Left Ventricular Reverse Remodeling Outcomes Evaluation in Patients With Aortic Regurgitation After Surgical Treatment
Conditions: Aortic Valve Regurgitation, Mitral Valve Regurgitation, Left Ventricle Dilated, Left Atrium Dilated, Systolic Left Ventricular Heart Failure, Diastolic Heart Failure
Sponsor: Petrovsky National Research Centre of Surgery

 
 
 
 
 
 
 
 
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CLINICAL RESEARCH PROTOCOL  
  
  
  
1. TITLE OF THE STUDY  
  
Assessment of outcomes of reverse remodeling of the left ventricle in patients with 
aortic valve insufficiency after surgical correction  
 
  
  
Protocol version 1.1   
Last updated: 20/03/2024 
Clinical trials Organization's Unique Protocol ID: 173538086 
 
  
  
  
  
2. SPONSORSHIP  
  
None, initiative study 
  
  
   
  
3. DETAILS  
  
Principal investigators: 
Charchyan Eduard Rafaelovich, Doctor of Medical Sciences, Professor, 
Corresponding Member of the RAS, Head of Cardiac Surgery Department No. 1 
Federal State Budgetary Research Institution “Russian research center of surgery 
named after academician B.V. Petrovsky” 
 
Bulynin Andrey Andreevich, Federal State Budgetary Research Institution “Russian 
research center of surgery named after academician B.V. Petrovsky”; 

 
 
 
 
 
 
 
 
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cardiovascular surgeon of Cardiac Surgery Department No. 1 BUZ VO 'Voronezh 
Regional Clinical Hospital No. 1' 
 
  
  
  
Document type: Protocol   
  
Document number: PRTCL- V 1.1   
  
Creation date of the first version: 01 October 2023 
  
Approval date (by all researchers): 01/05/2024  
  
Effective date: 01/05/2024  
  
NCT:  **********  
   
  
  
   
  
4. SIGNATURES  
  
RESEARCHERS' SIGNATURES 
I agree to conduct the study described above in accordance with the protocol, GCP, and 
applicable regulatory requirements. All information related to the study will be treated 
confidentially. 
 
Full Name 
Position 
Signature 
Date 
Charchyan Eduard 
Rafaelovich, MD, 
PhD, professor 
corresponding 
member of the 
RAS, head of the 
cardiac surgery 
department No. 1 
Petrovsky 
National Research 
Center of Surgery  
 
 
01.05.2024 
Bulynin Andrey 
Andreevich 
cardiovascular 
surgeon of the 
cardiac surgery 
department No. 1 
BUZ VO 
'Voronezh 
Regional Clinical 
Hospital No. 1' 
 
01.05.2024 

 
 
 
 
 
 
 
 
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5. CONFIDENTIALITY POLICY  
This document contains confidential information that should not be disclosed outside 
the research team, regulatory authorities, and members of the local ethics committee.  
  
 
 

 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
  
 
1. TITLE OF THE STUDY .................................................................................................. 1 
2. SPONSORSHIP ............................................................................................................... 1 
3. DETAILS ......................................................................................................................... 1 
4. SIGNATURES ................................................................................................................. 2 
5. CONFIDENTIALITY POLICY ........................................................................................ 3 
6. HISTORY OF CHANGES ............................................................................................... 6 
7. PROTOCOL SYNOPSIS .................................................................................................. 6 
8. ABBREVIATIONS ........................................................................................................ 10 
9. INTRODUCTION .......................................................................................................... 12 
9.1 Introduction and Research Hypothesis .................................................................... 12 
9.2 General Information ................................................................................................ 12 
9.3 Study Rationale ........................................................................................................ 12 
10. OBJECTIVES AND ENDPOINTS OF THE STUDY ................................................... 14 
10.1  
Objectives ........................................................................................................ 14 
11. Study design ................................................................................................................. 15 
11.1  
General Provisions ........................................................................................... 15 
11.2  
Definition of the study group ........................................................................... 15 
11.2.1 Inclusion Criteria .................................................................................................................................. 15 
11.2.2 Non-inclusion Criteria .......................................................................................................................... 15 
11.2.3 Exclusion Criteria ................................................................................................................................. 16 
12. ASSESSMENT METHODS AND PROCEDURES ...................................................... 17 
12.1  
Preliminary Screening (Visit 0) ....................................................................... 18 
12.2  
Early postoperative examination (Examination 2) .......................................... 18 
12.3  
Assessment 9-14 days after surgery (Examination 3) ...................................... 18 
12.4  
First outpatient visit (Examination 4) .............................................................. 18 
12.4  
Outcome assessment ........................................................................................ 20 
12.4.1 History taking ....................................................................................................................................... 20 
12.4.2 Demographic data ................................................................................................................................ 20 
12.4.3 Objective examination .......................................................................................................................... 20 
12.4.4 Height and weight ................................................................................................................................ 20 
12.4.5  
Electrocardiography (ECG) ........................................................................................................... 20 
12.4.6 
ECHO-cardiography ...................................................................................................................... 20 
12.4.7  
Questionnaires ............................................................................................................................... 21 
12.4.7 
6-Minute Walk Test ....................................................................................................................... 21 

 
 
 
 
 
 
 
 
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13.11  
Definition of the term 'End-of-study' ............................................................... 22 
15. PROTOCOL COMPLIANCE ....................................................................................... 22 
15.1  
Amendments to the Protocol ............................................................................ 22 
16. ACCESS TO STUDY DATA ......................................................................................... 23 
17. DATA PROCESSING AND STORAGE ....................................................................... 23 
17.1  
Data collection, primary information, and individual registration cards (IRC)
 
23 
18. ETHICAL ASPECTS ................................................................................................... 24 
18.1  
Ethical principles of conducting the study ....................................................... 24 
18.2  
Approvals ......................................................................................................... 24 
18.3  
Informed Voluntary Consent ........................................................................... 24 
18.4  
Patient Confidentiality ..................................................................................... 25 
19. FUNDING ................................................................................................................... 25 
20. CLINICAL TRIAL REPORT AND PUBLICATION POLICY ...................................... 26 
20.1  
Clinical trial report .......................................................................................... 26 
20.2  
Publication Policy ............................................................................................ 26 
21. PROPOSED STUDY SCHEDULE ............................................................................... 26 
22. APPENDICES ............................................................................................................. 26 
22.1 Appendix 1. “EQ-5D Quality of Life Questionnaire” .................................................. 26 
22.2 Appendix 2. “Minimal Transthoracic Echocardiography Protocol” ............................ 28 
24. REFERENCES ............................................................................................................ 47 
 
 
  
  
 
 

 
 
 
 
 
 
 
 
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6. HISTORY OF CHANGES  
  
Version  
Approval 
Date  
Summary of Changes  
Version 
1.0  
01.11.2023 
Initial Draft  
Version 
1.1 
20.03.2024 
Changes made regarding the development of the 
information booklet 
 
  
7. PROTOCOL SYNOPSIS  
  
Study Title  
Assessment of the left ventricle reverse remodeling outcomes 
in patients with aortic valve insufficiency after surgical 
correction 
Sponsor  
Investigator-Initiated Study  
Study Phase  
Phase III  
Hypothesis  
We hypothesize that surgical correction of functional mitral 
regurgitation during interventions for chronic aortic valve 
insufficiency in patients with significant dilatation of the left 
heart chambers affects the reverse remodeling of the left 
ventricle in the postoperative period. 

 
 
 
 
 
 
 
 
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Research 
objectives and 
tasks  
Research objective:  
 
To assess myocardial reverse remodeling in patients with 
significant left ventricular dilation caused by chronic aortic 
regurgitation, depending on the degree of mitral valve 
insufficiency and surgical approach. 
  
