Right Ventricular Function After Coronary Artery Bypass Grafting The SWEDEGRAFT Right-Heart-Substudy
Conditions: Coronary Artery Bypass Surgery, Right-Sided Heart Failure
Sponsor: Aarhus University Hospital Skejby

Protocol  
Version 1.6 
10.12.2020
 
                                                           
1 
 
 
Right Ventricular Function after  
Coronary Artery Bypass Grafting 
 
The SWEDEGRAFT Right-Heart-Substudy 
 
 
Principle investigator 
Ivy Susanne Modrau, MD, dr. med. 
Department of Cardiothoracic and Vascular Surgery 
Aarhus University Hospital 
Telephone: +45 24778856 
e-mail: ivy.modrau@skejby.rm.dk 
 
Supported by: 
NIH/NCRR Colorado CTSI Grant Number UL1 RR025780 (REDCap) 
Health Research Foundation of Central Denmark Region, Grant Nr. A3057 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
2 
 
TABLE OF CONTENTS 
Page 
 
ABBREVIATIONS 
 
SYNOPSIS 
 
Study title 
 
Objectives 
 
Design and outcomes 
 
Intervention and Duration 
 
Sample size and population 
 
STUDY TEAM ROASTER 
 
Principle Investigator 
 
Co-investigators 
 
PARTICIPATING STUDY SITES 
 
1 
HYPOTHESIS AND STUDY OBJECTIVES 
1.1. 
Hypothesis 
1.2.  
Primary Objective 
1.3.  
Secondary Objectives 
2.  
BACKGROUND AND RATIONALE 
1.1. 
Background 
1.2.  
Rationale 
3 
STUDY DESIGN AND OUTCOMES 
3.1. 
Study Design 
3.2. 
Primary Endpoint 
3.3. 
Secondary Endpoints 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1. 
Inclusion Criteria 
4.2. 
Exclusion Criteria 
4.3. 
Study Enrollment Procedures and Informed Consent 
4.4. 
Study Duration and Follow-up 
5. 
MATERIALS AND METHODS 
5.1. 
Screening evaluation 
5.2. 
Study treatment including postoperative management 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
3 
 
5.2. 
Endpoint Assessments 
5.3. 
Schedule of evaluations 
6. 
SAFETY ASPECTS 
6.1. 
Insurance 
6.2.  
Adverse Events  
7.  
STATISTICS CONSIDERATIONS 
7.1. 
General Design Issues  
7.2. 
Sample Size and Randomization  
7.3.  
Stopping rules 
7.4. 
Data Analyses 
8. 
DATA COLLECTION AND QUALITY ASSURANCE 
8.1. 
Data Collection 
8.2 
Data Management  
8.3. 
Training 
9. 
ECONOMY 
10. 
ETHICAL CONSIDERATIONS 
10.1.  Risk of study intervention 
10.2.  Conflict of interest 
10.3. Approval 
11. 
STUDY ORGANIZATION 
11.1. Steering Committee 
11.2. Delegation of Study-related tasks 
12.  
COOPERATION AND PUBLICATION POLICY 
13. 
PLANNED TIMELINE  
14. 
PERSPECTIVES  
15. 
REFERENCES 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
4 
 
ABBREVIATIONS 
3D 
= Three-dimensional 
Borg CR 10® 
 = BORG category-ratio 10 scale® 
CABG  
= Coronary Artery Bypass Grafting 
CRF 
= Case Report File 
CTA 
= Computerized Tomography coronary angiogram 
eGRF/1.73m2 (CKD-EPI) 
= Estimated Glomerular Filtration Rate according to the Chronic 
 
Kidney Disease EPIdemiology Collaboration equation 
eCRF  
= Electronic Case Report Form 
ECC 
= Extracorporeal Circulation 
EF 
= Ejection Fraction 
FAC  
= Fractional Area Change  
MACCE  
= Major Adverse Cardiac and Cerebrovascular Events 
NYHA  
= New York Heart Association 
ProBNP  
= Pro B-type Natriuretic Peptide 
REDCap  
= Research Electronic Data Capture 
RV 
= Right Ventricular  
RV-FWS  
= Right Ventricular Free Wall Strain  
RV-GLS 
= Right Ventricular Global Longitudinal Strain 
TAPSE 
= Tricuspid Annular Plane Systolic Excursion 
WMSI  
= Wall motion score index 
S’ 
= Systolic myocardial velocity 
SAQ-7  
= Seattle Angina Questionnaire 7 
 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
5 
 
SYNOPSIS 
 
Study Title 
Right ventricular function after coronary artery bypass 
grafting 
Primary Study Objective 
To assess the long-term impact of coronary artery 
bypass grafting on right ventricular function 
Study Design 
Prospective observational substudy of 
SWEDEGRAFT – A Nordic, multicentre, prospective, 
randomized, register based, clinical trial on no-touch 
vein graft in coronary surgery 
Primary outcome measure 
• 3D RV EF  
• RV-FWS 
• RV-GLS 
Secondary outcome measures 
• Fractional Area Change (FAC) 
• TAPSE 
• Systolic myocardial velocity (S’) 
• SAQ-7  
• NYHA class 
• Borg CR10® 
• ProBNP 
• Saphenous vein graft patency 
Study Intervention 
Non-emergent CABG with 
(1) conventional skeletonized saphenous vein grafts 
(2) no-touch saphenous vein grafts 
Duration 
SWEDEGRAFT enrollment period:          10/18-04/20 
Clinical follow-up:                                     01/21-11/22 
Sample Size 
Approximately 200 patients included in the 
SWEDEGRAFT study at Aarhus University Hospital 
Study Population 
Elective primary CABG patients with ECC 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
6 
 
STUDY TEAM ROSTER 
 
Principal Investigator: 
Ivy Susanne Modrau, MD 
Department of Cardiothoracic and Vascular Surgery 
Aarhus University Hospital 
Telephone: +45 24778856, e-mail: ivy.modrau@skejby.rm.dk 
 
Co-Investigators: 
Jesper Khédri Jensen 
 
Department of Cardiology, Aarhus University Hospital 
 
e-mail: jesper.k.jensen@auh.rm.dk 
 
 
Henrik Ølholm Vase 
 
Department of Cardiology, Aarhus University Hospital 
 
e-mail: henrvase@rm.dk 
 
 
Stefan Thelin (Principal Investigator SWEDEGRAFT trial) 
Department of Surgical Sciences, Thoracic Surgery 
Uppsala Clinical Research Center, Uppsala University, Sweden 
 
e-mail: stefan.thelin@akademiska.se 
 
 
 
Stefan James 
 
Department of Medical Sciences and Uppsala Clinical Research Center, 
 
Uppsala University, Sweden 
 
e-mail: stefan.james@ucr.uu.se 
 
PARTICIPATING STUDY SITES 
 
Department of Cardiothoracic and Vascular Surgery 
Aarhus University Hospital 
Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark 
 
Department of Cardiology 
Aarhus University Hospital 
Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark 
 
Uppsala Clinical Research Center 
Uppsala University 
751 85 Uppsala, Sweden 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
7 
 
1.  
AIM AND STUDY OBJECTIVES 
 
1.1. Hypothesis 
We propose that right ventricular (RV) systolic function is essentially preserved two years after 
coronary artery bypass grafting (CABG). Being a prevalence study, there is no actual 
hypothesis to test. 
 
