5 HF Total Expenditures: $27.9 Billion American Heart Association. Heart Disease and Stroke Statistics 2007 Update. N. Parikh CRT Talk 2008
6 Percent Change in U.S. Crude Death Rates from 1972-2000 by cause NHLBI Morbidity and Mortality Chart Book. 2004
7 HF TherapyJessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348:
8 Electrical Dyssynchrony Abnormal ventricular depolarization →Increased QRSdGenerates early and delayed ventricular contractionQRSd directly associated with EFBBB in 20% of HF patientsBBB in 35% of patients with severely ↓’ed EFBBBIndependent predictor of mortalityEspecially QRSd > 120 ms
9 Mechanical Dyssynchrony IntraventricularDelayed activation of one LV region vs anotherInterventricularDelayed activation of LV relative to RVGoal of CRTCorrect both intra- and interventricular dyssynchrony
10 Dyssynchrony - Mechanical ≠ Electrical Caveat – mechanical ≠ electrical dyssynchronyMechanical may be 2°Regional loading differencesFibrosisContractile strength of one part of wall vs. anotherCa++ cyclingMyofilament-Ca++ interactionsMechanical imaging methodsDetect muscle motion not activation process
11 Contributors to Electrical and Mechanical Dyssynchrony Abraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4,
12 Achieving Cardiac Resynchronization Atrial Synchronous Biventricular Pacing Improve coordinationAtria andBoth ventriclesPacing leadsRAARV apexAnterior wall of LVLV posterolateral wallVia lateral tributary of CSMain 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 patientCubbon R. BMJ. 338:
13 Achieving Cardiac Resynchronization Atrial Synchronous Biventricular Pacing Venous accessSubclavian veinLocal anestheticInfraclavicular incisionTarget veinID’ed via retrograde balloon angiography of CSLeads connected viaSQ generatorSimultaneous LV/RV pacingOverride intrinsic conductionBy setting AV delay < intrinsic PRCubbon R. BMJ. 338:
14 Cumulative Enrollment in Cardiac Resynchronization Randomized Trials 4000CARE HF3000MIRACLE ICDMIRACLEMUSTIC AFMIRACLE ICD IICumulative Patients2000MUSTIC SRCOMPANION1000PATH CHFPATH CHF IIMain 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 CD1999200020012002200320042005Results PresentedA. Goldman CRT Talk 2007.
15 Landmark Trials in CRTAbraham et al. JACC Cardiovascular Imaging. Vol 2. No. 4,
16 CRT Benefits Echocardiographic Clinical Improved EF/regional wall motionReversal of maladaptive remodeling (↓ LVESV)Reduction in severity of mitral regurgitationClinicalIncreased 6-minute hall walk distanceIncreased peak VO2 and treadmill exercise timeImproved QOL and NYHA functional class rankingTrend towards reduction in morbidity and mortality
17 Regional Wall Motion With CRT: Improved LVEF SeptumSeconds0.4Regional Fractional Area ChangeLateralThese 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.1Seconds0.4Adapted from Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.Adapted from Kawaguchi M, et al. J Am Coll Cardiol. 2002;39:N. Parikh CRT Talk 2008.Pacing OffPacing OnReferences: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:
18 Promotion of Reverse Remodeling in Class II CHF Control (n=85) CRT (n=69)Abraham et al., Circulation 2004; 110: N. Parikh CRT Talk 2008.