Main objectives of the study:  
1. 
To evaluate the short-term and long-term outcomes of 
aortic valve replacement for aortic valve insufficiency in 
patients with significant left ventricular dilation 
2. 
To compare the results of myocardial reverse 
remodeling depending on the strategy regarding 
functional mitral valve insufficiency at 3 and 12 months 
post-surgery 
3. 
To determine preoperative predictors of an unfavorable 
left ventricle function and architecture recovery 
prognosis.  
4. 
Assess the patients life quality 12 months after surgery 
5. 
Develop a clinical protocol for simultaneous surgical 
treatment of mitral regurgitation during aortic valve 
replacement in patients with significant left ventricular 
myocardial remodeling caused by chronic aortic 
regurgitation 
    
Study design  
This study is a multicenter, comparative, prospective  
Inclusion 
criteria  
 
 
 
1. Age over 18 years 
2. Proposed primary elective surgical intervention for 
chronic aortic regurgitation 
3. Presence of functional mitral regurgitation 
4. Left Ventricular End-Diastolic Volume 250 ml³ 
 
Exclusion 
criteria 
1. Infectious endocarditis 
2. Previous myocardial infarction 
3. Necessity for simultaneous myocardial revascularization 
4. Acute aortic regurgitation 
5. Previously established left ventricular dilation not 
associated with the development of aortic regurgitation 
6. Lack of informed consent 
Number of 
study subjects  
120 patients  

 
 
 
 
 
 
 
 
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Investigated 
procedure  
It is planned to study the initial and long-term results of left 
ventricle reverse remodeling in patients with aortic 
regurgitation, depending on the strategy chosen for the 
correction of functional mitral regurgitation and its severity. 
Duration of 
observation  
12 months after surgical treatment 
Methods of 
statistical 
evaluation  
The determination of the significance of differences between 
quantitative data of unrelated samples will be carried out using 
the Student's t-test under the condition of normal distribution; 
in the case of non-normal distribution, the Mann-Whitney test, 
White's test, Van der Waerden test, and Kolmogorov-Smirnov 
test are planned to be used. In the case of analyzing the 
significance of differences in quantitative data in related 
samples with a normal distribution, the paired Student's t-test is 
planned to be used; in the case of non-normal distribution, the 
Wilcoxon test and sign test will be used. Qualitative data 
analysis will be performed using the χ2 test and the McNemar 
test. To assess the reliability of the relationship between 
quantitative data, regression analysis, Pearson's correlation 
coefficient, Spearman's rank correlation coefficient, and 
Kendall's correlation coefficient are planned to be used. 
Descriptive and analytical statistical methods will be finalized 
after analyzing the sample size. To eliminate the influence of 
differences in baseline clinical parameters on the study 
outcome, a propensity score matching analysis (PSM) is 
planned between the ordinary 'Unmatched' groups using the 
nearest neighbor matching method for 1:1 pair matching. 
 
Demographic data and clinical indicators will be presented 
using descriptive statistics (absolute indicators and percentage 
shares for categorical variables, or mean ± standard deviation 
for normally distributed continuous variables; for continuous 
variables with non-normal distribution, the median and 
interquartile range will be specified). The significance of 
differences in repeated measurements will be analyzed using 
ANOVA. 
  
  

 
 
 
 
 
 
 
 
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Sample size  
Considering a clinically significant difference in left ventricle 
volumes 12 months after surgery, equal to 15 ml/m2, with a 
power of 80% and alpha of 5%, the sample size should be at 
least 64 patients in each group. 
 
The sample size usually depends on the standard deviation, 
which is determined based on the results of similar studies or, 
more often, a pilot study. Approximate indicators will be 
obtained by February 2024 after analyzing the RCHC sample 
within the framework of the dissertation research. 
 
 

 
 
 
 
 
 
 
 
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8. ABBREVIATIONS  
     
AAo – ascending aorta  
AVOA – amplitude of aortic valve opening  
AML – anterior mitral leaflet  
Ao – aorta  
AoArch – aortic arch  
AoRoot – aortic root  
AoV – aortic valve  
AR – aortic regurgitation  
AS – aortic stenosis  
ASA – atrial septal aneurysm  
ASD – atrial septal defect  
ASE – American Society of Echocardiography  
AVA – aortic valve area  
BSA – body surface area  
CFD – color flow Doppler  
CI – cardiac index  
CO – cardiac output  
CS – coronary sinus  
CWD – continuous wave Doppler mode  
DAO – descending aorta  
EDV – end-diastolic volume  
EF – ejection fraction  
EPSS – E point to septal separation of the mitral valve  
ESV – end-systolic volume  
A5CV – apical five-chamber view  
A4CV – apical four-chamber view  
IVC – inferior vena cava  
IVS – interventricular septum  
LA – left atrium  

 
 
 
 
 
 
 
 
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LAA – left atrial appendage  
LAX – long axis  
LAX Ao – longitudinal section of the aorta  
LAX LV – longitudinal section of the left ventricle  
LAX RVIT – longitudinal section of the right ventricular inflow tract  
LAX RVOT – longitudinal section of the right ventricular outflow tract  
LCC – left coronary cusp  
LPA – left pulmonary artery  
LV – left ventricle  
LVEF – left ventricular ejection fraction  
LVIDd – left ventricular internal diameter in diastole  
LVIDs – left ventricular internal diameter in systole  
LVIDV – left ventricular internal diastolic volume  
LVISV – left ventricular internal systolic volume  
LVOT – left ventricular outflow tract  
LVPW – inferolateral wall of the left ventricle  
M-mode – M-mode  
MR – mitral regurgitation  
MS – mitral stenosis  
MVA – mitral valve area  
NCC – non-coronary cusp  
PA – pulmonary artery  
PAP – pulmonary artery pressure  
PG – pressure gradient  
PHT – pressure half-time  
PML – posterior mitral valve leaflet  
PR – pulmonary regurgitation  
PS – pulmonary stenosis  
PV – pulmonary valve  
PWD – pulsed wave Doppler mode  
RA – right atrium  
RAP – right atrial pressure  
RVWT – right ventricular wall thickness  
RVIT – right ventricular inflow tract  

 
 
 
 
 
 
 
 
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RVOT – right ventricular outflow tract  
RVSP – right ventricular systolic pressure  
SAM – systolic anterior motion  
SAX APEX – short axis at the apex level  
SAX BASE – short axis at the base level 
 
9. INTRODUCTION  
9.1 Introduction and Research Hypothesis  
During surgical intervention for aortic valve insufficiency accompanied by 
hemodynamically significant functional mitral regurgitation, the surgeon faces the 
question of whether intervention on the mitral valve is necessary.   Secondary MR of 
varying degree is found in 60%-75% of patients who have undergone aortic valve 
replacement. [1] 
We hypothesize that the chosen strategy regarding moderate mitral regurgitation during 
the correction of aortic valve lesion in patients with significant left ventricular remodeling 
plays a crucial role in the course of reverse LV remodeling when assessed by transthoracic 
echocardiography 12 months post-surgery.  
  
9.2 General Information  
Adaptation of the cardiovascular system to increased preload is observed in a number of 
quite physiological conditions: child growth, pregnancy, intensive aerobic training, as 
well as in pathological processes: atrioventricular valve insufficiency, or systemic 
arteriovenous shunt. [2, 3] 
  
9.3 Study Rationale 
The heart is a terminally differentiated organ with very limited reparative capabilities at 
the cellular level. The number of heart cells does not change over a lifetime; according to 
some data, the volume of cellular repair does not exceed 1% of the cellular mass per year. 
Cardiomyocytes are incapable of completing mitosis due to the presence of a rigid 
cytoskeleton and, consequently, the impossibility of cytokinesis. Repair and 
compensation at the cellular level with the inability of cytokinesis involves a multiple 
increase in intracellular elements without completed division, which causes an increase 
in cytoskeleton stiffness. Aortic valve insufficiency is the third most common valvular 
heart defect. Severe and significant aortic valve insufficiency is associated with 
hemodynamically significant functional mitral valve insufficiency in more than one-third 
of cases. Aortic valve insufficiency should be considered pathogenetically and 
hemodynamically as a pressure and volume overload, while mitral regurgitation is a 
typical variant of isolated volume overload. Pressure overload causes cardiomyocyte 
hypertrophy due to the parallel layering of sarcomeres and disruption of energy couplings. 
Subsequent metabolic changes induce apoptosis and autophagy of cardiomyocytes with 
a progressive loss of functional cardiac cell mass; in the remaining functional 

 
 
 
 
 
 
 
 
