Left Ventricular Dyssynchrony and Cardiac Resynchronization Therapy

in Heart Failure

Airley E. Fish MD

Imaging Conference

August 19th 2009

Outline

• Introduction

• Rationale for CRT – Electrical dyssynchrony– Mechanical dyssynchrony

• CRT – Evidence for benefit– Summary of major trials

Outline

• Echocardiographic measures– M-Mode– Tissue Velocity– Strain Imaging– Three Dimensional Echo

• PROSPECT

• Future directions to predict CRT response

Source: National Hospital Discharge survey

HF Total Expenditures: $27.9 Billion

American Heart Association. Heart Disease and Stroke Statistics 2007 Update. N. Parikh CRT Talk 2008

Percent Change in U.S. Crude Death Rates from 1972-2000 by cause

NHLBI Morbidity and Mortality Chart Book. 2004

HF Therapy

Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348: 2007-2018.

Electrical Dyssynchrony

• Abnormal ventricular depolarization →– Increased QRSd – Generates early and delayed ventricular contraction

• QRSd directly associated with EF– BBB in 20% of HF patients– BBB in 35% of patients with severely ↓’ed EF

• BBB– Independent predictor of mortality– Especially QRSd > 120 ms

Mechanical Dyssynchrony

• Intraventricular– Delayed activation of one LV region vs another

• Interventricular– Delayed activation of LV relative to RV

• Goal of CRT– Correct both intra- and interventricular dyssynchrony

Dyssynchrony - Mechanical ≠ Electrical

• Caveat – mechanical ≠ electrical dyssynchrony– Mechanical may be 2°

• Regional loading differences• Fibrosis• Contractile strength of one part of wall vs. another

– Ca++ cycling– Myofilament-Ca++ interactions

– Mechanical imaging methods• Detect muscle motion not activation process

Contributors to Electrical and Mechanical Dyssynchrony

Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4, 486-497. 2009.

Achieving Cardiac Resynchronization Atrial Synchronous Biventricular Pacing

• Improve coordination– Atria and – Both ventricles

• Pacing leads– RAA– RV apex

• Anterior wall of LV

– LV posterolateral wall• Via lateral tributary of CS

Cubbon R. BMJ. 338:1064-1069. 2009

Achieving Cardiac Resynchronization Atrial Synchronous Biventricular Pacing• Venous access

– Subclavian vein– Local anesthetic– Infraclavicular incision

• Target vein– ID’ed via retrograde balloon

angiography of CS

• Leads connected via– SQ generator– Simultaneous LV/RV pacing

• Override intrinsic conduction– By setting AV delay < intrinsic PR

Cubbon R. BMJ. 338:1064-1069. 2009

Cumulative Enrollment in Cardiac Resynchronization Randomized Trials

0

1000

2000

3000

4000

1999 2000 2001 2002 2003 2004 2005

Results Presented

Cum

ulat

ive

Pat

ient

s

PATH CHF

MUSTIC SR

MUSTIC AF

MIRACLE

CONTAK CD

MIRACLE ICD

PATH CHF II

COMPANION

MIRACLE ICD II

CARE HF

A. Goldman CRT Talk 2007.

Landmark Trials in CRT

Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4, 486-497. 2009.

CRT Benefits

• Echocardiographic– Improved EF/regional wall motion– Reversal of maladaptive remodeling (↓ LVESV)– Reduction in severity of mitral regurgitation

• Clinical – Increased 6-minute hall walk distance– Increased peak VO2 and treadmill exercise time– Improved QOL and NYHA functional class ranking– Trend towards reduction in morbidity and mortality

Regional Wall Motion With CRT: Improved LVEF

Septum

Lateral

Pacing OffPacing On

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al F

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ion

al A

rea

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e

Seconds 0.40

Seconds 0.40

Adapted from Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.

Adapted from Kawaguchi M, et al. J Am Coll Cardiol. 2002;39:2052-2058.

