Prospective 4D CTA of BAV Competence
Conditions: Bicuspid
Sponsor: University of Pennsylvania

Prospective 4D CTA of BAV Competence 
 
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CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
 
 
Prospective 4D Computed Tomography Angiography Of The Bicuspid 
Aortic Valve Apparatus: A Comparison Of Bicuspid Aortic Valves With 
And Without Aortic Insufficiency 
 
 
 
Principal Investigator  
Nimesh D. Desai, M.D., Ph.D. 
Department of Surgery 
3400 Spruce Street 
Silverstein 6th Floor 
Philadelphia, PA 19104 
Phone: 215-713-4069 
Email: nimesh.desai@pennmedicine.upenn.edu 
Protocol Number 
 
 
IRB Number 
 
 
 
Grant Number 
 
This work is supported by a pilot grant from the Translational Bio-
Imaging Center (TBIC) of the Institute of Translational Medicine and 
Therapeutics (ITMAT) at the University of Pennsylvania 
 
 
 
 
Initial version 
April 2020 
Amended 
June 22, 2020 
Amended 
 

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Study Summary 
 
Title 
 
Prospective 4D Computed Tomography Angiography Of The Bicuspid Aortic 
Valve Apparatus: A Comparison Of Bicuspid Aortic Valves With And Without 
Aortic Insufficiency 
 
Short Title 
Prospective 4D CTA of BAV Competence 
IRB Number 
 
Protocol Number 
 
Methodology 
Longitudinal observational study  
Study Duration 
9 years 
Study Center(s) 
Single-center study (University of Pennsylvania) 
Objectives 
Primary: 
 
To use medical imaging to determine the anatomical parameters (e.g., 
aortic valve and aortic root dimensions and dynamics) of bicuspid 
aortic valve competence. 
Secondary: 
 
To understand the natural history of BAV disease, including the 
development of aortic insufficiency and/or stenosis.  
 
To determine the anatomical characteristics predictive of successful 
BAV repair. 
Number of Subjects 
60 subjects expected to enroll at Penn  

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Main Inclusion and 
Exclusion Criteria 
Inclusion criteria: 
 
At least 18 years of age 
 
Documented bicuspid aortic valve identified via clinical 
imaging (e.g., CT, MRI, or echocardiogram) with minimal 
calcification at the time of enrollment 
 
Participant must sign the informed consent form  
Exclusion criteria: 
 
Pregnancy (determined by point of care urine pregnancy test) 
 
Renal failure (estimated Glomerular Filtration Rate (eGFR) < 
30), precluding them from receiving intravenous contrast) 
 
Documentation of previous intravenous contrast allergy 
(unless they are having a CT with steroid preparation as part 
of routine clinical care) 
 
Previous aortic valve replacement 
Intervention  
 
The study involves annual 4D CTA imaging of the bicuspid aortic valve for a 
period of 5 years. CTA is often standard of care for BAV patients, but patients 
in this study will receive a higher radiation dose with a 4D imaging protocol. 
There may also be patients enrolled in the study who have a 4D CTA for 
research purposes when a routine CTA is not required for clinical care. 
Statistical 
Methodology 
Patients will be stratified into “competent” and “incompetent” BAV groups 
based on the severity of aortic insufficiency on routine echocardiography at the 
time of study enrollment. Geometrical and functional measurements (e.g., 
coaptation area, coaptation height, cusp surface area, aortic root diameters, 
valve orifice area, localized cusp thickness, and aortic cusp and root velocities) 
will be extracted from each 4D CTA scan to quantify valve morphology and 
dynamics at each study time point, as well as longitudinally. Measurements 
from the competent and incompetent BAV groups will be reported and 
compared.  
Data and Safety 
Monitoring Plan  
The PI will be responsible for the data quality management and the ongoing 
safety of subjects.  
 
Background and Study Rational 
1 
Introduction 
The bicuspid aortic valve (BAV) is the most common congenital heart disease. The purpose of this study 
is to better understand the anatomy of physiologically “normal”, or competent, BAVs without stenosis or 
insufficiency (AI) in order to support evidence-based standardization of BAV repair surgery. Men and 
women over 18 years of age with a diagnosis of BAV and minimal aortic valve calcification at baseline will 
undergo annual 4D computed tomography angiography (CTA) scans, transthoracic echocardiograms, 
and history and physical assessments over the course of the 5-year study period. Patients who are 
pregnant, have renal insufficiency (creatinine > 2 mg/dL), or who have a contraindication to intravenous 
contrast will be excluded. Patients will be stratified into study groups according to baseline AI: 
approximately half of patients will have no to mild AI at baseline and the other half will have moderate to 
severe AI at baseline. Anatomical measurements will be obtained from the 4D CTA scans and analyzed 
at each phase of the cardiac cycle, as well as longitudinally. The 4D CTA imaging and analysis will not 

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impact medical care of the study participants; the anatomical measurements will be used in the future as 
evidence-based standards for determining valve repair candidacy for BAV patients with AI.  
 
