Clinical trial NCT02114697
Conditions: Atherosclerosis
Keywords: Cancer survivorship Cardiovascular disease Stroke Transient ischemic attack (TIA)
Sponsor: Emory University
Start date: 2014-04-01; Completion date: 2017-07-01
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to assess a slimy substance that settles/deposits along blood vessel wall. This slimy substance is called plaque. Plaque could be made up of fat, calcium or both. Plaque deposition narrows the vessels. This leads to decreased blood flow to various parts of body. Blood vessels include vessels that supply to heart (coronary), vessels to brain (carotid), vessels to kidneys (renal) and vessels to legs (femoral). Decreased blood flow causes symptoms such as brain stroke, heart attack, leg pain. Similarly individuals at risk of cardiovascular disease can have certain markers elevated in their blood that can be measured by simple blood tests.

High or increased plaque deposition is seen in neck vessels of cancer patients who received radiation to chest or head and neck as part of their cancer treatment. Cancer survivors are at increased risk of plaque development and are therefore called high-risk population. Exercise +/- fat lowering medicine can potentially decrease plaque deposition and statins are one of the several fat lowering medications.

Detailed description:
Cardiovascular disease (CVD) and cancer are the leading causes of suffering and death amongst the American population. While an ever-increasing number of cancer survivors have a favorable outcome due to advances in cancer treatment; cancer survivors remain at high risk of developing CVD at an early age. There is scant information available on the pathogenic process that contributes to cardiovascular threat amongst cancer survivors and little is known about the interventions, which may interrupt or decrease the risk of CVD in this population. Importantly, early-subclinical markers may substantially precede clinical markers.

The objective of this project is to accurately determine the constituents and characteristics of atherosclerotic plaques in carotid arteries by magnetic resonance imaging (MRI) techniques in cancer survivors; at different data intervals: before and after administration of treatment (medical and life style modification) and then correlate contrast agent dynamics with serum markers of inflammation and other tests of cardiac or vascular dysfunction, where available.

The proposed study involves 100 asymptomatic patients who received prior chest or head and neck radiation therapy (HNXRT) as part of cancer treatment. MRI data (direct assessment of atherosclerosis) would be correlated with indirect measures of atherosclerosis (blood surrogate markers \& metabolomics).

The investigators intend to conduct an initial baseline MRI, blood tests (to correlate with surrogate markers of inflammation) and other tests whenever available of cardiac or vascular dysfunction. This cohort will be followed up with medication and/or life style modification regimen for a period of initially18 months and subsequently at 36 months. A repeat of all baseline studies (MRI and blood tests) would be performed as part of the 18 and 36-month follow-up. The plaque characteristics found at MRI will be correlated with results of blood tests (baseline, 18 and 36 months) and changes in one or both will be the expected end point of the study.

Arms: arm 1: Lifestyle modification is tailored to each participant and includes a recommended exercise regimen, a healthy diet and decreasing alcohol intake. arm 2: Participants will receive statin medication along with instruction about regular exercise.
Interventions: intervention 1: Statin therapy intervention 2: Lifestyle modification
Intervention descriptions: intervention 1: Statin therapy includes rosuvastatin 20 mg administered orally, once a day, for the duration of the trial, which is 3 years. Participants may also receive a different type of statin as prescribed by their cardiologist based on clinical judgement. intervention 2: Lifestyle modification includes a recommended exercise regimen, a healthy diet and decreasing alcohol intake for 3 years.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
Accelerated Atherosclerosis in High Risk Population Groups: An Assessment by 
Magnetic Resonance Imaging 
 
Protocol version date: May 01, 2015 
 
NCT02114697 
 
 
 
