Electrical Activation Mapping Guided Tailor Made Approach for Cardiac Resynchronization Therapy
Phase: NA
Conditions: Heart Failure
Sponsor: Chinese University of Hong Kong

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
 
 
Electrical Activation Mapping Guided 
Tailor Made Approach for Cardiac 
Resynchronization Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.0 BACKGROUND 
Electrical Activation Mapping Guided
Tailor Made Approach for Cardiac
Resynchronization Therapy

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
 
Cardiac resynchronization therapy (CRT) is an established therapy for 
symptomatic heart failure patients despite optimal medical therapy with 
prolongation of QRS duration on surface electrocardiogram. Several pivotal 
studies have demonstrated a significant benefit in terms of mortality and 
morbidity in patients described above.1-7 However, there are still 30 to 40% of 
studied patients being nonresponder to CRT, despite its proven benefit. The 
responder rate is particular poor in patients with non-LBBB pattern of conduction 
disturbance8-15 with one recent study showing non-LBBB patients has a responder 
rate of only 38%.15  The plausible reasons of lack of effect of CRT in these patients 
include relative less baseline electrical dyssynchrony, a homogenous type of 
conduction delay without a discrete line of block, lack of electrical ventricular 
uncoupling and inability to improve or even in some case worsening of electrical 
dyssynchrony with CRT.15-21The electrical activation response to conventional 
CRT varies between individual patients may not be predicted by baseline 
conduction disturbance.10,17,19,22 The prevalence of non-LBBB type of conduction 
disturbance is reported to be as high as 44% in heart failure patients with increase 
in QRS duration.23 Hence, a large proportion of heart failure patients with 
prolonged QRS duration will not benefit from CRT.   
 
The quest to improve CRT responder rate has been subject of intense research 
interest. Apart from screening for subgroup of heart failure patients with better 
responder rate to conventional CRT, another possibility is to improve the efficacy 
of current CRT delivery system. There are two major approaches that have been 
studied to improve CRT delivery namely selecting the optimal site for LV pacing 
and alternate method of CRT delivery other than pacing at single epicardial LV site. 
Study have demonstrated that targeting the LV lead to the site of latest mechanical 
contraction as determined by strain echocardiogram improved the responder 
rate.24 Other studies looks into local electrogram guided placement of LV lead to 
the latest electrically activated segment inside coronary sinus branch.25Regarding 
alternate way of CRT delivery, there are interests in using direct His-bundle pacing 
to overcome the longitudinal conduction delay in the His-Purkinjie system. It has 
been shown that significant narrowing of QRS duration and favorable clinical 
outcome when compare to conventional CRT can be achieved with direct His-
bundle pacing.26 Intuitively, direct-His bundle pacing may provide benefit over 
pre-excitation of the left ventricle by conventional CRT in patients with right 
bundle branch block (RBBB) pattern of conduction disturbance. Other potential 
method to improve CRT outcome is the delivery of multipoint pacing (two LV sites 
together with one RV site and two RV sites together with one LV site) by recruiting 
more myocardium to contract simultaneously.27-29 Pacing the LV endocardium as 
compared to epicardium via a coronary access has been shown to improve acute 
hemodynamic response but however there is no long-term clinical result of 
endocardial LV pacing comparing to epicardial LV pacing.30   
 
The ability to deliver CRT using different configuration provides opportunity to 
tailor made resynchronization therapy to heterogenous group of patient in terms 
of activation delay. This is in contrary to the current concept of a single 
configuration of CRT deliver suit all patients with widening of QRS duration 
disregard of pattern of activation delay. Hence the aim of our study is to 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
investigate whether there is an optimal configuration of CRT delivery that varies 
between patients with different pattern of activation delay.  
 
Previous study on noninvasive activation pattern has shown that responders 
showed higher degree of baseline dyssynchrony and greater improvement of 
dyssynchrony by CRT when compared to nonresponders.17-19 The optimal 
configuration of CRT delivery is defined by that result in the greatest improvement 
of electrical dyssynchrony. The acute change in electrical dyssynchrony indices 
will be compare between the optimal configuration and the conventional 
configuration, namely biventricular pacing with single LV lead in posterior or 
lateral branch of coronary sinus. A significant different between the two 
configurations would suggest that there indeed is an optimal configuration of CRT 
delivery and a tailor made strategy is feasible. To prove this concept of tailor made 
strategy, devices will be implanted to deliver CRT using the optimal configuration 
determined by noninvasive electrical activation mapping in non-LBBB patients. 
The medium term improvement of surrogate marker of LV systolic volume will be 
compared to that of a predefined level of 40%.  
 
