HF Total Expenditures: $27.9 Billion American Heart Association. Heart Disease and Stroke Statistics 2007 Update. N. Parikh CRT Talk 2008
Percent Change in U.S. Crude Death Rates from 1972-2000 by cause NHLBI Morbidity and Mortality Chart Book. 2004
HF Therapy Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348: 2007-2018.
Electrical Dyssynchrony Abnormal ventricular depolarization → –Increased QRSd –Generates early and delayed ventricular contraction QRSd directly associated with EF –BBB in 20% of HF patients –BBB in 35% of patients with severely ↓’ed EF BBB –Independent predictor of mortality –Especially QRSd > 120 ms
Mechanical Dyssynchrony Intraventricular –Delayed activation of one LV region vs another Interventricular –Delayed activation of LV relative to RV Goal of CRT –Correct both intra- and interventricular dyssynchrony
Dyssynchrony - Mechanical ≠ Electrical Caveat – mechanical ≠ electrical dyssynchrony –Mechanical may be 2° Regional loading differences Fibrosis Contractile strength of one part of wall vs. another –Ca ++ cycling –Myofilament-Ca ++ interactions –Mechanical imaging methods Detect muscle motion not activation process
Contributors to Electrical and Mechanical Dyssynchrony Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4, 486-497. 2009.
Achieving Cardiac Resynchronization Atrial Synchronous Biventricular Pacing Improve coordination –Atria and –Both ventricles Pacing leads –RAA –RV apex Anterior wall of LV –LV posterolateral wall Via lateral tributary of CS Cubbon R. BMJ. 338:1064-1069. 2009
Achieving Cardiac Resynchronization Atrial Synchronous Biventricular Pacing Venous access –Subclavian vein –Local anesthetic –Infraclavicular incision Target vein – ID’ed via retrograde balloon angiography of CS Leads connected via –SQ generator –Simultaneous LV/RV pacing Override intrinsic conduction –By setting AV delay < intrinsic PR Cubbon R. BMJ. 338:1064-1069. 2009
Cumulative Enrollment in Cardiac Resynchronization Randomized Trials 0 1000 2000 3000 4000 1999200020012002200320042005 Results Presented Cumulative Patients PATH CHF MUSTIC SR MUSTIC AF MIRACLE CONTAK CD MIRACLE ICD PATH CHF II COMPANION MIRACLE ICD II CARE HF A. Goldman CRT Talk 2007.
Landmark Trials in CRT Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4, 486-497. 2009.
CRT Benefits Echocardiographic –Improved EF/regional wall motion –Reversal of maladaptive remodeling (↓ LVESV) –Reduction in severity of mitral regurgitation Clinical –Increased 6-minute hall walk distance –Increased peak VO2 and treadmill exercise time –Improved QOL and NYHA functional class ranking –Trend towards reduction in morbidity and mortality
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;39:2052-2058. N. Parikh CRT Talk 2008.
Promotion of Reverse Remodeling in Class II CHF Control (n=85) CRT (n=69) Abraham et al., Circulation 2004; 110:2864-2868. N. Parikh CRT Talk 2008. P=0.04P=0.01P=0.02
Improvement in Mitral Regurgitation A. Goldman CRT Talk 2007.
CRT Improves Exercise Capacity * P < 0.05 Abraham et al., 2003.
CRT Improves Quality of Life and NYHA Functional Class * P < 0.05 Abraham et al., 2003.
Progressive Heart Failure Mortality 51% Relative Reduction with CRT Favors CRTFavors No CRT CONTAK CD (n=490) MIRACLE ICD (n=554) MIRACLE (n=532) MUSTIC (n=58) Overall (n=1634) Bradley DJ, et al. JAMA 2003;289:730-740. Overall odds ratio (95% CI) of 0.49 (0.25 - 0.93)
Summary of Major Trials Significant clinical benefit of CRT in patients with –Class III-IV HF –EF < 35% –QRS > 120 Improvements in symptoms and objective standards of HF 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: consistent > 30% non-response rate through most trials Bradley et al. JAMA 2003;289:730
CRT Complications Unsuccessful –Failure to implant LV lead <5% in large series –Eventual lead displacement <1% Uncomfortable diaphragmatic stimulation –2° L phrenic nerve coursing over posterolateral heart wall –Reposition intra-procedure, reprogram post-procedure Infection, risk of extraction <1% –Related to procedure time/?experience of electrophysiologist CS perforation /pericardial tamponade Refractory hypotension Bradycardia Asystole
M-Mode Echo - SPWMD Advantages & Disadvantages Advantages –Easy to perform –No specific U/S equipment needed –High temporal resolution (>1000-3000 fps) Disadvantages –Only quantify in regions perpendicular to U/S beam –Only assess anteroseptal & inferolateral wall motion –Only feasible in 50% of patients evaluated Difficult to determine timing of inward motion if –Wall akinetic or plateau in motion –Not consistently predictive for outcome after CRT
Tissue Velocity – Tissue Doppler Imaging Measurement of –Longitudinal tissue velocity (most commonly studied) –or myocardial deformation (strain) Both pulsed-wave TDI & color-coded TDI used to ID systolic v peak Both time to v peak & time to onset of systolic velocity used # and location of segments sampled (2, 6, or 12) has varied Both standard deviation & maximum difference of timing intervals used v peak measured during ejection only or both ejection & post-ejection periods Bax et al, Am J Card 2003. Bax et al, Am J Card 2004
Examples of tissue velocity waveforms. a, Double peaks (arrows) in anterolateral wall in NL subject. b, One of the double peaks (arrows) located at time of aortic valve opening in anterior wall in LBBB patient. c, Beat-to-beat variability in velocity of 2 peaks (arrows) during ejection. d, Postsystolic peak (*) higher than systolic velocity (arrow) in inferoseptal segment in LBBB patient. e, Positive deflection at aortic valve opening at downslope shoulder of presystolic velocity (arrow) is highest peak during ejection period. f, No positive velocity was found during ejection period and prominent presystolic (arrowhead) and postsystolic wave (*) observed in inferoseptal wall.
