1) This document discusses patient selection for cardiac resynchronization therapy (CRT). It covers the historical aspects and physiology of ventricular dyssynchrony as well as the role and importance of assessing dyssynchrony for patient selection. 2) Various echocardiography techniques for assessing mechanical dyssynchrony are described, including tissue Doppler imaging (TDI), speckle tracking, and 3D echocardiography. Major randomized controlled trials on CRT are also summarized. 3) While echocardiography is commonly used, the document notes that no single measure of dyssynchrony is recommended due to variability in results. Larger trials found CRT beneficial primarily in patients with prolonged QRS

1. PATIENT SELECTION FOR CRT
SHYAM SASIDHARAN

2. PLAN….
• Historical aspects
• Physiology & hemodynamics of “ dyssynchrony”
• Role of CRT
• Why is patient selection important?
• Assessment of dyssynchrony
• Major RCTs
• Current recommendations

3. History..
• In 1925, Wiggers showed that surface stimulation of the canine
myocardium reduced the maximal LV pressure derivative (LV
dP/dt max) and lengthened isometric contraction.
• 1980s,Grines et al described how a left bundle branch block
(LBBB) reduced the diastolic filling time and the septal
contribution to LV ejection
• In 1987, Mower devised and was granted a patent for the
concept of “biventricular pacing,” explicitly aimed at HF
treatment.
• By the 1990s, it was apparent that LV pacing was more
hemodynamically favorable than RV pacing.
• FDA approval - 2001

4. BACKGROUND
• 2% of the adult population in developed
countries has HF and about half will have an
LVEF <50%.
• 36% of those had an LVEF ≤ 35%
• Of these, 41% had a QRS duration ≥120 ms; 7%
had RBBB, 34% had LBBB or (IVCD) and 17%
had QRS ≥150 ms
• The annual incidence of LBBB is about 10% in
ambulatory patients with left ventricular systolic
dysfunction (LVSD) and chronic HF

5. Physiology of Dyssynchrony
• LV mechanical dyssynchrony is discoordinate
ventricular contraction resulting from either an
electrical timing delay or a functional
abnormality.
• Atrioventricular/interventricular/intraventricular
dyssynchrony
• Prolongation of the AV interval delays systolic
contraction, which might then encroach on early
diastolic filling

6. LBBB - PHYSIOLOGY
• early activation of the inter-ventricular septum,
• lateral wall prestretch,
• delayed lateral wall contraction in late systole
• further systolic stretch of the early activated
septum.
• late activation of the postero-lateral papillary
muscle results in suboptimal mitral valve closure
and mitral regurgitation
• When ventricular contraction is delayed,LV
diastolic pressures will exceed atrial pressure
causing diastolic mitral regurgitation.

9. CRT – MECHANISM OF ACTION
• Aims to restore AV, inter and intra-ventricular
synchrony, improving LV function, reducing
functional mitral regurgitation
• Inducing LV reverse remodelling, as evidenced
by increases in LV filling time and LVEF, and
decreases in LV end-diastolic and end-systolic
volumes, mitral regurgitation and septal
dyskinesis.

11. WHY “PATIENT SELECTION” IS CRUCIAL?
• 30-40 % of pateints in all major CRT trails were
“non responders”
• Defined by clinical improvement or reverse
remodelling
• Identify those with uncorrectable mechanical
dyssynchrony
• Quantification of LV dyssynchrony is of key
importance for optimum selection of patients for
CRT because only those patients with severe
mechanical dyssynchrony are likely to benefit.

12. DYSSYNCHRONY ASSESSMENT BY 2D ECHO
1.M MODE
septal-to-posterior wall motion delay (SPWMD) of at least 130 ms has been shown
to predict LV reverse remodeling and clinical outcome after CRT.

13. DOPPLER ECHO- PW
SIGNIFICANT IVMD ≥ 40ms

14. TISSUE DOPPLER ECHO
• Longitudinal LV shortening velocities using TD from
apical windows constitutes the largest body of
literature in the quantification of dyssynchrony and
is the principal method currently in clinical
use.
• Color-coded TD & Spectral pulsed TD
• Both provide similar mechanical information, data
obtained using each technique differ:
Pulsed TD has higher temporal resolution than
color-coded TD.
Pulsed TD measures peak instantaneous
velocity, while color-coded TD measures mean
velocity.