N. Parikh CRT Talk 2008.

Promotion of Reverse Remodeling in Class II CHF

Left Ventricular End Diastolic Diameter

200

250

300

350

400cm3

Base 6 Mo

Left Ventricular End Systolic Diameter

200

250

300

350

400cm3

Base 6 Mo

Left Ventricular Ejection Fraction

20

22

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26

28

30%

Base 6 Mo

Control (n=85) CRT (n=69)

Abraham et al., Circulation 2004; 110:2864-2868. N. Parikh CRT Talk 2008.

P=0.04 P=0.01 P=0.02

Improvement in Mitral Regurgitation

A. Goldman CRT Talk 2007.

CRT Improves Exercise Capacity

Average Change in 6 Minute Walk Distance

-40

-20

0

20

40

60

MIR

ACLE

MUS

TIC

SRCO

NTAK

CD

MIR

ACLE

ICD

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Control CRT

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* P < 0.05

Average Change in Peak VO2

00

1

2

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Control CRT

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Abraham et al., 2003.

CRT Improves Quality of Life and NYHA Functional Class

Average Change in Score

-20

-15

-10

-5

0

MIR

ACLE

MUS

TIC

SRCO

NTAK

CD

MIR

ACLE

ICD

Control CRT

* * * *

* P < 0.05

NYHA: Proportion Improving 1 or More Class

0%

20%

40%

60%

80%

MIRACLE CONTAKCD

MIRACLEICD

Control CRT

**

*

Abraham et al., 2003.

Progressive Heart Failure Mortality51% Relative Reduction with CRT

0.1 1.0 10.0Odds Ratio (95% CI)0.5

Favors CRT Favors No CRT

CONTAK CD (n=490)

MIRACLE ICD (n=554)

MIRACLE (n=532)

MUSTIC (n=58)

Overall (n=1634)

Bradley DJ, et al. JAMA 2003;289:730-740.

Overall odds ratio (95% CI) of 0.49 (0.25 - 0.93)

Summary of Major Trials• Significant clinical benefit of CRT in patients with

– Class III-IV HF– EF < 35% – QRS > 120

• Improvements in symptoms and objective standards of HF

• Meta-analysis– 29% decrease in HF hospitalization (13% vs. 17.4%)– 51% decrease in deaths from HF (1.7% vs. 3.5%)– Trend toward decrease in overall mortality (4.9% vs 6.3%)

• BUT: consistent > 30% non-response rate through most trialsBradley et al. JAMA 2003;289:730

CRT Complications• Unsuccessful

– Failure to implant LV lead <5% in large series– Eventual lead displacement <1%

• Uncomfortable diaphragmatic stimulation– 2° L phrenic nerve coursing over posterolateral heart wall– Reposition intra-procedure, reprogram post-procedure

• Infection, risk of extraction <1%– Related to procedure time/?experience of electrophysiologist

• CS perforation /pericardial tamponade

• Refractory hypotension

• Bradycardia

• Asystole

Intraventricular Mechanical Dyssynchrony

• M-Mode

• Tissue Velocity

• Strain Imaging

• Three Dimensional Echo

M-Mode - SPWMD

• Septal → posterior wall motion delay (SPWMD)– Time difference between peak inward motion of

• Ventricular septum• Posterior wall

– Obtained in parasternal short axis M-mode view– > 130 ms is significant to predict

• ↓ in LVESV index > 15% (sens 100%, spec 63% @ 1 mo)• ↑ in LVEF > 5%• Better prognosis at 6 months s/p CRT

Copyright ©2008 American Heart Association

Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008.

