Echocardiography in repaired Tetralogy of Fallot: Delineating the mechanisms of

RV dysfunction

Mark K. Friedberg, MD

The Labatt Family Heart Center, Hospital for Sick Children Toronto, Ontario, Canada

NO DISCLOSURES

Clinical problems

• Right ventricular dilatation and failure

• Left ventricular dysfunction

• Exercise intolerance

• Arrhythmia

• Sudden death

Mechanisms of ventricular dysfunction in TOF • Right Ventricular Hypertrophy

• Myocardial and contractile abnormalities: Fibrosis

• Large VSD patch

• Residual RVOTO, branch PS -> increased afterload

• PR, TR, residual shunts -> increased preload

• RBBB, prolonged QRS, electro-mechanical dyssynchrony -> pump inefficiency and contractile abnormalities

Pathophysiology of dysfunction in TOF

Geva, Journal of Cardiovascular Magnetic Resonance. 2011;13(1):9

Pre-operative TOF

Post-op RV enlargement and dysfunction

RV tissue velocities are reduced after TOF repair

Vogel, Circulation 2001;103;1669-1673

Strain and strain rate after TOF repair

Weidemann, Am J Cardiol 2002;90:133–138

-40

-30

-20

-10

0

1

TOF

Control

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

1

TOF

Control

RV longitudinal peak strain and strain rate

RV lateral wall strain RV lateral wall strain rate

-23.2±5.1 vs. -28.5±8.5, p<0.001 -1.46 ± 0.68 vs. -2.1±0.8, p=<0.001

Friedberg, AHJ, 2012

•Reduced RV longitudinal peak systolic SR was

associated with:

•decreased exercise peak VO2 (PE 0.14 (0.07), p=0.04)

•decreased % predicted peak VO2 (PE 0.07 (0.03) p=0.04).

Association with exercise capacity

Friedberg, AHJ, 2012

Diastolic function in TOF

Friedberg, Eur Heart J Cardiovasc Imaging. 2012

Longitudinal diastolic strain rate

Friedberg, Eur Heart J Cardiovasc Imaging. 2012

Strain studies 2015-2016 in rTOF Author Year Objective/Hypothesis Study design

Patients/ Groups

n Age (mean ± SD,

years) Strain Modality Strain walls Main results Comments/conclusion

Mai

nly

RV

ass

ess

me

nt

Chowdhury93

2015 Evaluate correlation between STE measures of RV function and changes in exercise capacity after PVR.

Retrospective, longitudinal. Multicenter Before and after transcath. PVR

rToF RV to PA Other

12 7 5

Youth and adults 32.3 ± 17.0

2D-STE LS LSR

RV-FW RV-SW RV-GLS

Improvements in RV LS (-16.9 ± 3.5% vs -19.7 ± 4.3%) and strain rate (-0.9 ± 0.4 vs.-1.2 ± 0.4 s-1, all p <0.01) after PVR.

STE predicted and not FAC or TAPSE improved outcomes in patients after PVR.

Almeida-Morais90

2016 Assess how RV-LS correlates with other parameters of RV function & CMR RV-EF .

Retrospective, cross-sectional

rToF

42 Adults 32 ± 8

2D-STE LS LSR

RV-GLS

RV-GLS=16.2 ± 3.7%, with linear correlation with TAPSE, (r=−0.40) and RV-EF (r=−0.45), all p<0.05

RV GLS correlated with echo parameters of RV function and CMR RV-EF .

Toro K91 2016 Evaluate the utility of strain for the assessment of RV systolic function.

Retrospective, cross sectional

rToF RV-EF≥45% RV-EF<45%

57 39 18

Children 12.6 ± 3.6 13.8 ± 3.7

2D-STE LS

RV-GLS

RV-GLS correlates with CMR RV-EF (r= −0.76) . RV GLS cutoff value of −18% had 78% sensitivity and 77% specificity for identifying RV-EF <45% (AUC 0.87).

RV GLS is useful to assess RV systolic function in rToF.

Gursu95 2016 RV function and volumes by STE and CMR, before and after PVR.

Retrospective, longitudinal, Before & after PVR

rToF 15 Children and youth 14.5 ± 4.5

2D-STE LS LSR

RV-FW RV-SW (mid)

Lower RV-LS and LSR before PVR was similar between asymptomatic and symptomatic patients. Significant improvement 6-months after PVR.

STE is useful to assess RV function in rToF before and after PVR.