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cardiomyocytes, polyploidization occurs, and simultaneously, a humoral response arises, 
the prolonged tension of compensatory mechanisms of which leads to worsening 
myocardial dysfunction. With volume overload, there is a progressive expansion of the 
left ventricular cavity due to the addition of new sarcomeres in sequence with the existing 
ones. Prolonged existence of volume overload also ultimately leads to the loss of 
functional cardiac cell mass and the development of systolic and diastolic heart failure. It 
should be noted that the elongation of the left ventricular cross-sectional circumference 
along the short axis due to progressive dilation, according to the Frank-Starling law, 
requires supraphysiological preload to achieve optimal contraction strength. Functional 
mitral regurgitation is a variant of increased preload. A sharp decrease in left ventricular 
preload with hemodynamically effective correction of functional mitral regurgitation 
simultaneously with the correction of the aortic defect can potentially impair left 
ventricular contractility in the early stages of reverse remodeling. It is evident that 
postoperative regression of mitral regurgitation is possible in cases where the reverse 
development of changes that caused mitral regurgitation is possible. For example, with 
normal sizes of the left ventricle and atrial tethering of the mitral valve against the 
background of persistent atrial fibrillation, isolated correction of aortic valve 
insufficiency is not able to reverse the arrhythmogenic fibrosis of the left atrium and, 
consequently, improve the grading of mitral regurgitation. Mitral regurgitation against 
the background of a significant increase in the end-systolic size of the left ventricle and a 
decrease in contractility may be characterized by a favorable prognosis of reverse 
development after correction of the aortic defect, provided there are no other causes of 
mitral regurgitation.  
There is a limited number of research studies dedicated to the reverse remodeling of the 
left ventricular myocardium and the spontaneous regression of functional mitral 
regurgitation after surgical correction of aortic stenosis; the degree of study of this issue 
in the context of aortic valve insufficiency is even lower. In the available studies, the main 
focus is on assessing the impact of hemodynamically significant functional mitral 
regurgitation, which has not undergone surgical correction during aortic valve 
replacement, on immediate and long-term survival, as well as the course of the mitral 
regurgitation itself. In many studies, fundamentally different causes of functional mitral 
regurgitation—such as aortic stenosis and aortic valve insufficiency—are not 
distinguished. None of the studies found evaluate the course of reverse remodeling of the 
left ventricle depending on the chosen strategy regarding the mitral valve. The obtained 
results and conclusions on the aforementioned issues are contradictory, exacerbating the 
ambiguity of the scarce data. There are also no studies that include patients exclusively 
with severe forms of left ventricular remodeling against the background of chronic aortic 
regurgitation. The duration of hemodynamically significant aortic valve insufficiency and 
the age of manifestation, as well as the patient's gender, are rarely analyzed. Thus, the 
study of reverse remodeling of the left ventricular myocardium in patients with chronic 
aortic valve insufficiency against the background of functional mitral regurgitation is of 
interest, remains unexplored, and is clinically relevant. 
  

 
 
 
 
 
 
 
 
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10. OBJECTIVES AND ENDPOINTS OF THE STUDY  
To study the impact of the volume of surgical treatment for chronic aortic valve 
insufficiency on the rate and degree of reverse myocardial remodeling in patients with 
significant left ventricular dilation against the background of chronic aortic 
regurgitation, depending on the degree of mitral valve insufficiency. 
  
 
10.1  
Objectives  
Primary objective:   
1. To assess the impact of functional mitral regurgitation on the rate and degree of 
reverse myocardial remodeling in patients with significant left ventricular dilation 
against the background of chronic aortic valve insufficiency after surgical correction 
of the aortic defect. 
  
Secondary objectives:   
1. To assess the relationship between the severity of preoperative functional mitral valve 
insufficiency and the patient's life quality 12 months after surgery. 
 
Research objectives: 
1. To assess the relationship between severity of functional mitral regurgitation and 
diastolic dysfunction of the left ventricle at 3 and 12 months after surgical 
correction of aortic regurgitation. 
2. To assess the relationship between the severity of functional mitral regurgitation 
and the dynamics of left atrial volume, evaluated by transthoracic ECHO-CG, at 3 
and 12 months after surgical correction of aortic regurgitation. 
 
 
10.2 Study endpoints 
  
Primary endpoints:   
1. Reduction of the left ventricle end-diastolic volume at 3 and 12 months after 
surgical correction of aortic regurgitation 
2. Freedom from readmission for heart failure related conditions 12 months after 
surgery 
  
Secondary endpoints:   
1. Patient quality of life according to the EQ-5D-5L questionnaire results. 
  
Exploratory endpoints:   
1. Left ventricle ejection fraction at 3 and 12 months after surgical correction of aortic 
regurgitation 

 
 
 
 
 
 
 
 
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2. Diastolic function of the left ventricle based on echocardiography results, assessed 
preoperatively and at 3 and 12 months after surgical correction of the aortic 
regurgitation (mean E/e’, DT)   
3. Indexed to BSA volume of the left atrium (according to transthoracic 
echocardiography results) preoperatively, as well as at 3 and 12 months after 
surgical treatment  
 
*BSA – body surface area, calculated using the Mosteller formula 
 
11. Study design  
 
11.1  
General Provisions  
A multicenter controlled comparative prospective cohort study is planned. 
 
It is known that chronic aortic valve insufficiency leads to significant remodeling of the 
left ventricle and development of functional mitral regurgitation. On one hand, residual 
mitral regurgitation may complicate the postoperative period by increasing the preload 
on the left ventricle; however, a dilated left ventricle after surgical correction of the 
aortic defect still requires supraphysiological preload during the most vulnerable period 
of early rehabilitation. As the volume of the left ventricle regresses, functional mitral 
regurgitation is also capable of regressing. A significant scientific task is to address the 
role of functional mitral regurgitation in the reverse remodeling of the left ventricle after 
correction of chronic aortic valve insufficiency. 
 
 
11.2  
Definition of the study group  
Patients who have undergone open surgical correction of aortic valve insufficiency 
with large eccentric left ventricle remodeling (EDV more than 250 ml). Men and 
women over 18 years old.  
11.2.1 Inclusion Criteria  
Potential study subjects must meet the following criteria: 
1. Age over 18 years 
2. Planned primary elective surgery for chronic aortic regurgitation 
3. Presence of functional mitral regurgitation 
4. Left Ventricular End-Diastolic Volume ³ 250 ml 
  
  
11.2.2 Non-inclusion Criteria  
1. Infectious endocarditis 
2. Previous myocardial infarction 
3. Necessity of simultaneous myocardial revascularization 
4. Acute aortic valve insufficiency of any etiology 
5. Previously established left ventricular dilation not associated with the 
development of aortic regurgitation 
6. Permanent or persistent form of atrial fibrillation 

 
 
 
 
 
 
 
 
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7. Ongoing pregnancy within the first 12 months after surgery 
8. Simultaneous participation in other studies 
9. Implanted heart pacemaker 
10. Refusal to sign informed consent 
 
During the population analysis, the research team reserves the right to add new exclusion 
criteria if required to achieve sample representativeness, due to the clinical situation, or 
common sense. 
 
11.2.3 Exclusion Criteria  
1. Acute coronary event diagnosed within 12 months after surgical correction of the 
aortic defect. 
2. Need for resynchronization therapy or permanent right ventricular pacing in the 
first 12 months after surgery. 
3. Re-do cardiac surgery for any reason within 12 months after the operation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
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Figure 1. ‘Principle scheme of forming the study working sample’ 
 
 
 
12. ASSESSMENT METHODS AND PROCEDURES   
An informed consent will be obtained from each subject prior to conducting any 
procedure related to the protocol of this study.  
  