1.2. Primary objectives 
The primary objective of this study is to investigate whether CABG is associated with reduced 
depression of RV function after mid-term follow-up. 
 
1.3.  Secondary objectives 
 
The secondary objectives of this study are to investigate whether: 
• Changes in standard two-dimensional (2D) echocardiographic measures of RV function are 
reflected by 3D echocardiography 
• RV dysfunction is correlated with impaired health-related quality of life as assessed by 
Seattle Angina Questionnaire-7 (SAQ-7) 
• RV dysfunction is correlated with functional capacity as assessed by New York Heart 
Association (NYHA) class and BORG category-ratio 10 scale (Borg CR10®) 
• RV dysfunction is correlated with the degree of revascularization/ graft patency as assessed 
by computerized tomography coronary angiogram (CTA) 
• RV dysfunction is correlated with clinical or biochemical signs of perioperative myocardial 
damage at the time of surgery 
• RV dysfunction is correlated with levels of Pro b-type natriuretic peptide (ProBNP) 
 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
8 
 
2.  
BACKGROUND AND RATIONALE 
 
2.1.  Background 
It has become evident that impaired RV function is an important predictor of adverse 
cardiovascular outcome in patients with ischemic heart disease independent of left ventricular 
function (Haddad 2008). Early RV failure as assessed by impaired RV ejection fraction through 
a pulmonary artery catheter is strongly and independently associated with increased two-year 
mortality (Bootsma 2017). Consequently, it is of major concern that RV dysfunction is a 
common and well-known phenomenon known to develop during and early after cardiac surgery 
(Alam 2003, Brookes 1998, Bootsma 2017, David 2006). The phenomenon has been 
demonstrated to persist for as long as one year after surgery (Roshanali 2008). 
A combination of different echocardiographic measures is applied to evaluate RV function as no 
single method is devoid of limitations, while cardiovascular magnetic resonance serves as gold 
standard (Mertens 2010). Modern two-dimensional (2D) echocardiographic assessment of RV 
function commonly includes RV speckle tracking strain analysis, RV fractional area change (RV 
FAC), tricuspid annular plane systolic excursion (TAPSE), and Doppler-derived RV systolic 
excursion velocity (S’ velocity) (Zaidi 2020 Br. Guidelines, Rudski 2010 Am Guidelines, Lang 
2015). Unfortunately, TAPSE and S’ velocity have proven to be of limited value in the 
postoperative setting, due to their angle dependency (Mertens 2010). 
3D echo-derived right ventricular ejection fraction (3D RV EF) has been proposed as an accurate 
parameter of global right ventricular performance as it correlates well to cardiac magnetic 
resonance (Nagata 2017, Lang 2015).  3D RV EF is not limited to isolated systolic aspects, such 
as the tricuspid annulus or the free wall of the RV. 3D RV EF appears to be an independent 
predictor of future adverse cardiac outcome (Nagata 2017). Myocardial strain measurement 
using speckle tracking echocardiography is a well-established and reproducible method used to 
reflect the systolic function of the ventricles and carries prognostic information (Kim 2018, 
Antoni 2010). Unlike other echocardiographic parameters of RV systolic function, strain values 
can assess intrinsic myocardial performance and can differentiate active movement from passive 
movement. Strain is a reliable and accurate way to measure RV systolic function and has been 
validated with MR (Lu 2015, Smiseth 2016). 
Because RV global longitudinal strain (RV-GLS) is a global parameter of RV systolic function 
compared with other conventional parameters, such as TAPSE and tricuspid S’ velocity, which 
represent the displacement degree of the basal segment of the RV free wall, it correlates better 
with RV systolic function and prognostic power than other conventional parameters (Fine 2013, 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
9 
 
Park 2015, Grant 2012).  Some authors showed that RV global longitudinal strain free wall (RV-
FWS) was better correlated than RV-GLS with RV EF according to cardiac magnetic resonance 
and it is optional to the user to include septum (Badano 2018).  
Several theories on the leading cause behind RV dysfunction after cardiac surgery have been 
proposed. Cardiopulmonary bypass and cardioplegia are unlikely causes, as the phenomenon has 
been observed equally following on- and off-pump CABG (Diller 2009). Ischemia has been 
suggested as an underlying cause for RV dysfunction after CABG. However, RV dysfunction 
seems to be equally present in patients with and without full revascularization of the right 
coronary artery (Hedman 2004, Roshanali 2008). Finally, pericardial disruption has been 
suggested as the most probable cause (Unsworth 2010).  Unsworth and colleagues performed 
serial transoesophageal echocardiographic measurements of RV longitudinal function by S’ 
velocity during CABG. Noteworthy, almost all reduction of RV S’ velocity associated with 
CABG occurred within the first three minutes after pericardial incision. 
Few prospective non-randomized studies support the superiority of 3D RV EF over 2D 
echocardiography for assessment of RV function in the postoperative setting. Keyl et al. 
conducted a pilot study comparing surgical aortic valve replacement through full sternotomy 
with transcatheter procedures (Keyl 2016). In both groups, 3D RV EF remained constant. 
Following open surgery, but not after transcatheter intervention, the geometry of RV contraction 
was modified as reflected by  significantly reduced TAPSE and significantly increased fractional 
shortening of the RV midcavity transverse diameter. Similarly, Tamborini and colleagues 
showed in patients undergoing open mitral repair that 3D RV EF was preserved, while TAPSE 
and S’ velocity were significantly reduced up to one-year follow-up (Tamborini 2009). These 
findings are supported by a previous study which showed no deterioration of RV function after 
aortic valve replacement through full sternotomy as measured by magnetic resonance imaging 
(Sandstede 2000). In summary, validated 2D echocardiographic measures for RV function might 
not reflect the altered RV contraction pattern including paradoxical interventricular septal 
motion and reduced long-axis function following open cardiac surgery. 
Little is known about the prognostic impact of RV dysfunction after cardiac surgery. It may be 
difficult to assess adverse effects of RV impairment in CABG patients as they may be masked 
by the beneficial effects of revascularization on left ventricular function. It has been shown that 
exercise capacity improves three months after CABG despite depressed RV function (Hedman 
2008). Furthermore, it has been demonstrated that reduced RV function was not associated with 
impaired NYHA class at 1-year follow-up (Roshanali 2008).   