19 Improvement in Mitral Regurgitation A. Goldman CRT Talk 2007.
20 CRT Improves Exercise Capacity Abraham et al., 2003.
21 CRT Improves Quality of Life and NYHA Functional Class Abraham et al., 2003.
22 Progressive Heart Failure Mortality 51% Relative Reduction with CRT Overall odds ratio (95% CI) of 0.49 ( )Favors CRTFavors No CRTCONTAK 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:
23 Summary of Major Trials Significant clinical benefit of CRT in patients withClass III-IV HFEF < 35%QRS > 120Improvements in symptoms and objective standards of HFMeta-analysis29% 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 trialsBradley et al. JAMA 2003;289:730
24 CRT Complications Unsuccessful Uncomfortable diaphragmatic stimulation Failure to implant LV lead <5% in large seriesEventual lead displacement <1%Uncomfortable diaphragmatic stimulation2° L phrenic nerve coursing over posterolateral heart wallReposition intra-procedure, reprogram post-procedureInfection, risk of extraction <1%Related to procedure time/?experience of electrophysiologistCS perforation /pericardial tamponadeRefractory hypotensionBradycardiaAsystole
26 M-Mode - SPWMD Septal → posterior wall motion delay (SPWMD) Time difference between peak inward motion ofVentricular septumPosterior wallObtained in parasternal short axis M-mode view> 130 ms is significant to predict↓ in LVESV index > 15% (sens 100%, spec 1 mo)↑ in LVEF > 5%Better prognosis at 6 months s/p CRT
28 M-Mode Echo - SPWMD Advantages & Disadvantages Easy to performNo specific U/S equipment neededHigh temporal resolution (> fps)DisadvantagesOnly quantify in regions perpendicular to U/S beamOnly assess anteroseptal & inferolateral wall motionOnly feasible in 50% of patients evaluatedDifficult to determine timing of inward motion ifWall akinetic or plateau in motionNot consistently predictive for outcome after CRT
29 Tissue Velocity – Tissue Doppler Imaging Measurement ofLongitudinal tissue velocity (most commonly studied)or myocardial deformation (strain)Both pulsed-wave TDI & color-coded TDI used to ID systolic vpeakBoth time to vpeak & time to onset of systolic velocity used# and location of segments sampled (2, 6, or 12) has variedBoth standard deviation & maximum difference of timing intervals usedvpeak measured during ejection only or both ejection & post-ejection periodsBax et al, Am J Card Bax et al, Am J Card 2004
30 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.
31 Tissue Velocity – Tissue Doppler Imaging Color-coded TDIOpposing wall time to vpeak delay of > msShort-term improvement in EFReverse remodeling at 6 monthsYu indexGlobal 12 (basal and mid) Segment Asynchrony Indexvpeak delay ≥ 33 ms predictive of reverse remodeling at 3 monthsNot replicated in RethinQResynchronization Therapy in Normal QRS (<130 ms)Study entry via delay of > 65 ms between two opposing wallsBax et al, Am J Card Bax et al, Am J Card Yu et al Circulation 2004.
34 Tissue Velocity - Tissue Doppler Imaging Advantages and Disadvantages Pulsed-wave TDIAdvantagesHigh temporal resolutionNo specific U/S equipment neededDisadvantagesNo simultaneous sampling in multiple segmentsRequires multiple imagesRequires different cardiac cycles to map entire heartTime consumingRenders tissue velocity peaks more difficult to identifySusceptible to translational motion/tethering effect
35 Tissue Velocity - Tissue Doppler Imaging Advantages and Disadvantages Color-coded TDIAdvantagesRelatively high temporal resolution (>100 fps)Sampling of multiple segments simultaneously from one imageAllows further parameter processing by offline analysis (displacement, strain rate, strain)DisadvantagesRequires high-end U/S equipmentSusceptible to translational motion or tethering effect
36 Strain Imaging TDI-derived and Speckle tracking Abnormal strain patternPremature early systolic shortening of septumAccompanied by lateral prestretchFollowed by postsystolic lateral wall shorteningCutoff value of radial dyssynchrony > 130 ms in time to peak radial strain in anteroseptal/inferolateral wallsPredicts ↓ in LVESV > 15% s/p CRTSensitivity 83%, specificity 80%
38 Strain imaging TDI-Derived Advantages and Disadvantages Relatively high temporal resolution>200 fps individual wall, >100 fps for whole apical viewsLess affected by tethering/translational motionDisadvantagesRequires specific softwareTime-consuming image analysisHighly dependent on image qualityNot feasible in all patientsDifficult in spherical, dilated heartsDifficult in highly angulated basal segmentsMixed results predicting success after CRT
