Functional Moderate to Severe Tricuspid Regurgitation in Adults undergoing Transcatheter Atrial Septal Defect

Closure

by

Yvonne Bach

A thesis submitted in conformity with the requirements for the degree of Master of Science

Institute of Medical Science University of Toronto

© Copyright by Yvonne Bach 2019

ii

Functional Moderate to Severe Tricuspid Regurgitation in Adults

undergoing Transcatheter Atrial Septal Defect Closure

Yvonne Bach

Master of Science

Institute of Medical Science University of Toronto

2019

Abstract

Background: A large proportion of patients continues to have moderate to severe tricuspid regurgitation (TR)

after transcatheter atrial septal defect (ASD) closure.

Objective: To determine the clinical significance of functional TR in ASD patients and identify the baseline

predictors of persistent TR after ASD closure.

Methods: Clinical data were collected from hard-copy and electronic records at the University Health Network

(UHN), Toronto, Canada. The clinical registry was linked to Ontario population-based health administrative

databases.

Results: Age ≥65 years, severe TR, and right ventricular systolic pressure (RVSP) were independent baseline

predictors of persistent TR. ICES analyses showed patients with baseline moderate to severe TR (n=750) were

not associated with higher cardiovascular mortality compared to patients with baseline mild/no TR (n=199)

after adjust for cardiovascular co-morbidities.

Conclusions: Perhaps offering early ASD closure or concomitant tricuspid valve intervention may be of benefit

to patients at risk for persistent TR.

iii

Acknowledgments I would like to express my sincerest gratitude to my supervisor Dr. Eric Horlick, for his undying

support and encouragement. You inspire me to aim higher and be confident in everything that I

do. I have learned the true meaning of teamwork, integrity, and leadership. I could not have

imagined a better mentor.

I would also like to thank my advisory committee members, Dr. Lusine Abrahamyan, Dr.

Douglas Lee, and Dr. John Parker for their constructive feedback in preparing me for the final

oral examination. Lusine – you helped me understand the importance of data quality,

methodology, and communication as a clinical researcher. Dr. Lee – thank you for being our

ICES liaison and for your expertise in data management and statistical analysis, a major

component of this study. Dr. Parker, your advice has been invaluable to the quality of content in

my research. To Drs Susanna Mak, Luc Mertens, and Luc Beauchesne – I appreciate your time

and commitment in chairing, appraising, and attending my thesis and oral examination.

Special acknowledgements to Christoffer Dharma and Jennifer Day for your work and

commitment to this project. Thank you to Chris for taking the time to answer my questions on

the analysis of ICES-derived data, it was an absolute pleasure to work with you. Jenn – thank

you for your help in reassessing echocardiograms for our imaging sub-study, it added great value

to my project.

Lastly, I would like to express my gratitude for my family and friends, who have been supportive

through the highs and lows associated with being a graduate student. To my mom and dad, thank

you for your unconditional love, the sacrifices and providing for us so that we can reach our

dreams. To my brother, Raymond, thank you for your calm presence and listening to my worries

and troubles. To my sister, Mandy, and her husband, Kenneth, thank you for all your support and

hospitality. To my friends and colleagues – Sarah, Elizabeth, Annam, Healey, Ashish, Sami,

Lukas, Rohan, Louise, Anna, Yang, Mary, Lynette, and Libo - thank you for the laughs and

encouragement that you have given me throughout the years. Boss and Chip – thank you for

always bringing a smile to my face.

iv

Statement of Contributions A large thank you to:

The ICES team for data linkage and conducting statistical analyses for the long-term outcomes

portion of my thesis: Dr Douglas Lee, Christoffer Dharma, Jiming Fang, Hadas Fischer, Tara

O’Neill.

Dr Lusine Abrahamyan for sharing the diagnostic codes used to define variables for ICES

linkage.

Jennifer Day for the comprehensive reassessment of the echocardiograms for the imaging sub-

study and providing stills of echocardiograms for the literature review.

Previous research students who helped in cleaning the clinical database.

Scholarships and grants from:

Canadian Institutes of Health Research (Canada Graduate Scholarship-Master’s)

Institute of Medical Science (Entrance Scholarship)

School of Graduate Studies (Conference Grant)

Cardiovascular Sciences Collaborative Program (Conference Grant)

v

Table of Contents Acknowledgments .......................................................................................................................... iii

Statement of Contributions ............................................................................................................ iv

Table of Contents .............................................................................................................................v

List of Abbreviations ..................................................................................................................... ix

List of Tables ...................................................................................................................................x

List of Figures ................................................................................................................................ xi

List of Appendices ........................................................................................................................ xii

Chapter 1 Literature Review ............................................................................................................1

Secundum atrial septal defect .....................................................................................................1

1.1 Classification and prevalence ..............................................................................................1

1.2 Genetic factors .....................................................................................................................2

1.3 Pathophysiology ...................................................................................................................3

1.4 Natural history and diagnosis ...............................................................................................4

1.4.1 Echocardiographic findings .....................................................................................5

1.4.2 Gated computed tomography .................................................................................10

1.4.3 Cardiac magnetic resonance imaging ....................................................................10

1.4.4 Right heart catheterization .....................................................................................11

1.5 Treatment ...........................................................................................................................12

1.6 Intermediate and long-term outcomes after ASD closure ..................................................17

1.6.1 Conservative versus surgical therapy .....................................................................18

1.6.2 Surgical versus catheter-based therapy ..................................................................19

1.7 Reverse cardiac remodeling after ASD closure .................................................................22

1.7.1 Structural changes ..................................................................................................22

1.7.2 Functional changes .................................................................................................23

1.7.3 Electrophysiological changes .................................................................................24

vi

1.7.4 Left ventricular remodeling ...................................................................................25

Functional tricuspid regurgitation .............................................................................................26

2.1 TR secondary to left-to-right atrial shunt ...........................................................................26

2.1.1 Mechanisms of functional tricuspid regurgitation .................................................26

2.1.2 Prevalence of functional TR before and after ASD closure ..................................27

2.1.3 Imaging modalities for the tricuspid valve and TR ...............................................28

2.1.4 Management of functional TR ...............................................................................34

2.1.5 Baseline predictors of persistent TR following isolated ASD device closure .......35

2.1.6 Long-term outcomes of ASD patients with functional TR ....................................39

2.2 Advancement in tricuspid valve devices ............................................................................42

Chapter 2 Rationale and Objectives ...............................................................................................45

Rationale ...................................................................................................................................45

3.1 Objectives ..........................................................................................................................46

Chapter 3 Methods .........................................................................................................................47

Single-centre retrospective study ..............................................................................................47

4.1 Study population ................................................................................................................47

4.2 Research ethics approval ....................................................................................................47

4.3 Study design .......................................................................................................................47

4.4 Data sources .......................................................................................................................48

4.4.1 Clinical registry ......................................................................................................48

4.4.2 Linkage to administrative databases ......................................................................48

4.5 Echocardiographic sub-study .............................................................................................51

4.6 Statistical analysis ..............................................................................................................51

4.6.1 Clinical registry ......................................................................................................51

4.6.2 Analysis of linked data ...........................................................................................52

Chapter 4 Results ...........................................................................................................................53

vii

Analysis of clinical registry ......................................................................................................53

5.1 Study population ................................................................................................................53

5.2 Echocardiographic sub-study .............................................................................................55

5.3 Right heart catheterization .................................................................................................56

5.4 Improved versus persistent TR after ASD closure ............................................................57

5.5 Independent baseline predictors of persistent TR ..............................................................58

5.6 Reverse cardiac remodeling ...............................................................................................60

Long-term outcomes from ICES-linked data ............................................................................62

6.1.1 Study population ....................................................................................................62

6.1.2 Baseline patient characteristics ..............................................................................62

6.1.3 Acute outcomes ......................................................................................................63

6.1.4 Long-term outcomes ..............................................................................................64

6.1.5 Unadjusted survival analysis for disease-specific mortality ..................................68

6.1.6 Adjusted survival analysis for all-cause mortality .................................................70

6.1.7 Adjusted survival analysis for cardiovascular mortality ........................................71

Chapter 5 Discussion .....................................................................................................................72

Main findings ............................................................................................................................72

7.1 Functional TR before ASD closure ....................................................................................72

7.1.1 Patients with pre-procedural moderate to severe TR are clinically different than patients with mild/no TR ................................................................................73

7.1.2 Structural abnormalities in the right heart are more pronounced in patients with pre-procedural moderate to severe TR ...........................................................73

7.2 TR resolution observed in majority of patients with baseline moderate to severe TR ......74

7.3 Older age, higher RVSP, and severe TR at baseline predict persistence of TR ................75

7.4 Positive reverse cardiac remodeling observed in all groups regardless TR grade .............76

7.5 Effect of TR and t-ASD closure on long-term clinical outcomes ......................................77

7.5.1 Unadjusted survival analysis ..................................................................................78

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7.5.2 Adjusted survival analysis .....................................................................................79

7.6 Clinical implications ..........................................................................................................81

7.6.1 Concomitant percutaneous TV intervention ..........................................................82

7.7 Limitations .........................................................................................................................83

7.8 Future directions ................................................................................................................85

7.9 Conclusions ........................................................................................................................86

Appendices ...................................................................................................................................104

Copyright Acknowledgments ......................................................................................................109

ix

List of Abbreviations AF: atrial fibrillation

AP: anteroposterior

ASD: atrial septal defect

ASO: Amplatzer septal occluder

CMR: cardiac magnetic resonance

CT: computed tomography

EF: ejection fraction

EROA: effective regurgitant orifice area

FAC: fractional area change

ICES: Institute of Clinical Evaluative Sciences

MPI: myocardial performance index

NYHA: New York Heart Association

PASP: pulmonary artery systolic pressure

PH: pulmonary hypertension

Qp:Qs: pulmonary to systemic flow ratio

RHC: right heart catheterization

RVSP: right ventricular systolic pressure

S’: peak systolic velocity

SL: septolateral

TA: tricuspid annulus

TAP: tricuspid annuloplasty

TAPSE: tricuspid annulus planar systolic excursion

TGH: Toronto General Hospital

TR: tricuspid regurgitation

TSLA: tricuspid septal leaflet angle

TTE: transthoracic echocardiography

TV: tricuspid valve

UHN: University Health Network

VC: vena contracta

x

List of Tables Table 1: Advantages and limitations of imaging modalities used for ASD ................................... 4

Table 2: Reference echocardiographic values for right heart assessment in a normal adult .......... 9

Table 3: Literature review of adults with ASD and functional TR ............................................... 28

Table 4: Reference values for normal tricuspid valve anatomy ................................................... 29

Table 5: Reference values for grading functional tricuspid regurgitation severity ...................... 31

Table 6: Literature review of baseline predictors of persistent TR .............................................. 36

Table 7: Coding definition of clinical variables used at ICES ...................................................... 49

Table 8: Results: Baseline patient characteristics derived from local database ............................ 54

Table 9: Results: Age- and sex-matched baseline echocardiographic characteristics .................. 55

Table 10: Results: Peri-procedural and index hospitalization characteristics .............................. 56

Table 11: Results: Uni- and multivariable logistic regression for persistent TR .......................... 58

Table 12: Results: Echocardiographic changes after percutaneous ASD closure ........................ 60

Table 13: Results: Baseline patient characteristics derived from ICES ....................................... 62

Table 14: Results: Acute outcomes stratified by pre-procedural TR grade .................................. 63

Table 15: Results: Long-term outcomes stratified by pre-procedural TR grade .......................... 64

Table 16: Results: Long-term outcomes stratified by TR improvement after device closure ...... 66

xi

List of Figures Figure 1: Secundum (Type II) ASD with a left-to-right interatrial shunt ....................................... 1

Figure 2: Right heart imaging in transthoracic echocardiography .................................................. 6

Figure 3: Unrepaired and repaired ASD in echocardiography ....................................................... 7

Figure 4: Schematic of transcatheter ASD closure ....................................................................... 14

Figure 5: Treatment algorithm for secundum ASD ...................................................................... 16

Figure 6: Measurements of tricuspid annulus diameter in echocardiography .............................. 29

Figure 7: Measurements of tricuspid regurgitation in echocardiography ..................................... 30

Figure 8: Percutaneous devices for tricuspid annulus ................................................................... 42

Figure 9: Percutaneous devices for tricuspid leaflet coaptation ................................................... 43

Figure 10: Study flow diagram from local database ..................................................................... 53

Figure 11: Distribution of patients based on pre- and post-procedural TR grade ........................ 57

Figure 12: ROC curve of the multiple logistic regression model of persistent TR ...................... 59

Figure 13: Study flow diagram from ICES-linked database ......................................................... 61

Figure 14: Unadjusted survival comparison between pre-procedural TR cohorts ....................... 67

Figure 15: Unadjusted survival comparison between post-procedural TR cohorts ...................... 68

Figure 16: Adjusted survival of all-cause mortality between pre-procedural TR cohorts ............ 69

Figure 17: Adjusted survival of cardiovascular mortality between pre-procedural TR cohorts ... 70

xii

List of Appendices Appendix 1: Diagnostic and billing codes used to define variables for ICES analyses ............. 102

Appendix 2: Comparison of patients with baseline mild and no TR .......................................... 106

Appendix 3: Comparison of study populations from clinical and ICES-linked registries ......... 106

Appendix 4: Comparison of comorbidity burden with clinical and ICES-linked data ............... 106

1

Chapter 1 Literature Review

Secundum atrial septal defect

1.1 Classification and prevalence Atrial septal defect (ASD) accounts for one third of congenital heart defects (CHD) diagnosed in

adulthood. There are four types of atrial septal defect. The most common type of ASD is ostium

secundum (75% of all atrial type defects), followed by ostium primum (15%) and sinus venosus

(10%) (Brickner, Hillis, & Lange, 2000). There is a rare fourth type of ASD; coronary sinus

ASD which is defined as the unroofing of the coronary sinus to the left atrium. Although ostium

primum and sinus venosus ASDs are prevalent in a 1:1 female-to-male ratio, the ratio is 2:1 for

ostium secundum ASD. The reason for this difference is unknown. Ostium primum defects are

also known as atrioventricular (AV) septal or endocardial cushion defects, as the defect occurs at

the level of the mitral and tricuspid valves. Sinus venosus defects are found near the superior

vena cava (SVC), in which the right atrium appears compartmentalized in two. Sinus venosus

ASD is associated with partial anomalous pulmonary venous return (APVD) – in 90 % of

patients, one or more pulmonary veins are connected to right atrium or SVC rather than the left

atrium (Van Praagh, Carrera, Sanders, Mayer, & Van Praagh, 1994). Secundum ASD (Figure 1),

a true defect of the interatrial wall can occur as a single, multiple, or fenestrated entity. About 1

percent of secundum defects are associated with anomalous pulmonary veins.

Figure 1. Secundum (Type II) ASD with a left-to-right interatrial shunt. Reprinted with permission from “Atrial Septal Defect” by Mayo Clinic.

2

1.2 Genetic factors Genetics contribute to abnormal atrial septal development during cardiac morphogenesis.

Although ASDs can arise from spontaneous genetic mutations, there are familial autosomal

dominant mutations associated with ASDs. Mutations to the gene that encodes for the homeobox

transcription factor NKX2-5 have been linked to human congenital heart disease (Schott et al.,

1998). NKX2-5 is required for the regulation of septation in cardiac development and

maintenance of the atrioventricular (AV) conduction throughout life. Up to ten different point

mutations of the NKX2-5 locus have been identified in humans with ASD, ventricular septal

defects (VSD), tetralogy of Fallot, and tricuspid valve (TV) abnormalities (Ikeda et al., 2002;

Schott et al., 1998).

Holt-Oram syndrome (HOS) is an autosomal dominant disorder caused by mutations of TBX5

transcription factor which affects limb and heart development including the interatrial septum

(Basson et al., 1997). In vivo studies have identified 6 mutations of the TBX5 gene that produce

a premature stop codon in the mRNA transcript (Li et al., 1997). TBX5 is expressed in the heart

and limb during gestation days 26-52 in human embryonic development and regulates the

expression of α-myosin heavy chain (MYH6) (Ching et al., 2005). Thus, downstream sarcomeric

gene mutations are also linked to inherited secundum ASDs. MYH6 is a structural protein

highly expressed in the atrium during embryonic development and required for proper atrial

septation. The allele in familial ASD patients expresses mutant MYH6 that disrupts the binding

site of the heavy chain to the actin light chain (Posch et al., 2011).

Another heterozygous mutation that causes human cardiac septal defects is found in the gene,

GATA4 (Garg et al., 2003). GATA4 is a transcription factor that is expressed during heart

development. The G296S missense mutation in GATA4 decreases its own transcriptional activity

and results in a gene product that has a decreased affinity for DNA. The mutated GATA4 protein

was also found to inhibit its interaction with TBX5 and vice versa, in which missense mutations

of TBX5 also affected the interaction with GATA4 and found in humans with similar septal

defects (Garg et al., 2003; Granados-Riveron et al., 2012). Thus, individual mutations of GATA4

and TBX5 or combined mutations of essential cardiac transcription factors cause disruption of

protein-protein interactions crucial for cardiac septal formation in humans.

3

1.3 Pathophysiology As a true defect of the fossa ovalis, a secundum ASD, results from the excessive resorption or

hypoplastic growth of the ostium secundum during fetal development (Rojas et al., 2010). A

residual “hole” is left in the interatrial wall, allowing a connection between the two atria.

Assuming that there is no reduced right ventricular compliance or tricuspid stenosis, after a baby

takes their first breath, higher pressure in the left atrium results in left-to-right atrial shunting

through the septal defect and leads to a series of adaptations which begin with right heart

enlargement. As the right ventricle enlarges, the interventricular septum is shifted to the left, and

left ventricular filling becomes impaired. This further propagates left-to-right atrial shunting and

increases right atrial pressure.

In general, hemodynamically significant shunting is usually observed ASDs greater than 10 mm

in diameter. Enlargement of the right atrium and ventricle is a physical sign of the significance of

an ASD and is generally associated with a pulmonary to systemic flow ratio (Qp:Qs) greater

than 1.5 (G. Webb & Gatzoulis, 2006). Long-term shunting can result in the normalization of RA

and RV size if the ASD is closed at an appropriate time. Remodeling is almost always seen,

although there is no guarantee that it will remodel to normal after 40 years old.

Prolonged shunting and subsequent right heart enlargement can also cause significant functional

tricuspid regurgitation (TR), atrial arrhythmias, and in rare occasions, pulmonary hypertension

(PH). TR occurs in the presence of ASD when extensive left-to-right shunting causes RV volume

overload. As the RV dilates, the papillary muscles of the tricuspid valve become displaced and

the TV annulus dilates. The loss of coaptation of the leaflets results in regurgitation from right

ventricle back into the right atrium. It is important to note that PH is not necessary for ASD

patients to develop functional TR.

Eisenmenger Syndrome (ES) may result from large secundum ASDs left untreated, although the

presence of pulmonary hypertension in young patients with ASD is distinctly unusual and

usually the implies the co localization of 2 diseases as opposed to a causative relationship. This

pathophysiological concept may result from any connection between the systemic and

pulmonary systems (e.g., ventricular septal defect, atrial septal defect, patent ductus arteriosus),

that is associated with elevated PA pressure and pulmonary vascular resistance, resulting in

reversed or bidirectional shunting (Daliento et al., 1998). In the context of an ASD, pulmonary

4

resistance can cause a reversal of the shunt via ASD from the right to left atrium. Patients

become hypoxic and present with cyanosis, clubbing of fingertips, and exercise intolerance.

1.4 Natural history and diagnosis Secundum ASDs are often missed during childhood and adolescence because of the high

adaptability in the compliant right heart and the subtlety of physical signs and symptoms. They

are usually diagnosed as incidental findings or because of nonspecific symptoms or

breathlessness and palpitations. In the former scenario, physical examinations,

electrocardiogram, ambulatory rhythm monitoring, and imaging tests for other illnesses can

reveal cardiac murmurs, arrhythmias, and right heart enlargement, prompting further testing and

ASD diagnosis. It is usually in the third or fourth decade in which a patient presents with signs

and symptoms such as dyspnea (i.e., shortness of breath), palpitations, syncope, fatigue, angina

(i.e., chest pain), cryptogenic stroke, and/or shows signs of right-sided heart failure. Once an

ASD is suspected, various diagnostic modalities can be used to confirm the presence of a

secundum ASD. The advantages and limitations of each modality is summarized in Table 1.

Table 1. Advantages and limitations of imaging modalities used for ASD

Modality Advantages Limitations Transthoracic echocardiography (TTE)

Non-invasive; cost-effective and relatively quick; primary diagnostic tool

Limited accuracy

Transesophageal echocardiography (TEE)

Higher spatial resolution than TTE; visualization of posterior cardiac structures; preferred diagnostic tool and planning for congenital or valve repairs(high sensitivity)

Semi-invasive; requires expert imaging echocardiographer

Gated magnetic resonance imaging (MRI)

Non-invasive; accurate in characterizing abnormal morphology and function; best for classifying type of ASD and quantifying shunt

Poor temporal resolution in infants and children unable to follow single breath-holding; limited portability; high cost

Gated computed tomography (CT)

Non-invasive; used more in infancy; best for viewing enlarged pulmonary arteries and RV dilatation and hypertrophy in ASD and PH patients

Variable temporal resolution; modest radiation exposure and contrast administration; beta-blocker administration to lower heart rate

Intracardiac echocardiography (ICE)/right heart catheterization (RHC)

Accurately diagnosis of ASD; accurate hemodynamic assessment (i.e., pulmonary arterial pressures); preferred imaging guidance during ASD procedure

Invasive; limited 3D evaluation and temporal resolution; vascular access site complications; high cost

5

1.4.1 Echocardiographic findings

Transthoracic echocardiography (TTE) is often the initial imaging study that detects RV and RA

enlargement. Since ASDs are easily missed on TTE, common causes of right heart enlargement

are examined first - pulmonary hypertension, tricuspid regurgitation, and pulmonary

stenosis/regurgitation. If an ASD is located on TTE, the size and type of ASD, as well as the

direction of the atrial shunt can be determined. Quantification of the RV is difficult due to its

crescent shape, and it is only until the last decade that echocardiographic measurements of the

RV were standardized. There are several optimal imaging views for the RV; apical four-chamber

(A4C), RV-focused depending on the area of interest (Lang et al., 2015). Due to the lack of

anatomic reference points in the RV, there is wide variability in the measurements taken from a

conventional A4C view. Linear dimensions of the RV are best measured with a RV-focused A4C

view. In most cardiac centres, 2-dimensional (2D) echocardiography is often the first line of

imaging and the areas of the right ventricle (Fig. 2A) and atrium (Fig. 2B) can be measured.