Sample of patients meeting the inclusion criteria 
Surgical treatment 
Signing of informed consent, inclusion in the study 
Patients without correction of 
mitral regurgitation  
 
Patients who underwent 
correction of mitral 
regurgitation  
Propensity score matching 
Primary analysis of ECHO-CG Petrovsky NRCS and BUZ VO VOKB 
No. 1 databases, screening for patients with inclusion criteria 
Observation for at least 12 months 
MR 
grade 0-
2 
MR 
grade 0-
2 
MR 
grade >2 
MR 
grade >2  
Application of exclusion parameters 

 
 
 
 
 
 
 
 
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12.1  Preliminary Screening (Visit 0)  
As part of the clinical work at the Petrovsky NRCS and BUZ VO VOKB No. 1, a 
screening of the medical documentation of patients scheduled for surgical treatment for 
aortic valve insufficiency will be conducted. Subjects who meet the inclusion criteria and 
do not have any exclusion criteria will be offered participation in the study. 
Patients may also be initially referred by other specialists from other medical institutions 
for planned surgical treatment of chronic aortic regurgitation. 
Subjects who express interest in participating in the study will be invited to Examination 
1. 
During Examination 1, patients will be offered an informational brochure, developed by 
the research team in collaboration with the Petrovsky NRCS research development 
department (print run of 200 copies), containing comprehensive information revealing 
the potential benefits and risks of participating in the study. After reviewing the 
information and having all relevant clarifying questions answered by the researcher, the 
subject will be given sufficient time to sign the voluntary informed consent. Voluntary 
informed consent must be obtained exclusively by a specialist qualified as a cardiologist 
or cardiovascular surgeon. Prior to obtaining voluntary informed consent, it is not 
possible to carry out any of the procedures provided for in this study. 
Examination 2 is carried out on the 2nd day after surgical treatment of aortic valve 
insufficiency in the intensive care unit before leaving for the specialized department 
intensive care unit.  
   
 
12.2 Early postoperative examination (Examination 2)  
An assessment of the surgical treatment initial results of will be conducted: stability of 
the pre-perfusion period, dosage of perioperative pharmacological support medications, 
features of the surgical intervention, and indicators of the body's internal environment. 
Mandatory study – transthoracic or transesophageal ECHO-cardiography. 
 
 
12.3 Assessment 9-14 days after surgery (Examination 3)  
A comprehensive assessment of the inpatient treatment stage is planned, according to 
Table 1. 
12.4 First outpatient visit (Examination 4)  
 
Routine registration of parameters reflecting the rate of reverse remodeling of the left 
ventricle, associated parameters, patient life quality, and analysis of adverse events 
occurring from Examination 3 to Examination 4 is planned. 
 
In the event that the patient cannot or does not wish to attend the examination, 
comprehensive information and task resolution will be conducted by phone. If the visit 
is postponed for any reason, the schedule of subsequent examinations will not be 
modified. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1. Procedures provided by the study protocol 
Examination Number 
0 
1 
2 
3 
4 
5 
Planned activities 
 
Screening 
Inclusion in 
the study 
ICU 
11 days 
3 months 
12 months 
(EOS) 
± 2 days  
± 7 days  
± 14 days  
Assessment of eligibility for study 
participation  
x  
  
  
  
  
  
Familiarization with the conditions 
of participation in the study and 
possible risks  
 
x 
 
 
 
 
Signing the informed consent  
 
x 
  
  
  
  
Medical history collection  
 
x 
  
  
  
  
General clinical evaluation 
 
x  
x  
x  
x  
x  
Anthropometry (height without 
shoes and weight in light clothing)  
 
x 
  
  
x  
x  
ECHO-cardiography  
 
x  
x  
x  
 x 
x  
Questionnaire completion  
 
x  
 
x  
x  
x  
6-minute walk test  
 
x 
 
x  
x  
x  
ECG 
 
x  
x 
x  
x  
x  
Assessment of complications since 
the previous examination  
 
 
x  
x  
x  
x  
NT-proBNP (optional) 
 
x  
  
  
x  
 x 
Myocardial MRI with gadolinium 
contrast enhancement (optional) 
 
x 
 
 
 
x 

 
 
 
 
 
 
 
 
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12.4  Outcome assessment   
12.4.1 History taking  
Detailed recording of medical history and life history is planned during Examination 1. 
  
12.4.2 Demographic data  
The date of birth and gender of each study participant will be entered into the database 
during Examination 1.  
 
12.4.3 Objective examination  
A standard clinical examination is provided as part of Examinations 1-5. 
 
     12.4.4 Height and weight  
Height in centimeters and weight in kilograms will be assessed during Examinations 1, 
4, 5. Body weight will be recorded to the nearest 0.1 kilogram [kg] in light clothing 
without shoes. Height will be recorded to the nearest 1 cm without shoes. 
  
 
12.4.5  
Electrocardiography (ECG)  
A standard 12-lead ECG (after 5 minutes of rest) will be performed (at Examination 1 
(baseline), examinations 3, 4, 5 according to the standard method (paper speed 50 
mm/sec, amplitude 10 mm/mV, with at least 5 seconds of recording available for each 
lead). Recording will be conducted using an automatic recorder with digital signal 
processing capability. Heart rate will be assessed, and potential disturbances in heart 
rhythm, conduction, and repolarization parameters, such as QT interval prolongation or 
atrioventricular block, will be recorded.  
  
12.4.6  
ECHO-cardiography  
ECHO-cardiography will be performed as part of Examinations 1-5. It is planned to 
perform transthoracic ECHO-cardiography and transesophageal intraoperative ECHO-
cardiography. The scope of the study during Examinations 1, 3-5 will correspond to the 
minimum 
transthoracic 
EAUD 
protocol 
(https://easud.org/sites/default/files/manuals/tte_protokol_eaud.pdf). Examination 2 
may be significantly hindered due to unsatisfactory visualization. All DICOM images 
obtained during the examination of each study participant will be stored in RAW format 
on a common DICOM server for all research centers. A selective cross-analysis of the 
standardized set of DICOM data, in accordance with EAUD, is planned to be conducted 
by physicians with more than 5 years of experience in cardiovascular imaging in the 
ultrasound modality.  

 
 
 
 
 
 
 
 
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- 
The assessment of myocardial contractility will be performed using the Simpson 
Biplane method, the General Electric “auto EF” algorithm, and Speckle 
Tracking analysis based on General Electric algorithms.  
- 
The standard transthoracic protocol in all cases will be supplemented by 
myocardial strain analysis with the recording of initial RAW DICOM data, as 
well as Global Longitudinal Strain, Strain Rate, and myocardial mechanical 
dispersion. 
  
 
  
 
12.4.7  
Questionnaires  
1. EuroQOL-5D (EQ-5D): EQ-5D is a standardized instrument for assessing the 
respondent's quality of life: in the form of a health profile - five questions 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each 
with five levels of severity, and a score obtained using the EQ-VAS visual analog 
scale. 
The questionnaire will be offered for completion during Examinations 1 and 3-5. The 
questionnaire is available only in Russian. Patients who do not have proficiency in 
Russian at the level of writing and reading will be excluded from periodic testing.  
 
12.4.7 6-Minute Walk Test 
This test is one of the methods for diagnosing heart failure, but it is used more for 
determining the functional class rather than confirming it. It also involves determining 
the endurance of patients to assess the effectiveness of therapy. 
The test is easy to perform, does not require complex equipment, and can be conducted 
both in inpatient and outpatient settings. The test allows for the assessment of patients' 
daily activity levels, and its results correlate well with quality-of-life indicators; 
moreover, they can be used as additional criteria for evaluating the effectiveness of 
treatment and rehabilitation of patients. 
 
The methodology for conducting this test involves using a straight corridor familiar to 
the patient, with zero incline and length markings every 3 meters, and separate 
markings for turnaround points are provided. After a preliminary rest period of 10 
minutes, the subject's pulse rate and blood pressure are measured. If there are no 
contraindications to performing the test, the subject is instructed to cover the maximum 
distance in 6 minutes, without running or sprinting, but a reduction in walking pace and 
short breaks are allowed. The time interval is measured by starting a countdown timer, 
which loudly signals with a sound at the end of 6 minutes. The doctor assesses the 
distance covered and the functional class. 
 
  
  

 
 
 
 
 
 
 
 
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13.11 Definition of the term 'End-of-study'  
  
The date of completion of the study is considered to be the day on which the last subject 
included in the study underwent Examination 5. 
  
Other aspects of study completion 
The principal investigator has the right to terminate the study at any time based on 
clinical or organizational considerations, while ensuring the interests of the study 
participants are protected.  
  
The completion of the study will be reported to the local ethics committee within 90 
days, or within 15 days if there was an early termination of the study. All researchers 
will inform the study participants about the premature termination, ensuring the 
continuation of qualified dynamic monitoring for previously included participants.  
  
