1. Airley E. Fish MD Imaging Conference August 19th 2009
Left Ventricular Dyssynchrony and Cardiac Resynchronization Therapy in Heart Failure
Airley E. Fish MD
Imaging Conference
August 19th 2009

2. Outline Introduction Rationale for CRT CRT Electrical dyssynchrony
Mechanical dyssynchrony
CRT
Evidence for benefit
Summary of major trials

3. Outline Echocardiographic measures PROSPECT
M-Mode
Tissue Velocity
Strain Imaging
Three Dimensional Echo
PROSPECT
Future directions to predict CRT response

4. Source: National Hospital Discharge survey

5. HF Total Expenditures: $27.9 Billion
American Heart Association. Heart Disease and Stroke Statistics 2007 Update. N. Parikh CRT Talk 2008

6. Percent Change in U.S. Crude Death Rates from 1972-2000 by cause
NHLBI Morbidity and Mortality Chart Book. 2004

7. HF Therapy
Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348:

8. 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

9. 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

10. 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

11. Contributors to Electrical and Mechanical Dyssynchrony
Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4,

12. 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
Main purpose: Illustrate for referral clinicians how the leads are placed to achieve cardiac resynchronization. Many outside the implant world may not be entirely aware of how the device is placed.
Key messages:
The implant procedure, while typically of longer duration, is similar to that of a standard pacemaker or implantable defibrillator implantation.
A key difference is the placement of a left ventricular lead via the coronary sinus opening.
Coronary venous anatomy varies significantly between patients. In a small percentage of cases it may not be possible to place the left ventricular lead transvenously. Some centers are opting for an epicardial approach if the transvenous approach is unsuccessful.
Additional information:
Standard pacing leads are placed in the right atrium and right ventricle. The LV lead is placed via the coronary sinus in a cardiac vein, preferably a lateral or postero-lateral vein in the mid part of the LV. The successful deployment of this lead to physician-guided development of left-heart delivery systems, and new LV leads to meet varying patient
Cubbon R. BMJ. 338:

13. 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:

14. Cumulative Enrollment in Cardiac Resynchronization Randomized Trials
4000
CARE HF
3000
MIRACLE ICD
MIRACLE
MUSTIC AF
MIRACLE ICD II
Cumulative Patients
2000
MUSTIC SR
COMPANION
1000
PATH CHF
PATH CHF II
Main purpose: Show that a large number of patients have been studied in completed and ongoing randomized controlled studies of CRT. Use in conjunction with previous slide.
Key messages:
Over 3000 patients have been enrolled in randomized controlled clinical trials presented to date.
When CARE-HF, another landmark trial assessing mortality and hospitalization, is reported, close to 4,000 patients will have been studied.
CONTAK CD
1999
2000
2001
2002
2003
2004
2005
Results Presented
A. Goldman CRT Talk 2007.

15. Landmark Trials in CRT
Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4,

16. CRT Benefits Echocardiographic Clinical
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

17. Regional Wall Motion With CRT: Improved LVEF
Septum
Seconds
0.4
Regional Fractional Area Change
Lateral
These echocardiogram (ECHO) and radial displacement tracings of the septal and lateral walls show how regional wall motion is improved by CRT. With pacing off, radial septal motion is initially inward but then shifts toward the right ventricle as the lateral wall contracts (paradoxic motion). CRT converts this to a more consistent inward motion. In the lateral wall, there is initial stretch followed by delayed contraction. CRT influences the phase, but not amplitude of motion; this stimulates contraction earlier, resulting in increased cardiac efficiency.1
Seconds
0.4
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:
N. Parikh CRT Talk 2008.
Pacing Off
Pacing On
References:
Kass DA. Ventricular resynchronization: pathophysiology and identification of responders. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.
Kawaguchi M, et al. Quantitation of basal dyssynchrony and acute resynchronization from left or biventricular pacing by novel ECHO-contrast variability imaging. J Am Coll Cardiol. 2002;39:

18. Promotion of Reverse Remodeling in Class II CHF
 Control (n=85)  CRT (n=69)
Abraham et al., Circulation 2004; 110: N. Parikh CRT Talk 2008.

19. Improvement in Mitral Regurgitation
A. Goldman CRT Talk 2007.

20. CRT Improves Exercise Capacity
Abraham et al., 2003.

21. CRT Improves Quality of Life and NYHA Functional Class
Abraham et al., 2003.

22. Progressive Heart Failure Mortality 51% Relative Reduction with CRT
Overall odds ratio (95% CI) of 0.49 ( )
Favors CRT
Favors No CRT
CONTAK CD (n=490)
MIRACLE ICD (n=554)
MIRACLE (n=532)
MUSTIC (n=58)
Overall (n=1634)
Odds ratio refers to odds of death from progressive heart failure among patients randomized to CRT or to no CRT. Odds ratio less than 1 favors CRT. Boxed area is proportional to the relative weight given to each trial in the statistical model.
Bradley DJ, et al. JAMA 2003;289:

23. 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

24. CRT Complications Unsuccessful Uncomfortable diaphragmatic stimulation
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

25. Intraventricular Mechanical Dyssynchrony
M-Mode
Tissue Velocity
Strain Imaging
Three Dimensional Echo

26. 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 1 mo)
↑ in LVEF > 5%
Better prognosis at 6 months s/p CRT

27. M-mode echocardiography with color-coded tissue velocity
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: Adapted from N. Parikh CRT Talk 2008.
Copyright ©2008 American Heart Association

28. M-Mode Echo - SPWMD Advantages & Disadvantages
Easy to perform
No specific U/S equipment needed
High temporal resolution (> 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

29. 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 Bax et al, Am J Card 2004

30. Examples of tissue velocity waveforms
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.

31. Tissue Velocity – Tissue Doppler Imaging
Color-coded TDI
Opposing wall time to vpeak delay of > 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 Bax et al, Am J Card Yu et al Circulation 2004.

32. Tissue Velocity Waveforms
Normal Subject
4-Chamber Apical Long Axis Chamber
Anderson, L. J. et al. Circulation 2008;117: Adapted from N. Parikh CRT Talk 2008
Copyright ©2008 American Heart Association

33. 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: Adapted from N. Parikh CRT Talk 2008
Copyright ©2008 American Heart Association

34. 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

35. 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

36. 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%

37. 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: Adapted from N. Parikh. CRT Talk 2008.
Copyright ©2008 American Heart Association

38. Strain imaging TDI-Derived Advantages and Disadvantages
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

39. Strain Imaging – Speckle Tracking Advantages and Disadvantages
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

40. 3-D Echo Measurement of dyssynchrony indexes Difference in
minimal segmental volume
and the standard deviation in time to minimal volume
among 16 segments

41. 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,

42. 3-D Echo Advantages and Disadvantages
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

43. 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)

44. PROSPECT Trial Chung, E. S. et al. Circulation 2008;117:2608-2616
Copyright ©2008 American Heart Association

45. PROSPECT Results 426 heart failure patients CRT response
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%

46. PROSPECT Results Chung, E. S. et al. Circulation 2008;117:2608-2616
Copyright ©2008 American Heart Association

47. 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

48. 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

49. Issues with PROSPECT Patient selection Technical Pathophysiological
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

50. 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

51. 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:

52. Future Directions Novel Speckle Tracking Strain
Delgado et al. JACC. 51:

53. 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:

54. 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:

55. 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).

56. 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.

57. 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:

58. 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