This study will be conducted in full accordance with all applicable University of Pennsylvania Research 
Policies and Procedures and all applicable Federal and state laws and regulations. All episodes of 
noncompliance will be documented. 
 
1.1 
Background and Relevant Literature  
 
The BAV is the most common congenital heart defect, reported to affect 0.5 – 2% of the population (Ward 
2000). Since BAVs are typically imaged after a patient has developed symptoms of aortic insufficiency 
(AI) or aortic stenosis (AS), little is known about the geometric and dynamic anatomical features of the 
functionally “normal” or competent BAV, defined as a BAV without stenosis or insufficiency. Moreover, 
there are gaps in knowledge of the natural progression of BAV competence to BAV pathology, which 
most frequently manifests as AI and/or AS. There is limited data to predict if and when asymptomatic BAV 
patients will need to receive intervention to repair or replace their aortic valve. 
 
BAV patients who present with AI typically range in age from 20 to 50 years old and, based on age at 
presentation, will survive several decades after intervention (Boodwhani et al. 2010). While aortic valve 
replacement is the conventional treatment for AI, it is not an ideal intervention in younger patients with 
non-stenotic BAVs. Bioprosthetic valves have limited durability in this patient population and will require at 
least one additional valve replacement over the patient’s lifetime (Aicher et al. 2011). Mechanical valves 
carry the risk of thromboembolic events and require life-long anti-coagulation, which limits quality of life in 
young patients (Salem et al. 2004). Therefore, BAV repair has become more widely adopted by surgeons 
in major cardiac centers in recent years, as early results have been satisfactory (Aicher et al. 2011, 
Svensson et al. 2014). However, repair strategies have not been standardized and are limited to single-
center reports in relatively small patient series. Furthermore, techniques to determine repairability of a 
BAV have been adopted from normal trileaflet aortic valve studies (Schäfers et al. 2013) and there are no 
existing research studies of functionally normal BAV characteristics, such as coaptation height and cusp 
height. Such studies would help to standardize BAV repair procedures, as they would define the 
anatomical and dynamic valve characteristics that are needed to recreate BAV competence during valve 
repair surgery. 
 
The goal of this research is to characterize the aortic valve and root geometry/dynamics of physiologically 
normal BAVs relative to BAVs with moderate to severe AI. While transesophageal echocardiography 
(TEE) is the most commonly used imaging modality to assess valve morphology and dynamics, it requires 
sedation and is not typically ordered for routine annual surveillance. In this study, 4D computed 
tomography angiography (CTA) imaging will be used to analyze aortic cusp motion and coaptation and to 
create four-dimensional BAV models to measure aortic root landmarks and valve characteristics over the 
cardiac cycle. The long-term goal of this research is to follow the natural history course of BAV syndrome 
and the development of AI or AS. 
 
2 
Study Objectives 
2.1 
Primary Objective 
 
 
To use medical imaging to determine the anatomical parameters (e.g., aortic valve and aortic root 
dimensions and dynamics) for BAV competence. 
2.2 
Secondary Objectives (if applicable) 
 
 
To understand the natural history of BAV disease, including the development of aortic 
insufficiency and/or stenosis.  

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 
To determine the anatomical characteristics predictive of successful BAV repair. 
3 
Investigational Plan  
3.1 
General Design 
 
This is a prospective observational study of patients with normally functioning (competent) and diseased 
(incompetent) BAVs. Patients will be stratified into two groups based on degree of baseline aortic 
insufficiency. Those patients with less than moderate (+2) AI will be in the “competent BAV” group, and 
those patients with greater than moderate (+2) AI will be in the “incompetent BAV” group. Each group will 
be limited to 30 patients. All patients will follow the same study time course and undergo the same study 
procedures, including an annual 4D CTA scan. The goal of this work is to describe differences in the 
anatomical and functional characteristics of BAVs in these two groups based on 4D CTA. 
 
Overview of study procedures (described in Section 5): 
 
Screening for study eligibility and informed consent  
 
4D CTA imaging at baseline and at 1-year intervals over a period of 5 years. (Annual CTA studies 
will be performed routinely in some or many of the patients, but the 4D protocol will be for 
research purposes.) 
 