However, 3-dimensional (3D) imaging should be obtained whenever possible to measure RV

volume, and thereby eliminating the variability in linear measurements.

6

Figure 2. (A) RV area and (B) RA area in apical 4 chamber view. RV systolic function evaluated by (C) RV fractional area change (i.e., 100 x (EDA-ESA)/EDA) and (D) tricuspid annulus planar systolic excursion (TAPSE) distance measured between end-diastole and peak systole by M-mode.

Estimates of RV size, however, may consistently be underestimated, which can be seen when

validating values against cardiac magnetic resonance (CMR) imaging (Shimada, Shiota, Siegel,

& Shiota, 2010). Chamber volumes and ejection fraction (EF) are dependent on age and gender;

BSA-indexed values showed smaller RV volumes and higher EFs in healthy women and elderly

populations (Maffessanti et al., 2013). 3DE-derived RVEF has been validated against CMR

(Shimada et al., 2010), and was found to be most reliable in grading systolic function. However,

2D FAC (Fig. 2C) and TAPSE (Fig. 2D) have been correlated with CMR- and radionuclide-

derived EF, respectively. Peak systolic velocity of the tricuspid annulus (S’) and myocardial

performance index (MPI) are yet to be validated. However, studies providing normal reference

values have only been published in recent years and continue to release new data. EF is a global

measure of RV systolic function and essential when parameters of longitudinal RV function (i.e.,

TAPSE and S’) are reduced and no longer indicative of the overall function of the RV. 2D FAC

7

is also an index of global RV function and has clinical importance when 3D echocardiography is

unavailable.

TTE investigation of the right heart helps determine the severity of RV and RA enlargement, size

and type of ASD, direction and quantification of atrial shunt (Qp:Qs), although it can be

inaccurate. If colour flow Doppler is applied, it can accentuate the size and direction of flow of

the ASD (Figure 3); a large width of the colour flow jet across the defect suggests a larger ASD

and a higher Qp:Qs. Pulse- and continuous-wave Doppler can be used for lower and higher

velocity flows across the ASD, respectively. A study showed that at satisfactory imaging

windows in 2D TTE, only 89% of secundum ASDs can be visualized (Shub et al., 1983), which

becomes a less sensitive diagnostic tool in older patients. An agitated saline contrast with

Valsalva maneuver can reveal nearly 100% of secundum ASDs.

Figure 3. (A) Colour Doppler of a left-to-right interatrial shunt through the secundum ASD. (B) Complete occlusion after percutaneous ASD closure.

Higher definition imaging via transesophageal echocardiography (TEE) is useful in providing

further detail of the defect and rule out other congenital defects that may cause right heart

enlargement, such as PAPVC or sinus venosus ASD. 3D TTE or TEE can also better determine

the defect size and provide a more accurate quantification of volume overload and systolic

function. Sex-dependent reference values of the right heart in normal adults are quite limited,

however, the most recent values reported by Lang et al. (2015) are summarized in Table 2. It is

essential to calculate right-sided pressures; pulmonary artery systolic pressure (PASP)/RVSP can

be estimated using a modified Bernoulli equation of the velocity of TR and right atrial pressure.

Qp:Qs ratio is best estimated using a combination of TTE (pulmonary flow, aortic flow) and

LA

RA

LA

RA

8

TEE (pulmonary and left ventricular outflow diameter) views (Martin, Shapiro, & Mukherjee,

2014). In most scenarios, diagnostic workup for an ASD is confirmed by TTE and TEE. If

uncertainty exists, CT or CMR imaging is recommended.

9

Table 2. Reference values for right heart assessment in a normal adult* TTE/TEE CMR CT Parameter Male Female Male Female Male Female RV size

Basal diameter (mm) 25-41 Mid diameter (mm) 19-35 Longitudinal diameter (mm) 59-83 Wall thickness (mm) 1-5 End-diastolic area indexed to BSA (cm2/m2) 5-12.6 4.5-11.5

End-diastolic volume indexed to BSA (mL/m2) 35-87 32-74 61-121 48-112 120-139 102-120 RV systolic function TAPSE (mm) ³17 FAC (%) ³35 S wave (cm/sec)

Pulsed Doppler ³ 9.5 Colour Doppler ³ 6.0

EF (%) ³ 45 52-72 51-71 MPI

Pulsed Doppler £ 0.43 Colour Doppler £ 0.54

RA size RA minor axis indexed to BSA (cm/m2) 1.9 ± 0.3 1.9 ± 0.3 2.6 ± 0.30 RA major axis indexed to BSA (cm/m2) 2.4 ± 0.3 2.5 ± 0.3 3.0 ± 0.32 2D volume indexed to BSA (mL/m2) 25 ±7 21± 6 54 ± 10 54±14 47±10

*Adult >18 years old; mean age differs between studies. Normal values reported as ranges (i.e., 95% CI) or mean ± SD for TTE/TEE, CMR, and CT assessment of the right heart (Fuchs et al., 2016; Kawel-Boehm et al., 2015; Lang et al., 2015) RA, right atrium; BSA, body surface area; TAPSE; tricuspid annulus planar systolic excursion; EF, ejection fraction; FAC, fractional area change; MPI, myocardial performance index.

10

1.4.2 Gated computed tomography

Gated computed tomography (CT) imaging of congenital heart defects is often used in infancy

due to their inability to perform a single breath hold required in CMR. It is also beneficial for

patients with pacemakers or defibrillators who require accurate assessment of RV structure and

function (A. J. Taylor et al., 2010). CT imaging is more accurate in measuring RV and PA

morphology than traditional echocardiography. However, temporal resolution of the heart is not

well captured by ungated CT because of the relatively fast motion of the heart – leading to

“blurry” edges of the cardiac chambers. A common solution to increase temporal resolution is

through retrospective or prospective electrocardiographic (ECG)-gating. Retrospective gating

acquires image data by applying certain points of the patient’s cardiac cycle to the data.

Prospective gating utilizes ECG signals to prospectively identify when imaging data will be

acquired, at which point the CT scan will be gated. Due to the high exposure of radiation,

intravenous administration of contrast material, and use of beta-blockers to lower heart rate that

are required in retrospective gating, the applications of CT imaging are limited. Normal values of

right heart structure and function in a healthy adult are listed in Table 2.

1.4.3 Cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging (MRI) is considered the “gold-standard” for non-invasive

imaging in accurately assessing ASD size and shunt, RV structure and function, and pulmonary

vasculature (Boxt, 2004; Hoey, Gopalan, Ganesh, Agrawal, & Screaton, 2009). In studies

comparing cardiac MRI and TEE sizing of ASD against balloon sizing technique/device size,

MRI-based measurements and the “true” ASD size/flow ratio/device size had higher correlation

coefficients than values obtained from TEE (Durongpisitkul et al., 2002; A. M. Taylor, Stables,

Poole-Wilson, & Pennell, 1999; Weber, Dill, Mommert, Hofmann, & Adam, 2002). The high

spatial and temporal resolution of gated-MRI also provides an accurate (Koch et al., 2001; Koch,

Poll, Godehardt, Korbmacher, & Modder, 2000; Moon, Lorenz, Francis, Smith, & Pennell, 2002)

and reproducible (Grothues et al., 2004; Mooij, de Wit, Graham, Powell, & Geva, 2008)

representation of both left and right ventricular volume and function. Imaging data acquisition is

quick and can be done within a single breath hold. Although echocardiography is sufficient in

diagnosing ASD and right heart enlargement for most cases, clinicians may require additional

imaging studies that provide more accurate and reliable assessments of the RV in patients with

11

complex cardiovascular morphology and/or other acquired heart disease such as pulmonary

hypertension. As such, an MRI study would be the best non-invasive tool in accurately

quantifying morphological and functional changes of the right heart (Table 2), and providing

valuable supplementary information when a patient is unable to tolerate TEE or when RV

dilatation needs to be ascertained in patients with small defects.

The limitations of MRI (cost, lack of portability, availability, and the high probability of ASD

patients having a pacemaker or defibrillator) make it impractical to diagnose all patients

suspected of an ASD (Table 1). 3D echocardiography has been extensively validated against

MRI/CT (Shimada et al., 2010; Sugeng et al., 2010), and has shown high inter-observer

agreement for quantitative assessment of systolic and diastolic volumes (Grothues et al., 2004;

Margossian et al., 2009). Thus, comprehensive investigations are non-essential unless suboptimal

echocardiographic windows or other conditions contributing to volume overload and ventricular

dysfunction are present.

1.4.4 Right heart catheterization

Invasive testing such as right heart catheterization (RHC) can be performed to confirm the

presence of a hemodynamically significant ASD and other common associated defects, as well as

provide a comprehensive assessment of pressures and oxygen saturations in the chambers and

great vessels. Right ventricular systolic pressure (RVSP), pulmonary artery systolic pressure

(PASP), and Qp:Qs measurements are important in deciding whether or not to close the ASD

when PH or Eisenmenger syndrome is suspected. The use of intracardiac echocardiography

(ICE) offers high resolution imaging of the ASD and RV. As most patients with ASD are not

diagnosed until the 4th or 5th decade, the presence of other acquired cardiac and noncardiac

diseases can affect accurate image acquisition and the diagnosis of congenital malformations.

The use of CMR/CT/RHC are becoming useful tools in the management of complex ACHD

cases.

12

1.5 Treatment Surgical ASD closure was the standard treatment for hemodynamically significant ASDs

beginning with the first reported cases in 1953 (Gibbon, 1954), and still remains a safe and

effective option in current adult congenital heart disease management guidelines (Stout et al.,

2018).

In a study that compared long-term outcomes of adults who were treated medically and

surgically, the stark difference in survival favored surgery (Attie et al., 2001). There are two

main surgical techniques used depending on the size of the defect; primary suture closure and

patch closure. Primary suture closure is often used for smaller defects by applying a continuous

suture to approximate the edges of the defect, whereas patch closure uses a pericardial or

synthetic patch to cover larger ASDs. Both methods are effective in completely eliminating the

interatrial shunt, with zero mortality and minimal morbidity post-repair (Doll et al., 2003;

Hopkins, Bert, Buchholz, Guarino, & Meyers, 2004; J. H. Khan, McElhinney, Reddy, & Hanley,

1999; Luo, Chang, & Chen, 2001). Surgical ASD closure has been beneficial in resolving

abnormal septal motion, commonly seen in ASD patients, by increasing LV volume and cardiac

output (Simmers, Sobotka, Rothuis, & Delemarre, 1994). Unlike the LV, the RV is more

sensitive to the adverse effects of cardiopulmonary bypass which is indicated by the significant

decrease in total excursion and peak lengthening and shortening rates of the RV after surgical

repair in several studies (Boldt, Kling, Dapper, & Hempelmann, 1990; Gonzalez et al., 1985).

The intrinsic composition of mainly longitudinal myocardial fibres (Kaul, Tei, Hopkins, & Shah,

1984; Pai, Bodenheimer, Pai, Koss, & Adamick, 1991), as well as its exposed position in the

mediastinum are thought to be the factors that contribute to RV susceptibility during open-heart

surgery. In addition to RV dysfunction, persistence of RV dilatation can be seen in more than

80% of patients up to five years after surgical closure in children (Meyer, Korfhagen, Covitz, &

Kaplan, 1982). Common peri- and post-operative complications include conductive

abnormalities (Berger, Vogel, et al., 1999), pericardial effusion, post-pericardiotomy syndrome

(Gill, Forbes, & Coe, 2009; Heching, Bacha, & Liberman, 2015; Rabinowitz, Meyer,

Kholwadwala, Kohn, & Bakar, 2018), pneumonia, and other inflammatory responses.

In 1976, King and Mills attempted the first transcatheter ASD closure in an adult female (King,

Thompson, Steiner, & Mills, 1976). Since their introduction, the development and refinement of

13

interatrial devices for ASD closure continue to evolve and have now become the standard of care

in treating adults with secundum ASDs. Device embolization, erosion, and residual shunting

were primary concerns in early transcatheter devices. However, the occurrences have

significantly reduced since their conception. The redesign of multiple abandoned devices led to

the first widely-accepted device known as the CardioSEAL in 1996 (Nassif et al., 2016). The

self-expanding, double umbrella discs had a significantly lower incidence of umbrella arm

fractures in small devices but remained an issue for larger defects until 1998 when a new model,

STARFlex, was introduced. In this design, a continuous Nitinol coiled wire spring was added to

the both umbrellas to serve as a self-centering mechanism which further reduced the risk of

fracturing (Hausdorf, Kaulitz, Paul, Carminati, & Lock, 1999). Both models received CE-

marking, however, were not approved by the FDA (although CardioSEAL was approved for

ventricular septal defect closure). Later models include the BioSTAR and BioTREK,

bioresorbable septal occlude devices that would resorb and be replaced by host tissue. Although

BioSTAR was CE-marked in 2007 (Baspinar, Kervancioglu, Kilinc, & Irdem, 2012; Morgan,

Lee, Chaturvedi, & Benson, 2010), and the fully resorbable BioTREK showed promising results

in preclinical trials (Baspinar et al., 2012), the bankruptcy of NMT Medical in 2011 following

the negative Closure I trial resulted in the devices being removed from the market.

At the same time, another catheter-based device known as the Amplatzer Septal Occluder (ASO)

was undergoing clinical trials. In 1997, the self-expanding and self-centering double-disc device

was introduced and claimed to minimize the risk of residual shunting and fractures seen in other

devices. This was achieved by the design and material used in manufacturing; the larger left

atrial disc is connected to the smaller right atrial disc by a waist, all of which is made of a one-

piece Nitinol mesh filled with Dacron threads. After the device is loaded, the left atrial disc is

deployed first, followed by the unfolding of the waist and right disc (Figure 4). The FDA

approval of the ASO in 2001 was supported by a multicentre trial conducted in 2000, which

showed that successful implantation was performed in 95.7% of attempted closures and 94.8% of

them had no major complications, surgical re-intervention, or large residual shunting at

discharge and 1-year follow-up (Du et al., 2002). Such findings were confirmed by larger studies

(Everett et al., 2009; J. W. Moore et al., 2014).

14

ASO device embolization and erosion encompassed ~50% of all adverse events (absolute rate of

adverse events = 1.2% over a 5.5 year collection period) (DiBardino, McElhinney, Kaza, &

Mayer, 2009). Additionally, the ASO had a lower risk of thrombus formation (numbers)

compared to the CardioSEAL and StarFLEX devices (Kaya et al., 2008; M. S. Kim, Klein, &

Carroll, 2007). There is clinical equipoise between transcatheter and surgical closure. However,

the former approach is generally the first line of treatment because it is less invasive and has

shorter recovery times. Intermediate follow-up studies report the safety and efficacy of

transcatheter closure (Villablanca et al., 2017). However, the higher residual shunting and

device-related adverse outcomes that are not present in surgical outcomes remain an issue. There

are currently a limited number of long-term outcome studies comparing the efficacy of both

treatment arms in lowering the incidence of major adverse cardiovascular events and

cardiovascular-related mortality, which will be discussed below.

Figure 4. Schematic of percutaneous closure of an ASD. Step 1) Delivery of the device through the inferior vena cava; step 2) deployment of left atrial disc; step 3) deployment of right atrial disc; and step 4) removal of catheter. Reprinted with permission from “ASD Device Closure” by Kids Heart Centre.

The recommendations for treating ASD in adults from the most recent American College of

Cardiology (ACC)/American Heart Association (AHA) guidelines for adult congenital heart

disease (ACHD) are summarized with class of recommendation and level of evidence (LOE) in

Figure 5 (Stout et al., 2018). Transcatheter or surgical closure is recommended if a patient with

isolated secundum ASD presents with a functional limitation and the following hemodynamic

properties: significant left-to-right shunt (i.e., pulmonary to systemic flow; Qp:Qs ³ 1.5:1), right

15

atrial/ventricular enlargement, pulmonary vascular resistance (PVR) < 1/3 of systemic vascular

resistance (SVR), and PASP < 50% of systemic pressure (Class I, LOE B). If a patient is

asymptomatic with a similar hemodynamic profile, ASD closure can be effective in preventing

exacerbation of right heart enlargement and physiological sequelae (Class IIa, LOE C). In the

scenario where there is a net left-to-right shunt but a PVR > 1/3 SVR and/or PASP > 50%

systemic pressure, patients should be referred to ACHD and PH centres for further evaluation, as

the usefulness of ASD closure is unclear (Class IIb, LOE C). In the 2015 European ACHD

guidelines, vasodilator challenge during RHC is recommended to assess the response of the

pulmonary arteries to inhaled nitric oxide or other targeted PH therapy. Patients with PVR ≥5

Wood units but <2/3 SVR or PASP <2/3 systemic pressure with or without the vasodilator

challenge can be considered for ASD closure (Class IIb, LOE C) (Baumgartner et al., 2010).

ASD closure is contraindicated in the presence of a right-to-left shunt, which is seen in severe

irreversible PH or Eisenmenger syndrome patients. Closure of the hole is potentially harmful and

can lead to right-sided heart failure. The unclosed ASD alleviates RV volume and pressure

overload. The treatment options for these individuals are pharmacological; endothelin receptor

antagonists such as Bosentan, PDE-5 inhibitors, or combination therapy is usually prescribed.

16

Figure 5. A treatment algorithm for secundum ASD. PVR; pulmonary vascular resistance; PASP, pulmonary

artery systolic pressure. Based on AHA/ACC ACHD guidelines by Stout et al. (2018).

There may be some benefit to close patients with diagnosis of i) paradoxical embolism, ii) PH

with a net left-to-right shunt greater than 1.5:1 and reversible by pulmonary vasodilators (e.g.

oxygen, nitric oxide, and/or prostaglandins), and iii) platypnea-orthodeoxia (Baumgartner et al.,

2010). Catheterization is the preferred method of closure as it is less invasive and has a reduced

impact on physical and psychological well-being. Approximately 85-90% of all secundum ASDs

can be closed percutaneously (Faccini & Butera, 2018), however, surgical ASD closure is

considered when the anatomy and size of the ASD is greater than 40 mm, presence of other

cardiac defects, risk for complications, and/or during concomitant heart surgery.

Isolated secundum ASD

Left-to-right atrial shunt

PVR <1/3 of SVR, PASP <50% of systemic, right heart

enlargement, and Qp:Qs ³ 1.5:1

Functionally impaired

Surgical or transcatheter

closure (Class I, Level B)

Asymptomatic

Surgical or transcatheter

closure (Class IIa, Level C)

PVR >1/3 of SVR and/or PASP ³ 50% of systemic

Consult with ACHD and PH

experts

Surgical or transcatheter

closure (Class IIb, Level C)

Right-to-left atrial shunt

Surgical or transcatheter closure should NOT be performed (Class III,

Level C)

17

ASD closure should be performed before pregnancy if the patient is planning to conceive.

Pregnancy is contraindicated if the patient has severe PH or Eisenmenger syndrome

(Baumgartner et al., 2010). However, if the ASD is diagnosed during pregnancy, percutaneous

closure with TEE or intracardiac echo (ICE) guidance can be offered after parturition. ASD

closure is contraindicated for pregnant women who have pulmonary hypertension. The risk of

developing paradoxical embolus, stroke, arrhythmia, or heart failure, although low, should be

closely monitored in patients with unclosed ASDs during pregnancy.

Follow-up recommendations for patients with unclosed or closed ASDs in the 2018 ACHD

guidelines are based on the patient’s “physiological stage,” defined in the ACHD Anatomic and

Physiological (AP) classification system (Stout et al., 2018). Patients in physiological stage A

(i.e., patients with NYHA I, no hemodynamic or anatomic sequelae, no arrhythmia, and normal

exercise capacity) should visit an ACHD specialist and have routine ECG and TTE testing once

every 3-5 years. For those in stage B, which is defined as NYHA II, mild RV

enlargement/dysfunction, trivial/small shunt, minor arrhythmia, and/or minimal exercise

incapacity – routine follow-up should be scheduled once every 2 years. Patients classified as

stage C (NYHA III, moderate ventricular enlargement/dysfunction, hemodynamically-significant

shunting, mild or moderate hypoxemia/cyanosis, mild or moderate pulmonary hypertension, and

treated arrhythmia) and D (NYHA IV, severe hypoxemia and pulmonary hypertension,

Eisenmenger syndrome, and arrhythmia unresponsive to treatment) should be followed by an

ACHD cardiologist every 6-12 months and 3-6 months, respectively.

1.6 Intermediate and long-term outcomes after ASD closure The long-term benefits of ASD closure in patients with reduced functional capacity,

hemodynamically-significant shunt and/or right heart enlargement in the absence of severe PH

are evident – lower rates of atrial arrhythmias, improved functional capacity, and decreased

RV/RA pressures (Brochu et al., 2002; Roos-Hesselink et al., 2003). Although there is a high

degree of long-term descriptive studies to support ASD closure in symptomatic patients, the

decision and long-term benefits of ASD closure for those with normal functional capacity have

been less clear. There is a consensus that intervention is reasonable for asymptomatic patients

with right heart enlargement in preventing morbidity and mortality associated with late ASD

presentation (Oster, Bhatt, Zaragoza-Macias, Dendukuri, & Marelli, 2018). In an intermediate

18

outcomes study that evaluated cardiopulmonary function after device closure in asymptomatic

patients, there was a significant improvement in peak oxygen uptake (VO2) and peak oxygen

pulse at 6-months follow-up (Giardini et al., 2004). Long-term follow-up studies that compare

survival and quality of life indices between conservative versus surgical and surgical versus

catheter-based therapies have been fundamental in optimizing outcomes for ASD patients.

1.6.1 Conservative versus surgical therapy

Since the introduction of surgical ASD repair, many retrospective studies have recommended

surgery to prolong the life expectancy of those diagnosed with isolated secundum ASD in young

adults (Gatzoulis, Redington, Somerville, & Shore, 1996). However, studies that compared long-

term outcomes between medical and surgical treatment, especially in older adults (i.e., >40 years

old), are limited. In the follow-up studies that compared long-term mortality and morbidity in

patients with isolated secundum ASD, surgical intervention was a preferred choice in treating

those with isolated ASD. In a randomized trial that compared clinical outcomes between

surgically and medically treated secundum ASD in patients over the age of 40 years, Attie et al.

found that age, mPAP by catheterization, and medical treatment were independent risk factors

for overall mortality after adjusting for age, mean PA pressure > 35 mmHg, history of atrial

arrhythmia, and cardiac index < 3.5L/m2. They concluded surgical ASD closure should be

strongly considered as the initial treatment for adults over 40 years old, a PASP pressure < 70

mmHg, and a Qp:Qs ³ 1.7 even if the patient is asymptomatic (Attie et al., 2001). As the first

study to randomize patients to medical surveillance or surgery, their findings were discrepant

with past non-randomized studies. For instance, Konstantinides et al. (1995) determined that the

medically treated group had a higher risk for overall mortality and functional deterioration,

(RR=3.23, 95% CI 1.18-9.10 and RR=4.76, 95% CI 1.82-12.5, respectively), the risk for new

onset of arrhythmias or cerebrovascular embolic events were similar between the two groups.

