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Prognostic Indicators and
Cardiac Remodeling
After CRT
Saverio Iacopino, FACC, FESC
Sant’Anna Hospital Catanzaro
Indications of CRT
CRT using BIV pacing can be considered in patients
with reduced EF and ventricular dyssynchrony (QRS
widht > 120 msec), who remain symptomatic (NYHA
III-IV) despite optimal medical therapy to improve:
 Symptoms (Class I, level A)
 Hospitalizations (Class I, level A)
 Mortality (Class I, level B)
ESC Guidelines
Prevalence and Prognosis of
Ventricular Dysynchrony
Increased All-Cause Mortality with
Wide QRS at 45 Months (3)
LBBB More Prevalent with
Impaired LV Systolic Function
Preserved
LVSF (1)
Impaired
LVSF (1)
Mod/Sev
HF (2)
P < 0.001
8%
49%
34%
24%
QRS <
120 ms
38%
1. Masoudi, et al. JACC 2003;41:217-23
2. Aaronson, et al. Circ 1997;95:2660-7
QRS >
120 ms
3. Iuliano et al. AHJ 2002;143:1085-91
Ventricular dysynchrony impairs diastolic and systolic function 4-6:
Reduced LV filling time; Increased mitral regurgitation; Depressed dP/dt
4. Grines, et al. Circulation 1989;79:845-53
5. Xiao, et al. Br Heart J 1991;66:443-7
6. Xiao et al. Br Heart J 1992;68:403-7
The only reliable predictive criterion of positive
response to CRT is the degree of QRS shortening
Limitations of ECG in the
Evaluation of Asynchrony
 It does not have enough sensitivity to detect the
presence of electromechanical delay in each
region of the left ventricle
 Some patients have mechanical asynchrony
without delay electric (hypertrophy, fibrosis,
collagen-ultrastructural changes of myocytes)
CRT: how many can benefit?
Clinical response (NYHA, QoL) : 60%-75% of patients
Objective response (e.g., ventricular reverse remodeling): 50%-60% of patients
Birnie et al. Curr Opin Cardiol 2006
Responders: Why Not ?
 DCM Etiology
 Variability of Dissinchrony
 Available contractility reserve
How the Current Predictors Are Reliable?
QRS width remains the selectium criterium of
dyssynchrony to identify patients suitable for CRT
Reduction of LVESV in Defining
“Prognostic Responder” to CRT
All-cause mortality
Survival
ESV≥10%
Reduction in LVESV ≥10% at 3-6 months
post-implantation predicts
all cause mortality (p = 0.0003)
ESV<10%
Discriminatory ability was quite modest:
sensitivity and specificity 70%
Yu CM et al. – Circulation 2005;112:1580-6
Reverse Remodeling After CRT
Relates Linearly to Prognosis
Death, heart transplantation and hospitalization for HF
37%
22%
12%
More extensive reverse
remodeling resulted in
lower mortality and
hospitalization
3%
Ypenburg C et al. – JACC 2009;53:483-90
New Criteria for Patient Selection?
Is contractility assessment the key for success?
A model of impulse conduction in impaired tissue ...