Annual office visits and echocardiography studies over the 5-year study period (standard of care) 
3.2 
Study Measures 
 
Image-derived measures of BAV morphology and dynamics 
Features of BAV morphology and motion will be extracted from 4D CTA images acquired at baseline and 
at 1-year intervals over a period of 5 years. Manual and automated segmentation and deformable 
modeling algorithms similar to those presented in (Pouch et al., 2012) and (Pouch et al., 2015) will be 
used generate a 4D model of the BAV apparatus in each 4D CTA scan, which will depict BAV 
morphology and dynamics over one complete cardiac cycle. The measures extracted from each model 
will include, but are not limited, to the following: 
 
Cusp surface areas over the cardiac cycle 
 
Cusp height (geometric and effective) 
 
Cusp free margin length 
 
Cusp thickness (including raphe thickness, if applicable) 
 
Commissural height 
 
Characteristics of cusp fusion (e.g., symmetric cusp geometry or cusp fusion angle for 
asymmetric valves) 
 
Aortic root dimensions (e.g., sinotubular junction diameter/area, sinus of Valsalva diameter/area, 
aortic annular geometry, ventriculoaortic junction diameter/area, root volume) 
 
Coaptation height at diastole 
 
Cusp displacement over the cardiac cycle 
 
Cusp velocity/acceleration over the cardiac cycle 
 
Geometry of the ascending aorta (e.g., aortic size) 
 
Measures from office visits, imaging studies, and interventions 
Relevant measurements will be recorded from annual office visits, other routine cardiac imaging studies 
(e.g., echocardiography or MRI), and interventions such as cardiac surgeries performed during the study 
period. These will include, but are not limited, to the following (all are collected as standard of care): 
 
Physical exam measurements and vital signs (e.g., height, weight, pulse) 
 
Severity of AI or AS (assessed on routine echocardiography) 
 
Measurements from other routine images (e.g., echocardiography or MRI) complementary to the 
4D CTA measures listed above  
 
Physical intraoperative measurements, such as cusp height (if an aortic surgery is performed 
during the study period) 

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 
Additional relevant information, such as: cardiovascular symptoms, New York Heart Association 
Classification, information about cardiac procedures/surgeries performed (e.g., intraoperative 
exam findings, surgical approach, prosthetics used, factors motivating the surgical plan) 
3.3 
Study Endpoints  
3.3.1 
Primary Study Endpoint 
 
The primary endpoint of this study is a set of 4D image-derived anatomical models of the BAV acquired at 
five one-year intervals. The anatomical and dynamic characteristics of the BAV will be analyzed over the 
cardiac cycle based on the 4D anatomical model generated from each 4D CTA study. The change in 
these characteristics (listed in Section 3.2) will be assessed over the 5-year period.  
3.3.2 
Secondary Study Endpoint 
 
The secondary endpoint of this study is severity of AI and/or AS, as assessed by routine 
echocardiography. 
4 
Study Population and Duration of Participation  
4.1 
Duration of Study Participation  
 
Estimated length of time to enroll all subjects: 2 years 
Length of subject’s participation in study: 5 years 
Analysis and publication of results: 2 years 
Projected overall duration of study: 9 years 
4.2 
Total Number of Subjects and Sites  
 
We aim to have approximately 40 patients with adequate data to include in the final analysis. We believe 
enrollment of 60 patients into our study will account for potential error in obtaining adequate scans or loss 
of data due to patient withdrawal from study. 
 
Penn is the only site at which patients will be enrolled. 
4.3 
Inclusion Criteria 
 
At least 18 years of age 
 
Documented bicuspid aortic valve identified via clinical imaging (e.g., CT, MRI, or 
echocardiogram) 
 
Participant must sign the informed consent form  
4.4 
Exclusion Criteria 
 
Pregnancy (determined from a point of care urine pregnancy test) 
 
Renal failure (estimated Glomerular Filtration Rate (eGFR) < 30), precluding them from 
receiving intravenous contrast) 
 
Documentation of previous intravenous contrast allergy (unless they are having a CT with 
steroid preparation as part of routine clinical care) 
 
Previous aortic valve replacement 
4.5 
Subject Recruitment  
 
The Cardiology and Cardiovascular Surgical clinics at the University of Pennsylvania Health System see 
a high volume of patients with BAVs for both aortic surveillance and treatment. For reference, from July 

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2011 to June 2018, one surgeon at our center performed aortic valve replacement on 344 patients with 
BAV. Many more have undergone repair or have only been followed with routine echocardiogram and CT 
scans as they have not yet met the indications for surgery.  
We will primarily using PennChart to identify patients scheduled in our cardiology and cardiac surgical 
clinics who have been diagnosed with BAV. Additionally, we will be identifying patients who receive an 
echocardiogram at Penn and are noted to have a BAV. After identification and screening via chart review, 
patients will be approached by a research coordinator, either in person (in clinic, heart and vascular 
testing center, or inpatient wards) or via telephone to gauge interest and, if interested, schedule them for a 
visit in our research clinic to sign consents. Finally, we will be identifying patients through the Penn 
Biobank to screen and, if they meet criteria, contact to gauge interest and schedule for a clinic visit. 
Privacy of individuals will be maintained by communicating only in private spaces within the hospital or by 
phone.  
4.6 
Vulnerable Populations:  
 
We will not enroll patients who are unable to provide consent themselves. Pregnant women and children 
are excluded from this study. Monetary compensation will not be provided for participation. 
 
