Transcript Cardiac Memory: Mechanoelectrical Remodeling

Cardiac Resynchronization
Therapy
Alena Goldman, MD
11/7/07
Harvard
Medical
School
Rationale for CRT
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Bundle branch block or other intraventricular
conduction delay can worsen HF due to systolic
dysfunction
Electrical ventricular dyssynchrony common in
advanced HF; correlated with increased mortality
Initial theory behind use of CRT was an idea that
hemodynamic benefits follow the correction of
dyssynchrony with CRT
CRT was developed in the early 90s and was FDA
approved as an adjunctive therapy for severe
systolic HF in 2001
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CRT: Moderate to severe
systolic heart failure with
wide QRS
Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348: 2007-2018. Copyright 2002 Massachusetts Medical Society.
All rights reserved.
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Prevalence of Electrical
Ventricular Dyssynchrony
in Heart Failure
Left Bundle Branch Block More Prevalent
with Impaired LV Systolic Function
Preserved LVSF
(1)
Impaired LVSF
(1)
8%
24%
Moderate/Severe
HF (2)
38%
1. Masoudi, et al. JACC 2003;41:217-23
2. Aaronson, et al. Circ 1997;95:2660-7
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Types of Dyssynchrony
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Mechanical: contractile
dyscoordination
Electrical: QRS width
Cause and effect relationship:
Electrical dyssynchrony leads to
inefficient contraction (exception when
mechanical dyssynchrony is present
despite normal QRS width)
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Mechanisms of
Mechanical Dyssynchrony
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Interventricular dyssynchrony: RV contracts before
LV; affects septal contribution to LV stroke volume
Intraventricular dyssynchrony: septum contracts
before the lateral wall (lateral wall can contract in
early diastole); early contraction is ineffective and
late contraction stretches early contracting
segments
Atrioventricular dyssynchrony
Negative LV remodeling: increased LVESV/increased
wall stress/increased demand/ reduced contractility
worsening LV systolic function
Impaired relaxation: LV diastolic dysfunction
Mitral regurgitation
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Discoordinate Motion
Adverse Effects on Global Function From RV-Pacing–Induced Dyssynchrony
Normal Sinus Rhythm
Acute Dyssynchrony (RV Pace)
LV Pressure (mm Hg)
80
40
0
30
60
90
LV Volume (mL)
Adapted from Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.
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CRT: Rationale
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CRT resynchronizes contraction
Improves contractile LV function
Is associated with reverse ventricular remodeling
Improves CO/CI; reduces PCWP
Improves diastolic function
Reduces frequency of ventricular arrythmias and
ICD therapies
Increases HRV
Improves NYHA Class symptoms: QOL, exercise
capacity, functional capacity
Reduces mortality, due to both HF and SCD (CareHF)
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Achieving Cardiac
Resynchronization
Goal: Atrial synchronous
biventricular pacing
Transvenous approach for left ventricular lead via
coronary sinus
Right Atrial
Lead
Back-up epicardial approach
Left Ventricular
Lead
Right Ventricular
Lead
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Regional Wall Motion
With CRT: Improved LVEF
Regional Fractional Area Change
Septum
0
Seconds
0.4
Lateral
0
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.
Seconds
Pacing Off
Pacing On
0.4
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Ventricular Reverse
Remodeling
With Resynchronization
P<0.001
P<0.001
Ejection Fraction (%)
End-Diastolic Dimension (mm)
7.5
6.5
30
20
6.0
10
Placebo
n=63
Control
CRT
n=61
6-month
Placebo
n=81
CRT
CRT
n=63
CRT 6-month
Adapted from Abraham WT, et al. N Engl J Med. 2002;346:1845-1853.
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Improvement with CRT MR
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AV Interval Optimization
LV
BV
12
8
4
0
1
-4
-8
AV delay
(0 to PR – 30 msec)
24
Change in dP/dtmax (%)
Change in Aortic PP (%)
16
LV
BV
18
12
6
0
1
-6
-12
AV delay
(0 to PR – 30 msec)
Adapted from Auricchio A, et al. Circulation. 1999;99:2993-3001.
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Systolic Function (Echo Index)
Synchronous vs NonSynchronous BV Pacing: Is
RV-LV Delay Important?
6
*
*
5
4
3
2
1
RV Preactivation
S
LV Preactivation
0
* P<0.01 vs. Simultaneous (s)
Sogaard P, et al. Circulation. 2002;106:2078-2084.
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Mortality/Morbidity From
Published Randomized,
Controlled Trials
Risk reduction with CRT
Study
(n random.)
Follow-up
Mor-tality &
Hosp.
Mortal. & HF
Hosp.
Mor-tality
HF Mort.
