COronary and MICrocirculatory Measurements in Patients With Aortic Valve, the COMIC AS Study.
Conditions: Aortic Stenosis, Coronary Artery Disease
Sponsor: Universitaire Ziekenhuizen KU Leuven

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COMIC AS study. 
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COronary and MICrocirculatory measurements in patients 
with Aortic valve Stenosis, the COMIC AS study. 
 
 
 
Version  4.0 April  2021 
 
Principle Investigator:  
Keir McCutcheon, MD PhD 
Co-principle investigators: 
Johan Bennett, MBBCh MD PhD  
Walter Desmet, MD PhD 
Christophe Dubois, MD PhD 
Co-investigators: 
 
Lennert Minten, MD 
Tom Adriaenssens, MD PhD 
 
 
 
 
Sander Jentjens, MD 
 
 
 
 
 
Peter Sinnaeve, MD PhD 
Maarten Vanhaverbeke, MD PhD 
Pierluigi Lesizza, MD 
 
 
Sponsor: University Hospitals Leuven, Herestraat 49, Leuven, Belgium. 
 
 
 

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CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................ 4 
STATEMENT OF COMPLIANCE ....................................................................................................................... 5 
PROTOCOL SUMMARY .................................................................................................................................. 6 
SCHEMATIC OF STUDY DESIGN ..................................................................................................................... 7 
FIGURE 1: Study flow. .................................................................................................................................... 7 
FIGURE 2: Secondary Objective. .................................................................................................................... 8 
SYSTEMATIC PROTOCOL STUDY SYNOPSIS .................................................................................................... 9 
Primary endpoint: ..................................................................................................................................... 9 
1. 
BACKGROUND ..................................................................................................................................... 12 
1. 
STUDY OBJECTIVES .............................................................................................................................. 15 
3.   STUDY DESIGN & INTERVENTIONS ........................................................................................................ 18 
3.1 Study Design .......................................................................................................................................... 18 
3.2 Study duration ....................................................................................................................................... 18 
3.3 Patient population ................................................................................................................................. 18 
3.4 Informed consent process ..................................................................................................................... 19 
3.5 Inclusion criteria .................................................................................................................................... 19 
3.6 Exclusion criteria ................................................................................................................................... 19 
3.7 Screening and enrolment process ......................................................................................................... 20 
3.8 Methodology ......................................................................................................................................... 21 
4. 
SCHEDULE OF EVENTS TABLE .............................................................................................................. 24 
5. 
FUNDING ............................................................................................................................................. 26 
6. ADVERSE EVENTS ..................................................................................................................................... 27 
6.1  Adverse events definition and classification ........................................................................................ 27 
6.2 Adverse device effects/serious adverse device effects ......................................................................... 29 
6.3 Expected adverse events ....................................................................................................................... 30 
7. WITHDRAWAL FROM STUDY/STUDY DISCONTINUATION ....................................................................... 31 
8. DATA COLLECTION ................................................................................................................................... 32 
8.1 Data collection ....................................................................................................................................... 32 
8.2  Protocol deviations ............................................................................................................................... 32 
8.3  Record retention by study site ............................................................................................................. 32 
8.4  Monitoring of data to source documents ............................................................................................ 32 

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9. STATISTICS AND ANALYSIS ....................................................................................................................... 33 
9.1 Sample Size ............................................................................................................................................ 33 
9.2 Statistical analysis .................................................................................................................................. 33 
10. REGULATORY REQUIREMENTS .............................................................................................................. 35 
10.1  Institutional Review Board and Ethics Committee: IRB/IEC ............................................................... 35 
10.2  Insurance ............................................................................................................................................ 35 
10.3  Confidentiality .................................................................................................................................... 35 
10.4 Publication Policy ................................................................................................................................ 36 
11. DEFINITIONS .......................................................................................................................................... 37 
12. REFERENCES .......................................................................................................................................... 38 
 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AS 
Aortic Stenosis 
CAD 
Coronary Artery Disease 
CFR 
Coronary Flow Reserve 
CRF 
Case Report Form 
CV 
Cardiovascular 
FFR 
Fractional Flow Reserve 
GLS 
Global Longitudinal Strain 
IC 
Informed consent 
iFR 
Instantaneous wave-free ratio 
IMR 
Index of Microcirculatory Resistance 
IRB 
Institutional Review Board 
LVEDP 
Left Ventricular End Diastolic Pressure  
LV 
Left Ventricular 
MACE 
Major Adverse Cardiovascular Events 
MI 
Myocardial Infarction 
MVD 
Microvascular Disease 
NA 
Not Applicable 
NHPR 
Non-Hyperemic Pressure Ratio 
NSTEMI 
Non-ST-elevation Myocardial Infarction 
RFR 
Resting full-cycle ratio 
SAE 
Serious Adverse Event 
SAP 
Statistical and Analytical Plan 
SPECT 
Single-photon emission computed tomography 
STEMI 
ST-elevation Myocardial Infarction 
SAVR 
Surgical aortic valve replacement 

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TAVI/R 
Transcatheter aortic valve implantation/ Replacement 
STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with Good Clinical Practice (GCP, ICH E6). The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without 
prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants.  
 
 
Principal Investigator: Prof. Dr. Keir McCutcheon 
 
Signed: 
Date: 15-04-2021  
 
 