extent of scar area and quantity of the
interstizial fibrotic tissue
Necrotic tissue
Healthy cells
Interstitial fibrotic tissue
presence and density of the
myocardial beta-receptors
Slow
conduction
Electrical
impulse
Dobutamine Eco-Stress
Test
Agricola et al. Cardiovascular Ultrasound 2004
LODO-CRT Trial - Preliminary Experience
A reverse remodelling was significantly related to Contractile
Reserve (r=0.63; p<0.00001)
At Multivariate logistic regression (including QRS duration):
Contractile Reserve (OR: 11.2; CI: 6.2-19.8; p<0.001)
CRT response
R
DSE test
R 25
response
NR 0
NR
2
Sensitivity: 100%
Specificity: 88%
15
Tuccillo B, Muto C et al., J Interv Card Electrophysiol. 2008 Nov;23(2):121-6
LODO-CRT - Methods
DSE test cut-off
A patient is considered responder to DSE test if the increase of LVEF at peak
stress is at least 5 points with respect to the value at rest
Sample size justification
 The nonresponse rate to CRT, evaluated by means of a remodeling end
point, ranges from 40% to 50% of patients. Thus, assumed responder rate is
estimated at 60% in this patient population
 The DSE responder-nonresponder ratio is estimated to be 3:1
 It is estimated that demonstration of LVCR using DSE (DSE-positive) will
increase CRT responder rate by 20% compared to the absence of DSEassessed LVCR
 15% lost-to-follow-up rate
270 patients followed-up for 12 months
Muto C. et al., Am H J. 2008
Low-dose Dobutamine Stress-echocardiography to Predict
Cardiac Resynchronization Therapy Response (LODO-CRT)
Trial - Baseline Characteristics of the Study Population
Saverio Iacopino, MD; Maurizio Gasparini, MD; Francesco Zanon, MD; Cosimo
Dicandia, MD; Giuseppe Distefano, MD; Antonio Curnis, MD; Roberto Donati, MD; Valeria Calvi,
MD; Carlo Peraldo Neja, MD; Mario Davinelli, PhD; Vanessa Novelli, BA; Carmine Muto, MD
297 patients enrolled
290 patients implanted
271 patients considered
for the analysis
CRT implant
success rate: 96%
19 incomplete baseline measures
- 8 LVESV not measured
- 11 echo not completed
- inadequate or missing data
Iacopino S. et al., CHF 2010
LODO-CRT – DSE Test
5 μg/Kg/min Dobutamine
infusion for 5 min
EF assessment at rest
End test
Yes
EF assessment
Cut-off reached?
No
10 μg/Kg/min Dobutamine
infusion for 5 min
End test
Yes
EF assessment
Cut-off reached?
No
Cut-off: increase of at
least 5% in EF value
with respect to rest
conditions
15 μg/Kg/min Dobutamine
infusion for 5 min
End test
Yes
EF assessment
Cut-off reached?
No
Iacopino S. et al., CHF 2010
20 μg/Kg/min Dobutamine
infusion for 5 min
Final EF assessment
LODO-CRT – Acute DSE Results
Test was interrupted in 3 patients due to ventricular
arrhythmias onset
99%
The test was feasible in
of the patients w/out
complications
LVEF at rest (%)
LVEF at peak-stress (%)
CR+ n (%)
26± 6
35±9
198 (73)
About 3 out of 4 patients showed presence of CR
This confirms preliminary experiences
Iacopino S. et al., CHF 2010
LODO-CRT – Acute DSE Results
DSE Test
CR - (62)
CR + (206)
p value
LVEF at rest (%)
26±5
26 ±6
0,184
LVEF at peak stress (%)
28 ±6
38 ±8
<0,001
Iacopino S. et al., CHF 2010
LODO-CRT – Acute DSE Results
ECHO measures
CR - 62 (23%)
CR + 206 (77%)
p value
LVEDD (mm)
71±9
66±8
0,001
LVESD (mm)
59±10
55±9
0,005
LVEDV (ml)
237±91
197±72
0,001
LVESV (ml)
178±74
145±59
0,001
LVEF (%)
26±5
27±6
0,433
IVMD (ms)
30±49
28±51
0,586
Inter-Ventricular delay presence n (%)
36 (58)
89 (43)
0,040
Q - Lateral wall delay (ms)
358±135
377±147
0,399
Q - E wave delay (ms)
493±106
522±96
0,052
8 (11)
24 (12)
0,878
E-A duration (ms)
405±159
381±133
0,336
E/A
1,6± 1,6
1,1±0,9
0,030
E wave deceleration time (ms)
126±56
174±83
0,002
Presence of restrictive pattern n (%)
31 (44)
45 (23)
<0,001
Mitral regurgitation
23 (38)
44 (22)
0,012
Delayed Lateral Contraction n (%)
Iacopino S. et al., CHF 2010
LODO-CRT – Etiology
106 (39%) patients have HF of ischemic origin
DSE test
LVEF at rest (%)
LVEF at peak stress (%)
CR + (%)
Iacopino S. et al., CHF 2010
Ischemic
Nonischemic
p value
26±5
36 ±9
76%
26±6
35±9
70%
0,600
0,394
0,270
LODO-CRT
Multivariable Logistic Regression
Iacopino S. et al., CHF 2010
Presence of Left Ventricular Contractile Reserve Predicts
Mid-term Response to Cardiac Resynchronization Therapy
Results from the LODO-CRT trial
Carmine Muto, Maurizio Gasparini, Carlo Peraldo Neja, Saverio Iacopino, Mario Davinelli,
Francesco Zanon, Cosimo Dicandia, Giuseppe Distefano, Roberto Donati, Valeria Calvi,
Alessandra Denaro, Bernardino Tuccillo
Muto C. et al., Heart Rhythm 2010
Baseline Characteristics
Muto C. et al., Heart Rhythm 2010
Distribution of CRT Response in the
Groups with and without LVCR
CRT responders in patients with LVCR: 145/185 (78%)
LVEF increase under DSE is significantly associated with CRT response (OR:1.35, c.i.