Another historical prospective non-randomized study did not find any significant difference in

survival, worsening of NYHA class, or major cardiovascular events between either treatment

group (Shah, Azhar, Oakley, Cleland, & Nihoyannopoulos, 1994).

The latter two studies present with selection and immortal bias. Medical and surgical treatment

groups may be inherently different; the decision for surgery was based on cardiologists and

cardiac surgeons’ judgment and the patient’s willingness to undergo open-heart surgery.

19

Immortal time bias – which is introduced when the time between decision to treat and the actual

treatment date is either misclassified or excluded from the analysis. For instance, in the study

conducted by Konstantinides et al. (1995), surgically treated patients belonged to the

conservative group until the date of ASD closure. The follow-up period started on the day of

diagnosis for all patients, whereas the follow-up period for the surgical cohort began on the day

of operation. The “immortal” time between diagnosis and surgery was excluded from the

analysis and thus, adverse cardiovascular events that occurred during conservative management

in the surgical cohort were not counted - biasing the results in favour of medical treatment. This

may explain why there was no significant difference in the incidence of new atrial

arrhythmias/cerebrovascular ischemic events between the two groups (RR 0.61 95% CI 0.35-

1.05).

1.6.2 Surgical versus catheter-based therapy

The Amplatzer septal occluder (ASO) was the first FDA and Health Canada approved atrial

septal device offered to patients in 1997 and 2000, respectively. The shift in standard of care was

influenced by the minimal invasiveness, lower complication rate, and shorter recovery time of

transcatheter closure (Butera et al., 2006; Du et al., 2002; Thomson, Aburawi, Watterson, Van

Doorn, & Gibbs, 2002). A total of 26 observational studies (n=14,559) that compared

transcatheter and surgical closure in adults and children were examined in a meta-analysis. The

follow-up ranged from in-hospital discharge to 9.9 years (Villablanca et al., 2017). Interestingly,

there were no randomized control trials found.

In the subgroup analysis of adults, results confirmed that transcatheter closure was superior to

surgery, with respect to total complications (RR 0.55, 95% CI 0.37-0.83), major complications

(RR 0.57, 95% CI 0.39-0.83), and length of hospital stay (difference of means -2.86 days,

p<0.001) (Villablanca et al., 2017). There was no difference between transcatheter and surgical

closure in terms of overall mortality (RR 0.69, 95% CI 0.45-1.04) and minor complication rates

(RR 0.50, 95% CI 0.24-1.01). Although the risk for residual shunting was higher in transcatheter

closure (RR 3.70, 95% CI 1.40-9.76), the need for re-intervention was comparable to the surgical

cohort (RR 1.03, 95% CI 0.28-3.84), which suggests that residual shunting seen after device

closure is likely to be clinically insignificant and the ASD can be considered closed. The single

independent predictor of total complications and death was age at intervention.

20

Another constraint of surgical intervention is the impact of cardiopulmonary bypass on

functional recovery after surgery. Dillon et al. found that both RV systolic and diastolic function

were seen to be impaired one week after surgical closure but preserved after device closure in

children (Dhillon, Josen, Henein, & Redington, 2002). More specifically, indices of RV

longitudinal function; total excursion, peak shortening, and peak lengthening rate significantly

decreased following surgery compared to only impaired peak shortening rate following device

closure. LV functional parameters were spared, regardless of technique. It is suggested that the

longitudinal myocardial fibres that make up most of the RV are particularly susceptible to the

effects of cardiopulmonary bypass (Brookes et al., 1998; Dhillon et al., 2002; Gonzalez et al.,

1985; Meyer et al., 1982). In contrast, there was one study that saw no difference in RV function

between the surgical and interventional group (Berger, Jin, et al., 1999). It is important to keep in

mind that these studies only show acute effects of ASD closure on bi-ventricular function in

young patients. Longer follow-up analysis in adults should be performed to establish whether RV

functional recovery post-surgical closure occurs, which in fact, shows a significant improvement

in global RV function (RV EF) a month after surgical repair (Vijayvergiya, Singh, Rana, Shetty,

& Mittal, 2014).

In terms of limitations, the meta-analysis did not have any RCTs, introducing selection bias.

Since transcatheter closure cannot be performed in patients with extremely large ASDs and

patients in the surgical cohort were more likely to be anatomically and physiologically complex,

which further biases the results in favour of transcatheter closure. Furthermore, the surgical and

catheterization techniques and definitions and reporting of adverse events varied across the

different studies. Although the longest follow-up was reported at 9.9 years, a large proportion of

patients were also lost to follow-up early on in the studies. Currently, surgical closure is still a

safe and effective option for ASD patients, and the decision is ultimately based on anatomy, cost,

preferences, co-morbidities, patient satisfaction, and expertise.

Transcatheter closure is an attractive option to patients based on a lower complication rate and

shorter length of stay. However, post-procedural issues such as residual shunting and device

embolization/erosion were introduced – different to those of surgical closure (e.g., stroke, patch

leakage and dehiscence, sternal infections). In particular, the concern for safety was brought up

when the ASO device was found to be associated with device erosion (1-3 cases per 1000

21

implants) (J. Moore et al., 2013). The occurrence of erosion and pericardial effusion, indicated

by sudden onset of chest pain and hemodynamic instability, are most likely seen within (75% in

24 hours) hours post-closure (Amin et al., 2004)- although it has been reported that cardiac

perforation can occur up to 8 years after implantation (Divekar, Gaamangwe, Shaikh, Raabe, &

Ducas, 2005).

In a study that employed the US FDA Manufacturer and User Facility Device Experience

(MAUDE) database, the frequency of ASO device adverse events were analyzed and compared

to the rates found in The Society of Thoracic Surgery database for surgical closure (DiBardino et

al., 2009). This group found no difference in the overall mortality for surgical and transcatheter

groups (0.13% vs 0.093%, p=0.649). Rescue operation due to adverse events was 2.1 times more

likely in patients who had device closure, although this was not statistically significant

(p=0.063). The need for surgery per adverse event as well as the overall mortality per adverse

event were significantly higher in patients with device closure – although this should be put in

perspective since the absolute proportion of major adverse events (1.21%) over a 5.5 year

collection period is relatively low. Device related complications such as device embolization

(0.62%) and erosion (0.28%) were significantly associated with overall mortality.

It is important for those involved with device implantation to be vigilant of managing patients

who may be at risk for device-related complications. Sudden onset of symptoms for erosion

include acute chest pain, which is usually accompanied with hemodynamic instability and

pericardial effusion. A common risk factor for cardiac erosion are deficient superior and/or

anterior rims that expose the device to the aorta or atrial roof. Although this was found in 90%

of cardiac erosions in an Amplatzer study (Amin et al., 2004), deficient rims are common in the

general ASD population, especially in patients with large ASDs, and cannot be the only factor.

Dynamic device movement in the heart, exaggerated cardiac movement (i.e., exercise) (Kitano,

Yazaki, Sugiyama, & Yamada, 2009; Santini et al., 2012), oversized devices (Amin, 2014),

occluder type (Happel et al., 2015; Hernandez Perez et al., 2013), older age (Amin et al., 2004),

and implantation technique have also been proposed to be predictors of device erosion.

Similar to the studies used in the meta-analysis, our group’s single-centre retrospective study at

the University Health Network, Toronto found a lower complication rate and shorter length of

22

stay in the transcatheter cohort at a median follow-up of 108 months. Event-free survival was not

significantly different. Overall mortality and cardiovascular-related events were collected using

Ontario public health registries, which reduced the number of patients lost to follow-up.

Selection bias was also minimized by excluding patients who had their ASDs closed during

1997-2003 – the period in which the standard of care was transitioning to catheter-based therapy.

1.7 Reverse cardiac remodeling after ASD closure

1.7.1 Structural changes

Right heart volume overload and enlargement as a result of long-term left-to-right shunting

increases the risk for late complications such as atrial arrhythmias, stroke, and right heart failure

(Akula et al., 2016; Balci et al., 2015; Kaya et al., 2010; Kort, Balzer, & Johnson, 2001;

Mangiafico et al., 2013; Monfredi et al., 2013; Pascotto et al., 2006; Salehian et al., 2005;

Schoen et al., 2006; Veldtman et al., 2001). This would suggest that structural changes of the RA

and RV following ASD closure may reduce associated risks and improve functional capacity. In

a prospective study, patients undergoing transcatheter closure were assessed with TTE at

baseline, within 24 hours, at 3-6 months, at 12 months, and at 24 months post-procedure (Kort et

al., 2001). There was a significant reduction in indexed RA area and indexed RV volume at 3-6

months after device closure. At 24-months post-closure, the indexed RV volume was similar to

the control group (i.e., structurally normal hearts), whereas the indexed RA area did not resolve

to normal. However, in a similar one-year follow-up study by Veldtman et al. (2001),

echocardiography showed significant reductions in RA length, which normalized by 6-months

following percutaneous ASD closure.

Positive cardiac remodeling was also observed in an older study cohort (mean age 69 years)

following transcatheter ASD closure (A. A. Khan et al., 2010). Unlike other studies that have a

younger patient cohort (Pascotto et al., 2006; Santoro et al., 2006), improvement of RV size took

place beyond 6 weeks but within 1-year of the procedure. This suggests that device closure is an

effective option, even for patients of advanced age, in favorably reversing RV enlargement

(although at a slower rate) and improving functional capacity.

The clinical impact of cardiac remodeling was investigated in a later study that tested for

potential correlations between right heart changes and patients’ quality of life after percutaneous

23

ASD closure (Mangiafico et al., 2013). They found significant improvement at 12-months

follow-up in right heart dimensions and RV systolic function, and significantly lower PA systolic

pressures in only the subgroup of patients who were over 40 years old. Furthermore, patients in

the older subgroup with NYHA II improved to NYHA I (75%), and 7 out of 16 patients with

NYHA I at baseline reported a subjective improvement of physical ability in their daily routine

after device closure.

1.7.2 Functional changes

Although improvements in RV size and RVSP/PASP determined by echocardiography have

been consolidated, the effects of ASD closure on RV function are not well defined. Many

echocardiographic studies reported a significant deterioration of global (MPI, RV EF, FAC)

and/or regional (S’ and TAPSE) RV function following percutaneous ASD closure (Agac et al.,

2012; Akula et al., 2016; Balci et al., 2015; Baykan et al., 2016; Foo, Lazu, Pang, Lee, & Tan,

2018; Monfredi et al., 2013; Wu et al., 2007; Zhang et al., 2009), whereas other prospective

follow-up studies saw no improvement or impairment in either the RV longitudinal function at 1-

week following closure (Dhillon et al., 2002) or RV global function at 1- and 6-month follow-

ups (Akula et al., 2016). Conversely, a retrospective study that used myocardial performance

index (MPI) as an indicator of global RV function found a significant improvement in RV

function at a mean follow-up of 95 days (Salehian et al., 2005).

The limitations of using MPI to assess RV function is that it is a measure of overall function (i.e.,

a combined measure of systolic and diastolic function). This may explain the discrepant results

seen in the studies that use only indices of systolic function. Both systolic and diastolic function

of the RV were separately measured immediately after transcatheter ASD closure, which

revealed significant impairment and improvement, respectively (Akula et al., 2016). There is also

systematic error associated with using MPI, as it can be falsely low in conditions with elevated

RA pressure (Lang et al., 2015), resulting in inaccurate grading of RV function pre- and post-

ASD closure. Lastly, the study that saw a decrease in RV MPI (i.e., improved RV global

function) was a retrospective study, with a follow-up period consisted of a wide range (8 to 270

days) (Salehian et al., 2005). Thus, it was unable to track changes of RV function at exact time

points.

24

A prospective study that measured MPI to evaluate RV functional changes 1 day, 1-, and 3-

months after percutaneous closure, confirmed that there indeed was an acute transient worsening

of RV MPI up until 1-month post-procedure, which recovered by the 3-month follow-up visit

(Wu et al., 2007). It was proposed that the transient deterioration of RV function may be

attributed to the low myocardial compliance seen in a relatively older cohort (58.4 ± 17.3 years),

resulting in delayed changes in RV ventricular mass in response to the sudden volume reduction

after ASD closure. Pulmonary arterial stiffness was found to be the only significant predictor of

RV functional recovery; the degree of stiffness in the pulmonary vasculature, assessed by

arteriography, was an independent predictor of RV functional recovery, assessed by DTI-derived

RV MPI, after percutaneous closure (Baykan et al., 2016). An MRI study that measured RV size

and function also saw an improvement in RV end-diastolic volume (EDV), RV end-systolic

volume (ESV), RV mass, tricuspid annular dilatation, and RVEF after device closure at 12-

months follow-up (Schoen et al., 2006). It was concluded that RV size and systolic function

showed significant sustained improvement post-procedure, although there is an initial worsening

of RV function, followed by normalization by 3-6 months.

The ability of the RV to properly relax and fill has been found to be an important prognosticator

in patients with RV impairment (Rudski et al., 2010). Echocardiographic parameters that assess

diastolic function include E/A ratio, deceleration time (DT), E/e’ ratio, and RA size. Impaired

RV diastolic function as a result of RV dilatation is prevalent in a large proportion of adults with

ASD, even when RV systolic function is normal. In a study that measured RV systolic and

diastolic function before and after device closure, ~67% of their patients had E/e’ > 6 at baseline,

indicating diastolic dysfunction (Akula et al., 2016). Compared to those with E/e’ < 6, this cohort

was older and had greater chamber dimensions at baseline. At 6-months post-device closure,

~65% of those with baseline diastolic dysfunction had an E/e’ < 6. Furthermore, the authors

observed that RV size regression took longer (duration was not stated) in patients with baseline

diastolic dysfunction (i.e, E/e’ > 6). This may be due to lower cardiac compliance seen in an

older cohort.

1.7.3 Electrophysiological changes

Electrical remodeling and RA geometric changes after ASD closure have been observed by a

limited number of studies (Fang et al., 2013; Santoro et al., 2004). Negative electrical

25

remodeling seen in AF patients is characterized by a shortened refractory period, greater spatial

dispersion of refractoriness, and conduction slowing of the RA. It is important to assess electrical

remodeling because despite restoration of right heart size and function, late-onset atrial

fibrillation post-closure (incidence ~4 %), surgical or percutaneous, is common (Gatzoulis,

Freeman, Siu, Webb, & Harris, 1999; Spies, Khandelwal, Timmermanns, & Schrader, 2008).

Although, it appears to be heavily dependent on age at time of closure. RA volume overload and

P-wave dispersion (Pd) on an ECG, are independent predictors of developing late-onset atrial

arrhythmia (Kojodjojo, Peters, Davies, & Kanagaratnam, 2007). Evidence of significant

reductions in RA dimensions and P-wave dispersion were seen early on after closure, indicating

positive geometric and electrical remodeling (Santoro et al., 2004). However, in other studies

that looked at RA remodeling at mid-term follow-up (3 months), persistent RA enlargement (i.e.,

incomplete RA normalization) was present in more than 50% of the patients (Fang et al., 2013;

Fang et al., 2011). Incomplete structural reverse remodeling of the RA may be due to long-

standing volume overloading before closure, and indeed, the extent of RA remodeling was found

to be inversely proportional to age at the time of closure (r=0.55, p=0.013) (Kort et al., 2001).

Thus, early ASD intervention may be beneficial in preventing residual RA enlargement and

corresponding conduction abnormalities, which may reduce the risk of developing atrial

fibrillation and subsequent thromboembolic events long after ASD closure.

1.7.4 Left ventricular remodeling

The right heart chambers are not the only ones subjected to reverse remodeling. In the presence

of the compliant left ventricle (LV), the decrease in LV preload results in a decrease in cardiac

output, by the Frank Starling mechanism – the intrinsic capability of the ventricle to increase or

decrease its contractility based on its end-diastolic volume. After percutaneous ASD closure,

echocardiographic findings show significant increases in LV EDD and LV EF, and a

complementary reduction in RV EDD as early as 24-hours post-procedure (Wu et al., 2007).

However, RV/LV ratio which indicates the magnitude of pre-closure volume overload, remained

unchanged and was not correlated with the capacity of cardiac remodeling after closure. In

contrast, other studies found that a high RV/LV ratio pre-closure predicted a higher degree of

positive remodeling (Du, Cao, Koenig, Heitschmidt, & Hijazi, 2001; Pascotto et al., 2006;

Santoro et al., 2006). A study that used MPI to measure LV function showed significant

26

improvement following closure, and the most effective parameter in predicting functional

recovery was baseline pulse-wave velocity (a measure of systemic arterial stiffness). This was

found to be the most effective parameter in predicting LV functional recovery (Baykan et al.,

2016).

Functional tricuspid regurgitation

2.1 TR secondary to left-to-right atrial shunt

2.1.1 Mechanisms of functional tricuspid regurgitation

Functional or secondary tricuspid regurgitation (TR) is defined as the backflow of blood from the

right ventricle to right atrium during systole, that is not due to primary tricuspid valve (TV)

disease. Functional TR is the most common form of severe TR in the Western world (Cohen,

Sell, McIntosh, & Clark, 1987), and has gained much-needed attention in recent years after TR

was found to be an independent prognosticator of cardiovascular-related mortality and adverse

outcomes in populations with PH, dilated or ischemic cardiomyopathy, or isolated TR

(Bustamante-Labarta et al., 2002; Hung et al., 1998; Lee et al., 2010; Nath, Foster, &

Heidenreich, 2004). Surgical correction of the TV showed no significant difference in survival

(Lee et al., 2010), although evidence is limited.

Functional TR is most often seen secondary to left-sided heart disease, such as mitral valve (MV)

stenosis, mitral regurgitation, and aortic stenosis. Pulmonary hypertension, right heart failure,

and chronic atrial fibrillation can also increase the risk of developing functional TR. The primary

mechanism by which these conditions lead to the progression of secondary TR is RV volume

overload and the subsequent dilatation of the tricuspid annulus (the fibrous band connecting the

atrium and ventricle). However, idiopathic functional TR due to isolated annular dilatation is not

associated with any co-morbidity or cardiovascular disease. It has been proposed that a 40%

dilatation of the tricuspid annulus is sufficient in significantly increasing the amount of TR

(Spinner et al., 2011), which is minimal compared to a 75% dilatation required to significantly

increase mitral regurgitation (MR) (He, Jimenez, He, & Yoganathan, 2003). In functional TR,

the tricuspid annulus dilates along the anterior and posterior leaflet; becoming more circular and

planar than its original triangular and saddle-shaped form (Fukuda et al., 2006).

27

Another proposed mechanism of functional TR is the displacement of the papillary muscles due

to RV dilatation. Similar to its left-sided counterpart, papillary muscle displacement of the RV

can lead to the tethering and loss of coaptation of the tricuspid leaflets (He, Fontaine,

Schwammenthal, Yoganathan, & Levine, 1997; Spinner et al., 2011). The disregard for papillary

muscles during surgical repair of the TV annulus (i.e., annuloplasty) may explain why residual

moderate to severe TR is fairly common in patients with pre-operative functional TR (~23%)

(Fukuda et al., 2005). Understanding the mechanisms and structural characteristics of functional

TR can improve the detection and management of the disease which is common among patients

with an ASD.

The impact of significant TR itself, limits the accuracy of determining right heart pressures in

Doppler echocardiography. For instance, RVSP which also reflects the PASP, can be

overestimated or underestimated in patients with severe TR (Ozpelit et al., 2015). It is important

to acknowledge the inaccuracy of using Doppler imaging to monitor progression and response to

treatment for PH in situations where moderate to severe TR are also likely to be present, such as

in patients with ASD and PH. RHC should be performed to confirm a diagnosis of PH. ASD

closure may be favorable if preoperative PAP is responsive to an acute vasodilator challenge - a

positive vasodilator test is defined as a reduction of at least 10 mmHg in the mean PAP and an

absolute mean PAP value of less than 40 mmHg after vasodilator administration during

catheterization study (Galie et al., 2016; Langleben et al., 2005; McLaughlin et al., 2009).

Studies have shown a significant reduction in PASP and RVSP after transcatheter ASD closure

in patients with baseline moderate and severe PH, however, the odds of normalization (PAP <40

mmHg) are low for those with higher baseline pressures and baseline moderate to severe TR

(Balint et al., 2008; Yong et al., 2009). It is important to clarify that RV enlargement due to left-

to-right atrial shunting is the main contributor to functional TR in ASD patients. Therefore, it is

not necessary for ASD patients with functional TR to have PH. Patients with functional TR

and/or PH should be considered as two subgroups and treated as such.

2.1.2 Prevalence of functional TR before and after ASD closure

RV dilatation and adverse remodeling incurred from a hemodynamically significant ASD is a

common phenomenon seen in adults with long-standing left-to-right atrial shunting. Despite the

comprehensive studies that evaluate mid- and long-term clinical and structural outcomes of

28

patients with closed or unclosed ASDs, there is currently a knowledge gap in the clinical impact

and management of ASD patients with concomitant functional moderate to severe TR. It has

been reported that approximately 27-55% of patients undergoing transcatheter ASD closure have

moderate to severe TR at the time of procedure, as summarized in Table 3 (Chen et al., 2017;

Fang, Wang, Yip, & Lam, 2015; Nassif et al., 2018; Takaya, Akagi, Kijima, Nakagawa, & Ito,

2017; Toyono, Krasuski, et al., 2009). Of those with baseline moderate to severe TR, 30-89%

continued to show moderate to severe TR at 3-30 months follow-up. All studies used qualitative

and semi-quantitative echocardiographic parameters in grading TR severity. In most ACHD

centres, current clinical practice does not require a detailed accurate assessment of the tricuspid

valve/annulus and TR during an ASD work-up.

