- Email: [email protected]
OS070. Shared genetic risk factors for preeclampsia and cardiovascular disease
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Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2 (2012) 175–239
OS068. 25-Hydroxyvitamin D and angiogenic factors in early-onset severe preeclampsia C. Robinson 1,*, C. Wagner 2, J. Baatz 2, B. Hollis 2, D. Johnson 1 (1 Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, United States, 2 Department of Pediatrics, Medical University of South Carolina, Charleston, United States) Introduction: Alterations in pro- and anti-angiogenic factors have been demonstrated to precede the clinical onset of preeclampsia. Objectives: The objective of this investigation was to understand the possible relationship of maternal vitamin D status and angiogenic factors at the diagnosis of early onset, severe preeclampsia (EOSPE). Methods: This prospective case-control study enrolled patients with EOSPE or healthy pregnancy. Plasma samples were obtained at the time of diagnosis of EOSPE and from a contemporaneous healthy control patient. 25-hydroxyvitamin D (25-OH-D) was assayed using radioimmunoassay. PlGF, VEGF, and s-Flt1 were assayed using ELISA. Results were analyzed with Kruskal–Wallis test between groups and Spearman correlation coefficients were calculated for 25-OH-D and angiogenic factors. Results: Fourty patients with EOSPE and 40 healthy controls were enrolled. Patients with EOSPE were noted to have greater deficiency of 25-OH-D (16.9 vs. 33.2 ng/mL; p < 0.001). PlGF and VEGF were significantly decreased while s-Flt1 was significantly increased in EOSPE relative to controls(table). Significant negative correlations were observed between plasma 25-OH-D and s-Flt1 ( 0.38; p < 0.001) and s-Flt1/PlGF ratio ( 0.32; p = 0.003). Significant positive correlations were noted between plasma 25-OH-D and PlGF (0.27; p = 0.02) and VEGF (0.25; p = 0.001). Vitamin D and angiogenic factors in EOSPE vs. control (median (IQR)).
25-OH-D (pg/mL) s-Flt1 (pg/mL) PlGF (pg/mL) VEGF (pg/mL)
EOSPE
Control
P value
17 (16) 33,000 (21,000) 22 (30) 0 (0)
33 (31) 2000 (1200) 500 (430) 7.2 (6.2)
<0.001 <0.0001 <0.0001 <0.0001
Conclusion: Vitamin D deficiency may be implicated in the regulation of angiogenic factors involved in the pathophysiology of EOSPE. Further analysis of the effects of Vitamin D on control of angiogenic factors in preeclampsia is needed.
Introduction: Preeclampsia (PE) is associated with alterations in the renin-angiotensin system due to the presence of autoantibodies that activate the major angiotensin receptor, AT1R. The resulting chronic activation of the AT1 receptor is believed to contribute to a pro-inflammatory state that is also characteristic of PE. Microarray analysis revealed a pronounced increase in the abundance of LIGHT, a potent member of the TNF superfamily that has emerged as a key factor mediating strong T-cell inflammatory responses and a contributor to autoimmune disease pathogenesis. Objectives: The goal of research described here is to determine the contribution of LIGHT to the pathophysiology of PE. Methods: An ELISA, specific for LIGHT was used to validate the results of the initial microarray analysis. Infusion experiments were used to determine the effects of elevated LIGHT in pregnant and non-pregnant mice. An adoptive transfer model of PE in pregnant mice was used to determine if AT1R agonistic autoantibodies (AT1AA) stimulate LIGHT production. The potential contribution of increased LIGHT to clinical features of PE in pregnant mice was evaluated by the use of neutralizing antibodies directed to the LIGHT receptors, HVEM and LTbR. Results: The use of a LIGHT-specific ELISA showed that the cytokine was significantly increased in the circulation and placentas of women with PE. The infusion of recombinant LIGHT into pregnant mice induced major clinical features of PE, including hypertension and proteinuria. Such changes were not observed when LIGHT was infused into not non-pregnant mice. LIGHT was significantly elevated in a pregnant mouse model of PE based on the introduction of IgG from women with PE. In this autoantibody-injection model of PE, the use of neutralizing antibodies to the LIGHT receptors, HVEM and LTbR, blocked autoantibodyinduced hypertension, proteinuria, elevated sFlt-1 production, impaired placental angiogenesis and endothelial dysfunction. Conclusion: Overall, our studies show that LIGHT is significantly elevated in women with PE and that elevated LIGHT contributes to pathophysiology of PE in an antibody-injection model of PE in pregnant mice. LIGHT-induced pathophysiology can be abrogated by the use of neutralizing antibodies directed at its receptors, HVEM and LTbR. These results indicate that LIGHT may have a previously unrecognized role in the pathophysiology of PE and that its detrimental effects are pregnancy-dependent. These findings immediately suggest novel therapeutic possibilities.
