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MINISTRY OF EDUCATION AND TRAININGS MINISTRY OF DEFENSE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES TRAN THI NGOC LAN ASSESSMENT OF CLINICAL, SUBCLINCAL CHARACTERI

MINISTRY OF EDUCATION AND TRAININGS

MINISTRY OF DEFENSE

108 INSTITUTE OF CLINICAL MEDICAL AND

PHARMACEUTICAL SCIENCES

TRAN THI NGOC LAN

ASSESSMENT OF CLINICAL, SUBCLINCAL CHARACTERISTICS, SPECKLE TRACKING ECHOCARDIOGRAPHY IN PATIENTS UNDERGOING

AORTIC VALVE REPLACEMENT

Industry/Specialty : Internal Medicine/Cardiology

DOCTORAL THESIS SUMMARY

HA NOI – 2024

THE THESIS WAS DONE IN: 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

This thesis will be presented at Institute Council at: 108 Institute of

Clinical Medical and Pharmaceutical Sciences

Day Month Year 2024

The thesis can be found at:

1 National Library of Vietnam 2 Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences

3 Central Institute for Medical Science Infomation and Tecnology

INTRODUCTION

Aortic valve disease (AVD) is common in the world, including Vietnam Aortic valve replacement (AVR) is an effective therapy which may reduce the potential risk of sudden death and improve left ventricular (LV) heart function as well Echocardiography is the standard investigation in the diagnosis and monitoring of patients before and after valve replacement surgery

Ejection fraction (EF) is the index of LV function most frequently used in clinical decision making and for recommending operation in patients with AVD However, because of its marked dependence on LV loading conditions, EF may not accurately reflect intrinsic LV performance In aortic stenosis, EF may be decreased due to afterload excess even when muscle function is normal, whereas it may be normal in aortic regurgitation when myocardial contractility is depressed Conventional measures of global LV systolic function such as EF can be preserved until end-stage disease due to development of concentric hypertrophy, and thus lacks accuracy in identifying subtle changes in myocardial contractility Upon development of an overtly impaired EF, AVR is associated with higher operative risk in cases where the LV dysfunction is not due to afterload mismatch Thus primary reliance on preoperative EF to indicate surgery in patients with AVD may be less beneficial Some studies previously demonstrated that LV global longitudinal strain (GLS) by 2D speckle tracking echocardiography (2D- STE) can detect early subtle myocardial dysfunction than EF The role of GLS in diagnosing and monitoring patients with AVR is an necessary issue that no study in Vietnam has mentioned Therefore, I

did the thesis: “Assessment of clinical, subclinical characteristics and speckle-tracking echocardiography in patients undergoing aortic valve replacement” with the following objectives:

1 Assessment of changes clinical, subclinical characteristics and left ventricular global longitudinal strain by 2D STE in patients undergoing aortic valve replacement duringsix- month follow-up

2 Association of left ventricular global longitudinal strain by 2D STE with echocardiographic and clinical characteristics in patients undergoing aortic valve replacement duringsix- month follow-up

STRUCTURE OF THE THESIS:

The thesis has 136 pages, including: Introduction (2 pages), Background (33 pages), Research objects and methods (25 pages), Results (32 pages), Discussion (39 pages ), Conclusion (2 pages), Recommendations (1 page) The thesis has 41 tables, 7 charts, 12 figures, 153 references, including 8 Vietnamese documents and 145

English documents

CHAPTER 1 OVERVIEW 1.1 Overview of aortic valve disease:

Common AVD is aortic stenosis (AS) or aortic regurgitation (AR) The cause is often due to rheumatism, degeneration or congenital The disease can progress for a long time without any symptoms The disease will rapidly worsen once symptoms begin to appear

1.1.1 Pathophysiology: AS or AR causes increased LV afterload,

which leads to LV hypertrophy (LVH) and remodeling towards heart failure, increased morbidity and mortality An increase in myocardial oxygen consumption and a decrease in myocardial oxygen supply will cause myocardial ischemia LV subendocardial ischemic lesions are affected earlier GLS depends primarily on subendocardial longitudinal muscle contractility, and thus impaired earlier than EF (mainly regulated by radial fibers)