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PROTOCOL SUMMARY 
 
Aortic stenosis (AS) is the most common primary valve disease leading to surgery or catheter 
intervention in Europe, with a growing prevalence due to the aging population. Severe AS is 
associated with significant morbidity and mortality and is treated by surgical valve replacement 
(SAVR) or transcatheter aortic valve implantation (TAVI). However, significant coronary artery 
disease (CAD) is reported in more than 60% of patients with AS, and this concomitant CAD needs 
to be correctly assessed because untreated significant CAD is associated with adverse outcomes. 
Current guidelines recommend intra-coronary pressure measurement using either fractional flow 
reserve (FFR) or non-hyperemic pressure ratios (NHPR) for the assessment of intermediate 
coronary artery lesions before revascularization. However, correctly identifying hemodynamically 
significant coronary stenoses by FFR or NHPR is difficult in patients with AS because of the 
hypertrophic remodeling related to the valve pathology, which interferes with coronary blood 
flow in the microcirculation and reduces the accuracy of FFR and NHPR. This has resulted in 
substantial controversy in this field of coronary artery disease and there is currently no clear 
guideline for the management of AS patients with concomitant CAD. Recent technological 
advances now permit the concomitant evaluation of FFR/NHPR and microcirculatory function at 
the time of cardiac catheterization. Using this technology, we will simultaneously evaluate the 
hemodynamic significance of coronary stenoses (using FFR and a NHPR - Resting Full cycle Ratio 
[RFR]) and the microcirculatory function (Index of Microcirculatory Resistance, IMR) in patients 
with AS and CAD prior to SAVR/TAVI.  One hundred patients with AS and intermediate CAD will 
be included in the study. Of them Eighty will undergo AVR and at least 58 will undergo the follow-
up at 6 Months. During routine pre-valve replacement cardiac catheterization, measurement of 
intermediate CAD lesions (by FFR and RFR) and IMR will be performed in duplicate using new 
software. These measures of CAD severity will be compared with a gold standard non-invasive 
test (single photon emission computed tomography [SPECT]). This will validate the use of RFR and 
determine if IMR can be used to improve the ischemia prediction of FFR. In addition, the patients 
undergoing TAVI the LVEDP will be measured immediately before and after valve implantation 
and  FFR, RFR and IMR will be measured after valve implantation.  Subsequently, when these 
patients undergo a post-intervention (whether SAVR or TAVI) evaluation 6 months after valve 
replacement, the effect of valve replacement on FFR, RFR and IMR (again in duplicate) will be 
determined. This will be the first study measuring these parameters before and 6 months after 
valve replacement. The data will be used to calculate a 'corrected' FFR (or RFR) based on 
microcirculatory function in these patients, which can then be used in the future to correctly 
evaluate CAD pre-intervention in patients with AS. This will translate into more efficient 
management of patients with AS. Fewer of these patients will unnecessarily undergo coronary 
artery bypass grafting or stenting when the CAD does not need to be treated and, conversely, in 
those who do require treatment of the CAD, revascularization can be carried out during a single 
surgery/intervention, avoiding multiple high risk procedures in patients who are already at high 
peri-operative/peri-interventional risk. 
 
 

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SCHEMATIC OF STUDY DESIGN 
FIGURE 1: Study flow. 
 
  
AS, aortic stenosis; AVR, aortic valve replacement (by surgery or transcatheter aortic valve implantation); TAVR, Transcutaneous 
aortic valve replacement; TTE, trans-thoracic echocardiography; IC, informed consent; SPECT, Single-photon emission 
computed tomography; FFR, fractional flow reserve; RFR, resting full cycle ratio; IMR, index of microcirculatory resistance; LV, 
left ventricle. 
 

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FIGURE 2: Secondary Objective. 
 
FFR, fractional flow reserve; RFR, resting full cycle ratio; IMR, index of microcirculatory resistance; iFR, 
instantaneous wave-free ratio; SPECT, Single-photon emission computed tomography; AS, aortic stenosis; MVD, 
microvascular/microcirculatory dysfunction. Yamanaka et al.1 compared FFR versus iFR with SPECT as the standard 
for ischemia. 
 

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SYSTEMATIC PROTOCOL STUDY SYNOPSIS 
 
 
Title 
COronary and MICrocirculatory measurements in patients with Aortic valve 
Stenosis, the COMIC AS study. 
Design 
A single centre, prospective, cohort study assessing the changes in intra-
coronary flow and pressure before and 6 months after aortic valve 
intervention. 
Objectives 
Primary endpoint: 
1. Aortic valve intervention results in a significant change in fractional 
flow reserve (FFR) 6 months after SAVR/TAVI. 
Secondary endpoints: 
2. Measurement of IMR in patients with AS prior to intervention and 6 
months after TAVI/SAVR. 
3. Corrected FFR (based on baseline IMR) correlates with the post-
intervention FFR. 
4. IMR at baseline improves the ischemia prediction of FFR (compared 
with SPECT). 
5. Comparison of the diagnostic performance of FFR and RFR with 
SPECT ischemia. 
Treatment 
There is no study-related intervention. Aortic valve intervention is carried out 
according to normal clinical practice. 
Follow-up 
Patients will under-go clinical assessment, TTE and cardiac catheterization 6 
months after aortic valve intervention. 
Inclusion 
criteria 
1. Patient undergoing the procedure is older than 18 years, has severe aortic 
valve stenosis (according to ESC guidelines) and is planned for cardiac 
catheterization as part of the pre-operative (SAVR) or pre-percutaneous 
(TAVI) work up. 

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2. The patient has an intermediate (50-90%) coronary lesion that requires 
further evaluation.  
3. The patient undergoing the procedure is male, or if female, has no 
childbearing potential or is not pregnant. 
Exclusion 
criteria 
1. The procedure is an emergency and/or the patient is unstable. 
2. Pregnancy or lactation 
3. Haemodynamically unstable patients 
4. Killip class III-IV heart failure 
5. Previous coronary artery by-pass in the artery being assessed 
6. Contra-indications for adenosine administration: severe asthma or pre-
existing type 2 AV-block 
7. No significant coronary artery disease (<50% stenosis on angiography). 
8. Critical coronary artery disease deemed by the Heart Team to require 
immediate revascularization 
9. Patients will be excluded from the SPECT study (secondary objective) if 
they have a left main coronary stenosis >50%, triple vessel disease, 
previous myocardial infarction in the same coronary artery & tandem 
lesions (separated by >10mm) requiring independent evaluation in the 
same coronary artery since these factors interfere with the SPECT 
analysis. 
Number of 
patients 
• 80 patients with pre- and post-intervention (TAVI or SAVR) 
catheterizations 
o Fifty Eight t (58) patients with pre- and post-interventions 
catheterizations will be sufficient to detect a reduction in the 
FFR from 0.82 to 0.79  with an alpha level of 0.05 and power 
of 0.80. A total sample of 100 with baseline measurements 
and subsequent 80 patients who will undergo (T)AVR without 
revascularisation and are eligible for a pre-and post-

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intervention catheterization will allow for a 25% drop-out 
during the follow up phase of the study. 
o This flow with patient numbers and dropout is illustrated in 
figure 1 for clarity.  
Study 
duration 
3  years (or earlier when the 80 pt’s with an aortic valve procedure without 
revascularisation will be included) 
 
 
 

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1. 
BACKGROUND 
 
 
Aortic stenosis (AS) is the most common primary valve disease leading to surgery or catheter 
intervention in Europe, with a growing prevalence due to the aging population. Severe aortic 
valve stenosis, defined by a mean gradient over the aortic valve of greater than 40mmHg or an 
aortic valve area of less than 1.0cm2,2 is associated with significant morbidity and mortality and 
is treated by surgical valve replacement (SAVR) or transcatheter aortic valve implantation 
(TAVI). However, significant coronary artery disease (CAD) is reported in more than 60% of 
patients with AS,3 and needs to be correctly assessed because untreated significant CAD is 
associated with adverse outcomes.4,5  
 