M-mode echocardiography with color-coded tissue velocity. a, Timing of ventricular septal (VS) wall motion difficult to define 2° severe hypokinesis & lack of distinct peaks. b, Color

coding of tissue velocity helps to identify exact wall motion timing as transition point of blue to red color for septal wall (arrows) & red to blue color for posterior wall (arrowheads) (right)

M-Mode Echo - SPWMD Advantages & Disadvantages

• Advantages– Easy to perform– No specific U/S equipment needed– High temporal resolution (>1000-3000 fps)

• Disadvantages– Only quantify in regions perpendicular to U/S beam– Only assess anteroseptal & inferolateral wall motion– Only feasible in 50% of patients evaluated

• Difficult to determine timing of inward motion if – Wall akinetic or plateau in motion

– Not consistently predictive for outcome after CRT

Tissue Velocity – Tissue Doppler Imaging• Measurement of

– Longitudinal tissue velocity (most commonly studied)– or myocardial deformation (strain)

• Both pulsed-wave TDI & color-coded TDI used to ID systolic vpeak

• Both time to vpeak & time to onset of systolic velocity used

• # and location of segments sampled (2, 6, or 12) has varied

• Both standard deviation & maximum difference of timing intervals used

• vpeak measured during ejection only or both ejection & post-ejection periods Bax et al, Am J Card 2003. Bax et al, Am J Card 2004

Examples of tissue velocity waveforms. a, Double peaks (arrows) in anterolateral wall in NL subject. b, One of the double peaks (arrows) located at time of aortic valve opening in anterior wall in LBBB patient. c, Beat-to-beat variability in velocity of 2 peaks (arrows) during ejection. d, Postsystolic peak (*) higher than systolic velocity (arrow) in inferoseptal segment in LBBB patient. e, Positive deflection at aortic valve opening at downslope shoulder of presystolic velocity (arrow) is highest peak during ejection period. f, No positive velocity was found during ejection period and prominent presystolic (arrowhead) and postsystolic wave (*) observed in inferoseptal wall.

Tissue Velocity – Tissue Doppler Imaging

• Color-coded TDI– Opposing wall time to vpeak delay of > 60-65 ms

• Short-term improvement in EF• Reverse remodeling at 6 months

– Yu index • Global 12 (basal and mid) Segment Asynchrony Index

• vpeak delay ≥ 33 ms predictive of reverse remodeling at 3 months

• Not replicated in RethinQ – Resynchronization Therapy in Normal QRS (<130 ms)– Study entry via delay of > 65 ms between two opposing walls

Bax et al, Am J Card 2003. Bax et al, Am J Card 2004. Yu et al Circulation 2004.

Copyright ©2008 American Heart Association

Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008

Tissue Velocity Waveforms

4-Chamber Apical Long Axis 2-Chamber

Normal Subject

Copyright ©2008 American Heart Association

Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008

BeforeCRT

After CRT

Apical 4 Ch Long axis 2 Chamber

Color-coded tissue velocity recordings from 12 LV segments before (a) and after (b) CRT in 65-year-old patient with NICMP whose LVEF improved by 17% at 6 months after CRT

Tissue Velocity - Tissue Doppler Imaging Advantages and Disadvantages

• Pulsed-wave TDI– Advantages

• High temporal resolution• No specific U/S equipment needed

– Disadvantages• No simultaneous sampling in multiple segments• Requires multiple images• Requires different cardiac cycles to map entire heart

– Time consuming– Renders tissue velocity peaks more difficult to identify

• Susceptible to translational motion/tethering effect

Tissue Velocity - Tissue Doppler Imaging Advantages and Disadvantages

• Color-coded TDI– Advantages

• Relatively high temporal resolution (>100 fps)• Sampling of multiple segments simultaneously from one

image• Allows further parameter processing by offline analysis

(displacement, strain rate, strain)

– Disadvantages• Requires high-end U/S equipment• Susceptible to translational motion or tethering effect

Strain Imaging

• TDI-derived and Speckle tracking

• Abnormal strain pattern– Premature early systolic shortening of septum – Accompanied by lateral prestretch– Followed by postsystolic lateral wall shortening

• Cutoff value of radial dyssynchrony > 130 ms in time to peak radial strain in anteroseptal/inferolateral walls– Predicts ↓ in LVESV > 15% s/p CRT– Sensitivity 83%, specificity 80%

Copyright ©2008 American Heart Association

Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh. CRT Talk 2008.