Although not directly targeted, mentally disabled persons, economically or educationally disadvantaged 
persons, and/or employees or students of the University of Pennsylvania will not be denied enrollment 
and any special protections and/or additional safeguards will be undertaken in order to protect the rights 
and welfare of these subjects from coercion or undue influence as appropriate. 
5 
Study Procedures  
 
The procedures summarized in Section 3 are listed in Table 1. 
 
 
Table 1: Schedule of Study Procedures 
Study Phase 
Screening 
Observation Study Visits 
Visit Number 
 
1 
(Baseline) 
2 
3 
4 
5 
Years from Baseline Study 
 
0 
1 
2 
3 
4 
Review Inclusion/Exclusion 
Criteria 
X 
X 
X 
X 
X 
X 
Medical Record Review 
(routine office visits, imaging 
and laboratory studies, 
cardiac procedures) 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
4D CTA  
 
X 
X 
X 
X 
X 
Pregnancy Test 
 
X 
X 
X 
X 
X 
Adverse Event / 
Unanticipated Problems 
Assessment 
 
X 
X 
X 
X 
X 
 
 

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Does your study use MRI? (CAMRIS is the appropriate contact for all studies involving MRIs) 
 Yes  
 
X No (If No, no CAMRIS review needed) 
 
Does your study include pregnant women? 
  
 Yes  
 
X No 
 
Does your study involve the exposure to radiation, radiotracers and/or radiological imaging modalities?  
 
X Yes  
 
 No (If No, no RRSC review is needed)  
 
Will any of the radiation exposure result from procedures that are or could be performed solely as a result 
of a subject’s participation in the research protocol? 
X Yes  
 
 No  
 
Ultrasound  
 Yes  
 
X No (routine echocardiography only) 
 
 
Will your study be using CT Scans? (CACTIS is the appropriate contact for studies involving CT scans)  
X Yes  
 
 No 
 
Studies involving Nuclear Medicine: Will subjects be undergoing any of the following procedures specific 
to research: 
 MUGA 
 
(See Nuclear Medicine-Muga Scan) 
 PET/CT Scan 
 
(See PET/CT Scan) 
 Bone /DXA 
 
(See Bone Scan) 
 
X None of the above apply 
 
Check off all of the following procedures that will be performed in your research- each option you select 
will link to the template language document:  
 Apheresis/plasma exchange  
 Leukapheresis  
 Bone Marrow Biopsy or Aspirate  
 Use of AP clinical specimens  
 Biopsies- check those which apply  
 Blood draw  
X   None of the above apply 
 
 
5.1 
Screening  
 
The screening visit for eligibility assessment will include: 
 
Medical record review to verify documentation of a BAV, previous aortic interventions, 
presence of renal failure, contraindications to contrast agents, and pregnancy status. 
(Note: a pregnancy test will be performed prior to each 4D CTA study.) Pregnant women 
will be excluded from the study if they confirm pregnancy at the time of screening or if the 
pregnancy test prior to baseline imaging is positive. 
 
Informed consent 

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5.2 
Study Intervention or Observational Phase (Give this section a name that is 
relevant to the design of your study) 
5.2.1 
Baseline Imaging 
 
After being identified, screened, and have provided informed consent, all patients will undergo a baseline 
4D CTA imaging study. A pregnancy test will be performed in women prior to the 4D CTA study. Each 4D 
CTA scan will be performed according to established TAVR imaging protocols with modifications to limit 
radiation dose to approximately 5 mSv. 
 
 
Additional baseline information may be collected (standard of care): 
 
Other routine imaging studies (e.g., echocardiography or MRI) 
 
Physical exam 
 
Vital signs  
 
Laboratory tests, including creatinine level  
 
Quality of life assessments 
5.2.2 
Annual follow-up imaging and visits 
 
After baseline imaging, patients will have annual routine clinic follow up visits (1 year ± 90 days) that will 
consist of the following:  
 
Medical history and physical (standard of care) 
 
Transthoracic echocardiogram (standard of care)  
 
Laboratory studies, including creatinine level (standard of care) 
 
4D CTA (research). As annual CT scans are often standard of care in these patients, the 
research component will be the additional 4D imaging protocol, performed according to 
established TAVR imaging protocols with modifications to limit radiation dose to approximately 5 
mSv. 
5.3 
Unscheduled Visits and Surgeries 
Medical information and image data collected as standard-of-care at visits other than the scheduled 
annual follow-up may be included in the patient’s research record. For example, relevant information from 
cardiac imaging studies or office visits other than the annual follow-up will be documented, especially as it 
relates to the development of AI and/or AS and associated symptoms. If a patient requires aortic valve 
repair or replacement during the 5-year study period, information that is routinely acquired during the 
operation will be recorded (e.g., procedures performed, prosthetic devices used, pre- and post-operative 
imaging and exam measurements, etc.). 
5.4 
Subject Withdrawal  
 
Subjects may withdraw from the study at any time without impact to their care.  They may also be 
discontinued from the study at the discretion of the Investigator for lack of adherence to study procedures 
or visit schedules. Patients will be followed for any safety events. If a patient meets the indications for 
valve surgery during their participation in the study, they will remain in the study on their original study 
timeline, unless they require an aortic valve replacement, at which point they will end their study 
participation. It will be documented whether or not each subject completes the study.  
 

