3/12/2019 Conflict of Interest Disclosure Enhanced Assessment of - - PDF document

SLIDE 1

3/12/2019 1

Philip T. Levy MD

Assistant Professor of Pediatrics Harvard Medical School Division of Newborn Medicine Boston Children’s Hospital March 7th, 2019 12th International Conference Neonatal & Childhood Pulmonary Vascular Disease

Enhanced Assessment of Right Ventricular Function in Preterm Infants with Chronic Pulmonary Hypertension

Conflict of Interest Disclosure

• I have no financial relationships with a

commercial entity producing healthcare- related products and/or services.

Philip T. Levy

Learning objectives

I. Explore the (patho) physiologic relationship between the RV and its load in chronic PH (e.g. morphology, afterload, contractility) II. Identify emerging non-invasive quantitative indices

• f

RV mechanics in preterm infants with chronic PH. III. Review the neonatal literature that utilizes these measures to screen, diagnosis, & test the efficacy of management strategies. IV. Future initiatives (Composite score, coupling, 3D echocardiography) 20 grams

Adult Female Heart Adult Male Heart

250 grams 290 grams

Premature Heart

4 -15 grams

Term Heart

What are we actually looking at…

SLIDE 2

3/12/2019 2

The value of the right heart

“It is not the size of the man, but the size of his right heart that matters…” -

• Evander Holyfield (1996)

“Great beauty, great strength, and great riches are really and truly of no great use; a RIGHT HEART exceeds all…”

• Benjamin Franklin (1776)

Courtesy of McNamara and El-Khuffash

Cellular Metabolism

Target organ Hgb Work Sats

SVR BP

Cardiac output

CO = SV x HR

Blood O2 delivery Blood O2 consumption

RV performance

CO = SV x HR Pulmonary vasculature (Target organ flow)

Determinants of function Preload

amount of blood present in the ventricle at end diastole.

Afterload

the resistance against which the ventricle muscle must contract

Contractility

the intrinsic ability of the myocardium to contract

Heart rate

Force-frequency relationship

Stroke volume

Length-tension relationship Force-velocity relationship

Cellular homeostasis Cellular homeostasis

Right heart/lung interactions

Morphology Pulmonic Lymphatics Systemic Blood

(transport vehicle) Circulatory System

Right Left

Arteries, veins, capillaries

Heart

(pump)

Cardiovascular Vasculature

(transport network)

Pulmonic Right

 Embryology  Morphology  Genetic  Performance

C

• u

p l e d

Coupling = Δ Energy = Work

Right Ventricle

RV-PA Coupling RV Contractility RV Afterload =

RV-PA axis formation

Coupling mechanisms

RV Afterload

(PVR, PAP, compliance)

RV Performance (Contractility)

Adapted from. J Am Coll Cardiol 2017;69:236–43

Stage 1 Stage 2 Stage 3 RV Morphology

(Volume/thickness)

RV-PA axis

RV Contractility RV Afterload

Coupling Maintained Uncoupling

Hemodynamic profile of the right ventricle and its load in chronic PH

Uncoupling

RV failure

Coupled

SLIDE 3

3/12/2019 3

RV dysfunction

Low RV preload High RV afterload Impaired RV contractility

Reduce RV afterload Augment RV function Optimize RV preload

Jain et al. Seminars in Fetal & Neonatal Medicine 2015

RV performance and PH

Right heart/lung interactions

1. Opposition by the pulmonary valve (RV outflow tract) 2. Load imposed by the pulmonary vasculature tree 3. Blood (pressure and viscosity)

Right ventricle Pulmonary valve

RV afterload

External factors that oppose contraction

a. Resistance (R)

• Proximal artery and distal arteries/arterioles
• PVR = (mPAP – PCWP) / CO

b. Compliance (C)

• Storage capacity of vasculature (elasticity)
• Entire system (small arteries > large)
• PAC = Stroke volume / pulse pressure

c. Characteristic impedance (Z)

• Proximal artery
• Z = blood mass / compliance

Static (75%)

(% total afterload)

Pulsatile (25 %)

1%

Am J Physiol. 1999;277:H725-31

RV afterload

3 element Windkessel model

2 4 6 8 10 5 10 15

Pulmonary vascular resistance (woods units - mmHg - S/mL) P u lm

• n

a ry a rte ria l c a p a c ita n ce

(m L / m m H g )

Eur Heart J 2008;29:1688 –95.

