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Hypertension & Preeclampsia

Mark K. Santillan, MD &

Justin L. Grobe, PhD, FAHA

CCOM Center for Hypertension ResearchFrançois M. Abboud Cardiovascular Research Center

Obesity Research & Education InitiativeFraternal Order of Eagles’ Diabetes Research Center

Breakthroughs in Medicine at IOWA:Cardiovascular Research

Justin L. Grobe, PhD, FAHAPharmacology

Mark K. Santillan, MDObstetrics & Gynecology

Preeclampsia: One patient’s story

September 2012

• Headache

• Blurry vision

• High blood pressure

• Renal damage

• Protein in urine

• Shock

• Seizures

• Liver failure

• Kidney failure

• Pancreatic failure

Preeclampsia: One patient’s story

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Preeclampsia: One patient’s story

Easter 2014

What is preeclampsia?Common symptoms

• Increased blood pressure

• Protein in urine• Headache / vision

problems• Nausea / vomiting• Abdominal /

shoulder / back pain

• Weight gain• Anxiety /

shortness of breath

Preeclampsia effects on mothers

• Immediate risks• Seizure• Stroke• Organ failure• Death

• Life‐long risks• Hypertension

• Kidney disease

• Liver problems

• Stroke

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Preeclampsia effects on children

• Premature birth

• Death

• Increased risk for many diseases when surviving children become adults

• Hypertension• Diabetes• Obesity

Who gets preeclampsia?

Worldwide:• Affects 10% of all pregnancies• Kills 76,000mothers / year• Kills 500,000 infants / year

>500,000 / yearin the United States

Preeclampsia has complicated pregnancy for many famous mothers

Kim Kardashian(reality star)

Trista Sutter(Bachelorette)

Brooke Mueller(Charlie Sheen ex)

Mariah Carey(singer/producer)

Adriana Lima(model)

Michelle Duggar(actress)

Jane Seymour(actress)

Laura Bush(former 1st Lady)

Lady Sybil Crawley(fictional character

on PBS show“Downton Abbey”)

Debra Messing(actress)

Angelina Jolie(actress)

Jennifer Lopez(singer/actress)

Faith Hill(singer)

Marcia Cross(actress)

Lisa Marie Presley(actress)

Ann Curry(NBC news)

Sherri Shephard(actress / The View)

Leah Remini(actress )

Sophie Ellis‐Bextor(singer)

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How long has preeclampsia been recognized?

Hippocrates first described a woman experiencing preeclampsia ~400 BC

Statue of Hippocrates and patients in Kos, Greece

State-of-the-art “solution” = premature birth

26 weeks, 8.6 ounces

>2,400 years of progress…?!

Challenges abound for preeclampsia

Therapeutics

Preeclampsia

How can we safelytreat the afflicted?

How can we studythe disease?

How do we identifyat‐risk pregnancies?

No reliable early diagnostics 

currently exist

Current models do not recapitulate the early stages of 

the disease

No effective + safe treatments 

currently exist

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New ideas from new collaborations

Mark Santillan, MDHigh‐Risk Obstetrician

Justin Grobe, PhDHypertension Researcher In the fields of observation, chance 

favors only the prepared mind.

‒ Louis Pasteur (1822‐1895)Pioneer of the “germ theory of disease”(Lecture, University of Lille, Dec 7, 1854)

Subtypes of hypertension

All humanswith 

hypertension

Subtypes of hypertension

Low (27%)

High(16%)

Normal(57%)

Laragh JH. Circulation.1971; 44: 971-974.

Circulating Renin Activityin Essential Hypertensives

African AmericansElderlyRenal FailureHeart FailurePREECLAMPSIA

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Subtypes of hypertension

African AmericansElderlyRenal FailureHeart FailurePREECLAMPSIA

Same subset ofpatients that benefitfrom vasopressin blockade

Animal Models:DOCA‐saltsRA transgenicDahl Salt‐SensitivePsychogenic

Vasopressin blockade is a potent antihypertensivetherapy

Is there a role for vasopressin in preeclampsia?

What is vasopressin?

Santiago Ramón y Cajal(“The father of modern neuroscience” due to his microscopic study of neurons; 1906 Nobel with Camillo Golgi)

1894 –identifies bundles of nonmyelinated nerve fibers entering posterior pituitary

Farini (Venice), and von den Velden (Dusseldorf)1913 –mammalian posterior pituitary extracts decrease urine production in patients with DI, and reduce water diuresis in normal subjects

Berta V. Scharrer & Ernst A. Scharrer (students of Karl von Frisch, 1973 Nobel)(Escaped the holocaust by emigrating to the U.S. with $8 in their pockets)

1945‐1954 ‐ formally introduce concept of neurosecretion

Wolfgang Bargmann(A major figure in rebuilding German science after the World Wars)

1949‐1968 – demonstrates that the paraventricular nucleus and supraoptic nucleus produce neurohypohyseal hormones, and project to posterior pituitary