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Full Title:  
Accelerated Atherosclerosis in High Risk Population Groups: An Assessment by Magnetic 
Resonance Imaging   
Short Title:  
Accelerated Atherosclerosis Assessment by MRI 
Protocol Version History: 
Original Protocol:  Version 1, dated 02/14/2013  
Protocol Amendment 1: Version 2, dated 04/07/2014 
Protocol Amendment 2: Version 3, dated 05/01/2015 
Précis /Abstract:  
The objective of this project is to accurately determine the constituents and characteristics of 
atherosclerotic plaques in carotid arteries by magnetic resonance imaging (MRI) techniques in 
cancer survivors; at different data intervals: before and after administration of treatment 
(medical and life style modification) and then correlate contrast agent dynamics with serum 
markers of inflammation and other tests of cardiac or vascular dysfunction where available. 
The proposed study involves 100 asymptomatic patients who received prior chest or head and 
neck radiation therapy (HNXRT). MRI data (direct assessment of atherosclerosis) would be 
correlated with indirect measures of atherosclerosis (blood surrogate markers, metabolomics, 
Echocardiographic assessment and CT coronary calcium score). 
Atherosclerosis is a chronic inflammatory process in the walls of arteries leading to plaque 
formation. Broadly, this process leads to stenosis of the arterial lumen by formation of 
atheromatous core (smooth muscle thickening, lipid accumulation such as cholesterol, lipid 
laden macrophages, calcium etc.) between the intimal layer and media layer of the arterial wall. 
Over the course of time, necrosis in these fat cells occurs, which leads to extracellular 
accumulation of lipids. At this stage, plaque is separated from the lumen of the vessel wall by a 
thin fibrous cap (FC) tissue and endothelial layer. Thin fibrous cap is a weak structure and is 
vulnerable to rupture resulting in either thrombus formation or a thromboembolic event. 
Thrombus formation can lead to complete occlusion of an arterial lumen in spite of having mild 
or moderate stenosis. Besides ruptured plaque constituents might embolize (break away) and 
occlude a smaller downstream vessel leading to tissue damage. Research studies have 
demonstrated that necrotic lipid core with a thin fibrous cap presents a significant increased risk 
for plaque rupture resulting in a thromboembolism (1-6). Several scientific studies and 
publications have demonstrated that, of all etiologies of non-cancer mortality, cardiovascular 
disease (CVD) remains the most significant cause of morbidity and mortality in cancer survivors 
(7-11). 
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We hypothesize that non-invasive MRI techniques have the potential to accurately characterize 
the plaque constituents thereby indicating vulnerability of plaque. We intend to utilize 3 point 
Dixon (3 PD) and ultra short time to echo (UTE) MRI techniques to identify and measure plaque 
components such as hemorrhage, necrotic core and fibrous cap in carotid arteries. We intend to 
conduct an initial baseline MRI, blood tests (to correlate with surrogate markers of inflammation) 
and other tests whenever available of cardiac or vascular dysfunction (echocardiography and 
computerized tomography  studies). This cohort will be followed up with medication and/or life 
style modification regimen for a period of initially18 months and subsequently at 36 months. A 
repeat of all baseline studies (MRI and blood tests) would be performed as part of the 18 and 
36-month follow-up. 
We believe these studies would help in identifying the vulnerable plaque features in HNXRT 
patients and would provide us with a novel opportunity to identify and treat the disease early 
and hence in long run would reduce health related complications and health care costs. 
Introduction: 
Radiation therapy (XRT) is critical for the treatment of many benign and malignant neoplasms. It 
is well established that cancer survivors who have undergone XRT exhibit a long-term survival 
rate that significantly lags behind age and gender-matched population controls (7-11). Several 
scientific studies and publications have demonstrated that, of all etiologies of non-cancer 
mortality, cardiovascular disease (CVD) remains the most significant cause of morbidity and 
mortality in cancer survivors (7-11). Until recently radiation vasculopathy has attracted little 
research attention, because patients would often succumb to their malignancy before the 
vascular conditions manifested clinically (8). This is no longer the rule as more patients are now 
“outliving” their malignancies and are presenting with the long-term sequelae of cancer 
treatments (9). Sequelae and manifestations of accelerated atherosclerosis have been identified 
in the vasculature of almost every organ system (12-15). Atherosclerotic plaques that are 
susceptible to rupture, termed “vulnerable” or “unstable” consist of a large necrotic core made 
substantially of lipids and cell debris and a thin, collagen-poor fibrous cap (3, 16-18). Another 
characteristic of unstable plaques is that they contain numerous inflammatory cells. It has been 
documented that inflamed plaque and those with a large lipid core and thin fibrous cap are more 
likely to progress and cause clinical events than those without these features (19-21). 
Inflammation plays a major role in the onset, progression and destabilization of arterial plaque 
(22-27). Fig 1. Shows a brief overview of pathobiology and progression of arterial 
atherosclerosis.  
Fig 1: Overview of pathobiology and progression of arterial atherosclerosis  
3 
 


 
Therefore imaging the vasculature for both its inflammatory state and presence of type of 
disease is very important (28-30). The potential of magnetic resonance imaging (MRI) to 
characterize arterial plaques has been extensively studied (1, 31-33). MRI due to its ability of 
tissue characterization, superior resolution, lack of radiation, non invasiveness is an ideal 
modality for in vivo study of arterial plaques.  
There are no studies performed to date that have evaluated MRI arterial plaque characteristics 
in HNXRT and correlated with serum markers of inflammation, metabolomics, 
echocardiographic cardiac dysfunction assessment and computerized tomography (CT) 
coronary calcium scores.  Furthermore, no studies have been performed to look into 
associations between plaque contrast kinetics and morphology using anatomical MRI before 
and after initiation of medical and-/-or life style modification therapy. 
Aims 
The purpose of this study is to assess carotid artery MRI plaque characteristics in 100 
asymptomatic cancer survivors with history of chest, head and neck radiotherapy (HNXRT) and 
with subclinical atherosclerosis. Another objective is to analyze plaque changes in the same 
group after initiation of medical treatment for 18 and 36 months.  
The following specific aims (A), research questions (RQ) and hypotheses (H) will be addressed. 
A 1: To characterize the plaque constituents including fibrous cap (FC), lipid core and 
hemorrhage within the carotid plaque by MRI  
RQ 1a: What are the predominant plaque constituents?  
RQ 1b: Is there a predominance of complex and vulnerable plaque features in the neck arterial 
vasculature of cancer survivors?  
H 1: We hypothesize that there is a predominance of vulnerable plaque in carotid arterial 
vasculature of HNXRT patients due to the phenomenon of radiation vasculopathy. 
 