RV afterload

Constant (τ) = Resistance x Compliance

Early PVD

• Mild increase in PVR/PAP
• Normal RV performance
• Large decrease in

compliance

• Clinically silent

 Pulsatile

 Static  Pulsatile

 Static

Established PH

• Significantly increased PVR/PAP
• Abnormal RV performance
• Compliance depleted, small

decrease

• Symptomatic

SLIDE 4

3/12/2019 4

2 4 6 8 10 5 10 15

Pulmonary vascular resistance (woods units - mmHg - S/mL) P u lm

• n

a ry a rte ria l c a p a c ita n ce

(m L / m m H g )

N = 125 children

(n=36 with PH, mPAP > 20, PVRi > 3)

τ = R x C

Levy & Patel et al. J Am Soc Echocardiogr 2016;29:1056-65.

RV afterload

Constant (τ) = Resistance x Compliance

Early PVD Established PH

Layer 3

Circumferential

Layer 2

Longitudinal

Superficial

• blique

(subendocardium)

Layer 1 B

Superficial

• blique

(subepicardium)

Layer 1 A

Right Left

Courtesy of N. Silverman, Stanford

RV contractility

Myocardial muscle fiber orientation

Left Ventricle Superficial oblique (25%) Middle longitudinal (20%) Deep circumferential (60%) circumferential

Right Ventricle

Superficial oblique (20%) Deep longitudinal (80%) longitudinal Fiber orientation

(% of wall thickness)

Layer 1 Layer 2 Layer 3 Dominant layer

Courtesy of Professor RH Anderson

RV contractility

Myocardial muscle fiber orientation

• 1. Contraction of longitudinal

fibers pull the tricuspid valve towards apex.

• 2. Inward movement of the

RV free wall.

• 3. Traction of RV free wall

from connection to LV free wall at the Apex. RV

Apex Base

RV contractility

Peristaltic contraction patterns

Dominant pattern

SLIDE 5

3/12/2019 5

RV-PV Metabolism

Courtesy of McNamara and El-Khuffash

SVR

Blood O2 consumption

Pulmonary vasculature (Target organ flow) Hgb Work Sats

BP

Blood O2 delivery

RV performance

CO = SV x HR

Determinants of function Preload

amount of blood present in the ventricle at end diastole.

Afterload

the resistance against which the ventricle muscle must contract

Contractility

the intrinsic ability of the myocardium to contract

Heart rate

Force-frequency relationship

Stroke volume

Morphology Force-velocity relationship Length-tension relationship

• 1. Pressure-dependent
• TR velocity jet
• Septal wall motion
• RA / RV morphology
• LV eccentricity index
• Shunts / directions
• 2. PA acceleration time
• PAAT / RVET
• 1. IVC (?)
• 2. Volumes (?)
• 1. RV Areas
• Systolic
• Diastolic
• 4-ch / 3-ch
• 2. Dimensions
• RV inflow
• RV outflow
• 1. RV contractility
• dp/dt
• Strain rate
• 2. RV systolic function
• FAC / MPI / Strain
• TAPSE / Strain
• 3. RV diastolic function
• Tissue Doppler velocities
• Strain rate
• 1. Pressure-dependent
• TR velocity jet
• Septal wall motion
• RA / RV morphology
• LV eccentricity index
• Shunts / directions
• 2. PA acceleration time
• PAAT / RVET
• 1. RV contractility
• dp/dt
• Strain rate
• 2. RV systolic function
• FAC / MPI / Strain
• TAPSE / Strain
• 3. RV diastolic function
• Tissue Doppler velocities
• Strain rate
• 1. RV Areas
• Systolic
• Diastolic
• 4-ch / 3-ch
• 2. Dimensions
• RV inflow
• RV outflow

Echocardiographic evaluation of RV mechanics

Validation of quantitative measures

3- step approach

I. Reliability testing

• Feasibility
• Reproducibility (compare to gold standard)

II. Mechanistic approach

• Tell a story ? (react to changes in management)
• Maturational changes / Reference values