Protocol  
Version 1.6 
10.12.2020
 
                                                           
10 
 
2.2. Rationale 
There remains an unresolved contradiction between the undisputable echocardiographic signs of 
RV depression after cardiac surgery and the lack of clinical signs of RV failure. This study seeks 
to contribute to a better understanding of this phenomenon.  
We seek to determine the prevalence and scale of RV dysfunction two years after CABG by 
applying the latest available echocardiographic technology in RV evaluation. We expect the use 
of 3D imaging to provide better visualization of the RV’s complex shape in order to allow 
definitive assessment of potential RV depression after CABG. 
We aim to put the objective findings in relation to patient-reported outcome measures and 
prognosis. In addition to assessment of functional class by NYHA class, we will inquire into 
health-related quality of life with the disease-specific Seattle Angina Questionnaire 7 (SAQ-7) 
and functional capacity with the Borg CR 10® scale. Finally, we aim to examine the prognostic 
relevance of the phenomenon with a five- and ten-year follow-up of our patients for major 
adverse cardiac and cerebrovascular events (MACCE).  
 
 
3. 
STUDY DESIGN AND OUTCOMES 
 
3.1. Study design 
Prospective observational Right-Heart-Substudy of the SWEDEGRAFT trial at Aarhus 
University Hospital in Denmark. SWEDEGRAFT is a nordic, multicenter, prospective, 
randomized, register-based, clinical trial (ClinicalTrials.gov Identifier: NCT03501303). Primary 
objective of the trial is to compare mid-term patency saphenous vein grafts harvested and 
implanted with the no-touch technique as compared to the conventional skeletonized technique 
(Ragnarsson 2020). 
Patients for the current Right-Heart-Substudy will be recruited amongst the 269 patients included 
in the SWEDEGRAFT trial at Aarhus University Hospital from 10 September 2018 to 25 May 
2020. In the Right-Heart-Substudy, we aim to extend the scheduled two-year follow-up visit 
with a thorough echocardiographic assessment of the patients’ cardiac function and state of 
revascularization, and to follow our patients’ clinical outcome up to 10 years by review of patient 
electronic. SWEDEGRAFT data obtained under hospitalization (demographics, medical history, 
randomization, surgery, adverse events), at three-months telephone follow-up (questionnaire), 
and at two-year follow-up (SAQ-7 questionnaire, ECG, CTA) will be used in analysis and 
interpretation of the Right-Heart-Substudy results.  

Protocol  
Version 1.6 
10.12.2020
 
                                                           
11 
 
 
3.2. Primary outcome measures 
Primary outcome measure is RV function assessed by 3D echocardiography and RV strain 
measurements derived from two-dimensional speckle-tracking.  
 
3.3. Secondary outcomes measures 
 
At follow-up 24-30 months after surgery: 
• Full 2D/3D Echocardiography (specified in 5.3. Endpoint Evaluations) 
• Disease-specific health-related quality of life as assessed by SAQ-7 
• NYHA class 
• Borg CR 10® 
• Graft patency as assessed by CTA 
• Haemoglobin, ProBNP 
• ECG 
In-hospital variables: 
• RV function decrement (systolic RV function preoperative versus 2-year follow-up) as 
assessed by 2D echocardiography 
• Degree of revascularization according to the operations report (time of intervention) 
• Signs of perioperative myocardial damage (CK-MB, ECG, postoperative echocardiography) 
At 5- and 10-year follow-up major adverse cardiac and cerebrovascular events (MACCE) 
according to the electronic patient record: 
• Death from any cause (cardiovascular and non-cardio-vascular mortality). 
• Myocardial infarction 
• Repeat hospitalization due to cardiac cause 
• Cerebrovascular accident 
• Repeat revascularization 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
12 
 
 
4. 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1. Inclusion criteria 
SWEDEGRAFT inclusion criteria: 
• First-time non-emergent CABG patients 
• Need for at least one vein graft 
• Able to provide informed consent and accepted for isolated primary CABG. 
Additional inclusion criteria for the Right-Heart-Substudy: 
• Ability to meet for follow-up visit 
 
4.2. Exclusion criteria 
SWEDEGRAFT exclusion criteria: 
• No greater saphenous vein grafts available (previous vein stripping or poor vein quality) 
• Age > 80 years at the time of inclusion 
• Allergy to contrast dye 
• Renal failure with eGFR <15 ml/min at primary inclusion 
• Coagulation disorders 
• Excessive risk of wound infection 
• Participation in other interventional trial on grafts 
• Any condition that seriously increases the risk of non-compliance or loss of follow-up 
• Pregnant women or women of child bearing potential without negative pregnancy test 
Additional inclusion criteria for the Right-Heart-Substudy: 
• Inability to cooperate to transthoracic echocardiography 
 
4.3. Study Enrollment Procedures and Informed Consent 
 
At Aarhus University Hospital, 269 patients were enrolled into the SWEDEGRAFT trial. 
Patients were randomized from 10 September 2018 to 25 May 2020. Per initial SWEDEGRAFT 
protocol, patients were scheduled for follow-up visit after 2 years including interview (SAQ-7), 
measurement of eGFR, and electrocardiogram prior to CTA. A current amendment awaits 
approval to postpone follow-up visit with six months to compensate for the unforeseen delay 
caused by the COVID-19 pandemic. Consequently, follow-up is due 24-30 months after surgery. 
Eligible patients will together with the information regarding their scheduled SWEDEGRAFT 
follow-up 
visit 
receive 
written 
information 
regarding 
the 
Right-Heart-Substudy 
(“Deltagerinformation om deltagelse i et videnskabeligt forsøg”), and a brochure regarding 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
13 
 
volunteer’s rights in a health science research project (“Forsøgspersoners rettigheder i et 
sundhedsvidenskabeligt forsknings-projekt”). The information will emphasize that participation 
in any research project is voluntary and that she/he can any time without reason withdraw their 
consent and drop out. Patients must also be informed that withdrawing from the study will not 
affect their future medical care, treatment or benefits to which the patient is otherwise entitled. 
In consideration of the current threat of COVID-19, we chose to refrain from the usual 
recommendation to bring a companion for the follow-up visit according to hospital policy.  
Patients interested in participation will receive verbal information about the project by a research 
nurse in a quiet and undisturbed environment. All patients will be given the opportunity to ask 
questions about the study and will be given sufficient time to decide whether or not to participate 
in the study. The investigator is responsible for obtaining written informed consent from all 
patients prior to enrolment in the study. A copy of the informed consent form will be given to 
the patient. After informed consent has been obtained, an electronic case report form (eCRF) is 
created in the Research Electronic Data Capture (REDCap) electronic database hosted at Aarhus 
University (Harris 2009). Patients will be asked for permission to review their electronic records 
after five and ten years for clinical follow-up.  
 