A report on the conducted study will be compiled within 12 months from the date of 
study completion. 
  
  
 
15. PROTOCOL COMPLIANCE   
The researchers ensure compliance with the study protocol. In case, 
the researcher believes that a deviation from the protocol will optimize the study process 
or allow for obtaining extremely significant additional results, this should be considered 
an amendment to the protocol. If this amendment is not approved by the local ethics 
committee, it cannot be implemented. Thus, all proposed deviations from the protocol 
must be reported to the principal investigator and the local ethics committee. If 
approved, the changes made will be reflected in the 'History of Changes' section of the 
research protocol.  
  
  
 
15.1  Amendments to the Protocol   
Any changes to the protocol must be agreed upon in writing with the principal 
investigator and the local ethics committee. The above does not apply to protocol 
changes aimed at the immediate safeguarding of the health and safety of the research 
participant. The principal investigator should be notified of this fact within 10 working 
days. 
  
  
 

 
 
 
 
 
 
 
 
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16. ACCESS TO STUDY DATA  
Direct access will be provided to authorized representatives of the institutions where 
the study is conducted, as well as regulatory officials for monitoring, auditing, and 
inspections related to the study.  
 
17. DATA PROCESSING AND STORAGE   
 
17.1  
Data collection, primary information, and individual registration 
cards (IRC)  
All documentation related to the study, as well as information concerning the patients 
participating in it, is strictly confidential. The researcher must ensure the anonymity of 
the volunteers. In the IRK and other documents, volunteers should not be identified by 
their first and last names. The identification of volunteers is carried out using the first 
letters of the volunteer's last name, first name, and patronymic (FIO), date of birth 
(DD.MM.YYYY), and an individual number assigned to the volunteer upon inclusion in 
the study. Each volunteer is assigned a unique number by the Researcher, consisting of 
numeric and alphabetic designations, with the following structure: eight digits arranged 
sequentially from left to right, digits 1 to 6 are defined for this study by the following 
sequence: 11-RIS, which is the same for all volunteers, and the last two digits correspond 
to the serial number of the volunteer upon admission to the research center. Thus, the 
data provided by the Researcher for the identification of volunteers have the following 
format:  
digits 1-3 - the first letters of the volunteer's last name, first name, and patronymic; digits 
4-11 - the volunteer's date of birth (DD.MM.YYYY);  
digits 12-19 - a unique number assigned to the volunteer by the Investigator responsible 
for conducting the clinical trial, consisting of numerical and/or alphabetical designations 
and entered into the Clinical Trial Protocol. The Investigator must maintain a separate 
Identification Log of individual numbers, last names, dates of birth, addresses, phone 
numbers, and medical documentation numbers (if available). The researcher must keep 
documents strictly confidential that are not intended for disclosure in general cases, in 
particular, signed Informed Consent Forms and the Identification Log.  
The report and study documents will use only the initials, birth dates, and unique 
numbers of participant, which are part of the Individual Identification Code. The 
Individual Identification Code is established by the insurer after obtaining permission 
from the Ministry of Health and Social Development of the Russian Federation to 
conduct a clinical trial, based on the data provided by the Researcher of the volunteer 
participating in the clinical trial. The assigned individual identification code is not subject 
to change.  
All data about the volunteer obtained during the study is first entered into the primary 
documentation (documentation of the medical institution or physician maintained at the 
research center) and then transferred to the Individual Registration Card of the volunteer. 

 
 
 
 
 
 
 
 
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The data contained in the IRK must match the data in the primary documentation. The 
IRK must be completed no later than 5 days after the volunteer's visit to the research 
center. The IRK is maintained in digital format. Logging of changes made is mandatory. 
The principal investigator bears the final personal responsibility for the accuracy and 
authenticity of all clinical, instrumental, and laboratory data entered into the IRK.  
All records and documents related to the clinical study, including Individual Registration 
Cards, patient information sheets, and volunteer lists, are retained at the clinical 
institution where the study is conducted for 15 years after the study's completion.  
 
 
18. ETHICAL ASPECTS   
 
18.1 Ethical principles of conducting the study  
The study will be conducted in accordance with the current version of the Declaration 
of Helsinki, the provisions of the National Standard of the Russian Federation GOST 
R52379-2005 on Good Clinical Practice dated April 1, 2006, and the Order of the 
Ministry of Health of the Russian Federation dated April 1, 2016. No. 200n 'On the 
approval of the rules of good clinical practice' and the provisions of Good Clinical 
Practice (GCP).  
The material for conducting the study will be collected at two clinical sites: Petrovsky 
NRCS, Moscow and BUZ VO VOKB No.1, Voronezh.  
By signing the study protocol, the researcher agrees to adhere to the instructions and 
procedures described therein, as well as the principles of Good Clinical Practice, which 
they comply with. Regulatory approval will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be obtained before 
the patient undergoes any study-related procedures, including screening tests to 
determine eligibility criteria.  
 Approval for conducting the study is planned to be obtained at both centers from the 
local ethics committee of the RCHC.  
  
  
 
18.2  
Approvals   
The study protocol, informed voluntary consent form, individual patient registration 
card, and questionnaire forms must be approved by the local ethics committee and 
other regulatory officials, in accordance with current legislation, before the initiation of 
the study.  
 
18.3 Informed Voluntary Consent  
The investigator must obtain written informed consent from each participant prior to their 
participation in the study and before any study-related procedure is undertaken. Thus, 

 
 
 
 
 
 
 
 
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informed consent must be obtained at Examination 1 before performing any study-
related procedure. Before this, the investigator or their representative must inform each 
participant about the objectives, benefits, risks, and requirements related to the study.  
Only a qualified physician can obtain informed consent. 
The participant will be provided with an information and consent form written in clear 
and simple manner. He/she should be given enough time to clarify the details of the study 
and make an informed decision about participation. The researcher must answer all 
relevant questions that may arise from the patient. 
Two originals of the voluntary informed consent form must be completed, dated, and 
personally signed by the participant and the person responsible for obtaining informed 
consent. The participant will be provided with one signed original, and the second 
original will remain with the Investigator. 
The obtaining of informed consent must be clearly documented in the participant's 
individual registration card. The following aspects must also be recorded in the subject's 
medical record: 
• The date the informed consent form was provided to the subject. 
• The date written informed consent was obtained. 
• The name of the person who obtained the informed consent. 
• Any other relevant information regarding the consent acquisition process. 
Each patient included in the clinical study must have an individual participant card, 
which reflects data allowing the identification of the clinical study. (In particular, the 
study title, patient identifier in the study, date of signing the informed consent, 'date of 
completion of patient participation,' which must be filled in at Examination 5, the 
principal investigator's name, and the research group's contact number must be 
specified).  
   
 
18.4  
Patient Confidentiality   
Researchers ensure the confidentiality of participants, who will be identified only by 
their subject identification number in any database. All documents will be stored in a 
secure location. The study was conducted in accordance with the 'Personal Data 
Protection' law.  
19. FUNDING 
The study is initiative-driven, and no sponsorship is provided. 
  

 
 
 
 
 
 
 
 
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20. CLINICAL TRIAL REPORT AND PUBLICATION POLICY   
 
20.1  
Clinical trial report  
The clinical trial report must be prepared and signed by all study participants within 12 
months after the completion of the study. 
  
 
20.2  
Publication Policy   
The results of this study will be published in reputable medical journals. The information 
obtained may provide impetus for further research on reverse remodeling of the left 
ventricle in patients with chronic aortic regurgitation. 
Principle investigator is responsible for publishing the data obtained in this study. 
 
