance, and Limitations.

Establishing a diagnosis of ischemic heart disease (IHD) in women, including assessment for coronary microvascular dysfunction (CMD) when indicated, can be challenging. Access to performance of invasive testing when appropriate may be limited, and noninvasive imaging assessments have evolved. This review will summarize the various noninvasive imaging modalities available for the diagnosis of IHD and CMD in women, outlining indications, performance modalities, advantages, and limitations. While stress echocardiography and single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) are widely available and can detect IHD in women, their ability to specifically identify CMD is limited. Novel developments in cardiac magnetic resonance (CMR) imaging, including spectroscopy, and positron emission tomography (PET) have changed the diagnostic landscape. Coronary computed tomographic angiography (CCTA), while unable to diagnose CMD, is developing an emerging role in the risk stratification of ischemic syndromes. Despite the discovery of increased CMD prevalence in symptomatic women and technological advances in diagnostic imaging, practitioners are limited by user expertise and center availability when choosing a diagnostic imaging modality. Knowledge of this evolving field is imperative as it highlights the need for sex-specific assessment of cardiovascular syndromes.

Myocardial first pass perfusion assessed by cardiac magnetic resonance and coronary microvascular dysfunction in women with angina and no obstructive coronary artery disease

Coronary microvascular dysfunction (CMD) is associated with a poor prognosis even in absence of obstructive coronary artery disease. CMD can be assessed as a myocardial blood flow reserve by positron emission tomography (PETMBFR) and as coronary flow velocity reserve by transthoracic Doppler echocardiography (TTDECFVR). Impaired first-pass perfusion assessed by cardiac magnetic resonance (CMR) is an early sign of ischemia. We aimed to investigate the association between CMD and CMR first-pass perfusion. Women (n = 66) with angina pectoris and an invasive coronary angiogram (<50% stenosis) were assessed by TTDECFVR and in a subgroup of these (n = 54) also by PETMBFR. Semi-quantitative evaluation of first-pass perfusion at rest and adenosine stress was assessed by gadolinium CMR in all 66 women. Four measures of CMR perfusion reserve were calculated using contrast upslope, maximal signal intensity and both indexed to arterial input. Mean (standard deviation) age was 62 (8) years. Median (interquartile range) TTDECFVR was 2.3 (1.8;2.7) and PETMBFR was 2.7 (2.2;3.1). Using a cut-off of 2.0 for TTDECFVR and 2.5 for PETMBFR, 25 (38%) and 21 (39%) had CMD, respectively. CMR myocardial perfusion reserve from contrast upslope (CMR_MPRupslope) showed moderate but significant correlation with PETMBFR (R = .46, p < .001) while none of the other CMR variables were associated with CMD. A CMR_MPRupslope cut-off of 0.78 identified CMD, area under the curve 0.73 (p = .001). The results indicate that CMR_MPRupslope may be associated to PETMBFR; a measure of CMD. Further research is needed to validate and implement the use of CMR first pass perfusion in this population.

Prevalence of Coronary Endothelial and Microvascular Dysfunction in Women with Symptoms of Ischemia and No Obstructive Coronary Artery Disease Is Confirmed by a New Cohort: The NHLBI-Sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD).