Disclosure of interest
Disclosure of interest
None declared.
None declared.
doi:10.1016/j.preghy.2012.04.069
doi:10.1016/j.preghy.2012.04.070
OS069. Light, a TNF superfamily member, contributes to pathophysiology in a mouse model of preeclampsia W. Wang, R.A. Irani, Y. Zhang, R.E. Kellems, Y. Xia * (Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, United States)
OS070. Shared genetic risk factors for preeclampsia and cardiovascular disease M. Løset 1,*, M.P. Johnson 2, C. Pennell 3, R.-C. Huang 3, T. Mori 3, L. Beilin 3, P. Melton 2, L.T. Roten 1, A.-C. Iversen 1, R. Austgulen 1, C. East 4, J. Blangero 2, S.P. Brennecke 4,
Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2 (2012) 175–239
E.K. Moses 3 (1 Norwegian University of Science and Technology, Trondheim, Norway, 2 Texas Biomedical Research Institute, San Antonio, United States, 3 The University of Western Australia, Perth, Australia, 4 The Royal Women’s Hospital, Melbourne, Australia) Introduction: There is compelling evidence to support the hypothesis that a maternal constitutional predisposition to cardiovascular disease (CVD) is a key component in development of preeclampsia. In particular, CVD and preeclampsia share pathological features such as endothelial dysfunction and inflammation, and have several metabolic abnormalities in common. In support of this hypothesis, our recent genetic dissection of the Australian preeclampsia susceptibility locus on chromosome 2q22 revealed shared novel genetic risk factors for preeclampsia and CVD-related traits. Objectives: To replicate association between our recently reported 2q22 preeclampsia risk variants and CVD-related traits in an independent Australian population based cohort. Methods: Four independent SNPs from four genes, rs35821928 (LRP1B), rs17783344 (GCA), rs115015150 (RND3) and rs2322659 (LCT), were recently found to be significantly associated with preeclampsia susceptibility and CVD-related traits. These SNPs were genotyped in a large independent Australian cohort rich in quantitative CVD risk traits; The Western Australian Pregnancy Cohort (Raine) Study. This cohort comprises of blood samples from 1246 mothers and 1461 adolescents and clinical measures such as, but not limited to, anthropometric measures of adiposity and lipid-related measures. Genetic association analyses of these four potential preeclampsia susceptibility SNPs against the CVD-related risk traits were performed using the software package R. All statistical analyses assumed an additive model of gene action. Results: Several significant associations (p < 0.05) for all four SNPs with a variety of CVD-related risk traits were detected, both for the mothers and the adolescents. The LRP1B SNP was associated with HDL/cholesterol ratio, LDL cholesterol, triglycerides, skinfold measures and weight. The GCA SNP was associated with total cholesterol, HDL cho-
215
lesterol, serum insulin, hemoglobin, blood glucose, BMI and skinfold measures. The RND3 SNP was associated with triglycerides and waist-hip ratio. The LCT SNP was associated with hemoglobin, blood glucose and abdominal skinfold. Conclusion: We have recently identified genetic variants within the LRP1B, GCA, RND3 and LCT genes to be significantly associated with preeclampsia susceptibility and CVD-related risk traits. We have now demonstrated thatthese specific genetic variants are associated with CVDrelated risk traits in an independent population. Our collective findings provide substantial empirical data to support the hypothesis that genetic risk factors for preeclampsia and CVD are, at least in part, shared. Disclosure of interest None declared. doi:10.1016/j.preghy.2012.04.071
OS071. Effect of methyldopa on the cerebral circulation in chronic hypertensive pregnancies F.V. Araújo 1,2, F.C. Silva 2,3,*, R.A.M. de Sá 1,2, C.A. de Oliveira 1,2 (1 Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil, 2 Grupo Perinatal, Rio de Janeiro, Brazil, 3 Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil) Introduction: Women with chronic hypertension are at increased risk to develop cerebral complications during pregnancy, including eclampsia and stroke. There are only scant and conflicting data in the literature regarding cerebral blood flow in hypertensive pregnant women, especially in use of medication [1,2].There was particular interest in evaluating the blood flow through the vertebral arteries, as the posterior territory is the most affected, and the blood flow less well regulated [3]. Objectives: To evaluate the arterial cerebral blood flow by Doppler sonography of chronic hypertensive pregnant
Table 1 Independent t-test for differences between chronic hypertensive and normal blood pressure pregnant women.