Our group has been using echocardiogram to study mechanical dyssynchrony in 
patients with heart failure and pacing induced LV dysfunction in predicting 
response to CRT.31-47 However, in subsequent multi-center trial studying 12 
different echocardiographic parameters of mechanical dyssynchrony in 
predicting CRT response, no single echocardiographic measure of dyssynchrony 
was shown to improve patient selection for CRT.48 The results of the study further 
strengthen the concept that the response to conventional CRT therapy cannot be 
predicted by baseline dyssynchrony pattern. It is rather the degree of 
improvement from baseline that will predict response to CRT therapy. The degree 
of dyssynchrony improvement on the other hand is determined by the interaction 
of baseline electrical substrate and the activation change brings about by CRT. The 
electrical substrate is fixed but different configuration of CRT delivery, including 
different location of LV lead, can produce different changes in activation. In order 
to study the interaction of electrical substrate and change in activation brings 
about by CRT, a tool that allows global electrical mapping of both the LV and RV is 
considered to be important not only to elucidate important information like 
location of conduction block but also to study the interaction of the left and right 
ventricle.17-19,22  
 
 
2.0 STUDY OBJECTIVES 
 
The purpose is to prospectively study the feasibility to optimize configuration of 
CRT delivery for acute correction of electrical dyssynchrony using a noninvasive 
mapping of global electrical activation. 
 
 
Study Hypothesis 
 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Tailor-made configuration of CRT delivery is feasible and able to improve 
responder rate compare to single method of CRT delivery in candidates with 
known poor response to CRT. 
 
 
Primary outcome measure 
 
Responder rate of greater than 10% of LV end systolic volume reduction in 
patients undergoing tailor-made approach of CRT delivery at 6 months. The 
responder rate is to compare with pre-defined level of 40% for single method of 
CRT delivery namely biventricular pacing with LV lead in coronary sinus.  
 
 
Secondary outcome measures 
 
1. The acute electrical dyssynchrony indices of different methods of CRT 
delivery.  
2. The hemodynamic responses of different methods of CRT delivery. 
3. Procedure duration and implantation success rate of the optimal CRT 
delivery method as determined by the best improvement in electrical 
dyssynchrony indices. 
4. Cine images (PA, LAO 300, RAO 300) and Chest X ray (PA view) 
5. Peri-operative and 6 months follow-up complications rate: 
a. Thromboembolic event  
b. Dislodgement and migration of pacing leads 
c. Phrenic nerve stimulation  
d. Others 
6. Echocardiogram parameters at baseline and 6 months: left ventricular 
systolic and diastolic volume, left ventricular ejection fraction, degree of 
mitral regurgitation, strain imaging. 
7. NYHA class, 6 minute hall walk test and quality of life using Minnesota’s 
questionnaire at baseline and 6 months. 
8. Electrical parameters including threshold, sensitivity and lead impedance 
of pacing leads at implant and 6 months follow-up. 
 
 
3.0 PATIENT SELECTION CRITERIA 
 
Inclusion criteria: 
 
Adult (aged 18 or above) of both sexes 
Ischemic or non-ischemic cause of heart failure 
QRS duration > 120 ms, non -LBBB type of conduction disturbance  
NYHA class III or above 
Sinus rhythm 
Informed consent by the patient 
Already received stable dose of guideline directed medical therapy for at least 3 
months 
 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
Exclusion criteria 
 
LBBB* patients  
Pregnant women 
Participation in another study 
Patient with contraindication to left ventricle catheterization by a retrograde 
aortic approach (eg mechanical aortic valve, severe aortic stenosis and aortic 
dissection) 
 
*The definitions of LBBB (QRS duration ≥130 ms; QS or rS in lead V1; broad R 
waves in leads I, aVL, V5, or V6; and absent q waves in leads I, V5, and V6).  
 
 
4.0 STUDY DESIGN 
 
This is a prospective, single-center, non-randomized study, aiming to demonstrate 
the feasibility of tailor-made CRT delivery to optimize electrical dyssynchrony 
correction using noninvasive study of electrical activation in subgroup of patients 
with poor response to CRT. 
 
Study will be performed in accordance with Declaration of Helsinki. 
 
Recruitment Method 
 
Patients with relative narrow QRS complex and non-LBBB pattern of conduction 
disturbance who is referred for CRT therapy will be recruited for the study. The 
clinical care of the patients recruited will not be different to other patients 
receiving CRT. The study will be carried out in Prince of Wales Hospital, Hong 
Kong.  
 
 
5.0 STATISTICAL CONSIDERATION 
 
Hypothesis 
 
The null and alternative hypotheses are as follows: 
 
H0: The responder rate of tailor-made approach ≤ 40% 
HA: The responder rate of tailor-made approach > 40% 
 
Sample size was calculated employing binomial methods with the following 
assumptions were used: 
 
Expected responder rate for tailor-made approach =60% 
Historical control responder rate =40% 
Test significance level (a) = 0.05 (1-sided) 
Power= 80% 
 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
Based on the above assumptions, the sample size was calculated as 77. Accounting 
for the attrition of 20%, the total required sample size is 93 patients with device 
implanted. 
 
Statistical method for additional analysis 
 
All continuous data will be summarized with the number of non-missing data, 
mean ± standard deviation, median and range (minimum – maximum). T test will 
be used for the comparison between the groups. In case the assumption for t test 
is violated, then the equivalent nonparametric test, such as Wilcoxon rank sum 
test, Kolmogorov-smirnov test, will be used instead.The normality assumption 
will be tested by the normality test with the aid of QQ plot. 
 