Tissue Velocity – Tissue Doppler Imaging Color-coded TDI –Opposing wall time to v peak delay of > 60-65 ms Short-term improvement in EF Reverse remodeling at 6 months –Yu index Global 12 (basal and mid) Segment Asynchrony Index v peak delay ≥ 33 ms predictive of reverse remodeling at 3 months Not replicated in RethinQ –Resynchronization Therapy in Normal QRS (<130 ms) –Study entry via delay of > 65 ms between two opposing walls Bax et al, Am J Card 2003. Bax et al, Am J Card 2004. Yu et al Circulation 2004.
Tissue Velocity - Tissue Doppler Imaging Advantages and Disadvantages Pulsed-wave TDI –Advantages High temporal resolution No specific U/S equipment needed –Disadvantages No simultaneous sampling in multiple segments Requires multiple images Requires different cardiac cycles to map entire heart –Time consuming –Renders tissue velocity peaks more difficult to identify Susceptible to translational motion/tethering effect
Tissue Velocity - Tissue Doppler Imaging Advantages and Disadvantages Color-coded TDI –Advantages Relatively high temporal resolution (>100 fps) Sampling of multiple segments simultaneously from one image Allows further parameter processing by offline analysis (displacement, strain rate, strain) –Disadvantages Requires high-end U/S equipment Susceptible to translational motion or tethering effect
Strain Imaging TDI-derived and Speckle tracking Abnormal strain pattern –Premature early systolic shortening of septum –Accompanied by lateral prestretch –Followed by postsystolic lateral wall shortening Cutoff value of radial dyssynchrony > 130 ms in time to peak radial strain in anteroseptal/inferolateral walls –Predicts ↓ in LVESV > 15% s/p CRT –Sensitivity 83%, specificity 80%
Strain imaging TDI-Derived Advantages and Disadvantages Advantages –Relatively high temporal resolution >200 fps individual wall, >100 fps for whole apical views –Less affected by tethering/translational motion Disadvantages –Requires specific software –Time-consuming image analysis –Highly dependent on image quality –Not feasible in all patients Difficult in spherical, dilated hearts Difficult in highly angulated basal segments –Mixed results predicting success after CRT
Strain Imaging – Speckle Tracking Advantages and Disadvantages Advantages –Less affected by translational motion and tethering Nearly angle independent Can assess radial, circumferential, and longitudinal strain –Nearly automated analysis – less variability Disadvantages –Requires specific software –Less time resolution (>40-80 fps) Requires large sector size for imaging in dilated hearts –Highly dependent on image quality –Not feasible in all patients
3-D Echo Measurement of dyssynchrony indexes –Difference in minimal segmental volume and the standard deviation in time to minimal volume among 16 segments
Three Dimensional Echocardiography Uniform times to minimum volume indicate synchrony (A). The dyssynchronous left ventricle is characterized by variation in times to minimum volume (B). Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4, 486-497. 2009.
