Heart Failure and Related Risk-factors After Preeclampsia

Study Overview
=================
Brief Summary
-----------------
This study is a cross-sectional case-control study where classical as well as more innovative risk factors for CVD will be explored. In western countries, more women than men die of cardiovascular disease (CVD), making CVD in women an important public health issue. Misdiagnosis of CVD in women is frequently observed, posing the clinician for diagnostic and therapeutic dilemmas that can easily result in inadequate treatment and worse prognosis. Despite these challenges, CVD in women has been underexposed in scientific research. Women have gender-specific risk factors like a history of preeclampsia (PE) that contribute to their risk for CVD. PE complicates 5-10% of pregnancies, recurs in  25% and is associated with a 2-4 fold increased risk for CVD. Moreover, pre-symptomatic heart failure (HF) stage B occurs in 40% of women with a history of PE. HF stage B is thought to precede the development of the, mortality related, clinical HF stages C and D (structural heart disease in combination with symptomatic disease). Early detection and tailored intervention of women with stage B HF decreases progression to the clinical stages and might therefore improve clinical outcome and cardiovascular related mortality. Phenotypic presentation of HF is currently split up between systolic HF also called HF with reduced ejection fraction (HFrEF) and diastolic HF or HF with preserved ejection fraction (HFpEF). Women more often have HFpEF in contrast to men. Different pathophysiology and disease progression in women compared to men seems to be an important underlying factor. The current clinical HF diagnostic tools (e.g. natriuretic hormones and high sensitivity troponins) fail to identify early changes that prelude adverse cardiac remodelling and HF, and do not discriminate between HFrEF and HFpEF. Moreover, there are sex-related differences in biomarker levels for detection of CVD. As a result, clinicians are forced to wait for the failing heart to become clinically evident before they can intervene. Therefore, there is an urgent need to assess novel biomarkers that could help select high risk women needing further follow up and intervention. Biomarkers may not only improve early diagnosis but may also unravel disease pathways of HFpEF. Especially when combined with measurements of subclinical, surrogate risk markers. Objectives To determine the impact of PE on incidence of macro-and micro-vascular dysfunction reflected by surrogate measures for coronary artery disease (CAD) and HFpEF. To perform a genome wide association study (GWAS) and associate novel biomarker expression levels with endothelial function, cardiac diastolic function and IMT measurement. To identify risk factors and surrogate measures for CVD in a) former PE patients without HFpEF, b) former PE patients with HFpEF and c) healthy parous controls. Study population Cases: women with a history of PE Controls: women with uncomplicated pregnancies in the history. Measurements will be performed in clusters at postpartum intervals of: ½-2, 5-10, 10-15 and 15-30 years. Number of inclusions will be: 425, 350, 282 and 233 for each follow-up group respectively. Primary endpoints The prevalence of macro- and microvascular dysfunction in former PE patients. Novel biomarker detection in former PE patients associated with HF in general and HFpEF in particular. Secondary endpoints Lifestyle (questionnaire) Cognitive ability (questionnaire) Depression score (questionnaire) Metabolic syndrome (MetS) Arterial endothelial function (Flow mediated dilation (FMD)) Intima Media Thickness (IMT) Glycocalyx thickness (by means of the Glycocheck) Venous function (plethysmograph) Electrocardiogram (ECG) Ergometry

Official Title
-----------------
Queen of Hearts Research Program. Identifying the Risk on Heart Failure After Preeclampsia.

Conditions
-----------------
Heart Failure, Cardiovascular Diseases, Pre-Eclampsia

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Cases Women aged ≥ 18 years ½ till 30 years after the complicated pregnancy Experienced PE in any pregnancy. PE defined as hypertension (systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg) developed after 20 weeks of pregnancy with the development of proteinuria (≥ 300 mg/ 24 hours). Women who had their last delivery at least 6 months ago. Controls Women aged ≥ 18 years ½ till 30 years after the pregnancy that matches the sequence number of pregnancy of the specifically matched case. Experienced pregnancies that were not complicated by foetal or maternal placental syndrome (pregnancy induced hypertension, preeclampsia, HELLP-syndrome). Women who had their last pregnancy at least 6 months ago. Women with a negative family history for PE (mother and sisters did not experience PE). Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: Cases Women with auto-immune diseases prior to the complicated pregnancy. Chronic hypertension prior to the complicated pregnancy. Renal disease prior to the complicated pregnancy. Pregnant women Women who do not want to be informed about the results of the tests, or women who do not want their general practitioner and specialist(s) to be informed about the test results. Control group: Women with auto-immune diseases Chronic hypertension prior to the matched pregnancy. Women with IUGR in the matching pregnancy (p<10) Solutio placentae in the matching pregnancy Pregnant women Women who do not want to be informed about the results of the tests, or women who do not want their general practitioner and specialist(s) to be informed about the test results.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Women with a history of preeclampsia (cases)<br>Cases: women with a history of preeclampsia. Measurements will be performed in a postpartum interval from 0.5 years until 30 years after the first complicated pregnancy. This group will further be subdivided in a subgroup with Heart Failure and a group without Heart Failure. | |
| Women with a history of uncomplicated pregnancy (controls)<br>Controls include women with a history of uncomplicated pregnancies. The controlgroup will further be subdivided in a subgroup with Heart Failure and a group without Heart Failure. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The prevalence of Heart Failure (number with percentage) | Heart Failure will be assessed with the transthoracic echocardiography based on the criteria of the American Heart Association. The sub classification for Heart Failure with preserved ejection fraction (EF) will be made (EF >55%) | At time of assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Structural en Functional Cardiac Measurements | The objective is to estimate structural and functional cardiac measurements with the TTE based on the ASA guidelines. | At time of assessment | 
| Metabolic syndrome | The objective is to assess the prevalence of constituents of the Metabolic syndrome based on the WHO criteria. The prevalence will be reported in number with percentage. | At time of assessment | 
| Arterial endothelial function (Flow mediated dilation (FMD)) | The objective is to estimate NO mediated endothelial function of the brachial artery with ultrasound by FMD and sublingual NTG administration. FMD will be reported in relative increase in diameter (%). | At time of assessment | 
| Common Carotid Intima media thickness | The objective is to estimate IMT of the common carotid artery in cm using ultrasound. | At time of assessment | 
| Glycocalyx thickness en microvascular tortuosity | The objective is to estimate the glycocalyx dimensions using sublingual orthogonal polarization spectral (OPS) measurements. Derivative of the glycocalyx (perfused boundary region) will be reported in um. Tortuosity will be reported based on a score system. | At time of assessment | 
| Cognitive, Lifestyle and Depression rates | To evaluate subjective cognitive functioning and depression rates and lifestyle behavior in formerly preeclamptic women with heart failure compared to controls. | At time of assessment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heart Failure, Diastolic Dysfunction, Pre-Eclampsia, Endothelial dysfunction, Biological Markers, MicroRNAs, Circulating cells