21. PROPOSED STUDY SCHEDULE   
Start date: May 2024  
  
End date: May 2029   
 
Report preparation date: within 12 months from the end of the study 
22. APPENDICES 
22.1 Appendix 1. “EQ-5D Quality of Life Questionnaire” 
Title in Russian: Quality of Life Questionnaire EQ-5D 
Original title European Quality of Life Questionnaire (EQ-5D) 
Source: 
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. 
Ann Med. 2001 Jul; 33(5): 337 - 43. doi: 10.3109/07853890109002087. PMID: 
11491192. 
Brooks R, Boye KS, Slaap B. EQ-5D: a plea for accurate nomenclature. J Patient Rep 
Outcomes. 2020 Jul 3; 4(1): 52. doi: 10.1186/s41687-020-00222-9. PMID: 32620995; 
PMCID: PMC7334333. 
Russian population health-related quality of life indicators calculated using the EQ-5D-
3L questionnaire/E.A. Aleksandrova, A.R. Khabibullina, A.V. Aistov [et al.]//Siberian 
Scientific Medical Journal. - 2020. - Vol. 40. - No. 3. - P. 99 - 107. - DOI 
10.15372/SSMJ20200314. 
 
Type - questionnaire 
Purpose: assessment of quality of life 
 
English EQ-5D-Y-5L Paper Self-Complete 
 
Under each heading, please choose the ONE answer that best describes your health TODAY. 
 
MOBILITY (walking about) 
I have no problems walking about  
 
 
 
o 
I have a little bit of a problem walking about  
 
 
o 

 
 
 
 
 
 
 
 
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I have some problems walking about  
 
 
 
o 
I have a lot of problems walking about  
 
 
o 
I cannot walk about  
 
 
 
 
o 
LOOKING AFTER MYSELF 
I have no problems washing or dressing myself  
 
o 
I have a little bit of a problem washing or dressing myself  
o 
I have some problems washing or dressing myself  
 
o 
I have a lot of problems washing or dressing myself  
 
o 
I cannot wash or dress myself  
 
 
 
o 
 
DOING USUAL ACTIVITIES (for example, going to school, hobbies, sports,playing, doing things with family or friends) 
I have no problems doing my usual activities   
 
o 
I have a little bit of a problem doing my usual activities   
o 
I have some problems doing my usual activities  
 
o 
I have a lot of problems doing my usual activities  
 
o 
I cannot do my usual activities  
 
 
 
o 
HAVING PAIN OR DISCOMFORT 
I have no pain or discomfort  
 
 
 
o 
I have a little bit of pain or discomfort  
 
 
o 
I have some pain or discomfort  
 
 
 
o 
I have a lot of pain or discomfort  
 
 
 
o 
I have extreme pain or discomfort  
 
 
 
o 
FEELING WORRIED, SAD OR UNHAPPY 
I am not worried, sad or unhappy 
 
 
 
o 
I am a bit worried, sad or unhappy  
 
 
 
o 
I am quite worried, sad or unhappy   
 
 
o 
I am really worried, sad or unhappy   
 
 
o 
I am extremely worried, sad or unhappy  
 
 
o 
 
 
The best health you can 
imagine 
• We would like to know how good or bad your 
health is TODAY. 
• This line is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Please mark an X on the line to show how your 
health is TODAY. 
• Now, write the number you marked on the line 
in the box below. 
YOUR HEALTH TODAY =  
 
 

 
 
 
 
 
 
 
 
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The worst health 
you can imagine 
 
22.2 Appendix 2. “Minimal Transthoracic Echocardiography Protocol” 
 
Minimum transthoracic echocardiographic protocol: recommendations of the 
Eurasian Association of Specialists in Ultrasound and Functional Diagnostics  
  
B.V. Blagodir  
Recommendations adopted on 27.09.2018. (voting protocol No. 1 from 28.09.2018).  
  
1. Introduction.  
Recent advancements in echocardiography have facilitated the integration of new 
principles and methodologies into the routine work of an echocardiographer. This 
necessitates the implementation of a minimal echocardiographic protocol to 
ensure the quality collection of necessary data, improve quality, and standardize 
the performance of transthoracic echocardiographic examinations. The Eurasian 
Association of Ultrasound and Functional Diagnostics Specialists (EAUD) 
organized on 27.09.2018. The forum 'Ural Echocardiographic Protocol,' where 
44 specialists unanimously voted for its adoption.  
EAUD 
offers 
a 
minimal 
step-by-step 
protocol 
for 
comprehensive 
echocardiographic examination to obtain the most detailed information about the 
heart, its structures, and the assessment of cardiac function. When pathological 
morphological and/or functional abnormalities are detected, additional data is 
required, which is not included in this guideline and will be considered in 
subsequent guidelines.   
  
2. Requirements for the ultrasound device.  
• 2D mode with Tissue Harmonic Imaging (THI)  
• Standard M-mode  
• CFD  
• PWD  
• CWD  
• TDI-PW  
• ECG module for image synchronization and highly accurate verification 
of the corresponding phase of the cardiac cycle.  
  
3. Preparation for the study.  

 
 
 
 
 
 
 
 
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a. Familiarize yourself with the referral, indications, and diagnosis.  
b. Preparation of equipment: electrodes, ultrasound gel, clean bed linen, sensor.  
c. Familiarize yourself with the medical documentation and previous echo reports 
for comparison.  
g. Enter the patient's data into the ultrasound device, check the name, date of 
birth, height, weight, and medical record number.  
d. Ask the patient to lie down on the couch, attach 3 ECG electrodes, and adjust 
the height of the couch.  
e. Start scanning with either the left or right hand.  
• It depends on the features of the echo lab and/or personal preferences. 
It's better to be proficient with both hands.  
• Scanning with the right hand – the patient lies with their back to you. 
The patient's body should be embraced with the hand. The patient can 
lean on you. For the right hand, this is a comfortable position, as it 
relieves tension. This position may be suboptimal in the operating room, 
in case of injury, as well as in cases of hygiene issues with the patient.  
• Examination with the left hand – the patient is lying face towards you. 
The hand is placed on the couch. The patient requires a pillow behind 
their back. This position provides better visibility of the sensor and the 
patient's chest, allowing contact with it. This position is not optimal if 
the patient has a cough, so if they are not wearing a mask, you need to 
provide one for yourself.  
f. Patient position.  
• Subcostal access – the patient lies on their back.  
• Suprasternal access – the patient lies on their back, chin up, and turns 
their head slightly to the left.  
• Right parasternal access – the patient lies on their right side.  
  
4. Duration of the study.  
The average duration of one study, including patient preparation, familiarization 
with medical documentation, obtaining images, quantitative calculations, and 
report writing, is 40-45 minutes. However, for a complete study, some patients 
require more time to obtain additional information, while others require less time.  
    
  
Section 
(mode)  
Measurements  
Exclude  
Image  

 
 
 
 
 
 
 
 
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LAX LV 
(2D)  
At the end of 
diastole:  
a. Right ventricle  
RVWTd, 
RVOTprox.  
IVSd, LVIDd, 
LVPWd.  
b. Left ventricle: 
IVSd, LVIDd, 
LVPWd, LVmass, 
RWT.  
  
At the end of systole:  
LVIDs, LA diam  
  
Note:  
1. The linear 
dimensions of the 
left ventricle are 
measured just 
beyond the ends 
of the mitral 
valve leaflets.  
2. EF LV by 
Teicholz can be 
used to assess 
the overall 
contractile 
function of the 
left ventricle only 
in the absence of  
• 
chamber dilation  
• 
wall thickening 
• 
 contractility impairment  
• 
valve anomalies.  
• 
Left ventricular hypertrophy  
• 
Normal values:  
  
RVWT (1 – 5 mm)  
RVOTprox (20 – 30 mm)  
IVS (female 6-9 mm; male 6-
10 mm)  
LVIDd (female 37.8-52.2 mm; 
male 42.0-58.4 mm)  
PWT (female 6-9 mm; male 6-
10 mm)  
LVIDs (female 21.6-34.8 mm; 
male 25.0-39.8 mm)  
LA (female 27 – 38 mm; male 
30 – 40 mm)  
LVmass (female 67-162 g, 
male 88-224 g)  
RWT (≤0.42)  
EF LV 53-73%  
  
     
  
  
  
  
  
  
  
  
 
 
local 
contractility 
disorders!  
  
 
 

 
 
 
 
 
 
 
 
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LAX Ao  
(2D)  
In mid-systole:  
LVOT diam – I-I  
method  
AoAnnulus – I-I 
method  
  
Note: LVOTdiam 
measurement  
is conducted  
 proximal and  
 
parallel to the 
plane of the aortic 
valve from the 
inner edge  
 
 
of the septal  
endocardium 
to 
the inner edge of 
the anterior leaflet 
of the mitral valve 
within 5-10 mm 
from 
the 
aortic 
valve.  
  