1.1.2 Clinical symptoms: angina, dyspnoea and syncope in AS/fatigue,

palpitations, dyspnoea on exertion as most common symptoms in AR) Both severe AS and severe AR patients may deteriorate into irreversible myocardial dysfunction such as left ventricular heart failure which may increase the risk of sudden death

1.1.3 Electrocardiogram: Signs of left ventricular hypertrophy 1.1.4 Echocardiography: Definition of AS or AR severity were based

on recommendations by the European Association of Echocardiography

and American Society of Echocardiography

Aortic Stenosis: Any one of the three criteria: a aortic valve area

<1.0 cm2, a peak velocity ≥4.0 m/s, or a mean gradient ≥40 mmHg can

be considered to suggest severe AS

Aortic regurgitation: Any one of the criteria: Jet width ≥45% of

LVOT; venacontracta width (VC) >6 mm; regurgitant volume (RVol) ≥ 45 ml/beat, Regurgitant fraction (RF) ≥ 40%, effective regurgitant orifice area (EROA) ≥ 0,2 cm2 can be suggest severe AR

1.1.5 Management of AVD

- Medical management: can improve symptoms but does not

improve patient prognosis When symptoms appear, surgery is needed

- Balloon aortic valvuloplasty: Immediate and long-term results are

not very good, about 90% of restenosis after one year

- Transcatheter aortic valve implantation (TAVI): High cost is still a

major barrier

- Aortic valve replacement (AVR): A technique to remove the

damaged valve and replace it with an prothesis valve Indications for surgery according to ACC/AHA 2020

- Medications treatment of post-operative heart failure: foundational drugs to improve symptoms and prognosis (ACC 2020)

1.2 Speckle-tracking Echocardiography 2D in assessing GLS in patients undergoing aortic valve replacement surgery (AVRS):

Principles: 2-dimensional strain imaging is a new technique which

uses standard B-mode images for speckle tracking analysis, in which the speckled pattern (acoustic backscatter generated by the reflected ultrasound beam) is followed frame by frame This speckle pattern is unique for each myocardial region and it is relatively stable throughout the cardiac cycle The displacement of this speckled pattern is considered to follow myocardial movement and a change between speckles represents myocardial deformation

Strain is defined as the fractional change in length of a myocardial segment relative to its baseline length Strain myocardial is the total deformation during the cardiac cycle relative to the initial length at the onset of the cardiac cycle, and is expressed in percentages This implies that longitudinal shortening (systolic) result in a negative The term global longitudinal strain (GLS) refers to the average strain of all segments

In the early stages of AVD, the myocardium in the mid and epicardium is not affected while the endocardial layer is damaged due to ischemia Therefore, the circumferential strain and torsional deformation of the LV are still maintained normally, helping to preserve the pumping function and the EF while the GLS, which is mainly driven by the endocardial layer, will decline GLS is the most important strain because 70% of the LV myocardium is oriented longitudinally

The normal value of GLS is -18.9±2.5% (American Society of Echocardiography)

Chapter 2 RESEARCH SUBJECTS AND METHODS2.1 Subjects of study:

2.1.1 Inclusion criteria: AVR was performed on 170 patients at Hanoi

Heart Hospital Patients were divided into 2 groups:

Aortic Stenosis (AS): (96 patients): including patients with pure AS

or AS with mild AR≤1/4

Aortic Regurgitation (AR): (74 patients): including patients with

pure severe AR ≥3/4 or severe AR ≥3/4 with mild AS

2.1.2 Exclusion criteria

- Patients underwent AVR concomitant other diseases such as mitral valve replacement, repair of congenital heart defects, and coronary artery bypass grafting

- Mixed Aortic Valve (defined by concomitant severities of AS and AR: AR ≥2/4 combined with moderate or severe AS)