Current guidelines recommend intra-coronary pressure measurement using either fractional 
flow reserve (FFR) or non-hyperemic pressure ratios (NHPRs) for the assessment of intermediate 
coronary artery lesions before revascularization.6 A FFR of ≤0.80 or a NHPR of ≤0.89 is 
considered to indicate that a coronary lesion is significant. Non-hyperemic pressure ratios 
include the instantaneous wave-free ratio (iFR) and the resting full cycle ratio (RFR), which have 
been shown to be comparable.7 However, correctly identifying hemodynamically significant 
coronary stenoses is difficult in patients with AS because of the hypertrophic remodelling 
related to the valve pathology.8 Aortic stenosis is associated with a significant increase in left 
ventricular (LV) mass resulting in pathological changes in coronary and LV hemodynamics, which 
are associated with coronary microvascular dysfunction.9,10  
 
With the development of microvascular dysfunction, intra-coronary pressure measurements 
become less reliable and, currently, whether FFR, or the NHPRs, can reliably detect myocardial 
ischemia in patients with severe AS is controversial, making it difficult for physicians to correctly 
determine whether or not coronary lesions should be revascularized prior to TAVI or at the time 
of SAVR. Yamanaka et al.1 recently reported a strong correlation of iFR with FFR in patients with 

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AS and intermediate CAD. They determined that the optimal iFR threshold for detecting 
ischemia compared with 99mTc single-photon emission computed tomographic (SPECT) 
myocardial perfusion imaging was 0.82, while the cut-off for FFR was 0.83. This is in contrast to 
the large, outcome-based randomized controlled studies in patients without AS,11,12 and 
different to the current guideline cut-offs of ≤0.89 for resting indices and ≤0.80 for FFR.6 The 
RFR threshold for detecting ischemia has not yet been determined in patients with AS. 
 
A more comprehensive study with performance of intra-coronary measurements before and 
after TAVI may help determine the effect of adverse LV remodelling and microvascular 
dysfunction on the hemodynamic measurement of coronary artery lesions in patients with 
severe AS. However, the timing of the follow-up measurements has not been clearly defined. 
Several studies have performed acute measurements pre- and post-TAVI8,13-15 but no invasive 
study (measuring FFR and/or resting indices) has been performed after allowing adequate time 
for reverse remodelling in order to really determine the effect of microvascular reverse 
remodelling on intra-coronary hemodynamic measurements. Exactly how long is needed after 
TAVI to ensure adequate myocardial and microvascular remodelling has occurred in order to 
appropriately use intra-coronary hemodynamic measurements is not known at this stage. One 
MRI-based study demonstrated a significant reduction in indexed LV mass from 76g/m² to 
68g/m² within a few days.16 In another study, echocardiographic ejection fraction and LV global 
longitudinal strain improved significantly when measured 10 days after TAVI.17 However, 
indexed LV mass improvement was only significant during long-term (months-to-years) follow 
up. In a more recent, echocardiographic-based study, indexed LV mass decreased from 117 
g/m² to 100 g/m² in a surgical aortic valve replacement (SAVR) group and 114 g/m² to 108 g/m² 
in a TAVI group after 3 months with further reductions at one year.18 Whether these global 
changes in LV remodelling translate into improvements in microvascular function, and hence 
improve the diagnostic accuracy of FFR is not yet known. 
 

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If TAVI/SAVR results in a significant improvement in LV remodelling and microvascular function, 
it should be expected that the current invasive gold-standard for measuring microvascular 
resistance (IMR; index of microcirculatory resistance)19 would improve several months after the 
valve intervention. If this is the case then the FFR measurement should be more accurate (as it 
is in patients without aortic stenosis). The question is whether a pre-TAVI/SAVR index (based on 
a combination of FFR and IMR) could be used in the future for assessing intermediate lesions in 
these patients. Developing a “corrected” FFR measurement of intermediate coronary artery 
lesions based on the presence or absence of microvascular dysfunction would be very useful in 
the pre-operative work-up of patients with aortic stenosis and would have important prognostic 
implications. This will be accomplished by first determining the FFR 6 months after intervention 
(TAVI or SAVR), when it is anticipated that the microvascular function would have returned to 
normal,20 and comparing this with the FFR prior to the intervention to determine if there is a 
significant change in the FFR after intervention. At the same time microvascular function will be 
assessed in order to develop a “corrected” FFR, which can be used in the future to determine 
whether or not coronary lesions need to be revascularized in patients with aortic stenosis. 
 
The theoretical model of a serial stenosis by the AS and the coronary narrowing in our study is 
explained in the figure 1 in the publication of Zelis at al.24 It is expected that the FFR will indeed 
decrease after TAVI and that there will be an acute (change of intercept) and chronic (change of 
slope) effect of the procedure on the coronary resistance. To separate these two issues we will 
try to measure the FFR immediately after TAVI and 6 months after TAVI. In addition the left 
ventricular filling pressure/ end-diastolic pressure (LVEDP) will be measured during the TAVI 
procedure immediately before and after valve implantation. The measurement (the delta 
LVEDP) will be an important marker of the “intercept” that changes acutely. To make sure the 
measurements of IMR, FFR and RFR are correct these will be performed twice and an average 
value will be used. This will also allow us to test the reproducibility.  
 
 

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1. 
STUDY OBJECTIVES 
Primary outcome 
1. Null hypothesis: TAVI/SAVR does not result in a significant change in FFR/RFR 6 months 
after intervention (Figure 1). 
a. If the null hypothesis is upheld, this suggests that FFR/RFR measurements in 
patients with AS is valid even in the presence of severe AS. 
b. If there is a significant decrease in FFR/RFR 6 months after aortic valve treatment, 
this suggests that the use of FFR/RFR to evaluate intermediate lesions in patients 
with severe AS is not valid and requires further investigation. 
Secondary outcomes 
2. Measurement of IMR in patients with AS prior to intervention and 6 months after 
SAVR/TAVI.  
a. Description of the range of IMR values in a cohort of patients with severe AS. 
i. Do all patients with severe AS have high microvascular resistance as 
assessed by IMR? 
ii. Does IMR change significantly 6 months after TAVI/SAVR? If there is a 
significant decrease in IMR then this indicates that microcirculatory 
function improves 6 months after aortic valve intervention. 
3. Null hypothesis: the “corrected” FFR (at baseline; based on baseline IMR) does not 
correlate with the post-intervention FFR. 
a. If the null hypothesis is upheld then a correction of FFR using baseline IMR does 
not improve the validity of FFR in patients with severe AS. 
4. Null hypothesis: using IMR at baseline does not improve the ischemia prediction of FFR. 
Ischemia is measured by SPECT (Figure 2). 
a. If the null hypothesis is upheld then IMR does not improve stratification of 
coronary ischemia based on FFR. 