1.08-1.68, p=0.008 for each 5-point increase of LVEF) (Univariable Logistic Regression)
LVCR presence at baseline is an independent predictor of response to CRT
(OR=5.59; c.i. 2.25-13.90; p<0.001) (Multivariable Logistic Regression)
Muto C. et al., Heart Rhythm 2010
Logistic Regression Analysis for
Identification of Independent
Predictors to Response to CRT
Predictors
response to CRT
ClinicalofResponse
QRS duration
No previous MI
Inter-V dyssynchrony presence
LVCR presence
Predictors
response to CRT
ECHOof Response
Hypertension
No previous revascularization
Left Ventricular End Systolic Diameter
Inter-V dyssynchrony presence
LVCR presence
Univariable analysis
OR p-value
95%CI
1.02 0.041
1.00
2.53 0.017
1.18
3.19 0.007
1.37
2.35 0.040
1.04
Multivariable analysis
OR
p-value
95%CI
1.05
5.42
7.44
5.31
Univariable analysis
OR
p-value
95%CI
2.33 0.020
1.14 4.76
2.84 0.002
1.47 5.48
0.96 0.014
0.93 0.99
6.09 <0.001
2.66 13.93
9.00 <0.001
4.10 19.73
3.38
2.57
0.005
0.028
1.43
1.11
7.98
5.98
Multivariable analysis
OR
p-value 95%CI
10.81
39.36
0.001
<0.001
2.69
9.73
43.47
159.21
Gasparini M. et al., JAMA submitted
Assessment of Survival Over Time to
MCE in Patients with and without
LVCR
Gasparini M. et al., JAMA submitted
Positive Predictive Value of LVCR and
inter-V Dyssynchrony Tests Combined
Gasparini M. et al., JAMA submitted
Study Limitations
The LODO-CRT is an observational trial
Results of this experience should in any case be
confirmed by a randomized study, before considering
the inclusion of the DSE test in the guidelines for CRT
patient selection
The cut-off used for the definition of response to
CRT is obviously arbitrary, although an
association between this cut-off value and the
long-term prognosis of these patients has been
shown
The interaction between AF and HF means that
neither can be treated optimally
without treating both
HF
promotes
aggravates
AF
Implantable CRT Device Diagnostics Identify Patients
with Increased Risk for Heart Failure Hospitalization.
ICD Diagnostics quantify HF Hospitalization Risk
Giovanni B. Perego, MD; Maurizio Landolina, MD; Giuseppe Vergara, MD; Maurizio
Lunati, MD; Gabriele Zanotto, MD; Alessia Pappone, MD; Gabriele Lonardi, MD;
Giancarlo Speca, MD; Saverio Iacopino, MD; Annamaria Varbaro, MS; Shantanu Sarkar,
PhD; Doug A. Hettrick, PhD; Alessandra Denaro, MS;
on behalf of the physicians of the Optivol-CRT Clinical Service Observational Group.