4.4. Study duration and follow-up 
We expect approximately 90% of the Danish SWEDEGRAFT patients to fulfil the additional 
inclusion criteria and consent for the Right-Heart-Substudy. To include 230 patients, the 
approximate duration of the enrolment period is 19 months. 
 
 
5. 
MATERIALS AND METHODS 
 
5.1. Screening evaluation 
All patients included in the main SWEDEGRAFT study at Aarhus University Hospital scheduled 
for follow-up visit including CTA are eligible for the current Right-Heart-Substudy.  
 
5.2. Study treatment including perioperative management 
All patients included in the SWEDEGRAFT trial at Aarhus University Hospital patients received 
oral prophylaxis with 75mg acetylsalicylic acid once daily without discontinuation prior to 
surgery. Anaesthesia was induced and maintained with propofol, sufentanil, rocuronium and 
sevoflurane. We performed standard CABG with employment of the left internal mammary 
artery, and either no-touch or conventional great saphenous vein grafts according to their 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
14 
 
randomization. We used cardiopulmonary bypass with goal-directed perfusion management and 
normo- or mild hypothermia (approximately 34°C). Myocardial protection was achieved with 
intermittent cold antegrade blood cardioplegia (Harefield solution). The pericardium stayed open 
at the end of surgery in all patients. We intend to register all details of revascularization including 
graft flow measurements and any cases of incomplete revascularization for retrospective 
analysis. 
Postoperative pain was treated with paracetamol, morphine-like analgesics and ketorolac. We 
resumed acetylsalicylic acid and statin therapy on the first postoperative day. Patients received 
subcutaneous dalteparin 5000 IE once daily until fully mobilized. Patients were monitored for 
perioperative myocardial infarction with continuous telemetry, intraoperative transoesophageal 
echocardiography, focus assessed transthoracic echocardiography at arrival on intensive care 
(repeated on indication), 12-lead electrocardiograms (at arrival and on morning after surgery), 
and creatinkinase-MB measurements (every six hours after end of surgery until decreasing CK-
MB values). 
 
5.3. Endpoint Evaluations 
 
5.3.1. Follow-up 2D/3D-echocardiography (24-30 months after surgery) 
The present Right-Heart-Substudy is designed to gain insight regarding the long-term impact of 
CABG surgery on right heart function. Hence, we scheduled a full 2D and 3D echocardiography 
with special focus on RV function at the time of SWEDEGRAFT two-year follow-up. We intend 
to use a GE VIVID E95 system (GE Medical System, Horten, Norway) with a 2.5-MHz 
transducer for transthoracic echocardiography.  
For all image analysis EchoPAC version 203 (GE-Vingmed Ultrasound, Horten, Norway) will 
be used. All measurements will be the averaged over three consecutive heart cycles (six in terms 
of atrial fibrillation) in end-expiration. 3D and 2D echocardiography will be performed 
according to international guidelines (Lang 2015). In case of poor 3D image quality 2D images 
and/or a contrast agent (SonoVue/Optison) will be used to opacify both ventricles.  
The following parameters will be recorded by 2-dimensional echocardiography: LVEF, left 
ventricular end-diastolic (LVEDV) and systolic volume (LVESV) is assessed by the biplane disc 
method. Left and right atrial volume will be assessed by biplane area-length method indexed by 
body surface area (BSA). The interventricular septum and the posterior wall thickness will be 
obtained from the parasternal view. LV mass is calculated and indexed according to BSA. RV 
systolic function is assessed by the 3D-RV EF volumetric method, RV S´ is measured by lateral, 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
15 
 
pulsed tissue Doppler velocities. In addition, TAPSE is obtained from the lateral tricuspid plane. 
RV strain is calculated at the RV free wall (RV-FWS), which is used as the main measure, 
according to the guidelines, and at the total RV wall, which includes the interventricular septum 
and free wall (RV-GLS) (Lang 2015).  
 
5.3.2. Preoperative 2D-Echocardiography 
A routine 2D-echocardiography has been performed in all patients two to three months prior to 
CABG at Aarhus University Hospital to assess cardiac function including contractility, chamber 
size, hypertrophy, valvular dysfunction, and pericardial or pleural effusions. The 
echocardiographic images were digitally stored for offline analysis using commercially available 
software (EchoPAC version 203, GE-Vingmed Ultrasound, Horten, Norway). 
 
 
The echocardiographic RV parameters available on preoperative as compared to follow-up 
2D/3D echocardiography including normal cutoff values are depicted in the following chart. 
 
RV Parameters 
Preop 
ECHO 
Follow-up 
ECHO 
Normal cutoff value 
References 
RV 3D EF  
Right ventricular ejection fraction (3D) 
 
 
> 45 % 
Lang 2015 
RV-FWS  
Right ventricular free wall strain 
 
 
− 28.7% ± 4.1 
Meris 2010 
RV-GLS  
Right Ventricular Global Longitudinal Strain 
( ) 
 
- 
- 
RV FAC  
Right ventricular fractional area change 
( ) 
 
> 35% 
Lang 2015 
TAPSE  
Tricuspid Annular Plane Systolic Excursion  
( ) 
 
> 17 mm 
Lang 2015 
Tricuspid S’ velocity  
Peak systolic tricuspid annular velocity 
 
 
> 9.5 m/s 
Lang 2015 
RAV  
Right Atrial Volume 
 
 
< 30 mL/m2 
Lang 2015 
RAESA  
Right Atrial End-Systolic Area 
 
 
< 18 mm2 
Lang 2015 
RVD 
Right Ventricular Diameter 
 
 
Base <41 mm 
Midtventricular <35mm 
Length <83 mm 
Lang 2015 
 
  
 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
16 
 
5.2.3. CTA 
According to the main SWEDEGRAFT protocol, study participants are scheduled for CTA 24-
30 months after surgery to assess patency of the saphenous vein grafts. Vein graft patency in 
patients with conventional skeletonized as compared to no-touch grafts represents the primary 
endpoint of the SWEDEGRAFT trial. The data set is then sent to Uppsala Clinical Research 
Center in encrypted form, without patient identification other than study number for further 
analyses and for compiling the study results. Patency is assessed and classified by blinded and 
independent cardiac radiologists at a core lab at Uppsala Clinical Research Center.  
Prior to CTA, all patients receive a blood sample to measure renal function to ensure an 
eGRF/1.73m2 (CKD-EPI) ≥ 35 ml/min. The optimal heart rate for CTA is below 60 
beats/minute. Thus, an electrocardiogram is performed to exclude bradycardia, atrioventricular 
block, and cardiac dysfunction. In the electronic patient record it will be noted that the patient 
has been examined according to the SWEDEGRAFT protocol. 
 