15. TDI…
• four standard imaging planes: apical four-
chamber view, apical two-chamber view, apical
long axis view, and parasternal short axis view at
the level of the mid-LV
• time-velocity plots in four segments for each
view.

16. TDI ..DETERMINING LV Ejection Interval

17. TDI… longitudinal tissue velocity

19. Color-coded Tissue Doppler - Dyssynchrony
• Opposing wall time delay
1.A4C
2.4 segment/12 segment model
• OWTD ≥65 ms has been found to predict both
clinical and echocardiographic responses to
CRT.

20. • Yu Index or the mechanical dyssynchrony index:
• Standard deviation (SD) of the time-to-peak
systolic velocity in the ejection phase in the 12
basal and mid-LV segments.
• A cut-off value ≥33 ms has been found to predict
reverse remodeling, defined as a 15% or more
decrease in LVESV after CRT.
• Maximum time delay technique:
• Maximum time-to-peak systolic velocity
difference among all 12 LV segments.
• A cut-off value ≥100 ms was found to predict
improvement after CRT
Color-coded Tissue Doppler - Dyssynchrony

21. SPECTRAL PULSED TDI

22. SPECTRAL PULSED TDI- DYSSYNCHRONY
• Surrogate for regional electromechanical coupling
(EMC) intervals defined..
• LV dyssynchrony - difference between the longest and
shortest EMC intervals in all the basal segments of the
LV
• Interventricular (LV-RV) dyssynchrony-difference
between EMC times in the basal lateral segment of the
RV and in the most delayed LV segment
• The sum of LV dyssynchrony and LV-RV dyssynchrony
yields the combined index of intraventricular and
interventricular mechanical dyssynchrony.
• A combined index of intra- and interventricular
dyssynchrony ≥102 ms was found to predict the
response to CRT.

23. Tissue Doppler Longitudinal Strain/
Strain Rate and Displacement Imaging
• Postprocessing of tissue velocity signals (color-
coded TD) yields information on myocardial
displacement and deformation.
• Displacement mapping is the integration of
myocardial velocity signals over time.
• Strain rate is the spatial derivation of tissue
velocity data.
• Strain, the integration of myocardial strain rate
over time, has the advantage of differentiating
active deformation from passive translational
motion.

25. SRI - DYSSYNCHRONY
• Delayed Longitudinal Contraction (DLC) if the
strain rate analysis demonstrates motion
reflecting true contraction and if the end of the
segmental contraction occurs after AVC.
• The strain-derived dyssynchrony index is the SD
of the time-to-peak longitudinal (negative)
strain within the entire cardiac cycle in the 12
segments of the LV.

26. TDI – RADIAL STRAIN
• Analysis is performed using the color-coded TD
image of the short axis view at the mid-ventricular
level
• Dyssynchrony is quantified by the time interval
between the peak positive strain in the anterior
septum and the posterior wall.
• An anterior septum to posterior wall delay of 130
ms has been found to predict response to CRT.

27. Tissue Synchronization Imaging
• Automated color coding of time-to-peak velocity
data
• Automatically detect peak positive velocity color
coding of the time-to-peak longitudinal
velocities in the following spectrum: green for
normal timing, yellow-orange for moderate
delay, and red for severe delay
• TSI color coding is used to guide the placement
of oval ROI as with color TD in the basal and
mid-segments from apical views.

29. Speckle Tracking Strain Echocardiography
• Speckle tracking can assess strain in the
longitudinal, circumferential, and radial
directions
• Radial Strain Dyssynchrony- Time delay
between the anterior septum and posterior wall
is determined by measuring the difference in the
time-to-peak positive strain between the two
opposing walls
• A cut-off value ≥130 ms has been found to
predict response to CRT

31. Longitudinal Strain Dyssynchrony
• Strain Delay Index: The sum of the difference
between the peak negative strain and peak end-
systolic strain across 16 LV segments is the
Strain Delay Index
• A Strain Delay Index cut-off value ≥25% was
found to predict response to CRT
• The Strain Dyssynchrony Index is calculated
from the SD of time-to-peak longitudinal strain
within the entire cardiac cycle in 12 LV
segments.

