HomeCirculationVol. 144, No. 9Challenging Statin Pleiotropy: Preeclampsia Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBChallenging Statin Pleiotropy: Preeclampsia Janet Wei, MD James K. Liao, MD C. Noel Bairey MerzMD Janet WeiJanet Wei https://orcid.org/0000-0002-1311-618X Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA (J.W., C.N.B.M.). Search for more papers by this author , James K. LiaoJames K. Liao https://orcid.org/0000-0001-9679-4252 Section of Cardiology, University of Chicago, IL (J.K.L.). Search for more papers by this author and C. Noel Bairey MerzC. Noel Bairey Merz Correspondence to: C. Noel Bairey Merz, MD, Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, 127 S San Vicente Blvd, AHSP Suite A3206, Los Angeles, CA 90048. Email E-mail Address: [email protected] https://orcid.org/0000-0002-9933-5155 Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA (J.W., C.N.B.M.). Search for more papers by this author Originally published30 Aug 2021https://doi.org/10.1161/CIRCULATIONAHA.121.056140Circulation. 2021;144:680–683This article is a commentary on the followingPravastatin Versus Placebo in Pregnancies at High Risk of Term PreeclampsiaArticle, see p 670Statins are increasingly being repurposed as immune modulatory agents for noncardiac systemic inflammatory diseases, including autoimmune disorders, inflammatory bowel disease, cognitive function/dementia, asthma, and inflammatory lung disease, including coronavirus disease 2019 (COVID 19).1 At present, 1 in 10 pregnancies result in term preeclampsia, which is the most common form of preeclampsia, is currently neither predictable nor preventable, increases morbidity and mortality risk to both the mother and baby, and elevates future premature cardiovascular disease (CVD) risk in women.2 Endothelial dysfunction and inflammation have been hypothesized to be involved in preeclampsia, suggesting they may be treatment targets, but relatively little investigation has been conducted.Although statins are traditionally used for lowering low-density lipoprotein (LDL)-cholesterol to reduce CVD risk, the relation between statin-related LDL-cholesterol lowering and systemic inflammatory diseases is not well characterized. In pregnancy, cholesterol is not routinely measured, in part, because of the known rise in cholesterol levels attributable to elevated placental steroid hormones, lack of normal pregnancy reference values, and limited treatment options in pregnancy. Although elevated maternal hypercholesterolemia has been linked to the development of preeclampsia, LDL-cholesterol appears to be less associated than total cholesterol, non–HDL-cholesterol, and triglyceride levels.3 In addition, women with familial hypercholesterolemia have not been demonstrated to have a higher risk of eclampsia, preeclampsia, or pregnancy-induced hypertension.4Rather, statin benefit in preeclampsia is hypothesized to rely on its noncholesterol pleiotropic effects. Statins are thought to improve endothelial function and reduce inflammatory cytokines by reducing C-reactive protein concentrations, inhibiting proinflammatory transcription factors, and blunting the T-helper cell immune response.1 Many of the proposed pleiotropic vascular effects of statins appear to involve restoring or improving endothelial function through increasing the bioavailability of nitric oxide, promoting reendothelialization, reducing oxidative stress, and inhibiting inflammatory responses.5 Yet more recent results from non–statin therapy CVD trials, including PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, ezetimibe, and bempedoic acid, challenge the concept of statin pleiotropy, dominantly failing to show differential benefit above that of LDL lowering.1Given the emerging stance of healthy moms = healthy babies rationale stimulating the testing of medication for health conditions that adversely impact the health of mothers and therefore babies during pregnancy, in this issue of Circulation, the work of Döbert et al6 is a welcome addition. Preliminary data from animal studies provided a strong rationale for the use of pravastatin in preeclampsia prevention, but human trials have been lacking. In their double-blind, placebo-controlled trial of 1120 women with singleton pregnancies at high risk of term preeclampsia, the authors evaluated the effects of pravastatin 20 mg daily versus placebo from 35 to 37 weeks of gestation until delivery. They found no benefit of pravastatin for reducing the incidence of preeclampsia, with no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, previous history of preeclampsia, adherence, and aspirin intake in prespecified subgroup analyses. There was also no difference in the treatment effects on sFlt-1 (soluble fms-like tyrosine kinase-1) concentrations and serum PlGF (placental growth factor), biomarkers that tend to be higher and lower in preeclamptic versus normal pregnancies, respectively.What are some potential explanations for these negative trial results? Serum sFlt-1/PlGF levels may start to elevate as early as 24 weeks gestation in some women who later develop term preeclampsia,7 thus starting pravastatin 20 mg at 35 weeks of pregnancy to reduce the later-term preeclampsia outcome within 4 to 6 weeks may be too little statin given too late in the disease process. A previous small clinical trial of pravastatin 10 mg starting at 12 to 17 weeks gestation had demonstrated promising trends toward higher PlGF and lower sFlt-1 levels with the statin,7 contrary to this study. Although cholesterol lowering was not measured in this trial, clinical CVD trials usually demonstrate outcome benefits after >4 months of statin therapy,8 whereas the shorter-term benefits are typically observed with more potent statins at higher doses.9 Thus, the lower potency and dose of the pravastatin may have contributed to the lack of benefit, because the more potent and higher dose atorvastatin has a documented shorter onset of benefit compared with other lower-intensity statins.8 Despite comparable