5.2.4. Seattle Angina Questionnaire-7 
According to the main SWEDEGRAFT protocol, patients will complete a SAQ-7 questionnaire 
at two-year follow-up. Patients are asked seven questions in order to measure their current health 
status with focus on three domains: Physical Limitation, Angina Frequency, and Quality of Life.  
The SAQ-7 is a well-established, valid, and reliable tool with prognostic value to measure health 
status in patients with coronary artery disease (Chan 2014). It results three subscales and a 
summary scale that extend from 0 (worst possible health state) to 100 (best possible health state).  
 
5.2.5. NYHA class  
We use the NYHA functional classification system for functional classification of patients with 
heart failure. The method has been revised since introduction in 1928, most recently in 1994 
(Dolgin 1994). Patients are placed in one of four categories based on how much they are limited 
by dyspnea during physical activity. Appendix 2 displays the official Danish version of the 
NYHA classification. Limitations of the NYHA functional classification system are its high 
interoperator variability (Raphael 2007), and the fact that it offers information about the onset 
of symptoms only (Ponikowski 2016).  
 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
17 
 
5.2.6. Borg CR 10® 
The Borg CR10® Scale ranges from 0 “Nothing at all” to the value of 10 “Maximal” with verbal 
descriptors missing for values 6 and 8. Patients are asked to rate their level of perceived 
breathlessness (dyspnoea) during exercise. Appendix 3 displays the official Danish version 
approved by the author in 2007. 
 
5.2.7. Laboratory Examination 
According to the SWEDEGRAFT protocol, all patients receive a blood sample to measure renal 
function to ensure an eGRF/1.73m2 (CKD-EPI) ≥ 35 ml/min prior to CTA. We supplement 
measurements of haemoglobin, and brain natriuretic peptide (BNP), in order to fully adjust our 
results for laboratory findings, which are important risk factors for heart failure. 
 
5.2.8. In-hospital details derived from electronic patient record 
• Details from the operations report (preoperative lesions, grafts incl. flow and pulsatile index, 
length of surgery, length of cardiopulmonary bypass, cross-clamp time, areas of incomplete 
revascularization) 
• Signs of perioperative myocardial damage (postoperative CK-MB, ECG, and 
echocardiography) 
 
5.2.9. Long-term Major Adverse Cardiac and Cerebrovascular Events  
According to SWEDEGRAFT protocol, the MACCE rate is registered at 2-year follow-up  
after review of the electronic patient record. MACCE are defined as:  
• Death from any cause (cardiovascular and non-cardio-vascular mortality). 
• Myocardial infarction 
• Repeat hospitalization due to cardiac cause 
• Cerebrovascular accident 
• Repeat revascularization 
We intend to review the electronic patient record for MACCE 5- and 10 years after surgery in 
order to correlate cardiac function to long-term clinical outcome. 
 
 
 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
18 
 
5.3. Schedule of evaluations 
 
 
Initial 
Hospitalization 
24-30 months 
Follow-up 
5-year 
Follow-up 
10-year 
Follow-up 
Initiation procedures 
 
 
 
 
Eligibility* 
 
 
 
 
Demographics* 
 
 
 
 
Informed consent & 
randomization* 
 
 
 
 
Surgery* 
 
 
 
 
Investigations 
 
 
 
 
Echocardiography  
       *(2D) 
         
(2D/3D) 
 
 
Haemoglobin, ProBNP 
 
 
 
 
12-lead ECG* 
 
 
 
 
eGFR* 
 
 
 
 
CTA* 
 
 
 
 
SAQ-7* 
 
 
 
 
NYHA class 
 
 
 
 
Borg CR 10® 
 
 
 
 
MACCE 
 
  * 
 
 
 
Borg CR 10®= BORG category-ratio 10 scale; CT= Computed Tomography; eGFR= estimated 
Glomerular Filtration Rate; ECG= Electrocardiogram; MACCE = Major Adverse Cardiac and 
Cerebrovascular Events; NYHA= New York Heart Association; Seattle Angina Questionnaire= 
SAQ-7. * Elements of the main SWEDEGRAFT study to be included in the Right-Heart-Substudy  

Protocol  
Version 1.6 
10.12.2020
 
                                                           
19 
 
6.  
SAFETY ASPECTS 
 
6.1. Insurance 
The investigators will be covered by the liability and work injury insurance taken out by Aarhus 
University Hospital. Participants are covered by the act on complaints and compensation within 
the health care system. 
 
6.2.  Adverse events 
All patients included in the study are given standard care. Per SWEDEGRAFT protocol, 
information about wound healing in the harvesting site on the leg are registered. No adverse 
events are anticipated in this observational study in conjunction with: 
• Transthoracic echocardiography 
• Acquisition of the NYHA class and Borg CR 10® 
• Determination of haemoglobin and ProBNP in the blood sample drawn for eGFR analysis 
• Review of the electronic patient record at 5- and 10-years.  
 
 
7.  
STATISTICS CONSIDERATIONS 
 
7.1. General design issues  
The SWEDEGRAFT study is an open-label randomized trial. However, evaluation of health 
status by means of questionnaires and echocardiographies will be performed by a study nurse 
and investigators blinded regarding the allocation to ensure unbiased ascertainment of outcomes. 
  
7.2. Determination of Sample Size and randomization 
 
The present Right-Heart-Substudy aims to determine the prevalence and scale of RV dysfunction 
as measured by 3D RV EF two years after CABG. To the best of our knowledge, no prior study 
has described the prevalence of chronic RV dysfunction after CABG applying this technology. 
The best prospective study available in this field of enquiry offers a follow-up of up to one year 
after CABG using 2D echocardiographic measurements (Roshanali 2008).  
As a prevalence study there is no hypothesis to test and the size of the study is determined by 
how accurately we want to determine the prevalence. Based on the formula suggested by 
Viechtbauer et al., a sample size of N=194 will suffice to identify impaired 3D RV EF (< 45%) 
with a prevalence down to 2% with a 98% confidence (Viechtbauer 2015). In order to ensure a 
complete dataset, we aim to include a total of 230 participants. 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
20 
 
 
7.3. Stopping rules 
Patients enrolled may withdraw voluntarily from study participation at any time and for any 
reason. If voluntary withdrawal occurs, the subject will be asked for permission to be followed 
for clinical outcome. 
 