32. PROSPECT TRIAL 2008
• Prospective, multicenter, nonrandomized trial
that enrolled 498 subjects with standard
indications for CRT.
• Ability of 12 echocardiographic indices of
mechanical dyssynchrony to predict response to
CRT
• High intraoperator and interobserver coefficient
of variation for the different parameters of
ventricular dyssynchrony.
• The study concluded that no single
echocardiographic measures of ventricular
mechanical dyssynchrony may be recommended
to improve patient selection for CRT .

33. ECHO CRT TRIAL 2013
• 809 patients with New York Heart Association
class III or IV heart failure, a LVEF ≤35%, a QRS
duration of < 130 msec, and
• Echocardiographic evidence of left ventricular
dyssynchrony
• CRT does not reduce the rate of death or
hospitalization for heart failure and may increase
mortality

34. ECHO IN DYSSYNCHRONY ASSESSMENT

35. ECHO IN DYSSYNCHRONY ASSESSMENT

36. RT3D ECHO & CMR
• In RT3D ECHO ,assessment of LV dyssynchrony
is based on analysis of regional volumetric
changes .
• Systolic Dyssynchrony Index (SDI) can be
derived from the dispersion of the time to
minimum regional volume for all 16 LV
segments.

38. CORE TRIALS
• In 2001, the safety and efficacy of CRT were first
addressed by both the MUSTIC and PATH-HF
• MUSTIC study, 67 patients with HF were
randomized to 3 months of off or on CRT.
• Compared with CRT-off, CRT-on improved
walking distance, quality of life, and peak oxygen
uptake

39. CORE TRIALS…
• In the PATH-HF study , improvements in
walking distance and peak VO2 were observed
after 12 months of biventricular pacing.
• It was the first study to show LV reverse
remodeling after CRT

40. MIRACLE
• MIRACLE study , the first double-blind CRT
trial
• 453 patients with HF were randomized to CRT-P
or to no pacing.
• At 6 months, CRT-P improved walking distance,
quality of life, exercise capacity, left ventricular
ejection fraction (LVEF) and peak VO2,
paralleling LV reverse remodeling

42. MIRACLE-ICD
• First explored by the added benefit of CRT
in patients receiving ICD
• Patients with HF receiving OMT underwent
CRT-D and were randomized to CRT on or off.
• After 6 months, CRT-D led to improved quality
of life and NYHA functional class, but not
walking distance.
• Essentially, CRT-D led to clinical improvements
without safety concerns.

43. COMPANION TRIAL
• First trial to compare CRT-P and CRT-D with OPT.
• Compared with OPT, CRT-P and CRT-D led to a
20% reduction in death or hospitalization from any
cause.
• Total mortality was least with CRT-D, and no
mortality benefit emerged for CRT-P.
• The incremental benefit of adding ICD to CRT was
apparent

44. CARE-HF
• The Cardiac Resynchronization-Heart Failure
study , which randomized patients to OPT with
or without CRT-P
• CRT-P reduced death from any cause or
unplanned hospitalizations as well as total
mortality after 29 months.
• CRT-P improved quality of life and LVEF,
induced LV reverse remodeling, and reduced
mitral regurgitation

45. COMPANION AND CARE HF
• The COMPANION trial and the CARE-HF study
established CRT as a treatment for HF (NYHA
functional class III or IV), impaired LV function,
and a wide QRS complex.
• Characteristics of device-treated patients were
similar, the control group was ICD plus OPT in
the COMPANION trial and OPT only in the
CARE-HF study.

46. CRT in MILD HF
• The efficacy of CRT-D in mild HF was suggested by
the CONTAK CD study, which demonstrated LV
reverse remodeling across NYHA functional classes
II to IV
• MIRACLE ICD II study included patients in NYHA
functional class II - CRT-D induced LV reverse
remodeling compared with ICD.
• MADIT-CRT randomized 1,820 patients in NYHA
functional class I and II to CRT-D or ICD,
• CRT-D reduced total mortality or HF events by 34%.
• Mainly driven by reductions in HF events, with no
difference in total mortality.