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6 
Statistical Plan 
6.1 
Sample Size Determination 
The sample size for this study is based on our previous work on automated heart valve analytics in 3D 
transesophageal echocardiography, wherein a minimum of 20 patients was needed to develop and 
evaluate the accuracy of semi-automated methods for reconstructing the mitral valve and tricuspid aortic 
valve apparatus in 3D images and to derive anatomical valve features similar to those described in 
Section 3.2 (Pouch et al. MedIA 2014; Pouch et al. MedIA 2015). Similar to the 4D CTA analysis 
proposed in this study, we used those image analysis techniques to carry out a statistical shape analysis 
of physiologically normal mitral annular geometry (Pouch et al., ATS 2014), as well as a comparison of 
normal vs. myxomatous valve morphology (Pouch et al., 2016), also with ~20 subjects per group. In this 
protocol, we propose to enroll 30 subjects in both the “competent BAV” and “incompetent BAV” groups; 
we anticipate this is the number needed to ensure that we obtain adequate image data from at least 20 
subjects in each group given the potential for suboptimal image quality or patient withdrawal. Based on 
our previous work, 20 patients per group is likely the minimum necessary as a starting point to 
demonstrate feasibility of BAV modeling in 4D CTA data. 
6.2 
Data Analysis 
6.2.1 
Baseline Data 
 
Baseline and demographic characteristics will be summarized by standard descriptive statistics (including 
mean and standard deviation for continuous variables such as age and standard percentages for 
categorical variables such as gender). 
6.2.2 
Analysis of Primary Outcome of Interest 
 
Post-processing of each 4D CTA data set will involve manual or semi-automatic image segmentation 
(labeling) and geometrical modeling of the BAV at each cardiac phase. Geometrical and functional 
measurements (e.g., coaptation area, coaptation height, cusp surface area, aortic root diameters, valve 
orifice area, localized cusp thickness, and aortic cusp and root velocities) will be extracted from the 4D 
CTA image segmentations to quantify valve morphology and dynamics at each study time point, as well 
as longitudinally. Measurements from the competent and incompetent BAV groups will be reported with 
standard descriptive statistics, including group means and standard deviations time-normalized with 
respect to the cardiac cycle at each study time point. Comparison of valve measurements in the two 
groups will be carried out with independent Student t-tests at multiple phases of the cardiac cycle with 
false discovery rate adjustment to account for multiple comparisons. We will perform additional statistics 
on longitudinal data. Comparable measurements will be made on standard-of-care echocardiography 
and/or MR image data when available.  
7 
Safety and Adverse Events 
Potential safety issues in this study are related to radiation and contrast for the 4D CT exam. An internal 
safety committee, including representation from Radiology and Cardiothoracic Surgery, will monitor for 
adverse events. All CTs will be reviewed on a quarterly basis concerning radiation dose. Moderate to 
severe contrast reactions will be reported to the IRB as severe adverse events and evaluated individually 
by the safety committee. Patients who have severe adverse events will be withdrawn from the study. Mild 
reactions to contrast will be reviewed quarterly to evaluate whether the participant should continue in the 
trial. 
8 
Study Administration, Data Handling and Record Keeping 
8.1 
Confidentiality 
 

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Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
All image data and non-image patient information will be associated with a study-specific subject ID. The 
link between the subject ID and patient identity will be maintained in a RedCap form that will only be 
accessible to the PI and designees. The data files (medical images and patient characteristics) used for 
offline analysis will be de-identified and associated with the study-specific patient ID, not a patient name 
or other PHI. These data files will be stored on a password protected NAS server, stored in a locked Penn 
clinical research facility, accessible only to authorized personnel only through the UPHS network and will 
be independent of the RedCap form. Date-shifting will be used to ensure confidentiality, and the date 
shifting scheme will be stored only in the RedCap form. Any data shared with other investigators will be 
de-identified and void of both direct and indirect identifiers. If data transport is necessary, only UPHS-
approved devices will be used.  
 
