Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05065996 |
| Other study ID # |
5063566 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2017 |
| Est. completion date |
December 31, 2024 |
Study information
| Verified date |
March 2024 |
| Source |
Kuopio University Hospital |
| Contact |
Saara Sillanmäki, PhD |
| Phone |
+358456334855 |
| Email |
saara.sillanmaki[@]kuh.fi |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Aortic aneurysm is a very common incidental finding in the diagnostic imaging of the chest.
It is especially common in middle aged men (up to 40 %). It is called as a silent killer,
since it can lead to aortic dissection and rupture without pre-existing symptoms. Mortality
of rupture can be up to 50 %. This is why it causes extensive human uncertainty and fear.
Currently, there are no methods to identify the high risk patients. That leads to a practice
where all patients are followed with repeated aortic imaging using expensive methods such as
magnetic resonance imaging (MRI) and computed tomography.
There is data, that modern 4D flow MRI parameters well describe the intra-aortic flow
conditions. This prospective clinical trial explore the value of 4D flow MRI parameters in
the prediction of aortic dilatation and rupture. The trial consists of three subtrials in
whitch the 4D flow MRI parameters are tested in clinical practice.
Description:
1. Purpose of the study The purpose of this study is to explore prognostic parameters for
aortic dilation. More specifically it is to identify prognostic imaging parameters which
could be used to identify patients at high risk for rapid aortic dilation and should be
intensively followed by imaging methods.
2. Subtrials
1. Clinical study 1 The aim of the first phase of the study targets to identify 4D MRI flow
parameters which are characteristic to dilated aorta and might be used to evaluate
future prognosis in patients with aortic dilatation or predisposing factors.
2. Clinical study 2 The second phase of the study aims to use identified flow parameters in
clinical imaging follow up to find out which parameters predict aortic dilation in real
life and thus could be used to select patients for more intensive imaging in future.
3. Study 3 - Molecular pathology, histology and genetics of aorta The aim of this part of
the study is to find out differences in molecular biology, histology, elasticity and
genetics of the aorta in patients having predisposing factors for aortic dilation.
Particularly, cellular factors influencing the formation of connective tissue and
vascular smooth muscle layer will be studied.
3. Methods
1. Patient population All patients and healthy volunteers will give their written informed
consent for the study. The Ethical Committee of Northern Savo hospital district has given
approval for the trial.
Study 1 The first phase of the study will include twenty patients with anatomical or
functional BAV or other disease predisposing to dilation of aorta scheduled for routine
aortic MRI in Kuopio University Hospital (KUH) Department of Radiology. 4D flow MRI will be
done right after the routine 2D MRI and it will extend the imaging time approximately 20
minutes. Twenty healthy voluntary controls will be recruited from the research group and
personnel of the department and they will be scheduled for the similar imaging procedure. The
main parameters analyzed from this one-off imaging data are peak flow velocity and
eccentricity of the flow, flow vorticity and wall shear stress. Also, parameters related to
aortic stiffness and geometry will be determined in this study. Comparison of the 4D flow MRI
parameters between the patients and healthy controls will be done, 4D flow parameters will
also be compared to conventional 2D flow parameters both in the study patients and in healthy
controls.
Study 2 For the follow-up study 100 patients will be recruited on the same manner as in the
case of the first study patients. The inclusion criteria will be: adult (age > 18 years),
previously documented aortic dilation, documented anatomical or functional BAV or other
inherited disorder, which caus-es increased risk for aortic dilation, no contraindication for
MRI. Similar aortic MRI will be performed as during the clinical study 1. However, the
follow-up imaging will be performed after 6 months from the first MRI and yearly for 5 years.
Same 4D and 2D flow parameters will be analyzed as in the first study. The special interest
will be appointed to the degree of aortic dilation and correlation between 4D (and 2D) flow
parameters to the aortic dimensions.
Clinical parameters All patients visiting outpatient clinic will have clinical examination
(auscultation, clinical signs for heart failure, hepatomegaly, peripheral edema, arterial
murmurs). 12-lead electrocardiography and basic laboratory analyses (hemoglobin, hematocrit,
sodium, potassium, creatinine, brain natriuretic peptide) will be performed. With patient
written permission, an additional tube of blood will be saved for future analysis and the
patient will be informed about the purpose of this sample.
Echocardiography Transthoracal echocardiography will be done by using routine clinical
methods. Special interest will be appointed to aortic valve anatomy and aortic dimensions.
Other signs of cardiac mani-festations will also be registered. Ventricular dimensions and
volumetric parameters as well as ventricular systolic and diastolic function will be
evaluated.
Aorta MRI Magnetic resonance angiography and 2D flow measurements Static imaging of the aorta
is done with an ECG- and respiratory-gated 3D SSFP (steady state free percession) sequence
[Kawel et al 2012]. Image stack is obtained in sagittal plane and processed at the
MPR-workstation to get images perpendicular to the axis of blood flow. The diameter of the
aorta is measured from outer wall to the outer wall. The widest diameter of the aorta is
de-termined and, as a routine, diameter of the aorta is measure at 8 pre-determined levels.
4D phase contrast MRI Blood flow in the aorta will be measured based on MRI phase contrast.