RCCAa PSVd RCCA PIe RCCA diameter RICAb PSV RICA PI RICA diameter RVAc PSV RVA RI RVA diameter
NBP group mean valuesf
CH group mean valuesg
Mean difference (95% CIh)
p-value
83.25 1.95 56.10 52.77 1.10 42.60 39.45 0.65 32.20
54.83 1.93 67.04 38.55 2.07 46.04 32.74 0.58 34.15
28.40 ( 34.96 to 21.85) 0.01 ( 0.20 to 0.1746) 10.98 (8.79 to 13,18) 14.22 ( 20,46 to 7,98) 0.96 (0,66 to 1,27) 3.45 (1,24 to 5,67) 6.71 ( 11,65 to 1,78) 0.06 ( 0,11 to 0,02) 1.97 ( 0,35 to 4,29)
< 0.0001 0.87 <0.0001 <0.0001 <0.0001 0.0023 0.0079 0.0029 0.0952
RI: resistance index. a RCCA: right common carotid artery. b RICD: right internal carotid artery. c RVA: right vertebral artery. d PSV: peak systolic velocity. e PI: pulsatilty index. f NBP: normal blood pressure. g CH: chronic hypertension. h 95% CI: 95% confidence interval.
Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2 (2012) 175–239
OS068. 25-Hydroxyvitamin D and angiogenic factors in early-onset severe preeclampsia C. Robinson 1,*, C. Wagner 2, J. Baatz 2, B. Hollis 2, D. Johnson 1 (1 Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, United States, 2 Department of Pediatrics, Medical University of South Carolina, Charleston, United States) Introduction: Alterations in pro- and anti-angiogenic factors have been demonstrated to precede the clinical onset of preeclampsia. Objectives: The objective of this investigation was to understand the possible relationship of maternal vitamin D status and angiogenic factors at the diagnosis of early onset, severe preeclampsia (EOSPE). Methods: This prospective case-control study enrolled patients with EOSPE or healthy pregnancy. Plasma samples were obtained at the time of diagnosis of EOSPE and from a contemporaneous healthy control patient. 25-hydroxyvitamin D (25-OH-D) was assayed using radioimmunoassay. PlGF, VEGF, and s-Flt1 were assayed using ELISA. Results were analyzed with Kruskal–Wallis test between groups and Spearman correlation coefficients were calculated for 25-OH-D and angiogenic factors. Results: Fourty patients with EOSPE and 40 healthy controls were enrolled. Patients with EOSPE were noted to have greater deficiency of 25-OH-D (16.9 vs. 33.2 ng/mL; p < 0.001). PlGF and VEGF were significantly decreased while s-Flt1 was significantly increased in EOSPE relative to controls(table). Significant negative correlations were observed between plasma 25-OH-D and s-Flt1 ( 0.38; p < 0.001) and s-Flt1/PlGF ratio ( 0.32; p = 0.003). Significant positive correlations were noted between plasma 25-OH-D and PlGF (0.27; p = 0.02) and VEGF (0.25; p = 0.001). Vitamin D and angiogenic factors in EOSPE vs. control (median (IQR)).