Table 3. Study comparison of adults undergoing percutaneous ASD closure with concomitant functional tricuspid regurgitation

Sample size (n)

Moderate to severe TR at baseline, n (%)

Persistent moderate to severe TR after closure, n (%)

Clinical /echocardiographic follow-up (months)

Nassif et al., 2018 172 64 (37) 27 (42) 45/6 Takaya et al., 2017 419 113 (27) 34 (30) 30/30 Chen et al., 2017 225 111 (49) 63 (57) 6/6 Fang et al., 2015 64 35 (55) 31 (89) 3/3 Toyono et al., 2009a 32 32 16 (50) 4 ± 3 days

Clinical/echocardiographic follow-up reported as median or mean ± SD. HR, hazards ratio; CI, confidence interval. aSubjects had their ASDs closed percutaneously (n=23) or surgically (n=9).

2.1.3 Imaging modalities for the tricuspid valve and TR

Functional TR is a common and progressive disease in many patients with ASD. A

comprehensive review of TV morphology is essential, now more than ever, in detecting

functional TR and guiding treatment due to the surge in transcatheter devices that are currently

undergoing clinical trials. TV morphology is best viewed under 3D- TTE or TEE because of its

anatomical location. Real-time 3D echocardiography (RT3DE) offers high spatial resolution and

allows the reviewer to visualize the tricuspid valve from both the ventricular and atrial side

(Anwar et al., 2007). The parameters and reference values in normal adults are summarized in

Table 4. Common quantitative parameters used to measure tricuspid annular dilatation are TA

circumference/diameter, TA area, and tricuspid septal leaflet angle (TSLA). A 2D TTE study of

healthy women and men reported mean TA diameters of 3.01 ± 0.47 cm and 3.15 ± 0.43 cm,

29

respectively (Dwivedi, Mahadevan, Jimenez, Frenneaux, & Steeds, 2014). In a 3D TTE study

that compared normal individuals and patients with mild to severe functional TR unrelated to

ASD, the maximum indexed TA areas were significantly larger in the latter group (5.6 ± 1.0 vs

7.5 ± 2.1 cm2/m2) (Fukuda et al., 2006).

Table 4. Reference values for normal tricuspid valve anatomy based on echocardiographic assessment

Parameter Reference values Tricuspid annulus (RT3DE)

TA area (cm2) 10.97

TV area (cm2) 4.8

SL annular diameter (cm) 3.37

AP annular diameter (cm) 4.11

Tricuspid leaflets (2D)

Tethering/tenting height (cm)

Male 0.71

Female 0.65

Reference values reported in means. Obtained from (Anwar et al., 2007; Dwivedi et al., 2014; Ring et al., 2012). RT3DE, real-time 3D echocardiography; TA, tricuspid annulus; TV, tricuspid valve; SL, septolateral; AP, anteroposterior.

In the context of an unclosed hemodynamically significant ASD, the mean TA diameter in

patients with no/mild TR was found to be 3.7 ± 0.7 cm, and 3.9 ± 0.6 cm in patients with

moderate/severe TR (Nassif et al., 2018). TA diameter can be measured along the septolateral

(SL) or anteroposterior (AP) plane (Fig. 6). 2D echocardiography accompanied with 3D imaging

improves the accuracy of measuring complex structures such as the tricuspid annulus, which is

best visualized at end diastole (R. T. Hahn, 2016).

30

Figure 6. (A) Septolateral (SL) annular diameter and (B) anteroposterior (AP) annular diameter in a patient with unrepaired ASD.

Coaptation mode is used to describe the function of the tricuspid leaflets during systole, and in

the presence of secondary TR, there is either partial (edge-to-edge) or complete loss of

coaptation (Dreyfus, Martin, Chan, Dulguerov, & Alexandrescu, 2015). Loss of coaptation may

be affected by annular dilatation during RV volume overload. It can be quantified by measuring

the coaptation height, defined as the surface of contact between the leaflets. In normal

conditions, it sits at the level of the annulus or right below it. Papillary muscle displacement as a

result of RV enlargement can cause tethering of the tricuspid leaflets and further disrupt proper

closure of the valve. Tethering (also known as tenting) height, area, and volume are parameters

used to measure the disruption of leaflet coaptation. Functional TR does not solely rely on leaflet

tethering - although if it is present, it is commonly and best observed using 3D echocardiography

at end systole (R. T. Hahn, 2016). A tenting height of >8 mm below the annular plane is

predictive of severe TR, and leaflet augmentation with tricuspid annuloplasty should be

considered (Dreyfus et al., 2015). With respect to ASDs, the stark differences seen in the TR jet

area (Figure 7A) and VC (Figure 7B) between patients with similar size shunts indicate that the

development of functional TR is multifactorial.

31

Figure 7. Semi-quantitative assessment of mild (left) versus moderate (right) functional TR secondary to ASD using (A) TR jet area and (B) VC.

Assessment of TR severity is often made through qualitative and semi-quantitative

echocardiographic variables. As summarized in Table 5, TV morphology, interventricular septal

motion, colour flow TR, flow convergence zone, continuous wave (CW) signal TR jet, and

inferior vena cava (IVC) diameter are qualitative variables used to describe TR severity, whereas

the following parameters are used in a semi-quantitative assessment of TR: colour flow central

jet area, jet area:RA area, vena contracta, proximal isovelocity surface area (PISA) radius,

hepatic vein flow, and tricuspid inflow (R. T. Hahn, 2016). Grading TR severity based on

qualitative and semi-quantitative analyses leads to a high degree of interobserver variability and

thereby, reduces the accuracy of the measurement.

32

Table 5. Grading functional tricuspid regurgitation severity with echocardiography

Parameter Mild Moderate Severe

Qualitative

TV morphology Mild thickening, limited prolapse

Moderate thickening, prolapse

Flail leaflet, ruptured papillary muscle, severe retraction, large perforation or vegetation

IVS motion Normal Typically normal Paradoxical/volume overload

Colour flow jet Small RA penetration

Moderate RA penetration

Severe RA penetration

Flow convergence zone Not visible, transient, small

Intermediate in size and duration

Large throughout systole

IVC diameter (cm) 1.2-1.7 (normal) 2.1-2.5 >2.5

Semi-quantitative

Colour flow central jet area (cm2)

<5 5-10 >10

VC (cm) <0.3 <0.6 ³0.7

PISA radius (cm) £0.5 0.6-0.9 >0.9

Hepatic vein flow Systolic dominance Systolic blunting Systolic flow reversal

Tricuspid inflow E-wave < 1m/sec or A-wave dominant

Variable E-wave ³ 1.0 m/sec

Quantitative

EROA by PISA (mm2) <20 20-39 ³40

EROA by 3D Unknown Unknown >75

Regurgitant volume by PISA

<30 30-45 ³45

RV and RA size Normal Normal/mild dilatation

Usually dilated

Reference values obtained from (R. T. Hahn, 2016; Lancellotti et al., 2010; Zoghbi et al., 2003). TV, tricuspid valve; IVS, interventricular septum; IVC, inferior vena cava; VC, vena contracta; PISA, proximal isovelocity surface area; EROA, effective regurgitant orifice area. Table adapted with permission from Hahn, R. (2016).

Although there are other imaging modalities that can better grade and quantify TR, such as

cardiac MRI, echocardiography remains the more economical and widely used option. Thus, a

standardized and validated grading scheme is important in accurately determining TR severity.

Grant et al. (2014) addressed the issue of interobserver variability to improve the accuracy of

grading TR severity by developing an algorithm in diagnosing the presence of severe TR (Grant,

Thavendiranathan, Rodriguez, Kwon, & Marwick, 2014). Severe TR is confirmed if the imaging

study shows a suggestive colour Doppler jet and at least one of the following: 1) IVC diameter >

2.5 cm and RA area > 18 cm2 in the absence of pulmonary valve disease or ASD; 2) TR jet area

> 10 cm2 and vena contracta width > 0.7 cm; 3) dense, triangular continuous wave (CW) jet

33

profile; and/or 4) holosystolic hepatic vein flow reversal. It is important to note that this

algorithm only detects severe TR, however, it is severe TR that is predictive of a poor prognosis

regardless of age, right atrial pressure biventricular function, RA pressure, RV size, and PASP

(Nath et al., 2004). Thus, quantification of TR may be beneficial if a patient is suspected of

having at least moderate TR.

Generally, quantitative measurements of functional TR are usually not taken in ASD patients

unless signs of significant right heart failure are present. However, as the impact of TR and

transcatheter TV interventions garner more attention, the quantification of TR will be necessary

in better assessing and treating moderate to severe TR. Effective regurgitant orifice area (EROA)

and regurgitant volume are two clinically valuable parameters used to quantify TR, which can be

measured using PISA, 3D colour Doppler, or quantitative Doppler imaging (R. T. Hahn, 2016).

Calculating the EROA by PISA is the simplest method to perform and has proven to be an

excellent correlation with other indices of valve insufficiency such as regurgitant stroke volume

(r=0.89) and regurgitant fraction (r=0.88) (Rivera et al., 1994). However, the elliptical shape that

is characteristic of the tricuspid regurgitant orifice makes it difficult to accurately measure the

PISA radius for calculation of the EROA, which ultimately results in an underestimation of the

true amount of TR (R. T. Hahn, 2016; Sugeng, Weinert, & Lang, 2007). 3D colour Doppler

imaging overcomes this limitation by locating the largest flow convergence zone and measuring

the 3D-derived PISA to calculate the EROA, which was highly correlated with 3D-derived vena

contracta (r=0.97) (de Agustin et al., 2013). Thus, vena contracta area measured by 3D colour

echocardiography can be used to bypass the measurement of PISA and directly quantify TR by

substituting ROA with VC area in calculating regurgitant volume (regurgitant volume = VC area

x TRVTI). Interestingly, VC area on its own, was shown to be closely correlated with validated

parameters used to quantify TR in standard 2D imaging studies (i.e., TR jet area and TR jet

area/RA area). Thus, VC area alone can quantify or grade TR by using cut-off values that have

yet to be confirmed. Lastly, 3D Doppler imaging can also improve accuracy of quantification of

the regurgitant volume by using relative stroke volumes. Diastolic stroke volume can be

calculated by multiplying the TV diastolic annular area by the velocity time integral at the

annulus (TVVTI) (R. T. Hahn, 2016). Subtracting the forward stroke volume from the diastolic

stroke volume gives a regurgitant volume. This method has yet to be validated.

34

2.1.4 Management of functional TR

The most recent ACHD guidelines for ASD management was published by the ACC/AHA in

2018 (Stout et al., 2018). They do not differ much from its former version published 10 years ago

(Warnes et al., 2008); surgical ASD closure is reasonable if the patient is already undergoing

surgical treatment for other congenital or acquired cardiac conditions (e.g., tricuspid

annuloplasty). Recommendations for TV intervention at the time of ASD closure have not yet

been addressed. This is problematic as there is no standard of care for treating ASD patients with

concomitant moderate to severe functional TR.

There are different surgical techniques for repairing the tricuspid valve and the decision for

intervention depends on the cause, morphology, and severity of TR and the patient’s age and

overall health. Tricuspid valve surgery of any kind is rarely done on its own because it is

associated with high postoperative in-hospital mortality (8.8%) (Zack et al., 2017), compared to

the lower mortality rates reported in isolated aortic (2%) or mitral (3%) valve surgery (Brown et

al., 2009; Gammie et al., 2009). Thus, it may be of value to consider surgical instead of

transcatheter ASD closure, and simultaneous TV intervention in patients who have major risk

factors for persistent TR and poor survival outcomes. Tricuspid annuloplasty (TAP) restores the

size and shape of the annulus as well as the coaptation of the leaflets. Non-ring annuloplasty,

also known as the De Vega procedure, or ring annuloplasty are the two main types of TAP and

are widely accepted surgical interventions of the dilated TA for patients with functional

moderate to severe TR. Valve replacement is often considered when it is not possible to salvage

the TV through annuloplasty or suture biscuspidization. It is usually the last resort to treating TR

as TV replacement is associated with worse peri-operative, midterm, and event-free survival

compared to TV repair in patients with organic tricuspid lesions (Singh et al., 2006). Currently,

bioprosthetic implants are the preferred choice for TV replacement.

In theory, concomitant TR correction during surgical ASD closure may reduce the number of

patients with persistent moderate to severe TR by restoring the size and shape of the annulus, as

well as the coaptation of the leaflets. This may improve long-term survival of patients with

preoperative significant functional TR. Indeed, Kim et al. found that patients with >mild TR

before closure were more likely to improve in TR grade if they had TAP (~90% vs ~60% in the

non-TAP group) (H. R. Kim et al., 2017). Despite significant TR grade reduction, patients with

35

significant TR (n=137) who underwent concomitant TAP (n=107) were not associated with

better or worse long-term event-free survival (mean follow-up duration 12.4±4.70 years, range 5

months-25.5 years). This may be due to the contrasting baseline characteristics between the

groups, impact of invasive surgery on the already high-risk patient group, and the intrinsic

irreversible histological abnormalities of the myocardium that are associated with age and TR

(Egidy Assenza et al., 2013; Jones & Ferrans, 1979); suggesting that a hemodynamically

significant ASD should be closed as early as possible. Not analysed in this study are the

preoperative determinants of persistent TR that was present in ~10% of the TAP group. Toyono

et al. found that 25% of patients who underwent TAP and ASD closure continued to show

residual TR and that baseline RV fractional area change, spherical index, and systolic pressure

were significant predictors of residual moderate to severe TR – although a multivariable analysis

was not performed (Toyono, Fukuda, et al., 2009). These findings suggest that dilatation of the

TA may not be the only mechanism behind the progression of functional TR. However, it is

agreed that early ASD intervention may maximize the extent of postoperative RV remodeling

and reduce the risk of persistent TR.

RV pressure overload as a result of pulmonary hypertension has been reported in 5-10% of

patients with unrepaired ASDs (Steele, Fuster, Cohen, Ritter, & McGoon, 1987). Although PH is

not the primary cause of functional TR in these patients, it may contribute to the exacerbation of

TR and the risk of residual TR. In fact, Toyono et al. found no significant change in RVSP after

surgical ASD closure and TAP. Pre- and post-operative RVSP were determinants of post-

operative TR (Toyono, Fukuda, et al., 2009). TR progression associated with PH is associated

with poor adverse outcomes and survival (Medvedofsky et al., 2017). Pulmonary vasodilators

have been suggested as treatment in reducing RV afterload and residual TR and improving long-

term outcomes after surgical repair which was observed in patients with other underlying cardiac

diseases (Gomez-Moreno et al., 2005; K. Kim, 2016).

2.1.5 Baseline predictors of persistent TR following isolated ASD device closure

The prevalence of functional moderate or severe TR before transcatheter ASD closure ranges

from 27-55% and of those individuals, 30-89% continued to show moderate to severe TR in

echocardiography at follow-up (Table 3) (Chen et al., 2017; Fang et al., 2015; Nassif et al., 2018;

36

Takaya et al., 2017). It appears that isolated transcatheter ASD closure, like surgical closure (H.

R. Kim et al., 2017; Toyono, Krasuski, et al., 2009), may be insufficient in lowering TR grade.

Key predictors of post-procedural moderate to severe TR after percutaneous ASD closure have

been widely reported in past studies (Table 6). Age and RVSP/PASP were the only clinical and

echocardiographic parameters shared among the studies. In the study published by Nassif et al.

(2018), a prediction model was generated based on weighted risk model scores that were

determined by their respective odds ratios and assigned to each predictor. The cumulative risk

score was 5: age >60 years (1), RA end-diastolic area >10cm2/m2 (1), RVSP >44 mmHg (2), and

TAPSE >2.3 cm (1). The probability of post-closure TR was predicted to be 90% and the actual

prevalence of moderate to severe TR at 6-months follow-up was 100% in patients who had a

cumulative score of 5 (C-index =0.85 95% CI 0.76-0.93). Chen et al. found only age (p=0.041)

and PASP (p=0.005) determined by echocardiography to be significant independent determinants

of post-closure moderate to severe TR at 6-months follow-up (Chen et al., 2017). Although they

did not report the odds ratio for either variable, a PASP > 45 mmHg could predict persistent TR

with 53% sensitivity and 79% specificity; and age over 65 years old had a 68% sensitivity and

79% specificity.

37

Table 6. Study comparison of independent predictors for persistent moderate to severe TR after percutaneous ASD closure Age RA-end diastolic area RVSP/PASP TAPSE Atrial fibrillation TAD TSLA Nassif et al., 2018

60 years (OR 2.57)

10 cm2/m2 (OR 3.36)

>44 mmHg (OR 6.44)

2.3 cm (OR 3.29)

- - -

Takaya et al., 2017

- - - OR 5.09 - -

Chen et al., 2017*

65 years (r=0.483)

- >45 mmHg (r=0.458)

- - - -

Fang et al., 2015

- - - - >3.5 cm (OR 6.08)

>30° (OR 1.22)

Toyono et al., 2009

- >60 mmHg (OR 3.44)

- - - -

Data are presented as cut-off values and odds ratio (OR) after multivariable logistic regression analyses *Study reported only the correlation coefficient (r). RA, right atrium; RVSP, right ventricular systolic pressure; TAPSE, tricuspid annular planar systolic excursion; TAD, tricuspid annulus diameter; TSLA, tricuspid septal leaflet angle.

38

Similar findings were made by Toyono et al. who reported that PASP > 60 mmHg (OR 3.44,

p<0.001) was the only independent determinant of persistent TR after percutaneous or isolated

surgical ASD closure (Toyono, Krasuski, et al., 2009). The major limitation was the very short

echocardiographic follow-up period of 4± 3 days post-closure, which did not provide enough

time to accurately determine the “true” proportion of patients with irreversible moderate to

severe TR. It is important to note that the TR jet area, pre- and post-ASD closure, was not

significantly different between the catheter-based and surgical group, and that both approaches

significantly reduced the amount of TR. However, the technique of ASD closure was not

included in their uni- and multivariable analysis of predicting improvement in TR grade - which

would have added a unique feature to their study.

A mid-sized retrospective study (n=225) reported age and RVSP as baseline predictors of

persistent TR post-transcatheter ASD closure (Chen et al., 2017), similar to Nassif et al. (2018).

In contrast, only permanent atrial fibrillation at baseline was the independent predictor of post-

closure TR in a study conducted by Takaya et al. (2017). Age, RA dilatation, and the subsequent

loss of atrial mechanical activity in patients with hemodynamically-significant ASDs were major

contributors of chronic AF (María Oliver et al., 2002). Chronic AF, in turn, can exacerbate RA

enlargement and impede the extent of RA reverse remodeling after ASD closure (Sanfilippo et

al., 1990). Thus, persistent moderate to severe TR after device closure may be due to the residual

RA volume overload that is often seen in older patients with permanent AF (Fang et al., 2011;

Najib et al., 2012). Unfortunately, RA measurements were not collected in their study

(Sanfilippo et al., 1990), which could have strengthened the conclusions that were made.

Surprisingly, only one study found TV anatomy to be the significant independent predictor of

moderate to severe TR after percutaneous ASD closure (Fang et al., 2015), rather than RV

remodeling. This may be due to the lack of TV assessment of the other studies. Fang et al. found

that patients who had a tricuspid annulus diameter greater than 3.5 cm and a tricuspid septal

leaflet angle (TSLA) greater than 30° was 6.1- (p=0.032) and 1.2- (p=0.001) times more likely to

have persistent moderate to severe TR, respectively. A comprehensive assessment of TV

structure was made during mid-systole in apical 4-chamber view; TA diameter and TSLA (i.e.,

the angle between the annulus plane and the imaginary line that joins the septal annulus with the

tip of the leaflet coaptation) measured the extent of TA dilatation and leaflet tethering,

39

respectively. Both of these changes are direct consequences of longstanding left-to-right atrial

shunting and subsequent RV volume overloading. However, there may be a synergistic effect

created by the tethering of the tricuspid leaflets that contributes to functional TR - which was

proposed when persistent/worsening regurgitation was observed even after TAP (Fukuda et al.,

2005; Tsang & Raja, 2012).

The independent determinants of persistent moderate to severe TR after isolated percutaneous

ASD closure were variable; age, RV volume and pressure overloading were the most common

predictors found. Only Toyono et al. included a comprehensive echocardiographic review of the

TV apparatus, in which significant TA dilatation and leaflet tethering due to longstanding

interatrial shunting were predictive of persistent TR, not RV remodeling. Prospective studies

with a detailed assessment of right heart and valvular anatomy are needed to validate such

findings.

2.1.6 Long-term outcomes of ASD patients with functional TR

The prognosis of significant TR, primary or secondary, has not been well defined. The cause of

TR and the common co-morbidities that contribute to its progression complicates our

understanding of the condition. In general, severe TR has been linked to worse survival rates

compared to patients with mild or no TR. A large retrospective study, 5223 patients (mean age

67 ± 13 years) who had an echocardiography study done were followed for a period of four years

based on their TR status (Nath et al., 2004). The primary cause of TR was not reported. Overall

mortality was significantly higher in those with moderate (28%) or severe TR (42%) compared

to those with mild (13%) or no (10%) TR. This was also observed after stratifying patients based

on PASP and LVEF. After adjusting for age, LVEF, IVC size, RV size and function, severe TR

continued to show a worse prognosis; HR= 1.31, 95% CI 1.05-1.66. A sub-group analysis that

selected patients with TR and a measurable PASP (i.e., patients with at least mild TR and

adequate TR envelope) was also performed. Only severe TR (HR=1.23, 95% CI 1.03-1.47),

PASP, and age were independently associated with decreased survival. The limitations of this

study did not address the patients’ source of TR, underlying co-morbidities (e.g., stroke,

coronary artery disease, diabetes), and exercise capacity that can affect long-term survival. The

causes of death (cardiovascular or non-cardiovascular) were also not identified.

40

Until recently, it was erroneously believed that TR would resolve on its own after treating the

underlying cause (e.g., left-sided heart disease, valvular disease, congenital heart defects). Of the

handful of studies that assess functional TR in the context of secundum ASD, the benefit of

isolated percutaneous ASD closure on TR progression and survival of this cohort remains

unclear. Currently, there are only two cohort studies that have reported long-term outcomes

based on TR severity after percutaneous ASD closure. In the most recent study by Nassif et al.

(2018), the follow-up period started 6 months after device closure when patients were classified

as having improved or persistent TR based on their post-closure echocardiogram. At a median

follow-up of 45 months (30-76 months), patients with persistent TR had higher adverse event

rates (cardiovascular death and hospitalization for heart failure) than patients with improved TR,

with an unadjusted HR= 6.2; 95% CI 1.5-26 and log rank of p=0.004. Patients with moderate to

severe TR after device closure showed more symptoms of dyspnea (30% vs 16%) and peripheral

edema (41% vs 16%) at latest follow-up than those who had improved TR. Long-term outcomes

of patients with improved TR versus patients with baseline <mild TR were not included in the

Kaplan-Meier analysis. This would have addressed the question of whether improved TR after

isolated ASD closure is sufficient in improving survival rates that are similar to those of patients

who never had moderate to severe TR.

