Transcript LV Dssynchrony and Cardiac Resynchronization Therapy in Heart

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 Patients
Cumulative Enrollment in Cardiac
Resynchronization Randomized Trials
4000
CARE HF
MIRACLE ICD
3000
MIRACLE
MUSTIC AF
2000
1000
MIRACLE ICD II
MUSTIC SR
COMPANION
PATH CHF
PATH CHF II
CONTAK CD
0
1999
2000
2001
2002
2003
Results Presented
A. Goldman CRT Talk 2007.
2004
2005
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
Regional Fractional Area Change
Septum
0
Seconds
0.4
Lateral
0
Seconds
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.
Pacing Off
Pacing On
0.4
Promotion of Reverse Remodeling in
Class II CHF
3
cm
400
Left Ventricular End
Diastolic Diameter
3
cm
400
P=0.04
350
Left Ventricular End
Systolic Diameter
%
Left Ventricular
Ejection Fraction
30
P=0.01
350
28
P=0.02
26
300
300
24
250
200
250
Base
6 Mo
200
22
Base
 Control (n=85)
6 Mo
 CRT (n=69)
Abraham et al., Circulation 2004; 110:2864-2868. N. Parikh CRT Talk 2008.
20
Base
6 Mo
Improvement in Mitral Regurgitation
A. Goldman CRT Talk 2007.
CRT Improves Exercise Capacity
Average Change in 6 Minute
Walk Distance
m
*
60
*
3
mL/kg/min
*
40
Average Change in Peak VO2
20
0
-20
*
2
*
*
1
0
Abraham et al., 2003.
CRT
* P < 0.05
CL
E
ICD
D
Control
MI
RA
CO
NT
AK
C
SR
TIC
MU
S
CL
E
MI
RA
ICD
D
Control
MI
RA
CL
E
NT
AK
C
CO
MU
S
TIC
SR
0
MI
RA
CL
E
-40
*
CRT
CRT Improves Quality of Life and
NYHA Functional Class
Average Change in Score
NYHA: Proportion Improving
1 or More Class
0
80%
-5
*
40%
-15
*
Control
Abraham et al., 2003.
20%
ICD
*
MI
RA
CL
E
NT
AK
C
CO
TIC
D
*
SR
*
MU
S
MI
RA
CL
E
*
60%
-10
-20
*
CRT
0%
* P < 0.05
MIRACLE CONTAK MIRACLE
CD
ICD
Control
CRT
Progressive Heart Failure Mortality
51% Relative Reduction with CRT
Overall odds ratio (95% CI) of 0.49 (0.25 - 0.93)
Favors CRT
Favors No CRT
CONTAK CD
(n=490)
MIRACLE ICD
(n=554)
MIRACLE (n=532)
MUSTIC (n=58)
Overall (n=1634)
0.1
0.5
1.0
Odds Ratio (95% CI)
Bradley DJ, et al. JAMA 2003;289:730-740.
10.0
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 trials
Bradley 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
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)
Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008.
Copyright ©2008 American Heart Association
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.
Tissue Velocity Waveforms
Normal Subject
4-Chamber
Apical Long Axis
2-Chamber
Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008
Copyright ©2008 American Heart Association
Apical 4 Ch
Long axis
2 Chamber
Before
CRT
After
CRT
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
Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008
Copyright ©2008 American Heart Association
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%
Before CRT
After CRT
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).
Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh. CRT Talk 2008.
Copyright ©2008 American Heart Association
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 Tracking
Advantages 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)
PROSPECT Trial
Chung, E. S. et al. Circulation 2008;117:2608-2616
Copyright ©2008 American Heart Association
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%
PROSPECT Results
Chung, E. S. et al. Circulation 2008;117:2608-2616
Copyright ©2008 American Heart Association
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 & endsystolic strain across 16 segments
• Cardiac MRI
– Synchrony
– Strain
• Location of LV pacing lead
– Concordance of
• LV lead position
• Site of latest mechanical activation
Future Directions
Novel 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 Directions
Novel 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
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.
Lim et al. Circulation. 118:1130-37. 2008.
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