Computed Tomography Estimated Right Ventricular Function and Exercise Capacity in Patients With Continuous-flow Left Ventricular Assist Devices
Phase: NA
Conditions: Heart Failure
Sponsor: Finn Gustafsson

General information 
 
Date:  
Nov 2021 
 
Title of study:  
Computed tomography estimated right ventricular function and exercise capacity in patients with 
continuous-flow left ventricular asssist devices. 
 
Clinical trials identifier:  
NCT02658136 
 
Trial editor  
Mette Holme Jung, MD and Kiran Mirza MD 
Department of Cardiology B. Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark.  
 
Sponsor and responsible study investigator  
Finn Gustafsson, DMSc, Chief Physician. Department of Cardiology B. Rigshospitalet, Blegdamsvej 9, 
2100 Copenhagen Ø, Denmark. E-Mail: finn.gustafsson@rh.regionh.dk. Telephone: +45 35 45 97 43.  
 
Investigator  
Mette Holme Jung, MD, Department of Cardiology B. Rigshospitalet, Blegdamsvej 9, 2100 
Copenhagen Ø, Denmark.  
 
Time Schedule  
Period of inclusion: 01.12.2015 (or when the protocol is approved) until 19 participants are enrolled in 
the trial. The estimated duration of the trial is two years.  
 
Contact  
Mette Holme Jung, MD, Department of Cardiology B. Rigshospitalet, Blegdamsvej 9, 2100 
Copenhagen Ø, Denmark. E-Mail: metteholmejung@dadlnet.dk. Telephone: +45 35 45 95 49.  
 
The Ethics Committee  
Videnskabelig Etisk Komité. Region Hovedstaden, Hillerød, Denmark.  
 

Study protocol background  
Introduction to mechanical circulatory support (MCS).  
When pharmacological therapy becomes insufficient in advanced end-stage heart failure (HF) 
transplantation remains the gold standard of therapies. However, due to a severe lack of donor organs, 
MCS is an alternative option for some eligible patients. Mechanical circulatory support in the form of a 
left ventricular assist device is a pump supporting the left ventricle by pumping blood from the apex to 
the ascending aortae. The pump is powered by externally placed batteries that are connected to the pump 
by a driveline penetrating the abdominal wall (Figure 1). Today we only use continuous-flow left 
ventricular assist devices (CF-LVAD) based upon results from clinically controlled trials. The CF-
LVAD can be utilized either as a bridge-to-transplantation (BTT) or as life-long support called 
destination therapy (DT). Implantation with a CF-LVAD increases survival and improves quality of life 
(1). In addition functional status is improved post-implant, however, it is not normalized and peak 
oxygen uptake (peak VO2) remains severely reduced (2). At University Hospital Rigshospitalet we use 
a CF-LVAD called the HeartMate II and lately also it’s successor the HeartMate III. The number of 
implantations is markedly increasing (3) and this fact underlines the need to monitor the treatment 
carefully which includes focus on optimizing QOL and limitting the extent of adverse events. While the 
effect of right ventricular (RV) failure early after pump implantation, and its effect on outcome has been 
extensively studied (4-6), the effects of late RV failure on exercise capacity and QOL has been sparsely 
described. Thus the purpose of this study is to examine RV function and the association to exercise 
capacity in CF-LVAD patients.  
 
Right ventricular function and pulmonary circulation.  
A well functioning RV is of crucial importance in HF patients eligible for a CF-LVAD (5). In the 
abscens of shunts total cardiac output (TCO) will equal RV output and is provided solely by the device 
when the aortic valve (AV) is closed. As TCO is dependent on RV output the latter is a potential 
limiting factor in a required exercise-induced increase in cardiac output.  
Unloading the left ventricle with a CF-LVAD results in immediate increased preload and decreased 
afterload on the right side that can result in initial worsening RV function early after implant. 
Subsequently, with RV adaptation, the decreased right-sided filling pressures will frequently lead to 
improvements in RV function for example demonstrated by diminished tricuspid regurgitation (TR). In 
contrast when persistent impaired RV contractility develops it is often secondary to onset of pulmonary 
artery hypertension or disadvantageous alterations in the mechanical interventricular relationship post-
implant. Also intraoperative RV injury exposes a risk of developing RV failure (4, 7-9). 
Defining RV failure  
Variuous definitions of RV failure is used but will often include some of the following: Need for 
inotropic agents > 14 days postoperatively, use of pulmonary vasodilators such as inhaled nitric oxide > 
48 hours, central venous pressure > 18 mmHg and cardiac index <2.3 l/min/m2 (with normal left atrial -
or pulmonary capillary wedge pressure) and/or the need for RV circulatory support/asssist device. 
Depending on the defining criteria the incidence of RV failure after LVAD implantation varies 
considerably from 5-44% (5, 7, 10-13).  
 
