Saverio Iacopino, FACC, FESC

1. Prognostic Indicators and Cardiac Remodeling After CRT Saverio Iacopino, FACC, FESC Sant’Anna HospitalCatanzaro

2. 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

3. 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 Preserved 8% 49% LVSF (1) 34% Impaired 24% LVSF (1) QRS < QRS > Mod/Sev 38% 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

4. The only reliable predictive criterion of positive response to CRT is the degree of QRS shortening

5. 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

6. 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

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

8. How the Current Predictors Are Reliable?

9. QRS width remains the selectium criterium of dyssynchrony to identify patients suitable for CRT

10. All-cause mortality ESV≥10% Survival ESV<10% 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

11. 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 37% 22% 12% 3% Ypenburg C et al. – JACC 2009;53:483-90

12. 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 Electrical impulse

13. Dobutamine Eco-Stress Test Agricola et al. Cardiovascular Ultrasound 2004

14. 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

16. 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

17. 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

18. LODO-CRT – DSE Test 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 Yes End test No Cut-off: increase of at least 5% in EF value with respect to rest conditions 10 μg/Kg/min Dobutamine infusion for 5 min Yes End test No 15 μg/Kg/min Dobutamine infusion for 5 min Yes End test No 20 μg/Kg/min Dobutamine infusion for 5 min Final EF assessment Iacopino S. et al., CHF 2010

19. 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

20. LODO-CRT – Acute DSE Results Iacopino S. et al., CHF 2010

21. LODO-CRT – Acute DSE Results Iacopino S. et al., CHF 2010

22. LODO-CRT – Etiology 106 (39%) patients have HF of ischemic origin Iacopino S. et al., CHF 2010

23. LODO-CRT Multivariable Logistic Regression Iacopino S. et al., CHF 2010

24. 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

25. Baseline Characteristics Muto C. et al., Heart Rhythm 2010

26. 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

27. Logistic Regression Analysis for Identification of Independent Predictors to Response to CRT Clinical Response ECHO Response Gasparini M. et al., JAMA submitted

28. Assessment of Survival Over Time to MCE in Patients with and without LVCR Gasparini M. et al., JAMA submitted

29. Positive Predictive Value of LVCR and inter-V Dyssynchrony Tests Combined Gasparini M. et al., JAMA submitted

30. 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

31. The interaction between AF and HF means thatneither can be treated optimally without treating both promotes HF AF aggravates

32. 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

33. 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

34. Long-Term Effects of CRT CRT response=reduction in LVESV >10% Gasparini M. JACC 2006; 48, 734-43

36. Patient Characteristics (N=490) J Am Coll Cardiol 2011;57:549-555

37. eGFR subgroups J Am Coll Cardiol 2011;57:549-555

38. 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

39. All-cause Mortality in the 3 eGFR subgroups eGFR ≥90 eGFR 60-90 Event-free survival eGFR <60 p<0.001 Follow-up (months) RJ Van Bommel et al. J Am CollCardiol 2011;57:549-555

40. Changes in eGFR from Baseline to 6 Months Follow-up, Responders vs. Non-responders (N=133) Change in eGFR (ml/min) p<0.05 RJ Van Bommel et al. J Am CollCardiol 2011;57:549-555

41. 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