1. What do we know about preeclampsia?

2. Preeclampsia: a two stage disorder Stage 1: Reduced Placental perfusion abnormal implantation Stage 2: Maternal Syndrome ???

3. Stage I Reduced placental perfusion

4. Placental Hypoperfusion in Preeclampsia “... a diffuse hypoxia or relative maternal ischemia of the placenta is the proximate or precipitating cause of preeclampsia and the associated placental insufficiencies. “ Page 1948

5. Placental Hypoperfusion in Preeclampsia evidence Abnormal implantation Association with microvascular diseases (diabetes, hypertension etc.) Association with large placentas (hydrops, multiple gestation, hydatidiform mole) Direct measurements (wash out and Doppler) Animal models of preeclampsia

6. Spiral Arteries (non-pregnant)

7. Spiral Artery (pregnant)

8. Stage II Maternal Syndrome (not just hypertension and proteinuria)

9. Pathological Changes Liver: Hemorrhage and necrosis Adrenal: Hemorrhage and necrosis Brain: Petechial hemorrhage Heart: Subendocardial necrosis Kidney: Glomerular endotheliosis

10. Pathophysiological Changes Reduced perfusion to many (all?) organs Vasoconstriction Increased sensitivity to pressors* Activation of coagulation cascade* Loss of fluid from intravascular space* *Present before clinical disease

11. Hypothesis Endothelial dysfunction is a central pathophysiological factor in preeclampsia.

12. Endothelial Injury in Preeclampsia evidence Morphological Functional increased sensitivity to pressors activation of coagulation endothelial “leak” altered vessel responses in vitro Biochemical markers

13. Biochemical Evidence of Endothelial Activation in Preeclampsia Increased circulating vWF Increased TXA2/PGI Increased endothelin Increased circulating VCAM Increased thrombomodulin Reduced nitric oxide excretion Reduced prostacyclin excretion* Increased cellular fibronectin* Increased growth factor activity* Increased platelet turnover* *present before clinically evident disease

14. Postulated Role of Endothelial Cells in Preeclampsia Endothelial Activation/Injury Increased Vasopressors (Endothelin, ?PDGF) Activation of Coagulation Increased Vascular Permeability Reduced organ perfusion (abnormal renal function) Reduced intravascular volume Increased "Functional" volume? Increased blood pressure Edema Fetal Placental Unit (Trophoblast) Reduced Perfusion (decreased spiral artery invasion, increased trophoblastic tissue, microvascular disease)

15. Preeclampsia: a two stage disorder Stage 1: Reduced Placental perfusion abnormal implantation Stage 2: Maternal Syndrome ???

16. Reduced perfusion Is it sufficient to cause preeclampsia? IUGR babies must have reduced perfusion Only 30% infants of preeclamptics IUGR Insulin resistance and obesity => large infants and preeclampsia Abnormal implantation identical in preeclampsia, IUGR, 1/3 Preterm birth

17. Maternal Fetal Interactions in the Pathogenesis of Preeclampsia

18. Genetic polymorphisms in preeclampsia Angiotensinogen variant in Utah and Japan not Pittsburgh, England of Siberia MTHFR variant in Japan and Italy not Pittsburgh or Utah Lipoprotein lipase in Pittsburgh but not North Carolina

19. “Maternal Constitution” Behavioral e.g.Obesity, smoking, “stress”, diet Genetic e.g. Increased CO, decreased endothelial relaxation, immunology, insulin resistance, thrombophillia Environment e.g.Toxins, infection

20. Risk Factors for Preeclampsia (revisited) 1. Hypertension 2. Diabetes 3. Collagen vascular disease 4. Obesity 5. Black race 6. Insulin resistance (gestational diabetes) 7. Elevated plasma homocysteine 1-3 could reduce placental perfusion 1-7 risk factors for atherosclerosis

21. Preeclampsia and atherosclerosis Similar risk factors Endothelial diseases Long range preeclampsia outcome Dyslipidemia

22. Preeclampsia and atherosclerosis Similar risk factors Endothelial diseases Long range preeclampsia outcome Dyslipidemia

23. Preeclampsia Future cardiovascular disease In 45 year follow up of women with eclampsia in first pregnancy no increase in CVD compared to controls with unknown pregnancy hx. Eclampsia later pregnancy => increased later CVD risk. Women pregnant but never developing preeclampsia have lower CVD risk than general female population.

24. Preeclampsia and atherosclerosis Similar risk factors Endothelial diseases Long range preeclampsia outcome Dyslipidemia

25. Dyslipidemia of preeclampsia Increased free fatty acid* Increased triglycerides* Increased LDL cholesterol Reduced HDL Increased small dense LDL *Present at 18-20 weeks gestation

26. Small Dense LDL is Increased in Preeclampsia

27. Preeclampsia and atherosclerosis Similar risk factors Endothelial diseases Long range preeclampsia outcome Dyslipidemia ? Similar pathophysiology?

28. Atherosclerosis oxidation hypothesis Small dense LDL have preferential access and reside longer in subendothelial space protected from circulating anticoagulants Small dense LDL are more easily oxidized The resulting ox-LDL is toxic: Alters endothelial function Recruits monocytes => foam cells