Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population

Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia

Early hypercholesterolemia contributes to vasomotor dysfunction and injury associated atherogenesis that can be inhibited by nitric oxide

ObjectiveAtherosclerosis results in vasomotor dysfunction, in part, through impairment of nitric oxide (NO) dependent vasodilation. It is unclear whether blood vessels are dysfunctional in an early environment of hypercholesterolemia alone and if this contributes to the vascular injury response. We hypothesize that early hypercholesterolemia, prior to gross vascular changes, contributes to vasomotor dysfunction and the vascular injury response. The efficacy of NO therapy to protect against the injury response in this setting was also assessed.MethodsThe effect of oxidized low density lipoprotein (oxLDL) and inducible NO synthase (iNOS) gene transfer on rat aortic smooth muscle cell (SMC) proliferation was measured with 3H-thymidine incorporation. Common carotid arteries (CCA) from wild-type C57BL6 (WT or C57) and apolipoprotein E deficient (ApoE KO) mice fed normal or Western diets for 6 to 8 weeks were tested for vasomotor function using an arteriograph system. Studies were repeated after CCA injury. The effect of iNOS gene transfer on morphometry by histology and vasomotor responses in injured CCAs in ApoE KO was examined.ResultsOxLDL increased SMC proliferation by >50%. In SMC expressing iNOS, NO production was unaffected by oxLDL and reduced oxLDL and still inhibited SMC proliferation. Endothelium dependent vasorelaxation was reduced in uninjured CCAs from ApoE KO and C57 mice on the Western vs normal diet (ApoE 39% ± 2% vs 55% ± 13%; C57 50% ± 13% vs 76% ± 5%, P < .001) and was increased with longer durations of hypercholesterolemia. Endothelium-dependent and independent vasodilator responses were severely disrupted in C57 and ApoE KO mice 2 weeks following CCA injury but both recovered by 4 weeks. CCA injury in ApoE KO mice resulted in the formation of atheromatous lesions while C57 mice showed no change (intima 27,795 ± 1829 vs 237 ± 28 μm2; media 46,306 ± 2448 vs 11,714 ± 392 μm2, respectively; P < .001). This structural change in the ApoE KO reduced distensibility and increased stiffness. Finally, iNOS gene transfer to injured CCA in ApoE KO mice dramatically reduced atheromatous neointimal lesion formation.ConclusionsEarly hypercholesterolemia impairs endothelial function, with severity being related to duration and magnitude of hypercholesterolemia. Severe hypercholesterolemia leads to atheromatous lesion formation following injury and stresses the role of vascular injury in atherogenesis and suggests different mechanisms are involved in endothelial dysfunction and the injury response. Despite these changes, iNOS gene transfer still effectively inhibits atheroma formation. These findings support early correction of hypercholesterolemia and emphasize the potential role for NO based therapies in disease states.Clinical RelevanceHypercholesterolemia results in the development of atherosclerosis, which leads to the blockage of arteries. However, it also impairs the behavior of arteries long before atherosclerotic plaques form. This study reveals the early impact of diet and hypercholesterolemia on arterial behavior and on response to injury and supports early correction of this problem

Abstract 16839: Maternal Placental Vascular Malperfusion Lesions Associated With Increased Cardiometabolic Risk and Reduced Microvascular Density in Women a Decade After Delivery: Which Placental Features Matter?

Introduction: Maternal vascular malperfusion (MVM) lesions in the placenta are commonly found in women with adverse pregnancy outcomes associated with increased CVD in later life. Minimal criteria for MVM include vasculopathy, accelerated villous maturation and increased syncytial knots, and villous infarction upon pathologic examination; expanded definitions have included presence of fibrin deposition (intervillous or perivillous) or low placental weight (&lt;10 th %). Hypothesis: Women with a history of MVM lesions would have evidence of cardiometabolic risk factors and peripheral microvascular changes a decade after delivery independent of pregnancy outcome. Methods: A total of 469 women with placental pathology data available were evaluated at 8-10 years postpartum. Placental specimens were reviewed by a perinatal pathologist. Cardiometabolic variables were measured at the time of the study visit. Sidestream dark field imaging was used to assess the sublingual microcirculation. We compared the median size (diameter) of microvessels, density (total length of perfused microvessels/mm 2 ) and penetration of red cells into the glycocalyx of vessels 5-25μm diameter (perfused boundary region, PBR) in women 8-10 years after pregnancy, using the minimal MVM criteria (compared to none). Expanded criteria were examined alone. Significance =*p&lt;0.05 vs no MVM lesions. Results: Women with minimally defined MVM lesions in their placentas had higher diastolic blood pressure (79mmHg MVM vs. 75 mmHg No MVM*), LDL (111mg/dL MVM vs. 101 mg/dL No MVM*), Cholesterol (185 mg/dL MVM vs. 175mg/dL No MVM*) and insulin (14mg/dL MVM vs. 12mg/dL No MVM*), along with smaller-sized microvessels (median 8.75±1.1 μM vs. 9.06±0.7 μM*), and a lower density of perfused microvessels compared to women without MVM lesions (3590±1260mm/mm 2 MVM vs. 3970±820 mm/mm 2 No MVM*) a decade after delivery. Glycocalyx PBR was smaller in women with prior MVM vs. women without lesions (2.01±0.23μm vs. 2.09±0.15μm, P=0.02). Similar results were not seen in subjects with either presence of fibrin or small placenta in the absence of other MVM criteria. Discussion: Using minimal criteria MVM was associated most strongly with maternal cardiometabolic and microvascular differences a decade later. </jats:p

Lipidomics Reveals Elevated Plasmalogens in Women with Obesity Who Develop Preeclampsia

Objective: Preeclampsia (PE) is a prevalent pregnancy disorder worldwide with limited preventative treatments available. Obesity triples the risk for PE, yet only 10% of women with obesity develop PE. The factors that distinguish PE from uncomplicated pregnancies in the context of obesity have not been fully established. Methods: We studied a cohort of women with obesity throughout pregnancy to identify lipid mediators and/or biomarkers of PE. Blood samples were collected at each trimester and analyzed by both targeted lipidomics and standard lipid panels. Individual lipid species were compared by PE status at each trimester, as well as by self-identified race (Black vs. White) and fetal sex. Results: Standard lipid panels and clinical measurements revealed few differences between PE and uncomplicated pregnancies. Targeted lipidomics, however, identified plasmalogen, phosphatidylethanolamine, and free fatty acid species that were elevated in the third trimester of women with PE. Furthermore, race and trimester of pregnancy were considerable sources of plasma lipidomic variation in women with obesity. Conclusions: First and second trimester individual plasma lipid species do not predict the development of PE in obese women. In the third trimester, PE patients have elevated levels of plasmalogens&mdash;a class of lipoprotein-associated phospholipids that have been implicated in the response to oxidative stress