7.4. Data analyses 
Tracking of outcome measures will begin at randomization and continue until death or end of 
follow-up (10 years after CABG). Continuous variables will be presented as mean ± standard 
deviation (SD) if normally distributed, otherwise as median with interquartile range (25th and 
75th percentile), minimum and maximum values. Discrete variables will be presented in 
frequencies and percentages. Kaplan-Meier plots will be constructed to visualize time to event 
variables and log-rank tests will be used. 
All statistical analyses will be done using Stata 15.0 (Stata Corp., College Station, USA). 
Statistical assistance is provided by the Department of Biostatistics, Aarhus University. 
 
 
8. 
DATA COLLECTION AND QUALITY ASSURANCE 
 
8.1. Data collection 
Study data are collected and managed using REDCap electronic data capture tools hosted at 
Aarhus University (Harris 2009). REDCap is a secure, web-based application designed to 
support data capture for research studies, providing: 1) an intuitive interface for validated data 
entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless data downloads to common statistical packages; and 4) procedures for 
importing data from external sources. An eCRF will be constructed for data registration.  
Study data from the main SWEDEGRAFT trial are stored in the PheedIT data capture tool hosted 
at Uppsala Clinical Research Center, and acknowledged as sole property of sponsor Stefan 
Thelin. We have requested permission from the SWEDEGRAFT sponsor and steering 
committee to utilize data from Aarhus patients for the purpose of the Right-Heart-Substudy. 
Relevant data (demographics, medical history, surgery, randomization, 3-month telephone 
follow-up and the SAQ-7 questionnaire) will be imported into Aarhus University REDCap 
electronic database for analysis and interpretation of the Right-Heart-Substudy results. 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
21 
 
 
9.2 
Data management  
 Data will be handled, processed, and archived according to the guidelines of the Data Protection 
Agency. Each participant will be given an identification number at enrolment. Each 
identification number will have an eCRF. The list over identification codes will be deleted at the 
end of the study. All trial data including Trial Master File, eCRF, the source datasheet of the 
CRF, and the list over identification codes will be stored in the external server REDCap with 
continuous backup. REDCap data are kept for 10 years. Information on study participants will 
be protected according to the Act of Processing of Personal Data, and the Health Act. No study 
data will be given to third parties or insurance companies. Clinical findings of relevance for 
patient health will as soon as available be passed on to the physician responsible for patient care. 
 
9.3. Training 
All investigators and research nurses conducting this study provide a Good Clinical Practice 
certificate prior to start of the study. All technicians performing echocardiographic procedures 
will be required certification organized by the European Association of Cardiovascular Imaging 
(EACVI). 
 
 
10. 
ECONOMY 
 
The main SWEDEGRAFT study is funded by non-commercial unrestricted grants 
(Vetenskapsråd 17,2 Millioner SEK, Hjärt-Lungfonden 5 Millioner SEK). Partial salary support 
for the principal investigator Ivy S. Modrau, and the co-investigator Jesper K. Jensen is provided 
by a grant of the Health Research Foundation of Central Denmark Region, and the Department 
of Cardiology at Aarhus University Hospital, respectively. The Department of Clinical Medicine 
at Aarhus University covers costs for statistical assistance. Expenses for 3D echocardiographies, 
biochemical analysis, study trial nurse, secretary assistance for data entry, and REDCap 
datamanager will be applied for at non-commercial private and public foundations. 
The funding sources have no role during on protocol, trial conduction, analysis or interpretation 
of data, and publication of the results. Participation in the study confers no financial benefit on 
the patients, but the expenses for transportation are reimbursed. 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
22 
 
11. 
ETHICAL CONSIDERATIONS 
 
11.1. Risk of study intervention 
We expect an additional expenditure of time (approximately 60-90 minutes for 
echocardiography, NYHA and Borg CR 10 assessment), but no increased risk for 
SWEDEGRAFT patients who consent to participate in the Right-Heart-Substudy. The current 
study involves no increased risk of discomfort or bruising due to blood sampling, as haemoglobin 
and ProBNP are analyzed in the SWEDEGRAFT blood sample scheduled for control of renal 
function prior to computed tomography. 
We believe that the risk of study participation is minimal and outweighed by the value of the 
knowledge gained through this study. Participants will not derive any individual benefit from 
study participation. Costs of transportation to the clinical follow-up visit are refunded through 
participation in the main SWEDEGRAFT study. 
 
11.2. Conflict of interest 
 
The study has been initiated solely by the investigators. The investigators have no conflict of 
interest to declare and no commercial interest to conduct the study.  
 
11.3. Approval 
 
The main SWEDEGRAFT study was approved by the regional Human Research Ethics 
Committee in Uppsala, Sweden (Registration number 2016/363, with amendments 2019-00155 
and 2019-04214) and the Central Denmark Region Committees on Biomedical Research Ethics 
(Identification number 1-10-72-207-18, 2 August 2018; amendments 30 October 2019). Prior to 
start of the Right-Heart-Substudy, approval will be applied for at both committees.  The substudy 
will be registered at www.clinicaltrials.gov. All patients are required written informed consent 
before participation. The protocol follows the Declaration of Helsinki-II and Consort guidelines. 
The trial will be performed in compliance with Good Clinical Practice.  
 
 
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
23 
 
12 
COOPERATION AND PUBLICATION POLICYs 
 
The study is performed in collaboration between the Department of Cardiothoracic and Vascular 
Surgery at Aarhus University Hospital, the Department of Cardiology at Aarhus University 
Hospital, the Institute for Clinical Medicine at Aarhus University, and the Department of 
Surgical Science, Thoracic Surgery at Uppsala University. The department of Cardiology at 
Aarhus University dispose over all the knowledge and equipment needed for carrying out the 
echocardiographic analyses. 
Results, whether positive, negative or inconclusive, will be published in the best peer-reviewed 
scientific journals possible and be presented at international conferences meetings in the field of 
cardiology. All above-mentioned investigators are expected to receive authorships according to 
the Vancouver declaration.  
 
