EARLY Identification of MYOcardial Impairment in Primary Biliary Cholangitis
Conditions: Primary Biliary Cholangitis, Cardiovascular Abnormalities
Sponsor: RenJi Hospital

 
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Morphological, Functional and Tissue Characterization of Silent Myocardial 
Involvement in Patients with Primary Biliary Cholangitis 
 
Early Identification of Myocardial Impairment in PBC (EARLY-MYO-
PBC) 
 
Protocol Number 
201709P-01 
Version (Date) 
2.0.0 (September 25, 2017) 
NCT No. 
NCT03545672 
 
 
 
 
 
 

 
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STUDY PROTOCOL SYNOPSIS 
Title 
Morphological, Functional and Tissue Characterization of Silent Myocardial 
Involvement in Patients with Primary Biliary Cholangitis 
Sponsor 
Investigator-Initiated Trial (IIT) 
Primary Objectives 
1. The incidence of cardiac involvement (LGE and T2-STIR positive) 
Late gadolinium enhancement (LGE) indicates myocardium viability in patients 
which can be recognized by regional high signal area in cardiac image. 
Meanwhile, T2-STIR positive indicate the myocardium edema. The outcome 
assessments base on the presence of myocardium late gadolinium enhancement 
and T2-stir positive in all participants 
2. Quantitative assessment in cardiac injury 
T1 mapping–derived extracellular volumes (ECV) were used to detect changes in 
the myocardium interstitial matrix. ECV was calculated according to the ECV 
formula including T1 mapping value. 
 
Study Design 
EARLY-MYO-PBC study was a prospective, three-center, multi-modality cardiac 
imaging study (Trial Registration: NCT03545672) designed to early identify silent 
myocardial impairment in PBC patients. We hypothesized that myocardial injuries 
could occur at the early-stage of PBC without presenting any reported cardiac clinical 
manifestation. 
Participants undergoing cardiovascular magnetic resonance (CMR) were enrolled. 
Demographic, serological, and cardiac imaging data were prospectively collected. All 
participants were free of cardiac discomfort or a prior history of heart disease and had 
normal electrocardiographic results. 
(1) CMR Protocol  
All images were acquired and then processed in a core lab 1. The LV volumetric 
and systolic assessment was performed with cine imaging by whole-heart 
coverage using a balanced, steady-state, free precession sequence in combination 
with parallel imaging and retrospective gating during a gentle, expiratory breath 
hold. T2 maps were acquired in several contiguous short axis slices, using a multi-
echo GraSE black-blood sequence. An electrocardiogram-triggered, STIR T2-
weighted multi-slice spin-echo sequence also was performed to determine edema 
and the T2 ratio. T2*-mapping is used for detecting iron deposition. Native and 
post-contrast myocardial T1 mapping were used to determine the ECV. A MOLLI 
R5.1 sequence was used for T1 mapping, and a “5-3-3” scheme (in seconds) was 
chosen. The scheme was performed on a 3 mid-diastolic LV short-axis slice 
(basal, mid-ventricle, and apex) before and 15 min after a bolus intravenous 
injection of 0.15 mmol/kg gadobutrol (Bayer Healthcare, Berlin, Germany). 
Segmented LGE images with at least three matching slices and native T1 images 
were also acquired. Visual assessment of LGE positive (LGE+) was recorded. The 
detailed methods and acquisition parameters can be found in publication 2: 
Arthritis 
& 
Rheumatology 
web 
site 
at 
http://onlinelibrary.wiley.com/doi/10.1002/art.40671. 

 
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(2) Image Analysis  
All contours were manually examined, adjusted if necessary and assessed. 
Myocardial deformation was voxel-tracked to acquire LV global circumferential 
strain (GCS), global longitudinal strain (GLS) and global radial strain (GRS). The 
LGE was examined for the presence of regional fibrosis. T1, ECV images were 
examined for extent of extracellular volume. Reported T1 values were derived 
with the operator blinded to the LGE images. Hematocrit was acquired on the 
same day in all subjects. 
 
Number of Subjects 
Enrollment:120[anticipate] 
PBC group: 60[anticipate] 
Healthy group:60[anticipate] 
Enrollment Criteria 
Inclusion criteria were:  
(1) All patients were PBC older than 18 without any cardiac symptoms.  
(2) The diagnosis of PBC was established when patients met at least two of three 
criteria:  
1) elevated alkaline phosphatase or γ-glutamine transpeptidase;  
2) positive anti-mitochondrial antibodies (AMA) or specific antinuclear antibody 
(ANA) (sp100, gp210) positive;  
3) histological findings of chronic and non-suppurative inflammation, which 
surrounds and destroys interlobular and septal bile ducts. 
 
Exclusion criteria were : 
(1) having cardiac discomfort or a prior history of heart disease, abnormal 
electrocardiographic results; stress echocardiography proved wall motion 
abnormality, coronary CT or angiography proved coronary artery stenosis >50% when 
Framingham risk score was over 10.  
(2) having cirrhosis or other known liver diseases such as viral hepatitis, alcohol-
induced liver injury, drug-induced liver injury, and inherited metabolic liver disease.  
(3) life expectancy of less than 6 months due to any condition.  
(4) for magnetic resonance safety reasons: standard metallic contraindications to 
CMR, or severe infection and renal failure (i.e., an estimated glomerular filtration rate 
< 30 ml/min/1.73 m2);  
(5) patient with any medical conditions that in the opinion of the investigators will 
not be appropriate to participate in the study. 
Safety Assessments 
Participants will be assessed for AEs at scanning while on the study.  Adverse events 
will be graded according to the CTCAE v4.03.  Type, incidence, severity, timing, 
seriousness, and relatedness of AEs and laboratory abnormalities will be reported. 
Endpoints 
1.LGE and T2-STIR 
2.ECV mapping 
Statistical Analysis 
Continuous variables are expressed as median (quartile) and categorical variables 
as numbers and percentages. Ventricular volume was acquired by both 
echocardiography and CMR; the latter was used for analysis. For continuous 
variables, the Mann-Whitney U test was used to compare between two groups. 

 
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Categorical variables were compared using the Pearson’s chi-squared test or Fisher’s 
exact test. Logistic regression was used to identify the predictors of elevated ECV. 
Variables with P value <0.1 in univariable analyse were included into multivariable 
anaylse. Comparisons of variables between controls and PBC groups were adjusted 
for age and body surface area with covariance analysis. The interobserver 
reproducibility of CMR measurements was assessed using the interclass correlation 
coefficient (ICC), as well as intraclass coefficient analysis. The methods of sample 
size calculation could be found in supplementary materials. Statistical analysis was 
performed primarily using the SPSS 20.0 (SPSS Inc, Chicago, IL) system. P<.05 was 
statistically significant. 
Sample Size Calculation. This study aimed to explore clinically silent myocardial 
impairments in PBC patients without presenting any reported cardiac clinical 
manifestation. According to previous CMR studies 3,4, ECV is one of the most 
valuable and sensitive indices reflecting myocardial change. In our pre-test including 
10 PBC and 10 controls, the mean of ECV was 30% and 24%, respectively. The 
standard deviation of ECV in the entire group was 0.3. A margin of 4% was expected 
to differentiate between PBC and controls group. On the basis of margin and sample 
ratio (nPBC/nControl=1) and a type I error (two-side) of 5% and a power of 0.8, the 
final sample size required at least 42 subjects in each group.