A 2: Determine the correlation between plaque inflammation (direct measure by MRI) with 
serum markers of inflammation through blood tests (hsCRP, LpPLA2, IL-6) and metabolomics 
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and other tests of cardiac or vascular dysfunction (echocardiography and computerized 
tomography  coronary calcium score studies).  
RQ 2: Is there any correlation between the direct and surrogate markers of inflammation?  
H 2: We hypothesize that there is a predictable correlation between the direct and surrogate 
measures of inflammation. 
 
A 3: To assess the longitudinal change in the artery plaque characteristics (inflammation and 
morphology) with treatment.  
RQ 3: Is there a predictable relationship between inflammation (pattern of enhancement-
/contrast kinetics) and vulnerable features within a plaque?  
H 3: We hypothesize that changes in plaque characteristics pre and post treatment would 
correlate with contrast agent dynamics over time.  
 
A 4: To determine the efficacy of comprehensive treatment (life style modification + statin) 
versus (life style modification + placebo).  
RQ 4: Is one regimen better than the other in cancer survivors with subclinical atherosclerosis? 
H 4: We hypothesize that comprehensive treatment (life style modification + statin) would have 
better inflammation control and favorable plaque modification than life style modification alone 
as measured by parameters in (A2 & A3). 
 
Research Strategy:  
Subjects:  
We intend to recruit 100 asymptomatic cancer survivors who had prior history of chest, head 
and neck radiotherapy (HNXRT). Our potential participants are patients of The Winship Cancer 
Institute who are being invited to return to The Survivorship Clinic as part of an ongoing funded 
trial at Emory Survivorship clinic (Novel testing for subclinical cardiovascular disease in 
lymphoma survivors, IRB 00057029). 
Inclusion criterion:  
Age 22 and above with prior head and neck or chest irradiation, six months or more post head 
and neck irradiation, documented subclinical cardiovascular disease (inflammatory markers in 
the serum, pre-existing plaques [detected by ultrasound, CT or MRI], asymptomatic major 
arterial stenosis, and not being considered for arterial surgery or endovascular treatment.  
Exclusion criterion:  
Recurrence of cancer (with or without treatment), planned surgical or endovascular intervention 
for revascularization of carotid arteries at the time of enrollment, renal failure, eGFR < 45 
(calculation based on serum creatinine levels, race, age and gender), medically unstable or 
hematologic, renal, or hepatic dysfunction, non-atherosclerotic arterial stenosis (dissection), 
presence of stents or external clips that can cause artifacts impairing accurate interpretation of 
MRI data, contraindications to MRI: cardiac pacemaker, metal implants, metal in eyes, pregnant 
5 
 


or nursing women, claustrophobia, allergy to MRI contrast; physical or mental impairment that 
would limit the patient’s ability to comply with the medical instructions or study procedures. 
Setting:  
The research will be coordinated through the Emory School of Medicine, Department of 
Radiology in partnership with The Winship Cancer Institute, Survivorship Clinic, Department of 
Cardiology and The Stroke Center. All the aspects of clinical and research assessment and 
follow-up will be provided within The Emory Healthcare System. 
Sample Size:  
We base the power analysis on aim 2 and 3 as mentioned above. Aim 2 is based on correlation 
between plaque inflammation (direct measure by MRI) with serum markers of inflammation and 
other tests of cardiac function. As the data is not available for us at this point, we will assume 
the “true” correlation is ≥ 0.7. We conducted the power analysis based on a correlation test 
using the fisher-Z transformation. We aim for a type-I error of 0.05 and also to achieve a power 
of 0.99. Based on these set conditions, on power analysis; if we have 64 measurements / 
subjects, then we will have a 99% power to detect the “true” correlation between measurements 
given a significant level (0.05).   
Our goal or aim 3 is to check the change in the artery plaque characteristics where the interest 
is in the estimation of the association between the parameters for carotid artery plaque 
characteristics (Ktrans, 
p, and vessel wall area) and of inflamm
 within the plaque. There 
will be 3 measurements (taken approximately 18 months apart of these parameters for each 
subject (initial/baseline measurement, second set at 18 months and third set at 36 months). We 
are interested in estimating the slopes between Ktrans for each of the subjects, and obtaining 
the weighted slope via the use of linear mixed effects model (34) where we model the within-
subject measurements using the variance-covariance structure of autoregressive with lag 1. 
Our goal 3 is to check the change in the artery plaque characteristics between 0 and 18 months, 
from 18 months to 36 months and also compare a difference between 0, 18 and 36 months. We 
used an ANOVA model to perform power analysis. We assume the effect size between the 
three measurements is 0.28. This implies that 92 subjects can achieve greater than 99% power 
to detect the true difference given the significant level is 0.05. To account for a potential attrition 
rate of ~10%, we will recruit 100 subjects.  
We chose the larger sample size as the final sample size. All the power calculation is calculated 
based on statistical software R with package “pwr”. 
Heath Evaluation of Patients:  
Antecedents and Screening: Demographic/clinical variables assessed include age, gender, 
marital status, education, ethnicity, occupation, type of lymphoma, chemotherapy agents used 
and dosage, and total RT dosage. During screening, the short BLESSED cognitive screening 
tool (BOMC) is used to exclude those with scores > 11 indicating cognitive impairment that 
would interfere with participation. The Shortened WHO Rose Angina Questionnaire (Rose) will 
6 
 