LDL-lowering effects between simvastatin 40 mg and simvastatin 10 mg/ezetimibe 10 mg, simvastatin 40 mg produced greater flow-mediated dilation (improved endothelial function) than simvastatin 10 mg/ezetimibe 10 mg.10 The findings of this study support the notion of statin pleiotropy that is dose dependent and is in addition to the benefits of LDL lowering. Last, the use of a hydrophilic statin, pravastatin, which has less vascular wall permeability than that of lipophilic statins, may be far less effective in preventing the detrimental effects of preeclampsia proinflammatory cytokines. It is also possible that the cytokine-mediated sFlt-1 and PlGF levels measured in the study, which did not differ by group in the present study, are not affected in the short term by the pleiotropic effects of a low-dose statin (Figure5). The low use of aspirin in the present study compared with the common use with statins in CVD trials may have also been a factor.Download figureDownload PowerPointFigure. Pleiotropic effects of statins. Plus sign indicates enhanced/activated; minus sign, inhibited. AT1 indicates angiotensin 1; ET-1, endothelin 1; hs-CRP, high-sensitivity C-reactive protein; MMPs, matrix metalloproteinases; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; ROS, reactive oxygen species; SMC, smooth muscle cell; TF, tissue factor; t-PA, tissue-type plasminogen activator; and TXA2, thromboxane A2. Modified from Liao5 with permission. Copyright © 2005, Elsevier.Over the past decade, emerging data regarding statin safety in pregnancy has questioned the original classification of all statins as category X medication. Statins have not been shown to be independently associated with increased risk of congenital malformations when taken in the first trimester,11 with no adverse perinatal effects observed when taken in the second and third trimesters in 2 small double-blinded placebo-controlled randomized clinical trials.7,12 In these 2 trials, both daily pravastatin 10 mg and 40 mg initiated between 12 and 17 weeks or 24 and 32 weeks, respectively, resulted in drug concentrations in umbilical cord and maternal blood near or below the lowest level of quantification of the assay, supporting the limited transplacental transfer of the hydrophilic pravastatin. Although pravastatin reduced maternal cholesterol levels, umbilical cord blood cholesterol levels and infant birthweight did not differ.7 As expected with an intermediate pravastatin dose with short duration at the end of the third trimester, Döbert and colleagues’ study provides some additional reassurance for the lack of signal for adverse fetal, neonatal, or maternal adverse outcomes. Consideration of a second-trimester potent statin might be considered in future trials, although sample size may be prohibitive unless a preeclampsia risk predictive model can be developed for the second trimester.Attempts to improve the prediction of preeclampsia have increased in the past decade, with the inclusion of angiogenic markers sFlt-1 and PlGF and blood pressure thresholds. An important contribution of the current investigation6 is the validation and demonstrated effectiveness of the Bayesian model that detects term preeclampsia 75% with a clinically relevant 10% screen positive. This Bayesian model includes maternal demographic characteristics and medical history, and late third-trimester mean arterial pressure and maternal serum sFlt-1 and PlGF levels, as well. Thus, new trials testing additional interventions can now be planned with appropriate power/sample size for this important and common condition in pregnant women.In summary, although knowledge gaps remain regarding the pleiotropic effect of statins in CVD and noncardiac systemic inflammatory diseases, the current study adds to the evidence that statins likely confer the majority of benefit through LDL lowering. In addition, substantially more knowledge gaps remain in our understanding of the pathophysiology of preeclampsia, and the mechanistic links between preeclampsia and future CVD in women, as well, in part because of the previous stance of excluding pregnant women in research studies. We and others have documented mechanistic links between adverse pregnancy outcomes including preeclampsia with subsequent premature hypertension,13 ischemic heart disease with coronary microvascular dysfunction,14 and left ventricular hypertrophy and myocardial fibrotic scar.15 The National Heart, Lung, and Blood–sponsored NuMoM2b-HHS (Nulliparous Pregnancy Outcomes Study-Monitoring Mothers-to-Be Heart Health Study)14 is exploring these gaps, and future investigation, including well-designed and rigorous randomized, controlled trials such as Döbert and colleagues, should be conducted in women during pregnancy.Sources of FundingThis work was supported by contracts from the National Heart, Lung and Blood Institutes, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U01 64829, U01 HL649141, U01 HL649241, 1R01HL146158, 1U54AG065141, K23HL125941, 1R03 AG032631, Grants for Catalyzing Research Clusters grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124 and UL1TR000064, and the Edythe L. Broad Women’s Heart Research Fellowship, the Constance Austin Women’s Heart Health Fellowship, both at Cedars-Sinai Medical Center, Los Angeles, California, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, the Linda Joy Pollin Women’s Heart Health Program, and the Erika Glazer Women’s Heart Health Project.Disclosures Dr Merz serves on the Board of Directora for iRhythm and has received fees paid through Cedars-Sinai Medical Center from Abbott Diagnostics and Sanofi. Dr Wei has served on an advisory board for Abbott Vascular. Dr Liao reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 682.https://www.ahajournals.org/journal/circCorrespondence to: C. Noel Bairey Merz, MD, Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, 127 S San Vicente Blvd, AHSP Suite A3206, Los Angeles, CA 90048. Email [email protected]org

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