Joynt103

2016 Characterize changes in RV size and function in patients with PS, compared to those with rToF with similar PR.

Retrospective, cross sectional 2:1 Matching by age and PR%

PR patients PS after valvotomy rToF

71 24

47

Adults 40.7 ± 13.3 39.1 ± 12.5

CMR FT LS CS

RV-FW RV-CS RVOT

PS patients had preserved RV-EF and better RV-CS, LS and RVOT strain compared with rToF. Greater differences in RV-CS than LS. Late gadolinium enhancement in the RVOT was more frequent in patients with TOF (70.2% vs 45.8%).

Differential effects on RV systolic function between PS and rToF, largely related to differences in the RVOT.

Anwar102

2017 Characterize regional RV systolic function by comparing patients with rTOF to patients with valvar PS.

Retrospective, cross sectional Matched by PR% and duration

PR patients PS after balloon dilation rToF

26 13

13

Children 15.2 ± 3.6 14.5 ± 2.5

CMR FT LS

RV-GLS RVOT

Normal and similar RV-EF between rToF and PS. RV-GLS was worse in both groups compared to normal but comparable to each other. RVOT LS was worse than RV GLS in rToF, but not in PS.

LS is diminished in PS and rToF subjects with preserved RV EF. Transannular patch could explain worse RVOT strain in rToF.

LV

asse

ssm

en

t

Yamada122

2016 Assess the location and time course of LV dysfunction in patients with rToF using layer-specific strain analysis.

Prospective, longitudinal

rToF Healthy controls 1=4-10 years 2=11-20 years 3=21-43 years

66 113

Adults Children (4-43 years)

2D-STE LS CS

LV-GLS Endo Mid Epi

Basal and papillary endocardial CS values were decreased in rToF 1 compared with controls. Except for papillary epicardial CS, basal/papillary CS and LS of all 3 layers were decreased in rToF compared with controls. Except for papillary epicardial CS, all other values were decreased in rToF compared with controls.

Potential sub-endocardial damage in the LV basal and papillary levels in young patients with rTOF, extending from endocardium to epicardium and from base to apex.

Biv

entr

icu

lar a

sses

sme

nt

Menting120

2015 Assess LV and RV global and regional function by STE strain and its relation with conventional parameters of RV function in rToF.

Prospective, cross-sectional

rToF Healthy controls

94 85

Adults 32.8 ± 9.5

2D-STE LS LSR

RV-FW RV-SW RV-GLS LV-GLS

Lower RV-FW strain than controls, especially in the apical segment (-15.9 ± 7.4 vs.-28.2+7.7%, P<0.001), and lower RV-LSR. LV-GLS was also lower, mainly due to low septal strain.

RV-FW strain and SR are decreased in rToF adults, especially in apical segments suggesting apical function Is most affected rTOF RVs

Li88

2015 Evaluate RV and LV function in asymptomatic rToF patients and identify parameters of early dysfunction.

Retrospective, cross sectional Matched by age and gender

rToF Healthy controls

56 35

Children 5.4 ± 4.1 5.7 ± 4.9

2D-STE LS LSR CS RS

RV-FW LV-GLS LV-CS LV-RS

Regional and global RV LS and SR were impaired in children with rTOF. LV CS, RS and SR were reduced in patients with rToF, but not LV-GLS. RV GLS and SR were related to RV-EF (r=-0.64, r2=-0.60) and PR (r= -0.48; r2 = -0.49).

STE can identify early RV and LV systolic dysfunction in rToF patients with preserved RV-EF.

Latus97

2015 Assess RV & LV function and interventricular interactions in rTOF patients with & without RVOTO.

Retrospective, cross sectional Matched by age and type of surgery

rToF RVOTO No RVOTO

54 27 27

Youth and adults 16.2 ± 6.9

CMR-FT LS CS RS

RV-LS RV-CS RV-RS LV-LS LV-CS LV-RS

RVOTO group showed higher RV-CS and RV-RS values, whereas RV-LS did not differ between the groups. Interventricular dyssynchrony was higher in the group without RVOTO while LV-LS and LV intraventricular synchrony were impaired in the RVOTO group.

Residual RVOTO is associated with better RV strain and less interventricular dyssynchrony and may therefore reduce RV remodeling.

Yim96

2016 Assess the impact of surgical PVR on ventricular mechanics in pediatric rTOF patients.

Retrospective, longitudinal Before and after PVR

rToF 50 Children 12.6 ± 3.4

2D-STE LS CS

RV-FW LV-GLS LV-CS

LV and RV LS were reduced early post-operatively, followed by recovery of biventricular systolic strain by mid-term follow-up, even increasing in individual segments above pre-operative values. Patients with larger pre-operative RV volumes had lower RV strain post-operatively.

An increase in global and regional RV strain beyond pre-operative values suggests RV reverse remodeling and adaptation in children after PVR.