III. Therapeutic Models

• Efficacy a patient management strategies
• Make a clinical difference

Simultaneous cath & Echo Clinical and Preclinical studies Clinical disease modeling

PAAT = 120 msec RVET = 250 msec PAAT:RVET = 0.48

Normal

PAAT RVET

PAAT = 74 msec RVET = 280 msec PAAT:RVET = 0.26

PH

RVET PAAT

Afterload (PVR, PAP) Compliance

RV afterload

RV systolic time intervals

a. Resistance (R)

• Proximal artery and distal arteries/arterioles
• PVR = (mPAP – PCWP) / CO

b. Compliance (C)

• Storage capacity of vasculature (elasticity)
• Entire system (small arteries > large)
• PAC = Stroke volume / pulse pressure

c. Characteristic impedance (Z)

• Proximal artery
• Z = blood mass / compliance

Static (75%)

(% total afterload)

Pulsatile (25 %)

1%

Am J Physiol. 1999;277:H725-31

RV afterload : PA acceleration time

Constant (τ) = Resistance x Compliance

SLIDE 6

3/12/2019 6

RV afterload

Preterm infants with chronic PH

RV afterload

Preterm infants with chronic PH

For detection of chronic PH:

• PAAT < 47 msec
• PAAT:RVET < 0.28

At 32 weeks PMA resulted in a sensitivity of 89% and a specificity of 93% with a combined AUC of 0.9306 (CI 0.89-0.97)

Patel et al. JASE 2019 (In review)

40 60 80 100 120 40 60 80 100 120

Preterm, + cPH

N= 12

Term, Healthy

n=100

RV afterload PA acceleration time

Preterm, No cPH

n= 68

* P < 0.01 * P < 0.01

J Pediatr 2018; 197:48-56.e2

Clinical significance

Novel insights: PVD at 1 year corrected age

RV, right ventricle LV, left ventricle IVS, interventricular septum

24

www.tnecho.com (Images) Animations, Malcom and Evans

RV afterload

Eccentricity index

SLIDE 7

3/12/2019 7

Flattened Septum “Pancaked” Decreased LV function Flattened Septum “Pancaked” Decreased LV function

Normal strucutre Normal strucutre

25

www.tnecho.com (Images) Animations, Malcom and Evans

RV afterload

Eccentricity index

LV RV LV RV

D1 = 2.3 D2= 1.4 D1 = 2.0 D2= 2.0 26

RV afterload

Eccentricity index = D1 / D2

Normal EI = 2.0 / 2.0 = 1 cPH EI = 2.3 / 1.4 = 1.6

RV afterload

Eccentricity index

RV afterload

Association of eccentricity index > 1.3 with cPH

Abraham et al. Echocardiography 2016

SLIDE 8

3/12/2019 8

RV afterload

Association of eccentricity index > 1.3 with cPH

RV myocardial mechanics

How do we measure?

Change in cavity dimensions

• Fractional area of

change (FAC)

Examples:

Displacement and velocity of a single point

• Tricuspid annular

plane systolic excursion (TAPSE)

• Tissue Doppler

imaging (TDI)

Deformation imaging of a segment

• Deformation/strain

RV myocardial mechanics

3 approaches

Courtesy of Afif El- Khuffash

V

LV LA RA RV

V

LV LA RA RV

RV focused apical 4 – chamber view (inflow) FAC % = 100 x [RV EDA (cm2) – RV ESA (cm2)] RV EDA (cm2)

RV end- diastolic area (RV EDA) RV end- systolic area (RV ESA)

Fractional area of change (FAC)

Δ cavity dimension

FAC = 35% = 100 x [4.5(cm2) – 2.9 cm2)] 4.5 (cm2)

4.5 cm 2.9 cm

SLIDE 9

3/12/2019 9

Fractional area of change (FAC)

Δ cavity dimension

15 20 25 30 35 40 45

RV FAC (%)

1 DOL 3 DOL 32 weeks PMA 36 weeks PMA Reference cohort (No BPD/PH) cPH at 36 weeks

* * * P < 0.01

Fractional area of change (FAC)

Δ cavity dimension

Levy et al. J Am Soc Echocardiog 2015

RV Apex Base Base RV

Apex Base

• Contraction of the deep longitudinal

fibers pull the tricuspid valve from the base towards the apex during systole.

