Cardiac Resynchronization Therapy Alena Goldman, MD 11/7/07 Harvard Medical School.

Cardiac Cardiac Resynchronization Resynchronization TherapyTherapy

Alena Goldman, MDAlena Goldman, MD

11/7/0711/7/07

Harvard Medical School


Rationale for CRT

Bundle branch block or other Bundle branch block or other intraventricular conduction delay can intraventricular conduction delay can worsen HF due to systolic dysfunctionworsen HF due to systolic dysfunction

Electrical ventricular dyssynchrony Electrical ventricular dyssynchrony common in advanced HF; correlated with common in advanced HF; correlated with increased mortalityincreased mortality

Initial theory behind use of CRT was an Initial theory behind use of CRT was an idea that hemodynamic benefits follow the idea that hemodynamic benefits follow the correction of dyssynchrony with CRTcorrection of dyssynchrony with CRT

CRT was developed in the early 90s and CRT was developed in the early 90s and was FDA approved as an adjunctive was FDA approved as an adjunctive therapy for severe systolic HF in 2001therapy for severe systolic HF in 2001


CRT: Moderate to CRT: Moderate to severe systolic heart severe systolic heart failure with wide QRSfailure 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.


Prevalence of Prevalence of Electrical Ventricular Electrical Ventricular Dyssynchrony in Heart Dyssynchrony in Heart FailureFailureLeft Bundle Branch Block More Prevalent

with Impaired LV Systolic Function

38%

24%

8%

Moderate/SevereHF (2)

Impaired LVSF(1)

Preserved LVSF(1)

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


Types of DyssynchronyTypes of Dyssynchrony

Mechanical: contractile Mechanical: contractile dyscoordinationdyscoordination

Electrical: QRS widthElectrical: QRS width Cause and effect relationship: Cause and effect relationship:

Electrical dyssynchrony leads to Electrical dyssynchrony leads to inefficient contraction (exception inefficient contraction (exception when mechanical dyssynchrony is when mechanical dyssynchrony is present despite normal QRS present despite normal QRS width)width)


Mechanisms of Mechanisms of Mechanical Mechanical DyssynchronyDyssynchrony InterInterventricular dyssynchrony: RV contracts ventricular dyssynchrony: RV contracts

before LV; affects septal contribution to LV stroke before LV; affects septal contribution to LV stroke volumevolume

IntraIntraventricular dyssynchrony: septum contracts ventricular dyssynchrony: septum contracts before the lateral wall (lateral wall can contract before the lateral wall (lateral wall can contract in early diastole); early contraction is ineffective in early diastole); early contraction is ineffective and late contraction stretches early contracting and late contraction stretches early contracting segmentssegments

AtrioventricularAtrioventricular dyssynchrony dyssynchrony Negative LV remodeling: increased Negative LV remodeling: increased

LVESV/increased wall stress/increased demand/ LVESV/increased wall stress/increased demand/ reduced contractility reduced contractility worsening LV systolic worsening LV systolic functionfunction

Impaired relaxation: LV diastolic dysfunctionImpaired relaxation: LV diastolic dysfunction Mitral regurgitationMitral regurgitation


Discoordinate MotionDiscoordinate Motion

Normal Sinus Rhythm

30 60 90

0

40

LV Volume (mL)

80

Acute Dyssynchrony (RV Pace)L

V P

ress

ure

(m

m H

g)

Adapted from Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.

Adverse Effects on Global Function From RV-Pacing–Induced Dyssynchrony


CRT: RationaleCRT: Rationale

CRT resynchronizes contractionCRT resynchronizes contraction Improves contractile LV functionImproves contractile LV function Is associated with reverse ventricular Is associated with reverse ventricular

remodelingremodeling Improves CO/CI; reduces PCWPImproves CO/CI; reduces PCWP Improves diastolic functionImproves diastolic function Reduces frequency of ventricular arrythmias Reduces frequency of ventricular arrythmias

and ICD therapiesand ICD therapies Increases HRVIncreases HRV Improves NYHA Class symptoms: QOL, Improves NYHA Class symptoms: QOL,

exercise capacity, functional capacityexercise capacity, functional capacity Reduces mortalityReduces mortality, due to both HF and SCD , due to both HF and SCD

(Care-HF)(Care-HF)


Achieving Cardiac Achieving Cardiac ResynchronizationResynchronization

Goal: Atrial synchronous biventricular pacing

Transvenous approach for left ventricular lead via coronary sinus

Back-up epicardial approach

Right AtrialLead

Right VentricularLead

Left VentricularLead


Regional Wall Motion Regional Wall Motion With CRT: Improved With CRT: Improved LVEFLVEF Septum

Lateral

Pacing OffPacing On

Reg

ion

al F

ract

ion

al A

rea

Ch

ang

e

Seconds 0.40

Seconds 0.40

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.


