Non-Invasive Method for Evaluation of Cardiac Resynchronization Therapy
Conditions: Heart Failure, Pacemaker DDD, Cardiomyopathies, Heart Diseases, Cardiovascular Diseases
Sponsor: Oslo University Hospital

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New nonivasive method for  
evaluating acute response to cardiac 
ressynchronization therapy  
(NIME-CRT) 
 
 
NCT ID not yet assigned 
Unique Protocol ID: 218564 
 
18.05.2023 
 
 
 
 
 
 
 
 

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Project management 
The project will be led by senior scientist Dr. ing. Espen W. Remme. He is an expert in cardiac 
mechanics and has extensive experience with monitoring heart function with different devices, and 
with left bundle branch block (LBBB) and cardiac resynchronization therapy (CRT) studies. He has 
positions at the Intervention Center and Institute for Surgical Research at Oslo University Hospital, 
Rikshospitalet. The research groups there have long term experience in studies of LBBB and CRT 
studies including the patient studies CRID, IMPACT 1 and 2 among others. The research activity of the 
department including our group has been ranked with top grade “excellent” the last two evaluations 
by the international expert panel appointed by the Research Council of Norway. Head of the Section 
for Arrhythmias, OUS, Erik Kongsgård (Dr. med), and his team will be responsible for medical 
treatment of the patients at Rikshospitalet. Additional experienced clinical personnel and research 
fellows will be involved for organizing, collecting and analyzing the measured data. 
Project design 
Background 
Cardiac Resynchronization Therapy (CRT) has been one of the most important advancements in the 
past decade for patients with dyssynchronous heart failure (left bundle branch block – LBBB), where 
the lateral wall of the left ventricle (LV) is late activated. Hence, the early activated region contracts 
while the late activated region continues to stretch in beginning of systole, causing inefficient 
pressure rise and ejection of blood out of the LV. LBBB can be treated with a pacemaker that paces 
both sides of the LV in order to restore a normal contraction. CRT is shown to cost-effectively reduce 
mortality and morbidity, and improve quality of life [1]. 
CRT is effective in selected patients for improving heart function and life expectancy, however, around 
30-40% of patients who undergo this procedure do not benefit from it [2]. These patients do not 
respond to this therapy and their situation might even worsen, with complications occurring in up to 
10% of them. If such a high percentage of these procedures are ineffective, there are a substantial 
amount of resources that are wasted annually worldwide and could be saved by identifying patients 
that are non-responders as the device would not be placed, no CRT follow up sessions would 
be needed, and there would be no pacemaker lead-associated thrombosis and infections. 
Due to the large proportion of patients that do not respond to CRT, there is much research aiming to 
improve the selection criteria for whom should receive CRT, which according to current guidelines 
include heart failure status, ejection fraction, left bundle branch block, and ECG QRS duration [3]. This 
assessment is made well in advance of the CRT implantation. However, assessment of acute response 
during implantation may be a complimentary method. During this procedure the clinician tests 
several pacing lead locations using an external pacing device. The package with the expensive 
implantable pacemaker is not opened until the end of the procedure. Hence, if non-responders can 
still be identified during this procedure, unnecessary device implantation, costs, and complications 
can be avoided.  

