This document summarizes a presentation on cardiac resynchronization therapy (CRT). It discusses how CRT works to restore synchronized heart contraction in patients with heart failure and ventricular dyssynchrony. It reviews several important clinical trials that demonstrated the benefits of CRT in reducing mortality and hospitalization. The document also discusses current guidelines for CRT, factors that can reduce the effectiveness of CRT, and ongoing areas of research around using CRT in populations with narrow QRS or mild heart failure symptoms.

1. Cardiac Resynchronisation therapy
Asfandiar Ali
Resident
Adult Cardiology
Moderator: Yawer Saeed
May 2022
Section of Cardiology
Don’t stop until you are
proud

2. DISCLOSURE
• NONE

3. SAYNO TO DISSYNCHRONY,
BE THATIN HEARTOR IN LIFE

4. INTRODUCTION
IMPORTANT CLINICAL
STUDIES OF
PATIENTS WITH HF
AND WIDE
QRS COMPLEX
MECHANICAL
BENEFITS OF CRT
REDUCING THE
RATE OF
CRT NONRESPONSE
DETAILS OF
PROCEDURE
MARKERS OF
DYSSYNCHRONY
CRT
CURRENT
CONTROVERSY
AND FUTURE
DIRECTIONS
CURRENT
ACC/AHA/HRS
GUIDELINES

5. INTRODUCTION
• Systolic heart failure is a major problem globally & While pharmacologic therapy has drastically
improved outcomes in patients with systolic heart failure, hospitalizations from systolic heart
failure continue to increase and remain a major cost burden.
• Ventricular dyssynchrony arises because of delayed ventricular activation and contraction of the
ventricle, thereby disturbing the normally coordinated heartbeat
• In a dyssynchronously beating ventricle, one or more ventricular segments contract out of time
with the rest of the ventricle, which reduces the heart’s pumping efficiency by wasting energy and
worsening valvular regurgitation
• Approximately one third of patients with systolic heart failure (HF) and New York Heart Association
(NYHA) functional class III or IV symptoms suffer from dyssynchronous ventricular contraction4
• The aim of CRT is to restore mechanical synchrony by electrically activating the heart in a
synchronized manner
• There is strong evidence from randomized controlled trials showing that CRT combined with optimal
medical therapy improves HF symptoms, left ventricular ejection fraction (LVEF), and quality of life
(QOL),
while decreasing heart failure hospitalizations and reducing mortality

6. MARKERS OF DYSSYNCHRONY
• The American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm
Society (HRS) and Heart Failure Society of America (HFSA) guidelines for the use of cardiac
resynchronization therapy use a QRS duration of more than 120 ms on the 12-lead
electrocardiogram as a marker of ventricular dyssynchrony
• As the QRS complex represents ventricular depolarization, it follows that a wide QRS denotes
prolonged ventricular conduction time and nonsimultaneous activation of the ventricular walls.

7. • Cardiac resynchronization therapy is typically accomplished by adding a left ventricular pacing lead
to a standard pacemaker or defibrillator system, which typically includes right atrial and right
ventricular leads
• After cannulation of the coronary sinus, retrograde venography is performed to identify
coronary sinus anatomy. The pacing lead is then advanced into the target vein, ideally in the area of
the left ventricle with the greatest delay in contraction
• Optimal lead placement is dependent on the presence of an acceptable target vein, adequate
pacing capture threshold, lack of stimulation of the phrenic nerve and/or diaphragm, and lead
stability

9. MECHANICAL BENEFITS OF CRT
1. cardiac resynchronization therapy has been shown to decrease all 3 types of dyssynchrony
2. Intraventricular dyssynchrony within the left ventricle, which is often most prominent between the
early-activated interventricular septum and late activated posterolateral wall
3. Interventricular (V-V) dyssynchrony between the left and right ventricles, which is most often the
result of delayed activation of the left ventricle due to left bundle branch block
4. Atrioventricular (A-V) dyssynchrony secondary to prolonged AV nodal conduction coupled with His-
Purkinje system dysfunction.
5. Another benefit of pacing from the left ventricular lateral wall is early activation of the anterolateral
papillary muscle, which can decrease the severity of mitral regurgitation.
6. Mitral regurgitation also can be reduced over time because of reverse remodeling
induced by CRT, which reduces left ventricular cavity size, thus reducing mitral annular diameter
and allowing mitral leaflet coaptation