Ventricular Reverse Ventricular Reverse RemodelingRemodeling

With ResynchronizationWith Resynchronization

Adapted from Abraham WT, et al. N Engl J Med. 2002;346:1845-1853.

En

d-D

iast

olic

Dim

ensi

on

(m

m)

Eje

ctio

n F

ract

ion

(%

)6.0

6.5

7.5

10

20

P<0.001

Placebon=81

CRTn=63

CRTn=61

P<0.001

Placebon=63

30

CRT 6-monthControl 6-month CRT


Improvement with CRT Improvement with CRT - MR- MR


AV Interval AV Interval OptimizationOptimization

AV delay(0 to PR – 30 msec)

AV delay(0 to PR – 30 msec)

LVBV

Ch

ang

e in

Ao

rtic

PP

(%

)

Ch

ang

e in

dP

/dt m

ax (

%)

24

18

12

6

0

-12

-6

16

12

8

4

0

-8

-41 1

LVBV

Adapted from Auricchio A, et al. Circulation. 1999;99:2993-3001.


Synchronous vs Non-Synchronous vs Non-Synchronous BV Pacing: Synchronous BV Pacing: Is RV-LV Delay Is RV-LV Delay Important?Important?

* P<0.01 vs. Simultaneous (s)Sogaard P, et al. Circulation. 2002;106:2078-2084.

RV Preactivation S LV PreactivationSys

toli

c F

un

ctio

n (

Ech

o I

nd

ex) * *

6

5

4

3

2

1

0


Mortality/Morbidity Mortality/Morbidity From Published From Published Randomized, Randomized, Controlled TrialsControlled Trials

Risk reduction with CRTRisk reduction with CRT

Study Study (n random.)(n random.) Follow-upFollow-up

Mor-tality & Mor-tality & Hosp.Hosp.

Mortal. & HF Mortal. & HF Hosp.Hosp. Mor-talityMor-tality HF Mort.HF Mort. HF Hosp.HF Hosp.

MIRACLEMIRACLE11 (n=453) (n=453) 6 Mo6 Mo NRNR 39%*39%* 27%27% NRNR 50%*50%*

MIRACLE ICDMIRACLE ICD22 (n=369) (n=369) 6 Mo6 Mo 2%2% 0%0% 0%0% NRNR NRNR

Contak CDContak CD33 (n=490) (n=490) 3-6 Mo3-6 Mo NRNR NRNR 30%30% NRNR 18%18%

Meta-analysisMeta-analysis44 (n=1634) (n=1634) 3-6 Mo3-6 Mo NRNR NRNR 23%23% 51%*51%* 29%*29%*

* P < 0.05 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]

NR = Not reported in publication

Individual trials were not powered for mortality or hospitalization


Cumulative Enrollment Cumulative Enrollment in Cardiac in Cardiac Resynchronization Resynchronization Randomized TrialsRandomized Trials

0

1000

2000

3000

4000

1999 2000 2001 2002 2003 2004 2005

Results Presented

Cum

ulat

ive

Patien

ts

PATH CHF

MUSTIC SR

MUSTIC AF

MIRACLE

CONTAK CD

MIRACLE ICD

PATH CHF II

COMPANION

MIRACLE ICD II

CARE HF


Patient selectionPatient selection

Current recommendations for bi-Current recommendations for bi-ventricular pacing are based on ventricular pacing are based on evidence of electrical (NOT evidence of electrical (NOT mechanical) dyssynchronymechanical) dyssynchrony


Can We Predict Can We Predict Responders?Responders? Electrical dyssynchrony/Wide QRS complexElectrical dyssynchrony/Wide QRS complex

– Widely used, but only broadly correlates with acute Widely used, but only broadly correlates with acute responseresponse

– Weak predictor of chronic responseWeak predictor of chronic response Mechanical dyssynchronyMechanical dyssynchrony

– More direct target of CRTMore direct target of CRT– Used to follow responce Used to follow responce – Measures of wall dyssynchrony (MRI, ECHO, TDI) Measures of wall dyssynchrony (MRI, ECHO, TDI)

best correlate with acute and chronic best correlate with acute and chronic responsivenessresponsiveness

Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.