- Atrial fibrillation / poor acoustic window

2.2 Research Methodology: This study was implemented at At Hanoi

Heart Hospital, from January 2020 to December 2022 after taking

informed consent from every enrolled patients

Research design: descriptive cross-sectional, longitudinal follow-up

6 months after surgery

2.3 Study procedures

2.3.1 Preoperative: questioning medical, clinical and subclinical

examination, echocardiography, 2D Speckle-tracking echocardiography according to the research medical record form

2.3.2 Aortic valve replacement surgery: 2020 American College of

Cardiology (ACC) and American Heart Association (AHA) Guideline

- In asymptomatic patients with severe AS and low surgical risk, AVR is reasonable when the serum B-type natriuretic peptide (BNP) level is >3 times normal or increase in aortic velocity ≥0.3 m/s per year - In asymptomatic patients with very severe AS (defined as an aortic velocity of ≥5 m/s) and low surgical risk

Aortic Regurgitation

- In symptomatic patients with severe AR - In asymptomatic patients with chronic severe AR and LV systolic dysfunction (LVEF ≤55%), aortic valve surgery is indicated if no other cause for systolic dysfunction is identified

- In asymptomatic patients with severe AR and normal LV systolic function (LVEF >55%), aortic valve surgery is reasonable when the LV is severely enlarged (LVESD >50 mm or indexed LVESD >25 mm/m2)

- In asymptomatic patients with severe AR and EF >55% and low surgical risk, when there is a progressive decline in LVEF on at least 3 serial studies to the low–normal range (LVEF 55% to 60%) or a progressive increase in LV dilation into the severe range (LV end diastolic dimension LVEDD >65 mm)

2.3.3 Postoperative: Patients were treated with vitamin K antagonist

anticoagulants, optimal treatment of heart failure with drugs to improve prognosis and symptoms Clinical examination (NYHA, CCS) We performed electrocardiogram, echocardiography pre AVR then at one week, one month, 3 months, 6 months post AVR

2.4 Speckle-tracking Echocardiography:

Equipment: Phillip A70 ultrasound (USA), S5-1 probe.

2D- STE technique: All the images were analysed using QLAB.

For data acquisition, three complete cardiac cycles (3 consecutive heart beats only) were stored digitally, with patients held in a breath holding state in left lateral supine position For STE analysis, 2D speckle tracking analyses were performed on standard routine grey scale images of the apical 2-, 3-, and 4-chamber views Frame rate from 50 to 80 frames/second Select the Auto Strain LV program, the software will

automatically recognize the section of views, automatically border the area of interest, and the region of interest width adjusted to include the entire myocardium For data evaluation, the left ventricle was divided into six walls (septal, lateral, anterior, inferior, anteroseptal, posterior) and each wall into three segments (basal, mid and apex) Longitudinal strain was calculated for each of the 18 segments The software automatically calculates the average of segmental peak strain (Global longitudinal strain).

2.5 Parameters variables:

- NYHA (classification heart failure according to the New York

Heart Association) CCS (classification of angina according to the

Canadian Cardiovascular Society)

- Electrocardiogram: Signs of left ventricular hypertrophy,

Sokolow-Lyon SV1+RV5 ≥35mm

- Echocardiography: The echocardiographic measurements of the

left ventricular end-diastolic diameter (Dd), Left ventricular volume diastolic (Vd) and LAVI (Left atrial volume index) were performed according to recommendations of the American Society of Echocardiography Ejection fraction (EF) was obtained by the modified biplane Simpson method LV mass was calculated according to the formula proposed by Devereux et al and indexed for body surface area (LVMI) LVMR was defined as the difference between LVMI before and after six months AVR

- GLS: (Global Longitudinal Strain) by Speckle-tracking

Echocardiography 2D

2.6 Statistical analysis: All statistical analyses were performed using

SPSS 20.0 Continuous variables were presented as mean ± 1 standard Categorical variables were presented as frequencies and percentages Univariate regression equation to determine the correlation of GLS with EF or LVMI Using ROC diagram to determine the cut-off point of GLS capable of separating the risk of non-recovery of EF and NYHA after surgery P-value of < 0,05 was considered significant statistical

CHAPTER 3 RESEARCH RESULTS

From January 2020 to December 2022, Total 170 patients undergoing AVR were enrolled in the study: 96 patients with AS and 74 patients with AR

