Airley E. Fish MD Imaging Conference August 19th 2009 Left Ventricular Dyssynchrony and Cardiac Resynchronization Therapy in Heart Failure Airley E. Fish MD Imaging Conference August 19th 2009

Outline Introduction Rationale for CRT CRT Electrical dyssynchrony Mechanical dyssynchrony CRT Evidence for benefit Summary of major trials

Outline Echocardiographic measures PROSPECT M-Mode Tissue Velocity Strain Imaging Three Dimensional Echo PROSPECT Future directions to predict CRT response

Source: National Hospital Discharge survey

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 Main purpose: Illustrate for referral clinicians how the leads are placed to achieve cardiac resynchronization. Many outside the implant world may not be entirely aware of how the device is placed. Key messages: The implant procedure, while typically of longer duration, is similar to that of a standard pacemaker or implantable defibrillator implantation. A key difference is the placement of a left ventricular lead via the coronary sinus opening. Coronary venous anatomy varies significantly between patients. In a small percentage of cases it may not be possible to place the left ventricular lead transvenously. Some centers are opting for an epicardial approach if the transvenous approach is unsuccessful. Additional information: Standard pacing leads are placed in the right atrium and right ventricle. The LV lead is placed via the coronary sinus in a cardiac vein, preferably a lateral or postero-lateral vein in the mid part of the LV. The successful deployment of this lead to physician-guided development of left-heart delivery systems, and new LV leads to meet varying patient 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 4000 CARE HF 3000 MIRACLE ICD MIRACLE MUSTIC AF MIRACLE ICD II Cumulative Patients 2000 MUSTIC SR COMPANION 1000 PATH CHF PATH CHF II Main purpose: Show that a large number of patients have been studied in completed and ongoing randomized controlled studies of CRT. Use in conjunction with previous slide. Key messages: Over 3000 patients have been enrolled in randomized controlled clinical trials presented to date. When CARE-HF, another landmark trial assessing mortality and hospitalization, is reported, close to 4,000 patients will have been studied. CONTAK CD 1999 2000 2001 2002 2003 2004 2005 Results Presented 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 Clinical 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 Seconds 0.4 Regional Fractional Area Change Lateral These echocardiogram (ECHO) and radial displacement tracings of the septal and lateral walls show how regional wall motion is improved by CRT. With pacing off, radial septal motion is initially inward but then shifts toward the right ventricle as the lateral wall contracts (paradoxic motion). CRT converts this to a more consistent inward motion. In the lateral wall, there is initial stretch followed by delayed contraction. CRT influences the phase, but not amplitude of motion; this stimulates contraction earlier, resulting in increased cardiac efficiency.1 Seconds 0.4 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. Pacing Off Pacing On References: Kass DA. Ventricular resynchronization: pathophysiology and identification of responders. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13. Kawaguchi M, et al. Quantitation of basal dyssynchrony and acute resynchronization from left or biventricular pacing by novel ECHO-contrast variability imaging. J Am Coll Cardiol. 2002;39:2052-2058.

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.

Improvement in Mitral Regurgitation A. Goldman CRT Talk 2007.

CRT Improves Exercise Capacity Abraham et al., 2003.

CRT Improves Quality of Life and NYHA Functional Class Abraham et al., 2003.

Progressive Heart Failure Mortality 51% Relative Reduction with CRT Overall odds ratio (95% CI) of 0.49 (0.25 - 0.93) Favors CRT Favors No CRT CONTAK CD (n=490) MIRACLE ICD (n=554) MIRACLE (n=532) MUSTIC (n=58) Overall (n=1634) Odds ratio refers to odds of death from progressive heart failure among patients randomized to CRT or to no CRT. Odds ratio less than 1 favors CRT. Boxed area is proportional to the relative weight given to each trial in the statistical model. Bradley DJ, et al. JAMA 2003;289:730-740.

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 Uncomfortable diaphragmatic stimulation 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

Intraventricular Mechanical Dyssynchrony M-Mode Tissue Velocity Strain Imaging Three Dimensional Echo

M-Mode - SPWMD Septal → posterior wall motion delay (SPWMD) Time difference between peak inward motion of Ventricular septum Posterior wall Obtained in parasternal short axis M-mode view > 130 ms is significant to predict ↓ in LVESV index > 15% (sens 100%, spec 63% @ 1 mo) ↑ in LVEF > 5% Better prognosis at 6 months s/p CRT

M-mode echocardiography with color-coded tissue velocity M-mode echocardiography with color-coded tissue velocity. a, Timing of ventricular septal (VS) wall motion difficult to define 2° severe hypokinesis & lack of distinct peaks. b, Color coding of tissue velocity helps to identify exact wall motion timing as transition point of blue to red color for septal wall (arrows) & red to blue color for posterior wall (arrowheads) (right) Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008. Copyright ©2008 American Heart Association

M-Mode Echo - SPWMD Advantages & Disadvantages 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 vpeak Both time to vpeak & 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 vpeak 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 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 vpeak 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 vpeak 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 Waveforms Normal Subject 4-Chamber Apical Long Axis 2-Chamber Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008 Copyright ©2008 American Heart Association

Apical 4 Ch Long axis 2 Chamber Before CRT After CRT Color-coded tissue velocity recordings from 12 LV segments before (a) and after (b) CRT in 65-year-old patient with NICMP whose LVEF improved by 17% at 6 months after CRT Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh CRT Talk 2008 Copyright ©2008 American Heart Association

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%

Before CRT After CRT Radial strain curves from short-axis view of speckle tracking echocardiography: Significant timing difference found among time to peak radial strain before CRT (a), reduced after CRT (b). Anderson, L. J. et al. Circulation 2008;117:2009-2023. Adapted from N. Parikh. CRT Talk 2008. Copyright ©2008 American Heart Association

Strain imaging TDI-Derived Advantages and Disadvantages 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 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 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 Trial Chung, E. S. et al. Circulation 2008;117:2608-2616 Copyright ©2008 American Heart Association

PROSPECT Results 426 heart failure patients CRT response 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%

PROSPECT Results Chung, E. S. et al. Circulation 2008;117:2608-2616 Copyright ©2008 American Heart Association

PROSPECT Results 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 Technical Pathophysiological 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 Novel Speckle Tracking Strain Delgado et al. JACC. 51:1944-1952. 2008.

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 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. Lim et al. Circulation. 118:1130-37. 2008.

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