8.2 
Data Collection and Management  
 
A link between the patient’s medical record, name, and study-specific subject ID will be recorded in a 
RedCap form to which only the PI and designees will have access during the study. Images and 
electronic data forms containing PHI will be stored on computers or servers managed by the University of 
Pennsylvania Health System. When saving raw image data from the CT scanners, hospital-approved 
encrypted hard drives will be used for data transport. All papers with patient related study data (such as 
inclusion/exclusion forms, ICFs, imaging reports) will be stored in a locked binder closet within the 
Thoracic Aortic Surgery Program offices located at 5000 Ravdin Courtyard. 
 
All PHI will be stored in RedCap. The PHI will include name, medical record number, date of birth, 
encounter dates, and the randomly generated number by which all that patient’s dates in the database 
are shifted. Images will be anonymized and stored on a password protected NAS server, stored in a 
locked Penn clinical research facility, accessible only to authorized personnel only through the UPHS 
network. Any image data exported from the NAS server will be de-identified. Patient factors exported from 
the RedCap database for analysis will not include patient identifiers, such as patient name or MRN. The 
patient’s date of birth and all encounter dates will be time-shifted by the same number of days in a range 
between -60 and -5. The date-shift value will be randomly generated and stored in the RedCap form that 
will link the patient’s PHI to their study-specific ID. No published or presented materials will identify 
subjects by names or initials.  
 
8.3 
Records Retention 
 
The link between the patient’s medical record and subject ID will remain accessible in RedCap only to the 
PI and designees after completion of the study. The purpose of maintaining this link is if additional 
examination of the record is necessary to complete data entry, or if in a future follow-up study additional 

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information from the medical record may be needed to test future hypotheses. The PI will not access 
identifiable data for a future research study without prior IRB approval. 
 
The RedCap form and anonymized images will be stored indefinitely to support future follow-up studies. 
PHI will not be reused or disclosed to any other person or entity, except as required by law, for authorized 
oversight of the research project, or for other research for which the use or disclosure of PHI would be 
permitted. 
 
9 
Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
 
The study PI will be responsible for ensuring the ongoing quality and integrity of the research study.  
9.2 
Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
10 Ethical Considerations 
10.1 
Risks 
 
It is expected that at least half of the patients enrolled in this study will undergo annual CTA as standard 
of care as many BAV patients have dilatation of the ascending aorta. For research purposes, this group 
would receive a higher radiation dose for a 4D CTA of the aortic valve. There will also be study 
participants who would not require an annual CTA as part of their routine medical care. The latter group 
will receive a radiation dose for research purposes only. For all patients in the study, a standard 
transcatheter aortic valve replacement (TAVR) 4D CTA imaging protocol will be used with modifications to 
limit the radiation dose as close to 5 mSv as possible. Such modifications include restricting the scan 
such that only the necessary BAV anatomy is imaged with 4D CTA. (A 4D CTA of the entire chest is not 
necessary for this study, since the study focuses on a characterization of the BAV cusps and root.) The 
risks associated with ionizing radiation, IV contrast, and incidental findings are described below. 
 
Risks: CT imaging and ionizing radiation 
This research study involves exposure to radiation during the 4DCTA scan. Therefore, the patient will 
receive a radiation dose.  This radiation dose is not necessary for their medical care and will occur only 
as a result of their participation in the study.  At doses much higher than they will receive, radiation is 
known to increase the risk of developing cancer after many years.  At the doses they will receive, it is very 
likely that they will see no effects at all. 
 
Risk of pregnancy and ionizing radiation 
Pregnant women will be excluded from having CT scan due to the possibility of unforeseen side effects to 
the fetus. All female subjects that are capable of becoming pregnant must take a pregnancy test within 24 
hours prior to the CT exam to rule out pregnancy. A point of care pregnancy test (urine screening) will be 
carried out prior to each CT exam. 
CT scans produce x-rays. If there is a chance of pregnancy the patient should inform the study staff and 
the CT exam should be postponed. 

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CT contrast agent: ISOVUE 370 (non-ionic) 
Risk of IV contrast agents used in CT imaging 
Approximately 95% of CT contrast reactions are mild to moderate in degree and most resolve without 
treatment. However, life-threatening reactions and fatalities, mostly of cardiovascular origin, have 
occurred. People with heart disease, kidney disease, or allergies are more likely to have a severe 
reaction to contrast agents. The patient will be instructed to inform the study staff if the patient has a 
history of heart disease, kidney disease, or allergies. 
Common effects of iodinated IV contrast agents are: 
 
Feelings of overall warmth, especially in the bladder area after injection 
 
A metallic taste during the injection 
 
Warmth, burning sensation or momentary pain at the injection site during contrast injection  
 
Less common are nausea, vomiting, headache, hives and itching 
 
Rare, but serious reactions are rapid heartbeat, changes in blood pressure, heart attack, kidney 
failure, pulmonary edema, serious life-threatening allergic reaction. 
 
Risk of IV Placement: 
There is a possibility that multiple needle sticks will be necessary to ensure proper intravenous line 
placement. A small amount of pain or bruising may occur with intravenous catheter (IV) placement and 
there is a small risk of infection at the injection site. 
 