Who Responds to Who Responds to Cardiac Cardiac Resynchronization?Resynchronization?Responder Parameter(s)Responder Parameter(s) FindingFinding Limitation(s)Limitation(s)

NYHA III/IV, QRSNYHA III/IV, QRS 120 120 ms, EFms, EF 35%, LVEDD 35%, LVEDD 55 mm55 mm

Confirmed in RCTs of Confirmed in RCTs of over 2,500 patientsover 2,500 patients

~ 70% respond ~ 70% respond favorablyfavorably

QRS QRS 150/155 and/or 150/155 and/or dP/dt dP/dt 700 mm Hg/s 700 mm Hg/s

Correlated with Correlated with improved dP/dt improved dP/dt 1,21,2

Small studies, < 30 pts;Small studies, < 30 pts; No clinical endpointNo clinical endpoint not confirmed by not confirmed by MIRACLEMIRACLE

Difference in time to Difference in time to peak systolic contractionpeak systolic contraction

Correlated with Correlated with volumes volumes 3,4,53,4,5

Small studies, Small studies, 30 pts; 30 pts; Varying techniquesVarying techniques No clinical endpointNo clinical endpoint

No MI, significant mitral No MI, significant mitral regurgitation regurgitation

Correlated with Correlated with improved NYHAimproved NYHA66

Observational study;Observational study; not confirmed by not confirmed by MIRACLEMIRACLE

1. Circulation. 2000;101:2703-2709 2. Circulation 1999;99:2993-3001 3. Am J Cardiol 2002;91:684–688

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


Summary of Major Summary of Major TrialsTrials Significant clinical benefit of CRT in patients with class Significant clinical benefit of CRT in patients with class

III-IV HF, low EF, and QRS > 120III-IV HF, low EF, and QRS > 120– Improvement in symptomsImprovement in symptoms– Improvement in objective standards of HFImprovement in objective standards of HF

Meta-analysisMeta-analysis– 29% decrease in HF hospitalization (13% vs. 29% decrease in HF hospitalization (13% vs.

17.4%)17.4%)– 51% decrease in deaths from HF (1.7% vs. 3.5%)51% decrease in deaths from HF (1.7% vs. 3.5%)– Trend toward decrease in overall mortality (4.9% Trend toward decrease in overall mortality (4.9%

vs 6.3%) vs 6.3%) BUT: >30% non-responders consistent through most BUT: >30% non-responders consistent through most

trialstrialsBradley et al. JAMA 2003;289:730


Targeting Electrical Targeting Electrical Dyssynchrony: QRS Dyssynchrony: QRS DurationDuration Pros:Pros:

– QRS >120 msQRS >120 ms– LBBB>RBBBLBBB>RBBB– Correlation between QRS and response to CRT Correlation between QRS and response to CRT

modest (rmodest (r22 = 0.6) = 0.6) Cons:Cons:

– Evidence of LV dyssynchrony with QRS < 120Evidence of LV dyssynchrony with QRS < 120– Small trial in patients with QRS < 120 suggest Small trial in patients with QRS < 120 suggest

these patients may also benefit from CRTthese patients may also benefit from CRT


Imaging Measures of Imaging Measures of Mechanical Mechanical Dyssynchrony:Dyssynchrony: 20-30% of patients with evidence 20-30% of patients with evidence

of electrical dyssynchrony do not of electrical dyssynchrony do not benefit from CRT regardless of benefit from CRT regardless of baseline QRS duration and QRS baseline QRS duration and QRS narrowing with CRTnarrowing with CRT

Imaging allows direct Imaging allows direct visualization of mechanical visualization of mechanical dyssynchronydyssynchrony


Imaging TechniquesImaging Techniques

M Mode and 2DM Mode and 2D TDI with echoTDI with echo Myocardial strain imagingMyocardial strain imaging 3D Echo3D Echo CMRCMR


Other ModalitiesOther Modalities

Electrical activation pattern Electrical activation pattern during bi-V pacing by EP mappingduring bi-V pacing by EP mapping

Delta QRS during bi-V pacingDelta QRS during bi-V pacing


M-mode EchoM-mode Echo

InterInterventricular ventricular dyssynchrony/motdyssynchrony/motion delay – IVMDion delay – IVMD

Time difference Time difference between left and between left and right pre-ejection right pre-ejection intervalsintervals