Tricuspid annular plane systolic excursion (TAPSE) Displacement of a single point

M-mode cursor

Tricuspid annular plane systolic excursion (TAPSE) Displacement of a single point

Δ of single point

SLIDE 10

3/12/2019 10

Ape x RV Ape x RV

Tricuspid annular plane systolic excursion (TAPSE) Displacement of a single point Tricuspid annular plane systolic excursion (TAPSE) Displacement of a single point

0.2 0.6 1 1.4 1.8

TAPSE (cm)

32 weeks PMA Reference: No BPD / No PH

Chronic PH

36 weeks PMA One year CA| 1st week

Tricuspid annular plane systolic excursion (TAPSE) Displacement of a single point

* * * * P < 0.01

Patel al. JACC CI 2016

Tissue Doppler imaging (TDI)

Velocity of muscle movement of a single point along the myocardial wall

Child Preterm

Breatnach et al. Neonatology 2016;110:248–260

SLIDE 11

3/12/2019 11

Tissue Doppler imaging (TDI)

Velocity of muscle movement of a single point along the myocardial wall

RV strain imaging Deformation of a segment of myocardial tissue

R V L V

R i g h t V L e f t V e

• Deformation measures strain:

defined as the change in length of the myocardium relative to its resting length (expressed as a %).

• Longitudinal strain is the

dominant deformation of the RV that provides the major stroke volume during systole.

RV deformation

Speckle tracking echocardiography RV

RV deformation

Speckle tracking echocardiography

Speckle Pattern Speckle Pattern RV

SLIDE 12

3/12/2019 12

RV deformation

Speckle tracking echocardiography

Original Length – L (t0)

Frame 1 Unique Signature Patterns

Speckle Pattern Speckle Pattern

Speckles are like freckles

RV

New Length – L (t1)

Frame 2 Unique Signature Patterns

RV Speckle Pattern Speckle Pattern

RV deformation

Speckle tracking echocardiography

New Length – L (t2)

Frame 3 Unique Signature Patterns

RV Speckle Pattern Speckle Pattern

RV deformation

Speckle tracking echocardiography

New Length – L (t3)

Frame 4 Unique Signature Patterns

Speckle Pattern Speckle Pattern

RV deformation

Speckle tracking echocardiography RV

SLIDE 13

3/12/2019 13

New Length – L (t4)

Frame 5 Unique Signature Patterns

Speckle Pattern Speckle Pattern

RV deformation

Speckle tracking echocardiography RV STRAIN

(t)  L(t)  L(t0) L(t0)

“Global” strain curve Peak global strain value

Diastole S T R A I N Time

RV deformation

Strain curves GLS = - 20.6

Systole Base Mid Apex Peak strain rate value (systole) S T R A I N R A T E Time

RV deformation

Strain rate curves

Peak strain rate value (late diastole) Peak strain rate value (early diastole)

Validation of deformation measures

Speckle tracking echocardiography

SLIDE 14

3/12/2019 14

• Klein. J. Am Soc Echocardiog 2016;29:A19-A21

Even a high schooler can learn strain…

RV strain imaging Deformation of a segment of myocardial tissue

• 30
• 25
• 20
• 15
• 10

RV Longitudinal Strain (%)

One year CA 36 weeks PMA 32 weeks PMA 1st week of age

* * *

RV strain imaging Deformation of a segment of myocardial tissue

Levy / El Khuffash et al. JASE 2017 Reference: No BPD / No PH

Chronic PH

* P < 0.001

RV deformation

Prostacyclin therapy in pediatric PH

Hopper et al. Pulmonary Circulation 2018

SLIDE 15

3/12/2019 15

Morphology

Complex tripartite structure

Netter FH, Atlas of Human Anatomy

Coarse trabeculae Apical trabecular component Inlet component

Outlet component

PV SVC IVC TV Thin RV free wall

RV inflow RV outflow

RV focused Apical 4- chamber

Parasternal short axis

RVOT Prox RVOT Distal

Parasternal long axis

RVOT Prox

LV RV LA

Ao

RA RV

Ao PA

Morphology

Dimensions – linear measurements

V

LV LA RA RV

V

LV LA RA RV

RV end- diastolic area (RV EDA) RV end- systolic area (RV ESA)

Morphology

Dimensions – areas

Morphology

Preterm infants with chronic PH

SLIDE 16

3/12/2019 16

Good RV Poor RV Good LV Poor LV

Function

Normal function LV Dysfunction RV Dysfunction e.g. cPH

Ventricular interdependence

Influence of LV function on RV performance

Breatnach et al. Arch Dis Child Fetal Neonatal Ed. 2017;102:F446-50

RV + LV Dysfunction

*Approximate values extrapolated from a variety of sources; actual ‘normal’ is slowly being established and varies by gestation, postnatal age and (in some cases) metabolic demand.