Risks: CT Imaging and Incidental Findings 
It is possible that during the course of the research study, the research staff (and/or radiologist that 
reviews the CT scan) may notice an unexpected finding(s). Should this occur, the finding (s) will be 
considered by the appropriate medical personnel and the study principal investigator will inform them, if 
necessary. These finding(s) may or may not be significant, and may lead to further testing (such as 
additional imaging studies, or biopsy). This may result in anxiety or harm to the patient due to the 
additional testing. The costs of such additional testing will not be covered as part of this research study. 
 
10.2 
Benefits 
There is no direct benefit to study participants. The 4D CTA acquired in this study will not be used for 
clinical care or surgical decision-making for the participants but will likely benefit future BAV patients. The 
following paragraphs describe the ways in which the study may benefit patients in the future. 
 
This study may benefit BAV patients in the future since it will provide information that can help 
standardize the approach to BAV repair. For example, the thresholds on cusp height that are used to 
intraoperatively determine whether a BAV is repairable are based on tricuspid aortic valve data rather 
than physiologically normal BAVs. This study will produce a much-needed data set on physiologically 
normal BAV morphology that will provide quantitative evidence for cusp height thresholds and other 
measurements that drive intraoperative decision making. Thus, the knowledge gained from this study will 
help to determine whether a future patient is best suited for valve repair or valve replacement based on 
their pre-operative BAV morphological and dynamic characteristics. By providing descriptive information 
on how a pathological BAV should look and function after a successful valve repair, this research could 
make repair a viable and more accessible alternative treatment in BAV patients for whom valve 
replacement is not a suitable option.  
 
An additional benefit of the study is that it provides insight into the development of BAV pathology through 
longitudinal imaging. It is likely that many of the patients who are enrolled as part of the “incompetent 
BAV” group and some who are enrolled as part of the “competent BAV” group will need to undergo 
surgical intervention within 5 years of the baseline scan. By imaging participants with 4D CTA on an 
annual basis, the study will provide information on the detailed morphological and dynamic changes that 
the BAV apparatus undergoes as patients develop worsening symptoms that necessitate surgical 
intervention. To the best of our knowledge, longitudinal 4D images have not before been acquired in this 
clinical context and can provide new insights into the timing of surgical intervention for future patients.  

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The first-line imaging modality used for surgical planning is TEE, which requires sedation and is therefore 
conventionally performed in the operating room immediately before surgery. As a result, important 
decisions regarding the surgical plan (such as risk stratification for valve repair vs. replacement) are often 
made rapidly in the operating room. This study may demonstrate that in the future, 4D CTA could be an 
alternative image strategy that provides the surgeon and patient with information earlier in the surgical 
decision-making process (i.e., before the patient enters the operating room), which could decrease time 
under cardiopulmonary bypass. 
 
10.3 
Risk Benefit Assessment 
 
The risks involved in the study are minimal since the 4D CTA protocol will be modified to give the lowest 
necessary radiation dose (a target of 5 mSv, which is consistent with many routine diagnostic CT scans). 
While there are no direct benefits to the study participants, the information gained from the study could 
potentially have a significant impact on surgical management of BAV patients with AI. In the young BAV 
patient population with AI, BAV repair is preferable to the conventional treatment (BAV replacement) 
when the likelihood of a durable repair is high. However, image data on physiologically normal BAVs is 
not currently available to guide standardization of the procedure and develop better evidence-based 
criteria for predicting repair durability. Without such data, heart valve repair surgeries can go through 
decades of trial and error before a standardized approach is optimized, as was the case with mitral valve 
repair surgery. An additional benefit of this study is that it could potentially show that 4D CTA has BAV 
characterization capabilities that are not feasible with routine intraoperative echocardiography. Such a 
finding could lead to enhanced pre-operative planning abilities, which could reduce the time needed for 
intra-operative decision making and would provide the surgeon and the patient with more information 
about the likelihood of a durable BAV repair before they enter the operating room. 
10.4 
Informed Consent Process / HIPAA Authorization  
 
Study personnel will approach patients in clinic or via telephone after diagnosis of a BAV has been made, 
screening for inclusion and exclusion criteria has been performed, and the physician has spoken to the 
patient about research and feels it is appropriate for the study team to approach the patient. Patients will 
be interacting with an investigator in the outpatient clinic to gain informed consent and follow up 
information and via telephone to schedule visits. Only study personnel will be permitted to contact 
patients regarding their participation in this study. If at any point prior to signing informed consent a 
patient expresses a lack of interest in the study the patient will not be contacted again. If at any point after 
signing informed consent a patient expresses in writing a desire to withdraw from the study, the patient 
will be withdrawn from the study and will not be contacted about this study in the future. 
 