HF Hosp.
MIRACLE1 (n=453)
6 Mo
NR
39%*
27%
NR
50%*
MIRACLE ICD2 (n=369)
6 Mo
2%
0%
0%
NR
NR
Contak CD3 (n=490)
3-6 Mo
NR
NR
30%
NR
18%
Meta-analysis4 (n=1634)
3-6 Mo
NR
NR
23%
51%*
29%*
1. Abraham WT, et al. N Engl J Med 2002;346:1845-53
2. Young JB, et al. JAMA 2003;289:2685-94
3. Higgins SL, et al. JACC 2003; 42 1454-59
4. Bradley DJ, et al. JAMA 2003;289:730-740 [Includes
MIRACLE, MIRACLE ICD, Contak CD, and MUSTIC studies]
* P < 0.05
NR = Not reported in publication
Individual trials were not powered for
mortality or hospitalization
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Cumulative Patients
Cumulative Enrollment in
Cardiac Resynchronization
Randomized Trials
4000
CARE HF
MIRACLE ICD
3000
2000
1000
MIRACLE
MUSTIC AF
MIRACLE ICD II
MUSTIC SR
COMPANION
PATH CHF
PATH CHF II
CONTAK CD
0
1999
2000
2001
2002
2003
2004
2005
Results Presented
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Patient selection
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Current recommendations for biventricular pacing are based on
evidence of electrical (NOT
mechanical) dyssynchrony
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Can We Predict
Responders?
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Electrical dyssynchrony/Wide QRS complex
– Widely used, but only broadly correlates with acute
response
– Weak predictor of chronic response
Mechanical dyssynchrony
– More direct target of CRT
– Used to follow responce
– Measures of wall dyssynchrony (MRI, ECHO, TDI) best
correlate with acute and chronic responsiveness
Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.
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Who Responds to Cardiac
Resynchronization?
Responder Parameter(s)
Finding
Limitation(s)
NYHA III/IV, QRS 120 ms,
EF 35%, LVEDD 55 mm
Confirmed in RCTs of over
2,500 patients
QRS  150/155 and/or dP/dt
 700 mm Hg/s
Correlated with improved
dP/dt 1,2
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Difference in time to peak
systolic contraction
Correlated with 
volumes 3,4,5
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No MI, significant mitral
regurgitation
Correlated with improved
NYHA6
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1. Circulation. 2000;101:2703-2709
2. Circulation 1999;99:2993-3001
3. Am J Cardiol 2002;91:684–688
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~ 70% respond favorably
Small studies, < 30 pts;
No clinical endpoint
not confirmed by MIRACLE
Small studies,  30 pts;
Varying techniques
No clinical endpoint
Observational study;
not confirmed by MIRACLE
4. J Am Coll Cardiol 2002;40:1615-1622
5. J Am Coll Cardiol 2002;40:723–730
6. Am J Cardiol 2002;89:346-350
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Summary of Major Trials
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Significant clinical benefit of CRT in patients with class III-IV
HF, low EF, and QRS > 120
– Improvement in symptoms
– Improvement in 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: >30% non-responders consistent through most trials
Bradley et al. JAMA 2003;289:730
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Targeting Electrical
Dyssynchrony: QRS
Duration
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Pros:
– QRS >120 ms
– LBBB>RBBB
– Correlation between QRS and response to CRT
modest (r2 = 0.6)
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Cons:
– Evidence of LV dyssynchrony with QRS < 120
– Small trial in patients with QRS < 120 suggest
these patients may also benefit from CRT
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Imaging Measures of
Mechanical Dyssynchrony:
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20-30% of patients with evidence of
electrical dyssynchrony do not benefit
from CRT regardless of baseline QRS
duration and QRS narrowing with CRT
Imaging allows direct visualization of
mechanical dyssynchrony
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Imaging Techniques
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M Mode and 2D
TDI with echo
Myocardial strain imaging
3D Echo
CMR
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Other Modalities
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Electrical activation pattern during bi-V
pacing by EP mapping
Delta QRS during bi-V pacing
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M-mode Echo
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Interventricular
dyssynchrony/motion
delay – IVMD
Time difference
between left and
right pre-ejection
intervals
IVMD ≥ 50 ms
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M Mode Echo
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Intraventricular
Dyssynchrony
Septal-to-posterior wall
motion delay (SPWMD)
SPWMD ≥ 130 ms
SPWMD predicts improvement with CRT
(in 25 patients)
+20
r =-.70
P=.001
0
 LVESVI (mL/m2)
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-20
-40
-60
-80
-100
D 20
60
140
220
300
380
SPWMD (msec)
Adapted from Pitzalis MV, et al. J Am Coll Cardiol. 2002;40:1615-1622.
