and the Kidney

Long-Term Consequences of Placental Disease

By Michelle Hladunewich

bout 5 percent of suf- and Development Cohort. Data from over normal pregnancy, the RAS regulates ing the importance of assessing future vas- fer complications from abnormal 14,000 women with an average of 30 years pressure and volume status. Because the pla- cular risk on the basis of placental pathology. placental development. The process of follow-up noted the median age for car- centa has no autonomic innervation, it relies The recent discovery of endothelial pro- ofA placentation begins when blastocysts ad- diovascular events to be 56 years, with a cu- on angiotensin to regulate vascular resistance. genitor cells (EPCs) suggests that vascular here to the uterine endometrium, forming a mulative survival of 86 percent for women Although components of RAS have been repair and angiogenesis constitute a dynamic lineage of epithelial cells termed the invasive with early-onset pre- compared demonstrated to be upregulated in normal process that extends well beyond the embry- extravillous cytotrophoblast, which then in- with 98 percent for those with late-onset pregnancy, vascular insensitivity to angi- onic phase, modulated by numerous identi- vades the uterine wall to create the decidua, pre-eclampsia and 99 percent for those with otensin II (AngII) infusions has been dem- fied and as yet undiscovered cardiovascular transforming the spiral arteries into a low- healthy pregnancies (4). onstrated in healthy pregnant women, and risk factors. Endothelial progenitor cells may resistance uteroplacental circulation. AngII sensitivity is a demonstrated predictor mediate the noted differences in endothelial Impaired development of the uteropla- Pathophysiology for the development of pre-eclampsia (12). dysfunction between women with or with- cental vasculature, therefore, has its origins A potential mechanism for enhanced sen- out pre-eclampsia, and they are established Whether damage to the vascular endothe- sitivity is the presence of an immunoglobu- in the cardiovascular literature as biomarkers in the first trimester as a result of an ab- lium secondary to maternal placental syn- lin G autoantibody to the AT1 receptor of vascular disease. In women with maternal normal interaction between the invading drome results in an increased risk of future identified in the serum of women with placental syndrome manifest as pre-eclamp- extravillous cytotrophoblast and the mater- vascular disease, or whether pre-existing pre-eclampsia (13). Alternatively, upregula- sia, EPCs are decreased, with increased rates nal immune system, resulting in decidual factors underlie both the predisposition to tion of the AT1 receptor on the decidual, or of cellular senescence (18). As measured by vasculopathy, with small, poorly developed placental disease and the later development maternal, side of the has also been standard flow cytometry, EPCs have been spiral arteries. As these pregnancies progress, of vascular disease, is unknown. Studies, demonstrated (14). Such a maternal abnor- demonstrated to be significantly decreased in placental ischemia and infarction may result however, are noting common genetic and mality could result in abnormal placenta- a small group of women with pre-eclampsia in a maternal placental syndrome—pre-ec- physiologic links and, therefore, shared risk tion as well as future . as compared with healthy control individu- lampsia, , and/or the en- factors between pre-eclampsia and cardiovas- Furthermore, abnormalities in angiotensin als in the third trimester (19). suing adverse perinatal outcomes, including cular disease. sensitivity have been shown to remain into With both shared genetic and physiolog- fetal growth restriction and . There are several examples of common the . In a recent study, ic pathways between maternal placental and It was previously thought that the con- genetic pathways. Catechol-O-methyltrans- women with a history of pre-eclampsia cardiovascular disease, one might also expect sequences of maternal placental disease re- ferase (COMT) is responsible for the degra- were noted to have salt-sensitive hyperten- shared risk factors. A recent study that com- solved quickly and completely after delivery dation of both estrogens and catecholamines. sion, and in the salt-deprived state—a state bined data from two large population-based of the placenta. More recently, however, it Mice deficient in COMT, and hence wherein the RAS is maximally stimulated— studies with medical birth registry data iden- has become clear that placental disease, as 2-methoxyestradiol (2ME), have abnor- a major basis of the maternal placental syn- there was evidence of increased angiotensin tified 3225 singleton births with a prepreg- mal placentation and develop a phenotype sensitivity with respect to both aldosterone drome, is a marker of future vascular disease, that resembles human pre-eclampsia (5). nancy cardiovascular risk assessment (20). forecasting a vastly different health trajectory release and blood pressure response to AngII When adjustment was made for traditional In a mouse model of cardiovascular disease, infusion (15). than that of a woman who has had normal 2ME treatment can decrease atherosclerosis cardiovascular risk factors, including body placental function and a healthy pregnancy. There seems little doubt that the vascular mass index, blood pressure, and cholesterol by 52 percent and cholesterol by 19 percent endothelial cell is the primary target of ma- (6). Human data have also emerged for this in the women who developed pre-eclampsia Epidemiology ternal placental syndromes and is intimately during pregnancy, much of the risk for fu- shared genetic factor. A nested case-control involved in the