39 Strain Imaging – Speckle Tracking Advantages and Disadvantages Less affected by translational motion and tetheringNearly angle independentCan assess radial, circumferential, and longitudinal strainNearly automated analysis – less variabilityDisadvantagesRequires specific softwareLess time resolution (>40-80 fps)Requires large sector size for imaging in dilated heartsHighly dependent on image qualityNot feasible in all patients
40 3-D Echo Measurement of dyssynchrony indexes Difference in minimal segmental volumeand the standard deviation in time to minimal volumeamong 16 segments
41 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,
42 3-D Echo Advantages and Disadvantages Only one image needed for entire assessmentNearly automated analysisDisplay temporal/spatial distribution of timing in bull’s eye plotShort-term improvements in 3D dyssynchrony index s/p CRTDisadvantagesRequires high-end U/S equipment and probeLow temporal (15-25 fps) and spatial resolutionHighly dependent on image qualityIncomplete inclusion of the apexCannot perform if a-fib or frequent ectopyNo study to date shows 3D Echo predicts response to CRT
43 Interventricular Dyssynchrony Difference in preejection period between PW Dopplerin Ao and PACorrelates with QRSdTypically exceeds 40 ms in pts with QRSd >150 msShown to be predictive of post-CRT responseSCARTInterventricular dyssynchrony > 44 ms & smaller ESVCARE-HFInterventricular dyssynchrony > 49.2 msTissue velocity delay between RV & LV free wall not predictive of CRT effect (neither time to peak or onset)
45 PROSPECT Results 426 heart failure patients CRT response Mean age 68 yearsMean LV EF 23.6 ± 7%Mean QRSd 163 ± 22 msNYHA Class III 96%CRT responseHeart failure clinical composite scoreImprovement in 69%Relative change in LVESV at 6 monthsImprovement in 56%
47 PROSPECT Results Multiple echocardiographic parameters SPWMD (M mode) LV pre-ejection interval (pulsed wave Doppler)Delay between QRS onset and LV ejection onsetInterventricular delay (PWD)Difference between LV and RV pre-ejection intervalsLV 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 segmentsStand. Dev., time to peak systolic velocities (CC TDI)12 LV segments
48 PROSPECT Caveats & Conclusions Problem – high intra- & interobserver variabilityM-mode-derived septal-posterior wall motion delayDoppler imaging-derived parametersEchocardiographic measures of dyssynchrony aimed at improving patient selection criteria for CRT did not have a clinically relevant impact on ↑ response ratesEchocardiographic parameters of dyssynchrony did not have enough predictive value to be used as selection criteria for CRT beyond current indications
49 Issues with PROSPECT Patient selection Technical Pathophysiological 20.2% LVEF > 35%37.8% LVEDD < 65 mmTechnicalNonassessability of echocardiographic measuresHighest for M-mode and TDILow interobserver reproducibility?Better technology (3D, strain, CMR, etc.)PathophysiologicalInfluence of scar on non-responseLV dyssynchrony vs. LV lead positionInfluence of venous anatomy vs LV lead positioning
50 Future Directions Novel speckle tracking strain Combination of longitudinal and radial dyssynchronyStrain delay index – using speckle trackingSum of the difference between longitudinal peak & end-systolic strain across 16 segmentsCardiac MRISynchronyStrainLocation of LV pacing leadConcordance ofLV lead positionSite of latest mechanical activation
51 Future Directions Novel Speckle Tracking Strain Combination ofLongitudinal and radial dyssynchronyEasier, more accurate, more comprehensiveSensitivity 88%, specificity 80%for predicting CRT response in 190 HF patientsSignificantly better than either technique alone (p<0.0001)Gorscan et al. JACC. 50:
53 Future Directions - Strain Delay Index Using Speckle Tracking Sum of the difference betweenLongitudinal peak and end-systolic strainAcross 16 segments>’er in responders vs non-responders100 HF patients (35 ± 7 vs. 19 ± 6%, p< 0.001)Closely correlated with reverse remodelingBoth ischemic and nonischemic cardiomyopathyOptimal cutoff to predict CRT responseStrain delay index of > 25%Lim et al. Circulation. 118:
54 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:
55 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).
56 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.
57 Future Directions – LV Lead Placement ConcordanceLV lead positionSite of latest mechanical activationSpeckle tracking + CXRPost-CRT in 244 patientsIf concordant,Significant ↓ in LVESV189 ± 83 ml to 134 ± 71 mlP < 0.001Long-term follow-upBetter event-free survivalYpenburg et al. JACC. 52:
58 ACC/AHA/NASPE 2005 Guidelines Patients withLVEF < 35%Sinus rhythmNYHA functional class III or ambulatory class IV symptoms, despite optimal medical therapyCardiac dyssynchronyCurrently defined as a QRS duration > 120 msShould receive CRT unless contraindicatedClass: I, Level of Evidence: A