3.1 General characteristics of patients:

The mean age was 60.9±10.6 years, range from 27 to 89 years; 59.4% male The average BSA is 1.6 ± 0.1 m2 Average BMI was 22.3±2.9(kg/m2); Normal BMI accounts for the majority at 77.6% Common cardiac risk factors are: hypertension (41.8%); diabetes (15.9%); dyslipidemia (17.1%) and smoking (21.2%)

3.2 Assessment of changes clinical, subclinical characteristics and

GLS by 2D- STE in patients undergoing AVR duringsix- month follow-up

3.2.1 Changes in clinical characteristics

NYHA Classification

Chart 3.1 NYHA classification over six- month follow-up

Comments: Most patients dyspnea in NYHA class ≥ 2 AVR

significantly improved NYHA One month after surgery, no patients had NYHA class III or IV, most were NYHA class II (71.8%) At six months of follow-up, NYHA class I was the majority (68.0%)

CCS Classification: AVR improved the patient's angina One month

after surgery, CCS 3 decreased from 47.6% to 9.4%; no patients were in CCS 4 After 6 months, no patients were in CCS 3 or CCS 4; CCS 0 increased from 14.7% to 49.1%

0%20%40%60%80%100%

Preoperative 1 month

Postoperative

3 months Postoperative

6 months Postoperative

Complications: arrhythmia (17.1%); infection (6.5%); effusion

(pericardium, pleura) (5.9%); bleeding (1.8%); 1 AS patient death in the 2nd month after surgery due to cerebral hemorrhage (0.58%); 11 patients were rehospitalized for heart failure (6.5%)

Time in intensive care unit (ICU) and postoperative hospitalization

was 3.8 ± 1.6 days and 11.8 ± 4.7 days respectively

3.2.2 Changes in subclinical characteristics Blood tests: before aortic valve replacement, 48.8% of patients were

anemic; 67.1% of patients had NT-pro BNP > 300 pg/mL

Electrocardiogram: The Sokolow-Lyon index gradually decreased

at postoperative follow-up time points; p<0.001 Six- month follow-up, the Sokolow-Lyon in the AS group decreased from 37.5 ± 2.1 mm to 25.1 ± 3.8 mm and AR group decreased from 41.7 ± 2.8 mm to 28.8 ± 2.9 mm; p<0.001

Anatomical characteristics of the aortic valve: The tricuspid aortic

valve accounts for 63.5% The rheumatic and degenerative aortic valves account for 52.9% and 47.1%, respectively

Size and type of prosthetic aortic valve: Mechanical were implanted

in 121 patients (71.2%), mainly valve size 23 (28.1%) and 25 (19.0%) The 49 remaining patients (28.8%) received bioprostheses, mainly size 21 (44.9%) and size 23 (36.7%) Six months after surgery, all prothesis

valves had Doppler DVI index and aortic valve area (AVA) within

Table 3.13 Changes in LAVI and LVMI after 6 months of AVR

(g/m2) 186,9±29,1 170,3±28,7* 154,3±28,3* 138,7±28,4* 122,9±29,2*

Paired Student t test *: p<0,001 compared with preoperative

Comments:

AVR has already been demonstrated to reduce LVMI and LAVI in both AS and AR patients at all postoperative assessment points; p<0.001 LAVI decreased rapidly and returned to normal at third month of follow up while LVMI had not yet returned to normal values after 6 months postoperative follow-up

Changes LV chamber size in AR group: Mean values of Dd index and

Vd index decreased immediately 1 week after surgery and at postoperative follow-up times; p<0.001 At sixth month of postoperative follow up, Dd index decreased from 37.8 ± 5.5 mm/m2 to 27.8 ± 3.9 mm/m2; Vd index decreased from 114.7 ± 34.0 ml/m2 to 56.2 ± 15.4 ml/m2; p<0.001

Table 3.16: Changes in EF during 6-monthpostoperative follow-up

Aortic valve disease

Ejection fraction-EF Biplane (X±SD) (%)