future pathogenesis of vas- The first study to describe the relationship study assessed the three common haplo- ture vascular disease could be accounted for, cular disease. Flow-mediated vasodilation suggesting that women programmed to de- between pre-eclampsia and cardiovascu- types of the central region of the COMT (FMD) is a well accepted physiologic meas- lar disease used the Norwegian Medical gene wherein the haplotype translates into velop vascular disease also get placental vas- ure of endothelial dysfunction that has been cular disease and that both cardiometabolic Birth Registry (1). Although this study did COMT activity. The haplotype associated demonstrated to be associated with long- not show an increased risk of death among with low COMT activity was noted in 7 and endothelial dysfunction likely predate term adverse vascular consequences. En- and persist after pregnancy. women with pre-eclampsia who were de- percent of the population and was associated dothelial-dependent vasodilation is impaired livered at term, it did show almost a three- with recurrent pre-eclampsia (7). in women with pre-eclampsia compared Summary Statements fold increased risk of death and an eightfold In other studies attempting to determine with healthy gravid control individuals. Fur- increased risk of cardiovascular death in a relationship of haplotype to coronary artery thermore, there appears to be an association Maternal placental disease is now regarded as women who were delivered before 37 weeks, disease, low COMT activity was associated with uterine artery Doppler assessment, giv- a female-specific risk factor for future mor- interpreted as a surrogate marker for more with worse coronary outcomes, interacting en that the highest rates of impaired FMD bidity and mortality caused by vascular dis- severe disease. with higher homocysteine levels (8). The were noted in patients who also had abnor- ease. Future studies will continue to identify An increased risk of cardiovascular death T235 allele, an angiotensinogen gene poly- mal uterine artery flow (16). common pathways and potential treatment was also noted among women with preterm morphism, has been noted in women with Recent studies have also demonstrated targets. In the interim, it is critical that we delivery but without clinical pre-eclampsia. abnormal spiral artery modeling (9). The impaired endothelial-dependent, but not recognize the vulnerability of this patient This highlights a key component to un- ACOX2 gene polymorphism was studied endothelial-independent, vasodilation in the population, particularly women with severe derstanding which women are at risk for in the decidua basalis tissue of women with forearm vasculature months after delivery in manifestations of placental vascular disease. future vascular disease, inasmuch as a third pre-eclampsia and was noted to be downreg- women with a history of maternal placental Women with severe early-onset disease and of preterm deliveries are caused by placental ulated and inversely correlated to triglycer- disease that cannot be explained by adjust- fetal growth restriction require regular vas- implantation abnormalities. These findings ide levels (10). Finally, homozygotes for the ment for traditional cardiovascular risk fac- cular risk assessments, and placental disease have been confirmed and expanded by other nitric oxide synthetase gene polymorphism tors. In a recent study wherein the maternal should be ascertained in our patients’ histo- studies in which, in addition to an increased ASP298 had significantly lower flow-medi- phenotype was carefully classified, endothe- ries to assist with risk stratification. Cardio- risk of cardiovascular disease, an increased ated vasodilatation than those homozygous lial dysfunction, as determined by impaired vascular risk factors should be aggressively risk of cerebrovascular disease, peripheral for the GLU298 polymorphism at 12 weeks FMD, was observed in 93 percent and 89 targeted with lifestyle modifications and, if vascular disease, and end stage renal disease gestation, and this may prove important in percent of women with early-onset pre-ec- necessary, pharmacologic therapy. was also noted (2, 3). the vascular adaptation to pregnancy (11). lampsia (≤34 weeks gestation) and isolated In the Cardiovascular Health after Such genetic polymorphisms have been not- intrauterine growth rate (fetal growth below Michelle Hladunewich MD, MSc, FRCP(C), Maternal Placental Syndromes study, the ed to also contribute to hypertension, coro- the fifth centile without evidence of mater- is assistant professor of medicine at the Univer- importance of placental vascular disease nary artery disease, and even chronic kidney nal disease), respectively, compared with sity of Toronto and head of the division of ne- in long-term maternal outcome was again disease in other populations. 22 percent of women with late-onset pre- phrology and obstetric medicine at Sunnybrook highlighted, inasmuch as the worst survival Examples also exist of shared physiologic eclampsia—a value that did not differ sig- Health Sciences Centre. was noted in women with pre-eclampsia ac- processes. There is significant evidence to nificantly from that in a control population companied by fetal death (2). The societal suggest that alterations in the renin-angi- (17). Moreover, the findings appeared to be References effect of this increased vascular risk, however, otensin system (RAS) play a significant role driven by fetal growth restriction, paralleling 1. Irgens HU, et al. Long term mortality of is best demonstrated by the Child Health in the pathogenesis of pre-eclampsia. In the epidemiologic literature and highlight- mothers and fathers after pre-eclampsia: July 2011 | ASN Kidney News | 13