All categorical data will be tabulated with number of occurrence and percentage. 
Chi-square test will be used for the comparison between the groups. In case the 
expected counts in each cell is less than 5, then Fisher’s exact test will be used 
instead. 
 
Procedures for reporting any deviation(s) from the original statistical plan 
 
Any deviations from the statistical analysis plan will be documented. 
 
The treatment of missing, unused or spurious data, including drop-outs 
andwithdrawals. 
 
No imputation techniques will be used. 
 
 
6.0 PROTOCOL DESCRIPTION 
 
Patient informed consent 
 
The investigator is responsible for obtaining informed consent from each 
prospective study patient prior to the performance of any study related 
procedures. After a patient has been provided with the information of the study 
and given time to think on whether to participating into the study, the patient will 
be asked to sign and date a consent form. One copy of the signed patient consent 
form must be handed out to the patient and one must be filed by the investigator 
in the investigator files. After the patient and the investigator have signed and 
dated the consent form, the study data collection process may start. 
 
Patients meeting all the inclusion criteria and not meeting any of the exclusion 
criteria are eligible for the study. Data will be collected at the following study visits: 
Enrollment 
Noninvasive electrical activation and acute hemodynamic study 
Implant  
Pre-discharge (PDH) (≤ 72 hours post implant) 
Month 3 follow-up visit: 90 ± 14 days post implant 
Month 6 follow-up visit: 180 ± 14 days post implant 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
Table 1. Data collection for each scheduled visit 
 
 
Enrollment Implant 
* 
PDH* 
Month 
3 
Month 
6 
Patient Informed 
Consent 
x 
 
 
 
 
Echocardiogram 
x 
 
x 
x 
x 
Medical History 
x 
 
 
 
 
Cardiovascular 
Medication 
x 
x 
x 
x 
x 
NYHA Class 
x 
 
 
x 
x 
6MHW 
x 
 
 
x 
x 
SF-36QoL 
x 
 
 
x 
x 
12-lead 
electrocardiogram 
x 
x 
 
x 
x 
Cine images 
 
x 
 
 
 
Device Interrogation 
 
x 
x 
x 
x 
Adverse Event 
x 
x 
x 
x 
x 
Protocol Deviation 
x 
x 
x 
x 
x 
 
 
Figure 1. Study Flow Chart 
 
 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
Noninvasive mapping of electrical activation 
 
Ventricular activation maps will be acquired simultaneously with hemodynamic 
measurements using noninvasive mapping system (ECVUE, Medtronic Inc, USA).  
A thoracic computed tomographic scan will be acquired with the electrodes 
attached to the patient. Local ventricular activation times will be defined as the 
onset of the QRS complex or the pacing spike to the maximal negative slope of each 
unipolar electrogram.  
 
The following electrical dyssynchrony indices will be derived 
 
i) 
Total activation time (TAT) is defined as the time difference between 
the earliest and latest site of activation on the entire ventricular 
epicardium (LV and RV); 
ii) 
RVTAT is defined as the time difference between the earliest and latest 
site of activation on the RV ventricular epicardium; 
iii) 
LVTAT is defined as the time difference between the earliest and latest 
site of activation on the LV ventricular epicardium; 
iv) 
Ventricular electrical uncoupling (VEU) is defined as mean LV 
activation time minus mean RV activation time (LVTAT-RVTAT) 
v) 
Intra-LV electrical dyssynchrony index (ED) is the standard deviation 
of activation times at 500 sites on the LV epicardium, including the 
epicardial aspect of the septum. 
 
 
Placement of electrophysiology catheters for CRT delivery 
 
Pacing leads will be placed in high right atrium, His-bundle region, right 
ventricular apex, high septal RV, coronary sinus posterior/lateral branch, 
coronary sinus anterior branch, lateral and septal region of endocardial LV in 
order to deliver CRT in 8 different configurations as stated below: 
 
1) Conventional biventricular pacing with RV lead in right ventricular apex and  
LV lead in lateral or posterior branch of coronary sinus 
 
2) Biventricular pacing with the LV lead in coronary sinus in closest possible 
proximity to the latest electrical activation region (18 region) if it is different to 
the site tested in (1) 
 
3) Direct His-bundle pacing 
 
i) 
His bundle pacing catheter distal tip as cathode and RV lead proximal 
pole as anode  
ii) 
His bundle pacing catheter distal tip as cathode and proximal pole of 
LV lead placed in lateral or posterior branch of coronary sinus as 
anode. 
iii) 
His bundle pacing catheter distal tip as cathode and His bundle pacing 
catheter proximal pole as anode.  
 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
In subjects in sinus rhythm 
 
i) 
together with RV bipolar pacing with RV lead in RV apex. 
 
In subjects in AF 
i) 
together with RV bipolar and LV bipolar pacing 
 
 
4) Multi-point pacing 
 
i) 
Triple site pacing with two RV leads in the RV apex and high RV 
septum and LV lead in posterior or lateral branch of coronary sinus. 
ii) 
Triple site pacing with RV lead in the RV apex and one LV lead in 
posterior or lateral branch of coronary sinus and the other LV lead in 
anterior branch of coronary sinus. 
iii) 
Triple site pacing with RV lead in RV apex and one quadripolar LV 
lead in posterior or lateral branch of coronary sinus and pacing at 2 
sties stimultaneously from the quadripolar lead. 
 