10. MUSTIC TRIAL
CARE HF TRIAL
COMPANION TRIAL
REVERSE TRIAL
MIRACLE ICD TRIAL
MIRACLE TRIAL
TRIALS ON
CRT
MADIT-CRT TRIAL
RETHINQ TRIAL

11. MULTISITE STIMULATION IN
CARDIOMYOPATHY TRIAL
(MUSTIC TRIAL)
STUDY POPULATION
• EF less than 35%
• Sinus rhythm
• NYHA III-IV symptoms
• Left ventricular end diastolic
volume more than 60mm
• QRS duration > 150ms
Primary End points
• Exercise tolerance
• Quality of life improvement
• Peak oxygen consumption
( during Active biventricular
pacing for 3 months and backup
RV only pacing for another 3
months)
• REPORTED IN 2001
• ONE OF THE FIRST TRIAL DEMONSTRATING
SIGNIFACANT CLINAICAL IMPROVEMENT
WITH CRT
• SINGLE BLINDED CROSS OVER STUDY
RESULTS
Statistically significant improvement in
• 6 minutes walking distance
• Improved quality of life
• Improved oxygen consumption

12. MULTICENTER INSYNC
RANDOMIZAED CLINICAL
EVALUATION
(MIRACLE TRIAL)
STUDY POPULATION
• EF less than 35%
• Sinus rhythm
• NYHA III-IV symptoms
• Left ventricular end diastolic
volume more than 60 mm
• QRS duration > 130 ms
Primary End points
1. Deaths or hospitalization
secondary to heart failure
2. 6 minutes waking distance
3. Improvement in NYHA
function class
4. Quality of life
• Followed soon after the MUSTIC trial
• Sample size 453
• Randomization into CRT vs Control
groups
• Follow up time 6 months
RESULTS
Statistically significant improvement in
• Deaths or Hospitalization secondary to
heart failure
• Improvement in NYHA FC
• 6 minutes walking distance
• Improved quality of life
• Improved oxygen consumption

13. Results of MIRACLE TRIAL

14. MULTICENTER INSYNC
RANDOMIZAED CLINICAL
EVALUATION ICD
(MIRACLE ICD TRIAL)
STUDY POPULATION
• EF less than 35%
• Sinus rhythm
• NYHA III-IV symptoms
• Left ventricular end diastolic
volume more than 60 mm
• QRS duration > 130 ms
Primary End points
1. 6 minutes waking distance
2. Improvement in NYHA
function class
3. Quality of life
4. Oxygen consumption
• First Randomized trial that evaluated
the effectiveness of CRT with an ICD
• Sample size 369
• Follow up duration 6 months
• Randomization to CRT-ICD on and
CRT-ICD off groups
RESULTS
Statistically significant improvement in
• Improvement in NYHA FC
• 6 minutes walking distance
• Improved quality of life
• Improved oxygen consumption
The MIRACLE ICD trial also demonstrated that
• CRT does not interfere with the function of ICD
• The time required for the device to detect first VFIB did
not differ between the two groups
• CRT did not have a significant effect on the percentage
of patients who suffered ventricular
tachyarrhythmia's or inappropriate device shocks.

15. COMPANION TRIAL
STUDY POPULATION
• EF less than 35%
• Sinus rhythm
• NYHA III-IV symptoms
• QRS duration > 120 ms
Primary End points
• Composite end point of time to
hospitalization or deaths from
any cause
Secondary end points
• All cause Mortality
• First Randomized trial that was powered
to evaluate the Effect of CRT on Mortality
• Sample size 1520
• Randomization into 3 treatment arms
1. Optimal medical therapy alone (OMT)
2. OMT plus CRT with pacing only (CRT-P)
3. OMT plus CRT with
pacemaker/defibrillator (CRT-D)
• Patient were assigned in a 1:2:2 fashion
• Follow up period 1 year
RESULTS
• The CRT-D group, but not the
CRT-P group, had a significant
reduction in overall mortality as
compared to the group receiving OMT
alone
• The CRT-P group barely missed
statistical significance for overall
mortality (P = 0.059)

16. Results of COMPANION TRIAL
Kaplan-Meier curve showing overall survival in the cardiac resynchronization therapy-pacemaker (CRT-P)
group, CRT-defibrillator (CRT-D) group, and control group in the COMPANION trial. The CRT-D cohort showed
a significant reduction in all-cause mortality, while the CRT-P cohort barely missed statistical significance for
this end point.

