Preeclampsia Clinical Trial
Official title:
Identifying HDL Composition and Function in Preeclamptic and Normal Pregnancies and Volatile Organic Compounds in Maternal Saliva Characteristic of Preeclampsia
The study is design to assess if there is a correlation between diagnosis of preeclampsia and its severity to changes in HDL quality, in terms of composition and function and to determine whether preeclampsia-induced changes in VOCs in saliva can be used for the early diagnosis of preeclampsia.
Scientific background Preeclampsia is a syndrome characterized by the onset of hypertension
and proteinuria or other end-organ dysfunction. It develops after 20 weeks of gestation and
can cause significant maternal and fetal morbidity and mortality (1,2). The pathophysiology
of preeclampsia is thought to be developmental abnormalities of placental vasculature leading
to placental under-perfusion or ischemia. This ischemia is believed to mediate the release of
anti-angiogenic factors into the maternal circulation, causing endothelial dysfunction,
hypertension and end-organ injury (2). The elemental factor that leads to the development of
placental vasculature abnormalities is still to be elucidated. However, histological changes
in the placenta include atherosis (lipid laden cells in the wall of the arteriole), fibrinoid
necrosis, thrombosis, sclerotic narrowing of arterioles, and placental infarction, all of
which are similar to findings seen in atherosclerotic plaque (1-3). Another close association
between the mechanisms of preeclampsia and atherosclerosis was found in large epidemiological
studies that demonstrated a strong correlation between preeclampsia (PET) and the development
of cardiovascular disease later in life (4). Women with PET are more likely than those with
normal pregnancy to develop chronic hypertension, cardiovascular disease, stroke, diabetes
and end-stage renal disease (1,4).Common atherosclerotic diseases, such as hypertension,
chronic kidney disease (CKD), hypercholesterolemia and diabetes are strongly associated with
preeclampsia during pregnancy (5-6).
Large epidemiologic and experimental studies have shown an association between low levels of
high density lipids (HDL) in the blood and increased cardiovascular risk (7). The
cardioprotective properties of HDL are thought to be composed of several mechanisms,
including regulation of endothelial functions that enhance NO production and maintaining
endothelial integrity, as well as anti-inflammatory, anti-oxidative and anti-thrombotic
effects (8-9). However, pharmacological studies reported that increases in plasma HDL did not
improve cardiovascular outcomes (10-12).
At the same time, emerging data have revealed the importance of the quality of the HDL more
than its quantity. HDL from patients with CKD was found to lose its anti-atherogenic and
endothelial protective effects. In a study by Shroff et al. (13), HDL from patients with CKD
was incubated with a primary endothelial cell line. Several endothelial functions, such as
reduced NO production, permission of SO production, increased VCAM-1 expression and reduction
of cholesterol efflux capacity were decreased compared to those of HDL from healthy
individuals. These effects were associated with vascular dysfunction markers in those
patients, such as high levels of urate, angiopoeitin and IL-6, as well as poor vascular
function measurements, as measured by aortic pulse velocity and carotid intima media
thickness. These negative functions increased as CKD severity progressed and showed a partial
improvement after kidney transplantation (13).
Information regarding the composition and function of serum lipids and lipoproteins among
preeclamptic pregnancies compared to normal pregnancies is scarce. Early pregnancy
dyslipidemia, particularly hypertriglyceridemia appears to be associated with increased risk
of preeclampsia (14). However, equivocal results were found regarding paraoxonase 1 (PON1)
activity, which is an antioxidative enzyme found in HDL that inhibits low density lipid (LDL)
and HDL oxidation. PON1 activity is decreased in diseases associated with endothelial
activation and dysfunction including diabetes, hypercholesterolemia and cardiovascular
disease (15). Demir et al. (16) found low levels of HDL, ApoA1 and paraoxonase activity in
preeclamptic compared to normal pregnancies, whereas Acikgoz et al. (17) demonstrated
significantly higher PON1 activity in preeclamptic compared to normal pregnancies.
Saliva contains constituents that reflect a diseased or physiologic state of the human body
and hence could be utilized for diagnostic purposes. The sources and composition of whole
saliva (oral fluid) are unique and complex. Saliva consists of secretions from salivary
glands and gingival crevicular fluid, oral mucosa transudate, secretions from nasal and
pharyngeal mucosa, nonadherent bacteria, desquamated oral epithelial cells, keratin debris,
blood cells, and possibly food or medication residuals (18). Its functions include
lubrication, digestion, antimicrobial activity, facilitating remineralization of dental
enamel, and maintaining normal taste sensation (19). These important functions are achieved
by the various chemical components of saliva including water, inorganic compounds (ions),
organic compounds (non-proteins and lipids), protein/polypeptides, and hormones (19). The
search for reliable salivary biomarkers has developed rapidly, especially in oral cancers,
spurred by the fact that collecting saliva is simpler and less invasive than drawing blood.
Salvador-Moysén et al. (20) aimed to determine the usefulness of salivary cortisol as a
predictor of preeclampsia in adolescents. They found that cortisol concentrations >14.9
nmol/L were observed in the group that developed preeclampsia, whereas the control group had
values <10.1 nmol/L.
Volatile organic compounds (VOC) can be detected in the breath and blood and used for the
early detection and characterization of the development and progression of diseases (21).
Many of the VOC that are detected in the breath are systemic or endogenous and are produced
during physiological processes, but the metabolic routes behind their production are known
for only a few (22). Other VOCs are exogenous and result from external contamination through
inhaled air or ingested foods or drinks.
Solid phase microextraction (SPME) is a simple, automated, rapid technique for VOC detection
combined with gas chromatography-mass spectrometry (GC-MS) (20). To the best of our
knowledge, no studies have been conducted to identify VOC in saliva from preeclamptic women.
Objectives
1. There is a correlation between diagnosis of preeclampsia and its severity to changes in
HDL quality, in terms of composition and function.
2. Determine whether preeclampsia-induced changes in VOCs in saliva can be used for the
early diagnosis of preeclampsia.
Research goals
1. Assess:
HDL composition and function of normal and preeclamptic pregnancies at weeks 12-14
(second trimester), weeks 28-30 (third trimester) and at delivery Apo-A1 properties,
PON1 activity HDL size HDL lipid content HDL antioxidant activity (toward LDL and
macrophages) HDL-mediated cholesterol efflux from macrophages
2. Evaluate the effects of HDL from women with PET, normal pregnancies and non-pregnant
women, on primary endothelial culture regarding proteins, mRNA and miRNAs, which are
significant components in normal endothelial function and related to inflammatory
response.
3. Evaluate differences in the genomic and lipid profiles of cord blood and placentas from
women with PET, normal pregnancies and non-pregnant women
4. Identify VOC in saliva, as early biomarkers of PET during the second and third
trimesters and at delivery.
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