Previous research on RV function and exercise capacity in LVAD patients.  
In HF patients without mechanical circulatory support preserved RVEF has previously been shown to be 
significantly associated with higher peak %VO2 but not peak VO2 (14). Post-implant a small study 
found that poor RV function (defined as RV fractional area change) and limited reduction in pulmonar 
vascular resistence (PVR) was associated with shorter 6-minute walking distance (15). Another study 
found late-onset RV failure (defined as RV stroke work index < 4.0 g/m2 at all rotational speeds) to be 
significant associated with 6-minute walking distance and peak VO2 at three months post-implant (16). 
Raina et el found that pre-operative poor functional class (~INTERMACS score) was significant 

associated to post-operative RV failure (17). In contrast Baumwol et al did not find a difference in post-
implant NYHA classification between patients with and without RV failure (13). In a pioneering study 
of exercise capacity in the formerly used pulsatile LVADs Jaski et al found that despite a decrease in 
RV end-diastolic dimension, RV stroke volume showed a trend toward being higher with exercise 
compared with baseline. They concluded that increases in systemic flow with exercise appear to be 
limited by the pulsatile flow-LVAD complex and not by intrinsic RV function (18). Our group has 
formerly, in a subanalysis, examined the relationship between echocardiographic measures of RV 
function during rest and exercise capacity and found no association (19). However, as described below, 
echocardiography in CF-LVAD patients can be challenging, especially measuring parameters of RV 
function. 
Assessment of RV function in CF-LVAD patients.  
Echocardiographic signs of decreasing RV function are amongst others progressive TR, increasing RV 
size, limited RV fractional area change (RVFAC), increasing tricuspid annular plane systolic excursion 
(TAPSE), increased right atrial pressure and decreased global longitudinal strain of the RV free wall 
(10, 15, 17, 20-22). However, due to the positioning of the CF-LVAD inflow cannula (especially in the 
HeartMate III) it is challenging to obtain images from the apical view and thus visualizing the right-
sided free wall. Assessing RV function by magnetic resonance (MR) is gold standard (23) but is 
contraindicated with a CF-LVAD in situ. However, multi-detector computed tomography (MDCT) is 
shown to be comparable to MR in assessing RV function (24). Right ventricular ejection fraction 
(RVEF) by MDCT is highly reproducible (interobserver variablity 0.89 and intraobserver variablity 
0.99) and is not affected by acoustic windows. The echo-derived variable that best correlates with 
MDCT RVEF is M-mode RVFAC (23, 24). Thus to estimate RV function in this study we will, in 
addition to echocardiography, undertake cardiac computed tomography (CCT).  
 
Hypothesis  
Poor function of the right ventricle during exercise is related to exercise intolerance in CF-LVAD 
patients. 
Primary endpoint  
 Right ventricular ejection fraction during rest and exercise estimated by CCT.  
 Cardiopulmonary exercise testing (CPET) measuring peak oxygen uptake (peak VO2) in ml/kg/min.  
 
Methods  
Study cohort  
Stable HF patients with a CF-LVAD either as BTT or as DT. Before commencement of the study the 
protocol will be approved by the Local Ethics Committees. The trial will be registered at 
www.clinicaltrials.gov.  
 
Inclusion criteria  
 Outpatients from Department of Cardiology, University Hospital of Copenhagen, Rigshospitalet, 
Denmark.  
 Age ≥ 18 years.  
 Ischemic or non-ischemic cardiomyopathy.  
 Signed informed consent.  
 
Exclusion criteria  

 Unstable patients with the need for intravenous inotropic therapy.  
 CF-LVAD implantation less than one month ago.  
 eGFR < 45 ml/min.  
 Contrast allergy.  
 
Statistics  
The primary outcome of this study is to describe the association between CCT-derived RVEF and peak 
VO2 during exercise. Previous analyzes have estimated a 7.7% standard deviations in RVEF and 6.3 
ml/kg/min in peak VO2 in CF-LVAD patients (19, 23). As the current study is explorative we are not 
guided from previous studies on the correlation between RVEF and peak VO2 but we estimate that 
including 15 patients will suffice. Analyses will be performed using SAS 9.4 statistical software (SAS 
Institute, Inc., Cary, North Carolina). Statistical significance will be defined as a two-tailed p value 
below 0.05. Differences between groups will be assessed using paired or unpaired t-tests as appropriate. 
Continuous variables will be expressed as mean ± standard deviation if parametric, if non-parametric as 
median and interquatile range. Categorical variables will be described with frequency and percentage. 
Relation between continuous variables will be calculated as correlation coefficients, if data are 
parametric distributed using Pearson´s coefficient and otherwise Spearman's rank correlation 
coefficient.  
 