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There is no consensus on which hemodynamic parameter should be used to identify acute response 
during CRT implantation [4]. Our group has been investigating methods to measure this response for 
several years with different sensors and parameters to assess cardiac function in both animal and 
clinical studies. We have found that the inefficient dyssynchronous contractions slow down the time 
it takes for the LV to raise pressure and open the aortic valve to start the ejection. Hence, the duration 
of this preejection period (PEP) from first electrical activation of the ventricles to aortic valve 
opening, is the measurement that works best as the shortening of this interval with successful CRT 
(all regions of the LV wall contract at the same time and the pressure raises quickly) is a more reliable 
marker than other indexes currently being used during procedures [5]. It is also less affected than 
other indexes by changes in preload (amount of filling of the ventricle) that is common with CRT [6].  
We have performed a preliminary assessment of this idea in animal data recorded as part of a 
previous study, where the arterial pressure curve was measured invasively in the ascending aorta in 
addition to LV pressure by micro-tip catheters. LBBB was then induced in the animals and 
biventricular (BiV) pacing (i.e. CRT) was performed from different locations of the LV. From this data 
we measured the PEP interval from the Q wave in the ECG signal up to the upstroke of aortic pressure 
(AoP), as shown in Figure 1.  
Figure 1. Data from a representative animal. In the left panel the ECG and pressure signals from a dyssynchronous heartbeat of 
an animal with induced LBBB. The right panel shows a heartbeat of the same animal with a synchronous contraction. The 
dashed vertical lines mark the PEP. The first one marks the start of electrical activation (Q wave), while the second one marks 
aortic valve opening (AoP upstroke, marked with an orange dot). In the dyssynchronous case the PEP is prolonged compared 
to the synchronous case. 
Figure 2 shows data during 3 settings from the 7 animals in this preliminary study: first at baseline 
during normal electrical activation, then after LBBB had been induced, and during subsequent CRT to 
restore synchronous activation. The results show clear changes between each of them for every 
animal.  

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Figure 2.  Preliminary results from animal study. The PEP interval was measured in 7 different animals at 3 different moments: 
during normal electrical activation before ablation (baseline), after ablation and induction of LBBB and with CRT (i.e. BiV 
pacing). It can be observed in all cases that the duration is increased in LBBB and successful CRT restores the PEP interval back 
to a normal value. 
In our current study we propose a novel method to estimate the preejection period noninvasively, 
as the time elapsed between the Q wave of the ECG to the rise of the peripheral arterial pulse curve 
measured for example at the earlobe or in the arm or even finger. We have also done some case 
studies to test this concept in animals, as seen in Figure 3. In these animals a piezoelectric sensor over 
the skin (Figure 4B) was strapped around the lower limb ankle to measure the arterial peripheral 
pulse wave. This measurement is equal to the PEP plus the time required for the pulse wave to travel 
in the arteries to the peripheral location where the measurement is being taken. We hypothesize that 
this delay will remain constant for the same patient and any acute change in this time interval will 
therefore be a change in PEP. However, this will be tested by comparing sensors placed proximally 
and distally. 
Figure 3. Data from a representative animal. In the left panel the ECG, LV pressure and pulse wave signals from a synchronous 
heartbeat of an animal. The right panel shows a heartbeat of the same animal with a dyssynchronous contraction after LBBB 

