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

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.

Cases: women with a history of PE. Control group: women with uncomplicated pregnancies in the history H1: PP interval ½ -2 years: n = 2x 425 H2: PP interval 5-10 years: n = 2x 350 H3: PP interval 10-15 years: n = 2x 282 H4: PP interval 15-30 years: n = 2x 233