The measurement will be done by repeating the imaging pulse sequence without and with flow
weighting gradients for three dimensions with interleaved manner and the measurement. The
imaging parameters will be set according to 4D MRI flow measurement consensus statement
[Dyverfelt 2015] shortly: resolution of < 2.5x2.5x2.5 mm3, temporal resolution of 30 ms (time
resolution in flow in different cardiac phases), retrospective ECG synchronization and
respiratory motion compensation, flip an-gle close to Ernst angle and the flow weighting
gradient amplitude so that maximum flow of 10 % higher than expected maximum flow rate in the
aorta. The imaging volume will be cover the aor-tic valve, aortic arc and descending aorta at
the level of apex of myocardium. The data will be preprocessed to minimize contribution from
background phase offsets, gradient imperfections and phase wraps.
Flow parameters From the 4D flow images, several quantitative parameters will be extracted.
The main parame-ters are the ones describing flow distribution in the aorta, i.e. peak flow
velocity and eccentricity, flow vorticity and shear stress on the vessel walls. Furthermore,
several parameters related to aortic stiffness and geometry and function of aortic valve,
will be recorded. During follow-up, changes and prognostic value of the quantified parameters
will be evaluated.
In the purpose of validation 4D flow parameters will be compared to parameters extracted from
conventional 2D flow sequences.
Clinical follow-up protocol Patients recruited for the follow up study (study 2) will be
re-screened by aortic MRI after half year from the recruitment and yearly after the first
follow-up visit up to five years or according to clinical follow-up schedule. If the state of
the aortic dilation indicates more intensive follow-up will be used.
Statistical analyses Prognostic factors will be tested for statistical significance by
comparing flow parameters and as-sociated factors to the degree of aortic dilation by using
appropriate multivariate analysis . Statis-tical significance will be set at p<0.05 and high
statistical significance at p < 0.01. The data will be analyzed by using SPSS for Windows
program.
Study 3
The third subtrial will enroll 20+100 patients with severe aortic dilatation scheduled for
aortic operation. Human aorta samples are collected during routine aorta replacement surgery
from the removed vascular tissue. In addition to tissue samples, a blood sample will be
collected for genetic and molecular analysis. Patients have given their written permission
for the histological and blood samples before the operation. After resection, samples are
immediately transferred into liquid nitrogen (frozen samples), PFA-PBS (histological samples)
or to cell culture medium for cell isolation (endothelial cells, vascular smooth muscle
cells, fibroblasts). Frozen samples are stored in -70 °C and isolated cells in liquid
nitrogen. Histological samples will be processed into the paraffin and stored as a paraffin
blocks. Samples will be stored up to 10 years, and after which they are destroyed as a
biohazard waste. Raw data will be stored in electrical archive like European Genome-phenome
Archive (EGA).
Analyses Molecular biology and histology of the aorta samples are examined by RT-qPCR,
immunohisto-chemistry and multiphoton microscopy imaging. Expression of relevant genes e.g.
TGF-β, VEGF-family, COX-1 and 2, eNOS/Akt and pro-inflammatory cytokines is studied, and also
RNA -sequencing, identifying all expressed mRNAs simultaneously, can be used for finding
differences in expression of all aortic genes between different patient groups. FBN1 gene is
sequenced and looked for mutations or deletions.
Aorta vessel wall architecture and expression of relevant genes is visualized by multiphoton
mi-croscopy and immunohistochemistry. Isolated cells are used for Single Cell Analysis, which
allows studying one living cell and its molecular events at a time, and gives totally new
information about functions of different cells in vessel wall. Obtained data is divided in
disease- and age matching groups, and correlations between cardiac disease status, aortic
gene expression and aortic histology will be looked for. Data will also be connected and
compared to the pre-clinical mouse study described in Appendix 1, and human aorta MRI 4D flow
imaging study described in paragraph 3.4.
Biomechanics of histological aorta samples Biomechanical parameters such as the stiffness and
failure strength will be measured from the aorta samples. The measurements and analysis will
be done in collaboration with The BBC group in University of Eastern Finland. The
biomechanical parameters in the studied patients groups will be compared and used as a
parameter in multivariant statistical analyses. The results will also be compared and linked
to findings of histological and molecular biology.
Controls Samples for comparison to normal tissue will be collected from 10 organ donors
operated in Kuopio University Hospital. The samples will be handled as described in aortic
patients.
Mathematic modelling of aorta Imaging data of 20 patients will be send anonymously to JAMK
University of Applied sciences for mathematic simulation modelling of aortic flow and wall
stress.
4. Collaboration The clinical study is conducted multiprofessionally in Kuopio University
Hospital together with departments of clinical cardiology, cardiothoracic surgery (Heart
Center) and radiology (Clinical Imaging Center). The histopathological, molecular and genetic
studies are performed in the Department of Molecular Sciences in A I Virtanen Institute,
University of Eastern Finland (UEF). Biomechanical tests will be conduited in the Department
of Applied Physics in UEF.The mathematic modelling of the aortic images will be performed in
JAMK University of Applied Sciences. The acquired 4D MRI flow results will be analyzed and
validated according to standards of Kuopio University Hospital.
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