During delivery of CRT the output will be set at twice the capture threshold and 
pacing impulse will be deliver in VDD mode with an AV delay of 80msec and VV 
delay at 0msec for all leads in the ventricles.  
 
 
Acute hemodynamics studies 
 
Invasive LV hemodynamic measurements of LV dP/dt will be recorded using a 
micromanometer (Radi Medical Systems, St Jude Medical, USA) placed in the LV 
cavity.  
 
All measurements will be made with an average of 10 second recordings with no 
occurrence of premature atrial or ventricular beats during the recording and 1 
minute interval between changes in pacing settings.  
 
During sinus rhythm and the 7 configurations of CRT pacing as stated above both 
noninvasive electrical activation map and acute hemodynamic measurement will 
be recorded for analysis. 
 
 
Implantation of CRT device 
 
1) Conventional pacing configuration 
 
The CRT system will be implanted with standard technique for conventional 
pacing configuration. Only market released CRT devices and leads will be 
implanted. 
 
2) Epicardial LV pacing in the latest activation site  
 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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LV lead will be placed in the LV latest activation site or the site in closest proximity 
to the latest activation site and if necessary quadripolar or active fixation LV lead 
will be used to achieve stability. 
 
3) Direct His-bundle pacing 
 
i) In subjects in sinus rhythm 
For direct-His bundle pacing, standard techniques will be use to place an LV 
lead preferably in the posterolateral branch of the coronary sinus system, RV 
and right atrial lead. His pacing lead (SelectSecure, model 3830, Medtronic Inc, 
USA) supported using a dedicated delivery sheath (model C315, Medtronic Inc, 
USA) or a deflectable lead delivery sheath (model C304, Medtronic Inc ,USA) 
to the site showing His bundle signal on the mapping catheter. Multiple 
position to optimize QRS narrowing and threshold could be tested. The His 
pacing lead and the LV lead will be connected via a Y-adapter (model 5866-
38M, Medtronic Inc, USA). The HBP will be connected to the cathode and the 
LV tip to the anode of the Y-connector.  
 
ii) In subjects in AF 
The same as for subjects in sinus rhythm except the His pacing lead will be 
connected to the atrial port of the CRT device and LV lead into the LV port of 
the CRT device without the use of a Y adapter.  
 
4) Multiple point pacing 
 
For multiple point pacing, the septal RV and the bipolar LV leads will be connected 
to the LV port using a parallel Y-adapter (model 2872, Medtronic Inc, USA) for the 
2 RV leads group. Whilst the anterior bipolar and posterior/lateral LV lead will be 
connected using a parallel Y-adapter (model 2872, Medtronic Inc, USA) for the 2 
LV leads group. If simultaneous pacing from 2 sites o fthe quadripolar LV lead 
pacing is the optimal configuration, a quadripolar lead will be connected to the LV 
port. 
CRT programming 
Para meter 
Mandatory Device Setting 
Mode 
DDD or DDDR 
Base Rate 
≤ 60 min-1 
Max. Sensor Rate/Max. 
Tracking Rate 
140 min-1 
Mode Switch 
“On” if atrial tachyarrhythmia are 
suspected 
Paced AV Delay 
150 ms 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Sensed AV Delay 
120 ms 
V-V Delay 
0ms 
 
 
 
Adverse Events 
 
Definition  
 
Adverse Event (AE) is defined as any untoward medical occurrence in a 
patient who participates in a clinical investigation. This definition does not 
imply that there is a relationship between adverse event and the clinical 
investigation.  
 
Serious Adverse Event (SAE) is defined as an adverse event that  
a)  led to death 
b)  led to a serious deterioration in the health of the subject that  
i. resulted in a life-threatening illness or injury   
ii. resulted in a permanent impairment of a body structure or a body function 
  
iii. requiredin-patienthospitalizationorprolongationofexistinghospitalization 
  
iv. resulted in medical or surgical intervention to prevent permanent 
impairment to   
c) led to body structure or a body function to foetal distress, foetal death or a 
congenital abnormality or birth defect . 
 
 
List of Anticipated Adverse Events  
 
Possible adverse events (in alphabetical order) associated with the acute 
noninvasive activation mapping and hemodynamic study, include, but are not 
limited to the following:  
 
- Air embolism  
- Allergic reaction  
- Arterial or venous occlusion  
- Arterial, venous or cardiac perforation  
- Asystole  
- Bleeding  
- Cardiac tamponade  
- Death  
- Erosion  
- Exacerbation of heart failure  
- Infection   

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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Electrical Activation Guided CRT Study Protocol V2_ 20170709 
- Myocardial damage   
- Thromboembolism 
 
Possible adverse events (in alphabetical order) associated with the CRT 
device implantation, include, but are not limited to the following:  
 