Vincent Du Vigneaud1953 – suggests structure of vasopressin

Ernest Basil Verney1947 – demonstrates osmotic regulation of vasopressin, and renal site of action

1952 and beyond – Possible role in pregnancy suggested by several groups

Vasopressin: 2015 understanding

Signal

Vasopressin (AVP)

Neurophysin II Copeptin

Vasopressin (AVP)• 9 amino acids• 10 minute half‐life in blood (very short!)• Acts via 4 receptors to increase blood volume and pressure

Copeptin• Released in 1:1 ratio to vasopressin• No known biological function• Very useful as a biomarker for vasopressin

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Clinical Symptoms of PreE

Copeptin in Preeclampsia

Zulfikaroglu (2011):Copeptin↑ in PreE

(third trimester)

Foda (2012):Copeptin↑ in PreE

(at delivery)

Conception Birth

First Trimester Second Trimester Third Trimester

13 wk 26 wk

Copeptin is elevated when preeclampsia symptoms are already present…What about before symptoms show up?  

The Maternal-Fetal Tissue Bank @ Univ. Iowa

Clinical data& maternal blood

Cord blood

Placenta

Urine

Amniotic Fluid

• IRB‐approved biorepository

• Approach almost every mother receiving care at UIHC

• Have enrolled ~1,500 women

• Track medical records to know which moms develop preeclampsia

• Collected ~2,500 blood samples and ~450 placentas

• Make data and samples available to a wide range of researchers at UIHC and worldwide

Donna A.Santillan, 

PhD

Santillan, … & Santillan.  Eur J Obst & Gynecol and Repro Biol. 179: 94‐99.  2014.

Copeptin in preeclampsia

Santillan, … & Grobe.  Hypertension. 64(4): 852‐859, Oct. 2014.

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Clinical Symptoms of PreE

Copeptin in Preeclampsia

Zulfikaroglu (2011):Copeptin↑ in PreE

(third trimester)

Foda (2012):Copeptin↑ in PreE

(at delivery)

Yeung (Dec 2014):Copeptin↑ in PreE(16th week through birth)

Santillan (Oct 2014):Copeptin↑ in PreE(6th week through birth)

Conception Birth

First Trimester Second Trimester Third Trimester

13 wk 26 wk

Subset of Calcium for PreeclampsiaPrevention trial:  N=136 control, 169 PreE

53% & 70% non‐white

N=54 control, 50 PreE10% non‐white

Novel Diagnostics?Vasopressin / copeptin as the first objective early-pregnancy diagnostic test for preeclampsia

Why do we care about early diagnosis?

Snydal S.  Major changes in diagnosis and management of preeclampsia.  J Midwifery Womens Health.  59 (6): 596‐605.  2014.

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Copeptin predicts preeclampsia

Already in 1st trimester:“All‐comers test”Sensitivity = 88%Specificity = 81%PPV = 34%NPV = 98%

“No‐history moms only”Sensitivity = 92%Specificity = 94%PPV = 64%NPV = 99%

If we know nothing else about mom, this test is already better than any other

These are the moms we need to test;for them, this test is truly exceptional

Santillan, … & Grobe.  Hypertension. 64(4): 852‐859, Oct. 2014.

Moving research from bench to clinic

• Patent filed Feb 2014

• Describes use of vasopressin / copeptin to diagnose preeclampsia

• Currently negotiating with multiple major companies to get this assay into every general practitioner and obstetrician's toolkit, worldwide

• May someday supplement / replace standard urine pregnancy test kit for at‐home use(“Not pregnant” vs “Pregnant” vs “Pregnant… and go see your doctor now!”)

Iowans working together

The University of Iowa Healthcare Alliance1. Mercy Medical Center, Sioux City2. Oakland (NE) Mercy Hospital3. Baum‐Harmon Mercy Hospital, Primghar4. Mercy West Lakes, West Des Moines5. Mercy Medical Center, Des Moines6. Mercy Medical Center, North Iowa7. Mercy Medical Center, Centerville8. Mercy Medical Center, New Hampton9. Mercy Medical Center, Dyersville10. Mercy Medical Center, Dubuque11. Mercy Medical Center, Clinton12. Genesis Medical Center, DeWitt13. Genesis Medical Center, Silvis14. Genesis Medical Center, Aledo15. Genesis Medical Center, Davenport16. University of Iowa Hospital17. Mercy, Cedar Rapids18. Covenant Medical Center, Waterloo19. Sartori Memorial Hospital, Cedar Falls20. Mercy Hospital, Oelwein

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Novel Therapeutics?Vasopressin secretion & receptors as the first rational, specific, preventative / curative therapeutic for preeclampsia

SFLT1 viral model (tissue initiation)

RUPP model (vascular initiation)

Conception Birth

First Trimester Second Trimester Third Trimester

13 wk 26 wk

Temporal relationships

PoorPlacentation

ElevatedAVP

Secretion

ElevatedAVPAction

VascularDysfunction

ImmuneDysfunction

RenalDysfunction

AngiogenicDysfunction

ClinicalSymptoms

UADdysfunctionevident

Copeptinelevated

Angiogenicmarkersappear

OVERALL HYPOTHESIS

Boundary ofwidely‐acceptedmechanisms

Clinical Symptoms of PreE

Vasopressin & vascular dysfunction in human pregnancies

2nd TrimesterEndothelial function

Aortic stiffness

Blood pressure

Gary L. Pierce, PhD (Iowa HHP)

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Does vasopressin actually causepreeclampsia?