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b. If a significant proportion of patients with SPECT ischemia have a raised IMR this 
would support the hypothesis that IMR can be used to correct falsely high 
(negative) FFR measurements. 
5. Comparison of the diagnostic performance of FFR and RFR with SPECT ischemia (and 
compare with findings of Yamanaka et al1). 
6. Reproducibility of the FFR, RFR and IMR  
 
Expected outcomes 
Primary outcome: If the null hypothesis is upheld, this suggests that FFR/RFR measurements are 
valid even in the presence of severe AS. 
Secondary outcomes 
1. A description of the range of IMR values in a cohort of patients with severe AS will be 
a novel and important contribution to the field of interventional cardiology. 
Furthermore, the change in IMR (microvascular function) in response to valve 
replacement will be an important finding in this study. If there is a significant 
decrease in IMR then this indicates that microcirculatory function improves 6 months 
after aortic valve intervention. Since microvascular function predicts outcomes in 
patients with AS, IMR evaluation at 6 months after TAVI/SAVR might provide an 
additional method to risk stratify these patients even after correction of the valve 
pathology.21 
2. If the “corrected” FFR (at baseline; based on baseline IMR) does not correlate with 
the post-intervention FFR then a correction of FFR using baseline IMR does not 
improve the accuracy of FFR in patients with severe AS. 
3. Compared with SPECT, a correlation of FFR and RFR will be an important 
contribution. Firstly, this will be a validation of RFR as a resting measure of ischemia 
in AS patients. Secondly, these data will support the data of a previous study1 with a 
different resting measure of ischemia (iFR) or the findings may be in conflict with the 
previous study, which would be important. 

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4. Using SPECT as a standard of myocardial ischemia, IMR may improve the ischemia 
prediction of FFR. This would be an extremely important finding, supporting the 
routine use of IMR in patients with microvascular disease when coronary artery 
lesions need assessment by FFR. Because AS is an important clinical condition with 
reversible microvascular dysfunction, this provides an excellent naturally occurring 
model for the study of microvascular function and CAD. These findings will be useful 
in other groups of patients who also have microvascular dysfunction (including 
patients with heart failure, obesity, diabetes, liver disease, chronic kidney disease 
and heart transplant patients). Being able to factor-in microvascular dysfunction 
(using simultaneously measured microvascular resistance) at the time of FFR 
measurement will permit accurate assessment of the severity of CAD in these 
patients. This study has the potential to revolutionize the assessment of coronary 
artery lesions, not just in patients with AS, but in all patients with CAD since the 
validity of CAD assessment by FFR/NHPRs may, indeed, depend on microvascular 
function. 
5. We hypothesize that in AS patients the measurements will be reproducible such as in 
other patients, however we expect the RFR to be more reproducible than the FFR 
which we expect to be more reproducible than the IMR.  

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3.   STUDY DESIGN & INTERVENTIONS 
 
3.1 Study Design 
A single centre, prospective, cohort study. 
3.2 Study duration 
The anticipated duration of the study will be 3 years.  
3.3 Patient population 
Patients undergoing routine cardiac catheterization during preparation for TAVI or SAVR, who 
are found to have coronary artery disease, will be approached to take part. A transthoracic 
echocardiography (TTE) will take place at baseline and at 6 months. A TTE is  part of the routine 
care and almost without risk. The TTE will assess systolic function, diastolic function, right and 
left ventricular function, valvulair function, fluid status, pulmonary pressures and shear wave 
analysis to assess the stiffness of the heart . These two extra TTE’s will be necessary to 
standardize the assessment of the valve pathology, to ensure our patients are good candidates 
and to assess the status post intervention in comparison to before the valve procedure Cardiac 
catheterization is routinely performed in these patients and intra-coronary hemodynamic 
measurements are routinely used during the assessment of coronary artery disease. SPECT is 
used to confirm the presence of ischemia. Baseline measurements of coronary artery disease 
and coronary microvascular function (IMR) will be carried out during the baseline cardiac 
catheterization if intermediate coronary artery lesions (defined as a coronary artery stenosis in 
the proximal part of a major coronary artery of 50-90% stenosis). During the six-month cardiac 
catheterization the coronary artery disease is assessed. During this procedure an additional 
measure of microvascular function (IMR) will be performed. FFR is routine clinical practice, but 
the additional measurement of IMR will be investigatory. 
 

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3.4 Informed consent process 
Informed consent should be obtained in accordance to the applicable regulations, the declaration 
of Helsinki and Good Clinical Practice. All potential patients must give their written consent prior 
to any study specific procedures. If a patient might be eligible for the study (after a first check of 
the inclusion/exclusion criteria), the investigator or delegated staff should approach the patient 
to obtain the written informed consent. During this interview the background of the proposed 
study and the benefits and risks of the study participation should be explained in detail to the 
patient. It has to be emphasized that a patient’s participation in the trial is voluntary and that the 
patient may refuse to participate or withdraw from the trial, at any time, without penalty or loss 
of benefits to which the patient is otherwise entitled. The patient must be given ample time to 
read the whole patient information and to address questions before signing the consent form. 
The patient information and a copy of the signed consent form will be handed out to the patient. 
The patient information as well as the patient informed consent will have the approval of the 
institution's Review Board and/or Ethics Committee (IRB/IEC) prior to their usage. 
 
3.5 Inclusion criteria 
1. Patient is older than 18 years and is planned for a cardiac catheterization as part of the 
work up for TAVI or SAVR. 
2. Patient has severe aortic valve stenosis as defined by the European Society of Cardiology.2 
3. The coronary angiogram cardiac catheterization is elective.  
4. The patient has an intermediate (50-90%) coronary lesion that requires further evaluation.  
5. The subject is male, or if female, has no childbearing potential or is not pregnant. 
 
3.6 Exclusion criteria 
1. The procedure is an emergency and/or the patient is unstable. 
2. Pregnancy or lactation 
3. Haemodynamically unstable patients 

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4. Killip class III-IV 
5. Previous CABG 
6. Contra-indications for adenosine administration: severe asthma or pre-existing type 2 
AV-block 
7. No significant coronary artery disease (<50% stenosis on angiography). 
8. Critical coronary artery disease deemed by the Heart Team to require revascularization. 
9. Patients will be excluded from the SPECT study (secondary objective) if they have a left 
main coronary stenosis >50%, severe triple vessel disease, previous myocardial infarction 
in the same coronary artery & tandem lesions (separated by >10mm) requiring 
independent evaluation in the same coronary artery since these factors interfere with the 
SPECT analysis. 
3.7 Screening and enrolment process 
Only if all inclusion criteria are met/exclusion criteria are not met, can the patient be included in 
the study. 
 