Objective In a separate, contemporary cohort, we sought to confirm findings of the original Women's Ischemia Syndrome Evaluation (WISE). Background The original WISE observed a high prevalence of both invasively determined coronary endothelial and coronary microvascular dysfunction (CMD) that predicted adverse events in follow-up. Methods We comparatively studied the WISE-Coronary Vascular Dysfunction (CVD) cohort (2009-2011), with signs and symptoms of ischemia but without significant CAD, to the original WISE (1997-2001) cohort. CMD was defined as coronary flow reserve (CFR) ≤2.5, or endothelial dysfunction as epicardial coronary artery constriction to acetylcholine (ACH), or <20% epicardial coronary dilation to nitroglycerin (NTG). Results In WISE (n=181) and WISE-CVD (n=235) women, mean age in both was 54 years, and 83% were white (WISE) vs 74% (WISE-CVD, p=0.04). Use of hormone replacement therapy was less frequent in WISE-CVD vs WISE (46% vs 57%, p=0.026) as was presence of hypertension (40% vs 52%, p=0.013), hyperlipidemia (20% vs 46%, p<0.0001), and smoking (46% vs 56%, p=0.036). Similar rates were observed in WISE-CVD and WISE cohorts for CMD (mean CFR 2.7±0.6 vs 2.6±0.8, p=0.35), mean change in diameter with intracoronary ACH (0.2±10.0 vs 1.6±12.8 mm, p=0.34), and mean change in diameter with intracoronary NTG (9.7±13.0 vs 9.8±13.5 mm, p=0.94), respectively. Conclusions This study confirms prevalence of CMD in the contemporary WISE-CVD cohort similar to that of the original WISE cohort, despite a lower risk factor burden in WISE-CVD. Because these coronary functional abnormalities predict major adverse cardiac events, clinical trials of therapies targeting these abnormalities are indicated.

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.

SOME SITES OF INTIMATE MECHANISMS OF MYOCARDIAL ISCHEMIA IN MACRO AND MICROVASCULAR DYSFUNCTION

Objective: Microvascular dysfunction is the major mechanism of proven myocardial ischemia in patients with Cardiac syndrome X (CSX). Most of the patients with CSX are female and estrogen deficit is major factor for endothelial dysfunction. Aim: Our aim is to investigate the correlation between hormonal dysbalance and myocardial ischemia in patients with CSX and obstructive ischemic heart disease (IHD). We compare 17beta-Estradiol levels, alfa-estrogen receptor (alfa-ER) activity and marker for myocardial ischemia vascular endothelial growth factor (VEGF). Design and method: In the main group of patients with CSX (30 woman) and in patients with IHD (30 women) are measured the levels of VEGF, 17beta-Estradiol in serum by “sandwich” ELISA and rtPCR for alfa-ER activity. Control group of healthy subjects was used for VEGF analysis. Results: Comparing the levels of VEGF in main group with CSX and IHD and control group we found that the investigated growth factor as marker for ischemia has serum levels statistically higher as well as in group with CSX (57,94 ± 13,92 pg/ml) and in group with IHD (69,03 ± 10,10 pg/ml) than in health controls (47,68 ± 8,66 pg/ml): respectively 0,040 and 0,046. As expected, mean levels of 17beta-Estradiol are higher in IHD group than in CSX (12.21 vs 7.55 pg/ml) but unreceptively to that activity of alfa-ER is higher in the group of IHD than in CSX (1.4). This result could be explained by estrogen independed path for activation of alfa-ER, that is ischemia driven and mediated by growth factors as VEGF. Currently only in animal models this pathway is proven. Conclusions: In myocardial ischemia due to macro or microvessels disease endothelial dysfunction has proven role. Estrogen deficiency is leading cause for microvascular dysfunction in women with CSX, but alfa-ER could have hormone independent role in myocardial ischemia and further investigations are needed.

Endothelin type B (ETB) receptors: friend or foe in the pathogenesis of pre-eclampsia and future cardiovascular disease (CVD) risk?

In a recent issue of Clinical Science, Stanhewicz et al. investigated persistent microvascular dysfunction in women up to 16 months postpartum. The authors found sensitivity to the pressor effects of endothelin-1 (ET-1) was enhanced when compared with women who had a normotensive pregnancy. Importantly, the authors demonstrated that this effect was mediated via the endothelin type B (ETB) receptors. Therefore, the present study highlights the possibility that alterations in the localization of the ETB receptor contributes to the pathogenesis of pre-eclampsia and future cardiovascular disease (CVD) risk. Currently, there is great interest in the role of the endothelin system in pre-eclampsia. Targetting the endothelin system, potentially by modulating upstream pathways to prevent ETB receptor dysfunction, may improve health outcomes for women and their offspring during pre-eclampsia and later life.

Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia.

Microvascular dysfunction originating during a preeclamptic pregnancy persists postpartum and probably contributes to increased CVD risk in these women. One putative mechanism contributing to this dysfunction is increased vasoconstrictor sensitivity to endothelin-1 (ET-1), mediated by alterations in ET-1 receptor type-B (ETBR). We evaluated ET-1 sensitivity, ETAR, and ETBR contributions to ET-1-mediated constriction, and the mechanistic role of ETBR in endothelium-dependent dilation in vivo in the microvasculature of postpartum women who had preeclampsia (PrEC, n=12) and control women who had a healthy pregnancy (HC, n=12). We hypothesized that (1) PrEC would have a greater vasoconstrictor response to ET-1, and (2) reduced ETBR-mediated dilation. We further hypothesized that ETBR-blockade would attenuate endothelium-dependent vasodilation in HC, but not PrEC. Microvascular reactivity was assessed by measurement of cutaneous vascular conductance responses to graded infusion of ET-1 (10-20-10-8 mol/l), ET-1 + 500 nmol/l BQ-123 (ETAR-blockade), and ET-1 + 300 nmol/l BQ-788 (ETBR-blockade), and during graded infusion of acetylcholine (ACh, 10-7-102 mmol/l) and a standardized local heating protocol with and without ETBR-inhibition. PrEC had an increased vasoconstriction response to ET-1 (P=0.02). PrEC demonstrated reduced dilation responses to selective ETBR stimulation with ET-1 (P=0.01). ETBR-inhibition augmented ET-1-mediated constriction in HC (P=0.01) but attenuated ET-1-mediated constriction in PrEC (P=0.003). ETBR-inhibition attenuated endothelium-dependent vasodilation responses to 100mmol/l ACh (P=0.04) and local heat (P=0.003) in HC but increased vasodilation (ACh: P=0.01; local heat: P=0.03) in PrEC. Women who have had preeclampsia demonstrate augmented vasoconstrictor sensitivity to ET-1, mediated by altered ETBR signaling. Furthermore, altered ETBR function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.

P553Myocardial first pass perfusion assessed by cardiac magnetic resonance and coronary microvascular dysfunction in women with angina and no obstructive coronary artery disease: The iPOWER study

P553Myocardial first pass perfusion assessed by cardiac magnetic resonance and coronary microvascular dysfunction in women with angina and no obstructive coronary artery disease: The iPOWER study

Coronary microvascular dysfunction in women with nonobstructive ischemic heart disease as assessed by positron emission tomography.

Traditional approaches for risk assessment of ischemic heart disease (IHD) are based on the physiological consequences of an epicardial coronary stenosis. Of note, normal coronary arteries or nonobstructive coronary artery disease (CAD) is a common finding in women with signs and symptoms of ischemia. Therefore, assessment of risk based on a coronary stenosis approach may fail in women. Positron emission tomography (PET) quantifies absolute myocardial blood flow (MBF) which may help to elucidate other mechanisms involved such as endothelial dysfunction and alterations in the smooth muscle cell relaxation responsible for IHD in women. The objective of the present review is to describe the current state of the art of PET imaging in assessing IHD in women with nonobstructive CAD.

Abstract 12197: Increased Angiotensin II Sensitivity Contributes to Microvascular Endothelial Dysfunction in Women Who Have Had Preeclampsia

