Saverio Iacopino, FACC, FESC

Saverio Iacopino, FACC, Saverio Iacopino, FACC, FESCFESC

SantSant’’Anna HospitalAnna Hospital CatanzaroCatanzaro

Prognostic Indicators and Cardiac Remodeling

After 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

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

Increased All-Cause Mortality with Wide QRS at 45 Months (3)

34%

49%

QRS < 120 ms

QRS >120 ms

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

P < 0.001

LBBB More Prevalent with Impaired LV Systolic Function

38%

24%

8%

Mod/SevHF (2)

ImpairedLVSF (1)

PreservedLVSF (1)

1. Masoudi, et al. JACC 2003;41:217-232. Aaronson, et al. Circ 1997;95:2660-7

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 CRTReduction in LVESV ≥10% at 3-6

months post-implantation predictsall cause mortality (p = 0.0003)

Discriminatory ability was quite modest:

sensitivity and specificity 70%

Yu CM Yu CM et al. – et al. – CirculationCirculation 2005;112:1580-6 2005;112:1580-6

Surv

ival

All-cause mortality

ESV≥10%

ESV<10%

Reverse Remodeling After CRT

Relates Linearly to Prognosis

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

More extensive reverse remodeling resulted in

lower mortality and hospitalization

37%37%

22%22%

12%12%

3%3%

Death, heart transplantation and hospitalization for HF

Necrotic tissueHealthy cells

Interstitial fibrotic tissue

New Criteria for Patient Selection?

extent of scar area and quantity of the interstizial

fibrotic tissue

presence and density of the myocardial beta-receptors

Is contractility assessment the key for success?

A model of impulse conduction in impaired tissue ...

Electrical impulse

Slow conducti

on

Dobutamine Eco-Stress Test

Agricola et al. Cardiovascular Ultrasound 2004

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)

LODO-CRT Trial - Preliminary Experience

CRT response

DSE testresponse

R NR

R 25 2

NR 0 15

Sensitivity: 100%Specificity: 88%

Tuccillo B, Muto C et al., J Interv Card Electrophysiol. 2008 Nov;23(2):121-6

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

LODO-CRT - Methods

270 patients followed-up for 12 months

DSE test cut-offA 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

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 PopulationSaverio 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

Iacopino S. et al., CHF 2010

297 patients enrolled

290 patients implanted

271 patients considered for the

analysis

19 incomplete baseline measures

- 8 LVESV not measured- 11 echo not completed- inadequate or missing

data

CRT implant success rate: 96%

EF assessment at rest

EF assessmentCut-off reached?

No

Yes



No

No

Yes

Yes

Final EF assessment

End test

End test

End test

Cut-off: increase of at least 5% in EF

value with respect to rest conditions

LODO-CRT – DSE Test

10 μg/Kg/min Dobutamine infusion

for 5 min


for 5 min


for 5 min


for 5 min


LVEF at rest (%) 26± 6LVEF at peak-stress (%) 35±9

CR+ n (%)198 (73)

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 CRThis confirms preliminary experiences

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



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

Delayed Lateral Contraction n (%) 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



DSE test Ischemi

cNonischemi

c p

value

LVEF at rest (%) 26±5 26±6 0,600

LVEF at peak stress (%) 36 ±9 35±9 0,394

CR + (%) 76% 70% 0,270

106 (39%) patients have HF of ischemic origin

LODO-CRT – Etiology


LODO-CRT Multivariable Logistic

Regression


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


CRT responders in patients with LVCR: 145/185 (78%)

Distribution of CRT Response in the

Groups with and without LVCR


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)

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


Positive Predictive Value of LVCR and inter-V Dyssynchrony Tests

Combined


Study LimitationsThe 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

HFAF

promotes

aggravates

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

Gasparini M. JACC 2006; 48, 734-43

Long-Term Effects of CRT

CRT response=reduction in LVESV >10%

Patient Characteristics (N=490)Variable Responders

(n = 263)Non-responders

(n = 227)p-value

Age (years) 65 ± 10 66 ± 11 0.392

Gender M/F 202/61 190/37 0.070

Ischemic etiology (n) 129 (49%) 164 (72%) <0.001

QRS duration (ms) 159 ± 33 154 ± 31 0.130

Serum creatinine (µmol/l) 104 ± 30 127 ± 51 <0.001

eGFR (ml/min/1.73m2) 74 ± 26 64 ± 28 <0.001

LVEDV (ml)

Baseline 234 ± 86 219 ± 79 0.055

follow-up 179 ± 71* 223 ± 75 <0.001

LVESV (ml)

Baseline 176 ± 77 167 ± 70 0.181

follow-up 116 ± 58‡ 167 ± 66 <0.001

LVEF (%)

Baseline 26 ± 8 25 ± 8 0.293

follow-up 37 ± 9* 26 ± 8 <0.001

J Am Coll Cardiol 2011;57:549-555

eGFR subgroupsVariable 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) 71 ± 8 65 ± 8 56 ± 11 <0.001

Gender M/F 152/41 165/39 75/18 0.856

Ischemic etiology (n) 123 (64%) 121 (59%) 49 (53%) 0.200

QRS duration (ms) 161 ± 30 159 ± 33 147 ± 35 0.001

NYHA class 3.1 ± 0.3 3.1 ± 0.3 3.0 ± 0.2 0.160

6 MWT (m) 266 ± 99 308 ± 105 352 ± 98 <0.001

QoL score 37 ± 16 38 ± 18 33 ± 18 0.091

LVEDV (ml) 218 ± 77 235 ± 92 229 ± 72 0.127

LVESV (ml) 168 ± 71 177 ± 80 170 ± 64 0.423

LVEF (%) 24 ± 8 26 ± 8 27 ± 8 0.022

MR grade 1.7 ± 1.1 1.5 ± 1.1 1.1 ± 0.8 <0.001

J Am Coll Cardiol 2011;57:549-555

Differences in Response to CRT Between the 3 eGFR sub-

groups

<60 (n = 193) 60-90 (n = 204) 90 (n = 93)0%

20%

40%

60%

80%RespondersNon-responders

eGFR (ml/min)

**

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

All-cause Mortality in the 3 eGFR subgroups

0 12 24 36 48 600%

20%

40%

60%

80%

100%

Follow-up (months)

Even

t-fr

ee s

urv

ival

eGFR <60

eGFR ≥90

p<0.001

eGFR 60-90


Changes in eGFR from Baseline to 6 Months Follow-up, Responders vs. Non-

responders (N=133)

Responders Non-responders-8

-6

-4

-2

0

Ch

an

ge in

eG

FR (

ml/m

in)

p<0.05


Even though patient selection for CRT may not be altered by knowledge ofsome pre-implantation variables, it may help to place the individual patient in the appropriate part of the responsespectrum and aid in setting of expectations

Conclusion

Saverio Iacopino, FACC, FESC

Documents

Transcript of Saverio Iacopino, FACC, FESC