 
 

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3.8 Methodology 
 
Figure 1 summarizes the study flow. Patients admitted electively for a valve work-up and 
patients admitted through the Emergency department that have to undergo a valve work-up 
will be approached to take part in the study. All these patients undergo routine cardiac 
catheterization during preparation for TAVI or SAVR. If they are found to have intermediate 
coronary artery disease on the angiography, measurments to assess the severity of the lesions 
and microvascular function (further explained beneath) will be performed during the 
catheterisation. . Cardiac catheterization is routinely performed in these patients and intra-
coronary hemodynamic measurements are routinely used during the assessment of coronary 
artery disease. SPECT is also used to confirm the presence of ischemia. Baseline intra-coronary 
measurements of coronary artery disease and coronary microvascular function (IMR) will be 
carried out in duplicate during the baseline cardiac catheterization if intermediate coronary 
artery lesions (defined as a coronary artery stenosis in the proximal part of a major coronary 
artery of 50-90% stenosis by quantitative coronary analysis).  
 
During routine cardiac catheterization, patients with intermediate coronary artery lesions, will 
undergo hemodynamic assessment of the coronary stenosis according to current ESC 
guidelines.6 This entails the use of a pressure wire (Pressure Wire X, Abbott Medical) in the 
coronary artery distal to the stenosis in order to determine the pressure gradient over the 
stenosis. Prior to induction of hyperemia, Resting Full cycle Ratio (RFR) is measured before 
determining fractional flow reserve (FFR). In order to measure a FFR, adenosine at 
140µg/kg/min is administered via a peripheral venous infusion catheter. This is routine clinical 
practice. To address for factors that might cause small changes in these measurements, all 
measurements will be done twice, without an extra risk to the patient. Two measurements are 
frequently performed in clinical practice to get a robust measurement. This will also allow us to 
test the reproducibility of our measurements.  
 

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At this time three boluses of room-temperature saline are administered in order to measure the 
intra-coronary flow during hyperemia by the method of thermodilution.19 This extra step, which 
is investigational, adds no additional risk or cost to the patient. However, it permits the 
calculation of flow and microvascular resistance or IMR (index of microvascular resistance) using 
Coroflow® software (Coroventis, Uppsala, Sweden). IMR is already clinically indicated in several 
other groups of patients (with suspected microvascular dysfunction) and is used on a routine 
basis in patients in our cardiac catheterization laboratory. 
 
In order to assist the Heart Team in deliberation over the ischemic importance of intermediate 
coronary lesions, SPECT imaging is clinically indicated during the pre-operative/interventional 
work up. This will be carried out in the Department of Nuclear Medicine according to routine 
clinical practice under the guidance of Dr. Sander Jentjens. If adenosine cannot be used then 
regadenoson will be used.22 
 
Intra-coronary assessment of intermediate lesions is part of routine clinical practice. The 
decision to revascularize and the method of revascularization (percutaneous coronary 
intervention versus coronary artery bypass grafting) of patients with aortic stenosis based on 
intra-coronary measurements and non-invasive measures of ischemia (SPECT) is discussed by 
the Heart Team (including the cardiologist and cardiothoracic surgeon) and forms part of 
routine clinical practice. In patients who do not undergo immediate revascularization, the 
residual CAD should be reassessed after SAVR/TAVI. Current controversy about the validity of 
both intra-coronary and non-invasive tests in patients with AS necessitates further evaluation 
(after valve intervention) since coronary lesions should not be unnecessarily treated (Class III 
recommendation in the ESC guidelines6).  
 
In the patients who will undergo TAVI  measurements of LVEDP will be carried out during the 
TAVI procedure immediately before and after valve implantation. As the catheters are already 
present in the ventricle of the patient at this point this does not require and extra intervention 

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of risk (the pressure measured by the catheter will simply be recorded for the study data). 
Immediately following TAVI, intracoronary hemodynamic assessment of the intermediate study 
lesions will be performed with measurement of FFR, RFR and IMR. For this assessment the same 
arterial access used during TAVI will be used. Finally, during the six-month cardiac 
catheterization the coronary artery disease is assessed. During this procedure  additional 
measurements of microvascular function (IMR) will be performed. Again, FFR is routine clinical 
practice, given the ambiguity of earlier measurements in the presence of aortic valve stenosis, 
but the additional measurements of IMR will be investigatory. As discussed before the 
measurements will be performed in duplicate.  
 
Laboratory Procedures/Evaluations 
• At the time of admision routine laboratory blood and urine tests are performed including 
complete blood count, WBC differentiation, electrolytes, creatinine, , INR, pro-BNP, 
troponine, HbA1c, thyroid function and etc. This data will be collected.  
• Biological samples will be collected with everybody that signs the informed consent, at 
baseline and at 6 months follow-up.  
• A peripheral blood sample (4.0mL EDTA, 2.7 mLcitrate; 4.5mL LithiumHeparine, 5.0 mL 
Serum tube 2.5mL PaxGene® RNA tube) will be obtained to assess for biomarkers and 
platelet function. A urinary sample (14 mL) will be collected to asses for biomarkers related 
to aortic valve stenosis or microvascular dysfunction through the use of proteomic analysis. 
• Approval from the biobank has been obtained with a biobank application form (BB-GEN002-
F003) filled in and signed by the PI and Biobank Manager.  
 
