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

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Presentation on theme: "Cardiac Resynchronization Therapy Alena Goldman, MD 11/7/07 Harvard Medical School."— Presentation transcript:

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

2 Rationale for CRT Bundle branch block or other intraventricular conduction delay can worsen HF due to systolic dysfunction Bundle branch block or other intraventricular conduction delay can worsen HF due to systolic dysfunction Electrical ventricular dyssynchrony common in advanced HF; correlated with increased mortality Electrical ventricular dyssynchrony common in advanced HF; correlated with increased mortality Initial theory behind use of CRT was an idea that hemodynamic benefits follow the correction of dyssynchrony with CRT Initial theory behind use of CRT was an idea that hemodynamic benefits follow the correction of dyssynchrony with CRT CRT was developed in the early 90s and was FDA approved as an adjunctive therapy for severe systolic HF in 2001 CRT was developed in the early 90s and was FDA approved as an adjunctive therapy for severe systolic HF in 2001

3 Harvard Medical School CRT: Moderate to severe systolic heart failure with wide QRS Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348: Copyright 2002 Massachusetts Medical Society. All rights reserved.

4 Harvard Medical School Prevalence of Electrical Ventricular Dyssynchrony in Heart Failure 1. Masoudi, et al. JACC 2003;41: Aaronson, et al. Circ 1997;95:2660-7

5 Harvard Medical School Types of Dyssynchrony Mechanical: contractile dyscoordination Mechanical: contractile dyscoordination Electrical: QRS width Electrical: QRS width Cause and effect relationship: Electrical dyssynchrony leads to inefficient contraction (exception when mechanical dyssynchrony is present despite normal QRS width) Cause and effect relationship: Electrical dyssynchrony leads to inefficient contraction (exception when mechanical dyssynchrony is present despite normal QRS width)

6 Harvard Medical School Mechanisms of Mechanical Dyssynchrony Interventricular dyssynchrony: RV contracts before LV; affects septal contribution to LV stroke volume Interventricular dyssynchrony: RV contracts before LV; affects septal contribution to LV stroke volume Intraventricular dyssynchrony: septum contracts before the lateral wall (lateral wall can contract in early diastole); early contraction is ineffective and late contraction stretches early contracting segments Intraventricular dyssynchrony: septum contracts before the lateral wall (lateral wall can contract in early diastole); early contraction is ineffective and late contraction stretches early contracting segments Atrioventricular dyssynchrony Atrioventricular dyssynchrony Negative LV remodeling: increased LVESV/increased wall stress/increased demand/ reduced contractility  worsening LV systolic function Negative LV remodeling: increased LVESV/increased wall stress/increased demand/ reduced contractility  worsening LV systolic function Impaired relaxation: LV diastolic dysfunction Impaired relaxation: LV diastolic dysfunction Mitral regurgitation Mitral regurgitation

7 Harvard Medical School Discoordinate Motion Normal Sinus Rhythm LV Volume (mL) 80 Acute Dyssynchrony (RV Pace) LV Pressure (mm Hg) Adapted from Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13. Adverse Effects on Global Function From RV-Pacing–Induced Dyssynchrony

8 Harvard Medical School CRT: Rationale CRT resynchronizes contraction CRT resynchronizes contraction Improves contractile LV function Improves contractile LV function Is associated with reverse ventricular remodeling Is associated with reverse ventricular remodeling Improves CO/CI; reduces PCWP Improves CO/CI; reduces PCWP Improves diastolic function Improves diastolic function Reduces frequency of ventricular arrythmias and ICD therapies Reduces frequency of ventricular arrythmias and ICD therapies Increases HRV Increases HRV Improves NYHA Class symptoms: QOL, exercise capacity, functional capacity Improves NYHA Class symptoms: QOL, exercise capacity, functional capacity Reduces mortality, due to both HF and SCD (Care- HF) Reduces mortality, due to both HF and SCD (Care- HF)

9 Harvard Medical School Achieving Cardiac Resynchronization Goal: Atrial synchronous biventricular pacing Transvenous approach for left ventricular lead via coronary sinus Back-up epicardial approach Right Atrial Lead Right Ventricular Lead Left Ventricular Lead

10 Harvard Medical School Regional Wall Motion With CRT: Improved LVEF Septum Lateral Pacing Off Pacing On Regional Fractional Area Change Seconds0.40 Seconds0.40 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:

11 Harvard Medical School Ventricular Reverse Remodeling With Resynchronization Adapted from Abraham WT, et al. N Engl J Med. 2002;346: End-Diastolic Dimension (mm) Ejection Fraction (%) P<0.001 Placebo n=81 CRT n=63 CRT n=61 P<0.001 Placebo n=63 30 CRT 6-monthControl6-monthCRT