Interventions  
1/ Cardiac Computed Tomography (CCT)  
Using ECG-gated CCT (320-slice MDCT Toshiba VISION Edition Aquilion One Scanner) we will 
measure RVEF, RV end-diastolic and end-systolic volumes (RVEDV and RVESV) and peak diastolic 
filling rates (dV/dt). The same variables will be measured on the left side. Further we will estimate the 
position of the CF-LVAD cannulas. The analysis of the images will be performed by the Cardiac-
MDCT Research Unit at Rigshospitalet by means of Vitrea software (Vital images, USA). In each 
patient we will undertake two sequential CTs – one at rest and one immediate after two minutes of 
supine 25 Watt ergometer bike exercise (attaching a pair of foot pedals to the bedside in the examination 
room). If exercise testing, against expectations, is not possible due to technical limitations we will 
instead induce stress with a dobutamine infusion protocol (se details below). The CCTs will be 
undertaken with intravenous contrast injections in a big vein in the right elbow flexion; 5-6 ml/second 
and subsequently the retrospective scans will be performed. The total contrast dose will be 140 ml and 
the total radiation dose a maximum of 20 mSv. As defined in the section on “exclusion criteria” eGFR 
must be ≥ 45 ml/min. 
Dobutamine stress test (Secondary choice if exercise in CT room is not possible).  
A dobutamine stress test can be used if we are unable to undertake exercise in the CT room due to 
technical/space challenges. Dobutamine will mimic the effects of exercise on the heart by direct ß1 and 
ß2 stimulation with a dose-related increase in heart rate, blood pressure, and myocardial contractility. 
An intravenous line will be started in the patient´s left arm for injection of the dobutamine and an 
infusion pump will be connected. The dobutamine infusion will begin at a rate determined by the 
patient´s weight (Figure 2). The rate of the infusion will be increased every third minute until the target 
heart rate (determined by the doctor based on age and physical condition), or until the maximum dose of 
dobutamine has been reached (40 ug/kg/min). Plasma half-life of dobutamine is 2-3 minutes. 
Contraindication for dobutamine infusion is recent myocardial infarction, unstable angina, uncontrolled 
hypertension (>200/110 mmHg), severe aortic stenosis, atrial tachyarrhythmia with uncontrolled 
ventricular response and unwillingness to give consent. After dobutamine infusion is started the patient 
will be monitored continuously with evaluation of blood pressure, symptoms and ECG tracing. Post-
stress the patient is monitored for a minimum of 10 minutes and until symptoms are resolved. 

 
2/ Cardiopulmonary exercise testing (CPET)  
Cardiopulmonary exercise testing will be performed on an upright ergometer bicycle (Schiller CS-200, 
Schiller AG, Bar, Switzerland). Calibration before each test for gas, ambient conditions and flow, 
according to manufacturer´s instructions, will be performed. Breath-by-breath respiratory gas analysis 
measuring oxygen consumption (VO2), carbon dioxide excretion (VCO2) and expiratory minute 
ventilation (VE) will be undertaken. Peak oxygen uptake will be calculated as ml/kg/min. The 
participants will be encouraged to keep cycling until exhaustion and will be monitored with pulse 
oximetry and continuous 12-lead electrocardiogram during the exercise. Peak heart rate will be 
measured at the same time as peak VO2. The aim of exercise duration is 8-10 minutes and based upon 
prior experience the protocol starts at 25 Watt followed by 10 Watt increase/1 minute. The pedaling 
rotation will be maintained at 60-70 rpm.  
 
3/ Transthoracic echocardiography  
Echocardiography is performed, prior to CPET, according to current guidelines (11, 25) on an Philips 
iE33 cardiac ultrasound system (Philips Healthcare, Best, the Netherlands). The examination will 
include 2D, tissue doppler imaging (TDI) and pulsed –and continuous wave Doppler images that will be 
aquired in the parasternal long-axis view and in the apical 4 chamber and 5 chamber views. A minimum 
of three echocardiographic cine loops will be stored digitally for offline analysis using Philips Xcelera 
analysis software version 3.1. Echocardiograms will be analyzed by a reader blinded to clinical 
outcomes. Focus will be on measuring the following parameters: Tricuspid regurgitation (defined as; 0= 
none, 1= mild, 1.5= mild-moderat, 2= moderat, 2.5= moderat-severe and 3=severe), TAPSE (measured 
by M-mode from an apical RV view), RVFAC and estimates of right atrial pressure (obtained from 
inferior vena cava from subcostal view). Aortic valve opening and a potential LV recovery will also be 
evaluated.  
 