be utilized to screen for the presence of unrecognized coronary artery disease. This shortened 
screening questionnaire includes the three most predictive questions of angina, major coronary 
events, and coronary heart disease mortality. Assessment of patient heart disease knowledge 
will be made with the coronary heart disease (CHD) Knowledge Test, a 40 item multiple-choice 
instrument originally designed to assess self-care, risk factor management, and general 
knowledge of CHD. Scores are obtained by giving 1 point for each correct answer with higher 
scores indicating higher knowledge. Health evaluation and tests are conducted as part of ‘The 
Novel Testing for Subclinical Cardiovascular Disease in Lymphoma Survivors’ (ongoing funded 
trial at Emory Survivorship clinic, IRB 00057029). 
Variables and Measures:  
Blood will be drawn for testing in the MRI Research Laboratory at EMORY by a research nurse. 
The blood specimens will be drawn immediately before each MRI examination to measure 
routine laboratory testing of serum markers of inflammation (hsCRP, LpPLA2, IL-6) and 
metabolomics. Creatinine will be measured to calculate eGFR. In addition, the Framingham 
Risk Assessment Tool for General Cardiovascular Disease (FRAT) will be employed to 
determine the 10-year risk prediction for general cardiovascular events using the assessed 
values of age; history of diabetes, smoking, and hypertension; systolic blood pressure; and 
measured total and HDL cholesterol levels.  
Other tests:  
The following novel markers that will be assessed include measurement of serum levels of BNP, 
HS-CRP, and cTnI, Echocardiography for the assessment of systolic and diastolic function and 
structural defects, the presence of coronary artery calcium (CAC) and calcium score with the 
CT.  For all cancer survivors with HNXRT, the above tests (except hsCRP, LpPLA2, IL-6 and 
metabolomics) will be conducted as part of ‘The Novel testing for subclinical cardiovascular 
disease in lymphoma survivors’ (ongoing funded trial at Emory Survivorship clinic, IRB 
00057029). We intend to apply for a grant / fund to cover for tests not covered by ongoing 
funded trail at Emory Survivorship clinic, IRB 00057029. 
Examination Plan Overview:  
All participants will be given IRB approved informed consent. Those who decide to take part and 
give consent for the study would be enrolled in the research study. We would be taking snap 
shots with MRI at three data points and monitor treatment effects.  Overview of the research 
study is shown in Fig 2. A baseline MRI will be performed to assess arterial atherosclerotic 
constituents. Once the initial MRI has been performed, and in the case where subclinical 
disease is present i.e. elevated blood markers or arterial plaque on MRI. HNXRT cancer 
survivor patient with abnormal tests will be started on treatment, which includes life style 
modification and-/-or lipid lowering medication. Patients with positive tests would be divided 
randomly into two groups; one group will receive life style modification + statin therapy and the 
second group will receive life style modification alone. A repeat MRI and blood tests (2nd study) 
will be performed at 18 months after initiation of such treatment to assess changes in plaque 
morphology and enhancement characteristics. MRI findings of baseline and final would be 
7 
 


correlated with surrogate markers of inflammation, Echo and CT findings. A final set of MRI and 
blood tests will be performed at 36 months after initiation of such treatment to assess changes 
in plaque morphology and enhancement characteristics. MRI findings of baseline and final 
would be correlated with surrogate markers of inflammation, Echo and CT findings. 
Fig 2. Shows overview of the research study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment and Clinical Follow-Up: 
Patients enrolled in the “Accelerated Atherosclerosis in High Risk Population Groups: An Assessment by 
Magnetic Resonance Imaging” study will be evaluated in the cardiology clinic by Khusrow Niazi, MD, 
8 
 


