Heart Failure and Related Risk Factors after Preeclampsia

Part I
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.5 PE complicates 5-10% of first
pregnancies, recurs in ~25%, and is associated with a 2-4 fold increased risk
for CVD. Moreover, the 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 in 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 or 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 further 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.
Part II
Moreover, a quarter of women with a history of PE report symptoms like impaired
concentration and memory capabilities. Several neuropsychological test studies
showed measurable deterioration in cognitive function in the field of (working)
memory, attention and executive control after PE, with cognitive impairments
measurable up till 7 years after the problematic pregnancy suggestive for
cerebral small vessel disease (cSVD). cSVD refers to a group of pathological
processes that affect the small vessels of brain, including small arteries,
arterioles, venules and capillaries. cSVD is associated with derangement of the
blood-brain barrier (BBB) and may lead to ischemic lesions in the brain,
showing as cerebral white matter lesions at MRI,known for their strong relation
to cognitive impairment, micro bleedings and cerebrovascular diseases (CBVD).
Contrary, many women experience PE as a traumatic experience, which is further
enhanced by premature birth or death of the child. The symptoms and cognitive
impairments after PE are very similar to those of posttraumatic stress disorder
(PTSD). Several brain imaging studies showed that PTSD symptoms are associated
with altered functional brain activity and reduced volume of
amygdala/hippocampal regions. By integrated assessment, the interrelated or
separate involvement of dysfunctional neuronal and vascular components can be
unraveled.

Part I
- 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, and potential deterioration over time.
- 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, and changes over time.

Part II
- To evaluate the role of cardiac fibrosis and cardiac small vessel disease in
women with HF.
- To evaluate the role of cerebral small vessel disease on cognitive
functioning in women with HF.
- To perform a genome wide association study (GWAS) and associate novel and
conventional biomarker expression levels with cardiac and cerebral function
determined by Magnetic Resonance Imaging (MRI).

This study consists of 2 parts. Part one is a cross-sectional case-control
study where classical as well as more innovative risk factors for CVD will be
explored. Part two is a case control study to evaluate the relation between
reduced cognitive function in relation to PE and/or reduced cardiac function.
All participants within part 1 will be invited for follow-up measurements after
a minimum of 2 years.

The examinations all occur during one morning in the MUMC+. The visit lasts
approximately 5 hours. The only invasive procedure is a venapunction where 135
ml blood will be extracted, and access for infusion of Voluven is ensured. The
only unfavourable side effect can be a small hematoma (rare). The IMT and
endothelial function will be measured by experienced researchers. The IMT
measurement is performed within 10 minutes and is not invasive. For the
measurement of the FMD a blood pressure cuff will be placed around the forearm
and the pressure will be increased until 200 mmHg and kept at this pressure for
5 minutes. These 5 minutes are slightly uncomfortable for the patient, but
experience has shown that patients endure this examination well. After these
endothelium dependent tests, sublingual Nitroglycerin (NTG) will be
administered to test the endothelium independent response. NTG will be the only
medication provided. NTG has a very short bioactive period ( T1/2 = 1-4
min).There is a chance of minor and temporary development of adverse effects,
such as mild headache (36% of patients), facial flushing, head throbbing,
fainting, hypotension and or tachycardia. Clinically, participants will be
advised based on their risk profile following standard *cardiovasculair
risicomanagement*.(10) Transthoracic echocardiography will be performed by
qualified technicians at the cardiovascular department at the MUMC. Experience
shows that this investigation is not experienced as uncomfortable. All
measurements will be performed or supervised by an experienced researcher.
These investigations are already approved previously in other METC applications
(CMO-nr: 2008/226; 2009/004; 10-2-066). The other measurements (questionnaires,
blood pressure (BP), weight measurement, urine collection, IMT- and glycocalyx
measurement and venous compliance) do not cause any discomfort for the patient
beside the time that it takes. On the other hand, potential health improvement
and early detection of CV risk profiles and initiation of already existing
effective prevention strategies that improve lifestyle are important benefits.
Part II Participants who are selected for participating in part II need to
visit the hospital again to undergo the additional measurements (cardiac and
cerebral MRI, TCD, and neurocognitive tests). Participants will have to lay
down two hours for the cardiac MRI and 1.5 hours for the cerebral MRI. If that
is too long for the participant, the MRI*s will be divided in more sessions
(i.e. two times one hour with a break in between). Patients with
contra-indications for MRI, such as pacemakers, metal implants, vessel clips,
or metal splinters in the eye will be excluded from the study part II. The
administration of the contrast agents is relatively safe. The side effects of
the MRI contrast agent (Gadobutrol) are rare and are amongst others nausea
(0.25%), vomiting (0.05%), urticaria (0.04%), feeling of warmth, tachycardia,
wheals (for each 0.03%), dizziness, itching, vasodilatation, itchy throat (for
each 0.02%) and cough, dyspnoea, flushing, hives, generalized itching, oral
dryness, facial redness, sensation of heat, skin disorder and aggravated nausea
(for each, 0.01%). Out of 14 299 patients, two serious ADRs occurred (0.01%),
which were considered by the treating physician to be probable associated with
the administration of Gadobutrol; one patient had a severe anaphylactic
reaction and the other presented with itching and swelling in the throat. In
most cases side effects occur immediately after the start of contrast infusion,
and therefore patients will remain in the hospital under supervision for at
least 30 minutes after infusion is finished. Adenosine will be used for a
cardiac perfusion scan in the resting state and during stress induction. The
half-life of adenosine is <10 seconds and all side effects are therefore
most likely to be eliminated soon after stopping the infusion. The most
prevalent side effects are amongst others: >10% changes in cardiac rhythm or
heart frequency, dyspnoea, in <10% headache, dizziness, nausea, flushing,
angina pectoris, and anxiety. In <1% palpitations, severe bradycardia,
syncope, convulsions, hyperventilation, vomiting, transpiration, and general
aching. The neurocognitive tests are not invasive and last for approximately 1
hour. The TCD is also non-invasive and lasts approximately also for 15 minutes.