Microvascular rarefaction in vascular cognitive impairment and heart failure -VCI

Vascular cognitive impairment (VCI) is an umbrella term to cover all cognitive
disorders from mild cognitive impairment through fully developed dementia that
arise due to vascular dysfunction. Vascular dementia is the 2nd most common
type of dementia after Alzheimers Disease. The vascular dysfunction in VCI is
mainly due to cerebral small vessel disease (cSVD).
Heart failure with preserved ejection fraction (HFpEF) is diastolic heart
failure where the heart muscle has stiffened and therefore doesn*t fill
properly. About half of all patients with HF have HFpEF. It is a syndrome
involving microvascular dysfunction due to small vessel disease.
The development of VCI due to cSVD and of HFpEF are both linked to the presence
of comorbidities such as hypertension, diabetes, obesity and aging. Decreases
in capillary vessel density within a tissue, called microvascular rarefaction,
is a common feature of these comorbidities. For many of the comorbidities
associated with HFpEF and VCI, capillary rarefaction actually precedes disease
development. Significant evidence now suggests that capillary rarefaction may
exacerbate or drive comorbidities. In mice, induced rarefaction through
muscle-specific ablation of VEGF resulted in a 45% reduction of
insulin-stimulated whole-body glucose disposal during a euglycemic insulin
clamp. The decreased capillary density was proposed to impede insulin delivery
to muscles and adipose tissue leading to insulin resistance, a hypothesis that
has been corroborated in humans. Hypertensive patients also have lower
capillary density. Capillary rarefaction is present in young adults (23-33
years) with familial predisposition to hypertension that have yet to develop
hypertension.
Microvascular rarefaction is now thought to be at the core of why small vessel
diseases like HFpEF and VCI develop. Furthermore, cardiac microvascular disease
leading to a failing heart (HFpEF) and altered cerebral function often present
together. Disease progression in both HFpEF and VCI have been independently
linked to microvascular function. Both organs are especially sensitive to the
same types of insult. The brain and the heart have very high energy
requirements. The brain uses approximately 1/5th of the body energy and the
heart about 1/10th. Thus, reductions in perfusion in either organ are extremely
detrimental. In patients with HFpEF, the degree of microvascular rarefaction
correlates to the severity of left ventricular diastolic dysfunction. In VCI,
although we are increasingly able to measure cerebral microvascular function,
the knowledge about the role of microvascular function and rarefaction is
sparse.
As a secondary aim, we are interested in the role of platelet function in
cerebral small vessel disease. Platelets possess pro-inflammatory properties,
but the role of platelets in the development of cerebral endothelial
dysfunction is poorly characterized. We aim to characterize the interplay of
platelets, endothelium and microvascular function in the development of small
vessel disease.
As another secondary aim, we will investigate whether blood-brain barrier (BBB)
leakage, one of the assumend pathophysiological mechanisms in cSVD, can also be
detected by measuring gadolinium in tear fluid. There are some studies that
suggest that gadolinium may leak over the blood-retinal barrier and can be
found in ocular fluids, which may represent the eye involvement of cSVD. If so,
collection of tear fluid could possibly offer an alternative, faster and
cheaper way of assessing BBB leakage than MRI.

The main objective of CRUCIAL-VCI is to determine a surrogate MRI marker for
microvascular density in patients with VCI due to cSVD, and to relate this to
disease severity expressed as macrostructural brain damage and cognitive
function.
The secondary objectives are a) to investigate whether microvascular
rarefaction is a specific feature of cSVD and not just an ageing phenomenon, by
comparing VCI patients and healthy controls; b) to determine the relationship
between cerebral microvascular function and (i) rarefaction in the heart and
(ii) microvascular density in the eye and sublingual tissue; c) to identify and
characterize mi-RNAs related to rarefaction from circulating endothelial
derived microvesicles and the correlation with cerebral microvascular function
and structural MRI markers.

CRUCIAL-VCI is a single-center observational study.

The study requires a two-day visit to the hospital for VCI patients and a
one-day visit for controls. Duration of the MRI to acquire all sequences is
around two hours for VCI and one-and-half hours for controls. Venous injection
of gadobutrol contrast agent can cause an allergic reaction, although this is
very rare. Total dose of gadobutrol in controls is 0.2 mmol/kg and in VCI 0.3
mmol/kg. The latter dose is divided over two days. First day 0,2 mmol/kg and
second day 0,1 mmol/kg and in no case the maximum daily dose of 0,3 mmol/kg
will be exceeded. Blood samples will be taken by venous puncture. This may
result in some cases in a cutaneous hematoma. Cognitive testing may tire.
Collection of tear fluid can make the eyes dry temporarily (a few minutes to
hours).

VCI patients only: ECG, echocardiography, sublingual Glycocheck are
non-invasive and painless. OCT angiography of the eye requires administration
of mydriatic eye drops for pupil dilation. This results in a blurry vision
which lasts up to two hours. People are not allowed to drive during this
period. Part of the cardiac MRI is an adenosine stress test. Participants are
not allowed to drink coffee or caffeinated soft drinks in the preceding 12
hours. Injection of adenosine will simulate a condition of exercise. Adenosine
administration is often accompanied by sensations of chest tightness,
breathlessness and/or tachycardia. These sensations are harmless but might feel
uncomfortable. If a person finds it too uncomfortable we will stop the infusion
immediately and sensations will disappear shortly thereafter (T * <10sec). In
general, the adenosine stress test is well tolerated and lasts only 4 minutes.
It is a well-known test in clinical practise. Severe side effects such as
severe bradycardia are rare and participants will be monitored continuously.