“Normal data”

Preterm infants with chronic PH

Measurement Normal Term Normal Preterm cPH

TAPSE (mm) 8 – 11 6 - 8 < 6 Fractional area change (%) 32 – 46 35 – 50 < 31 PAAT (msec) 90 – 175 60 – 90 < 47 RV Strain (%) > - 25

• 20

< - 17 Eccentricity index 1 1 < 1.3

Future initiatives

• Coupling mechanisms
• RV three chamber view
• Composite score

RV Afterload

(PVR, PAP, compliance)

RV Performance (Contractility)

Adapted from. J Am Coll Cardiol 2017;69:236–43

Stage 1 Stage 2 Stage 3 RV Morphology

(Volume/thickness)

RV-PA axis

RV Contractility RV Afterload

Coupling Maintained Uncoupling

Hemodynamic profile of the right ventricle and its load in chronic PH

Uncoupling

RV failure

Coupled

SLIDE 17

3/12/2019 17

RV-PA Coupling RV Performance RV Afterload =

RV-PA axis formation

Coupling mechanisms

RV-PA Coupling TAPSE PAAT = RV-PA Coupling RV Strain PAAT =

20 40 60 80 0.0 0.5 1.0 1.5 2.0 2.5

TAPSE / PAATi

(mm)

E e s / E a

R = 0.76, p < 0.01

B

JACC Cardiovascular Imaging 2018 Conclusion: TAPSE / PAATi & RV LS / PAATi correlate with invasive RHC measures of RV-PA coupling (Ventricular elastance/Arterial Elastance)

Clinical assessment of RV-PV coupling

RV length – force relationship

A

Coupling (Ees/Ea) vs. TAPSE/PAAT

• 20
• 15
• 10
• 5

0.0 0.5 1.0 1.5 2.0 2.5

RV LS / PAATi Ees / Ea

R = 0.88, p < 0.01

Coupling (Ees/Ea) vs. Strain/PAAT

PH

(n=50)

No PH

(n=75)

Cardiac Catheritization

(mPAP > 20 mm Hg, sPAP > 35 mm Hg, PVRi > 3 WU x m2)

TAPSE / PAATi

* P < 0.001 100 80 60 40 20

• 15
• 10
• 5

R V LS / P AA Ti (%

) PH

n = 36

No PH

n = 89

PH

n = 36

No PH

n = 89

Levy PT & EL-Khuffash A. J Am Soc Echocardiogr. 2018;31:962-4 A B

Pulmonary hypertension

RV length – force relationship in children

50 100 150 200 250

* P < 0.001 * P = 0.004 + PH + BPD n=8 Term Healthy n=50 + PH No BPD n=4 No PH +BPD n=40 No PH No BPD n=28

Preterm-born

* P < 0.001

0.25 0.20 0.15 0.10 0.05

Levy at al. Pediatric Research 2018 (abstract)

TAPSE / PAAT

RV-PV coupling at 1 year of age

RV length – force relationship

SLIDE 18

3/12/2019 18

RV Strain

ESV/SV (coupling)

Adverse events

RV-PV Metabolism

Courtesy of McNamara and El-Khuffash

SVR

Blood O2 consumption

Pulmonary vasculature (Target organ flow) Hgb Work Sats

BP

Blood O2 delivery

RV performance

CO = SV x HR

Determinants of function Preload

amount of blood present in the ventricle at end diastole.