Introduction: Women with a history of preeclampsia have increased cardiovascular disease risk, however the mechanisms responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist post-partum. The putative mechanisms mediating this dysfunction include a reduction in nitric oxide (NO)-dependent dilation, and an increased sensitivity to angiotensin II (ang II). In this study, we evaluated endothelium-dependent dilation, ang II sensitivity, and the therapeutic effect of ang II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (PrEC, n=7) and control women who had a healthy pregnancy (HC, n=9). We hypothesized that PrEC would have 1) reduced endothelium-dependent dilation, 2) reduced NO-mediated dilation, and 3) increased sensitivity to ang II. We further hypothesized that losartan would increase endothelium-dependent dilation in PrEC. Methods: We assessed microvascular function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (ACh; 10 -10 -10 -1 M) and ang II (10 -20 -10 -4 M); and during ACh co-infusion with 15mM L-NAME (NO-synthase inhibitor) or 43μM losartan. Results: ACh-induced vasodilation was attenuated in PrEC compared to HC (PrEC -3.3±0.2 vs. HC -4.7±0.1 logEC50; p&lt;0.05). There was no difference between PrEC and HC during ACh co-infusion with L-NAME (PrEC -4.4±0.2 vs. HC -4.6±0.2 logEC50; NS). NO-mediated dilation was attenuated in PrEC compared to HC (PrEC 10±4 vs. HC 35±4%; p&lt;0.01). PrEC had a greater vasoconstriction response to ang II (PrEC -11.8±0.2 vs. HC -9.7±0.2 logEC50; p&lt;0.05. Losartan co-infusion improved the vasodilation response to ACh in PrEC (losartan -4.6±0.2 vs. ACh alone -3.3±0.2 logEC50; NS). Conclusions: These findings suggest that women who have had preeclampsia have impaired endothelium-dependent vasodilation which is mediated, in part, by reductions in NO signaling and increased sensitivity to ang II. Furthermore, losartan improved endothelium-dependent dilation, suggesting that ang II receptor blockade may have therapeutic potential to treat microvascular dysfunction in women who have had preeclampsia.

F5. Skin microvascular dysfunction in preeclampsia persists to the postpartum period

Introduction: Preeclampsia is a multisystem disorder characterised by endothelial and microvascular dysfunction that develops in ∼10% of pregnancies. This study will characterise skin microvascular reactivity using laser Doppler flowmetry in women with preeclampsia compared to matched controls during pregnancy and early postpartum.Methods: Women were recruited and studied on the diagnosis of preeclampsia and followed up for 6-months during postpartum period. Controls were matched for age, gestation and comorbidities. Skin blood flow corrected for mean arterial pressure (cutaneous vascular conductance; CVC) was measured using laser Doppler flowmetry (Periflux5000, Perimed AB, Sweden) on the dominant forearm. We measured the vasodilatory response to iontophoresis of acetylcholine (ACh; endothelial dependent) and sodium nitroprusside (SNP; endothelial independent) as well as local heating (initial axon-reflex and secondary nitric oxide-mediated). Results were analysed using repeated measures ANOVA.Results: Fourteen women with preeclampsia and 15 controls were included in this analysis. Compared to controls, women with preeclampsia had significantly decreased baseline CVC during pregnancy, which persisted to the postpartum (p < 0.01). There was a significant increase in the ratio of maximum vasodilatory response to ACh and SNP at both time points (p < 0.01). There was a trend towards a higher initial axon-reflex response to heat (p = 0.05), but no difference in the secondary peak response.Conclusions: This study is the first to demonstrate a significantly increased response to ACh compared to SNP during pregnancy that persisted in the postpartum period. In addition, we demonstrated that the response to heat may not recover in the early postpartum period. These findings indicate persistent microvascular dysfunction in women with preeclampsia.

Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women.