At the end of 
diastole:  
AoSinus (L-L 
method)  
STJ (L-L method) 
AoAsc prox (L-L 
method)  
• LVOT obstruction  
• Aortic dilation  
• Aortic calcification  
• Aortic dissection  
  
  
Normal values:  
  
LVOTdiam (18-22 mm)  
AoAnnulus (female 22-25 mm, 
male 23-29 mm)  
AoSinus (female 27-33 mm, 
male 31-37 mm)  
STJ (female 23-29 mm, male 
26-32 mm)  
AoAsc prox (female 23-31 mm, 
male 26-34 mm)  
  
  
  
  
  
  
  

 
 
 
 
 
 
 
 
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LAX LV 
(M-mode)  
M-mode 
at 
the 
level of the mitral 
valve: DE amp  
EF slope  
EPSS  
  
  
  
  
  
  
  
  
  
  
• 
Contractility impairment/ 
dyssynchrony/ paradoxical 
motion.  
• 
Mitral valve prolapse.  
• 
Early closure of the mitral 
valve (indicates increased 
left ventricular end-diastolic 
pressure – LVEDP).  
• 
Hemodynamic compromise 
in the presence of exudative 
pericarditis.  
 
 
  
Normal values:  
DEamp 18-28 mm  
EF slope 70-150 mm/sec  
EPSS ≤ 8 mm  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
M-mode 
at 
the 
level 
of 
the 
Valsalva sinuses: 
AVOA  
  
• Restriction of aortic valve 
opening  
• Early opening of the aortic 
valve  
• Mid-systolic closure of the 
aortic valve  
  
Normal values:  
ASC 15-26 mm  
  
  
  
  
  
  
LAX LV 
(CFD)  
  
  
• 
LVOT obstruction   
• 
aortic stenosis  
• 
aortic regurgitation  
• 
mitral stenosis   
• 
mitral regurgitation  
• 
Ventricular septal defect  
  
 
  
  
  
  

 
 
 
 
 
 
 
 
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LAX RVIT 
(2D)  
  
  
Diameter 
of 
the 
coronary sinus (CS) 
  
• prolapse/elongation of the 
leaflets  
• myxomatous / thickening / 
calcification with / without 
restriction of excursion  
• flailing tricuspid valve leaflet 
dilation of the tricuspid valve 
annulus  
• dilation of the coronary sinus  
  
Normal values:  
CS diam (4-10 mm)  
 
  
 
LAX RVIT 
(CFD)  
  
Evaluate the flow from the left 
atrium to the left ventricle  
 
 
 
• tricuspid stenosis  
• tricuspid insufficiency  
 
LAX RVIT 
(PWD)  
VE 
VA  
Right ventricular filling pattern 
 
 
 
  

 
 
 
 
 
 
 
 
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LAX RVIT 
(CWD)  
TV Vmax 
TR Vmax  
• 
Tricuspid stenosis  
• 
Tricuspid insufficiency  
• 
Calculate RVSP/SPAP  
  
Normal values:  
TV Vmax 30-70 cm/s  
TRVmax ≤ 2.5 m/s  
RVSP/SPAP ≤ 25 mm Hg  
  
  
  
  
LAX 
RVOT  
(2D)  
RVOTdistal  
MPAdiam*  
RPAdiam** 
LPAdiam**  
• Dilation of the right 
ventricle  
• RVOT obstruction  
• Subvalvular pulmonary 
stenosis  
• Semilunar prolapse  
  
  
  
  
 
 
 
  
pulmonary valve  
• Thickening/calcification 
of the pulmonary valve 
cusps with/without 
restriction  
of mobility  
• Dilation of the pulmonary 
artery  
• Narrowing of the 
pulmonary artery  
(supravalvular pulmonary 
stenosis)  
  

 
 
 
 
 
 
 
 
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LAX RVOT 
(M-mode)  
Amplitude of the a-
wave  
  
Note:  
  
Normally, the a-
wave is present on 
the motion graph 
of 
the 
right 
posterior 
cusp. 
Amplitude of the a-
wave is 2.7 mm.  
  
Absence or 
reduction   
of the amplitude of 
the a-wave  
< 2 mm, mid-
systolic 
closure 
(W-flight) 
indicates 
the 
presence 
of 
pulmonary 
hypertension  
  
 
  
  
Pulmonary hypertension  
  
  
  
  
LAX RVOT 
(CFD)  
  
•  
•  
•   
  
Pulmonary stenosis  
Pulmonary regurgitation  
Patent ductus arteriosus  
(PDA)  
  
Note:   
Moderate pulmonary 
regurgitation is a variant of 
normal.  
 
  
  
  
 

 
 
 
 
 
 
 
 
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LAX RVOT 
(PWD)  
Vmax RVOT 
PGmax RVOT  
RVOT obstruction  
  
  
  
  
LAX RVOT 
(CWD)  
PV Vmax  
PV Gmax  
PV Gmean  
PVA  
EDPR  
• Pulmonary stenosis  
• Pulmonary regurgitation  
• Pulmonary hypertension  
  
Normal values:  
PV Vmax 60-90 cm/s  
EDPR 0-5 mm Hg  
  
Note:  
An increase in EDPR of more than 5 
mm Hg indicates the presence of 
pulmonary hypertension.  
  
  
  
SAX BASE  
(2D)  
RVOTprox 
RVOTdistal  
MPAdiam*  
RPAdiam**  
LPAdiam**  
*if the diameter of 
the MPA is greater 
than that of the Ao  
**as needed  
  
• Dilation of the right ventricle  
• Prolapse/elongation  
• Myxomatous/thickening/calcification 
of the tricuspid and pulmonary valves 
with/without  
restriction of excursion  
• Flailing TV leaflet  
• Dilation of the TV annulus 
(TVannulus)  
• RVOT obstruction  
  
Normal values:  
RVOTprox 21-30 mm  
RVOTdistal 17-27 mm  
  
  

 
 
 
 
 
 
 
 
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SAX BASE 
(CFD)  
  
• Tricuspid stenosis  
• Tricuspid regurgitation  
• Pulmonary stenosis  
• Pulmonary regurgitation  
• RVOT obstruction  
• Ventricular septal defect  
 
• Atrial septal defect  
 
  
  
 
 
• Elongation and bulging of the atrial 
septum  
• Atrial septal aneurysm   
  
  
  
SAX BASE 
(CWD)  
TV Vmax  
TR Vmax  
TVA  
PV Vmax  
PV Gmax  
PV Gmean  
PVA  
EDPR  
• Tricuspid stenosis  
• Tricuspid regurgitation  
• Pulmonary stenosis  
• Pulmonary regurgitation  
• RVOT obstruction  
  
  
SAX  
BASAL/MV  
(2D)  
MVA 
(planimetry)  
• Prolapse/elongation of leaflets.  
• Myxomatous/thickening/calcification 
with/without restriction of excursion.  
• Local contractility disorder at the 
basal level  
  
  
  
  

 
 
 
 
 
 
 
 
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SAX LV  
(MID/APEX) 
(2D)  
  
Hypo-, a-, dyskinesia of the walls. 
Dilation of the right ventricle  
  
  
  

 
 
 
 
 
 
 
 
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A4CV 
(2D)  
EDVi  
ESVi  
EF LV  
LAVi  
RVD1  
RVD2  
RAsax  
RAlax  
RAA  
RAVi  
• Dilation of chambers  
• Hypertrophy  
• Reduction of global function  
• Valvular dysfunction  
  
Normal values:  
EDVi (female <61 ml/m2, male 
<74 ml/m2)  
ESVi (female <24 ml/m2, male 
<31 ml/m2)  
EF LV (female >52%, male 
>54%)  
LAVi (<34 ml/m2)  
RVD1 (25-41 mm)  
RVD2 (19-35 mm)  
RAlax (<53 mm)  
RAsax (<44 mm)  
RAA (<18 cm2)  
RAVi (female 15-27 ml/m2, 
male 18-32 ml/m2)  
  
Note:  
LAV is calculated using the 
disk summation method  
RAV is calculated using the 
area-length method  
  
  
  