25-OH-D (pg/mL) s-Flt1 (pg/mL) PlGF (pg/mL) VEGF (pg/mL)
EOSPE
Control
P value
17 (16) 33,000 (21,000) 22 (30) 0 (0)
33 (31) 2000 (1200) 500 (430) 7.2 (6.2)
<0.001 <0.0001 <0.0001 <0.0001
Conclusion: Vitamin D deficiency may be implicated in the regulation of angiogenic factors involved in the pathophysiology of EOSPE. Further analysis of the effects of Vitamin D on control of angiogenic factors in preeclampsia is needed.
Introduction: Preeclampsia (PE) is associated with alterations in the renin-angiotensin system due to the presence of autoantibodies that activate the major angiotensin receptor, AT1R. The resulting chronic activation of the AT1 receptor is believed to contribute to a pro-inflammatory state that is also characteristic of PE. Microarray analysis revealed a pronounced increase in the abundance of LIGHT, a potent member of the TNF superfamily that has emerged as a key factor mediating strong T-cell inflammatory responses and a contributor to autoimmune disease pathogenesis. Objectives: The goal of research described here is to determine the contribution of LIGHT to the pathophysiology of PE. Methods: An ELISA, specific for LIGHT was used to validate the results of the initial microarray analysis. Infusion experiments were used to determine the effects of elevated LIGHT in pregnant and non-pregnant mice. An adoptive transfer model of PE in pregnant mice was used to determine if AT1R agonistic autoantibodies (AT1AA) stimulate LIGHT production. The potential contribution of increased LIGHT to clinical features of PE in pregnant mice was evaluated by the use of neutralizing antibodies directed to the LIGHT receptors, HVEM and LTbR. Results: The use of a LIGHT-specific ELISA showed that the cytokine was significantly increased in the circulation and placentas of women with PE. The infusion of recombinant LIGHT into pregnant mice induced major clinical features of PE, including hypertension and proteinuria. Such changes were not observed when LIGHT was infused into not non-pregnant mice. LIGHT was significantly elevated in a pregnant mouse model of PE based on the introduction of IgG from women with PE. In this autoantibody-injection model of PE, the use of neutralizing antibodies to the LIGHT receptors, HVEM and LTbR, blocked autoantibodyinduced hypertension, proteinuria, elevated sFlt-1 production, impaired placental angiogenesis and endothelial dysfunction. Conclusion: Overall, our studies show that LIGHT is significantly elevated in women with PE and that elevated LIGHT contributes to pathophysiology of PE in an antibody-injection model of PE in pregnant mice. LIGHT-induced pathophysiology can be abrogated by the use of neutralizing antibodies directed at its receptors, HVEM and LTbR. These results indicate that LIGHT may have a previously unrecognized role in the pathophysiology of PE and that its detrimental effects are pregnancy-dependent. These findings immediately suggest novel therapeutic possibilities.
Disclosure of interest
Disclosure of interest
None declared.
None declared.
doi:10.1016/j.preghy.2012.04.069
doi:10.1016/j.preghy.2012.04.070
OS069. Light, a TNF superfamily member, contributes to pathophysiology in a mouse model of preeclampsia W. Wang, R.A. Irani, Y. Zhang, R.E. Kellems, Y. Xia * (Biochemistry and Molecular Biology, University of Texas Houston Medical School, Houston, United States)
OS070. Shared genetic risk factors for preeclampsia and cardiovascular disease M. Løset 1,*, M.P. Johnson 2, C. Pennell 3, R.-C. Huang 3, T. Mori 3, L. Beilin 3, P. Melton 2, L.T. Roten 1, A.-C. Iversen 1, R. Austgulen 1, C. East 4, J. Blangero 2, S.P. Brennecke 4,
Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2 (2012) 175–239
