Assessment of the pathophysioLogical bAsis of local tissue compliaNce using augmenteD iMAging techniques to identify Regional flow dynamiCs (LANDMARC): a study with focus on aorta ascendens

Aorta pathology, under which we consider aortic aneurysm and aortic dissection,
is a group of potentially fatal conditions that result from weakening of the
aortic vessel wall. Thoracic Aortic Aneurysm (TAA) has an incidence of 5.3 per
100,000 people per year and an expected death rate of 11.8 percent in the
presence of an aneurysm exceeding 6 cm. Aortic dissection has an incidence of
5-30 per 1 million people per year and a mortality risk of approximately 70
percent.
Aortic dissection can be classified according to the Stanford Classification
System: Type A involves the ascending aorta and may progress to involve the
arch and thoracoabdominal aorta, Type B involves the descending thoracic or
thoracoabdominal aorta distal to the left subclavian artery without involvement
of ascending aorta. Type A dissection is much more common than Type B
dissection (2/3rd of cases) and requires urgent surgery because of higher
mortality rates, while Type B dissections are typically managed conservatively
unless they are associated with complications such as unremitting pain,
aneurysmal expansion, and end-organ ischemia.

Aortic diameter is currently used as a gold standard in international
guidelines for prediction of aorta pathology (aortic aneurysm and aortic
dissection). Preventive surgical intervention leads to positive outcomes,
however, the most immediate moment for prophylactic aortic replacement is
difficult to determine. Preventive surgical intervention is therefore only
available for patients with severe aortic dilation. There is an indication for
preventive surgery of the aortic root and/or aorta ascendens in case an
internal diameter of >55 mm is established. Earlier intervention for diameters
that have not yet reached these cut-off values (45-50 mm) is required when
there has been a rapid increase in diameter (>5 mm each year), an affected
family history, a significant aortic valve insufficiency and/or pregnancy wish.
However, aortic diameter has proven to be insufficiently accurate for making
decisions about well-timed preventive interventions (to prevent, among other
things, aortic aneurysm/dissection). This is substantiated by the fact that
over 90% of the population fails to meet the guidelines for elective
(ascending) replacement and a majority presents themselves with aortic
dissection and ruptures with diameters below surgical thresholds. When focusing
on acute Type A aortic dissections (ATAC) for example, approximately 60% of the
ATAC took place in patients with mean aortic diameters <55 mm and mean aortic
diameters of <50 mm were observed in 40% of the patients. While the physics of
aortic wall tension support the use of aortic diameter as a reliable metric to
base decisions for prophylactic surgery, the concept of *one size fits all* has
fallen out of favor in the cardiothoracic community. Thus, additional data is
required, and new parameters need to be developed to detect aorta pathology
more adequately in an early phase.

Physiological increase in aortic length is part of the physiological aging
process, based on powerful pulsating forces within this aorta. This
subsequently leads to degradation of elastin fibers and thus structural
remodeling. Earlier research within the MUMC+ has confirmed that this
physiological increase in (ascending) aortic length is an adequate predictor
for aortic pathology, which leads to prevention of acute situation in 28% of
the cases. Total increasement of aortic length, based upon CT measures, from
age 20 to 80 years turned out to be approximately 66 mm in female and 59 mm in
male patients. Moreover, different percentages of increasement could be related
to various specific aortic segments: 142% ascending aorta, and 169% aortic arch.
Furthermore, additional research projects within the MUMC+ have shown that the
increase in aortic length is location dependent. By applying additional markers
on the ascending aorta, longitudinal strain (the elongation produced by
external stress) could be measured between these attached landmarks. By doing
this, a significant difference was observed between the outer and inner
curvature of the ascending aorta. For further understanding of the aspects of
(location dependent) physiological increase in (ascending) aortic length, data
on hemodynamics has proven to be particularly important, because of its
association with, among other things, hypertension.
4D-flow MR (four-dimensional flow magnetic resonance imaging) provides
comprehensive insight into aortic hemodynamics (wall shear stress, flow
eccentricity, flow vorticity). 4D-flow sequences have already been implemented
within the MUMC+, causing the project group to have demonstrable expertise with
these measurements already. This way, more asymmetrically distributed peak WSS
(Wall Shear Stress) values at the outer curvature and decreased WSS values at
the inner curvature were discovered, as well as a positive WSS gradient from
the sinotubular junction to the proximal ascending aorta. However, the exact
relationship between the WSS values (and other important hemodynamic parameters
(for example, flow eccentricity and flow vorticity)) and dynamic aortic
information (specifically longitudinal strain) remains undiscovered.