IVMD IVMD ≥ 50 ms≥ 50 ms


M Mode EchoM Mode Echo

IntraIntraventricular ventricular DyssynchronyDyssynchrony

Septal-to-posterior wall Septal-to-posterior wall motion delay (SPWMD)motion delay (SPWMD)

SPWMD SPWMD ≥ 130 ms≥ 130 ms

D 20 60 380140 220 300

SPWMD (msec)

r =-.70P=.001

+20

0

-20

-40

-60

-80

-100

LV

ES

VI

(mL

/m2)

SPWMD predicts improvement with CRT(in 25 patients)

Adapted from Pitzalis MV, et al. J Am Coll Cardiol. 2002;40:1615-1622.


TDI ImagingTDI Imaging

PW DopplerPW Doppler Reflects regional systolic velocityReflects regional systolic velocity Timed to the QRSTimed to the QRS Dyssynchrony criteria:Dyssynchrony criteria:

– 12 sample volume model (any 2 > 100 ms, 12 sample volume model (any 2 > 100 ms, SD > 33ms)SD > 33ms)

– 2 sample volume – basal septum and 2 sample volume – basal septum and lateral wall delay lateral wall delay ≥≥ 50ms 50ms

– Interventricular delay Interventricular delay ≥ 50ms≥ 50ms


TDI AssessmentTDI Assessmentfor Predicting for Predicting RespondersResponders

Adapted from Sogaard P, et al. J Am Coll Cardiol. 2002;40:723-730.


Patients with Intraventricular LV Patients with Intraventricular LV Dyssynchrony of ≥ 65 ms Have an Dyssynchrony of ≥ 65 ms Have an Excellent Response to CRTExcellent Response to CRT

85 patients with severe HF, LBBB, 85 patients with severe HF, LBBB, QRS duration > 120 msQRS duration > 120 ms

TDI prior to CRTTDI prior to CRT Dyssynchrony was defined as the Dyssynchrony was defined as the

maximum delay between the maximum delay between the time to peak systolic contraction time to peak systolic contraction velocity among four ventricular velocity among four ventricular walls (anterior, inferior, septal walls (anterior, inferior, septal and lateral)and lateral)

Bax et. Al., JACC 2004:1834-40


TDI as Predictor of TDI as Predictor of Response to CRT, Response to CRT, Cont’Cont’

Bax et. Al., JACC 2004:1834-40



Bax et. Al., JACC 2004:1834-40



ROC curve analysisROC curve analysis Sensitivity and Sensitivity and

specificity of 80% specificity of 80% to predict CRT to predict CRT response at a cut-off response at a cut-off level of 65 ms of LV level of 65 ms of LV dyssynchronydyssynchrony

Response defined as Response defined as improvement in improvement in NYHA class and 6 NYHA class and 6 min walkmin walk

Bax et. Al., JACC 2004:1834-40



Sensitivity and Sensitivity and specificity of 92% specificity of 92% to predict reverse to predict reverse LV remodelingLV remodeling

Defined as Defined as improvement of improvement of LVESV of ≥ 15%LVESV of ≥ 15%

Bax et. Al., JACC 2004:1834-40


Limitations of TDILimitations of TDI

Technical limitations: multiple Technical limitations: multiple peaks (can be seen even in peaks (can be seen even in structurally normal hearts), structurally normal hearts), artifact, experience of the artifact, experience of the operatoroperator

Examines motion, not contraction Examines motion, not contraction per seper se

Interpretation difficult in the Interpretation difficult in the setting of akinetic wall/scarsetting of akinetic wall/scar


Strain Rate AnalysisStrain Rate Analysis

Differentiates between tethering or Differentiates between tethering or passive motion of non-contractile passive motion of non-contractile myocardium of TDI alone and active myocardium of TDI alone and active contractioncontraction

Limitations: technical factors, artifacts, Limitations: technical factors, artifacts, low signal-to-noise ratio, difficult low signal-to-noise ratio, difficult image acquisitionimage acquisition

Radial strain is not well reproduced in Radial strain is not well reproduced in multiple studiesmultiple studies


Strain Rate Imaging: Strain Rate Imaging: Normal HeartNormal Heart

Breithardt et. Al, Eur Heart J, 2004: D16-24


Strain Rate Imaging: Strain Rate Imaging: Patient with LBBBPatient with LBBB

Onset of radial Onset of radial motion and strain motion and strain in inferoseptal, in inferoseptal, inferior and inferior and inferolateral wallsinferolateral walls