FACC, FSCAI who is the Director of Peripheral Vascular Intervention at Emory University and 
treats patients with carotid artery disease. All these patients will be randomized based on the 
last digit of their medical record number. If the last digit will be an even number they will then be 
given a statin, which they will take and will also be instructed about regular exercise. Patients 
will be made aware of the side effects of statins and about the procedures to report these side 
effects. Patients with the last digit being an odd number will ONLY be advised about exercise. 
All patients will have regular visits and patients on a statin will be followed up and evaluated for 
any adverse effects of the medication and for and for compliance at 18 and 36 months by the 
study preventive cardiologist. The preventive cardiologist or any other physician involved with 
care of the patient may elect for more frequent follow up as well as modification or 
discontinuation of the study prescribed therapy if deemed necessary based on his or her best 
clinical judgment. 
These patients will get routine clinical follow-up in the oncology (The Winship Cancer Institute 
Clinics) and cardiology clinics (Emory Hospital) as part of the ongoing routine clinical care.  
Within five weeks of initial MRI evaluation, our recruited research that demonstrate increased 
blood markers and/or atherosclerosis on MRI would be subjected to life style modification ± 
medical (statin) therapy. Department of Cardiology would prescribe and monitor statin therapy: 
Rosuva (20 mg once a day) with target LDL goal < 70; non-HDL goal < 100 and Aspirin (81 mg 
once a day). The rational for using rosuva 20 mg is because this dosage has already been 
successfully used in JUPITER Trial (35). The follow-up by Cardiology department would 
comprise educating the patients on life style modification and also how to monitor and report 
any adverse drug affects which if expected would be further assessed with laboratory testing 
with LFT’s and CBC. Any patients who suffer clinical side effects of treatment as part of our 
research would be taken off our study. Patients will continue to follow-up in the survivorship 
clinic and with the preventative cardiologist as indicated. 
The randomized therapy may be modified or discontinued at the discretion of any physician 
involved with a study patients’ care or the study-designated preventative cardiologist based on 
clinical judgment. This may occur during scheduled follow up with the study-designated 
preventative cardiologist or at any point. 
Life style modification will be tailored, implemented and followed up by Emory HeartWiseSM 
Risk Reduction Program. This Program will use several analytical tools including questionnaire 
(BOMC, Rose, FRAT, CHD Knowledge Test). These analytical tools, laboratory as well as 
imaging tests will help EmoryHeartWise Risk reduction Program devise the best life style 
modification and exercise strategy for our patients. 
Emory HeartWiseSM Risk Reduction 
Joint Proposal WCI/Preventive Cardiology- Emory HeartWiseSM Risk Reduction: 
Lifestyle Modifications in our high-risk patients with Subclinical Atherosclerosis 
12 week/3 months; 3 x / week, total 36 visits 
Recommend 6 Minute Walk Test (MWT) on Telemetry for each Patient: functional screen  
9 
 


 
Evaluation:     
1. A 6 Minute walk test on telemetry – screening tool for function and cardiovascular/    
    hemodynamic response. 
2. PHQ-9 (Patient Health Questionnaire) depression questionnaire 
3. Risk stratification – ACSM (American College of Sports Medicine) guidelines 
 
Exercise components: 
1. Create exercise prescription based on ACSM guidelines and results of 6 MWT. 
2. Orientation: safety principles of exercise, waist hip circumference; BMI (Body Mass Index);   
    risk factor identification. 
3. Brief meeting with Registered Dietitian (RD) for review of food intake/diary. 
4. 1x/month 10 -15 minute meeting with RD for review of food intake and plan.  
5. Minimum of 3x/week exercise program – based on FITT (frequency, intensity, time, and type)  
    principles. 
6. Individualized exercise prescription created and progressed by staff; tracked on flow sheets;  
    monitor blood pressure; if diabetes - Blood Glucose (BG) pre/post/during if necessary. 
The Healthy Exercise for Lymphoma Patients (HELP) trial was a randomized controlled trial 
looking at the benefits of 12 weeks supervised exercise program for cancer survivors compared 
to usual care (36). Improvements in health-related fitness and quality of life were maintained at 
the 6-month clinical follow up. The same model of secondary prevention through supervised, 
graded exercise as well as identifying and intervening with education and active participation in 
risk factor modification is being proposed to help high-risk patients identified with subclinical 
atherosclerosis.    
The premise of inclusion of exercise regimen in our study is that regular, moderate levels of 
exercise have been shown to be beneficial at lowering blood pressure, total cholesterol, low-
density lipoprotein, triglycerides, increasing high density lipoprotein, metabolic syndrome, insulin 
sensitivity, and all-cause mortality (37). Intensive lifestyle modification through education, 
support, and supervised exercise are the core components directed at risk factor reduction (38). 
Fig 3. (below) demonstrates risk factor modification for patients who completed a 12 weeks 
cardiac rehabilitation program compared to a larger cohort of cardiac rehabilitation patients in 
other parts of the country (39). The same model of prevention through supervised, graded 
exercise as well as identifying and intervening with education and active participation in risk 
factor modification is being proposed to help high-risk patients with subclinical atherosclerosis.   
10 
 