In the previous study (Nassif et al., 2018), long-term outcomes were stratified based on post-

closure TR grade, as opposed to Takaya et al.’s study that compared outcomes based on pre-

closure TR grade (Takaya et al., 2017). At a median follow-up of 30 months (1-104 months)

after device closure, patients with pre-closure moderate to severe TR had worse event-free

survival compared to those with mild TR (92% vs 98%; log-rank p<0.001). More importantly,

>90% of patients with baseline moderate to severe TR had no major cardiovascular events -

which suggests that percutaneous ASD closure is still a viable option regardless of TR severity.

Overall, the short follow-up duration and small sample size in both studies cannot confirm

whether isolated transcatheter ASD closure is sufficient in reducing the high mortality and

morbidity rates that are generally associated with moderate to severe TR (Lee et al., 2010; Nath

et al., 2004; Pozzoli, Buzzatti, Vicentini, M, & Alfieri, 2017).

Long-term outcomes of concomitant TV repair/replacement during surgical ASD closure have

also been studied (H. R. Kim et al., 2017; Toyono, Fukuda, et al., 2009). In a subgroup analysis

41

of patients with preoperative moderate to severe TR, Kim et al. compared the primary endpoint

(death) between isolated surgical ASD closure and concomitant TAP at 12.4 ± 4.7 years (mean ±

SD) follow-up (H. R. Kim et al., 2017). The TAP subgroup showed superiority in the

improvement of TR grade and freedom from significant TR (log rank p=0.02). However, overall

mortality was comparable between the TAP and non-TAP subgroups (log rank p=0.518). A

possible explanation for the lack of improvement was that TR is only an indication of

irreversible RV fibrosis and dysfunction caused by longstanding left-to-right atrial shunting

(Jones & Ferrans, 1979), and reducing the amount of TR (with or without TAP) does not

necessarily indicate an improvement in ventricular function after surgical ASD intervention. The

surgical impact of cardiopulmonary bypass on RV functional impairment may also explain the

insignificant difference in mortality. Furthermore, the survival rates of either subgroup were not

adjusted for important variables associated with mortality, such as age at time of procedure and

post-procedural TR grade.

In recent years, a more aggressive surgical approach to severe functional TR has been favoured.

In the 2017 ESC guidelines for valvular heart disease (Vahanian et al., 2017), concomitant TV

surgery is recommended for patients with severe, and even moderate and mild functional TR

undergoing left-sided heart surgery, which can induce positive reverse RV remodeling and

improve functional capacity. Isolated TV surgery is rarely performed due to its consistent high

post-operative mortality rates (8-10%) (Zack et al., 2017). However, it has been found to be

superior to medical therapy (Lee et al., 2010), which is reflected by the increasing number of

procedures done in recent years. Long-term outcomes after isolated TV surgery were

significantly worse in patients with preoperative anemia, renal/hepatic dysfunction, RV

dilatation, and postoperative significant TR after surgical repair or replacement of the TV (Lee et

al., 2010). Thus, it is unknown as to whether concomitant TAP is beneficial for patients

undergoing ASD closure who have pre-existing significant RV enlargement and may still be at

risk for persistent moderate to severe TR - which was present in ~10% of the patients who

underwent surgical ASD closure and TAP in Kim et al.’s study (H. R. Kim et al., 2017).

Transcatheter implantation of the aortic, pulmonary, and mitral valve have been confirmed to be

efficacious and safe in treating valvular incompetence and stenosis. Catheter-based treatments

for functional TR have only just begun their preclinical and early clinical trial periods. If proven

42

to be safe and effective, these devices would be an alternative to surgical TV surgery for patients

whose risk of cardiovascular mortality outweighs the potential benefits (e.g., elderly or patients

with previously-operated TV). There are currently three types of transcatheter TV interventions

for functional TR based on their mode of action and anatomic target, 1) annuloplasty devices; 2)

coaptation devices; and 3) heterotopic caval valve implantation (CAVI). The optimal treatment

option for patients with a hemodynamically ASD requires a deeper understanding of the

mechanisms behind moderate to severe TR secondary to longstanding left-to-right atrial

shunting, as well as the clinical and echocardiographic outcomes of isolated transcatheter ASD

closure in this subgroup.

2.2 Advancement in tricuspid valve devices Isolated surgical repair of the TV is associated with high mortality outcomes compared to any

other valve repair surgery and as a result, is rarely performed (Pozzoli et al., 2017; Zack et al.,

2017). The tricuspid valve has made itself the last cardiac valve to receive attention in

interventional cardiology due to its anatomical complexity and variability. Currently, the only

tricuspid device that is approved and marketed in the world is the Edwards Cardioband Tricuspid

Valve Reconstruction System – which targets and reduces the size of the annulus so that TR is

reduced (Miller, Thourani, & Whisenant, 2018) (Figure 8A). The results from the TrIcuspid

Regurgitation RePAIr With CaRdioband Transcatheter System (TRI-REPAIR) study evaluated

the performance and safety of the device until 30 days post-procedure (Nickenig et al., 2019).

There was an average 16% reduction in the SL annular diameter, which was observed at 6-

months follow-up. Another active clinical trial that targets the tricuspid annulus is the

Percutaneous Tricuspid Valve Annuloplasty System for Symptomatic Chronic Functional

Tricuspid Regurgitation (SCOUT) I study that uses the Trialign System from Mitralign (Rebecca

T. Hahn et al., 2017) (Figure 8B). This study measured the functional improvement and quality

of life of patients with severe TR after device implantation, which were significantly improved

along with the tricuspid EROA by PISA, a quantitative assessment of regurgitation.

43

Figure 8. Transcatheter devices designed to target the tricuspid annulus to improve functional TR. (A)

Edwards Cardioband Tricuspid Valve Reconstruction System and (B) Mitralign Percutaneous Tricuspid

Valve Annuloplasty System (also known as TriAlign). Reprinted with permission by Miller, et al. (2018)

and Hahn, et al. (2017).

Other companies focused on targeting other areas of the tricuspid valve to reduce TR, such as the

coaptation of the tricuspid leaflets. The TRILUMINATE trial was launched to test Abbott’s clip-

based transcatheter tricuspid valve repair (TTVR) system on asymptomatic patients with TR

(Curio et al., 2019). Like most other tricuspid devices, the TTVR system was adapted from the

MitraClip system, which secures a portion of the leaflets with a clip that prevents mitral

regurgitation. Edwards is also currently testing another tricuspid device, the FORMA Tricuspid

Transcatheter Repair system which is comprised of a spacer implanted in the regurgitant orifice

with a rail that is anchored in the RV (Figure 9). The spacer acts as the surface on which the

leaflets can coapt, and subsequently reduce TR (Campelo-Parada et al., 2015). The SPACER

trial, an early feasibility study showed significant reduction in right ventricular dimensions and

A A

B

44

clinical improvement at 1-year follow-up, although TR grade reduction was variable (Perlman et

al., 2017).

Figure 9. An example of a transcatheter device that reduces TR by providing a surface for the coaptation

of the tricuspid leaflets; Edwards FORMA device is inserted in the orifice and anchored in the RV

myocardium. Reprinted with permission from Campelo-Parada et al. (2015).

As larger clinical trials for percutaneous tricuspid devices are underway, results from early

feasibility studies show promise in treating millions of people suffering from severe TR.

Understanding the mechanism of primary and secondary TR as well as accurately visualizing the

tricuspid valve are necessary in diagnosing and identifying patients who may benefit from a

certain type of transcatheter tricuspid intervention. The challenge of doing so stems from the

complexity of assessing not only the tricuspid valve, but also the right ventricle. It appears that

the development of TV therapies will go hand-in-hand with understanding the process of

tricuspid valve disease.

45

Chapter 2 Rationale and Objectives

Rationale Understanding of the pathophysiology and diagnostic and therapeutic interventions on the

tricuspid valve have long been understudied in cardiology research. However, attention to the

mechanisms of right heart failure continues to grow after being recognized as an independent

predictor of poor survival outcomes. ASD is one of the most common congenital heart defects

affecting adults and is usually diagnosed when they present with functional incapacity that is

characteristic of RV enlargement and dysfunction.

Concomitant functional TR as a result of longstanding left-to-right shunting and subsequent RV

dilatation is a common feature among these patients. Moderate to severe TR is independently

associated with increased mortality. As such, early closure of hemodynamically significant

ASDs may be prudent. However, at this stage, patients with moderate to severe TR are more

likely older and consequently, less likely to experience the same extent of reverse cardiac

remodeling as a patient with moderate to severe TR whose ASD was closed at a younger age.

This may be a reason as to why ~30-89% of patients continue to have moderate to severe TR

after transcatheter ASD closure, although the determinants of persistent TR have been variable.

There are currently two long-term follow-up studies that report event-free survival rates of

patients with moderate to severe TR at the time of isolated transcatheter ASD closure. However,

they are limited in sample size and clinical data for adjusted survival analysis. Furthermore,

follow-up data in both studies were limited in follow-up duration and secondary outcome

measures, such as incidence of atrial fibrillation and ASD re-intervention, which would have

provided a more comprehensive story of this cohort.

TV surgery, such as tricuspid annuloplasty, at the time of surgical ASD closure may be a

reasonable option for treating patients that are at risk for persistent TR. Tricuspid annuloplasty or

TV replacement can be effective in reducing the amount of TR, however, the rate of peri-

operative death in isolated TV surgery is higher than other valvular procedures. Furthermore, not

all patients who undergo tricuspid annuloplasty experience improvement of their TR, which

46

suggests that there may be another mechanism other than TA dilatation that contributes to

functional TR (i.e., leaflet malcoaptation).

With the emerging TV devices that are undergoing clinical investigation, questions regarding the

benefits of catheter-based TV therapies during ASD closure will be raised. It is important that

ACHD specialists and interventionalists develop a predictive model for identifying patients at

risk for persistent TR after isolated ASD closure, and to confirm whether TR severity is a

prognosticator for worse mortality and morbidity outcomes. This would assist in defining the

non-existent guidelines for the management of ASD and other congenital heart defects that

contribute to right heart enlargement and functional TR.

It remains unclear whether transcatheter ASD closure is sufficient to reverse and prevent the

progression of functional TR when measured quantitatively. Furthermore, long-term follow-up

studies of patients with moderate to severe TR before and after ASD closure are limited. These

clinical questions are relevant to physicians involved in the management of those who could

benefit from ASD closure and adjunctive tricuspid valve intervention. The overall aim of this

project is to describe adult patients with TR who underwent transcatheter closure of ASD, and

compare their outcomes with those without TR.

3.1 Objectives The study objectives are as follows:

1) Compare clinical and procedural characteristics of patients who underwent ASD

device closure based on TR grade at baseline;

2) Identify independent baseline predictors of persistent moderate to severe TR;

3) Quantify the extent of positive cardiac remodeling following ASD closure in an

echocardiographic sub-study;

4) Compare long-term clinical outcomes between: 1) pre-procedural moderate to severe

TR and pre-procedural mild/no TR, and 2) improved TR vs persistent TR following

ASD closure, using linked population-based administrative health databases in

Ontario.

47

Chapter 3 Methods

Single-centre retrospective study

4.1 Study population The study population all adult patients (>18 years old) who underwent successful transcatheter

ASD closure at the Toronto General Hospital (TGH) from 1997-2016. Patients who met the

following conditions were excluded from the study:

1. Non-Ontario residents;

2. Missing/incomplete baseline and follow-up echocardiographic reports;

3. Those with concomitant partial/complete anomalous pulmonary venous connection

(APVC), Ebstein’s anomaly, or ventricular septal defect (VSD);

4. Those with primary tricuspid valve disease (i.e., rheumatic or congenital TV disease);

5. Those with tricuspid valve surgery (i.e., repair, replacement, annuloplasty) prior to ASD

closure.

4.2 Research ethics approval The study protocol was approved by the research ethics board of the University Health Network

(UHN). Considering the retrospective nature and no risk to the patient, patient consent

requirement was waived.

4.3 Study design This was a retrospective cohort study by extracting clinical data from electronic and paper-based

medical records. The patients were grouped into two cohorts based on their baseline TR severity

grade that was stated on their echocardiographic report; 1) baseline mild/no TR or 2) baseline

moderate to severe TR. The latter cohort was further stratified to either improved or persistent

TR groups based on the TR status reported on their latest follow-up echocardiogram. Improved

TR was defined as patients who had baseline moderate to severe TR and showed mild or no TR

at follow-up. Persistent TR was defined as patients who continue to show moderate to severe TR

at follow-up – which included patients who had a grade reduction from severe TR to moderate

TR after ASD closure.

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4.4 Data sources

4.4.1 Clinical registry

We reviewed and abstracted data from patients’ electronic medical records and paper charts

stored at UHN. Data was entered into a structured Microsoft Excel database and double-checked

by trained data abstractors for quality assurance. The abstracted information included patient

demographics (e.g., age), clinical characteristics (e.g., hypertension), peri-procedural data, and

follow-up information were retrieved.

4.4.2 Linkage to administrative databases

The clinical registry was linked to Ontario population-based health administrative databases

housed at the Institute for Clinical Evaluative Sciences (ICES). ICES datasets are linked using

the Ontario Health Insurance Plan (OHIP) number, after linkage stripped of individual

identifiers, and assigned an ICES key number (IKN) to maintain anonymity but allow for person-

level identification of health service utilization and health outcomes including vital status. A

Data Creation Plan (DCP) with detailed description of study variables and their sources (i.e.,

Ontario databases), were submitted to ICES for data analysis. After data linkage, all data

analyses were conducted at ICES an aggregate data reported back to study investigators.

Patients who met the following conditions were excluded from the ICES-linked database:

1. Invalid IKN;

2. Repeat IKN;

3. Non-linkable Registered Persons Database (RPDB);

4. Index procedure done in 1997;

5. Non-Ontario residents;

6. Exclude patients with other congenital heart defects that cause RV enlargement:

I. partial/complete anomalous pulmonary venous drainage;

II. ventricular septal defect;

III. patent ductus arteriosus;

IV. Ebstein’s anomaly;

7. Previous tricuspid valve surgery (i.e., repair, replacement, annuloplasty) prior to ASD

closure;

49

8. Unavailable echocardiographic reports at baseline.

The clinical baseline and follow-up variables obtained are listed in Appendix Table 2, along with

the corresponding International Classification of Diseases (ICD), Versions 9 and 10; Canadian

Classification of Diagnostic, Therapeutic and Surgical Procedures (CCP); Canadian

Classification of Interventions (CCI); and OHIP billing codes. The registries used included:

Registered Persons Database (RPDB), Discharge Abstract Database (DAD), National

Ambulatory Care Reporting System (NACRS), OHIP, and ICES-derived cohorts (Hypertension

(HYPER), Congestive Heart Failure (CHF), Chronic Obstructive Pulmonary Disease (COPD),

Ontario Diabetes Dataset (ODD), Ontario Registrar General – Deaths (ORGD)). The type of

information extracted from each database are described in Table 7.

Baseline characteristics such as hypertension, diabetes, heart failure, atrial fibrillation/flutter,

chronic obstructive pulmonary disease (COPD), coronary artery disease, stroke, myocardial

infarction, and the Charlson comorbidity index were retrieved with a 2-year lookback window

from the index procedure date. All-cause mortality, cardiovascular-related death, and composite

hospitalization for congestive heart failure (CHF) and/or atrial fibrillation (AF) were prespecified

as primary outcomes. Secondary outcomes included new onset of AF, new onset of CHF, acute

myocardial infarction (MI), any stroke (hemorrhagic or ischemic), transient ischemic attack

(TIA), any open-heart surgery, and catheter-based interventions (ASD re-intervention, tricuspid

valve intervention).

Follow-up period started on the day of index procedure (with the exception of acute outcomes

which started within 30 days after the index discharge date) and ended on the last available date

updated by the Ontario health registries. Although all-cause mortality was available until

December 2018, the ORGD (Vital Statistics – Death) registry used to ascertain causes of death

only ran until December 2016.

50

Table 7. Description of Ontario population-based health administrative databases

Database Description Registered Persons Database (RPDB) Population and demographics database that provides information of all Ontario

residents eligible for OHIP in a given year; used to confirm Ontario residency status

and demographics

Canadian Institute for Health Information Discharge Abstract

Database (CIHI DAD)

Health services database that provides information on hospital admissions/discharge

and same day surgeries throughout Canada; used to collect length of index

hospitalization, hospitalization within 30 days of index discharge, and all-cause

hospitalizations, and any ASD or TV surgeries post-ASD closure

CIHI National Ambulatory Care Reporting System (NACRS) Health services database that provides information on emergency and ambulatory

services used and costs throughout Canada; used to collect any emergency visits

with 30 days of index discharge, hospital and community-based ambulatory care

Ontario Registrar General – Deaths (ORGD) Population and demographics database that provides information of vital statistics,

date and cause of death; used to collect all-cause and cardiovascular mortality

OHIP Claims Database Health services database that provides information on outpatient family physician

and specialist visits, laboratory tests, diagnostic and therapeutic procedures billed to

the Ontario Ministry of Health and Long-Term Care

ICES-derived cohorts

Chronic condition cohorts developed at ICES using linked data algorithms

Hypertension (HYPER)

Congestive heart failure (CHF)

Chronic Obstructive pulmonary disease (COPD)

Ontario Diabetes Database (ODD)

51

4.5 Echocardiographic sub-study An in-depth review of the right heart in a subset of patients was conducted by an expert cardiac

sonographer at TGH. Patients with pre-procedural moderate to severe TR and complete

echocardiographic studies were retrieved from electronic imaging storage systems at UHN or

archived CD-ROMs during the patient’s referral. 2D transthoracic echocardiograms were

reviewed and measurements were made in accordance with the American Society of

Echocardiography (ASE) guidelines (Lang et al., 2015). Patients were age (±3 years)- and sex-

matched (1:1) to patients with baseline mild/no TR. Indices of RV enlargement, RV dysfunction,

TA dilatation, and quantity of TR were re-assessed and measured with syngo Dynamics

v.VA20E_HF02 (Siemens Medical Solutions USA, Inc., Michigan, USA).

Two echocardiographic assessments were performed:

1) Age- and sex-matched comparison between pre-procedural TR severity cohorts; and

2) Paired measurements before and after ASD closure to assess the extent of reverse

cardiac remodeling.

4.6 Statistical analysis

4.6.1 Clinical registry

Data were presented as means and standard deviations (SD) for continuous variables and as

counts and percentages for categorical variables. Comparison of clinical and procedural

characteristics between the baseline mild/no TR and baseline moderate to severe TR cohorts was

performed using the Welch’s t test and Chi-square test, depending on variable type. Paired t-test

was used for echocardiographic sub-analyses to compare information between age- and sex-

matched cohorts, as well as measurements before and after intervention. Inter-observer

agreement between the original observer and the re-assessor in the grading of TR was denoted by

weighted (linear) Cohen’s kappa.

Uni- and multivariable logistic regression analysis was used to identify the predictors of

persistent moderate to severe TR. Baseline predictors of persistent moderate to severe TR used in

the univariable analysis were chosen based on literature review and consultation with clinical

52

experts. Variables with almost no missing values and a p-value < 0.05 in the univariable analysis

were considered for the multivariable logistic regression analysis. A backwards elimination

process was used and adjusted odds ratios and corresponding 95% confidence intervals were

reported. Clinically meaningful interactions were tested. A measure of goodness of fit for binary

outcomes in a logistic regression model was determined by the concordance (C)-statistic.

Statistical analysis were performed in R v.3.4.1 (R Foundation for Statistical Computing,

Vienna, Austria) and Prism v.7.0 (GraphPad Software, Inc., San Diego, CA, USA).

4.6.2 Analysis of linked data

Baseline and short-term outcomes tables were generated from the linked data at ICES and were

presented as mean ± SD for continuous variables and as counts and percentages for categorical

variables. Long-term outcomes were given in person-years (PY) and 95% confidence intervals

for categorical variables due to small cell output. Statistical differences between pre-procedural

moderate to severe TR and pre-procedural mild/no TR cohorts; improved TR and persistent TR

cohorts were calculated using the student t-test or Chi-square test, depending on variable type.

Overall and cardiovascular mortality were presented as Kaplan-Meier curves. Unadjusted and

adjusted survival analyses (including the adjusted hazard ratio) for cardiovascular mortality were

conducted using the Gray’s method and the Fine-Gray subdistribution hazard model,

respectively. Adjusted survival analysis and generation of adjusted hazard ratio for all-cause

mortality was conducted with the Cox proportional hazards model. The covariates included in

the regression analyses were age, sex, atrial fibrillation, coronary artery disease, congestive heart

failure, hypertension, diabetes, chronic obstructive pulmonary disease, and Charlson comorbidity

index.

53

Chapter 4 Results

Analysis of clinical registry

5.1 Study population From 1997 to 2016, 1508 patients underwent transcatheter ASD closure at the Toronto General

Hospital. Transcatheter ASD closure was performed using the Amplatzer Septal Occluder (St.

Jude Medical, St. Paul, Minnesota) or the CardioSEAL Septal Occluder (NMT Medical, Boston,

Massachusetts). From the local database, 704 of the patients were excluded from the clincal

registry leaving a total of 804 in the study sample (Figure 10). A large proportion of patients who

were excluded were those with either a missing baseline or follow-up echocardiographic report

or both. The mean age was 48 years (±16 years) and 70 % of the study population was female.

Patients were stratified based on their TR severity status reported in the baseline

echocardiograms taken before ASD closure: 186 (23%) patients with no TR, 443 (55%) patients

with mild TR, 146 (18%) patients with moderate TR, and 29 (4%) patients with severe TR

(Figure 11). Patients with pre-procedural mild or no TR were found not to be clinically different

from one another and therefore, pooled together as one cohort (Appendix 1). Patients with severe

and moderate TR were also combined due to their relatively small cohort size. Patients with pre-

procedural moderate to severe TR were further stratified to improved (n=109, 17%) or persistent

(n=66, 10%) TR subgroups, which was based on their follow-up echocardiogram report. The

median echocardiographic follow-up time was 4 months (range 1-178 months).

54

Figure 10. Study flow diagram of patients who underwent transcatheter atrial septal defect closure at the

Toronto General Hospital, Toronto, Canada based on baseline functional tricuspid regurgitation. PAPVC,

partial anomalous pulmonary venous connection; VSD, ventricular septal defect; PDA, patent ductus

arteriosus; TV, tricuspid valve.