Afterload

the resistance against which the ventricle muscle must contract

Contractility

the intrinsic ability of the myocardium to contract

Heart rate

Force-frequency relationship

Stroke volume

Morphology Force-velocity relationship Length-tension relationship

• 1. Pressure-dependent
• TR velocity jet
• Septal wall motion
• RA / RV morphology
• LV eccentricity index
• Shunts / directions
• 2. PA acceleration time
• PAAT / RVET
• 1. IVC (?)
• 2. Volumes (?)
• 1. RV Areas
• Systolic
• Diastolic
• 4-ch / 3-ch
• 2. Dimensions
• RV inflow
• RV outflow
• 1. RV contractility
• dp/dt
• Strain rate
• 2. RV systolic function
• FAC / MPI / Strain
• TAPSE / Strain
• 3. RV diastolic function
• Tissue Doppler velocities
• Strain rate

Echocardiographic evaluation of RV mechanics

• Hemodynamics response of the RV in chronic PH is highly

coordinated process that is linked through programmed structural, functional and genetic mechanisms.

• RV contractility adapts in response to changes in RV afterload.

(Coupling)  Disruption to these maturational patterns may lead to abnormal RV-PV coupling.

• Clinical need to test the efficacy of patient management strategies

with non-invasive measures to screen/diagnosis/follow.

Summary

Right ventricle response to increase load in cPH

Curr Treat OptionsCardio Med (2019) 21:6 DOI 10.1007/s11936-019-0710-y Pediatric and Congenital Heart Disease (G S ingh, S ection Editor)

C

• mprehensive Noninvasive

E valuation of R ight Ventricle-P ulmonary C irculation Axis in P ediatric P atients with P ulmonary Hypertension

P ei-N i Jone, M D

*

D unbar D . Ivy, M D

R eview

Neonatology 2016;110:248–260 DOI: 10.1159/000445779

Novel E chocardiography Methods in the Functional As s es s ment of the Newborn Heart

C

• lm R

. B reatnach

a P

hilip T. Levy

d, e Adam T

. J ames

a Orla F

ranklin

b

Afif E l-K huffash

a, c R eceived: J anuary 25, 2016 Accepted after revision: March 24, 2016 Published online: J une 10, 2016

• Identify cardiovascular compromise earlier
• Guide therapeutic intervention
• Monitor treatment response
• Improve overall outcome

Curr Treat Options Cardiovasc

• Med. 2019;21:6

Excellent references

SLIDE 19

3/12/2019 19

Bhattacharya et al. Curr Treat Options Cardiovasc Med 2019 Feb 15;21(2):10

Echocardiographic evaluation of RV mechanics

Preterm infants with chronic PH

Indirect assessment

• f RV afterload

Estimation of vascular hemodynamics Assessment of RV performance

Boston Children’s Hospital Harvard Medical School Anne and Robert H. Lurie Children’s Hospital Northwestern University Feinberg School of Medicine University of Nebraska Medical Center

Collaboration acknowledgement

The Rotunda Hospital Royal College of Surgeons in Ireland Hospital for Sick Children / Mount Sinai Hospital University of Iowa Carver College of Medicine

• St. Louis Children’s Hospital

Washington University School of Medicine Johns Hopkins School of Medicine Texas Children's Hospital, Baylor College of Medicine

Additional

RV RA PA Rotate the probe counterclockwise from the apical 4-chamber view

RV focused apical 3 – chamber view

Imaging the right ventricle

Animations, Malcom and Evans J Am Soc Echocardiogr 2014;1293-304

SLIDE 20

3/12/2019 20

RV focused apical 3 – chamber view (inflow + outflow)

Dimensions – areas

Morphology

RV end- diastolic area RV end- systolic area

J Am Soc Echocardiogr 2014;1293-304 Radial Longitudinal Circumferential Circumferential - Longitudinal

Base Apex

Twist (o)

Torsion (o/cm)

Geyer et al. J Am Soc Echocardiogr 2010;23:351-69

Normal Strain

(perpendicular)

Shear Strain

(parallel)

Deformation

L V L V Left Ventricle

Circumferential - Radial Radial - Longitudinal

L V

Longitudinal

Normal Strain

(perpendicular)

Shear Strain

(parallel)

Deformation RV global longitudinal strain

(Focused RV apical 4-chamber view)

RV free wall longitudinal strain

(Focused RV apical 4-chamber view)

RV inferior wall longitudinal strain

(RV apical 3-chamber view)

R V R V R V

Right Ventricle