Acceleration of arrhythmias (caused by device)  
Angina pectoris  
Air embolism  
Allergic reaction  
Asystole  
Bleeding  
Cardiac tamponade  
Chronic nerve damage  
Death  
Erosion  
Exacerbation of heart failure  
Excessive fibrotic tissue growth  
Extracardiac stimulation (phrenic nerve, diaphragm, chest wall)  
Extrusion  
Fluid accumulation  
Formation of hematomas or cysts  
Histotoxic reaction  
Infection  
Loss of capture  
Myocardial damage  
Oversensing / undersensing  
Palpitations due to documented arrhythmias 
Phrenic nerve stimulation 
Pneumothorax  
Thromboembolism 
Venous occlusion  
Venous or cardiac perforation  
 
 
Adverse Events Recording and Reporting   
 
Safety surveillance and reporting will be done for all patients enrolled in the 
study. This will be started from the time patient provides with the informed 
consent until the last study visit has been performed or the patient has died 
or the patient concludes his participation into the study.   
 
All Serious Adverse Event is to be documented and reported to the research 
ethics committee within 24 hours of notification.  
 
As soon as the final details are available for the AE, the information should be 
reported on the AE case report form:   

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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- Hospitalization details (if applicable)  
- Diagnostic test information (if applicable)  
- Treatment given (if applicable)  
- Final medical diagnosis and cause  
- Patient condition  
- Final AE status  
- Seriousness of AE based on final medical diagnosis and cause  
- Relationship of AE to clinical investigation based on final medical diagnosis 
and cause   
 
 
Study Termination  
 
All reasonable efforts should be made to retain the patient in the clinical 
investigation until completion of the clinical investigation.  
 
If a patient concludes their participation in the study, the future care and 
management will not be affected, whether it is voluntary or otherwise:  
- 
A patient completes the study (Month 6 follow-up).  
- 
A patient / family member may request to withdraw from the clinical 
investigation at any time with no effect to the patient’s present care.   
- 
A patient dies.  
- 
An investigator may withdraw a patient from the study at any time as 
according to the best interest to the patient.   
 
 
Risks associated with Participation in the Clinical Investigation  
 
The risks involved with this study are comparable to those associated with the 
implant of any CRT. 
 
The additional risks are related to the computerized tomography of the heart with 
possible complication of contrast injury to kidney and allergic reaction. Other 
additional risks are related to pre-implantation electrical activation study which 
involves putting in pacing catheters and pressure monitoring catheters in the 
body with possible risk of injury to the heart, blood vessel, bleeding, wound 
complications and infection. 
 
 
Risk Minimization Actions  
 
Additional risks may exist. Risks can be minimized through compliance with this 
CIP, performing procedures in the appropriate hospital environment, adherence 
to subject selection criteria, close monitoring of the subject's physiologic status 
during research procedures and/or follow-ups. 
 
 
Anticipated Benefits  

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
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The proposed tailor made method of CRT delivery may improve the outcome 
inpatient that will be recruited in the study with high incident of non responding 
to CRT by improving electrical dyssynchrony correction. 
 
 
 
 
REFERECES 
 
1. Bristow, M.R., Saxon, L.A., Boehmer, J. et al, Cardiac-resynchronization 
therapy with or without an implantable defibrillator in advanced chronic 
heart failure. N Engl J Med. 2004;350:2140–2150. 
 
2. Cleland, J.G., Daubert, J.C., Erdmann, E. et al, The effect of cardiac 
resynchronization on morbidity and mortality in heart failure. N Engl J Med. 
2005;352:1539–1549. 
 
3. Tang, A.S.L., Wells, G., Talajic, M. et al, Cardiac-resynchronization therapy 
for mild-to-moderate heart failure. N Engl J Med. 2010;363:2385–2395. 
 
4. Bradley, D.J., Bradley, E.A., Baughman, K.L. et al, Cardiac resynchronization 
and death from progressive heart failure: a meta-analysis of randomized 
controlled trials. JAMA. 2003;289:730–740. 
 
5. Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J, 
Sherfesee L, Wells GA, Tang AS. An individual patient meta-analysis of five 
randomized trials assessing the effects of cardiac resynchronization 
therapy on morbidity and mortality in patients with symptomatic heart 
failure. Eur Heart J 2013;34:3547–3556. 
 
6. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, 
Breithardt OA, et al. ESC guidelines on cardiac pacing and cardiac 
resynchronization therapy: the task force on cardiac pacing and 
resynchronization therapy of the European Society of Cardiology (ESC). 
Developed in collaboration with the European Heart Rhythm Association 
(EHRA).European Society of Cardiology (ESC); European Heart Rhythm 
Association (EHRA). Europace 2013;15(8):1070–118.  
 