Patients with moderate to severe TR at baseline (n=175) were significantly older than patients

with mild/no TR (n=629) and has more females, a higher prevalence of atrial fibrillation/flutter

(AF), coronary artery disease (CAD), heart failure, and hypertension compared to the baseline

mild/no TR cohort (Table 8).

n=1508 underwent transcatheter ASD closure between 1997-2016

n=804

n=175 with baseline

moderate/severe TR

n=109 improved to at least mild TR

n=66 continued to have moderate to severe TR

n=186 with baseline no TRn=443 with baseline mild TR

Exclude: n=582 incomplete

echocardiographic reports

n=102 non-Ontario residents

n=20 PAPVC, Ebstein’s

anomaly, VSD, PDA, or TV

intervention

55

Table 8. Baseline patient characteristics in clinical registry

N=804 Baseline mild or no TR n=629

Baseline moderate to severe TR n=175

p-value

Age (years) 48 ± 16 45 ± 15 57 ± 17 <0.001 Female 565 (70) 425 (68) 140 (80) 0.002 Height (cm) 165.8±9.1 166.5 ± 9.3 163.6 ± 9.6 <0.001 Weight (kg) 72.8±17.2 73.7 ± 17.3 69.7 ±16.3 0.005 BMI (m/kg

2) 26.4±5.7 26.5 ± 5.7 26.0 ± 5.8 0.278

BSA (m2) 1.8±0.2 1.8 ± 0.2 1.7 ± 0.2 <0.001

Atrial fibrillation/flutter 88 (11) 30 (5) 58 (34) <0.001 CAD

72 (9) 45 (7) 27 (15) <0.001

Stroke/TIA 79 (10) 68 (11) 11 (6) 0.075

Heart failure 14 (2) 7 (1) 7 (4.0) 0.010 Hypertension 171 (21) 115 (18) 56 (33) <0.001 Diabetes 56 (7) 42 (7) 14 (8) 0.456

Hyperlipidemia 154 (19) 116 (18) 38 (23) 0.223

Data are presented as mean ± SD or frequencies (%).

BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; TIA, transient ischemic

attack.

5.2 Echocardiographic sub-study A total of 76 patients’ baseline echocardiograms were re-reviewed by a research sonographer.

From the 175 patients with baseline moderate to severe TR, 46 patients had baseline and follow-

up imaging studies available for reassessment at UHN. Each patient was randomly age (±3

years)- and sex-matched in a one-to-one fashion with patients from the pre-procedural mild/no

TR cohort. Of the 46 patients, 16 were left unmatched due to large differences in age. Therefore,

the comparison of baseline echocardiographic characteristics was comprised of 30-matched

pairs, for a total of 60 patients. Cohen’s kappa (linear weights) was 0.894, indicating strong

agreement in the grading of TR between the original and current observer. In other words,

approximately 79% of TR grading in the present study was reliable (McHugh, 2012).

A comprehensive assessment of right heart structure and function, TR, and TV anatomy was

performed by the re-reviewer (Table 9). The pre-procedural moderate to severe TR subgroup

(n=30) had significantly larger RA areas and RV volumes compared to the pre-procedural

mild/no TR subgroup (n=30) at baseline. Right heart pressures were also significantly higher.

Global systolic function, indicated by RV FAC, was normal in both subgroups with no

significant differences. Longitudinal systolic function indices, TAPSE and S’, were not reported

because of suboptimal imaging windows. With regard to TV anatomy, both SL and AP annular

56

diameters suggested that patients in the pre-procedural moderate to severe TR subgroup had

significantly more dilated tricuspid annuli.

Table 9. Age (±3 years)- and sex-matched baseline echocardiographic characteristics

Baseline mild or no TR n=30

Baseline moderate to severe TR n=30

Mean of differences

p-value

RA area indexed (cm2/m

2) 18.9 ± 4.5 27.3 ± 7.5 +7.2 ± 7.3 <0.001

RA pressure (mmHg) 4 ± 3 8 ± 4 +3 ± 5 0.005 RVEDD (cm) 4.5 ± 0.8 5.1 ± 0.7 +0.7 ± 0.9 <0.001 RV area indexed (cm

2/m

2) 16.4 ± 4.6 20.3 ± 4.3 +3.9 ± 6.2 0.002

RV volume (mL) 116 ± 30 151 ± 29 +35 ± 26 <0.001 RVSP (mmHg) 30 ± 9 48 ± 17 +18 ± 16 <0.001 RV FAC (%) 40 ± 8 42 ± 9 +2 ± 11 0.356

TR jet area (cm2) - 6.7 ± 4.5 - -

Vena contracta (cm) - 6.3 ± 1.7 - -

SL annular diameter (cm) 3.5 ± 0.5 4.2 ± 0.6 +0.7 ± 0.7 <0.001

AP annular diameter (cm) 3.5 ± 0.4 3.9 ± 0.6 +0.3 ± 0.7 0.012

Data are presented as mean ± SD.

RVEDD, right ventricular end-diastolic diameter; FAC, fractional area change; SL, septolateral; AP,

anteroposterior.

5.3 Right heart catheterization Hemodynamic data derived from right heart catheterization (RHC) were taken during or before

the procedural date, prior to device closure of the ASD (Table 10). Although approximately two-

thirds of the data for the right heart pressures and saturations were not found, patients with

moderate to severe TR had higher pulmonary and right heart pressures - consistent with what

was found in the echocardiographic sub-study. Oxygen saturation levels within the superior and

inferior vena cava were significantly lower in those with pre-procedural moderate to severe TR.

There was no statistically significant difference observed in the Qp:Qs (1.9 ± 0.8 vs 2.1 ± 0.7,

p=0.175) and balloon size of the ASD (21.0 ± 6.3 mm vs 21.7 ± 6.8 mm, p=0.299) between the

two groups. The composite frequency of minor and major peri-procedural complications (i.e.,

access-site bleeding, device-related, conductive abnormalities, allergic reaction to anesthetics,

and/or switch to urgent surgery) was low (<10%) regardless of pre-procedural TR grade.

57

Table 10. Right heart catheterization and index hospitalization characteristics

Baseline mild or no TR

n/629 Baseline moderate to severe TR

n/175 p-value

PA systolic pressure

(mmHg)

34 ± 12 259 43 ± 13 71 <0.001

PA diastolic pressure

(mmHg)

14 ± 5 253 16 ± 1 71 0.023

PA mean pressure (mmHg) 22 ± 7 252 27 ± 8 71 <0.001 RV systolic pressure

(mmHg)

38 ± 19 246 46 ± 12 71 <0.001

RV diastolic pressure

(mmHg)

10 ± 4 243 11 ± 4 71 0.269

RA mean pressure (mmHg) 8 ± 3 248 10 ± 5 70 0.004 SVC O2 saturation (%) 72 ± 6 233 69 ± 8 62 <0.001 IVC O2 saturation (%) 77 ± 7 121 74 ± 6 38 0.021 PA O2 saturation (%) 82 ± 6 230 82 ± 6 64 0.944

Qp:Qs 1.9 ± 0.8 215 2.1 ± 0.7 57 0.175

ASD balloon sizea (mm) 21.0 ± 6.3 - 21.7 ± 6.8 - 0.299

Complications during

procedure or index

hospitalization, n (%)b

40 (6) - 15 (9) - 0.311

Data are presented as mean ± SD or frequencies (%). aSize of the largest ASD if there was >1 defect. bComplications include device erosion/embolization, arrhythmia, access-site complications, bleeding, deep

venous thrombosis (DVT)/pulmonary embolism (PE), allergic reactions, gastrointestinal (GI) issues and/or

switch to urgent surgery.

PA, pulmonary artery; SVC, superior vena cava; IVC, inferior vena cava; Qp:Qs, pulmonary-to-systemic flow

ratio.

5.4 Improved versus persistent TR after ASD closure The distribution of post-procedural TR status is illustrated in Figure 11. At a median follow-up

of 4 months (range 1-178 months), echocardiographic reports showed that of the 175 patients

with pre-procedural moderate to severe TR, 109 (62%) improved to at least mild TR and 66

(38%) continued to have moderate to severe TR. Approximately 91% of the entire sample size

was free of significant functional TR after device closure (compared to 78% at baseline,

p<0.001).

58

TR grade at median 4-months follow-up

None/Mild Moderate Severe Total

Baseline TR

grade

None/Mild 599 27 £5 629

Moderate 103 37 6 146

Severe 6 13 10 29

Total 708 77 19 804

Figure 11. Pre- and post-closure TR based on echocardiographic reports (p<0.001). TR grade reported as

percentages and number of patients.

5.5 Independent baseline predictors of persistent TR Baseline clinical and structural variables collected from electronic medical records were used in

an univariable analysis to measure significant associations between baseline characteristics and

persistent moderate to severe TR. The variables used were chosen based on clinical expertise,

past literature, and data availability (Table 11). Age at the time of procedure, atrial

fibrillation/flutter, hypertension, RVSP, severe TR, TR jet area, and VC were found to be

significant predictors of persistent TR in univariable analysis. Multivariable logistic regression

analysis of age, atrial fibrillation/flutter, RVSP, and severe TR revealed that age ³65 years

(adjusted OR 4.53; 95% CI 1.95-10.8), RVSP ³45 mmHg (adjusted OR 2.49; 95% CI 1.05-

78

91

18

64 3

0

10

20

30

40

50

60

70

80

90

100

Baseline FU

% o

f pat

ient

s

SevereModerateNone/Mild

59

5.96), and severe TR (adjusted OR 6.24; 95% CI 2.20-19.9) to be the independent predictors of

residual moderate to severe TR. The C-statistic (i.e, area under the ROC curve) of the logistic

regression model was calculated to be 0.804, 95% CI 0.734-0.874 (Figure 12).

Table 11. Uni- and multivariable logistic regression for persistent moderate to severe TR (n=175)

Baseline characteristics Univariable analysis Multivariable analysis OR (95% CI) p-value OR (95% CI) p-value

Clinical Age ³ 65 years 6.85 (3.37-13.2) <0.001 4.53 (1.95-10.8) <0.001 Female 0.89 (0.43-1.82) 0.846

Atrial Fibrillation/flutter 5.11 (2.56-10.3) <0.001

Hypertension 1.96 (1.01-3.41) 0.04

Echocardiographic

RVEDD ³3.9 cm 2.51(0.83-7.22) 0.136

RV dysfunction ³moderate 2.67 (0.70-8.66) 0.132

RV FAC £ 30%* 0.31 (0.02-2.23) 0.298

TAPSE £ 2.3 cm* 4.50 (0.69-25.1) 0.100

RVSP ³45 mmHg 6.13 (2.99-12.5) <0.001 2.49 (1.05-5.96) 0.006 Severe TR 9.18 (3.64-23.3) <0.001 6.24 (2.20-19.9) <0.001 Moderate mitral regurgitation 1.16 (0.37-3.68) 0.788

Moderate pulmonary

regurgitation*

2.00 (0.22-30) 0.575

TR jet area ³10 cm2* 11.3 (2.08-55.8) 0.003

Vena contracta ³ 7 mm* 16.4 (4.01-52.6) <0.001

SL annular diameter ³ 43 mm* 2.63 (0.791-8.67) 0.148

AP annular diameter ³ 40 mm* 1.26 (0.42-3.93) 0.782

Catheterization

ASD balloon size > 22 mm 0.82 (0.42-1.61) 0.614

PAP mean ³25 mmHg* 1.20 (0.44-3.27) 0.713

Qp:Qs ³2.1* 0.70 (0.24-1.98) 0.592

*Large proportion of missing values.

TAPSE, tricuspid annular plane systolic excursion; SL, septolateral; AP, anteroposterior; PAP, pulmonary

artery pressure; Qp:Qs, pulmonary to systemic flow.

60

Figure 12. Receiver Operating Characteristic (ROC) curve of the multiple logistic regression model of

persistent TR, C-statistic = 0.804 (95% CI 0.734-0.874).

5.6 Reverse cardiac remodeling In our imaging sub-study, echocardiographic data before and after ASD closure in the same

patient was assessed (Table 12). Overall, there was evidence of positive reverse cardiac

remodeling in patients regardless of TR severity. Across the study sample (n=76), both patients

with pre-procedural mild/no TR (n=30) and moderate to severe TR (n=46) had statistically

significant reduction in RA area, RV volume, RVEDD, and RVSP at a median 4-months follow-

up. When patients with pre-procedural moderate to severe TR were classified to either improved

(n=21) or persistent (n=25) TR cohorts, both subgroups showed significantly smaller right heart

sizes, SL annulus diameters, lower right heart pressures, and smaller TR jet areas and VC. As

observed, RV FAC was significantly reduced after device closure in the improved TR subgroup.

61

Table 12. Echocardiographic changes after percutaneous ASD closure

Baseline mild or no TR n=30

Baseline moderate to severe TR

n=46

Improved TR (n=21) Persistent TR (n=25)

Baseline D (%) p-value Baseline D (%) p-value Baseline D (%) p-value

RA area indexed (cm2/m2)

18.9 ± 4.5 -3.8±4.3 (-20) <0.001 25.1 ± 6.2 -7.4± 5.8 (-29) <0.001 31.2 ± 8.7 -6.2 ± 5.9 (-20) <0.001

RA pressure (mmHg)

4 ± 3 -0.3±3.3 (-8) 0.694 7 ± 4 -2 ± 5 (-29) 0.035 11 ± 5 -6 ± 6 (-55) <0.001

RVEDD (cm) 4.5 ± 0.8 -0.4 ± 0.8 (-10) 0.005 5.1 ± 0.7 -1.1±0.9 (-22) <0.001 5.1 ± 0.6 -0.5±0.7 (-11) <0.001

RV area indexed (cm2/m2)

16.4 ± 4.6 -3.4 ± 4.3 (-21) <0.001 19.8 ± 4.0 -5.9 ± 4.1 (-30) <0.001 21.3±5.5 -5.7±4.5 (-29) <0.001

RV volume (mL) 116 ± 30 -17 ± 25 (-15) 0.001 146 ± 23 -42 ±33 (-29) <0.001 162 ±38 -42 ± 29 (-26) <0.001

RVSP (mmHg) 30 ± 9 -3 ±7 (-10) 0.046 42 ± 14 -10±12 (-25) 0.001 54±17 -12± 13 (-22) <0.001

RV FAC (%) 40 ± 8 -1 ± 9 (-3) 0.642 44±9 -7±7 (-16) <0.001 38±6 -2 ± 8 (-5) 0.198

TR jet area (cm2) - - - 5.2±3.1 -2±3 (-38) 0.024 12 ± 6 -6± 5 (-50) <0.001

Vena contracta (cm)

- - - 5.4±1.5 -1.8±1.4 (-33) <0.001 7.5±2.3 -1.4± 2.5 (-19) 0.008

SL annular diameter (cm)

3.5 ± 0.5 -0.3±0.7 (-9) 0.016 4.1±0.5 -0.5±0.6 (-12) 0.001 4.2 ± 0.7 -0.3± 0.7 (-7) 0.036

AP annular diameter (cm)

3.5 ± 0.4 -0.2 ± 0.5 (-6) 0.059 3.9 ± 0.6 -0.2 ± 0.5 (-5) 0.103 3.9± 0.6 -0.05± 50. (-1) 0.668

Data are presented as mean ± SD. Values are based on a re-review of available imaging echocardiograms at UHN.

62

Long-term outcomes from ICES-linked data 6.1.1 Study population

After linking clinical registry data to ICES databases and applying the exclusion criteria for long-

term outcome analysis, a total of 949 patients were included in the study sample (Figure 13).

Figure 13. Study population flow diagram.

IKN, ICES key number; RPDB, Registered Persons Database.

6.1.2 Baseline patient characteristics

From 949 patients included in the sample, 750 (79%) patients had pre-procedural mild/no TR

and 199 (21%) patients had pre-procedural moderate to severe TR. Baseline characteristics of the

sample are shown in Table 13. Although mean Charlson comorbidity index (CCI) in both groups

was less than 1, the proportion of patients who had a CCI ³1 was more than double in patients

with moderate to severe TR (22% vs 10%, p<0.001).

n=1508 underwent transcatheter ASD closure between 1997-2016

n=949

n= 199 with baseline moderate/severe TR

n=119 with baseline and follow-up

echocardiographic reports

n=46 persistent TR

n=73 improved TR

n=80 with no post-procedural

echocardiographic reports

n=750 with baseline mild/no TR

Exclude: n=105 invalid IKNs

n=415 unavailable baseline echocardiogram

reports

n=7 non-linkable to RPDB or non-Ontario

residents

n=6 index procedure in 1997

n=26 PDA, VSD, Ebstein’s, PAPVC, or

previous TV surgery

63

Table 13. Baseline patient characteristics n=949 Baseline mild or no

TR

n=750

Baseline moderate

to severe TR

n=199

p

Age (years) 48 ± 16 45 ± 15 58 ± 16 <0.001 Female 656 (69) 497 (66) 159 (80) <0.001 Height (cm) 166.2 ± 9.9 167 ± 9.9 163.3 ± 9.4 <0.001 Weight (kg) 72.9 ± 17.1 73.5 ± 17.1 70.6 ±17.0 0.031 BMI (m/kg

2) 26.4 ± 5.5 26.3 ± 5.4 26.4 ± 5.9 0.833

BSA (m2) 1.80 ± 0.23 1.91 ± 0.23 1.75 ± 0.22 <0.001

Atrial fibrillation/flutter 119 (13) 67 (9) 52 (26) <0.001 CAD

197 (21) 141 (19) 56 (28) 0.004

Prior MI 21 (2) 13 (2) 8 (4) 0.051

Stroke/TIA 24 (3) 18 (2) 6 (3) 0.623

Heart failure 85 (9) 44 (6) 41 (21) <0.001 Hypertension 305 (32) 206 (28) 99 (50 <0.001 Diabetes 94 (10) 66 (9) 28 (14) 0.027 Pulmonary hypertension

145 (38) 89 (31) 56 (62) <0.001

COPD 87 (9) 59 (8) 28 (14) 0.007 Charlson comorbidity index 0.25 ± 0.80 0.19 ± 0.65 0.48 ± 1.18 <0.001

Index ³1 121 (13) 78 (10) 43 (22) <0.001 Data are presented as mean � SD or frequencies (%).

BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; TIA, transient ischemic

attack

6.1.3 Acute outcomes

Acute outcomes were compared between pre-procedural TR severity (mild/no vs moderate-to-

severe TR). These were defined as emergency room visits and hospital admissions within 30

days after index discharge date, as well as the length of stay during index hospitalization.

There were no significant differences between the pre-procedural mild/no TR and moderate to

severe TR groups with respect to the number of emergency department visits (16% vs 15%,

p=0.874) or hospitalizations (3% vs 4%, p=0.776) within 30 days after the index discharge date

(Table 14). The mean length of stay during the index hospitalization was approximately one day

for both groups and also not statistically significant different between the groups (p=0.430). Pre-

procedural TR severity are not associated with adverse events within 30 days of transcatheter

ASD closure. The cohort sizes for short-term outcomes are smaller than the original sample sizes

generated from ICES-linked data. This is a result of excluding patients whose index/discharge

dates from the CIHI DAD database did not match the dates recorded in the clinical registry. The

decision to exclude these patients stem from the possibility that the index procedure/discharge

64

from CIHI DAD could be miscounted as a separate event (i.e., another hospitalization) if the date

from the clinical registry was used – overestimating the rate of adverse events.

Table 14. Comparison of acute outcomes stratified by pre-procedural TR grade

n=949 Baseline mild or no TR n=750

Baseline moderate to severe TR n=199

p

Any ED visit within 30 days

after procedure discharge

152/878 (17) 122/693 (18) 30/185 (16) 0.874

Any hospitalization within

30 days after procedure

discharge

31/878 (4) 23/693 (3) 8/185 (4) 0.776

Length of stay during index

hospitalization (days)

1.00 ± 1.22 1.02 ± 1.33 0.94 ± 0.68 0.430

Data are presented as mean ± SD or frequencies (%).

6.1.4 Long-term outcomes

The median follow-up period after ASD device closure was 10.9 years (IQR 6.82-13.8 years) in

the total cohort. Once again, any open heart surgeries and catheter-based interventions had a

smaller sample size due to the exclusion of patients whose index/discharge dates from the CIHI

DAD database did not match the dates recorded in the clinical registry. The denominator for

these variables were the same as the sample sizes used in the acute outcomes analysis (Table 14).

Due to small cell sizes that were generated for some of the adverse events, frequencies for all

outcomes were reported per 1000 person-years (PY), (95% CI). As shown in Table 15, patients

with baseline moderate to severe TR had significantly higher rates of overall mortality (22.5 vs

6.8 per 1000 PY, p<0.001), CV-related death (9.6 vs 2.8 per 1000 PY, p=0.001), and composite

hospitalization for CHF or AF (49.1 vs 22.3 per 1000 PY, p<0.001) compared to the mild/no TR

cohort.

65

Table 15. Comparison of rates of long-term outcomes per 1000 person-years n=949 Baseline mild/no TR

n=750 Baseline moderate to severe TR n=199

p-value

Primary outcomes Overall death 10.0 (8.2-12.2) 6.9 (5.3-9.0) 22.3 (16.6-30.0) <0.001 CV-related 4.1(3.0-5.8) 2.7 (1.7-4.4) 9.6 (5.9-15.6) <0.001 CHF/AF hospitalization 12.4 (10.4-14.8) 8.9 (7.1-11.3) 26.3 (20.1-34.6) <0.001

Secondary outcomes New onset AF 11.5 (9.6-13.8) 9.9 (8.0-12.4) 17.7 (12.7-24.7) 0.006 New onset CHF 5.8 (4.5-7.5) 5.0 (3.6-6.8) 9.1 (5.7-14.5) 0.041 Stroke 2.4 (1.6-3.6) 2.2 (1.3-3.5) 3.5 (1.7-7.4) 0.290 TIA 1.0 (0.5-1.9) 1.3 (0.7-2.4) 0 (0.0-) 0.032 Myocardial infarction 2.5 (1.7-3.8) 2.4 (1.5-3.8) 3.0 (1.4-6.8) 0.633

Cardiac proceduresa Any open-heart surgery 1.7 (1.1-2.8) 1.8 (1.1-3.0) 1.5 (0.5-4.7) 0.799

ASD surgery 0.4 (0.2-1.1) 0.4 (0.1-1.2) 0.5 (0.1-3.6) 0.811 TV surgery 0.2 (0.1-0.8) 0.3 (0.1-1.0) 0 (0.0-) 0.999

Catheter-based interventions ASD re-intervention 0 (0.0-) 0 (0.0-) 0 (0.0-) 1.000 TV intervention 0.1 (0.0-0.7) 0 (0.0-) 0.5 (0.1-3.6) 0.999

Rates are reported as 1000 PY (95% CI). aDenominator for cardiac procedures are n=878, n=293, and n=185 (total, baseline mild/no TR, baseline moderate to severe TR, respectively).