Radial strain curves from short-axis view of speckle tracking echocardiography: Significant timing difference found among time to peak radial strain before CRT (a), reduced after CRT (b).

Before CRT After CRT

Strain imaging TDI-Derived Advantages and Disadvantages

• Advantages– Relatively high temporal resolution

• >200 fps individual wall, >100 fps for whole apical views– Less affected by tethering/translational motion

• Disadvantages– Requires specific software– Time-consuming image analysis– Highly dependent on image quality– Not feasible in all patients

• Difficult in spherical, dilated hearts• Difficult in highly angulated basal segments

– Mixed results predicting success after CRT

Strain Imaging – Speckle TrackingAdvantages and Disadvantages

• Advantages– Less affected by translational motion and tethering

• Nearly angle independent• Can assess radial, circumferential, and longitudinal strain

– Nearly automated analysis – less variability

• Disadvantages– Requires specific software– Less time resolution (>40-80 fps)

• Requires large sector size for imaging in dilated hearts

– Highly dependent on image quality– Not feasible in all patients

3-D Echo

• Measurement of dyssynchrony indexes– Difference in

• minimal segmental volume • and the standard deviation in time to minimal volume • among 16 segments

Three Dimensional Echocardiography

Uniform times to minimum volume indicate synchrony (A). The dyssynchronous left ventricle is characterized by variation in times to minimum volume (B).

Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4, 486-497. 2009.

3-D Echo Advantages and Disadvantages

• Advantages– Only one image needed for entire assessment– Nearly automated analysis– Display temporal/spatial distribution of timing in bull’s eye plot– Short-term improvements in 3D dyssynchrony index s/p CRT

• Disadvantages– Requires high-end U/S equipment and probe– Low temporal (15-25 fps) and spatial resolution– Highly dependent on image quality– Incomplete inclusion of the apex– Cannot perform if a-fib or frequent ectopy– No study to date shows 3D Echo predicts response to CRT

Interventricular Dyssynchrony

• Difference in preejection period between PW Doppler– in Ao and PA

- Correlates with QRSd- Typically exceeds 40 ms in pts with QRSd >150 ms- Shown to be predictive of post-CRT response

- SCART - Interventricular dyssynchrony > 44 ms & smaller ESV

- CARE-HF - Interventricular dyssynchrony > 49.2 ms

• Tissue velocity delay between RV & LV free wall not predictive of CRT effect (neither time to peak or onset)

Copyright ©2008 American Heart AssociationChung, E. S. et al. Circulation 2008;117:2608-2616

PROSPECT Trial

PROSPECT Results

• 426 heart failure patients– Mean age 68 years– Mean LV EF 23.6 ± 7%– Mean QRSd 163 ± 22 ms – NYHA Class III 96%

• CRT response– Heart failure clinical composite score

• Improvement in 69%

– Relative change in LVESV at 6 months• Improvement in 56%

Copyright ©2008 American Heart Association

Chung, E. S. et al. Circulation 2008;117:2608-2616

PROSPECT Results

PROSPECT Results• Multiple echocardiographic parameters

– SPWMD (M mode)– LV pre-ejection interval (pulsed wave Doppler)

• Delay between QRS onset and LV ejection onset

– Interventricular delay (PWD)• Difference between LV and RV pre-ejection intervals

– LV filling time, relation to cardiac cycle length (PWD)– Delay in peak systolic velocity (Color-coded TDI)

• 2 segments (basal septum & lateral wall)

– Delay in onset of systolic velocity (CC TDI)• 6 basal LV segments

– Stand. Dev., time to peak systolic velocities (CC TDI)• 12 LV segments

PROSPECT Caveats & Conclusions

• Problem – high intra- & interobserver variability– M-mode-derived septal-posterior wall motion delay– Doppler imaging-derived parameters

• Echocardiographic measures of dyssynchrony aimed at improving patient selection criteria for CRT did not have a clinically relevant impact on ↑ response rates

• Echocardiographic parameters of dyssynchrony did not have enough predictive value to be used as selection criteria for CRT beyond current indications

Issues with PROSPECT

• Patient selection– 20.2% LVEF > 35%– 37.8% LVEDD < 65 mm

• Technical – Nonassessability of echocardiographic measures

• Highest for M-mode and TDI

– Low interobserver reproducibility• ?Better technology (3D, strain, CMR, etc.)