To determine the association between device-determined
diagnostic indices, including intrathoracic impedance, and
heart failure (HF) hospitalization
Journal of Interventional Cardiac Electrophysiology 2008
558 HF patients indicated for
CRT-D were prospectively
collected from 34 centers.
Device-recorded
intrathoracic impedance
fluid index threshold
crossing event (TCE), mean
activity counts,
tachyarrhythmia events,
night heart rate (NHR) and
heart rate variability (HRV)
were compared within
patients with vs. without
documented HF
hospitalization.
Journal of Interventional Cardiac Electrophysiology 2008
Long-Term Effects of CRT
CRT response=reduction in LVESV >10%
Gasparini M. JACC 2006; 48, 734-43
Patient Characteristics (N=490)
Variable
Age (years)
Gender M/F
Ischemic etiology (n)
QRS duration (ms)
Serum creatinine (µmol/l)
eGFR (ml/min/1.73m2)
LVEDV (ml)
Baseline
follow-up
LVESV (ml)
Baseline
follow-up
LVEF (%)
Baseline
follow-up
Responders
(n = 263)
65 ± 10
Non-responders
(n = 227)
66 ± 11
p-value
202/61
129 (49%)
159 ± 33
104 ± 30
74 ± 26
190/37
164 (72%)
154 ± 31
127 ± 51
64 ± 28
0.070
<0.001
0.130
<0.001
<0.001
234 ± 86
179 ± 71*
219 ± 79
223 ± 75
0.055
<0.001
176 ± 77
116 ± 58‡
167 ± 70
167 ± 66
0.181
<0.001
26 ± 8
37 ± 9*
25 ± 8
26 ± 8
0.293
<0.001
0.392
J Am Coll Cardiol 2011;57:549-555
eGFR subgroups
Variable
eGFR <60
ml/min/1.73m2
N = 193
eGFR 60-90
ml/min/1.73m2
N = 204
eGFR ≥ 90
ml/min/1.73m2
N = 93
p-value
Age (years)
Gender M/F
Ischemic etiology (n)
QRS duration (ms)
71 ± 8
152/41
123 (64%)
161 ± 30
65 ± 8
165/39
121 (59%)
159 ± 33
56 ± 11
75/18
49 (53%)
147 ± 35
<0.001
0.856
0.200
0.001
NYHA class
6 MWT (m)
QoL score
3.1 ± 0.3
266 ± 99
37 ± 16
3.1 ± 0.3
308 ± 105
38 ± 18
3.0 ± 0.2
352 ± 98
33 ± 18
0.160
<0.001
0.091
LVEDV (ml)
LVESV (ml)
LVEF (%)
MR grade
218 ± 77
168 ± 71
24 ± 8
1.7 ± 1.1
235 ± 92
177 ± 80
26 ± 8
1.5 ± 1.1
229 ± 72
170 ± 64
27 ± 8
1.1 ± 0.8
0.127
0.423
0.022
<0.001
J Am Coll Cardiol 2011;57:549-555
Differences in Response to CRT
Between the 3 eGFR sub-groups
80%
*
*
60-90 (n = 204)
 90 (n = 93)
60%
Responders
Non-responders
40%
20%
0%
<60 (n = 193)
eGFR (ml/min)
RJ Van Bommel et al. J Am Coll Cardiol 2011;57:549-555
All-cause Mortality in the 3
eGFR subgroups
eGFR ≥90
Event-free survival
100%
80%
eGFR 60-90
60%
eGFR <60
40%
20%
p<0.001
0%
0
12
24
36
48
60
Follow-up (months)
RJ Van Bommel et al. J Am Coll Cardiol 2011;57:549-555
Change in eGFR (ml/min)
Changes in eGFR from Baseline to 6 Months
Follow-up, Responders vs. Non-responders
(N=133)
0
-2
-4
-6
p<0.05
-8
Responders
Non-responders
RJ Van Bommel et al. J Am Coll Cardiol 2011;57:549-555
Conclusion
Even though patient selection for CRT
may not be altered by knowledge of
some pre-implantation variables, it may
help to place the individual patient in
the appropriate part of the response
spectrum and aid in setting of
expectations