13  
PLANNED TIMELINE 
Protocol complete  
November 
 
2020 
Approval from Science Ethics committee 
December 
 
2020 
Enrollment 
January 2021  
- 
November 2022 
Data collection 
January 2021 
-  
November 2032 
Data analysis 
August 2018  
-  
December 2032  
Publication 
 
 
2023 and 2032 
 
 
14  
PERSPECTIVES 
In Denmark, more than 45 CABG operations are conducted per 100 000 inhabitants per year 
(Eurostat 2020). The current study will clearly define the prevalence and scope of significant RV 
depression following this common surgical procedure. We expect to resolve the apparent 
contradiction of undisputable echocardiographic signs of RV depression after cardiac surgery 
and the lack of clinical signs of RV failure.   
 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
24 
 
15 
REFERENCES 
Use the "Insert Citation" button to add citations to this document. 
 
 
Alam M, Hedman A, Nordlander R, Samad B. Right ventricular function before and after an 
uncomplicated coronary artery bypass graft as assessed by pulsed wave Doppler tissue imaging 
of the tricuspid annulus. Am Heart J 2003;146: 520-6 
 
Antoni ML et al. Prognostic Value of Right Ventricular Function in Patients After Acute 
Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention. Cardiovasc 
Imaging 2010;3:264-271 
 
Badano LP, Kolias TJ, Muraru D, et al. Standardization of left atrial, right ventricular, and right 
atrial deformation imaging using two-dimensional speckle tracking echocardiography: a 
consensus document of the EACVI/ASE/Industry Task Force to standardize deformation 
imaging. Eur Heart J Cardiovasc Imaging 2018;19:591-600 
 
Bootsma IT, de Lange F, Koopmans M, Haenen J, Boonstra PW, Symersky T, et al. Right 
Ventricular Function After Cardiac Surgery Is a Strong Independent Predictor for Long-Term 
Mortality. 
J 
Cardiothorac 
Vasc 
Anesth. 
2017;31:1656–62. 
Available 
from: 
http://dx.doi.org/10.1053/j.jvca.2017.02.008 
 
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377–81 
 
Brookes CIO, White PA, Bishop AJ, Oldershaw PJ, Redington AN, Moat NE. Validation of a 
new intraoperative technique to evaluate load- independent indices of right ventricular 
performance in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 
1998;116:468–76  
 
Chan PS, Jones PG, Arnold SA, et al. Development and validation of a short version of the 
Seattle 
Angina 
Questionnaire. Circ 
Cardiovasc 
Qual 
Outcomes 2014;7:640–7. 
doi:10.1161/CIRCOUTCOMES.114.000967 
 
Cohen DJ, Van Hout B, Serruys PW, et al. Quality of life after PCI with drug-eluting stents or 
coronary-artery bypass surgery. N Engl J Med 2011;364:1016-26. 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
25 
 
Dalén M, Oliveira Da Silva C, Sartipy U, Winter R, Franco-Cereceda A, Barimani J et al. 
Comparison of right ventricular function after ministernotomy and full sternotomy aortic valve 
replacement: a randomized study. Interact CardioVasc Thorac Surg 2018;26:790–7 
 
David JS, Tousignant CP, Bowry R. Tricuspid annular veloity in patients undergoing cardiac 
operation using transesophageal echocardiography. J Am Soc Echocardiogr 2006;19: 329-34 
 
Diller G, Wasan B, Kyriacou A, Patel N, Casula R, Athanasiou T, Francis D, Mayet J. Effect of 
coronary artery bypass surgery on myocardial function as assessed by tissue doppler 
echocardiography. Eur J Cardiothorac Surg 2009; 34: 995-9 
 
Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria 
Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th 
ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994 
Eurostat Statistics explained. Cardiovascular diseases statistics [Internet]. 2016 [cited 2020 Sep 
29]. Available from:  
http://ec.europa.eu/eurostat/statistics-explained/index.php/Cardiovascular_diseases_statistics 
 
Fine NM, Chen L, Bastiansen PM, et al. Outcome prediction by quantitative right ventricular 
function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc 
Imaging 2013;6:711-21 
 
Grant AD, Smedira NG, Starling RC, Marwick TH. Independent and incremental role of 
quantitative right ventricular evaluation for the prediction of right ventricular failure after left 
ventricular assist device implantation. J Am Coll Cardiol 2012;60:521-8 
 
Haber I, Metaxas DN, Geva T, Axel L. Three-dimensional systolic kinematics of the right 
ventricle. Am J Physiol Heart Circ Physiol 2005;289:1826–33 
 
Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, 
part II: pathophysiology, clinical importance, and management of right ventricular failure. 
Circulation 2008;117:1717–31. doi: 10.1161/CIRCULATIONAHA.107.653584 
 
Hamada-Harimura Y, Seo Y, Ishizu T, Nishi I, Machino-Ohtsuka T, Yamamoto M, Sugano A, 
Sato K, Sai S, Obara K, Yoshida I, Aonuma K; for the ICAS-HF Investigators. Incremental 
prognostic value of right ventricular strain in patients with acute decompensated heart failure. 
Circulation Cardiovascular Imaging 2018;11:e007249. 
doi:10.1161/CIRCIMAGING.117.007249 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
26 
 
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data 
capture (REDCap) - A metadata-driven methodology and workflow process for providing 
translational research informatics support. J Biomed Inf. 2009;42:377–81 
 
Hedman A, Alam M, Zuber E, Nordlander R, Samad BA. Decreased right ventricular function 
after coronary bypass grafting and its relation to exercise capacity: a tricuspid annular motion-
based study. J Am Soc Echocardiogr 2004;17(2): 126-31 
 
Iacoviello M, Citarelli G, Antoncecchi V, Romito R, Monitillo F, Leone M, Puzzovivo A, 
Lattarulo MS, Rizzo C, Caldarola P, Ciccone MM. Right ventricular longitudinal strain 
measures independently predict chronic heart failure mortality. Echocardiography 2016; 
33:992–1000. doi: 10.1111/echo.13199 
 
Il’Giovine ZJ, Mulder H, Chiswell K, Arges K, Tomfohr J, Hashmi A, Velazquez EJ, Kisslo JA, 
Samad Z, Rajagopal S. Right ventricular longitudinal strain reproducibility using vendor-
dependent and vendor-independent software. J Am Soc Echocardiogr 2018;31:721.e5–32.e5. 
doi: 10.1016/j.echo.2018.01.008 
 
Jamal F, Bergerot C, Argaud L, Loufouat J, Ovize M. Longitudinal strain quantitates regional 
right ventricular contractile function. Am J Physiol Heart Circ Physiol 2003;285:H2842-7 
 
Keyl C, Schneider J, Beyersdorf F, Ruile P, Siepe M, Pioch K et al. Right ventricular function 
after aortic valve replacement: a pilot study comparing surgical and transcatheter procedures 
using 3D echocardiography. Eur J Cardiothorac Surg 2016;49:966–71 
 
Kim HM et al. Myocardial Strain in Prediction of Outcomes After Surgery for Severe Mitral 
Regurgitation. JACC Cardiovasc Imaging 2018;11:1235-1244. doi: 10.1016/j.jcmg.2018.03.016 
 
Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster 
E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, 
Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by 
echocardiography in adults: an update from the American Society of Echocardiography and the 
European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39.e14 
 