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TDI Imaging
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PW Doppler
Reflects regional systolic velocity
Timed to the QRS
Dyssynchrony criteria:
– 12 sample volume model (any 2 > 100 ms, SD >
33ms)
– 2 sample volume – basal septum and lateral wall
delay ≥ 50ms
– Interventricular delay ≥ 50ms
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TDI Assessment
for Predicting Responders
Adapted from Sogaard P, et al. J Am Coll Cardiol. 2002;40:723-730.
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Patients with Intraventricular LV
Dyssynchrony of ≥ 65 ms Have an
Excellent Response to CRT
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85 patients with severe HF, LBBB, QRS
duration > 120 ms
TDI prior to CRT
Dyssynchrony was defined as the
maximum delay between the time to
peak systolic contraction velocity
among four ventricular walls (anterior,
inferior, septal and lateral)
Bax et. Al., JACC 2004:1834-40
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TDI as Predictor of
Response to CRT, Cont’
Bax et. Al., JACC 2004:1834-40
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TDI as Predictor of
Response to CRT, Cont’
Bax et. Al., JACC 2004:1834-40
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TDI as Predictor of
Response to CRT, Cont’
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ROC curve analysis
Sensitivity and
specificity of 80% to
predict CRT response
at a cut-off level of 65
ms of LV dyssynchrony
Response defined as
improvement in NYHA
class and 6 min walk
Bax et. Al., JACC 2004:1834-40
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TDI as Predictor of
Response to CRT, Cont’
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Sensitivity and
specificity of 92%
to predict reverse
LV remodeling
Defined as
improvement of
LVESV of ≥ 15%
Bax et. Al., JACC 2004:1834-40
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Limitations of TDI
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Technical limitations: multiple peaks
(can be seen even in structurally
normal hearts), artifact, experience of
the operator
Examines motion, not contraction per
se
Interpretation difficult in the setting of
akinetic wall/scar
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Strain Rate Analysis
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Differentiates between tethering or passive
motion of non-contractile myocardium of
TDI alone and active contraction
Limitations: technical factors, artifacts, low
signal-to-noise ratio, difficult image
acquisition
Radial strain is not well reproduced in
multiple studies
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Strain Rate Imaging:
Normal Heart
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Strain Rate Imaging:
Patient with LBBB
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Onset of radial
motion and strain in
inferoseptal, inferior
and inferolateral
walls
Interregional delay
in onset of regional
thickening
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3D Echo
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Better spatial resolution
High level post processing
Evaluate all walls simultaneously
Need more data
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3D Echo
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PROSPECT Study
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Predictors of Response to CRT
ESC Congress Reports 2007
Prospective study evaluating role of
echo in predicting response to CRT
Primary end-point: clinical composite
score (CCS) and LVESV
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PROSPECT Study, Cont’
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Echo prior to CRT or CRT-D
Echo post with AV delay optimization
Training of participating sites
Repeat echo in 6 months
Baseline characteristics: 426 patients,
avearage QRS 160 ms, LVEF 24%,
most with LBBB, NYHA class III and IV
sxs
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PROSPECT Study, Cont’
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At 6 months
Overall CCS improvement rate is
75.6% for non-ischemic and 63.7% for
ischemic patients
Overall LVESV improvement rate is
63% for non-ischemic and 50.3% for
ischemic patients
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PROSPECT Study, Cont’
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Substantial inter-core lab variability in
all TDI based dyssynchrony measures
At the same time, the presence of a
single mechanical delay (MD) measure
added 11-13% response to CCS and
13-23% to LVESV
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PROSPECT Study:
Conclusion
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No single measure of mechanical
dyssynchrony may be recommended
to improve patient selection for CRT
Methodology to determine mechanical
dyssynchrony needs further
elaboration
Ghio, et. al
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Conclusions
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CRT is an effective adjunctive non-pharmocological
therapy for patients with advanced heart failure due
to systolic left ventricular dysfunction with evidence
of electrical and mechanical dyssynchrony
Many imaging modalities exist to evaluate for
mechanical LV dyssynchrony
TDI based measures do not appear to be good
predictors that could improve patient selection for
CRT
Up to 30% of patients, selected based on current
guidelines, are non-responders
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Conclusions, Cont’
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TDI based measures are helpful in
following/optimizing patients post bi-V implant (AV
delay optimization, V-V optimization)
More studies required to evaluate TDI modalities in
patients with narrow QRS and RBBB with evidence
of mechanical dyssynchrony
Echo guided LV (and maybe RV) lead placement,
especially in patients with prior transmural infarct
3D echo
CMR data (especially with development of CMR
compatible leads)
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