Correla on ≠ causa on!

Vasopressin can cause mom’s symptoms

• Pregnancy‐dependent hypertension

• Proteinuria

• Renal glomerular endotheliosis

Santillan, … & Grobe.  Hypertension. 64(4): 852‐859, Oct. 2014.

Vasopressin can cause baby’s symptoms

• In utero growth restriction• Spontaneous fetal death• Programming of adult disease

• Hypertension• Renal problems• Obesity

Programming Adult Disease:

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V1B receptorGαq/11

PLC‐PIP2‐DAG‐IP3‐PKCACTH release

V2 receptorGαs

AC‐cAMP‐PKAWater retention

Block vasopressin to treat preeclampsia?

V1A receptorGαq/11

PLC‐PIP2‐DAG‐IP3‐PKCVascular contractionNeuronal function

Cullin‐5SOCS/BC‐box/eloBC/cul5/RING‐

E3 ligase complex

RelcovaptanTolvaptan Nelivaptan

Conivaptan

Preliminary findings – V1A / V2involvement

• Blocking V1A+V2 receptors appears to reverse maternal & fetal consequences of elevated vasopressin during gestation

• Future studies will dissect role of V1A versus V2

Complementary data from the literature

V2 receptorV1A receptor

Vasopressin

Vascularcontraction

Waterretention

RGS2

Anne Staff’s group from Oslo, Norway:

2013 – Loss‐of‐expression mutation in RGS2 correlates with preeclampsia(3'UTR C1114G polymorphism (rs4606); Odds ratio 1.43, P=0.017)

2014 – Same mutation independently correlates with severe hypertension later in mother’s life

Loss of “brake” on vasopressin signaling correlates with preeclampsia and its life‐long consequences on survivors

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Moving research from bench to clinic

• Patent filed Feb 2014

• Describes various approaches to treat preeclampsia by interfering with vasopressin secretion or action

• Drugs to block secretion and action already exist; working to get pharmaceutical company owners of those drugs to test safety and use during pregnancy

Take-home points

• Preeclampsia is a devastating disease of late pregnancy, for which there has been little progress in >2,400 years.

• Vasopressin is strongly predictive of the onset of the disease – we can now diagnose by 6 weeks into pregnancy (months before symptoms appear).

• Vasopressin is probably causative for preeclampsia. Ongoing work is aimed at developing novel treatment options which target this system.

• Working to move discoveries into the clinic!

Curt D. Sigmund, PhD

Genetics

Gary L. Pierce, PhD

Human Physiology

Katherine N. Gibson‐Corley, DVM, PhDPathology

Our multidisciplinary team at Univ. of Iowa

Donna A.Santillan, PhDMolecular Biology

Justin L. Grobe, PhD, FAHA

Pharmacology

Gideon K.D. Zamba, PhDBiostatistics

Mark K. Santillan, MDObstetrics

Eric J. Devor, PhD

Molecular Biology

Stephen K. Hunter, MD, 

PhDObstetrics

Kimberly K. Leslie, MDObstetrics

Kamal Rahmouni, 

PhDPharmacology

Anne E. Kwitek, PhDGenetics

Allyn L. Mark, MD

Internal Medicine

Frank M. Faraci, PhDVascular Biology

Postdocs, Students & Technicians:Sabrina M. Scroggins, PhDJeremy A. SandgrenJames Y. MinNicole A. Pearson, MPHMonika Ahuja, MCAWendy S. HamiltonBrenda J. BoeseDeidre K. Fleener, RN

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American Heart AssociationStrategically Focused Research Network

University of Iowa Center (Sigmund)Population (Santillan)

Does copeptin work as a diagnostic for all moms?

Clinical (Pierce)Does AVP predict vascular problems in women?

Basic (Grobe)Which AVP receptors are involved,and might represent new targets?

American Heart AssociationStrategically Focused Research Network

Acknowledgments

Funding, Resources & Facilities:Roy J. Carver Trust

American Heart AssociationMaternal Fetal Tissue Bank

Center for Hypertension ResearchDepts. of Ob/Gyn & Pharmacology

Institute for Clinical & Translational ScienceCarver College of Medicine

Our staff, students & collaborators

Our patients

Kelli Carlson

And thank you for your attention, time, and interest!