Interregional Interregional delay in onset of delay in onset of regional regional thickeningthickening


3D Echo3D Echo

Better spatial resolutionBetter spatial resolution High level post processingHigh level post processing Evaluate all walls simultaneouslyEvaluate all walls simultaneously Need more dataNeed more data


3D Echo3D Echo


PROSPECT StudyPROSPECT Study

Predictors of Response to CRTPredictors of Response to CRT ESC Congress Reports 2007ESC Congress Reports 2007 Prospective study evaluating role Prospective study evaluating role

of echo in predicting response to of echo in predicting response to CRTCRT

Primary end-point: clinical Primary end-point: clinical composite score (CCS) and LVESVcomposite score (CCS) and LVESV

Ghio, et. al


PROSPECT Study, PROSPECT Study, Cont’Cont’ Echo prior to CRT or CRT-DEcho prior to CRT or CRT-D Echo post with AV delay Echo post with AV delay

optimizationoptimization Training of participating sitesTraining of participating sites Repeat echo in 6 monthsRepeat echo in 6 months Baseline characteristics: 426 Baseline characteristics: 426

patients, avearage QRS 160 ms, patients, avearage QRS 160 ms, LVEF 24%, most with LBBB, NYHA LVEF 24%, most with LBBB, NYHA class III and IV sxsclass III and IV sxs

Ghio, et. al


PROSPECT Study, PROSPECT Study, Cont’Cont’ At 6 monthsAt 6 months Overall CCS improvement rate is Overall CCS improvement rate is

75.6% for non-ischemic and 75.6% for non-ischemic and 63.7% for ischemic patients63.7% for ischemic patients

Overall LVESV improvement rate Overall LVESV improvement rate is 63% for non-ischemic and is 63% for non-ischemic and 50.3% for ischemic patients 50.3% for ischemic patients

Ghio, et. al


PROSPECT Study, PROSPECT Study, Cont’Cont’ Substantial inter-core lab Substantial inter-core lab

variability in all TDI based variability in all TDI based dyssynchrony measuresdyssynchrony measures

At the same time, the presence of At the same time, the presence of a single mechanical delay (MD) a single mechanical delay (MD) measure added 11-13% response measure added 11-13% response to CCS and 13-23% to LVESVto CCS and 13-23% to LVESV

Ghio, et. al


PROSPECT Study: PROSPECT Study: ConclusionConclusion No single measure of mechanical No single measure of mechanical

dyssynchrony may be dyssynchrony may be recommended to improve patient recommended to improve patient selection for CRTselection for CRT

Methodology to determine Methodology to determine mechanical dyssynchrony needs mechanical dyssynchrony needs further elaborationfurther elaboration

Ghio, et. al


ConclusionsConclusions

CRT is an effective adjunctive non-CRT is an effective adjunctive non-pharmocological therapy for patients with pharmocological therapy for patients with advanced heart failure due to systolic left advanced heart failure due to systolic left ventricular dysfunction with evidence of ventricular dysfunction with evidence of electrical and mechanical dyssynchronyelectrical and mechanical dyssynchrony

Many imaging modalities exist to evaluate for Many imaging modalities exist to evaluate for mechanical LV dyssynchronymechanical LV dyssynchrony

TDI based measures do not appear to be TDI based measures do not appear to be good predictors that could improve patient good predictors that could improve patient selection for CRTselection for CRT

Up to 30% of patients, selected based on Up to 30% of patients, selected based on current guidelines, are non-responders current guidelines, are non-responders


Conclusions, Cont’Conclusions, Cont’

TDI based measures are helpful in TDI based measures are helpful in following/optimizing patients post bi-V implant following/optimizing patients post bi-V implant (AV delay optimization, V-V optimization)(AV delay optimization, V-V optimization)

More studies required to evaluate TDI modalities More studies required to evaluate TDI modalities in patients with narrow QRS and RBBB with in patients with narrow QRS and RBBB with evidence of mechanical dyssynchronyevidence of mechanical dyssynchrony

Echo guided LV (and maybe RV) lead placement, Echo guided LV (and maybe RV) lead placement, especially in patients with prior transmural especially in patients with prior transmural infarctinfarct

3D echo3D echo CMR data (especially with development of CMR CMR data (especially with development of CMR

compatible leads)compatible leads)

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Cardiac Resynchronization Therapy Alena Goldman, MD 11/7/07 Harvard Medical School.

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