• Pathophysiological– Influence of scar on non-response– LV dyssynchrony vs. LV lead position– Influence of venous anatomy vs LV lead positioning

Future Directions

• Novel speckle tracking strain– Combination of longitudinal and radial dyssynchrony

• Strain delay index – using speckle tracking– Sum of the difference between longitudinal peak & end-

systolic strain across 16 segments

• Cardiac MRI – Synchrony– Strain

• Location of LV pacing lead– Concordance of

• LV lead position• Site of latest mechanical activation

Future DirectionsNovel Speckle Tracking Strain

• Combination of– Longitudinal and radial dyssynchrony

• Easier, more accurate, more comprehensive• Sensitivity 88%, specificity 80%

– for predicting CRT response in 190 HF patients

• Significantly better than either technique alone (p<0.0001)

Gorscan et al. JACC. 50:1476-83. 2007.

Future DirectionsNovel Speckle Tracking Strain

Delgado et al. JACC. 51:1944-1952. 2008.

Future Directions - Strain Delay Index Using Speckle Tracking

• Sum of the difference between– Longitudinal peak and end-systolic strain– Across 16 segments

• >’er in responders vs non-responders– 100 HF patients (35 ± 7 vs. 19 ± 6%, p< 0.001)– Closely correlated with reverse remodeling

• Both ischemic and nonischemic cardiomyopathy

• Optimal cutoff to predict CRT response– Strain delay index of > 25%

Lim et al. Circulation. 118:1130-37. 2008.

Future Directions - Strain Delay Index Using Speckle Tracking

Lim et al. Circulation. 118:1130-37. 2008.

A, Strain delay index is the sum of the wasted energy, ie, ( ES– peak) caused by LV dyssynchrony across the 16 myocardial segments (colored curves) of the LV.

B, After CRT, the increase ( ) of global strain curve (white dashed curve) is supposed to be proportional to strain delay index.

Future Directions Cardiac MRI - Synchrony

Progressive deformation of the grid (A) allows measurement of the time course of deformation in the principal axes of each segment (B). The parametric display (C) shows the time course of contraction, which can be shown to be synchronous (upper row) or dyssynchronous (lower row).

Future Directions - Cardiac MRI - Strain

Regional variance of strain (A) cannot differentiate identical variance of time to peak contraction between segments with delayed contraction clustered in 1 portion of the left ventricular wall (A, top), versus dispersion of delay through the heart (A, bottom); only the former displays dyssynchrony. The regional variance vector of principal strain (B) is based on the product of unit vectors with a scalar representing time at maximal shortening or instantaneous magnitude of shortening. Regional strain uniformity (C) provides a relative ratio of first/zero-order magnitudes derived by Fourier analysis. The heart with clustered regions (A, top) shows delays in 1 territory versus the other so this plot appears sinusoidal. Hearts with more variability (A, bottom) yield a higher frequency waveform.

Future Directions – LV Lead Placement

• Concordance– LV lead position– Site of latest mechanical

activation

• Speckle tracking + CXR– Post-CRT in 244 patients

• If concordant,– Significant ↓ in LVESV– 189 ± 83 ml to 134 ± 71 ml– P < 0.001– Long-term follow-up

• Better event-free survival

Ypenburg et al. JACC. 52:1402-9. 2008.

ACC/AHA/NASPE 2005 Guidelines

• Patients with – LVEF < 35%– Sinus rhythm– NYHA functional class III or ambulatory class IV

symptoms, despite optimal medical therapy – Cardiac dyssynchrony

• Currently defined as a QRS duration > 120 ms

• Should receive CRT unless contraindicated

• Class: I, Level of Evidence: A