66

Table 16 shows the stratification of pre-procedural moderate to severe TR patients based on TR

status in their follow-up echocardiographic report. In the ICES-linked database, 119 of the 199

patients had available follow-up reports. Similar to the analysis conducted with the local

database, 46 (38.7%) of the 119 patients continued to have persistent moderate to severe TR.

Patients with persistent TR had significantly higher rates of overall mortality (32. 2 vs 8.1 per

1000 PY, p=0.002) and composite hospitalization for heart failure or AF (52.9 vs 9.5 per 1000

PY, p<0.001). New onset of CHF (18.4 vs 4.1 per 1000 PY, p=0.017) and AF (29.9 vs 9.5 per

1000 PY, p=0.002) were significantly higher in the persistent TR cohort.

67

Table 16. Long-term outcomes stratified based on TR improvement after transcatheter ASD closure n =119 Improved TR

n=73 Persistent TR n= 46

p-value

Primary outcomes Overall death 17.0 (11.0-26.4) 8.1 (3.6-18.1) 32.2 (19.1-54.4) 0.003 CV-related 5.1 (2.1-12.2) 0 (0.0-) 13.7 (5.7-32.8) 0.999 CHF/AF hospitalization 25.5 (17.9-36.5) 9.5 (4.5-19.8) 52.9 (35.2-79.6) <0.001

Secondary outcomes New onset AF 17.0 (11.0-26.4) 9.5 (4.5-19.8) 29.9 (17.4-51.5) 0.011 New onset CHF 9.4 (5.2-16.9) 4.1 (1.3-12.6) 18.4 (9.2-36.8) 0.016 Stroke 1.7 (0.4-6.8) 0 (0.0-) 4.6 (1.2-18.4) 0.999 TIA 0 (0.0-) 0 (0.0-) 0 (0.0-) 1.000 Myocardial infarction 3.4 (1.3-9.1) 0 (0.0-) 9.2 (3.5-24.5) 0.999

Cardiac proceduresa Any open-heart surgery 0.9 (0.1-6.0) 1.4 (0.2-9.6) 0 (0.0-) 0.999

ASD surgery 0.9 (0.1-6.0) 1.4 (0.2-9.6) 0 (0.0-) 0.999 TV surgery 0 (0.0-) 0 (0.0-) 0 (0.0-) 1.000

Catheter-based interventions ASD re-intervention 0 (0.0-) 0 (0.0-) 0 (0.0-) 1.000 TV intervention 0.9 (0.1-6.0) 0 (0.0-) 2.3 (0.3-16.3) 0.999

Rates are reported as 1000 PY (95% CI) aDenominator for cardiac procedures are n=116, n=72, and n=44 (total, improved TR, persistent TR, respectively).

68

6.1.5 Unadjusted survival analysis for disease-specific mortality Unadjusted cumulative incidence curves for death of any cause (Figure 14A) and CV-related

(Figure 14B) mortality were compared between the pre-procedural mild/no TR and moderate to

severe TR cohorts. Taking into account non-cardiac death as the competing risk, the cumulative

probability of dying due to cardiovascular causes was still found to be significantly higher in the

pre-procedural moderate to severe TR group (Gray’s test p=0.0003).

Figure 14. Unadjusted cumulative incidence of (A) all-cause mortality and (B) cardiovascular death

stratified by pre-procedural moderate to severe TR (blue) and mild/no TR (red).

A

B

69

Similarly, Figure 15 reports cumulative incidence of unadjusted mortality by the presence or

absence of TR improvement after ASD device closure. The cumulative incidence of death from

any cause in the persistent TR cohort was significantly higher than those who improved at

follow-up (log-rank p=0.003) (Figure 15A). The cumulative probability of cardiovascular

mortality in the persistent TR cohort was significantly higher than the improved TR cohort

(Gray’s test p=0.006) (Figure 15B). The clinical significance of these mortality rates is

inconclusive due to the large number of patients who were lost to follow-up and censored (i.e.,

the number of patients at risk was low).

B

70

Figure 15. Unadjusted cumulative of (A) all-cause mortality and (B) cardiovascular death stratified by

improved (blue) and persistent (red) TR.

6.1.6 Adjusted survival analysis for all-cause mortality

The difference in survival between the groups was compared in adjusted analysis using Cox

proportional hazards. The model was adjusted for age, sex, atrial fibrillation/flutter, coronary

artery disease, heart failure, hypertension, diabetes, chronic obstructive pulmonary disease, and

Charlson comorbidity index (Figure 16). Patients with baseline mild/no TR had a significantly

higher probability of overall survival than those with moderate to severe TR (adjusted HR 1.7,

95% CI 1.1-2.6, p=0.021). Other independent predictors of overall mortality following device

closure were age (p<0.001), COPD (p=0.018), and Charlson comorbidity index (p=.0.002). The

effect of covariates on overall survival was not analyzed in the improved and persistent TR

cohorts due to its limited sample size.

Figure 16. Adjusted overall survival curves for baseline moderate to severe TR and mild/no TR

(p=0.021). Time-to-event begins on the date of index procedure and ends at any death or until last

available follow-up date (December 31, 2018).

71

6.1.7 Adjusted survival analysis for cardiovascular mortality The subdistribution hazard ratio for cardiovascular mortality was derived from the Fine-Gray

model (adjusted HR= 1.61, 95% CI 0.76-3.41). As shown in Figure 17, the probability of

experiencing CV death (for a patient who is alive or experienced a competing event) was not

significantly different between the baseline moderate to severe TR and mild/no TR groups

(p=0.214). Age (p<0.001) and Charlson comorbidity index (p=0.003) were independent

predictors of cardiovascular mortality.

Figure 17. Adjusted cumulative incidence of cardiovascular death between baseline moderate to severe

TR and mild/no TR cohorts (p=0.214). Time-to-event begins on the date of index procedure and ends at

CV death or until last available follow-up date (December 31, 2016).

72

Chapter 5 Discussion

Main findings The present study is the largest and longest follow-up study to-date that focuses on functional

tricuspid regurgitation in the adult ASD population.

The major findings are as follows:

1) ASD patients with pre-procedural moderate to severe TR are clinically different from those

with mild/no TR;

2) isolated transcatheter ASD closure successfully reduces TR grade to at least mild in 62% of

patients with pre-procedural moderate to severe TR;

3) independent baseline predictors of persistent TR at short-term echocardiographic follow-up

are age, RVSP, and severe TR grade;

4) echocardiographic sub-study showed reverse cardiac remodeling after ASD closure in all

groups regardless of TR grade- although the amount of remodeling may be different;

5) patients with pre-procedural moderate to severe TR were associated with higher rates of

secondary adverse outcomes – composite hospitalization for heart failure or atrial fibrillation,

new onset of heart failure, and new onset of AF);

6) patients with pre-procedural moderate to severe TR were independently associated with a

higher overall mortality than patients with mild/no TR (adjusted HR 1.7, 95% CI 1.1-2.6,

p=0.024). However, adjusted HR for cardiovascular mortality was statistically insignificant

(adjusted HR= 1.49, 95% CI 0.70-3.15, p=0.304).

7.1 Functional TR before ASD closure The underlying mechanisms of functional (secondary) TR are believed to be TA dilation and TV

leaflet tethering as a result of right heart chamber dilatation and papillary muscle displacement in

the RV (Hung, 2010). Long-term left-to-right interatrial shunting is known to be main

73

contributor of secondary TR in ASD patients (Chen et al., 2017; Fang et al., 2015; H. R. Kim et

al., 2017; Nassif et al., 2018; Takaya et al., 2017; Toyono, Fukuda, et al., 2009; Toyono,

Krasuski, et al., 2009). Simultaneously, right heart chamber dilatation can increase the risk of

atrial conduction abnormalities, RV dysfunction, and although rare, pulmonary hypertension and

Eisenmenger syndrome. The progression of these conditions can ultimately lead to congestive

heart failure.

7.1.1 Patients with pre-procedural moderate to severe TR are clinically different than patients with mild/no TR

From the ICES-linked data, our study shows that patients with pre-procedural moderate to severe

TR were significantly older, well into their 5th decade of life (Table 13). They also had

significantly higher rates of AF (26 vs 9%), pulmonary hypertension (62 vs 31%), diabetes (14

vs 9%), heart failure (21 vs 6%), COPD (14 vs 8%), hypertension (50 vs 28%), and CAD (15 vs

7%) - all of which contribute to a higher Charlson comorbidity index, which was indeed

observed in this cohort (0.48 ± 1.18 vs 0.19 ± 0.65). Charlson comorbidity index is a score used

to predict the 10-year survival in patients with multiple comorbidities (age, MI, CHF, peripheral

vascular disease, TIA/CVA, dementia, COPD, connective tissue disease, peptic ulcer disease,

liver disease, diabetes, hemiplegia, chronic kidney disease, solid tumour, leukemia, lymphoma,

AIDS) (Charlson, Pompei, Ales, & MacKenzie, 1987). The probability of 10-year survival is

calculated by the following equation (1), where CCI is the Charlson comorbidity index.

Theoretically, a 50-year old patient living with diabetes, heart failure, and COPD would have a

CCI of 4 and a 10-year survival probability of 53% (derived from equation 1).

10-year survival probability = 0.983^(eCCIx0.9) (1)

7.1.2 Structural abnormalities in the right heart are more pronounced in patients with pre-procedural moderate to severe TR

A consistent set of observations were made with an age- and gender-matched imaging sub-study

(Table 9). Patients with pre-procedural moderate to severe TR showed significantly larger atria

(RA area indexed; +7.2 ± 7.3 cm2/m2) and ventricles (RVEDD; +0.7 ± 0.9 cm), as well as larger

SL (+0.7 ± 0.7 cm) and AP (+0.3 ± 0.7 cm) tricuspid annular diameters. This is similar to a study

conducted by Fang et al. (2015), which found significant remodeling of the right heart and

74

tricuspid apparatus prior to device closure of ASD in adults. Although our study was unable to

take measurements of tethering of the tricuspid leaflets (tethering height or TSLA), it has been

proposed that similar to secondary MR, secondary TR may also be a consequence of the

displacement of RV papillary muscles as the RV enlarges (He et al., 1997; Hung, 2010;

Lancellotti et al., 2010). Thus, increased tethering of the leaflets along with TA dilatation can

result in the loss of coaptation of the tricuspid leaflets.

With respect to right heart pressures, patients with pre-procedural moderate to severe TR had

significantly higher RV (RVSP; +18 ± 16 mmHg) and RA (+3 ± 5 mmHg) pressures compared

to patients with mild/no TR (Table 9). This may be a result of an increase in RV preload incurred

through the unrepaired ASD over long periods of time. Furthermore, the higher prevalence of

pulmonary hypertension observed in the baseline moderate to severe TR cohort may contribute

to the exacerbation of pressure overloading. The intrinsic compensatory property of the Frank-

Starling mechanism proposes that an increase in end-diastolic volume is met by an increase in

systolic pressure to maintain stroke volume. Consequently, the only parameter preserved in both

subgroups was the systolic function of the RV, indicated by the RV FAC (40 ± 8% vs 42 ± 9%).

7.2 TR resolution observed in majority of patients with baseline moderate to severe TR

In general, TR jet area and vena contracta significantly decreased, however, 38% of patients with

baseline moderate to severe TR continued to show moderate to severe TR at a median of 4-

months echocardiographic follow-up. This was consistent with two recent studies that found 30-

42% of patients with baseline moderate to severe TR had persistent TR following percutaneous

ASD closure (Nassif et al., 2018; Takaya et al., 2017). Due to the retrospective nature of this

study, sequential follow-up imaging after one year was not performed at the centre. Perhaps, the

actual proportion of patients who improved is underestimated as reverse cardiac remodeling has

been shown to occur up to a year after ASD closure (Foo et al., 2018; Mangiafico et al., 2013;

Schoen et al., 2006). Furthermore, the rate of remodeling is slower in older populations (Du et

al., 2001; Santoro et al., 2006). In our imaging sub-study (Table 12), patients in the persistent TR

cohort still experienced significant reductions in right heart size and pressure, SL annular

diameter, and TR colour jet- however, it was insufficient in lowering the TR grade to at least

mild. Longer and more comprehensive RV-focused imaging studies with 3D echocardiography

75

or CMR would be beneficial in detecting the long-term effects of ASD closure on TR reduction

and right heart remodeling.

7.3 Older age, higher RVSP, and severe TR at baseline predict persistence of TR

The independent baseline predictors of persistent TR were found to be: 1) age ³65 years old

(adjusted OR 4.53, 95% CI 1.95-10.8), 2) RVSP ³45 mmHg (adjusted OR 2.49, 95% CI 1.05-

5.96), and 3) severe TR (adjusted OR 6.24, 95% CI 2.20-19.9). This is in agreement with

previous studies which found that determinants of persistent TR following percutaneous ASD

closure were age and PA systolic pressure (Chen et al., 2017; Nassif et al., 2018). The predictive

accuracy of the logistic regression model was strong, as the C-statistic (i.e., area under the ROC

curve, Figure 12) was calculated to be 0.80 (95% CI 0.73-0.87). However, the interpretation of

the C-statistic is limited to only the accuracy of discriminating patients who experience the

outcome (i.e., patient who has persistent TR will almost always yield a higher risk score)

(Fawcett, 2006). Nassif et al. published the first predictive model that assigns a relative risk score

to age, RA end-diastolic area, RVSP, and TAPSE (C-statistic=0.85, 95% CI 0.76-0.93). It is

plausible that pulmonary hypertension (indicated by high baseline RVSP) and reduced

compliance that is associated with increased age are primary contributors of TR persistence even

after significant reduction of RV volume. Perhaps offering earlier ASD intervention before a

patient progresses to severe TR may reduce the risk of having persistent TR after closure.

However, this may be difficult since many patients are undiagnosed until symptoms of severe

RV enlargement/dysfunction and atrial fibrillation appear.

Unfortunately, we did not have optimal echocardiographic windows or enough statistical power

to use tenting height or tricuspid septal leaflet angle in our multivariable analysis, which was

observed by Fang et al. (2015) who saw significant associations between TAD, TSLA, and

persistent TR. Contrary to other studies, this group showed that persistent functional TR was

determined only by pre-operative changes in tricuspid valve morphology, rather than pre-

operative RV remodeling. This was the only study that published comprehensive

echocardiography measurements in adults with ASD. However, their sample size of patients with

baseline moderate to severe TR was relatively small (n=64). Furthermore, their uni/multivariable

76

analyses did not include other important variables such as atrial fibrillation, which was the only

independent predictor of persistent TR found in another study (Takaya et al., 2017). In the past,

there has been no consensus on the baseline predicors of persistent TR. With the results of the

current study, age and RVSP appear to be the most agreed upon variables (Chen et al., 2017;

Nassif et al., 2018; Toyono, Krasuski, et al., 2009).

7.4 Positive reverse cardiac remodeling observed in all groups regardless TR grade

Another area of interest in our imaging sub-study assessed right heart changes that occurred in

each patient in follow-up (Table 12). This revealed the presence of significant reverse cardiac

remodeling after device closure of the ASD. Reduction in RV end-diastolic diameter, volume,

and RVSP were observed across all subgroups, regardless of pre- and post-procedural TR status,

although patients with improved TR had larger RV changes than both baseline mild/no TR and

persistent TR subgroups. The significant change in the septolateral (SL) annular diameter, which

was not seen in the anteroposterior (AP) annulus, is characteristic of the pathophysiology of

functional TR. Dilatation of the tricuspid annulus occurs along the anterior and posterior leaflets

(i.e., SL annulus), creating a more planar valve (Hung, 2010). The significant decrease in SL

annular diameter after ASD closure in both improved (-12%, p=0.001) and persistent (-7%,

p=0.036) TR subgroups corresponded to the significant improvement in TR jet area (-38% vs -

50%) and vena contracta (-33% vs -19%). Perhaps the significantly higher baseline

measurements of the tricuspid annulus and lower degree of reduction in the SL annular diameter

observed in the persistent TR cohort are also key predictors of TR persistence.

Although patients with persistent moderate to severe TR had significant reductions in RV size

and pressure, TA diameter, and quantity of TR, isolated t-ASD closure was not sufficient in

lowering the grade of functional TR to at least mild. This may be due to the larger baseline

values of their RV and TA indices, which would require more time to remodel and thus, not

captured during the short follow-up period for echocardiograms in the present and previous

studies. Furthermore, persistence of moderate to severe TR may also be a consequence of the

slower rate of reverse RV remodeling that is associated with older age (Du et al., 2001; Kaya et

al., 2010; Santoro et al., 2006). A longer and more comprehensive RV-focused imaging study is

required to determine the proportion and baseline predictors of patients who continue to have

77

moderate to severe TR at 1-year follow-up, and confirm whether the extent of reverse

remodeling in the right heart is associated with resolution of moderate to severe TR.

If persistent TR is confirmed to be related to irreversible RV or TA dilatation, offering isolated t-

ASD closure as early as possible may optimize the extent of positive cardiac remodeling that

would be enough for TR to improve to at least mild. Concomitant tricuspid annuloplasty or

replacement at the time of ASD closure can also be explored. However, Toyono et al. (2009)

found that residual moderate to severe TR was seen in a small proportion of ASD patients even

after concomitant surgical TV annuloplasty. This suggests that TA dilatation was not solely

responsible for the development of functional TR, and that there may be other underlying

mechanisms (e.g., leaflet tethering, pulmonary hypertension, persistent RV dilatation) that could

contribute to its progression.

7.5 Effect of TR and t-ASD closure on long-term clinical outcomes

The study sample size generated from the ICES-linked data was slightly larger than the study

sample from the clinical registry. This is due to variation in exclusion criteria of the two analyses

described in the Methods section (refer to Methods 4.1 and 4.4). In the clinical database, any

patient without a baseline or follow-up echocardiographic report was excluded at the beginning

of the study (n=804). In the ICES-linked database, patients with a pre-procedural

echocardiographic report were kept in the baseline analysis and were only excluded for long-

term outcomes analyses if they did not have a follow-up echocardiographic report (n=949). The

study populations derived from the ICES-linked and clinical registries were compared. As shown

in Appendix 3, excluding patients without a follow-up echocardiogram generated a population

that is clinically identical to the one from ICES.

Linkage of the clinical registry to Ontario population-based health administrative databases

allowed us to obtain accurate incidences for a larger variety of outcomes immediately following

ASD closure. Hospital admissions for heart failure and emergency department visits within 30

days after index discharge were not significantly different in patients with baseline moderate to

severe TR and baseline mild/no TR. However, the impact of significant functional TR on major

cardiovascular adverse events was evident in long-term follow-up analyses. The prevalence of

78

hospitalizations due to CHF/AF in patients with moderate to severe TR (26.3 per 1000 PY) was

more than double that of the cohort with £ mild TR (8.9 per 1000 PY). Further stratification of

pre-procedural moderate to severe TR patients revealed an even larger difference in HF/AF

hospitalizations between the improved (9.5 per 1000 PY) and persistent (52.9 per 1000 PY) TR

groups. These secondary outcome measures are important in defining a better understanding of

the clinical course that patients with unresolved TR take.

The incidence of developing AF after transcatheter ASD closure was significantly higher in

patients with pre-procedural moderate to severe TR compared to patients with mild/no TR (9.2

vs 4.6 per 1000 PY); and patients with persistent TR compared to those with improved TR (20.7

vs 2.7 per 1000 PY). Although closing the ASD eliminates left-to-right volume overloading,

unresolved significant TR becomes a primary source of RA enlargement and stretch, which can

lead to development of AF and subsequent HF. In fact, the incidence of HF in patients with pre-

procedural moderate to severe TR was 9.2 per 1000 PY compared to 5.0 per 1000 PY in patients

with mild/no TR. exaggerated in the persistent vs improved TR cohorts (18.4 vs 4.1 per 1000

PY, p=0.017). This confirms that residual TR after t-ASD closure is associated with worse

morbidity outcomes and suggests that patients at risk for persistent TR (38% of patients with pre-

procedural moderate to severe TR) should be considered for more aggressive management.

7.5.1 Unadjusted survival analysis

The present study is the largest (n=949) and longest (median 10.9 years, IQR 6.82-13.8 years)

follow-up study to-date. Comparable to the study conducted by Takaya et al. (2017), we showed

that patients with pre-procedural moderate to severe TR were three times more likely to

experience cardiovascular death than patients with mild/no TR (9.6 vs 2.7 per 1000 PY) (Table

15). Although this difference was statistically significant between the two groups, the absolute

rate of CV mortality (8%) was low - similar to the adverse event rate (<10%) reported by Takaya

et al. (2017). When unadjusted survival probabilities were analyzed (Figure 14B), cumulative

incidence of CV death was significantly higher in the pre-procedural moderate to severe TR

cohort (Gray’s test p<0.001).

In another long-term follow-up study, Nassif et al. (2018) reported event-free survival rate based

on TR severity after ASD closure (benchmark = 6-month follow-up) instead of baseline TR

79

grade. Patients with persistent TR were six times more likely to experience an adverse event

(hospitalization due to heart failure or cardiovascular death) compared to patients with improved

TR (p<0.001). These findings were in agreement with our current study (Table 16); when pre-

procedural moderate to severe TR patients from the present study were stratified into persistent

(n=46) and improved (n=73) TR cohorts, the rate of CV death was 13.7 per 1000 PY and 0,

respectively. However, this sample size was underpowered to test for statistically significant

differences.

7.5.2 Adjusted survival analysis

It is important to note that both long-term follow-up studies were unable to adjust survival curves

for significant co-morbidities that are known risk factors of CV mortality/adverse events (Nassif

et al., 2018; Takaya et al., 2017). Furthermore, they computed the statistical significance (p-

value) of survival rates using the log rank test, which ignores the immortal time bias introduced

by patients who experienced a competing event (i.e., non-cardiovascular death). The main

clinical outcome for both studies was defined as the composite of CV death or hospitalization for

heart failure. In our study, the main clinical outcome measure was solely CV death and the

subdistribution hazard ratio for CV-death was determined by the Fine-Gray model.