 

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4. 
SCHEDULE OF EVENTS TABLE 
 
Procedures 
Screening 
Baseline 
At the time of 
TAVI 
6-month follow-up 
Assess inclusion and 
exclusion criteria 
x 
 
 
 
Informed consent 
x 
 
 
 
Enrolment 
x 
 
 
 
Patient characteristics 
 
x 
 
x 
Transthoracic 
echocardiography 
 
x 
 
x 
Cardiac catheterization 
and FFRs 
 
x 
 
x 
IMR measurements 
during Catheterization 
 
x 
 
x 
Blood sampling 
 
x 
 
x 
Urine sampling 
 
x 
 
x 
SPECT 
 
x 
 
(x) 
Transthoracic 
echocardiography 
 
x 
 
x 
LVEDP measurement (2x) 
 
 
x 
 
IMR and FFR 
measurements 
 
 
x 
 
Adverse events 
 
x 
 
x 
Serious adverse events 
 
x 
 
x 
 
Timeline 
Objective 
First half 
2020 
Second 
half 2020 
2021 
2022 
First half 
2023 
Second half 
2023 

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Ethics approval 
 
 
 
 
 
 
Patient recruitment 
 
 
 
 
 
 
Second catheterization 
 
 
 
 
 
 
Analysis Secondary 
Objective (FFR versus 
RFR analysis) 
 
 
 
 
 
 
Analysis Primary 
Objective (FFR changes 
at 6 months) 
 
 
 
 
 
 
 
 
 
 

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5. FUNDING 
 
Item 
Cost per item (€) 
Number needed 
Total cost (€) 
 PaxGene tubes  
11 
400 
 4400,00 
Regadenasone 
140 
80 
11 200,00 
Pressure Wire X 
220 
40 
8 800,00 
Total cost of study 
 
 
 24 400,00 
 
 
 

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6. ADVERSE EVENTS 
 
During the course of this clinical investigation adverse events might occur. These adverse events 
will be determined by the investigator during the scheduled patient follow-ups. All serious 
adverse events must be reported within 24 hrs from acknowledgement. Other adverse events 
should only be reported whenever they affect one or more of the predefined endpoints of the 
study. These include all myocardial infarctions (any definition), stent thromboses and coronary 
revascularizations, even when these would not result in death, hospitalization, prolonged 
hospitalization or persistent disability. These adverse events must be reported on the respective 
Adverse Event Form. 
 
6.1 Adverse events definition and classification 
An adverse event (AE) is any untoward medical occurrence in a patient whether or not related to 
the investigated treatment. Any current condition that is recorded as a pre-existing condition 
either in the medical history of physical examination section, unless there is a change in nature, 
severity, or degree of incidence, is not an AE. 
 
Classification of the adverse events has to be done according to the following criteria: 
 
Intensity 
Mild: patient’s daily activities are not limited 
Moderate: patient’s daily activities are limited 
Severe: patient is not able to perform daily activities 
 
Relation to Study Device 
1=not related 
2=possibly related 
3=probably related 

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4=definitely related 
 
Relation to the study devices will be assessed by help of the following criteria: timely relation of 
the event to the procedure, known risks of the device and intervention, concomitant diseases, 
concomitant measures and medication, other possible explanations, as applicable. Additional 
criteria might exist depending on the study setup and adverse event. Documentation about 
judgement and causality assessment has to be available for review in the source data. 
 
Relation to procedure 
1=not related 
2=possibly related 
3=probably related 
4=definitely related 
 
Relation to the procedure will be assessed by help of the following criteria: timely relation of the 
event to the procedure, known risk of the intervention, concomitant diseases, concomitant 
measures and medication, other possible explanations, as applicable. Additional criteria might 
exist depending on the study setup and adverse event. Documentation about judgement and 
causality assessment has to be available for review in the source data. 
 
Seriousness of the Adverse Event 
In case any of the following criteria is applicable to the Adverse Event it classifies as SAE. The 
Adverse Event: 
- 
results in death; 
- 
is life threatening, 
- 
requires inpatient hospitalization or prolongation of existing hospitalization, 
- 
results in persistent or significant disability/incapacity, 
- 
is a congenital anomaly/birth defect 

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This also applies to adverse events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent one of 
the other outcomes listed above. 
 
The assessment of “seriousness” is independent from any relation to the investigational device. 
 
Hospitalization is defined by a medical need for inpatient hospitalization. For procedures that are 
commonly performed ambulant and require inpatient hospitalization solely based on nonmedical 
needs (e.g. logistical reasons) this criterion could be considered not applicable by the investigator. 
Proper documentation of the reasons for decision is required in this case. 
Events that are planned (e.g. elective surgery) and documented prior to study entry will not be 
recorded as (serious) adverse event. Medication received during this activity will be recorded. 
 
6.2 Adverse device effects/serious adverse device effects 
 
An adverse device effect is any untoward and unintended response to a medical device. This 
includes any event resulting from insufficiencies or inadequacies in the instructions for use or the 
deployment of the device as well as any event that is result of a user error. 
 
An adverse device effect is classified as serious if it has resulted in any of the consequences 
characteristic of a serious adverse event or that might have led to any of these consequences if 
suitable action had not been taken or intervention had not been made or if circumstances had 
been less opportune. 
 
 
 

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6.3 Expected adverse events 
 
As with any coronary intervention, there are possible risks and the possibility of developing 
complications: 
Death, myocardial infarction, emergent repeat hospital intervention, bailout stenting, emergency 
CABG, aneurysm, pseudo aneurysm, distal embolization, air embolization, vessel spasm, 
fistulisation, haemorrhage, infection, restenosis of the vessel (greater than 50% obstruction), 
rupture of the vessel, stent migration/embolization, thrombosis (acute, subacute or late), failure 
to deliver the stent(s) to the intended site, occlusion, dissection, arrhythmias, prolonged angina, 
cardiac tamponade, perforation, hypotension, haematoma, allergic reaction, fever, stroke, renal 
failure, balloon rupture, dissection of non-treated site, retained pieces of dilatation catheter, 
stent compression, angina pectoris, bleeding complications, endocarditis, hemodynamic changes 
to flow, injury of the coronary artery, ischemia, palpitations, pulse arrhythmia, pyrogenic 
reaction, sepsis/infection, unstable angina, ventricular fibrillation. 
 
However, the additional risk related to additional investigation-related measurements 
(measurement of the IMR and LVEDP), is extremely low. 
 

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7. WITHDRAWAL FROM STUDY/STUDY DISCONTINUATION 
 
A patient’s participation in the trial is voluntary and the patient may refuse to participate or 
withdraw from the trial, at any time, without penalty or loss of benefits to which the patient is 
otherwise entitled. 
 
Drop outs are defined as patients: 
- 
who decided not to continue the study/not to perform the follow-up visits for whatever 
reason 
- 
who died 
 
When a participant is withdrawn from the study, follow-up by phone call will be continued, unless 
the patient does not provide consent to follow-up. However, all data collected prior to 
discontinuation from the study will be retained in the database. 
 
 
 
 
 

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8. DATA COLLECTION 
 
8.1 Data collection 
The investigator or an individual designated by the investigator is responsible for recording all 
data from the study in patient’s medical history and Case Report Form. 
 
8.2 Protocol deviations 
A protocol deviation is defined as an event where the clinical investigator or site personnel did 
not conduct the study according to the clinical investigation plan. 
 
