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Prognostic Indicators and Cardiac Remodeling After CRT. Saverio Iacopino, FACC, FESC. Sant ’ Anna Hospital Catanzaro. Indications of CRT. Symptoms (Class I, level A) Hospitalizations (Class I, level A) Mortality (Class I, level B).

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Prognostic Indicators and Cardiac Remodeling

After CRT

Saverio Iacopino, FACC, FESC

Sant’Anna HospitalCatanzaro

indications of crt
Indications of CRT

Symptoms (Class I, level A)

Hospitalizations (Class I, level A)

Mortality (Class I, level B)

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:

ESC Guidelines

prevalence and prognosis of ventricular dysynchrony
Prevalence and Prognosis of Ventricular Dysynchrony

Increased All-Cause Mortality with

LBBB More Prevalent with

Wide QRS at 45 Months (3)

Impaired LV Systolic Function

P < 0.001




LVSF (1)




LVSF (1)






120 ms

120 ms

HF (2)

1. Masoudi, et al. JACC 2003;41:217-23

3. Iuliano et al. AHJ 2002;143:1085-91

2. Aaronson, et al. Circ 1997;95:2660-7

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)

Limitations of ECG in the Evaluation of Asynchrony

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
Responders: Why Not ?
  • DCM Etiology
  • Variability of Dissinchrony
  • Available contractility reserve

All-cause mortality




Reduction of LVESV in Defining

“Prognostic Responder” to CRT

Reduction in LVESV ≥10% at 3-6 months post-implantation predicts

all cause mortality (p = 0.0003)

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

More extensive reverse

remodeling resulted in lower mortality and hospitalization





Ypenburg C et al. – JACC 2009;53:483-90


Necrotic tissue

Healthy cells

Interstitial fibrotic tissue

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

presence and density of the myocardial beta-receptors

Slow conduction




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)

Sensitivity: 100%

Specificity: 88%

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

  • 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 DSE-assessed LVCR
  • 15% lost-to-follow-up rate

Sample size justification

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

CRT implant

success rate: 96%

290 patients implanted

19 incomplete baseline measures

- 8 LVESV not measured

- 11 echo not completed

- inadequate or missing data

271 patients considered for the analysis

Iacopino S. et al., CHF 2010



EF assessment

Cut-off reached?

EF assessment

Cut-off reached?

EF assessment

Cut-off reached?

EF assessment at rest

5 μg/Kg/min Dobutamine infusion for 5 min


End test


Cut-off: increase of at least 5% in EF value with respect to rest conditions

10 μg/Kg/min Dobutamine infusion for 5 min


End test


15 μg/Kg/min Dobutamine infusion for 5 min


End test


20 μg/Kg/min Dobutamine infusion for 5 min

Final EF assessment

Iacopino S. et al., CHF 2010


LODO-CRT – Acute DSE Results

Test was interrupted in 3 patients due to ventricular arrhythmias onset

The test was feasible in 99% of the patients w/out complications

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

Iacopino S. et al., CHF 2010


LODO-CRT – Acute DSE Results

Iacopino S. et al., CHF 2010


LODO-CRT – Etiology

106 (39%) patients have HF of ischemic origin

Iacopino S. et al., CHF 2010



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

Clinical Response

ECHO Response

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 thatneither can be treated optimally without treating both






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
Patient Characteristics (N=490)

J Am Coll Cardiol 2011;57:549-555

egfr subgroups
eGFR subgroups

J Am Coll Cardiol 2011;57:549-555

differences in response to crt between the 3 egfr sub groups
Differences in Response to CRT Between the 3 eGFR sub-groups



eGFR (ml/min)

RJ Van Bommel et al. J Am CollCardiol 2011;57:549-555

all cause mortality in the 3 egfr subgroups
All-cause Mortality in the 3 eGFR subgroups

eGFR ≥90

eGFR 60-90

Event-free survival

eGFR <60


Follow-up (months)

RJ Van Bommel et al. J Am CollCardiol 2011;57:549-555

changes in egfr from baseline to 6 months follow up responders vs non responders n 133
Changes in eGFR from Baseline to 6 Months Follow-up, Responders vs. Non-responders (N=133)

Change in eGFR (ml/min)


RJ Van Bommel et al. J Am CollCardiol 2011;57:549-555


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