7. Russo AM, Stainback RF, Bailey SR, Epstein AE, Heidenreich PA, Jessup M, 
et al. ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate 
use criteria for implantable cardioverter–defibrilla- tors and cardiac 
resynchronization therapy: a report of the American College of Cardiology 
Foundation appropriate use criteria task force, Heart Rhythm Society, 
American Heart Association, American Society of Echocardiography, Heart 
Failure Society of America, Society for Cardiovascular Angiography and 
Interventions, Society of Cardiovas- cular Computed Tomography, and 
Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 
2013;61(12):1318–68. 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
Page 15 
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8. Sipahi, I., Chou, J.C., Hyden, M., Rowland, D.Y., Simon, D.I., Fang, J.C. Effect of 
QRS 
morphology 
on 
clinical 
event 
reduction 
with 
cardiac 
resynchronization therapy: meta-analysis of randomized controlled trials. 
Am Heart J. 2012;163:260–267 
 
9. Peterson, P.N., Greiner, M.A., Qualls, L.G. et al, QRS duration, bundle-branch 
block morphology, and outcomes among older patients with heart failure 
receiving cardiac resynchronization therapy. JAMA. 2013;310:617–626. 
 
10. Eschalier R, Ploux S, Ritter P, Haïssaguerre M, Ellenbogen KA, Bordachar 
P.Nonspecific intraventricular conduction delay: Definitions, prognosis, 
and implications for cardiac resynchronization therapy. Heart Rhythm. 
2015 May;12(5):1071-9. 
 
11. Nery PB, Ha AC, Keren A, Birnie DH. Cardiac resynchronization therapy in 
patients with left ventricular systolic dysfunction and right bundle branch 
block: a systematic review. Heart Rhythm 2011;8 (7):1083–7. 
 
12. ByrneMJ,HelmRH,DayaS,OsmanNF,HalperinHR,BergerRD,etal. Diminished 
left ventricular dyssynchrony and impact of resynchronization in failing 
hearts with right versus left bundle branch block. J Am Coll Cardiol 
2007;50(15):1484–90.  
 
13. Zareba, W., Klein, H., Cygankiewicz, I. et al, CRT effectiveness by QRS 
duration and morphology in the MADIT-CRT patients. Heart Rhythm. 
2010;7:24–25. 
 
14. Gold MR, Thébault C, Linde C, Abraham WT, Gerritse B, Ghio S, St John 
Sutton M, Daubert JC. Effect of QRS duration and morphology on cardiac 
resynchronization therapy outcomes in mild heart failure: results from the 
Resynchronization Reverses Remodeling in Systolic Left Ventricular 
Dysfunction (REVERSE) study. Circulation. 2012 Aug 14;126(7):822-9. 
 
15. Hara H, Oyenuga OA, Tanaka H, Adelstein EC, Onishi T, McNamara DM, 
Schwartzman D, Saba S, Gorcsan J 3rd. The relationship of QRS morphology 
and mechanical dyssynchrony to long-term outcome following cardiac 
resynchronization therapy. Eur Heart J. 2012 Nov;33(21):2680-91. 
 
16. Haghjoo, M., Bagherzadeh, A., Farahani, M., Haghighi, Z.O., Sadr-Ameli, M.A. 
Significance of QRS morphology in determining the prevalence of 
mechanical dyssynchrony in heart failure patients eligible for cardiac 
resynchronization: particular focus on patients with right bundle branch 
block with and without coexistent left-sided conduction defects. Europace. 
2008;10:566–571. 
 
17. Ghosh S, Silva JN, Canham RM, Bowman TM, Zhang J, Rhee EK, Woodard PK, 
Rudy Y. Electrophysiologic substrate and intraventricular left ventricular 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
Page 16 
Electrical Activation Guided CRT Study Protocol V2_ 20170709 
dyssynchrony in nonischemic heart failure patients undergoing cardiac 
resynchronization therapy. Heart Rhythm. 2011 May;8(5):692-9. 
 
18. Ploux S, Eschalier R, Whinnett ZI, Lumens J, Derval N, Sacher F, Hocini M, 
Jaïs P, Dubois R, Ritter P, Haïssaguerre M, Wilkoff BL, Francis DP, Bordachar 
P. Electrical dyssynchrony induced by biventricular pacing: implications 
for patient selection and therapy improvement. Heart Rhythm. 2015 
Apr;12(4):782-91 
 
19. Ploux, S., Lumens, J., Whinnett, Z. et al, Noninvasive electrocardiographic 
mapping to improve patient selection for cardiac resynchronization 
therapy: beyond QRS duration and left bundle branch block morphology. J 
Am Coll Cardiol. 2013;61:2435–2443. 
 
20. Auricchio, A., Fantoni, C., Regoli, F., Carbucicchio, C., Goette, A., Geller, C., 
Kloss, M., Klein, H. Characterization of left ventricular activation in patients 
with 
heart 
failure 
and 
left 
bundle-branch 
block. 
Circulation. 
2004;109:1133–1139. 
 
21. Auricchio A, Lumens J, Prinzen FW. Does cardiac resynchronization 
therapy benefit patients with right bundle branch block: cardiac 
resynchronization therapy has a role in patients with right bundle branch 
block. Circ Arrhythm Electrophysiol. 2014 Jun;7(3):532-42. 
 
22. Varma N, Jia P, Rudy Y. Electrocardiographic imaging of patients with heart 
failure with left bundle branch block and response to cardiac 
resynchronization 
therapy. 
J 
Electrocardiol. 
2007 
Nov-Dec;40(6 
Suppl):S174-8. 
 