17. CARE-HEART FAILURE TRIAL
(CARE-HF TRIAL)
STUDY POPULATION
• EF equal or less than 35%
• Sinus rhythm
• NYHA III-IV symptoms
• QRS duration > 120 ms
Primary End points
• composite of all-cause mortality or
hospitalization for a major
cardiovascular event
Secondary End points
• all-cause mortality.
• Followed COMAPANION trial in 2005
• Sample size 813
• Randomization in OMT group CRT-P
group
• OMT group 404
• CRT-P group 409
• Of note only 8% of people were
having QRS between 120-150, rest
were having QRS> 150
RESULTS
• Compared to OMT alone, CRT-P was
associated with a significant reduction in
all-cause mortality and hospitalization for
major cardiovascular events at 29
months
• CARE-HF was the first trial to show
definitively that CRT-P, even in the
absence of ICD therapy, had a mortality
benefit

18. Combined end point of mortality and/or heart
failure hospitalization
all-cause mortality
Results of CARE-HF trial

19. CURRENT
ACC/AHA/HRS
GUIDELINES
Class I (‘‘Indicated’’)
• Treatment with CRT (with or without
an ICD) is indicated for patients with
sinus rhythm, LVEF of 35% or less,
QRSd of 120 ms or more, and NYHA
class III or ambulatory class IV HF
symptoms despite optimal medical
therapy
Class IIa (‘‘Reasonable’’)
• Treatment with CRT (with or
without an ICD) is considered
reasonable for patients with sinus
rhythm, LVEF of 35% or less, and
NYHA class III or ambulatory class IV
HF symptoms despite optimal
medical therapy, who have frequent
dependence on ventricular pacing
Class IIa (‘‘Reasonable’’)
• Treatment with CRT (with or
without an ICD) is
considered reasonable for patients
in atrial fibrillation (AF), LVEF of
35% or less, QRSd of 120 ms or
more, and NYHA class III or
ambulatory class IV HF symptoms
despite optimal medical therapy
Class IIb (‘‘May Be Considered’’)
• Treatment with CRT may be considered
for patients with sinus rhythm, LVEF of
35% or less, and NYHA class I or class II
HF symptoms, who are undergoing
implantation of a permanent
pacemaker/ICD with anticipated
frequent ventricular pacing

20. Class III (Not Indicated)
• Treatment with CRT is not indicated for
asymptomatic patients with reduced
LVEF in the absence of other
indications for pacing, or for those
whose functional status and life
expectancy are limited predominantly
by chronic noncardiac conditions

21. REDUCINGTHE RATE OF CRT NONRESPONSE
• Despite randomized controlled trials showing significant average improvements in morbidity and mortality
as a result of CRT, the number of patients who do not improve symptomatically remains high at 30%.
• for biventricular pacing to have any effect, pacing must occur. If the patient’s own heart rate
exceeds the device’s programmed lower rate limit, pacing is inhibited and the potential benefits
of resynchronization are missed completely
• Biventricular pacing appears to be of greatest benefit when the ventricle is paced frequently (as
close to 100% as possible)
• The presence of ischemic cardiomyopathy (rather than nonischemic cardiomyopathy) has been
shown to be an independent predictor for CRT nonresponse.
• A large scar burden with nonviable myocardium in the area of pacing, especially with a severely
enlarged and remodeled ventricle, can cause high capture thresholds and can influence mechanical
function.

22. CURRENT
CONTROVERSY
& FUTURE
DIRECTIONS
Patients with AF
Patients with a
relatively narrow QRSd
(120 ms)
Patients with right
bundle branch block
(RBBB)
Patients with NYHA
class I and II HF (ie,
asymptomatic or mildly
symptomatic)

23. Do patients with heart failure who have AF respond as well to CRT
as do patients in sinus rhythm?
• A meta-analysis of prospective cohort studies( totaling 1164 patients) comparing the
impact of CRT on patients in AF versus those in sinus rhythm showed similar
improvement in LVEF between the 2 groups.
• However, the benefit in functional outcome (measured by NYHA functional class, 6-
minute walking distance, for patients with AF was less than that for patients in sinus
rhythm.
• To achieve a high percentage of biventricularly paced beats in patients with AF, often
it is necessary to slow conduction through the AV node ( by the use of Beta blocker/
calcium channel blocker/ digoxin or catheter ablation of AV node).