8.3 Record retention by study site 
All study records and reports will remain in file at the study sites for a minimum of 25 years after 
completion of the study and will further be retained in accordance with local applicable law and 
guidelines. 
 
8.4 Monitoring of data to source documents 
A Case Report Form will be completed at the study site for each subject enrolled in the study. The 
case report forms will contain a record of the subject’s eligibility to enter the study, medical 
history, pre procedure work up and clinical laboratory results, concurrent medications, plus a 
record of all devices used during the procedure, all procedural complications and adverse events, 
discharge, follow up, and any non-scheduled visit involving a late adverse event requiring 
hospitalization or additional procedures. The case report forms will be monitored at the site to 
verify source data accuracy and provide quality assurance.  
 

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9. STATISTICS AND ANALYSIS 
 
9.1 Sample Size 
The sample size for the primary objective (change in FFR after aortic valve intervention) is based 
on previous measurements of FFR in patients with aortic stenosis, where a standard deviation of 
the data was reported.8,14,23 An expected mean FFR of 0.82 with a standard deviation of 0.08 
was used in the calculation. Fifty eight  (58) patients with pre- and post-interventions 
catheterizations will be sufficient to detect a reduction in the FFR from 0.82 to 0.79 with an 
alpha level of 0.05 and power of 0.80. A total sample of 100 patients with baseline 
measurements of which 80 patients will undergo (T)AVR without revascularisation (20% will 
undergo revascularisation) and  in this way are eligible for pre-and post-intervention 
catheterization will allow for a 25 % drop-out during the follow-up phase of the study. Missing 
values will predominantly be at random. Therefore, the primary endpoint will be assessed using 
complete case analysis. To account for missing values, the number of patients will be increased 
from 58  to 80 (since missing data will be excluded from analysis). 
 
For the secondary objective (comparison of FFR versus RFR): approximately 10-20% will have 
left main CAD, triple vessel disease, prior myocardial infarction or tandem lesions and will not 
be eligible for SPECT. One Hundred  patients with baseline measurements will allow a 20% drop-
out to end up with 80 patients with both baseline SPECT and invasive measurements. Yamanaka 
et al.1 found that a sample of 80 patients was necessary to determine the optimal cutoff value 
of iFR for indicating myocardial ischemia. Since RFR and iFR have an extremely high correlation 
(0.99),7 the same number of patients (80) is expected to achieve an area under the ROC curve of 
0.70 with 0.90% power at a significance level of 0.05 in a 2-sided test. 
9.2 Statistical analysis 
All quantitative variables will be tested for normal distribution according to the Kolmogorov-
Smirnov test. Statistical analyses will be performed via the SPSS statistical software package, 

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applying a significance level of ≤0.05. Continuous variables will be expressed as mean ± SD. 
Comparisons will be done with paired t-, Wilcoxon rank signed, Mann-Whitney U- or Kruskal-
Wallis test when appropriate. The chi-square test will be applied for categorical variables and 
results will be expressed as n (%). Analysis will be performed to compare the intra-coronary 
measurements (FFR, RFR, IMR) prior to intervention (group 1) versus 6 months after intervention 
(group 2). Descriptive statistics (mean/median, standard deviation and percentiles for continuous 
data; percentage for categorical data) and graphical representation (boxplots, histograms and 
density plots) will be used to compare both groups’ characteristics. Intra-coronary measurements 
in both groups will then be compared and tested using statistical tests (paired t-, Wilcoxon rank 
signed test). The correlation between FFR and RFR will be analyzed using Pearson correlation 
coefficient. The diagnostic performance of RFR in indicating SPECT myocardial ischemia will be 
evaluated using receiver operating characteristic (ROC) curve analysis. 
 
 
 

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10. REGULATORY REQUIREMENTS 
 
10.1 Institutional Review Board and Ethics Committee: IRB/IEC  
 
The clinical investigation plan as well as other study documents required by the ethics committee 
will be submitted for getting approval from the IRB/IEC. 
 
10.2 Insurance 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, 
Sponsor shall assume, even without fault, the responsibility of any damages incurred by a Study 
subject and linked directly or indirectly to the participation to the study, and shall provide 
compensation therefore through its insurance.  
 
10.3 Confidentiality 
Patient confidentiality will be maintained throughout the study. It will be ensured that the 
information can always be tracked back to the source data, if required. Data relating to the study 
might be made available to regulatory authorities) preconditioned the data are treated 
confidentially and that the patient’s privacy is guaranteed. 
 
 
 

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10.4 Publication Policy 
The study results will be disseminated, valorized and published via abstracts and publications in 
high-index, peer-reviewed journals. Also, the results will be presented at several international 
(EuroPCR, TCT, etc.) and national (Belgian Society of Cardiology (BSC), Belgian Working Group of 
Interventional Cardiology (BWGIC) congresses and symposia. 
 
1. Intellectual Property 
Any Intellectual Property conceived or reduced to practice under this Agreement solely by 
Principal Investigator, Institution’ (UZ Leuven, Belgium) or local study site’ employees shall be 
owned by the Institution (“Institution Intellectual Property”); provided, however, no Institution 
Intellectual Property shall include Confidential Information provided by the local study sites. To 
the extent permitted by the policy of a medical-professional journal, medical institution, 
educational institution, or medical association relating to any publication or presentation of study 
data or results hereunder, ownership of the copyright in any publication, abstract, or presentation 
approved under this section will belong to the Institution (UZ Leuven). 
 
2. Publication 
The Principal Investigator shall have the right, and shall use reasonable efforts, to publish or 
otherwise publicly disclose study data and results and shall have the final authority to determine 
the scope and content of any publications originating from the study provided that before 
publishing, Institution shall submit copies of any proposed publication or presentation to all co-
investigators for review. Institution shall in good faith consider any comments provided by any 
co-investigator and shall delete any Confidential Information identified prior to submission. 
 
 
 
 

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11. DEFINITIONS 
 
Coronary angiography (CA): an invasive procedure usually carried out through the radial or 
femoral artery. Once a sheath has been positioned in a peripheral artery, catheters are used to 
inject an iodine-based contrast into the coronary arteries in order to permit their visualization. 
Right and left heart catheterization (RHC): an invasive procedure that involves catheterization of 
the right heart and pulmonary arteries via a peripheral (usually jugular or femoral) vein and the 
left heart as per coronary angiography often with measurement of left ventricular pressure. Often 
performed at the same time as a coronary angiogram. 
Cardiac catheterization: a broad term covering both coronary angiography and right and left 
heart catheterization. 
Percutaneous coronary intervention (PCI): a percutaneous procedure (as per coronary 
angiography) with an intervention aimed at restoring normal flow in one/more of the coronary 
arteries. 
Severe aortic stenosis: detailed assessment of severe aortic stenosis can be found in the ECS 
guideline for Valvular Heart Disease.2 In patients with normal left ventricular function, severe AS 
is characterized by a mean gradient over the aortic valve of at least 40mmHg or an estimated 
valve area of less than 1.0cm2. 
 