47. REVERSE TRIAL
• 610 patients in NYHA functional class I/II with
primary prevention ICD indications were
randomized to CRT-on or CRT-off.
• Compared with CRToff,CRT-on did not reduce
composite HF endpoints,nor did it improve
quality of life or walking distance,
• But it improved LVEF and reduced HF
hospitalizations.

48. RAFT TRIAL
• RAFT compared CRT-D with ICD in NYHA
functional class II or III patients.
• The primary endpoint of total mortality or HF
hospitalization occurred in 33.2% in the CRT-D
group and in 40.3% in the ICD group (hazard
ratio:0.75; 95% confidence interval: 0.64 to
0.87).
• Addition of CRT to an ICD reduced rates of
death and hospitalization for heart failure

53. CRT & RV PACING
• HF is common during RV pacing.
• DAVID (Dual Chamber and VVI Implantable
Defibrillator) trial and the MOST (MOde
Selection Trial), RV pacing was associated with
increased HF hospitalizations
• Lending support for using CRT in patients with
LV dysfunction and conventional indications for
pacing

54. BLOCK HF & BIOPACE
• 691 patients with HF and conventional indications
for pacing were randomized to CRT or RV pacing.
•
• After 37 months, CRT was associated with a 26%
reduction in the primary composite endpoint of
total mortality, urgent HF care, or an increase in LV
end-systolic volume.
• Supports CRT over conventional RV pacing in
patients with LV dysfunction.
• More definitive evidence is expected from the
BIOPACE (Biventricular Pacing for Atrioventricular
Block to Prevent Cardiac Desynchronization) study

55. CRT IN AF
• In AF CRT can only correct VV and intraventricular
dyssynchrony.
• CRT delivery is also hampered by high intrinsic
ventricular rates and irregularity, leading to reduced
capture, fusion, and pseudofusion
• Gasparini et al. explored the outcome of CRT, in
combination with either ablation or rate-slowing drugs,
in patients with permanent AF.
• Over a median follow-up of 37 months patients receiving
AF + ablation had risks of total and cardiac mortality
comparable to those of patients in sinus rhythm.
• Randomized data on the effects of CRT in patients with
AF are lacking.

56. CRT & NARROW QRS
• 2 most recent multicenter RCTs LESSER-EARTH
trial EchoCRT failed to show a mortality benefit
from adding CRT to ICD in this patient group.
• In LESSEREARTH, CRT did not improve clinical
outcomes or induce LV reverse remodeling. Indeed,
there was a suggestion of potential harm.
• In Echo-CRT, patients with a QRS duration ≥ 130
ms, LVEF ≤35%and mechanical dyssynchrony
underwent CRT-D implantation and were then
randomized to CRT-on or -off.
• The trial was stopped prematurely for futility after
finding increased mortality with CRT-D.

57. QRS MORPHOLOGY
• REVERSE study confirmed the reduction in the
composite clinical endpoint only in patients with
LBBB .
• MADIT-CRT study showed a reduction in the
primary endpoint in patients with LBBB QRS
morphology only
• Survival benefit of CRT-D was observed in patients
with LBBB QRS morphology while patients with non-
LBBB morphology showed no effect and possibly
harm related to CRT-D

58. QRS MORPHOLOGY..
• RAFT showed a greater benefit in patients with LBBB
vs. non-LBBB morphology.
• Non-LBBB QRS morphology with a QRS .160 ms
experienced a modest reduction in the primary
outcome
• ? potential benefit of CRT in non-LBBB QRS
morphology in the presence of a marked QRS
prolongation (QRS ≥160 ms).
• Meta-analysis by Cleland et al.involving data from
CARE-HF, MIRACLE) REVERSE, MIRACLE ICD
suggested that only QRS duration predicted the
magnitude of the effect of CRT on outcomes.

59. RBBB & CRT
• By multivariable analysis, prolonged PR interval
and right bundle branch block (RBBB) were the
only predictors of non-favourable outcome.
•
• The 5% of patients with RBBB had a particularly
high event rate in CARE HF study.
• Data from the Medicare ICD Registry,which
included 14 946 patients, showed that CRT-D
was not effective in patients with RBBB, as
shown by the increased mortality at 3 years of
RBBB as compared to LBBB

73. PRIMARY PREVENTION OF SCD IN NYHA FC III/IV

76. THANK YOU