E.K. Moses 3 (1 Norwegian University of Science and Technology, Trondheim, Norway, 2 Texas Biomedical Research Institute, San Antonio, United States, 3 The University of Western Australia, Perth, Australia, 4 The Royal Women’s Hospital, Melbourne, Australia) Introduction: There is compelling evidence to support the hypothesis that a maternal constitutional predisposition to cardiovascular disease (CVD) is a key component in development of preeclampsia. In particular, CVD and preeclampsia share pathological features such as endothelial dysfunction and inflammation, and have several metabolic abnormalities in common. In support of this hypothesis, our recent genetic dissection of the Australian preeclampsia susceptibility locus on chromosome 2q22 revealed shared novel genetic risk factors for preeclampsia and CVD-related traits. Objectives: To replicate association between our recently reported 2q22 preeclampsia risk variants and CVD-related traits in an independent Australian population based cohort. Methods: Four independent SNPs from four genes, rs35821928 (LRP1B), rs17783344 (GCA), rs115015150 (RND3) and rs2322659 (LCT), were recently found to be significantly associated with preeclampsia susceptibility and CVD-related traits. These SNPs were genotyped in a large independent Australian cohort rich in quantitative CVD risk traits; The Western Australian Pregnancy Cohort (Raine) Study. This cohort comprises of blood samples from 1246 mothers and 1461 adolescents and clinical measures such as, but not limited to, anthropometric measures of adiposity and lipid-related measures. Genetic association analyses of these four potential preeclampsia susceptibility SNPs against the CVD-related risk traits were performed using the software package R. All statistical analyses assumed an additive model of gene action. Results: Several significant associations (p < 0.05) for all four SNPs with a variety of CVD-related risk traits were detected, both for the mothers and the adolescents. The LRP1B SNP was associated with HDL/cholesterol ratio, LDL cholesterol, triglycerides, skinfold measures and weight. The GCA SNP was associated with total cholesterol, HDL cho-
215
lesterol, serum insulin, hemoglobin, blood glucose, BMI and skinfold measures. The RND3 SNP was associated with triglycerides and waist-hip ratio. The LCT SNP was associated with hemoglobin, blood glucose and abdominal skinfold. Conclusion: We have recently identified genetic variants within the LRP1B, GCA, RND3 and LCT genes to be significantly associated with preeclampsia susceptibility and CVD-related risk traits. We have now demonstrated thatthese specific genetic variants are associated with CVDrelated risk traits in an independent population. Our collective findings provide substantial empirical data to support the hypothesis that genetic risk factors for preeclampsia and CVD are, at least in part, shared. Disclosure of interest None declared. doi:10.1016/j.preghy.2012.04.071
OS071. Effect of methyldopa on the cerebral circulation in chronic hypertensive pregnancies F.V. Araújo 1,2, F.C. Silva 2,3,*, R.A.M. de Sá 1,2, C.A. de Oliveira 1,2 (1 Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil, 2 Grupo Perinatal, Rio de Janeiro, Brazil, 3 Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil) Introduction: Women with chronic hypertension are at increased risk to develop cerebral complications during pregnancy, including eclampsia and stroke. There are only scant and conflicting data in the literature regarding cerebral blood flow in hypertensive pregnant women, especially in use of medication [1,2].There was particular interest in evaluating the blood flow through the vertebral arteries, as the posterior territory is the most affected, and the blood flow less well regulated [3]. Objectives: To evaluate the arterial cerebral blood flow by Doppler sonography of chronic hypertensive pregnant
Table 1 Independent t-test for differences between chronic hypertensive and normal blood pressure pregnant women.
RCCAa PSVd RCCA PIe RCCA diameter RICAb PSV RICA PI RICA diameter RVAc PSV RVA RI RVA diameter
NBP group mean valuesf
CH group mean valuesg
Mean difference (95% CIh)
p-value
83.25 1.95 56.10 52.77 1.10 42.60 39.45 0.65 32.20
54.83 1.93 67.04 38.55 2.07 46.04 32.74 0.58 34.15
28.40 ( 34.96 to 21.85) 0.01 ( 0.20 to 0.1746) 10.98 (8.79 to 13,18) 14.22 ( 20,46 to 7,98) 0.96 (0,66 to 1,27) 3.45 (1,24 to 5,67) 6.71 ( 11,65 to 1,78) 0.06 ( 0,11 to 0,02) 1.97 ( 0,35 to 4,29)
< 0.0001 0.87 <0.0001 <0.0001 <0.0001 0.0023 0.0079 0.0029 0.0952
RI: resistance index. a RCCA: right common carotid artery. b RICD: right internal carotid artery. c RVA: right vertebral artery. d PSV: peak systolic velocity. e PI: pulsatilty index. f NBP: normal blood pressure. g CH: chronic hypertension. h 95% CI: 95% confidence interval.