Women with coronary microvascular dysfunction (CMD) and no obstructive coronary artery disease (CAD) have increased rates of heart failure with preserved ejection fraction (HFpEF). The mechanisms of HFpEF are not well understood. Ectopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in other metabolic diseases. We investigated the prevalence of myocardial steatosis and diastolic dysfunction in women with CMD and subclinical HFpEF. In 13 women, including eight reference controls and five women with CMD and evidence of subclinical HFpEF (left ventricular end-diastolic pressure >12 mmHg), we measured myocardial triglyceride content (TG) and diastolic function, by proton magnetic resonance spectroscopy and magnetic resonance tissue tagging, respectively. When compared with reference controls, women with CMD had higher myocardial TG content (0.83 ± 0.12% vs. 0.43 ± 0.06%; P = 0.025) and lower diastolic circumferential strain rate (168 ± 12 vs. 217 ± 15%/s; P = 0.012), with myocardial TG content correlating inversely with diastolic circumferential strain rate (r = -0.779; P = 0.002). This study provides proof-of-concept that myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with CMD and no obstructive CAD. Detailed longitudinal studies are warranted to explore specific treatment strategies targeting myocardial steatosis and its effect on diastolic function.

Altered retinal flicker response indicates microvascular dysfunction in women with preeclampsia.

Flicker-induced dilatation is reduced in patients with cardiovascular risk, and the following arteriolar constriction is reduced with aging, leading to a reduced arteriolar amplitude and, thereby, indicating microvascular endothelial dysfunction. As endothelial dysfunction is associated with preeclampsia, we assessed retinal flicker response during pregnancy and postpartum. Between 2006 and 2013, women were recruited from University Hospital Jena and Prenatal Diagnostic Center Erfurt, Germany, of which 34 women with preeclampsia, 45 women with normal pregnancy, and 22 nonpregnant controls were included in the study. Women with normal pregnancy were matched for age, nulliparity, smoking, previous gestational hypertensive disorders, and family history of cardiovascular disease. Nonpregnant women were age-matched, nulliparous, nonsmoking, without family history of cardiovascular disease. Retinal vessel measurement using Dynamic Vessel Analyzer consisted of 50-seconds baseline acquisition, followed by three 20-second flicker and 80-second relaxation periods. Arteriolar constriction and arteriolar amplitude were reduced during pregnancy (P=0.001 and P=0.008) and postpartum (P=0.018 and P=0.034) in women with preeclampsia, adjusted for age, body mass index, mean arterial pressure, baseline diameter, and family history of cardiovascular disease. Flicker-induced dilatation was unchanged within the groups and throughout the study period. The unchanged flicker-induced dilatation may support a preserved autoregulatory competence of the microvasculature, and the diminished arteriolar amplitude, mainly because of the absence of the arteriolar constriction, indicates a commenced retinal microvascular dysfunction in women with preeclampsia during pregnancy and postpartum. Mechanisms responsible for altered retinal flicker response in preeclampsia need to be clarified in further studies.

Renal function and coronary microvascular dysfunction in women with symptoms/signs of ischemia.

ObjectivesChronic kidney disease (CKD) is more prevalent among women and is associated with adverse cardiovascular events. Among women with symptoms and signs of ischemia enrolled in the Women’s Ischemia Syndrome Evaluation (WISE), a relatively high mortality rate was observed in those with no obstructive coronary artery disease. Coronary microvascular dysfunction or reduced coronary flow reserve (CFR) was a strong and independent predictor of adverse outcomes. The objective of this analysis was to determine if renal function was associated with coronary microvascular dysfunction in women with signs and symptoms of ischemia.MethodsThe WISE was a multicenter, prospective, cohort study of women undergoing coronary angiography for suspected ischemia. Among 198 women with additional measurements of CFR, we determined the estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. We tested the association between eGFR and CFR with regression analysis.ResultsThe median eGFR was 89 ml/min. The eGFR correlated with CFR (r = 0.22; P = 0.002). This association persisted even after covariate adjustment. Each 10-unit decrease in eGFR was associated with a 0.04-unit decrease in CFR (P = 0.04).There was a strong interaction between eGFR and age (P = 0.006): in those ≥60 years old, GFR was strongly correlated with CFR (r = 0.55; P<0.0001). No significant correlation was noted in those <60 years old.ConclusionsReduced renal function was significantly associated with lower CFR in women with symptoms and signs of ischemia. Coronary microvascular dysfunction warrants additional study as a mechanism contributing to increased risk of cardiovascular events in CKD.