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induction. The dashed vertical lines mark the PEP, plus the time that the pulse wave takes to travel to the back limb where the 
measurement is being taken noninvasively by a piezoelectric sensor on the skin. The first vertical line marks the start of 
electrical activation (Q wave), while the second marks the upstroke of the pulse wave. In the dyssynchronous case the time 
interval is prolonged compared to the synchronous case. 
The key aspect of our proposed methodology is to avoid invasive procedures that might entail some 
risk for the patient while still giving reliable feedback to the clinician. These measurements should be 
reliable and given during the procedure as different lead placements and pacing configurations are 
tested. We therefore plan to develop an auto detection algorithm that allows us to get the acute 
response in real time. 
Aims of the study 
We will investigate the capabilities of a noninvasive device to assess the cardiac function of a patient 
through its PEP. Different locations on the hand and arm will be tested to see which one is best to 
measure arterial pulse waves for this purpose, without getting in the way of clinicians or adding 
discomfort to the patient. The study has two different hypotheses regarding the suitability of the 
method for assessing acute response to CRT: 
Hypothesis 1 
During CRT implantation patients that are responders to the treatment will demonstrate a 
significantly shortening of the PEP compared to non-responders. We will perform PEP measurement 
during impanation while response will be defined 6 months follow up as a ≥15% reduction of LV end 
systolic volume (ESV) by echocardiographic examination. Fifteen percent reduction of LV ESV is a 
common definition of response to CRT as before CRT implantations the LV is dilated, and successful 
resynchronization results in systolic contraction to a lower ESV and over time reverse remodeling 
results in a smaller LV. Patients will also be followed after 1 and 2 years to note hard end-points such 
as mortality, heart transplants. This will be a proof of concept study to indicate if such non-invasive 
PEP measurements can be used to decide if a patient should receive CRT or not. 
Hypothesis 2 
Patients who have had CRT implanted at Rikshospitalet the last half a year, will be investigated at 
their 6 month CRT-control and response will be defined 6 months follow up as a ≥15% reduction of 
LV end systolic volume (ESV) by echocardiographic examination as above. We hypothesize that there 
will be a significant shorter PEP with CRT turned on (synchronous activation) compared to when CRT 
is turned off (dyssynchronous activation). Furthermore the reduction in PEP from CRT OFF to CRT 
ON will be larger in patients classified as responders compared to patients classified as non-
responders. 
Hypothesis 3 – additional echocardiographic recordings 
In animals we have previously observed and published the findings that CRT acutely reduces both 
end systolic (ESV) and diastolic volumes (EDV). A reduction of end diastolic volume is an effective 
reduction of preload which according to the Frank-Starling mechanism reduces functional indices 
such as ejection fraction, stroke volume, strain, and more. Thus, improvements in LV function by CRT 
may be apparently concealed by this preload reduction. However, if the such an acute reduction in 

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volume as observed in our animal model, will also occur in humans is uknown. This is of importance 
in order to interpret potential changes in preload dependent measurements to evaluate how heart 
function changes when CRT is turned on. We hypothesize that there will be a reduction in ESV and 
EDV from CRT OFF to CRT ON as measured by volumes from echocardiography. 
Furthermore, in an ongoing animal study we see that the abnormal septal motion in LBBB (CRT OFF) 
causes a reduced septal early diastolic lengthening velocity (septal e’) which confounds the use of the  
E/e’ index to estimate LV filling pressure (E is the velocity of the early diastolic filling wave through 
the mitral valve by echocardiography). CRT acutely increased septal e’ in the animals while lateral e’ 
was relatively unaltered, suggesting lateral E/e’ should be used to evaluate LV filling pressure in these 
patients and not the average of septal and lateral e’. We want to confirm that the same observation as 
seen in animals is present also in patients, which will strengthen the findings in our ongoing study. 
Finally, in a recent paper we showed data indicating that septal dysfunction is driving the 
development of heart failure in LBBB. As these patients have an echocardiographic exam the day 
before CRT implantation, it will allow a longitudinal study as we will perform echocardiography on 
the patients also after 6 months. In line with our previous paper, we hypothesize that CRT responders 
will have a reverse remodeling where there will be most recovery of septal function quantified by 
regional strain and non-invasive pressure-strain regional myocardial work indices. 
 
Methods and material 
Patients 
Two different patient populations will be used in this study for the two hypotheses. On one hand, up 
to 40 patients admitted for CRT implantation according to current ESC/AHA guidelines at the 
Department of Cardiology, Rikshospitalet, Oslo University Hospital will be included in this study. 
While we will also include another 40 patients admitted for routine checkups of their CRT devices to 
test hypothesis 2. This is an observational study that will serve as proof of concept; therefore data 
must be registered and analyzed before a statistical calculation of the sample size can be made.   
However, the rational for choosing 40 patients in each of the two substudies is as follows. Based on 
the animal data, we see a distinct difference in the PEP measurements between synchronous and 
dyssynchronous activation. Hence, we expect that we should see clear statistical differences with 
relatively few patients in the two groups of responders and non-responders. In order for the method 
to be of clinical value to ultimately decide if a patient should not receive CRT, the differences should 
also be so clear that few patients are needed to demonstrate this difference. We rather arbitrary 
believe we must have at least 10 in the group with fewest patients to have confidence in the general 
validity of the results in this group. Given a CRT response rate of 1/3, this would require 30 patients.  
In addition we estimate that 20% of patients may be excluded due to poor signal quality or 
unattainable data and we could have a higher response rate; therefore we have ended up with 40 
patients for each of the two substudies which adds to a total of 80 patients for the whole study. 
However, this number may be revised during the project once we gain data to perform a proper power 
analysis. 