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Three-Dimensional time-of-flight MR angiography:  
An axial three-dimensional spoiled gradient echo (3D-SPGR) MR angiogram will be used for 
scout images and to locate regions of stenosis. The acquisition will consist 40 to 60 contiguous 
slices. A field-of-view (FOV) of 12 cm to 16 cm at the region of interest will be used. Additional 
scan parameters are: Slice thickness = 2.0 mm, matrix = 256 x 256, receiver bandwidth = 32 
KHz, flip angle = 45o, TR = 32 ms, TE = 4.7 msec, number of signal averages = 2. Maximum-
intensity pixel projection (MIP) images will be created from all the image sections obtained 
during the 3D-SPGR acquisition.   
High Resolution Anatomical Images:  
T1 weighted (T1W), T2 weighted (T2-W) and proton density weighted imaging (PDWI) using a 
double inversion-recovery fast spin echo sequence and 3-point Dixon (3-PD) imaging will be 
performed. All black-blood scans will be cardiac gated. The following scanning parameters will 
be common to all three of the contrast-weighted scans:  Section thickness = 2.0 mm, matrix = 
512 x 384, receiver bandwidth = 62.5 KHz, ETL = 24, FOV: right-left - 12 cm to 16 cm; anterior-
posterior – 0.75 * right-left dimension, Number of signal averages = 2.  The specific weighting 
parameters are:  T1-W: TE = 10 ms, TR = 1 R-R interval; T2-W: TE = 45 ms, TR = 2 R-R 
intervals; PDW: TE = 10 ms, TR = 2 R-R intervals. 
DCE 2D SPGRl:  
Dynamic contrast-enhanced (DCE) two-dimensional T1-W SPGR pulse sequence will be used 
for dynamic contrast-enhanced imaging of the arterial plaque.  The following scan parameters 
will be used: Slice thickness = 2.0 mm, FOV: right-left - 12 cm to 16 cm; anterior-posterior – 
0.75 * right-left dimension, matrix = 256 x 160, receiver bandwidth = 32 KHz, flip angle = 60o, 
TR = 120 ms, TE = 2.9 msec. Twelve to fifteen double-oblique slices will be acquired during 
each scan. The orientation of the slices will be the same as those of the black-blood images. A 
baseline non-contrast scan will first be acquired. Then 0.1 mmol/kg of Gd-DTPA will be injected 
by a power injector at a rate of 2 mL/sec simultaneous to the contrast enhanced acquisition. A 
total of 20 similar image acquisitions will be performed with no time elapsing between scans 
after the injection.  
Baseline, Intermediate and Final MRI: 
Each subject will undergo similar scan protocol at baseline, intermediate and final MRI. 
Anatomical landmarks will be used to match images (baseline, intermediate and final) in the 
same patient from the three time points spread over an intervals of 18 months. These 
landmarks include arterial bifurcations, vertebrae, proximity of other vessels and patterns of fat 
and muscle. Since the slice volume would be planned centered at the area of interest for all the 
studies (initial and repeat); the exact Z-location of each slice would be known and reproducible 
for acquisition and comparative measurements. 
Specific Aims: 
12 
 


A # 1: Characterization of plaque constituent’s i.e. fibrous cap (FC), fat and hemorrhage within 
the carotid artery plaque by multiple MRI sequences: 3-point Dixon (3PD) and MCW sequences 
(3-D TOF, T1W, T2W & PDW)].  
Rationale: Using MRI we will determine the plaque characteristics, which may help understand 
the increase risk of stroke in this patient population. 
Data analysis: The plaque size and morphology (vessel wall area) will be determined as 
described in section below.   
Expected results: We anticipate that the plaque morphology will be accurately and more 
importantly reliably determined and followed up by a combination of MCW and 3PD sequences.  
Measurement of Changes in Carotid Plaque Size, Characteristics and Morphology Using 
Multiple-Contrast-Weighted High-Resolution MR Imaging:  
To minimize errors and to improve contrast to noise ratio, five contiguous images centered at 
the point of interest will be analyzed and the results will be averaged. The vessel wall area will 
be calculated by measuring the area of the lumen and the total artery area (vessel wall area = 
total artery area – lumen area).  The vessel wall area and total artery area will be determined by 
tracing contours along the boundaries. The areas will be calculated using a semi-automated 
analysis tool (MASS Analytical Software, Medis Medical Imaging Systems, Leiden, The 
Netherlands). In the selected images, the maximum, minimum and average wall thickness will 
also be measured.   
Identification of plaque constituents will be facilitated by multiple contrast-weighted MR images 
and also 3-point Dixon (selective water/fat) (17, 40). Table 1 & 2 shows the MR signal intensities 
that are associated with the various plaque components depending on the type of weighting that 
is used. The different signal intensities that result from the use of MCW (table 1) and 3-point 
Dixon technique (table 2) images improve the accuracy of identifying the plaque constituents.   
Table 1. Criteria for identifying intraplaque hemorrhage and lipids using 3-point Dixon technique. 
Plaque Feature 
Water 
Fat 
Calcification 
Hypo-intense 
Hypo-Intense 
Hemorrhage 
Hyper-Intense 
Hypo-intense 
Lipid 
Hypo-Intense 
Hyper-intense 
 
 
Table 2. Criteria for identifying intraplaque hemorrhage and lipids using MCW imaging. 
Plaque Feature 
TOF 
T1W-BB-FSE 
T2W-BB-FSE 
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Calcification 
Hypo-Intense 
       Hypo-Intense 
Hypo-Intense 
Hemorrhage 
Hyper-Intense 
Hyper-Intense  
to Iso-Intense 
Hypo-Intense  
to Iso-Intense 
Lipid 
Hypo-Intense 
Hyper-Intense 
to Iso-Intense 
Hypo-Intense  
to Iso-Intense 
 