Population based cohort study. BMJ 16. Brodszki J, et al. Vascular mechanical sights into future vascular risk. Circula- progenitor cells increase during normal 2001; 323:1213–1217. properties and endothelial function in tion 2010; 122:1846–1853. pregnancy but are reduced in women 2. Ray JG, et al. Cardiovascular health pre-eclampsia with special reference to 18. Sugawara J, et al. Decrease and senes- with preeclampsia. Reprod Sci 2010; after maternal placental syndromes bilateral uterine artery notch. Acta Obstet cence of endothelial progenitor cells in 17:643–652. (CHAMPS): Population-based ret- Gynecol Scand 2008; 87:154–162. patients with preeclampsia. J Clin Endo- 20. Romundstad PR, et al. Hypertension rospective cohort study. Lancet 2005; 17. Yinon Y, et al. Vascular dysfunction in crinol Metab 2005; 90:5329–5332. in pregnancy and later cardiovascular 366:1797–1803. women with a history of preeclampsia 19. Luppi P, et al. Maternal circulating risk: Common antecedents? Circulation 3. Vikse BE, et al. Previous preeclampsia and intrauterine growth restriction: In- cd34+vegfr-2+ and cd133+vegfr-2 + 2010; 122:579–584. and risk for progression of biopsy-ver- ified kidney disease to end-stage renal disease. Nephrol Dial Transplant 2010; 25:3289–3296. 4. Mongraw-Chaffin ML, et al. Preec- lampsia and cardiovascular disease death: Prospective evidence from the child health and development studies ASN cohort. Hypertension 2010; 56:166– 171. 5. Kanasaki K, et al. Deficiency in cate- chol-o-methyltransferase and 2-meth- Learning oxyoestradiol is associated with pre-ec- lampsia. Nature 2008; 453:1117–1121. 6. Bourghardt J, et al. The endogenous estradiol metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient Center mice. Endocrinology 2007; 148:4128– Now online: 4132. ASN’s premier educational resources 7. Roten LT, et al. A low COMT activity haplotype is associated with recurrent preeclampsia in a Norwegian popula- Renal Week On-Demand tion cohort (HUNT2). Mol Hum Re- View nearly 300 hours of educational content presented during prod 2011, in press. Renal Week 2010. 8. Voutilainen S, et al. Functional COMT Val158met polymorphism, risk of acute Educational Symposia FREE coronary events and serum homo- cysteine: The Kuopio ischaemic heart View eight Educational Symposia from Renal Week 2010 and disease risk factor study. PLoS One get 1 hour of CME credit for each. Topics include secondary 2007; 2:e181. hyperparathyroidism, ESA, hyponatremia, mineral and bone 9. Morgan T, et al. Angiotensinogen t235 disorders, transplant immunosuppression, catheter outcomes, expression is elevated in decidual spiral , and the Keap1-Nrf2 pathway. arteries. J Clin Invest 1997; 100:1406– 1415. Renal WeekEnds Online 10. Johansson A, et al. Identification of ACOX2 as a shared genetic risk factor Access the online version of the popular condensed version of for preeclampsia and cardiovascular dis- Renal Week 2010 and gain CME credit. ease. Eur J Hum Genet 2011, in press. 11. Savvidou MD, et al. Endothelial nitric BRCU Online oxide synthase gene polymorphism and Prepare for certi† cation and recerti† cation exams from your maternal vascular adaptation to preg- home or of† ce with the Board Review Course & Update nancy. Hypertension 2001; 38:1289– 1293. Online. 12. Oney T, Kaulhausen H. The value of the angiotensin sensitivity test in the early diagnosis of hypertensive disorders Online Learning | The ASN Advantage in pregnancy. Am J Obstet Gynecol 1982; www.asn-online.org/learningcenter 142:17–20. 13. Wallukat G, et al. Agonistic autoanti- bodies directed against the angiotensin II AT1 receptor in patients with preec- lampsia. Can J Physiol Pharmacol 2003; 81:79–83. 14. Herse F, et al. Dysregulation of the cir- culating and tissue-based renin-angi- otensin system in preeclampsia. Hyper- tension 2007; 49:604–611. 15. Saxena AR, et al. Increased sensitivity to angiotensin II is present postpartum in women with a history of hyperten- sive pregnancy. Hypertension 2010; 55:1239–1245.

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