12 Harvard Medical School Improvement with CRT - MR

13 Harvard Medical School AV Interval Optimization AV delay (0 to PR – 30 msec) LV BV Change in Aortic PP (%) Change in dP/dt max (%) LV BV Adapted from Auricchio A, et al. Circulation. 1999;99:

14 Harvard Medical School Synchronous vs Non- Synchronous BV Pacing: Is RV-LV Delay Important? * P<0.01 vs. Simultaneous (s) Sogaard P, et al. Circulation. 2002;106: RV Preactivation SLV Preactivation Systolic Function (Echo Index) * *

15 Harvard Medical School Mortality/Morbidity From Published Randomized, Controlled Trials Risk reduction with CRT Study (n random.) Follow-up Mor-tality & Hosp. Mortal. & HF Hosp. Mor-tality HF Mort. HF Hosp. MIRACLE 1 (n=453) 6 Mo NR39%*27%NR50%* MIRACLE ICD 2 (n=369) 6 Mo 2%0%0%NRNR Contak CD 3 (n=490) 3-6 Mo NRNR30%NR18% Meta-analysis 4 (n=1634) 3-6 Mo NRNR23%51%*29%* * P < Abraham WT, et al. N Engl J Med 2002;346: Young JB, et al. JAMA 2003;289: Higgins SL, et al. JACC 2003; Bradley DJ, et al. JAMA 2003;289: [Includes MIRACLE, MIRACLE ICD, Contak CD, and MUSTIC studies] NR = Not reported in publication Individual trials were not powered for mortality or hospitalization

16 Harvard Medical School Cumulative Enrollment in Cardiac Resynchronization Randomized Trials

17 Harvard Medical School Patient selection Current recommendations for bi- ventricular pacing are based on evidence of electrical (NOT mechanical) dyssynchrony Current recommendations for bi- ventricular pacing are based on evidence of electrical (NOT mechanical) dyssynchrony

18 Harvard Medical School Can We Predict Responders? Electrical dyssynchrony/Wide QRS complex Electrical dyssynchrony/Wide QRS complex –Widely used, but only broadly correlates with acute response –Weak predictor of chronic response Mechanical dyssynchrony Mechanical dyssynchrony –More direct target of CRT –Used to follow responce –Measures of wall dyssynchrony (MRI, ECHO, TDI) best correlate with acute and chronic responsiveness Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.

19 Harvard Medical School Who Responds to Cardiac Resynchronization? Responder Parameter(s) FindingLimitation(s) NYHA III/IV, QRS  120 ms, EF  35%, LVEDD  55 mm Confirmed in RCTs of over 2,500 patients ~ 70% respond favorably ~ 70% respond favorably QRS  150/155 and/or dP/dt  700 mm Hg/s Correlated with improved dP/dt 1,2 Small studies, < 30 pts; Small studies, < 30 pts; No clinical endpoint No clinical endpoint not confirmed by MIRACLE not confirmed by MIRACLE Difference in time to peak systolic contraction Correlated with  volumes 3,4,5 Small studies,  30 pts; Small studies,  30 pts; Varying techniques Varying techniques No clinical endpoint No clinical endpoint No MI, significant mitral regurgitation Correlated with improved NYHA 6 Observational study; Observational study; not confirmed by MIRACLE not confirmed by MIRACLE 1. Circulation. 2000;101: Circulation 1999;99: Am J Cardiol 2002;91:684– J Am Coll Cardiol 2002;40: J Am Coll Cardiol 2002;40:723– Am J Cardiol 2002;89:

20 Harvard Medical School Summary of Major Trials Significant clinical benefit of CRT in patients with class III-IV HF, low EF, and QRS > 120 Significant clinical benefit of CRT in patients with class III-IV HF, low EF, and QRS > 120 –Improvement in symptoms –Improvement in objective standards of HF Meta-analysis Meta-analysis –29% decrease in HF hospitalization (13% vs. 17.4%) –51% decrease in deaths from HF (1.7% vs. 3.5%) –Trend toward decrease in overall mortality (4.9% vs 6.3%) BUT: >30% non-responders consistent through most trials BUT: >30% non-responders consistent through most trials Bradley et al. JAMA 2003;289:730

21 Harvard Medical School Targeting Electrical Dyssynchrony: QRS Duration Pros: Pros: –QRS >120 ms –LBBB>RBBB –Correlation between QRS and response to CRT modest (r 2 = 0.6) Cons: Cons: –Evidence of LV dyssynchrony with QRS < 120 –Small trial in patients with QRS < 120 suggest these patients may also benefit from CRT