23. Lund LH, Jurga J, Edner M, Benson L, Dahlström U, Linde C et al Prevalence, 
correlates, and prognostic significance of QRS prolongation in heart failure 
with reduced and preserved ejection fraction. Eur Heart J 2013;34:529–
539 
 
24. Khan FZ, Virdee MS, Palmer CR, Pugh PJ, O'Halloran D, Elsik M, Read PA, 
Begley D, Fynn SP, Dutka DP. Targeted left ventricular lead placement to 
guide cardiac resynchronization therapy: the TARGET study: a randomized, 
controlled trial. J Am Coll Cardiol. 2012 Apr 24;59(17):1509-18. 
 
25. Gold MR, Birgersdotter-Green U, Singh JP, Ellenbogen KA, Yu Y, Meyer TE, 
Seth M, Tchou PJ. The relationship between ventricular electrical delay and 
left ventricular remodelling with cardiac resynchronization therapy. Eur 
Heart J. 2011 Oct;32(20):2516-24 
 
26. Lustgarten DL, Crespo EM, Arkhipova-Jenkins I, Lobel R, Winget J, Koehler 
J, Liberman E, Sheldon T. His-bundle pacing versus biventricular pacing in 
cardiac resynchronization therapy patients: A crossover design 
comparison.Heart Rhythm. 2015 Jul;12(7):1548-57. 
 

Electrical Activation Guided CRT Study                                                                                  Card/ M&T/ CUHK 
 
Page 17 
Electrical Activation Guided CRT Study Protocol V2_ 20170709 
 
27. Anselme F, Bordachar P, Pasquié JL, Klug D, Leclercq C, Milhem A, Alonso C, 
Deharo JC, Gras D, Probst V, Piot O, Savouré A. Safety, feasibility, and 
outcome results of cardiac resynchronization with triple-site ventricular 
stimulation compared to conventional cardiac resynchronization. Heart 
Rhythm. 2016 Jan;13(1):183-9 
 
28. Lenarczyk R, Kowalski O, Sredniawa B, Pruszkowska-Skrzep P, Mazurek M, 
Jędrzejczyk-Patej E, Woźniak A, Pluta S, Głowacki J, Kalarus Z. Implantation 
feasibility, procedure-related adverse events and lead performance during 
1-year 
follow-up 
in 
patients 
undergoing 
triple-site 
cardiac 
resynchronization therapy: a substudy of TRUST CRT randomized trial. J 
Cardiovasc Electrophysiol. 2012 Nov;23(11):1228-36. 
 
29. Bordachar P, Alonso C, Anselme F, Boveda S, Defaye P, Garrigue S, Gras D, 
Klug D, Piot O, Sadoul N, Leclercq C. Addition of a second LV pacing site in 
CRT nonresponders rationale and design of the multicenter randomized 
V(3) trial. J Card Fail. 2010 Sep;16(9):709-13. 
 
 
30. Morgan JM, Biffi M, Gellér L, Leclercq C, Ruffa F, Tung S, Defaye P, Yang Z, 
Gerritse B, van Ginneken M, Yee R, Jais P; ALSYNC Investigators. ALternate 
Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre 
study of left ventricular endocardial pacing for cardiac resynchronization 
therapy. Eur Heart J. 2016 Jan 18. pii: ehv723. 
 
31. Fang F, Zhang Q, Chan JY, Razali O, Azlan H, Chan HC, Sanderson JE, Xie JM, 
Yu CM. Early pacing-induced systolic dyssynchrony is a strong predictor of 
left ventricular adverse remodeling: Analysis from the Pacing to Avoid 
Cardiac Enlargement (PACE) trial. Int J Cardiol. 2012. 
 
 
32. Zhang Q, van Bommel RJ, Chan JYS, Delgado V, Liang Y, Schalij MJ, Bax JJ, 
Fang F, Yip GW, Yu CM. Diverse patterns of longitudinal and radial 
dyssynchrony in patients with advanced systolic heart failure. Heart 2011 
Apr;97(7):574-8. 
 
33. Fang F, Chan JYS, Yip GW, Xie JM, Zhang Q, Fung JW, Lam YY, Yu CM. 
Prevalence and determinants of left ventricular systolic dyssynchrony in 
patients with normal ejection fraction received right ventricular apical pacing: 
a real-time three-dimensional echocardiographic study. Eur J Echocardiogr. 
2010 Mar;11(2):109-18. 
 
34. Zhang Q, van Bommel RJ, Fung JW, Chan JYS, Bleeker GB, Ypenburg C, Yip 
G, Liang YJ, Schalij MJ, Bax JJ, Yu CM. Tissue Doppler velocity is superior 
to strain imaging in predicting long-term cardiovascular events after cardiac 
resynchronisation therapy. Heart. 2009 Jul;95(13):1085-90. 
 