24. CRT & NARROW QRS (<120MS)
THE
RESYNCHRONIZATION
THERAPY IN NARROW
QRS (RETHINQ TRIAL)
• First Randomized
control trial that
demonstrated the
effect of CRT in
patients with Narrow
QRS.
STUDY POPULATION
• EF 35% or Less
• NYHA class III
• QRS < 120
• Evidence of M
• mechanical dyssynchrony on
ECHO
PRIMARY END POINT
• Peak O2 consumption at 6
months
• Improvement in NYHA class
• Quality of Life
RESULTS
• The study failed to
demonstrate an
improvement in the
primary end points

25. CRT & NARROW QRS (<120MS)
• The RethinQ trial showed that CRT is not beneficial in patients with
systolic heart failure and QRSd of less than 120 ms
• Similar Trial ECHOCRT demonstrated the same Results
So in conclusion CRT is not Indicated In Patient with a Narrow QRS i-e QRS
duration Less than 120

26. CRT and NYHA class I & II
Does CRT cause reverse remodeling in asymptomatic or
mildly symptomatic left ventricular dysfunction, and thereby
slow progression of disease?
Resynchronization
Reverses Remodeling in
Systolic Left Ventricular
Dysfunction
(REVERSE) trial
Multicenter Automatic
Defibrillator Implantation
With Cardiac
Resynchronization Therapy
(MADIT-CRT) trial

27. CRT & NYHA class I & II
Resynchronization
Reverses Remodeling
in Systolic Left
Ventricular
Dysfunction
(REVERSE) Trial
• Design parallel,
blinded, Randomized
• Sample size 610
• NYHA Class I 18%
• NYHA class II 82%
• Randomization in
CRT-ON & CRT-OFF
• Follow up 5 years
STUDY POPULATION
• LV dysfunction (≤40%)
• Prolonged QRS duration
(≥120 ms)
• NYHA class I-II
• Optimal medical therapy
• No indication for
permanent pacing
PRIMARY END POINTS
• composite of all-cause
mortality
• heart failure hospitalization
• progression to a higher HF
class
• worsening global assessment
score.
RESULTS
• The study did show a
statistically significant
reduction in the
composite end point (34%
worsening in CRT-off versus
19% in CRT-on, P50.01)

28. CRT & NYHA class I & II
MADIT-CRT TRIAL
• Design parallel,
blinded, Randomized
• Sample size 1820
• ICM NYHA Class I
14% class II 40%
• NICM NYHA class II
45%
• Randomization into
3:2 into CRT-D or ICD
alone groups
• Follow up 7 years
STUDY POPULATION
• LV dysfunction (≤30%)
• Prolonged QRS duration
(≥120 ms)
• ICM NYHA class I-II
• NICM NYHA class II
• Optimal medical therapy
• Normal sinus rhythm
PRIMARY END POINTS
• composite of all-cause
mortality
• heart failure hospitalization
RESULTS
• there was a 29% reduction
in this combined end point in the
CRT-D group compared to the
group with ICD alone (P= 0.003)
• Reduction in primary end point was
driven primarily by 41% reduction
in Heart failure events alone
• No significant difference in
mortality

29. • Both REVERSE and MADIT-CRT trials
concluded that CRT may indeed be useful in slowing
the progression of mildly symptomatic systolic HF
• Therefore Patient with asymptomatic or Mild heart failure
(NYHA class I & II) with QRS equal or more than 120ms
benefits from Cardiac resynchronization therapy.

30. CRT and RBBB
How the addition of a left ventricular lead could improve synchrony
in patients whose right ventricular activation is delayed?
• RBBB can mask underlying concomitant delay in the left bundle
branch
• The benefit of CRT for patients with RBBB is an area of active investigation, and
further analysis of a larger cohort of patients is needed
• Currently, the ACC/AHA/HRS guidelines do not discriminate with regard to
specific QRS morphology in their CRT recommendations