22 Harvard Medical School Imaging Measures of Mechanical Dyssynchrony: 20-30% of patients with evidence of electrical dyssynchrony do not benefit from CRT regardless of baseline QRS duration and QRS narrowing with CRT 20-30% of patients with evidence of electrical dyssynchrony do not benefit from CRT regardless of baseline QRS duration and QRS narrowing with CRT Imaging allows direct visualization of mechanical dyssynchrony Imaging allows direct visualization of mechanical dyssynchrony

23 Harvard Medical School Imaging Techniques M Mode and 2D M Mode and 2D TDI with echo TDI with echo Myocardial strain imaging Myocardial strain imaging 3D Echo 3D Echo CMR CMR

24 Harvard Medical School Other Modalities Electrical activation pattern during bi-V pacing by EP mapping Electrical activation pattern during bi-V pacing by EP mapping Delta QRS during bi-V pacing Delta QRS during bi-V pacing

25 Harvard Medical School M-mode Echo Interventricular dyssynchrony/motion delay – IVMD Interventricular dyssynchrony/motion delay – IVMD Time difference between left and right pre-ejection intervals Time difference between left and right pre-ejection intervals IVMD ≥ 50 ms IVMD ≥ 50 ms

26 Harvard Medical School M Mode Echo Intraventricular Dyssynchrony Intraventricular Dyssynchrony Septal-to-posterior wall motion delay (SPWMD) Septal-to-posterior wall motion delay (SPWMD) SPWMD ≥ 130 ms SPWMD ≥ 130 ms D SPWMD (msec) r =-.70 P=  LVESVI (mL/m 2 ) SPWMD predicts improvement with CRT (in 25 patients) Adapted from Pitzalis MV, et al. J Am Coll Cardiol. 2002;40:

27 Harvard Medical School TDI Imaging PW Doppler PW Doppler Reflects regional systolic velocity Reflects regional systolic velocity Timed to the QRS Timed to the QRS Dyssynchrony criteria: Dyssynchrony criteria: –12 sample volume model (any 2 > 100 ms, SD > 33ms) –2 sample volume – basal septum and lateral wall delay ≥ 50ms –Interventricular delay ≥ 50ms

28 Harvard Medical School TDI Assessment for Predicting Responders Adapted from Sogaard P, et al. J Am Coll Cardiol. 2002;40:

29 Harvard Medical School Patients with Intraventricular LV Dyssynchrony of ≥ 65 ms Have an Excellent Response to CRT 85 patients with severe HF, LBBB, QRS duration > 120 ms 85 patients with severe HF, LBBB, QRS duration > 120 ms TDI prior to CRT TDI prior to CRT Dyssynchrony was defined as the maximum delay between the time to peak systolic contraction velocity among four ventricular walls (anterior, inferior, septal and lateral) Dyssynchrony was defined as the maximum delay between the time to peak systolic contraction velocity among four ventricular walls (anterior, inferior, septal and lateral) Bax et. Al., JACC 2004:

30 Harvard Medical School TDI as Predictor of Response to CRT, Cont’ Bax et. Al., JACC 2004:

31 Harvard Medical School TDI as Predictor of Response to CRT, Cont’ Bax et. Al., JACC 2004:

32 Harvard Medical School TDI as Predictor of Response to CRT, Cont’ ROC curve analysis ROC curve analysis Sensitivity and specificity of 80% to predict CRT response at a cut-off level of 65 ms of LV dyssynchrony Sensitivity and specificity of 80% to predict CRT response at a cut-off level of 65 ms of LV dyssynchrony Response defined as improvement in NYHA class and 6 min walk Response defined as improvement in NYHA class and 6 min walk Bax et. Al., JACC 2004:

33 Harvard Medical School TDI as Predictor of Response to CRT, Cont’ Sensitivity and specificity of 92% to predict reverse LV remodeling Sensitivity and specificity of 92% to predict reverse LV remodeling Defined as improvement of LVESV of ≥ 15% Defined as improvement of LVESV of ≥ 15% Bax et. Al., JACC 2004:

34 Harvard Medical School Limitations of TDI Technical limitations: multiple peaks (can be seen even in structurally normal hearts), artifact, experience of the operator Technical limitations: multiple peaks (can be seen even in structurally normal hearts), artifact, experience of the operator Examines motion, not contraction per se Examines motion, not contraction per se Interpretation difficult in the setting of akinetic wall/scar Interpretation difficult in the setting of akinetic wall/scar

35 Harvard Medical School Strain Rate Analysis Differentiates between tethering or passive motion of non-contractile myocardium of TDI alone and active contraction Differentiates between tethering or passive motion of non-contractile myocardium of TDI alone and active contraction Limitations: technical factors, artifacts, low signal-to-noise ratio, difficult image acquisition Limitations: technical factors, artifacts, low signal-to-noise ratio, difficult image acquisition Radial strain is not well reproduced in multiple studies Radial strain is not well reproduced in multiple studies