3-D Echo Advantages and Disadvantages Advantages –Only one image needed for entire assessment –Nearly automated analysis –Display temporal/spatial distribution of timing in bull’s eye plot –Short-term improvements in 3D dyssynchrony index s/p CRT Disadvantages –Requires high-end U/S equipment and probe –Low temporal (15-25 fps) and spatial resolution –Highly dependent on image quality –Incomplete inclusion of the apex –Cannot perform if a-fib or frequent ectopy –No study to date shows 3D Echo predicts response to CRT
Interventricular Dyssynchrony Difference in preejection period between PW Doppler –in Ao and PA -Correlates with QRSd -Typically exceeds 40 ms in pts with QRSd >150 ms -Shown to be predictive of post-CRT response -SCART -Interventricular dyssynchrony > 44 ms & smaller ESV -CARE-HF -Interventricular dyssynchrony > 49.2 ms Tissue velocity delay between RV & LV free wall not predictive of CRT effect (neither time to peak or onset)
PROSPECT Results 426 heart failure patients –Mean age 68 years –Mean LV EF 23.6 ± 7% –Mean QRSd 163 ± 22 ms –NYHA Class III 96% CRT response –Heart failure clinical composite score Improvement in 69% –Relative change in LVESV at 6 months Improvement in 56%
Multiple echocardiographic parameters –SPWMD (M mode) –LV pre-ejection interval (pulsed wave Doppler) Delay between QRS onset and LV ejection onset –Interventricular delay (PWD) Difference between LV and RV pre-ejection intervals –LV filling time, relation to cardiac cycle length (PWD) –Delay in peak systolic velocity (Color-coded TDI) 2 segments (basal septum & lateral wall) –Delay in onset of systolic velocity (CC TDI) 6 basal LV segments –Stand. Dev., time to peak systolic velocities (CC TDI) 12 LV segments
PROSPECT Caveats & Conclusions Problem – high intra- & interobserver variability –M-mode-derived septal-posterior wall motion delay –Doppler imaging-derived parameters Echocardiographic measures of dyssynchrony aimed at improving patient selection criteria for CRT did not have a clinically relevant impact on ↑ response rates Echocardiographic parameters of dyssynchrony did not have enough predictive value to be used as selection criteria for CRT beyond current indications
Issues with PROSPECT Patient selection –20.2% LVEF > 35% –37.8% LVEDD < 65 mm Technical –Nonassessability of echocardiographic measures Highest for M-mode and TDI –Low interobserver reproducibility ?Better technology (3D, strain, CMR, etc.) Pathophysiological –Influence of scar on non-response –LV dyssynchrony vs. LV lead position –Influence of venous anatomy vs LV lead positioning
Future Directions Novel speckle tracking strain –Combination of longitudinal and radial dyssynchrony Strain delay index – using speckle tracking –Sum of the difference between longitudinal peak & end- systolic strain across 16 segments Cardiac MRI –Synchrony –Strain Location of LV pacing lead –Concordance of LV lead position Site of latest mechanical activation
Future Directions Novel Speckle Tracking Strain Combination of –Longitudinal and radial dyssynchrony Easier, more accurate, more comprehensive Sensitivity 88%, specificity 80% –for predicting CRT response in 190 HF patients Significantly better than either technique alone (p<0.0001) Gorscan et al. JACC. 50:1476-83. 2007.
Future Directions - Strain Delay Index Using Speckle Tracking Sum of the difference between –Longitudinal peak and end-systolic strain –Across 16 segments >’er in responders vs non-responders –100 HF patients (35 ± 7 vs. 19 ± 6%, p< 0.001) –Closely correlated with reverse remodeling Both ischemic and nonischemic cardiomyopathy Optimal cutoff to predict CRT response –Strain delay index of > 25% Lim et al. Circulation. 118:1130-37. 2008.
Future Directions - Strain Delay Index Using Speckle Tracking Lim et al. Circulation. 118:1130-37. 2008. A, Strain delay index is the sum of the wasted energy, ie, ( ES– peak) caused by LV dyssynchrony across the 16 myocardial segments (colored curves) of the LV. B, After CRT, the increase ( ) of global strain curve (white dashed curve) is supposed to be proportional to strain delay index.
Future Directions Cardiac MRI - Synchrony Progressive deformation of the grid (A) allows measurement of the time course of deformation in the principal axes of each segment (B). The parametric display (C) shows the time course of contraction, which can be shown to be synchronous (upper row) or dyssynchronous (lower row).
Future Directions - Cardiac MRI - Strain Regional variance of strain (A) cannot differentiate identical variance of time to peak contraction between segments with delayed contraction clustered in 1 portion of the left ventricular wall (A, top), versus dispersion of delay through the heart (A, bottom); only the former displays dyssynchrony. The regional variance vector of principal strain (B) is based on the product of unit vectors with a scalar representing time at maximal shortening or instantaneous magnitude of shortening. Regional strain uniformity (C) provides a relative ratio of first/zero-order magnitudes derived by Fourier analysis. The heart with clustered regions (A, top) shows delays in 1 territory versus the other so this plot appears sinusoidal. Hearts with more variability (A, bottom) yield a higher frequency waveform.
Future Directions – LV Lead Placement Concordance –LV lead position –Site of latest mechanical activation Speckle tracking + CXR –Post-CRT in 244 patients If concordant, –Significant ↓ in LVESV –189 ± 83 ml to 134 ± 71 ml –P < 0.001 –Long-term follow-up Better event-free survival Ypenburg et al. JACC. 52:1402-9. 2008.
ACC/AHA/NASPE 2005 Guidelines Patients with –LVEF < 35% –Sinus rhythm –NYHA functional class III or ambulatory class IV symptoms, despite optimal medical therapy –Cardiac dyssynchrony Currently defined as a QRS duration > 120 ms Should receive CRT unless contraindicated Class: I, Level of Evidence: A