The LANDMARC study aims to reveal the undiscovered relationship between the WSS
values and aortic strain. By doing this, it strives to achieve a better
understanding of the origin, pathogenesis, and clinical presentation of
cardiovascular disease (with focus on aorta pathology).

The LANDMARC study will take place in line with the FIBAA-bank (*Correlatie
tussen cardiovasculaire FIBroseringsgraad en Aorta elongatie, dilatatie en
Atria dilatatie (FIBAA-bank): een biobank & databank onderzoek met focus op
aorta en atria* (METC-number 2022-3164)). FIBAA-bank is performed under
supervision of Dr. E Bidar (Cardiothoracic Surgery Department MUMC+) as well,
and is also based on the concept of (hemo)dynamic processes being responsible
for the development of cardiovascular pathology. FIBAA-bank demonstrates that
adjustments of cardiovascular cells are based on changes in (hemo)dynamic
values/processes, and that biomechanical interactions are incredibly important
for the functional adaptations of these cells. It also demonstrates that the
balance between mechanical stress and tissue properties is said to be disrupted
when cardiovascular pathology occurs, which manifests itself through impairment
of tissue specific features within concepts such as elasticity and compliance.
The FIBAA-bank focusses mainly on correlation of the degree of tissue fibrosis
to the degree of aortic elongation. The LANDMARC study, however, aims to link
these outcomes to parameters (WSS values) derived from advanced multimodality
imaging techniques used specifically for this purpose. This way, our
hypothesis, which states that increased aortic WSS values indeed lead to
increased (ascending) aortic strain, can be examined.

In combination with data from the FIBAA-bank, the LANDMARC study will hopefully
provide more accurate information for future risk stratification models for
cardiovascular pathology (with focus on aortic disease).






Primary Objective:
- Indication of the association between WSS (peak WSS and WSS gradient)
(through 4D-flow MR and CT) and aortic strain.

Secondary Objective:
- Indication of the association between (hemo)dynamic processes within the body
(aortic elongation/aortic strain) and (patho-)physiological changes (degree of
cardiovascular tissue fibrosis).

Additional objectives:
- Association between WSS (peak WSS and WSS gradient) (through 4D-flow MR and
CT) and aortic diameter.
- Association between flow curves (through 4D-flow MR and CT) and exact
location of aortic elongation.

In this prospective cohort, single-center study, 4D-flow MR and CT will be used
to obtain more precise data on (hemo)dynamic processes within the
cardiovascular system. Multiple imaging techniques are utilized, so that
individual advantages of techniques (e.g. temporal and spatial resolution) can
be merged, and advantages will accumulate. Obtained data can then be combined
with data extraction from the established biobank in order to achieve a better
understanding of the origin, pathogenesis and clinical presentation of
cardiovascular disease.

This observational study will take place at MUMC+ within the departments of
Cardiothoracic Surgery, Radiology and Cardiology.

The LANDMARC study takes place in line with the FIBAA-bank, which received METC
approval already (METC-number 2022-3164).


Through the LANDMARC study, patients can undergo additional postoperative
imaging. Therefore, participants will undergo more existing advanced imaging
techniques than would be necessary in general follow-up. This will be an
additional MR-scan with 4D-flow protocol and an additional postoperative
CT-scan (CT thoracic aorta).
A (4D-flow) MR does not entail any risks in terms of radiation but takes extra
time (approximately 45-60 minutes, where patients have to lay still on their
back and occasionally hold their breath a few seconds). The physical burden is
therefore very low, which means that the examination can be performed without
any problems both immediately after the operation or a few months afterwards.
We aim to combine this scan with regular follow-up appointments, so that
patients do not have to visit the hospital more often than necessary according
to regular care. The moment at which the scan is performed (directly
postoperatively/several months after the operation) has no influence on the
final results of the examination. It is therefore wise to wait for a suitable
moment with regard to general postoperative follow-up planning in order to
combine appointments.
A CT scan will take about 5-10 minutes and will lead to radiation exposure. The
estimated effective dose will be less than 10 mSv per scan. This effective dose
will be the same as the effective dose used in regular patient care. Therefore,
an increased risk or complication rate due to this scan is not expected.