36 Harvard Medical School Strain Rate Imaging: Normal Heart Breithardt et. Al, Eur Heart J, 2004: D16-24

37 Harvard Medical School Strain Rate Imaging: Patient with LBBB Onset of radial motion and strain in inferoseptal, inferior and inferolateral walls Onset of radial motion and strain in inferoseptal, inferior and inferolateral walls Interregional delay in onset of regional thickening Interregional delay in onset of regional thickening

38 Harvard Medical School 3D Echo Better spatial resolution Better spatial resolution High level post processing High level post processing Evaluate all walls simultaneously Evaluate all walls simultaneously Need more data Need more data

39 Harvard Medical School 3D Echo

40 Harvard Medical School PROSPECT Study Predictors of Response to CRT Predictors of Response to CRT ESC Congress Reports 2007 ESC Congress Reports 2007 Prospective study evaluating role of echo in predicting response to CRT Prospective study evaluating role of echo in predicting response to CRT Primary end-point: clinical composite score (CCS) and LVESV Primary end-point: clinical composite score (CCS) and LVESV Ghio, et. al

41 Harvard Medical School PROSPECT Study, Cont’ Echo prior to CRT or CRT-D Echo prior to CRT or CRT-D Echo post with AV delay optimization Echo post with AV delay optimization Training of participating sites Training of participating sites Repeat echo in 6 months Repeat echo in 6 months Baseline characteristics: 426 patients, avearage QRS 160 ms, LVEF 24%, most with LBBB, NYHA class III and IV sxs Baseline characteristics: 426 patients, avearage QRS 160 ms, LVEF 24%, most with LBBB, NYHA class III and IV sxs Ghio, et. al

42 Harvard Medical School PROSPECT Study, Cont’ At 6 months At 6 months Overall CCS improvement rate is 75.6% for non-ischemic and 63.7% for ischemic patients Overall CCS improvement rate is 75.6% for non-ischemic and 63.7% for ischemic patients Overall LVESV improvement rate is 63% for non-ischemic and 50.3% for ischemic patients Overall LVESV improvement rate is 63% for non-ischemic and 50.3% for ischemic patients Ghio, et. al

43 Harvard Medical School PROSPECT Study, Cont’ Substantial inter-core lab variability in all TDI based dyssynchrony measures Substantial inter-core lab variability in all TDI based dyssynchrony measures At the same time, the presence of a single mechanical delay (MD) measure added 11-13% response to CCS and 13-23% to LVESV At the same time, the presence of a single mechanical delay (MD) measure added 11-13% response to CCS and 13-23% to LVESV Ghio, et. al

44 Harvard Medical School PROSPECT Study: Conclusion No single measure of mechanical dyssynchrony may be recommended to improve patient selection for CRT No single measure of mechanical dyssynchrony may be recommended to improve patient selection for CRT Methodology to determine mechanical dyssynchrony needs further elaboration Methodology to determine mechanical dyssynchrony needs further elaboration Ghio, et. al

45 Harvard Medical School Conclusions CRT is an effective adjunctive non-pharmocological therapy for patients with advanced heart failure due to systolic left ventricular dysfunction with evidence of electrical and mechanical dyssynchrony CRT is an effective adjunctive non-pharmocological therapy for patients with advanced heart failure due to systolic left ventricular dysfunction with evidence of electrical and mechanical dyssynchrony Many imaging modalities exist to evaluate for mechanical LV dyssynchrony Many imaging modalities exist to evaluate for mechanical LV dyssynchrony TDI based measures do not appear to be good predictors that could improve patient selection for CRT TDI based measures do not appear to be good predictors that could improve patient selection for CRT Up to 30% of patients, selected based on current guidelines, are non-responders Up to 30% of patients, selected based on current guidelines, are non-responders

46 Harvard Medical School Conclusions, Cont’ TDI based measures are helpful in following/optimizing patients post bi-V implant (AV delay optimization, V-V optimization) TDI based measures are helpful in following/optimizing patients post bi-V implant (AV delay optimization, V-V optimization) More studies required to evaluate TDI modalities in patients with narrow QRS and RBBB with evidence of mechanical dyssynchrony More studies required to evaluate TDI modalities in patients with narrow QRS and RBBB with evidence of mechanical dyssynchrony Echo guided LV (and maybe RV) lead placement, especially in patients with prior transmural infarct Echo guided LV (and maybe RV) lead placement, especially in patients with prior transmural infarct 3D echo 3D echo CMR data (especially with development of CMR compatible leads) CMR data (especially with development of CMR compatible leads)


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