If complex plaques are present in any of the study subjects, the area of lipid core regions, the 
thickness of fibrous caps and the size of calcifications will be measured.   
A # 3: To assess the longitudinal change in the carotid artery plaque characteristics 
(inflammation and morphology) as therapy progresses during the study period. Also to see if 
there is a predictable relationship between inflammation (pattern of enhancement) and 
vulnerable features within a plaque 
Rationale: High-resolution MRI methods have shown that changes in the size and morphology 
of arterial plaques occur over time following the initiation of therapy (17, 40, 41). DCE-MRI 
parameters in plaques have been shown to correlate with histopathological measurement of 
inflammatory cell content and neovasculature (42, 43). For e.g. carotid artery wall thickness has 
been measured by MRI and has been associated with serum markers of inflammation (44). High 
resolution anatomical MRI has demonstrated that changes in the size of carotid artery plaques 
occur over time in patients who were receiving therapy (41). It is our hypothesis that the 
characteristics of arterial plaques in this patient population will change favorably over the 
duration of this study (36 months) and these changes will be measurable by DCE and high 
spatial resolution MRI.   
Data analysis: The DCE-MRI dynamic enhancement parameters (Ktrans and 
p) will be 
determined as described in section below. The plaque size and morphology (vessel wall area) 
will be determined as described in SA # 1.   
Statistical analysis:  The three parameters mentioned above (Ktrans,  
p, vessel wall
continuous variables. Before performing the statistical modeling we will check first to see if the 
distributions of these variables are normal; otherwise, we will use log transformation prior to the 
modeling of these parameters. We will first compute the mean, median, and standard deviation 
at each time point for these parameters. We will plot these data by patient over the 3 time points 
to examine the longitudinal profiles. We will use the linear mixed effects model (random 
coefficient model with random intercept and slope) with these parameters serving as dependent 
variables. The independent variables will be the time indicator and other potential confounders 
that we may need to control (e.g. age, gender, race, and body mass index). The interest in this 
model is the coefficient associated with the time indicator, which allows us to obtain the adjusted 
population mean estimate of these parameters at each of these time points. Since we have the 
best linear unbiased prediction estimates of the random intercepts and slopes for each subject, 
14 
 


we will be able to examine individual subject profiles and assess the temporal trend for each 
subject. Thus this random coefficient linear mixed effects model will allow us to obtain the 
overall adjusted mean estimate (Ktrans, 
p, vessel wal
for each of the individual subjects, overall across all above mentioned time points, and at each 
of the time points.  
To assess the association between the vessel wall area, and Ktrans and 
p, we will also u
linear mixed effects models (random coefficient models) to obtain the estimates of fixed effects. 
We will carry out 2 analyses in these models, we will use vessel wall area as the dependent 
variable and Ktrans and 
p, one at a time, as
potential confounders if necessary. The slope estimate from these models is interpreted as a 
measure of adjusted association between the changes in plaque size and morphology, and 
DCE-MRI dynamic enhancement parameters. 
Assessment of Arterial Plaques by Measuring Contrast Agent Dynamics Using MR Images:  
The dynamics of the contrast enhancement will be quantified using a generalized kinetic model 
that was proposed by Tofts, et al (45) which is based on two compartments, the blood plasma 
and the extravascular extracellular space (EES).  Ktrans and 
p will be calculat
model, which assumes that the signal intensity of the contrast agent in the tissue compartment 
and the blood plasma compartment are linearly proportional to the total concentrations of the 
contrast agent in the tissue, Ct and the blood plasma, Cp (42, 43, 45). This approach assumes 
that there is an exponential decay in the concentration of the contrast agent in the plasma 
described by the equation, where Ai is the initial plasma concentration and m1 is the plasma 
signal decay rate.   
For e.g. in case of carotid arteries, the values for Ai and m1 will be determined by an ROI 
placed in the lumen of the jugular vein on each image in the time-course at each section 
location. Ct will be found by identifying regions of enhancement within the plaque. A sample of 
pixels large enough to cover the enhancing regions will be taken.  The average of the sample 
pixels for each image at a given location will be used as input values for the kinetic model.  The 
kinetic analysis will be performed using a workstation tool by the two co-investigators and 
repeated to assess for the inter-observer and intra-observer variability.  
Expected results:  
We anticipate that the ktrans and 
p parameters th
the size of the plaques (vessel wall area) will change in a favorable way over the time course of 
the study due to institution of treatment (medicines and life style modification). We anticipate 
that changes in the vessel wall (plaque and vessel wall remodeling) as measured by high-
resolution MRI will change in a way that is predicted by the change in the DCE-MRI 
inflammation parameters but that changes in the DCE-MRI inflammation parameters will 
precede those of the morphological changes. We expect this because previous studies have 
shown changes in inflammatory cell content occur with-in three months of the initiation of statin 
therapy, whereas changes in plaque morphology as measured by high-resolution anatomical 
15 
 