Leong DP, Grover S, Molaee P, et al. Nonvolumetric echocardiographic indices of right 
ventricular systolic function: validation with cardiovascular magnetic resonance and relationship 
with functional capacity. Echocardiography 2012;29 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
27 
 
López-Candales A, Dohi K, Rajagopalan N, Edelman K, Gulyasy B, Bazaz R. Defining normal 
variables of right ventricular size and function in pulmonary hypertension: an echocardiographic 
study. Postgrad Med J 2008;84:40-5 
 
Lu KJ, Chen JX, Profitis K, et al. Right ventricular global longitudinal strain is an independent 
predictor of right ventricular function: a multimodality study of cardiac magnetic resonance 
imaging, real time threedimensional echocardiography and speckle tracking echocardiography. 
Echocardiography 2015;32:966-74 
 
Meluzin J, Spinarova L, Bakala J, Toman J, Krejci J, Hude P, Kára T, Soucek M. Pulsed Doppler 
tissue imaging of the velocity of tricuspid annular systolic motion. A new, rapid, and non-
invasive method of evaluating right ventricular systolic function. Eur Heart J 2001;22:340–8 
 
Meris A, Faletra F, Conca C, Klersy C, Regoli F, Klimusina J, Penco M, Pasotti E, Pedrazzini 
GB, Moccetti T, Auricchio A. Timing and magnitude of regional right ventricular function: a 
speckle tracking-derived strain study of normal subjects and patients with right ventricular 
dysfunction. J Am Soc Echocardiogr 2010;23:823–31 
 
Mertens LL, Friedberg MK. Imaging the right ventricle–current state of the art. Nat Rev Cardiol 
2010;7:551–63 
 
Morris DA, Krisper M, Nakatani S, Köhncke C, Otsuji Y, Belyavskiy E, Radha Krishnan AK, 
Kropf M, Osmanoglou E, Boldt LH, Blaschke F, Edelmann F, Haverkamp W, Tschöpe C, 
Pieske-Kraigher E, Pieske B, Takeuchi M. Normal range and usefulness of right ventricular 
systolic strain to detect subtle right ventricular systolic abnormalities in patients with heart 
failure: A multicentre study. Eur Heart J Cardiovasc Imaging 2017;18:212–23. doi: 
10.1093/ehjci/jew011 
 
Nagata Y, Wu VC, Kado Y, Otani K, Lin F, Otsuji Y, Negishi K, Takeuchi M. Prognostic value 
of right ventricular ejection fraction assessed by transthoracic 3D echocardiography. Circ 
Cardiovasc Imaging 2017;10:e005384. DOI: 10.1161/CIRCIMAGING.116.005384 
 
Okada DR, Rahmouni HW, Herrmann HC, Bavaria JE, Forfia PR, Han Y. Assessment of right 
ventricular function by transthoracic echocardiography following aortic valve replacement. 
Echocardiography 2014;31:552-7 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
28 
 
Park SJ, Park JH, Lee HS, et al. Impaired RV global longitudinal strain is associated with poor 
long-term clinical outcomes in patients with acute inferior STEMI. JACC Cardiovasc Imaging 
2015;8:161-9 
 
Ponikowski P, Voors AA, Anker SD et al. ESC Scientific Document Group. 2016 ESC 
Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 
2016;37:2129-200 
 
Ragnarsson S, Janiec M, Modrau IS, Dreifaldt M, Ericsson A, Holmgren A, Hultkvist H, 
Jeppsson A, Sartipy U, Ternström L, Per Vikholm MD, de Souza D, James S, Thelin S. No-
touch saphenous vein grafts in coronary artery surgery (SWEDEGRAFT): Rationale and design 
of a multicenter, prospective, registry-based randomized clinical trial. Am Heart J 2020;224:17-
24. doi: 10.1016/j.ahj.2020.03.009. Epub 2020 Mar 13. 
 
Raphael C, Briscoe C, Davies J, Whinnett ZI, Manisty C, Sutton R, Mayet J, Francis DP. 
Limitations of the New York Heart Association functional classification system and self-
reported walking distances in chronic heart failure. Heart 2007;93:476–82. doi: 
10.1136/hrt.2006.089656 
 
Roshanali F, Yousefnia MA, Mandegar MH, Rayatzadeh H, Alinejad S. Decreased Right 
Ventricular Function after Coronary Artery Bypass Grafting. Tex Heart Inst J 2008;35: 250-5 
 
Rudski LG et al. Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: 
A Report from the American Society of Echocardiography. J Am Soc Echocardiogr 
2010;23:685-713 
 
Sandstede JJ, Beer M, Hofmann S, Lipke C, Harre K, Pabst T et al. Changes in left and right 
ventricular cardiac function after valve replace- ment for aortic stenosis determined by cine MR 
imaging. J Magn Reson Imaging 2000;12:240–6 
 
 
Smiseth OA, Torp H, Opdahl A, Haugaa KH, Urheim S. Myocardial strain imaging: how useful 
is it in clinical decision making? Eur Heart J 2016;37:1196-207 
 
Sousa-Uva M, Neumann FJ, Ahlsson A, Alfonso F, Banning AP, Benedetto U, et al. 2018 
ESC/EACTS Guidelines on myocardial revascularization. Eur J Cardiothorac Surg 2019;55:4–
90. 
 

Protocol  
Version 1.6 
10.12.2020
 
                                                           
29 
 
Tamborini G, Muratori M, Brusoni D, Celeste F, Maffessanti F, Caiani EG, Alamanni F, Pepi 
M. Is right ventricular systolic function reduced after cardiac surgery? A two- and three-
dimensional echocardiographic study. Eur J Echocardiogr 2009;10:630–64 
 
Unsworth B, Casula RP, Kyriacou AA, Yadav H, Chukwuemeka A, Cherian A, Stanbridge RL, 
Athanasiou T, Mayet J, Francis, DP. The right ventricular annular velocity reduction caused by 
coronary artery bypass graft surgery occurs at the moment of pericardial incision. Am Heart J 
2010; 159: 314-22. doi:10.1016/j.ahj.2009.11.013 
 
Viechtbauer W, Smits L, Kotz D, Budé L, Spigt M, Serroyen J, Crutzen R. A simple formula for 
the calculation of sample size in pilot studies. J Clin Epidemiol 2015;68:1375-9 
 
Zanobini M, Saccocci M, Tamborini G, Veglia F, Di Minno A, Poggio P, Pepi M, Alamanni F, 
Loardi C. Postoperative echocardiographic reduction of right ventricular function: is pericardial 
opening modality the main culprit? Biomed Res Int 2017:4808757. doi: 10.1155/2017/4808757