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Inclusion criteria hypothesis 1: 
x
Referred for CRT implantation at Oslo University Hospital, Rikshospitalet based on the 
standard guideline criteria below: 
R Sinus rhythm. 
R New York Heart Association functional class II and III heart failure on optimal medical 
therapy. 
R Left bundle branch block. 
R QRS duration larger than 130 ms. 
R Left ventricular ejection fraction lower than 35%. 
Inclusion criteria hypothesis 2: 
x
Previously performed CRT implantation at Oslo University Hospital, Rikshospitalet, based on 
the standard guideline criteria described in the point above. 
Noninvasive measurements 
There are different commercial technologies that would allow us to get the needed recordings, as 
shown in Figure 4. We will use an IR Plethysmograph – Ear Clip II - MLT1060EC (Figure 4 A) attached 
to the earlobe of the patient and directly connected to a PowerLab® recording unit. In addition to 
that, a Finameter will be placed on the finger of the patient, which will serve as an additional, more 
distal, peripheral arterial pulse curve and give continuous recordings of arterial pressure. 
Hemodynamic recordings will also include heart rate and ECG that are standard measurements in 
these procedures. 
A
 
B
 
C
 
D 
 

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Figure 4. Different commercial technologies that could be used to measure a peripheral arterial pulse wave: Infrared 
photoplethysmograph which is be attached to the earlobe (ADInstruments, A). Finger pulse transducers that uses a piezo-
electric sensor (ADInstruments, B). Wearable wrist cuff based on different types of sensor modules (E4 wristband, C and 
Simband, D).  
Echocardiographic examination 
A complete echocardiographic examination is performed the day before CRT implantation as part of 
the standard procedure at our hospital. After 6 months these patients will be called in for their 
standard CRT 6 months control. In addition to this standard CRT control, we will also perform another 
echocardiographic exam at this time which will allow us to evaluate changes in ESV to classify the 
patient as a responder or non-responder. Echocardiographic images will be performed both with the 
CRT ON and CRT OFF at this 6-months control and compared with the images acquired the day before 
CRT implantation. 
Statistical analysis plan (SAP) 
 
Results will be presented in mean ± standard deviation or confidence intervals (CIs). 
Comparison between two groups will be performed with paired Students t-tests or chi-square test as 
appropriate. Univariate and multivariate linear regression analyses will be used to identify predictors 
of reverse remodeling.  
 
Time schedule 
We aim to start inclusion of patients March 2023. We hope to include 1-2 patients per week who are 
going to get CRT implantation, which means we will then finish the first set of measurements in 2024. 
Then subsequent 6 months follow up which will then be from third quarter 2023 to 2025. The 
hypothesis 2 substudy we aim also to start March 2023 and include about 2 patients a week for CRT 
control. Inclusion should then finish by end of 2023. We will follow the patients for 2 more years 
(2027) to note the harder end-points. We expect several abstracts and journal papers to be written 
from this material. The end of registrations will be 2027, but subsequent papers may take 2 more 
years to finish and our experience is that such data will be included in spin-off papers not yet planned. 
Hence, we have set the final date for publication from this material as end of 2031. 
Health information 
In addition to the PEP measurements, we will note down standard echocardiographic parameters for 
assessment of heart function such as EF and volumes as well as heart failure relevant information 
such as blood pressure, type of heart disease, and heart related drugs, as well as age, gender, weight 
and height. Additional blood test data will be collected and registered at 6 months CRT control. Data 
will be handled in compliance with the rules and regulation for patient research data at Oslo 
University Hospital and stored in dedicated, secured servers. The patient data will be stored de-
identified and the key will be stored separately in dedicated server area according to the regulations. 
Only project members will be able to obtain access to the key and the patient data. 