The Fine-Gray model allows us to evaluate the effect of covariates on the cumulative incidence

function (CIF) in situations where competing events (i.e., non-CV mortality) are present. Before

drawing conclusions from the results of the model, it is essential to understand that the

exponentiated regression coefficients (i.e., hazard ratio) derived from the Fine-Gray model can

be interpreted two ways; 1) the effect of covariates on the subdistribution hazard function and 2)

the effect of covariates on the CIF. In the former interpretation, one can infer that the

exponentiated regression coefficient describes the magnitude and direction of the relative change

in the instantaneous rate of the occurrence of the event (e.g., CV death) in those subjects who are

event-free or who have had a competing event (e.g., non-CV death) (Austin & Fine, 2017). In

this case, it must be accepted that the time after a patient experiences a competing event

represents “immortal” time since they are kept in the risk set. In the second interpretation, one

cannot infer that the numerical value of the subdistribution hazard ratios describes the magnitude

of the effect of the covariate on the CIF (i.e., the probability of the event). Thus, what can only

80

be inferred is the direction of the association between the covariate and the incidence (i.e.,

probability) of the event.

In the present study, the effect of pre-procedural moderate to severe TR on all-cause and CV

mortality is represented by the adjusted hazard ratio = 1.66 (95% CI 1.07-2.59) and 1.49 (95% CI

0.70-3.15), respectively (Figure 16-17). It can be safely inferred pre-procedural moderate to

severe TR grade is associated with a 66% increase in the rate of overall mortality. Similarly, pre-

procedural moderate to severe TR grade is associated with a 49% increase in the rate of CV

death (although statistically insignificant) in patients who are currently event-free or have

already experienced a competing event (i.e., non-cardiovascular death). Alternatively, one can

also safely infer that pre-procedural moderate to severe TR is associated with an increase of the

incidence/probability of overall mortality and CV death, although the magnitude of this effect is

unknown.

Contrary to what was expected, pre-procedural was not independently associated with CV death

after adjusting survival rates in the present study. There are two possible explanations for this

finding; 1) most patients with pre-procedural moderate to severe TR experienced improvement

of TR to at least mild after isolated transcatheter ASD closure, and 2) it is the absolute quantity

of TR, and not TR grade, that is associated with poor survival outcomes. Since median imaging

follow-up was 4 months, it is plausible that more than 62% of the pre-procedural moderate to

severe TR cohort experienced TR resolution beyond the date of their follow-up echocardiogram,

resulting in an underestimation of the effect of TR severity on long-term survival. In the second

scenario, perhaps using a more accurate quantitative index of TR, such as EROA, would be a

more appropriate benchmark for stratifying survival outcomes. The significant right heart

remodeling and reduction in TR jet area and vena contracta observed across all TR cohorts

(Table 12) in our imaging sub-study supports both of these explanations.

With the largest and longest follow-up study to-date, our study reveals the significance of TR

secondary to longstanding ASD shunting on adverse cardiovascular events and recapitulates the

importance of addressing this population in the ACHD guidelines.

81

7.6 Clinical implications ASD is a common congenital heart defect that presents in adulthood as a result of longstanding

RV volume overloading. RV dilatation is associated with a myriad of structural and electrical

abnormalities, such as atrial fibrillation and functional TR. Since TR severity has been found to

be an independent predictor of mortality (Lee et al., 2010; Nath et al., 2004), it is important that

TR is accurately measured and diagnosed before and after ASD closure. Similar to AF, TR

resolution after isolated ASD closure is not guaranteed and should be closely monitored in

patients with persistent TR which, in the present study, was composed of 38% of patients with

pre-procedural moderate to severe TR. We identified age, RVSP, and severe TR at baseline to be

independent predictors of persistent TR. Our multivariable logistic regression model was found

to be a strong predictive model (C-statistic = 0.804, 95% CI 0.734-0.874). In other words, there

is an 80% chance that a randomly selected patient in the persistent TR cohort was positive for the

proposed predictors compared to a randomly selected patient in the improved TR cohort

(Hosmer & Lemeshow, 2000). However, rigorous testing of the model on an external cohort is

required. It is also essential to elucidate the long-term clinical outcomes and symptomatic

improvement of patients with persistent TR vs improved TR. Once validated, ACHD specialists

would be able to better identify patients at risk for persistent TR and consider options for

managing the ASD.

It is imperative that cardiologists study TR improvement as a target of ASD closure since

isolated tricuspid valve repair/replacement is associated with high peri-procedural mortality.

Offering tricuspid annuloplasty (TAP) at the time of surgical ASD closure may be one option to

prevent future isolated TV interventions. In a recent study that assessed patients after surgical

ASD closure and concomitant TV repair, Kim et al. (2017) found no effect on long-term survival

despite significant reduction in TR grade. However, a large limitation of their survival analysis

(non-TAP vs TAP) was that survival was not adjusted for important confounders, such as age or

heart failure.

The management of functional TR in this population has only been recently addressed by Webb

and Opotowsky (2017), which concludes that referring physicians must use judgment and

consider surgery for pre-procedural moderate to severe TR patients who seem unlikely to

improve with isolated ASD closure, or prepare the patient for a staged treatment: device closure

82

with reassessment of TR and symptoms at 1-2 years follow-up. However, the exciting prospect

of catheter-based tricuspid valve therapies proposes another option for the treatment of ASD

patients with baseline moderate to severe TR.

7.6.1 Concomitant percutaneous TV intervention

With the emerging percutaneous interventions that are targeted in improving functional TR, it

would be interesting to study the effectiveness of such devices on lowering the risk of persistent

moderate to severe TR after concomitant ASD closure. However, the underlying mechanism of

functional TR in the context of an ASD must be elucidated hat the correct device may be

recommended for optimal TR reduction. Comprehensive imaging studies are required to assess the

extent of reverse right heart remodeling in order to determine whether it is the lack of TA diameter

reduction or absence of normalization of leaflet coaptation that is independently associated with

persistent functional TR after ASD closure. If it is the former, perhaps offering percutaneous

tricuspid annuloplasty (e.g., Edwards Cardioband Tricuspid Valve Reconstruction system) during

ASD closure may be of benefit to patients at risk for residual torrential TR. If it is the latter, these

individuals may benefit more from concomitant implantation of a coaptation device such as the

Abbott TriClip system. Of course, the future of TV intervention in the management of the ACHD

population depends on the durability and long-term outcomes of novel catheter-based tricuspid

therapies.

7.6.1.1 Case-study: percutaneous ASD closure followed by tricuspid device implantation

An elderly woman (>70 years old) with pulmonary hypertension and severe tricuspid regurgitation

was referred for percutaneous tricuspid valve repair. A diagnosis of secundum ASD was made

prior to TV intervention. The patient’s medical problems also included hypoxemia and atrial

fibrillation treated with anticoagulation. Her functional status was reported to be NYHA II-

III. Cardiac catheterization confirmed a hemodynamically significant ASD and percutaneous

closure was recommended to alleviate systemic hypoxemia by eliminating the right-to-left shunt

that was thought to be potentiated by the effects of PH. At 3-months follow-up, the patient felt

slight symptomatic improvement. She continued to have AF and was on reduced home oxygen.

Her TTE showed little change – severe RV dilatation with moderately reduced function and severe

83

TR. At this point, percutaneous implantation of a device undergoing clinical trial was offered to

and accepted by the patient, as surgical TV repair or replacement was considered too high risk.

Immediately after device implantation, there was a 50% reduction in the effective regurgitant

orifice. Her recovery was complicated by a major fall one month after procedure which resulted

in a long hospitalization. She became significantly decompensated and inactive. A few months

following tricuspid intervention, catheterization and TTE studies showed residual PH and severe

TR, respectively. The patient remained at NYHA functional class III and treated with supplemental

oxygen. Consequentially, the device has been recently discontinued in its multi-centre early

feasibility trial- results from this study have not yet been published. Other tricuspid valve systems

are currently undergoing early clinical trials and it would benefit clinicians managing ASD patients

to accurately identify patients at risk of persistent TR who may benefit from adjunctive tricuspid

valve intervention.

7.7 Limitations The retrospective design of the present study limits our complete understanding of ASD patients

with concomitant functional TR. Although the clinical registry was linked to population-based

health databases at ICES, digital storage of laboratory tests such as echocardiograms in Ontario

are not yet built. Furthermore, retention of imaging studies at UHN is only legally mandatory for

up to ten years from the date it was taken. As such, there is a possibility of misclassification bias

due to the short imaging follow-up time (median 4 months, range 1-178 months) used as a

benchmark for classifying patients into the improved or persistent TR cohort; patients who did

not show TR improvement at the time of their follow-up echocardiogram may have had

improvement afterwards, underestimating the impact of isolated ASD closure on TR resolution.

Another type of bias, known as immortal time bias, is also introduced in the long-term outcome

analyses between patients with improved and persistent TR. The time from index procedure (i.e.,

start of follow-up period) to the follow-up echocardiogram is considered immortal time since it is

assumed that the patient is free of adverse events during this time. A patient classified as a

“improved TR” patient may have had an adverse event before truly improving and thus,

underestimating the true benefits of TR improvement on long-term outcomes. This could have

been ameliorated by changing the start of the follow-up period to the date of the post-procedural

84

echocardiogram. However, the date that follow-up echocardiograms were taken was not linked to

the ICES-derived database.

The large proportion of unavailable data in both clinical and ICES-linked databases prevented us

from using some important baseline variables, such as pulmonary hypertension and tricuspid

valve measurements, in our multivariable analysis of persistent TR. Echocardiographic data

extracted from original reports was limited to basic measurements of RV morphology and

function, and the number of echocardiograms available for reassessment was low. Parameters

measuring pre-procedural remodeling of the RV and tricuspid apparatus may have strengthened

the accuracy of predicting patients at risk for persistent TR after device closure. Furthermore, the

comorbidity burden was not well-documented in patient charts at UHN, which led to a

significant underestimation of the prevalence of heart failure, coronary artery disease, and

hypertension, when compared to data retrieved using the Ontario health registries (Appendix 4).

This suggests that the clinical variables extracted from patient records at UHN that were not

unavailable at ICES may be underreported (e.g., pulmonary hypertension).

Our adjusted survival analyses were limited to comparing outcomes based on patients’ baseline

TR grade. Due to the relatively small sample of patients with pre-procedural moderate to severe

TR (n=119) derived from the ICES-linked database, we did not have the statistical power to

adjust and compare overall and cardiovascular mortality between patients with improved or

persistent TR after ASD closure. Elucidating an independent association between post-

procedural TR severity and cardiovascular mortality would help explain why pre-procedural TR

severity had no statistically significant effect on adjusted survival outcomes (adjusted HR= 1.49,

95% CI 0.70-3.15).

As we begin to recognize functional TR as an important outcome measure in the management of

ACHD patients, the quantitation of TR should be as accurate as possible. Furthermore, imaging

studies should be stored indefinitely as they provide a wealth of information in improving patient

care and outcomes. A prospective validation study of our predictive model for persistent TR, and

a comprehensive analysis of clinical and imaging data (e.g., 3D TEE/CMR) at baseline and 2-, 6-

, and 12-month follow-up would address the limitations of the current study.

85

7.8 Future directions This study was the largest and longest follow-up study to-date compared to published literature.

Primary and secondary outcomes were retrieved using relatively accurate public health data in

Ontario. From our study, we definitively showed that patients with pre-procedural moderate to

severe TR were more likely to experience a major adverse event (e.g., hospitalization/new onset

for CHF and AF) and die from a cardiovascular cause after isolated ASD closure. One can safely

assume that those with persistent moderate to severe TR also have a higher risk of major adverse

outcomes, including CV mortality.

Our findings from the multivariable logistic regression analysis for the baseline predictors of

persistent TR would allow us to develop a weighted risk score model. This can then be validated

with an external cohort of patients with ASD and concomitant moderate to severe TR undergoing

transcatheter ASD closure. Once consolidated, the model would benefit clinicians in identifying

patients at risk for persistent TR and manage them more aggressively to optimize long-term

outcomes (G. D. Webb & Opotowsky, 2017).

The “true” proportion of patients that experiences TR improvement and the baseline

determinants of TR persistence have yet to be verified. The course of TR and RV remodeling

post-ASD closure should be studied to gain a better understanding of the extent of post-closure

cardiac remodeling and determine whether these patients need closer monitoring after ASD

closure. A prospective single-arm echocardiographic with validated CMR study and a quality of

life survey administered at baseline, and 2-, 6-, 12-, and 24-month post-ASD device closure

would address questions that were unaddressed by previous studies.

Another area of interest is that of the CE-marked and commercially available Edwards

Cardioband system that reduces tricuspid annular size and TR severity (Figure 8A). A

randomized control trial that assigns ASD patients with secondary moderate to severe TR to

either the concomitant percutaneous TV annuloplasty treatment group or isolated percutaneous

ASD closure control group can assist in defining recommendations for managing adults with

ASD and TR. This is applicable in other areas of ACHD or acquired heart disease where RV

dilatation and significant functional TR are observed (Roberts et al., 2011).

86

7.9 Conclusions This study is the longest and largest follow-up study that provides accurate data on long-term

outcomes and survival of patients with significant functional TR undergoing transcatheter

closure of atrial septal defect. TR significantly improved in both pre-procedural mild/no TR and

moderate to severe TR cohorts – even though a substantial proportion of the latter cohort

continued to have moderate to severe TR after device closure, at intermediate follow-up.

Persistent TR is best predicted by the combination of age, RVSP, and severe TR at baseline. No

significant difference in cardiovascular mortality has been observed between pre-procedural

mild/no TR and moderate to severe TR cohorts, although the composite of hospitalization for

heart failure or atrial fibrillation, and the new onset of such events, were significantly higher in

patients with baseline moderate to severe TR. Although we concluded that there is no significant

difference cardiovascular mortality between the cohorts, it may be beneficial for patients with

moderate to severe TR to be managed by an ACHD specialist throughout their lives for

symptomatic relief and optimization of quality of life.

87

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Appendices Appendix 1. Coding definition of clinical variables used for baseline and long-term follow-up analyses

Variable ICD9 ICD10 CCI CCP OHIP billing Hypertension

ICES-derived cohorts Diabetes Chronic obstructive pulmonary disease Coronary artery disease 410-414 I20-I25 1IJ50, 1IJ57, 1IJ76 481, 4802, 4803,

4809 410, 412, 413, Z434, G298, R742, R743

Death CV-related death (includes cerebrovascular)

390–434, 436–448 I00-I79

Non-CV death 001-389, 460-676, 680-999, E800-E999, V01-V82

A00-D48, D50-D89, E00-E90, F00-H95, J00-K93, L00-P96, Q00-T98, V01-Y98, Z00-Z99, U00-U99

Stroke Transient ischemic attack (TIA) 435

G450, G451, G452, G453, G458, G459, H34.0

All stroke (excludes TIA) 430, 431, 434, 436, 362.3

I60, I61, I63 (excluding I63.6), I64, H34.1

Acute myocardial infarction 410 , 411, 413

I20 (Subcode R94.30, Subcode R94.31), I21, I22

Heart failure 428, 428(1-9) I50 428 Atrial fibrillation/flutter 42731, 42732 I48 427, Z437 Pacemaker implantation 1HB53, 1HZ53, 1HD54,

1HD53 49.7, 49.71, 49.72, 49.73, R752

105

49.74, 49.84, 49.83

Any open heart surgery CABG 1IJ76 48.1 Tricuspid valve surgery

1HS80 (excluding 1HS80GPBD, 1HS80GPFE), 1HS90

47.26, 47.27

Mitral valve surgery

1HU80 (excluding 1HU80GPBD, 1HU80GPBP, 1HU80GPFF, 1HU80GPFE), 1HU90

47.22, 47.23

Aortic valve surgery

1HV80 (excluding 1HV80GPBD, 1HV80GPBP, 1HV80GPFE), 1HV90

47.24, 47.25

Pulmonary valve surgery

1HT80 (excluding 1HT80GPBD, 1HT80GPBP, 1HT80GPFE), 1HT90

47.28, 47.29

Heart transplant 1HZ85, 1HY85 45.6, 49.5 Open ASD surgery

1HN80 (excluding 1HN80GPGX and 1HN80GPFL)

47.52, 47.61

Closure of fistula, structures adjacent to valves 1HX86

Repair of atrium 1HM78LA, 1HM80LA 47.6 Other open surgeries involving atrium 1HM57LA, 1HN71LA,

1HN87LA

Repair of ventricle 1HP78LA, 1HP80LA Other open surgeries involving ventricle 1HP82,1HP83, 1HP87,

1HR71LA, 1HR80LA 47.34

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Repair, structures adjacent to valves 1HX78, 1HX78,

1HX80,1HX83 47.39, 47.35

Repair, construction of IVS 1HR80, 1HR84, 1HR87 47.7, 47.9 Division, structures adjacent to valves 1HX71 49.1, 49.12, 49.2

Removal of foreign body, NEC 1HZ56LA

Partial excision, structures adjacent to valves without tissue

1HX87

Implantation/removal of internal device 1HP53, 1HP55 Repair by decreasing size, annulus NEC

1HW78LA, 1HW79LAXXA, 1HW79LAXXL, 1HW79LAXXN

Destruction/division of cardiac conduction system

1HH59LAAD, 1HH59LAAW, 1HH59LAGX, 1HH71LA, 1HH71PN

Surgeries on right heart structures 1HJ82 Heart NEC (including implantation and removal of device)

1HZ87, 1HZ57LA, 1HZ53LAFR, 1HZ53LAFS, 1HZ53LAKP, 1HZ53LANK, 1HZ53LANL, 1HZ53LANM, 1HZ53LANN, 1HZ53QANK, 1HZ53QANL, 1HZ53QANM, 1HZ53SYFR,

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1HZ53SYFS, 1HZ55LAFS, 1HZ55LAKP, 1HZ55LANK, 1HZ55LANL, 1HZ55LANM, 1HZ56LA, 1HZ57LA, 1HZ70LA, 1HZ80LA, 1HZ80LAXXA, 1HZ80LAXXK, 1HZ80LAXXL, 1HZ80LAXXN, 1HZ80LAXXQ, 1HZ80WKAG, 1HZ87LA, 1HZ87LAXXA, 1HZ87LAXXL, 1HZ87LAXXN, 1HZ87LAXXQ

Construction/reconstruction, aorta with pulmonary artery with IVS 1LA84 47.8 Construction/reconstruction, IVS with IAS and heart valves 1LC84

Percutaneous interventions ASD re-intervention 1HN80GPGX and

1HN80GPFL Tricuspid valve intervention 1HS80GPBD,

1HS80GPFE

ICD, International Classification of Diseases; CCI, Canadian Classification of Interventions; CCP, Canadian Classification of Diagnostic, Therapeutic and Surgical Procedures; OHIP, Ontario Health Insurance Plan; ICES, Institute of Clinical Evaluative Sciences; CABG, coronary artery bypass graft; IVS, interventricular septum; ASD, atrial septal defect; IAS, interatrial septum; NEC, not elsewhere classified.

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Appendix 2. Baseline patient characteristics

n=629 Baseline no TR n=186

Baseline mild TR

n=443 p-value

Age (years) 45 ± 15 43 ± 14 46 ± 16 0.024 Female 425 (68) 118 (63) 307 (69) 0.162

Height (cm) 167 ± 9 169 ± 10 166 ± 9 <0.001 Weight (kg) 74 ± 17 74 ± 19 73 ± 17 0.551

BMI (m/kg2) 27 ± 6 26 ± 6 27 ± 6 0.190

BSA (m2) 2± 0 1.8±0.2 1.8±0.2 0.159

Atrial fibrillation/flutter 31 (5) 8 (4) 23 (5) 0.840

CAD 19 (3) 2 (1) 17 (4) 0.075

Stroke/TIA 68 (11) 22 (12) 46 (10) 0.577

Hypertension 115 (18) 21 (11) 94 (21) 0.003 Diabetes 42 (7) 11 (6) 31 (7) 0.728

Hyperlipidemia 116 (18) 34 (18) 82 (19) >0.999

Data are presented as mean ± SD or frequencies (%).

BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; TIA, transient ischemic

Appendix 3. Study population derived from clinical registry and ICES-linked database TGH-derived sample

n=804 ICES-derived sample n=949

Age (years) 48 ± 16 48 ± 16

Female 565 (70) 656 (69)

Height (cm) 165.8±9.1 166.2 ± 9.9

Weight (kg) 72.8±17.2 72.9 ± 17.1

BMI (m/kg2) 26.4±5.7 26.4 ± 5.5

BSA (m2) 1.8±0.2 1.80 ± 0.23

Data are presented as mean ± SD or frequencies (%).

BMI, body mass index; BSA, body surface area.

Appendix 4. Comparison of baseline variables using definitions from clinical registry and ICES-linked

database

ICES data n=949

TGH data

n=949 p-value

Atrial fibrillation/flutter 119 (13) 115 (12) 0.834

CAD 197 (21) 48 (5) <0.001

Heart failure 85 (9) 25 (3) <0.001

Hypertension 305 (32) 206 (22) <0.001 Diabetes 94 (10) 73 (8) 0.105

Data are presented as frequencies (%).

CAD, coronary artery disease

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Copyright Acknowledgments Figure 1: Reprinted with permission from “Atrial Septal Defect” by Mayo Clinic.

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Figure 4: Reprinted with permission from “Atrial Septal Defect: Management Approach in

Children” by Nagre, S., 2016. Annals of Woman and Child Health, 2, L-3. 2016 by the Pacific

Group of e-Journals.

Figure 8A: Reprinted with permission from “The Cardioband transcatheter annular reduction

system” by Miller et al., 2018. Annals of Cardiothoracic Surgery, 7, 743. 2018 by AME

Publishing Company.

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Figure 8B: Reprinted with permission from “Early Feasibility Study of a Transcatheter Tricuspid

Valve Annuloplasty” by Hahn et al., 2017. JACC, 69, 1800. 2017 by the American College of

Cardiology Foundation.

Figure 9: Reprinted with permission from “First-in-Man Experience of a Novel Transcatheter

Repair System for Treating Severe Tricuspid Regurgitation” by Campelo-Parada et al., 2015.

JACC, 66, 2477. 2015 by the American College of Cardiology Foundation.

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Table 5: Adapted with permission from “State-of-the-Art Review of Echocardiographic Imaging

in the Evaluation and Treatment of Functional Tricuspid Regurgitation” by Hahn et al., 2016.

Circ Cardiovasc Imaging, 9, 7. 2016 by the American Heart Association, Inc.

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