4/ Blood sampling  
As the first thing on the day of the study a blood sample will be drawn from a peripheral vein. A total of 
no more than 45 ml is collected at one time; 25 ml is directly analyzed for lactate dehydrogenase, 
haptoglobin, free plasma hemoglobin, hemoglobin, INR, platelets, lactate, creatinine, eGFR, amylase, 
AST, ALT, bilirubin, potassium, calcium, sodium, cholesterol, leukocytes, CRP and pro-BNP. After the 
direct analysis the sample will be destroyed.  
The remaining 20 ml is stored in an approved biobank and subsequently analysed for Mid-regional pro-
atrial natriuretic peptide (MR-proANP) , Copeptin, Mid-regional pro-adrenomedullin (MR-proADM) 
and C-terminal pro-endothelin-1 (se details in the section “Biobank: Handling of biological material”  
below). 
Radiation hygiene  
Under the two CCT scans each patient will receive a total radiation dose of a maximum of 20 mSv 
depending on weight, heart rate and rhythm during the scan. It can be calculated that, theoretically, the 
lifetime risk of developing a deadly cancer increases by 0.05% for each 10 mSv the patient receives. 
Thus the lifetime risk of dying of a cancer increases from 25% to 25.1% in each patient.  
Sivert definition: 1 Sivert is the radiation hygienic measure of the biological effect of one dose ionizing 
radiation. Other terms for the same is “dose equivalent” and “effect dose”. 1 Sv = 1 Sivert = 100 rem = 
1 J/kg (Calculation by “Statens Institut for Strålebeskyttelse).  
4/ Risks associated with a dobutamine stress test: Chest pain, high blood pressure, palpitations, irregular 
heartbeats, dizziness and nausea.  
 
Reporting adverse events /side effects  
All events during the trial which might constitute a safety concern for the participant or jeopardise the 
execution of the trial will be reported to the Ethics Committee immediately. 

Ethical considerations  
The trial will be initiated following approval from the Ethics Committee and from the Data Protection. 
The trial will comply with the requirements stated in the Declaration of Helsinki II. As described we 
estimate that the rarely seen risks and side effects are easily justified by the potential benefits for the 
participants. Trial participants will receive adequate information on the purpose, metod, advantages and 
risks associated with participating in the trial (orally and in writing). Before participants are included we 
will collect an informed written consent. Participants are furthermore informed that it is possible to 
withdraw from the trial at any given time and that this decision will have no effect on future treatment 
and follow-up. 
Informed consent 
Patients that are supported with a CF-LVAD can participate in the study if they meet all the inclusion -
and exclusion criteria listed above. Before contacting the patients we will seek information on exclusion 
criteria in the patient records. Information can be passed from physician in charge of treatment to 
principal investigator. Patients with contrast allergy, decreased kidney function, CF-LVAD implantation 
less than one month ago and unstable patients requiring intravenous inotropes are excluded. 
Furthermore we will seek information on the inclusion criteria and make sure that patients are 18 years 
or older. If all criteria are met we will supply the patient with written information introducing the study 
and offer the patient to be included in the study.  
The investigator will be responsible for:  
-Trial participants receiving adequate information on the purpose, metod, advantages and risks 
associated with participating in the trial (orally and in writing). Before participants are included an 
informed written consent will be collected. Participants are furthermore informed that it is possible to 
withdraw from the trial at any given time without any explanation and that this decision will have no 
effect on future treatment and follow-up.  
-That the participant has the opportunity to ask questions and are allowed time to consider the given 
information. The information will be given in a quiet setting and without any pressure. The participant 
will be offered to bring a third party under the process of information.  
-Before any trial procedures are initiated the participant must sign a dated informed consent. The 
investigator will safely store the original written consent and the participant will receive a copi of this. 
The group and the Ethics Committee have to approve a revised version in case of any modifications to 
the protocol.  
 
Procedure for obtaining informed consent  
The contact to the participant will take place from The Department of Cardiology B, Rigshospitalet. A 
written consent to participate is made when the participant has a comprehensive picture of the given 
information and after the required time for consideration to acceptance. This consent will be given to Dr 
Mette Holme Jung or Dr Kiran Mirza, The Department of Cardiology B, Rigshospitalet.