Orwat94

2016 Assess if CMR myocardial deformation relates to symptoms and provides prognostic information

Prospective, multicenter, longitudinal

rToF No CV events CV events

372 352 20

Adults 16 IQR 12,20 18 IQR 14,25

CMR-FT LS CS

RV-LS RV-CS LV-LS LV-CS

LV-CS and RV-LS were independent predictors of outcome . LV LS, RS, CS and RV LS were related to the risk of death and near-missed death.

CMR myocardial deformation parameters relate to symptoms and clinical deterioration in patients with ToF and predict adverse outcome independent of established risk markers.

Kawakubo113

2016 Evaluate RV/LV function and to investigate the agreement between semi-automatic and manual measurements.

Retrospective, cross sectional

Ischemic Non-Ischemic rToF

13 18 21

Adults 47 ± 19

CMR-FT LS

RV-FW LV-FW

The optimal LS cut-off for diagnoses the LV and RV dysfunction were: LV-FW =-7.8%; sensitivity, 83%; specificity, 91%, RV-FW =-15.7%; sensitivity, 92%; specificity, 68%). Excellent correlations between manual and semi-automatic measurements for LV and RV-FW.

The semi-automatic LS analysis can evaluate LV and RV dysfunction.

Berganza*133

2016 Evaluate the correlation of CMR-FT ventricular strain to conventional CMR ventricular function parameters

Retrospective, cross sectional

rToF Healthy controls

17 17

Children 12.4 ± 6.3 14.1 ± 4.5

CMR-FT 2D 3D LS CS RS

RV-LS RV-CS RV-RS LV-LS LV-CS LV-RS

3D LV-CS was reduced in rToF patients (-10.1 ± 3 vs. -14.71 ± 1.9%, p< 0.01). Strong correlation between 3D LV-CS 3D and indexed RV end diastolic volume, as well as a strong correlation between 2D LV-LS and RV-EF.

3D CS can detect early myocardial dysfunction before reduction in EF.

Mese129

2016 Investigate echo STE GLS and GCS at rest and during exercise in rToF

Prospective, cross sectional

rToF Healthy controls

20 20

Children 13.5 ± 0.3 13.9 ± 0.3

2D-STE LS CS

RV-GLS LV-GLS LV-CS

RV STE during exercise had low feasibility. A progressive reduction in LV-GLS occurred in rToF during exercise, while LV-CS did not change significantly.

Myocardial deformation analysis during exercise can enhance detection of sub-clinical ventricular dysfunction in rToF.

Larios an

d Fried

be

rg, Cu

rr Op

in C

ardio

l. 20

17

Why is RV strain reduced after TOF repair?

8y girl doing well after TOF repair

PR is associated with reduced regional contractility

Frigiola, Circulation 2004;110;II-153-II-157 Eyskens, EJE, 2010, 11, 341

Short-term changes in RV deformation following PVR

n Pre PVR

(mean ± SD)

Post PVR

(mean ± SD)

p- value

Strain IVS % 10 -7.04 ± 9.1 -14.10 ±6.4 0.02

Strain RV % 10 -14.56 ± 13.9 -23.53 ±6.3 0.04

Strain Rate IVS (s-1) 10 -0.29± 1.1 -1.06 ±0.5 0.049

Strain Rate RV (s-1) 10 -1.53± 1.1 -2.07 ±0.7 0.13

Septal Strain% Pre-Post PPVI

-30.00

-25.00

-20.00

-15.00

-10.00

-5.00

0.00

5.00

10.00

15.00

20.00

pre post

Sep

tal

Str

ain

%

Series1

Series2

Series3

Series4

Series5

Series6

Series7

Series8

Series9

Series10

Moiduddin, Am J Cardiol. 2009;104:862

N=50 Early: 2.230.61 months post-PVR Mid: 14.93.8 months post-PVR

Regional RV strain mid-term after surgical PVR

Yim, Int J CV Imag 2017 ;33:711-720

Strain and SR after PVR in TOF

Knirsch, Pediatr Cardiol; 2008 29:718–725

PVR for RV volume loading

• Decreased RVEDVi and RVESVi

• Subjective improvement

• Unchanged RV EF • • Unchanged exercise

capacity

Harrild, Circulation, 2009

Function after PVR in TOF: Relief of volume load

Coats, European Heart Journal;2007, 28, 1886

Function after PVR in TOF: Relief of pressure load

Coats, Circulation. 2006;113:2037-2044

Its not volume loading alone: TOF vs. ASD

Dragulescu, IJC, 2012

RV strain

RV strain rate

There appear to be other factors driving RV

dysfunction in rTOF

Regional fibrosis in TOF

Babu-Narayan, Circulation. 2006;113:405-413

RV regional wall motion abnormalities in TOF

Vogel, Circ 2001;103;1669-1673

Normal TOF

Reduced deformation is associated with prolonged QRS

Weidemann, Am J Cardiol 2002;90:133–138

Am Heart J 2013;165:551-7

N=48

-100

0

100

200

300

400

TOF

Control

146.0±159 vs. 71.0±92 ms, p=0.008

RV mechanical delay

Friedberg, Am Heart J 2013;165:551-7

Association between RV strain, delay &exercise

Increased RV delay was associated with:

Decreased RV longitudinal strain (PE 6.31 (2.30), p=0.007)

Decreased RV strain rate (PE 11.32 (3.84), p=0.004).

Increased interventricular (RV-LV) delay was associated with:

Increased QRS duration (EST 0.129, SE 0.058, p=0.03)

Reduced RV ejection fraction (EST -2.95, SE 1.275, p=0.02).

Reduced RV longitudinal peak systolic SR was associated with:

Decreased exercise peak VO2 (PE 0.14 [0.07], P = .04)

Percentage predicted peak VO2 (PE 0.07 [0.03], P = .04).

Friedberg, Am Heart J 2013;165:551-7

D’Andrea et al. Eur J Echo March 2004

Interventricular Delay in TOF

Inverse relation between max workload during exercise

and InterV-delay (r= -0.52; p=0:01)

Interventricular Delay in TOF

Yim, In progress

Higher PV-Ao PEP delay negatively correlated with: • %VO2max (r=-0.25, p=0.03) • %VO2max at AT (r=-0.33,

p=0.008).

LV dysfunction in TOF

J Am Soc Echocardiogr 2012;25:494-503

LV circumferential and radial strain are significantly reduced in children and adolescents

after TOF repair and are associated with pulmonary regurgitation and RV dilatation.

Exercise induced dispersion in children after

tetralogy of Fallot repair

Roche, Heart, 2010

ISSN: 1524-4539 Copyright © 2009 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online

72514Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX

DOI: 10.1161/CIRCULATIONAHA.108.816546 2009;119;1370-1377; originally published online Mar 2, 2009; Circulation

Tal Geva Rachel M. Wald, Idith Haber, Ron Wald, Anne Marie Valente, Andrew J. Powell and

Tetralogy of FallotRight Ventricular Function and Exercise Capacity in Patients With Repaired

Effects of Regional Dysfunction and Late Gadolinium Enhancement on Global

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Patients with subnormal exercise capacity had more global and regional RV dysfunction. Subnormal exercise capacity was more closely associated with RVOT EF than global RV EF.

RV electro-mechanical dyssynchrony in TOF

Wei Hui, Cameron Slorach, Andreea Dragulescu, Luc Mertens, Bart Bijnens and Mark K. FriedbergInefficiency in Children After Repair of Tetralogy of Fallot

Mechanisms of Right Ventricular Electromechanical Dyssynchrony and Mechanical

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TX 75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas,Circulation: Cardiovascular Imaging

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Electro-mechanical dyssynchrony in TOF

Right-sided septal flash in a TOF patient Left –sided septal flash in a TOF patient

Pulmonary RV Resynchronization

Janousek, Circ Cardiovasc Imaging. 2017 Sep;10(9). pii: e006424

Am J Cardiol 2015;115:676

pulmonary regurgitation -circles

pulmonary stenosis squares

mixed triangles

RVEDV correlated with pre-

procedure QRS duration (r 0.34, p

<0.002) but there was no correlation

after PPVI.

Am J Cardiol 2011;107:309–314

Is CRT indicated? • 16 year old; TOF/PA

• PV replacement (25mm mosaic valve, age 8y)

• Poor RV function (MRI RVEF 25%, RVEDVi 125 ml/m2, LVEF 49% LVEDVi 79 ml/m2)

• No RVOTO/PA stenoses,

• Low RV pressure : RVSp ~41 mmHg (sBP 113 mmHg)

• Unable to obtain VO2; workload 97 W (60%

predicted).

• ECG: RBBB, LAD, QRS ~ 170ms

Is CRT indicated?

Summary Regional RV dysfunction in TOF is important and

correlates with reduced global function and exercise

intolerance

Regional wall motion abnormalities may correlate with

propensity for arrhythmia

RV electromechanical dyssynchrony is associated with

RV systolic and diastolic dysfunction and may be a

pathophysiological factor in RV regional and global

dysfunction, exercise intolerance and heart failure

beyond PR alone

The value of RV dyssynchrony as a measure of

dysfunction and as a predictor of outcomes is unknown

Thank you