  
  
  
  
  
  
  
A4CV  
(M-mode)  
TAPSE  
Right ventricular dysfunction  
  
Normal value:  
TAPSE >17 mm  
 

 
 
 
 
 
 
 
 
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A4CV  
(CFD)  
  
• Mitral stenosis  
• Mitral regurgitation  
• Tricuspid stenosis  
• Tricuspid regurgitation  
• Atrial septal defect  
 
• Ventricular septal defect 
 
 
  
A4CV  
(PWD)  
VE MV  
VA MV  
E/A MV  
DT MV  
Adur  
VE TV  
VA TV  
E/A TV  
DT TV  
S  
D  
ARdur  
• Diastolic dysfunction of the 
left ventricle  
 
• Diastolic dysfunction of the 
right ventricle  
 
  
Normal values:  
E/A MV 1.0-1.5  
DT MV 160-220 msec  
S>D  
AR<150 msec  
Adur<ARdur  
  
   
   
A4CV  
(CWD)  
MV Vmax  
MR Vmax  
MVA  
TV Vmax  
TR Vmax  
TVA  
RVSP/SPAP  
• Mitral stenosis  
• Mitral regurgitation  
• Tricuspid stenosis  
• Tricuspid regurgitation  
• Pulmonary hypertension  
  
   

 
 
 
 
 
 
 
 
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A4CV  
(TDI PW)  
e’ lat E/e’ 
lat 
e' 
med E/e’ 
med  
E/e’ avg  
Diastolic dysfunction of the left 
ventricle   
  
Normal values:  
e' lat >10 
cm/s e' med 
>7 cm/s E/e’ 
lat <13 cm/s  
E/e’ med <15 cm/s  
E/e’ avg <14 cm/s  
   
A5CV 
(2D)  
  
• Mitral stenosis  
• SAM with/without LVOT 
obstruction  
• Aortic sclerosis/stenosis  
• Dilation of chambers  
• Local contractility of the 
ventricular walls  
  
 
  
A5CV  
(CFD)  
  
• LVOT obstruction  
• Mitral stenosis  
• Mitral regurgitation  
• Aortic stenosis  
• Aortic valve insufficiency  
• Ventricular septal defect  
 
  
A5CV  
(CWD)  
MV Vmax  
MR Vmax  
MV PHT  
AoV Vmax  
AR PHT  
LVOT Vmax  
TV Vmax  
TR Vmax  
RVSP/SPAP  
• LVOT obstruction  
• Mitral stenosis  
• Mitral regurgitation  
• Aortic stenosis  
• Aortic valve insufficiency  
  

 
 
 
 
 
 
 
 
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3C (2D)  
  
• Dilation of chambers  
• Reduced contractility  
• Left ventricular hypertrophy  
• LVOT obstruction  
 
 
Pathology of the mitral 
and aortic valves  
Aortic aneurysm   
and  
3C  
(CFD)  
MV Vmax  
MR Vmax  
AoV  
  
  
• Mitral stenosis  
• Mitral regurgitation  
• Aortic stenosis  
• Aortic regurgitation  
• LVOT obstruction  
 
  
  
3C  
(PWD)  
LVOT Vmax  
LVOT obstruction  
 
  
3C  
(CWD)  
MV Vmax  
MR Vmax  
MVA  
AoV Vmax  
AR PHT  
AVA  
• Mitral stenosis  
• Mitral regurgitation  
• Aortic stenosis  
• Aortic valve insufficiency  
 
  

 
 
 
 
 
 
 
 
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2C 
(2D)  
EDVi  
ESVi  
EF LV  
LAVi  
• Dilation of chambers  
• Dilation of the DAO  
• Thrombosis of the left atrial 
appendage  
• Local contractility disorder  
 
• Reduced contractility of the left 
ventricle  
  
 
  
2C  
(CFD)  
  
• Mitral stenosis  
• Mitral regurgitation  
  
2C  
(CWD)  
MV Vmax  
MR Vmax  
MVA  
• Mitral stenosis  
• Mitral regurgitation  
  
   
3C RVIT  
(CFD,  
CWD)  
TV Vmax  
TR Vmax  
RVSP/SPAP  
The best section that provides the 
ideal 
Doppler 
angle 
for 
assessing 
tricuspid 
regurgitation and calculating 
RVSP/SPAP in cases where 
other sections had a suboptimal 
Doppler angle.  
   

 
 
 
 
 
 
 
 
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Sub SAX 
BASE  
(2D, CFD)  
  
Atrial septal defect (ASD) 
 
 
  
Note:  
This is the ideal section for 
assessing the atrial septal 
defect, as it provides the ideal 
Doppler angle.  
   
Sub A4CV 
(2D)  
RVWT  
• Right ventricular hypertrophy  
• Pericardial effusion  
• Lipohypertrophy of the 
interatrial septum  
• Hemodynamic compromise in 
tamponade  
   
Sub A4CV 
(CFD)  
  
• Atrial septal defect  
• Ventricular septal defect  
• Mitral regurgitation  
• Tricuspid insufficiency  
   

 
 
 
 
 
 
 
 
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Sub IVC  
(2D /   
M-mode)  
IVC diam insp 
IVC diam 
expir  
• Dilation of the inferior vena 
cava 
• Assess 
the 
inspiratory 
collapse of the inferior vena 
cava  
• Determine the right atrial 
pressure (RAP) (RAP = 
3/8/15).  
  
Note:  
IVC diameter according to the 
ASE guidelines is measured at 
the entry proximal to the hepatic 
vein.  
  
Normal values:  
IVC diam expir (12-21 mm).  
  
 
  
  
  
  
Sub DAO  
(2D)  
DAO diam  
• Dilation   
• Aneurysm   
• Dissection  
• Atherosclerosis  
  
Normal values:  
DAO diam (<30 mm).  
  
 

 
 
 
 
 
 
 
 
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Sub DAO 
(PWD)  
PSV AT  
• Distal effects of aortic 
coarctation  
• Distal effects of aortic 
stenosis   
  
Normal values  
AT <80 msec  
Hemodynamically significant 
proximal events: AT ≥100 
msec.  
 
 
  
  
Supra LAX 
(2D)  
AAo diam  
AoArch diam  
DAO prox  
• Aneurysm   
• Dissection   
• Atherosclerosis  
• Coarctation  
  
  
Supra LAX 
(CFD /  
PWD)  
PSV AАo  
PSV DAO  
  
Dissection 
Coarctation  
  
Normal values:  
PSV AАo (< 200 cm/s)  
PSV DAO (<200 cm/s)  
  
  
  
 
 
 

 
 
 
 
 
 
 
 
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23. REFERENCES 
  
Moazami N., Diodato M. D., Moon M. R., Lawton J. S., Pasque M. K., Herren R. L., 
Guthrie T. J., Damiano R. J. Does functional mitral regurgitation improve with isolated aortic 
valve replacement? // J Card Surg. ‒ 2004. ‒ T. 19, № 5. ‒ C. 444-8. 
2. Ruel M., Kapila V., Price J., Kulik A., Burwash I. G., Mesana T. G. Natural history and 
predictors of outcome in patients with concomitant functional mitral regurgitation at the time of 
aortic valve replacement // Circulation. ‒ 2006. ‒ T. 114, № 1 Suppl. ‒ C. I541-6. 
3. Melenovsky V. Cardiac Adaptation to Volume Overload // Cardiac Adaptations: 
Molecular Mechanisms / Ostadal B., Dhalla N. S. ‒ New York, NY: Springer New York, 2013. 
‒ C. 167-199. 
4. Mostafa S. A. Echocardiographic variables associated with mitral regurgitation after 
aortic valve replacement for aortic valve stenosis // The Egyptian Heart Journal. ‒ 2013. ‒ T. 
65, № 2. ‒ C. 135-139. 
5. Fukumoto S., Hsieh C. M., Maemura K., Layne M. D., Yet S. F., Lee K. H., Matsui T., 
Rosenzweig A., Taylor W. G., Rubin J. S., Perrella M. A., Lee M. E. Akt participation in the 
Wnt signaling pathway through Dishevelled // J Biol Chem. ‒ 2001. ‒ T. 276, № 20. ‒ C. 
17479-83.