MRI occur at approximately twelve to eighteen months following the initiation of statin therapy 
(19, 41, 42). 
A # 2: To investigate the relation between direct measures of plaque inflammation (MRI) and 
indirect measures of inflammation (blood serum markers of inflammation, Echocardiographic 
and CT studies) as therapy progresses. 
Rationale: DCE-MRI studies have shown a correlation between the number of macrophages 
and amount of neovasculature and the patterns of dynamic contrast enhancement (42, 43). Our 
hypothesis is that over a longer period of time (36 months); there would be a correlation 
between these two (direct and indirect measures of inflammation). 
Data analysis: The DCE-MRI dynamic enhancement parameters (Ktrans and 
p) will be 
determined as described in section SA # 3 above. Samples will be drawn for serum markers of 
inflammation (hsCRP, LpPLA2, IL-6). Relationship if any between the inflammation within the 
plaque and serum markers will be observed. 
Expected results: We expect a predictable correlation between the inflammatory markers in the 
blood and inflammation present within the vessel wall/plaque seen on the initial and post 
treatment sampling; this expectation is based on prior literature (19, 22, 46, 47). 
We will carry out the modeling using SAS/STAT procedure MIXED.  
A # 4: To determine the efficacy of comprehensive treatment (life style modification + statin) 
versus life style modification alone. 
Rationale: The effects and efficacy of various combinations of treatment have not been studied 
in the context of radiation vasculopathy and accelerated atherosclerosis. 
Data analysis:  The techniques described in sections above (A1 to A3) would be used in 
combination to determine plaque-remodeling, inflammation within the plaque and serum 
markers of inflammation and compare efficacy of different treatment regimens. Each patient will 
get MRI examinations before and after treatment and therefore patients will serve as their own 
control. 
Expected results: We anticipate that the efficacy of comprehensive treatment would outperform 
the results obtained with life style modification alone. 
We will carry out the modeling using SAS/STAT procedure MIXED.  
Project Timeline:  
The equipment and resources are currently in place to begin patient examinations immediately 
upon receiving funding. We anticipate the recruitment of all 100 patients from the existing pool 
of patients at the Emory Clinics (Survivorship Clinic) within the 12 months of funding. The time 
from baseline MRI and initial follow-up MRI study will be 18 months which would give us time to 
observe therapy related changes in the plaque morphology and inflammation, observe 
correlation between plaque inflammation and inflammatory markers in the serum and also with 
16 
 


cardiac functional status as assessed by echocardiography and CT. The 2nd set of follow up 
MRI and blood tests at 36 months would serve as the end point for final analyses of the long 
term effects of the instituted treatment regimen. Thus, if the co-investigators responsible for 
statistical models receive the complete data 3 months after the end of the studies, it is expected 
to take another 3 months to complete the entire work. So realistically the project should be 
completed in 39 months. 
Adverse Event Reporting:  
We do not expect any serious physical adverse events from this research study. Participating in 
this study involves very few/minimal risks. Study staff will work with patients to minimize any 
stress or discomfort with the study procedures. The study involves a blood draw, which may 
cause slight bruising or pain at the site where the blood is drawn. In addition, bleeding, 
dizziness, fainting or feeling lightheaded, nausea, hematoma or infection may occur because of 
drawing your blood. The blood will be drawn from expert/trained staff so this will be less likely to 
happen.   
The Computed Tomography (CT) for coronary artery calcification (CAC) and Echocardiogram 
are both non-invasive procedures. CT exams are generally painless, fast and easy. The risks 
associated with CAC screening are small (48). The echocardiogram is very safe, painless and 
uses ultrasound waves, for which there are no known risks.  
We do not expect any serious physical adverse events from MRI examinations. Due to recent 
concerns related to the use of gadolinium-based contrast agents in patients with renal 
dysfunction and risk of nephrogenic systemic fibrosis (NSF), serum creatinine levels will be 
measured from blood drawn before each MRI examination (49). Patients with normal renal 
function values will be administered contrast and this approach virtually eliminates any 
possibility of NSF. 
Statin treatment might cause some side effects in few individuals which would be closely 
monitored by symptoms and followed by blood tests; if any side effects occur, the medication 
would be immediately stopped; patients would be taken off the study protocol and they would 
continue their routine follow up in The Survivorship and Cardiology clinics.   
Subjects will be provided with telephone numbers of the PI, co-investigators and the Emory 
University IRB. Any adverse events will be appropriately documented and reported through the 
Department of Radiology Safety Committee.  
17 
 


Contact Information 
Faisal Khosa, MD, TI, FFRRCSI, FRCPC, DABR 
American Roentgen Ray Society Scholar (2013-2015) 
Assistant Professor in Radiology and Imaging Sciences 
Department of Radiology and Imaging Sciences 
EUH Midtown, Emergency Radiology Division 
550 Peachtree St. NE. 
Atlanta GA, 30308 
Cell: 6179906181 
Phone: 404-686-5612   Fax:  404-686-5709 
Faisal.khosa@emoryhealthcare.org 
Khusrow Niazi, MD, FACC, FSCAI 
Director, Peripheral Vascular Intervention 
Emory University 
Atlanta, GA 
Cell: 404-569-8757 
Office: 404-778-6099 
Fax: 404-778-0560 
kniazi@emory.edu 
 
Data and Safety Monitoring Plan (DSMP): There might be a minimal risk due to breach in 
confidentiality of the patient information, which we plan to overcome by keeping all personal 
facts and data private and confidential, and will use it strictly for research purposes. In order to 
maintain confidentiality, we will use a participant number rather than patient names on study 
records where we can. All patient records will be identified by an individual code number and 
the record of subject identifiers and corresponding reference codes will be stored in a locked 
cabinet in the protected and monitored research office building. All the results will be presented 
and published as group data. Agencies such as the Food and Drug Administration and the 
Emory University Human Investigations Committee have the right to review these records. We 
will keep the records private to the extent allowed by law. We will do this even if outside review 
occurs. 
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