Losartan for Improved Vascular Endothelial Function After Preeclampsia (LIVE-PE)

Angiotensin II Receptor Inhibition to Improve Microvascular Function in Women Who Have Had Preeclampsia

Women who develop preeclampsia during pregnancy are more likely to develop and die of cardiovascular disease later in life, even if they are otherwise healthy. The reason why this occurs is unclear but may be related to blood vessel damage and increased inflammation that occurs during the preeclamptic pregnancy and persists postpartum. The purpose of this investigation is to determine the mechanisms contributing to this lasting blood vessel damage and to test whether taking a medication that blocks angiotensin II receptors (losartan) decrease these negative effects in women who have had preeclampsia. Identification of these mechanisms and treatment strategies may lead to better clinical management,of cardiovascular disease risk in these women.

In this study we use the blood vessels in the skin as a representative vascular bed. Using a minimally invasive technique (intradermal microdialysis for the local delivery of pharmaceutical agents) we examine the blood vessels in a nickle-sized area of the skin in women who have had preeclampsia. We make these measurements after the subjects take a placebo and after they take losartan (an angiotensin II receptor blocker) to test whether this treatment improves vascular function in these women. As a compliment to these measurements, we also draw blood from the subjects and isolate the inflammatory cells to test how sensitive their inflammatory responses are following the placebo and the losartan treatment.

Study Overview

• Status: Recruiting
• Conditions: Preeclampsia Postpartum
• Intervention / Treatment: Drug: Losartan Potassium; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Kaila Brustkern, BS; Phone Number: 319-467-3096; Email: kaila-brustkern@uiowa.edu
• Study Contact Backup: Name: Anna Stanhewicz, PhD; Phone Number: 319-467-1732; Email: anna-stanhewicz@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa
      • Contact: Anna Stanhewicz, PhD; Phone Number: 319-467-1732; Email: anna-stanhewicz@uiowa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Post-partum women,

• 18 years or older,
• who have delivered within 24 months of the study visit
• who have had a preeclamptic pregnancy diagnosed by their obstetrician and confirmed according to the American College of Obstetricians and Gynecologists criteria for preeclampsia. [This information will be self-reported by the subjects.]
• Using an effective method of birth control and not planning to become pregnant in the next 6 months.

Exclusion Criteria:

• skin diseases,
• current tobacco use,
• diagnosed or suspected hepatic or metabolic disease including chronic kidney disease (CKD) defined as reduced eGFR < 60 mL/min/1.73m2,
• statin or other cholesterol-lowering medication,
• current antihypertensive medication,
• history of hypertension prior to pregnancy,
• history of gestational diabetes,
• current pregnancy or breastfeeding,
• body mass index <18.5 kg/m2,
• allergy to materials used during the experiment.(e.g. latex),
• known allergies to study drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Losartan; 6 weeks of daily (50mg/day) oral losartan potassium tablet	Drug: Losartan Potassium; subjects ingest 50mg losartan potassium tablet daily for 6 weeks
Placebo Comparator: Placebo; 6 weeks of daily oral placebo tablet	Drug: Placebo; subjects ingest placebo tablet daily for 6 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microvascular endothelial function following systemic AT1 receptor inhibition	cutaneous vascular vasodilator response to exogenous acetylcholine perfusion; measured with laser-Doppler flowmetry coupled with intradermal microdialysis delivery of acetylcholine alone or co-infused with L-NAME	at the completion of 6 weeks of oral losartan treatment
Microvascular endothelial function following placebo	cutaneous vascular vasodilator response to exogenous acetylcholine perfusion; measured with laser-Doppler flowmetry coupled with intradermal microdialysis delivery of acetylcholine alone or co-infused with L-NAME	at the completion of 6 weeks of placebo treatment
Microvascular angiotensin II sensitivity following systemic AT1 receptor inhibition	cutaneous vascular constrictor response to exogenous ang II perfusion; measured by laser-Doppler flowmetry coupled with intradermal microdialysis delivery of angiotensin II	at the completion of 6 weeks of oral losartan treatment, and 2) at the completion of 6 weeks of placebo treatment
Microvascular angiotensin II sensitivity following placebo	cutaneous vascular constrictor response to exogenous ang II perfusion; measured by laser-Doppler flowmetry coupled with intradermal microdialysis delivery of angiotensin II	at the completion of 6 weeks of placebo treatment
Central and Peripheral Vascular Stiffness following systemic AT1 receptor inhibition	carotid-femoral and carotid-brachial Pulse Wave velocity; measured by applanation tonometry using the Sphygmocor pulse wave analysis system	at the completion of 6 weeks of oral losartan treatment
Central and Peripheral Vascular Stiffness following placebo	carotid-femoral and carotid-brachial Pulse Wave velocity; measured by applanation tonometry using the Sphygmocor pulse wave analysis system	at the completion of 6 weeks of placebo treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
circulating inflammatory cytokines	plasma measurement of circulating inflammatory cytokines; measured by ELISA in plasma samples	a total of 2 times throughout the study: 1) at the completion of 6 weeks of oral losartan treatment, and 2) at the completion of 6 weeks of placebo treatment
PBMC inflammatory sensitivity	isolated peripheral blood mononuclear cell inflammatory responses to ang II and LPS; measured by assessing inflammatory cytokines (ELISA) in cell culture supernatants collected from PBMCs treated with ang II or LPS for 24 hours	a total of 2 times throughout the study: 1) at the completion of 6 weeks of oral losartan treatment, and 2) at the completion of 6 weeks of placebo treatment

Collaborators and Investigators

• Sponsor: Anna Stanhewicz, PhD
• Investigators: Principal Investigator: Anna Stanhewicz, PhD, University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2020
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: November 10, 2020
• First Submitted That Met QC Criteria: November 16, 2020
• First Posted (Actual): November 17, 2020

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: September 13, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pregnancy Complications; Hypertension, Pregnancy-Induced; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Pre-Eclampsia; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: 202006148

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No