Comments: Mean values of EF in the AS and AR group improved

respectively from a baseline 61.4 ± 11.1% to 71.8 ± 9.8% and 58.8 ± 11.1% to 69.8 ± 9.6% (p<0.001) at six months follow up examination

after a minor dip at 1st week follow up

3.2.3 Changes in GLS during 6-month follow-up postoperative Table 3.17: Changes in GLS during 6-month follow-up postoperative

Aortic valve disease

Global longitudinal strain (GLS) (X±SD) (%)

1 week 1 month 3 months 6 months ASGLS -16,1±3,5 -15,8±3,6 -17,2±3,0 -18,5±2,2 -19,4±1,9

p <0,001 <0,001 <0,001 <0,001 AR GLS -14,7±3,2 -14,2±3,3 -15,6±2,9 -17,4±2,1 -18,7±1,9

p <0,001 <0,001 <0,001 <0,001

Comments: Mean values of GLS in the AS and AR group improved

respectively from a baseline -16,1±3,5% to -19,4±1,9% and -14,7±3,2% to -18,7±1,9% (p<0.001) at six months follow up examination after a

minor dip at 1st week follow up

3.3 Association of GLS by 2D STE with echocardiographic and clinical characteristics in patients undergoing AVR during six- month follow-up

3.3.1 Correlation of GLS with echocardiographic characteristics 3.3.1.1 Correlation between GLS and EF

Patient stratification

Current guidelines define abnormal EF as <50% As patients with impaired EF already have reduced GLS, the additional incremental prognostic value of GLS in severe AVD patients with normal EF was explored by dichotomizing them into two groups based on the median GLS value (-18,9%)

Table 3.18: Patient stratification based on GLS and EF values

Aortic valve disease

EF<50% (n1=35)

EF≥50% (n2=135) Impaired GLS

GLS>-18,9%

Preserved GLS GLS≤- 18,9% AS (n1=96) 16 (16,7%) 44 (45,8%) 36 (37,5%)

AR (n2=74) 19 (25,7%) 52 (70,3%) 3 (4,1%)

Total (n=170) 35 (20,6%) 96 (56,5%) 39 (22,9%)

Comments: Among 170 patients studied, 35 had impaired EF

and 135 had preserved EF Patients with impaired EF had impaired GLS 45.8% of AS patients and 70.3% of AR patients had impaired GLS despite preserved EF

a Aortic Stenosis b Aortic Regurgitation

Figure 3.4: Correlation between GLS and EF before AVR

Comments: GLS correlated significantly with EF; p<0.001 The

inverse correlation equation: AS group: GLS= – 0.247 x EF– 0.947; r= 0.776

AR group: GLS= – 0.240 x EF – 0.529; r= 0.833

Figure 3.5: Preoperative GLS in predicting EF recovery at 6-month

postoperative follow-up

Comments: The area under the ROC curve was 0.968; 95%

confidence interval; p<0.001 The cut-off point separating the group with postoperative EF ≥ 50% at 6 months of follow-up of the GLS index was -11.85% with a sensitivity of 0.895 and a specificity of 0.920

From the preoperative GLS cut-off point was -11.85%, we evaluated the association between preoperative GLS and 6-month postoperative EF recovery in Table 3.20

Table 3.20: Preoperative GLS in predicting recovery of postoperative

EF at 6-month follow-up

Preoperative GLS

EF at 6-month postoperative follow-up

OR

p-value EF<50% EF≥50%

Comments: Patients with a preoperative GLS ≥ -11.85% had a

97.8-fold higher risk of nonrecovery of postoperative EF (EF<50%) than patients with a GLS<-11.85% at 6 months follow-up; p<0.001

3.3.1.2 Correlation between GLS and LVMI:

Before AVRS: GLS and LVMI were strongly linearly correlated,

p<0.001 AS group: GLS= 0.101 x LVMI – 33.351; r = 0.855

AR group: GLS= 0.097 x LVMI – 32.28; r = 0.877 After surgery 6 months: The more preoperative GLS decreased, the worse the regression of LV mass, p<0.001

3.3.2 Association of GLS with clinical characteristics