 

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12. REFERENCES 
 
1. 
Yamanaka F, Shishido K, Ochiai T, et al. Instantaneous Wave-Free Ratio for the Assessment of 
Intermediate Coronary Artery Stenosis in Patients With Severe Aortic Valve Stenosis: Comparison With 
Myocardial Perfusion Scintigraphy. JACC Cardiovascular interventions 2018; 11(20): 2032-40. 
2. 
Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular 
heart disease. European heart journal 2017; 38(36): 2739-91. 
3. 
Goel SS, Ige M, Tuzcu EM, et al. Severe aortic stenosis and coronary artery disease--implications 
for management in the transcatheter aortic valve replacement era: a comprehensive review. Journal of 
the American College of Cardiology 2013; 62(1): 1-10. 
4. 
Sankaramangalam K, Banerjee K, Kandregula K, et al. Impact of Coronary Artery Disease on 30-
Day and 1-Year Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement: A Meta-
Analysis. Journal of the American Heart Association 2017; 6(10). 
5. 
De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy 
in stable coronary disease. The New England journal of medicine 2012; 367(11): 991-1001. 
6. 
Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial 
revascularization. European heart journal 2019; 40(2): 87-165. 
7. 
Svanerud J, Ahn JM, Jeremias A, et al. Validation of a novel non-hyperaemic index of coronary 
artery stenosis severity: the Resting Full-cycle Ratio (VALIDATE RFR) study. EuroIntervention : journal of 
EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of 
Cardiology 2018; 14(7): 806-14. 
8. 
Wiegerinck EM, van de Hoef TP, Rolandi MC, et al. Impact of Aortic Valve Stenosis on Coronary 
Hemodynamics and the Instantaneous Effect of Transcatheter Aortic Valve Implantation. Circulation 
Cardiovascular interventions 2015; 8(8): e002443. 
9. 
Ahmed B. New insights into the pathophysiology, classification, and diagnosis of coronary 
microvascular dysfunction. Coronary artery disease 2014; 25(5): 439-49. 
10. 
Garcia D, Camici PG, Durand LG, et al. Impairment of coronary flow reserve in aortic stenosis. 
Journal of applied physiology (Bethesda, Md : 1985) 2009; 106(1): 113-21. 
11. 
Davies JE, Sen S, Dehbi HM, et al. Use of the Instantaneous Wave-free Ratio or Fractional Flow 
Reserve in PCI. The New England journal of medicine 2017; 376(19): 1824-34. 
12. 
Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-Year Outcomes with PCI Guided by Fractional Flow 
Reserve. The New England journal of medicine 2018; 379(3): 250-9. 
13. 
Pesarini G, Scarsini R, Zivelonghi C, et al. Functional Assessment of Coronary Artery Disease in 
Patients Undergoing Transcatheter Aortic Valve Implantation: Influence of Pressure Overload on the 
Evaluation of Lesions Severity. Circulation Cardiovascular interventions 2016; 9(11). 
14. 
Scarsini R, Pesarini G, Zivelonghi C, et al. Physiologic evaluation of coronary lesions using 
instantaneous wave-free ratio (iFR) in patients with severe aortic stenosis undergoing transcatheter 
aortic valve implantation. EuroIntervention : journal of EuroPCR in collaboration with the Working Group 
on Interventional Cardiology of the European Society of Cardiology 2018; 13(13): 1512-9. 
15. 
Scarsini R, Pesarini G, Lunardi M, et al. Observations from a real-time, iFR-FFR "hybrid approach" 
in patients with severe aortic stenosis and coronary artery disease undergoing TAVI. Cardiovascular 
revascularization medicine : including molecular interventions 2018; 19(3 Pt B): 355-9. 
16. 
Dobson LE, Musa TA, Uddin A, et al. Acute Reverse Remodelling After Transcatheter Aortic Valve 
Implantation: A Link Between Myocardial Fibrosis and Left Ventricular Mass Regression. The Canadian 
journal of cardiology 2016; 32(12): 1411-8. 

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17. 
Sato K, Kumar A, Jones BM, et al. Reversibility of Cardiac Function Predicts Outcome After 
Transcatheter Aortic Valve Replacement in Patients With Severe Aortic Stenosis. Journal of the American 
Heart Association 2017; 6(7). 
18. 
Ngo A, Hassager C, Thyregod HGH, et al. Differences in left ventricular remodelling in patients 
with aortic stenosis treated with transcatheter aortic valve replacement with corevalve prostheses 
compared to surgery with porcine or bovine biological prostheses. European heart journal cardiovascular 
Imaging 2018; 19(1): 39-46. 
19. 
Kobayashi Y, Fearon WF. Invasive coronary microcirculation assessment--current status of index 
of microcirculatory resistance. Circulation journal : official journal of the Japanese Circulation Society 
2014; 78(5): 1021-8. 
20. 
Camuglia AC, Syed J, Garg P, et al. Invasively assessed coronary flow dynamics improve following 
relief of aortic stenosis with transcatheter aortic valve implantation. Journal of the American College of 
Cardiology 2014; 63(17): 1808-9. 
21. 
Zhou W, Bajaj N, Gupta A, et al. Coronary microvascular dysfunction, left ventricular remodeling, 
and clinical outcomes in aortic stenosis. Journal of nuclear cardiology : official publication of the 
American Society of Nuclear Cardiology 2019. 
22. 
Iskandrian AE, Bateman TM, Belardinelli L, et al. Adenosine versus regadenoson comparative 
evaluation in myocardial perfusion imaging: results of the ADVANCE phase 3 multicenter international 
trial. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology 
2007; 14(5): 645-58. 
23. 
Ahmad Y, Gotberg M, Cook C, et al. Coronary Hemodynamics in Patients With Severe Aortic 
Stenosis and Coronary Artery Disease Undergoing Transcatheter Aortic Valve Replacement: Implications 
for Clinical Indices of Coronary Stenosis Severity. JACC Cardiovascular interventions 2018; 11(20): 2019-
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Zelis, J. M., et al. (2020). "Why Can Fractional Flow Reserve Decrease After Transcatheter Aortic 
Valve Implantation?" Journal of the American Heart Association 9(5): e04905.