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Page 18 
Electrical Activation Guided CRT Study Protocol V2_ 20170709 
35. Zhang Q, Fang F, Yip GW, Chan JYS, Shang Q, Fung JW, Chan AK, Liang YJ, 
Yu CM. Difference in prevalence and pattern of mechanical dyssynchrony in 
left bundle branch block occurring in right ventricular apical pacing versus 
systolic heart failure. Am Heart J. 2008 Nov;156(5):989-95.  
 
36. Fung JW, Lam YY, Zhang Q, Yip GW, Chan WW, Chan GC, Chan JYS, Yu CM. 
Effect of left ventricular lead concordance to the delayed contraction 
segment on echocardiographic and clinical outcomes after cardiac 
resynchronization 
therapy. 
J 
Cardiovasc 
Electrophysiol. 
2009 
May;20(5):530-5. 
 
37. Zhang Y, Yip GW, Chan AK, Wang M, Lam WW, Fung JW, Chan JYS, 
Sanderson JE, Yu CM. Left ventricular systolic dyssynchrony is a predictor of 
cardiac remodeling after myocardial infarction. Am Heart J. 2008 
Dec;156(6):1124-32.  
 
38. Zhang Q, Fung JW, Chan JYS, Yip G, Lam YY, Liang YJ, Yu CM. Difference 
in long-term clinical outcome after cardiac resynchronisation therapy between 
ischaemic and non-ischaemic aetiologies of heart failure. Heart. 2009 
Feb;95(2):113-8. 
 
39. Zhang Q, Fung JW, Yip GW, Chan JYS, Lee AP, Lam YY, Wu LW, Wu EB, 
Yu CM. Improvement of Left Ventricular Myocardial Short-axis, but not Long-
axis Function or Torsion after Cardiac Resynchronization Therapy-An 
Assessment by Two-Dimensional Speckle Tracking. Heart. 2008 Jan 15. 
 
40. Van de Veire NR, Yu CM, Ajmone-Marsan N, Bleeker GB, Ypenburg C, De 
Sutter J, Zhang Q, Fung JW, Chan JYS, Holman ER, van der Wall EE, Schalij 
MJ, Bax JJ. Triplane tissue Doppler imaging: a novel three-dimensional 
imaging modality that predicts reverse left ventricular remodelling after cardiac 
resynchronisation therapy. Heart. 2008 Mar;94(3):e9. 
 
41. Yu CM, Gorcsan J 3rd, Bleeker GB, Zhang Q, Schalij MJ, Suffoletto MS, Fung 
JW, Schwartzman D, Chan JYS, Tanabe M, Bax JJ. Usefulness of tissue 
Doppler velocity and strain dyssynchrony for predicting left ventricular reverse 
remodeling response after cardiac resynchronization therapy. Am J Cardiol. 
2007 Oct 15;100(8):1263-70.  
 
42. Fung JW, Chan JYS, Yip GW, Chan HC, Chan WW, Zhang Q, Yu CM. Effect 
of left ventricular endocardial activation pattern on echocardiographic and 
clinical response to cardiac resynchronization therapy. Heart. 2007 
Apr;93(4):432-7. 
 
43. Yu CM, Chan JYS, Zhang Q, Yip GW, Chan CK, Kum LC, Wu L, Lee AP, 
Lam YY, Fung JW. Benefits of cardiac resynchronization therapy for heart 
failure patients with narrow QRS complexes and coexisting systolic asynchrony 
by echocardiography. J Am Coll Cardiol. 2006 Dec 5;48(11):2251-7. 

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Page 19 
Electrical Activation Guided CRT Study Protocol V2_ 20170709 
 
44. Yu CM, Zhang Q, Yip GW, Chan JYS, Lee PW, Wu LW, Lam YY, Kum LC, 
Chan HC, Chan S, Fung JW. Are left ventricular diastolic function and diastolic 
asynchrony important determinants of response to cardiac resynchronization 
therapy? Am J Cardiol. 2006 Oct 15;98(8):1083-7.  
 
45. Fung JW, Zhang Q, Yip GW, Chan JYS, Chan HC, Yu CM. Effect of Cardiac 
Resynchronization Therapy in Patients with Moderate Left Ventricular Systolic 
Dysfunction and Wide QRS Complex: A Prospective Study. J Cardiovasc 
Electrophysiol. 2006 Sep 20. 
 
46. Yu CM, Zhang Q, Fung JW, Chan HC, Chan JYS, Yip GW, Kong SL, Lin H, 
Zhang Y, Sanderson JE. A novel tool to assess systolic asynchrony and identify 
responders of cardiac resynchronization therapy by tissue synchronization 
imaging. J Am Coll Cardiol. 2005 Mar 1;45(5):677-84. 
 
47. Zhang Q, Yu CM, Fung JW, Zhang Y, Chan JYS, Chan HC, Yip GW, 
Sanderson JE. Assessment of the effect of cardiac resynchronization therapy on 
intraventricular mechanical synchronicity by regional volumetric changes. Am 
J Cardiol. 2005 Jan 1;95(1):126-9. 
 
48. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, 
Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J 3rd, St John 
Sutton M, De Sutter J, Murillo J. Results of the Predictors of Response to CRT 
(PROSPECT) trial. Circulation. 2008 May 20;117(20):2608-16.