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Ethical considerations 
This project entails very low risk as all the technology needed is noninvasive and is already in the 
hospital. The study involves patients who have already been referred to CRT implantation or 
configuration and they will undergo this procedure independently of the study. The planned clinical 
study is easy to carry out and will not cause any extra discomfort for the patient. The only added time 
to the examination time will be the time taken to place the sensors and the testing of CRT settings 
which entails a very small risk for the patient and will be performed by trained clinicians. 
During the 6-months CRT-control, they will get an additional echocardiographic examination which 
has no risks. These patients will thus benefit from this extra echocardiographic investigation which 
can give added clinical information in exchange for the extra time it takes to perform such an 
examination. 
Source of funding 
 
We have received 3 year postdoc funding from the South-Eastern Norway Regional Health Authority 
to perform this project (HSØ grant project # 2022049).  
Clinical and scientific impact 
The present study may provide a novel noninvasive method for assessment of the acute response to 
pacing. The results of this study will be published as abstracts to scientific conferences and are 
expected to result in one or more journal papers which will be part of the PhD of the research fellow. 
The results of the study can be of great value for researchers in addition to healthcare workers and 
patients as it could be used in all CRT implantation procedures and help to identify non-responders. 
This method would also help guide the optimal placement of the pacemaker leads during 
implantation. As it would detect any misplacement or if, in some patients with infarct, a scar is 
preventing the pulse from the pacing lead to propagate. It would therefore help identify patients who 
do not benefit from this therapy and avoid implanting unnecessary devices; and optimize both lead 
position and pacemaker settings.  
Adjustment of pacemaker settings is a potential subsequent use of the method. Patients come 
routinely back for control of the CRT. Our method could be an easy way to give the clinician feedback 
on changes to the CRT settings during such controls. 
Together with our technology transfer office, Inven2, we are currently looking into the possibility for 
patenting and commercializing the method. 
Furthermore, the echocardiographic measurements can help improve our understanding acute 
response parameter which may be confounded by acute preload alterations, which parameters to use 
when estimating LV filling pressure in LBBB patients, and which mechanisms drive heart failure 
development in LBBB patients. 

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References 
  
[1] 
A. M. Feldman et al., “Cost Effectiveness and Regulatory Considerations Cost Effectiveness of 
Cardiac Resynchronization Therapy in the Comparison of Medical Therapy , Pacing , and 
Defibrillation in Heart Failure (COMPANION) Trial,” J. Am. Coll. Cardiol., vol. 46, no. 12, pp. 
2311–2321, 2005. 
[2] 
WT. Abraham, WG Fisher, AL Smith, DB Delurgio, AR Leon, E Loh et al. Cardiac 
resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–53. 
[3] 
M Brignole, A. Auricchio, G. Baron-Esquivias et al. 2013 ESC Guidelines on cardiac pacing and 
cardiac resynchronization therapy. European Heart Journal (2013) 34, 2281–2329 
[4] 
E. Boe et al., “Left ventricular end-systolic volume is a more sensitive marker of acute 
 response  
to cardiac resynchronization therapy than contractility indices : insights 
 from an experimental  study,” vol. i, no. C, pp. 347–355, 2019. 
[5] 
H. H. Odland et al., “Time-to-peak dP / dt – the link between electrical activation and 
mechanical function in cardiac resynchronization therapy,” Submitted. 
[6] 
M. Villegas-Martinez et al., “Abstract – Duration of the preejection phase is less preload 
dependent and therefore a better marker of response to cardiac resynchronization therapy 
than maximum pressure rise,” EHRA 2020, 2020.