AS739 - Cardiovascular disease, preeclampsia, and fetal microchimerism

Investigator Names and Contact Information

Introduction/Intent

Cardiovascular disease (CVD) is the leading cause of death among women world-wide and significant sexual dimorphism in CVD phenotypes exist with women experiencing more microvascular disease, heart failure with preserved ejection fraction, and diastolic dysfunction than men. Reproductive events may contribute to this sexual dimorphism. Preeclampsia, new-onset hypertension after 20 weeks gestation with proteinuria and/or other organ system dysfunction, is a major contributor to worldwide maternal morbidity and mortality, affecting 3-8% of pregnancies. Hypertension, endothelial dysfunction, and angiogenic imbalance as hallmarks of preeclampsia underscore a cardiovascular foundation to this condition. Several large epidemiologic studies have established strong a link between preeclampsia and later-life CVD suggesting a role for reproductive events in CVD development. Women with a history of preeclampsia develop CVD along an accelerated pathway and there exists a dose repose (multiple episodes of preeclampsia) and a severity response (more severe phenotypes of preeclampsia) that further multiply this risk. Although shared risk-factors between preeclampsia and CVD likely explain much of this connection, epidemiologic and emerging translational data suggests that after controlling for relevant metabolic parameters, a component of CVD risk conferred by pregnancy, and specifically preeclampsia, also plays a role. It is thus biologically plausible that preeclampsia itself may cause enduring injury to the cardiovascular system resulting in later-life CVD.

Once considered an impermeable barrier perfectly separating mother and fetus, the placenta is now known to be a dynamic organ through which biologic material is bidirectionally exchanged with both immediate and long-term consequences for the mother and fetus. One lasting biologic legacy of pregnancy is the transplacental transfer of cells between mother and fetus, termed microchimerism. Obstetric factors influence fetal cell transfer into the maternal compartment with increased transfer during a preeclampsia pregnancy compared to normal pregnancies. These small number of fetal-origin cells can persist for decades within the maternal compartment and evidence suggests that they play a role in post-reproductive health, including some autoimmune diseases, malignancies, and possibly CVD. Given increased fetal microchimerism (FMc) during preeclampsia and the CVD risk associated with preeclampsia, the link between persistent FMc and later-life CVD risk in those with a history of preeclampsia warrants further investigation. We hypothesize that FMc may represent a durable pregnancy-related factor that persists at higher levels following a preeclampsia pregnancy, compared to normal pregnancy, and influences CVD development later in life.

Here we propose novel studies designed to investigate FMc as a potential link between preeclampsia and later-life CVD. Specifically, we will use data and biologic specimens unique to the Women’s Health Initiative (WHI) study given its robust adjudication of CVD outcomes, capture of reproductive history, inclusion of a multi-ethnic cohort, and storage of key biologic specimens. The considerable number of participants in WHI allows for the selection of a curated cohort (i.e., women with CVD who had preeclampsia or not) that would not otherwise be practical for prospective recruitment. We have worked with the WHI Help Desk and determined that there are sufficient participants to complete the proposed work (approximately N=123 with CVD and a history of preeclampsia; N=1489 with CVD and no history of hypertensive disorders of pregnancy, such as preeclampsia or gestational hypertension). Of note, studies remote from pregnancy without paired offspring samples preclude the use of targeted FMc detection. In this case, the detection of male origin FMc is standardly employed and has been widely used in prior studies investigating the association of persistent FMc and later-life adult health and disease. We will thus utilize this same approach for the proposed study.

Specific Aim: To quantify FMc persistence among women with evident CVD and a pregnancy history of preeclampsia compared to those without a history of a hypertensive pregnancy. We hypothesize that CVD in those with a history of preeclampsia (cases) is associated with persistent FMc and at quantitatively higher levels than in those without a history of hypertensive pregnancies (controls). Using DNA extracted from buffy coat, we will detect and quantify male FMc in each sample using a qPCR-based approach (targeting SRY). We will measure the association of CVD and male FMc prevalence and concentration based on preeclampsia status. We will consider, at minimum, the following covariates in all models: age at sample collection, gravidity (number of prior pregnancies), race/ethnicity, smoking status, hypertension, diabetes, hormone replacement therapy, and critically, the number of cells tested in each sample.

Results from this study have the potential to catalyze crucial studies in large populations to advance our understanding of the reproductive origins of adult diseases. Specifically, selection of this curated cohort will accelerate future studies by our group with WHI using both data and other stored biospecimens (e.g., plasma).