All subjects for this study will be provided a consent form describing this study providing sufficient 
information for subjects to make an informed decision about their participation in this study. Please see 
protocol attachments for a copy of the Informed Consent Form.  This consent form will be submitted with 
the protocol for review and approval by the IRB for the study.  The formal consent of a subject, using the 
IRB-approved consent form, must be obtained before that subject undergoes any study procedure.  The 
subject must sign the consent form, and the investigator-designated research professional obtaining the 
consent. Subjects will be consented by the study Principal Investigator or appropriate designee. Potential 
subjects will review the consent form in detail with the person designated to consent and have the ability 
to take the consent home for further review.  
 
11 Study Finances 
11.1 
Funding Source 
This study is funded through a pilot grant awarded by the Institute for Translational Medicine and 
Therapeutics. The original proposal is attached. 

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11.2 
Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
11.3 
Subject Stipends or Payments 
There are no subject payments or stipends. 
12 Publication Plan 
Publication will adhere to the policies of the University of Pennsylvania and the Perelman School of 
Medicine. 
13 References 
 
Ward C. Clinical significance of the bicuspid aortic valve. Heart. 2000;83(1):81-5. PubMed PMID: 
10618341; PMCID: PMC1729267. 
 
Boodhwani M, de Kerchove L, Glineur D, Rubay J, Vanoverschelde JL, Noirhomme P, El Khoury G. 
Repair of regurgitant bicuspid aortic valves: a systematic approach. J Thorac Cardiovasc Surg. 
2010;140(2):276-84 e1. doi: 10.1016/j.jtcvs.2009.11.058. PubMed PMID: 20488466. 
 
Aicher D, Kunihara T, Abou Issa O, Brittner B, Graber S, Schafers HJ. Valve configuration determines 
long-term results after repair of the bicuspid aortic valve. Circulation. 2011;123(2):178-85. doi: 
10.1161/CIRCULATIONAHA.109.934679. PubMed PMID: 21200006. 
 
Salem DN, Stein PD, Al-Ahmad A, Bussey HI, Horstkotte D, Miller N, Pauker SG. Antithrombotic therapy 
in valvular heart disease--native and prosthetic: the Seventh ACCP Conference on Antithrombotic and 
Thrombolytic Therapy. Chest. 2004;126(3 Suppl):457S-82S. doi: 10.1378/chest.126.3_suppl.457S. 
PubMed PMID: 15383481. 
 
Svensson LG, Al Kindi AH, Vivacqua A, Pettersson GB, Gillinov AM, Mihaljevic T, Roselli EE, Sabik JF, 
3rd, Griffin B, Hammer DF, Rodriguez L, Williams SJ, Blackstone EH, Lytle BW. Long-term durability of 
bicuspid 
aortic 
valve 
repair. 
Ann 
Thorac 
Surg. 
2014;97(5):1539-47; 
discussion 
48. 
doi: 
10.1016/j.athoracsur.2013.11.036. PubMed PMID: 24680032. 
 
Schafers HJ, Schmied W, Marom G, Aicher D. Cusp height in aortic valves. J Thorac Cardiovasc Surg. 
2013;146(2):269-74. 
 
Pouch AM, Wang H, Takabe M, Jackson BM, Gorman JH, 3rd, Gorman RC, Yushkevich PA, Sehgal CM. 
Fully automatic segmentation of the mitral leaflets in 3D transesophageal echocardiographic images 
using multi-atlas joint label fusion and deformable medial modeling. Med Image Anal. 2014;18(1):118-29. 
 
Pouch AM, Tian S, Takebe M, Yuan J, Gorman R, Jr., Cheung AT, Wang H, Jackson BM, Gorman JH, 
3rd, Gorman RC, Yushkevich PA. Medially constrained deformable modeling for segmentation of 
branching medial structures: Application to aortic valve segmentation and morphometry. Med Image Anal. 
2015;26(1):217-31. 
 
Pouch AM, Jackson BM, Lai E, Takebe M, Tian S, Cheung AT, Woo YJ, Patel PA, Wang H, Yushkevich 
PA, Gorman RC, Gorman JH, 3rd. Modeling the Myxomatous Mitral Valve With Three-Dimensional 
Echocardiography. Ann Thorac Surg. 2016;102(3):703-10. 
 
Pouch AM, Vergnat M, McGarvey JR, Ferrari G, Jackson BM, Sehgal CM, Yushkevich PA, Gorman RC, 
Gorman JH, 3rd. Statistical assessment of normal mitral annular geometry using automated three-
dimensional echocardiographic analysis. Ann Thorac Surg. 2014;97(1):71-7. 
 

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14 Attachments 
The following documents are attached: 
 
Informed consent form 
 
Research proposal funded by the Translational Biomedical Imaging Center (TBIC) of the Institute 
for Translational Medicine and Therapeutics at Penn.