Discrepancy between Electrical and Mechanical Dyssynchrony in Patients with Heart Failure and an Electrical Disturbance RYUDO FUJIWARA, M.D., AKIHIRO YOSHIDA, M.D., PH.D., KOJI FUKUZAWA, M.D., PH.D., ASUMI TAKEI, M.D., PH.D., KUNIHIKO KIUCHI, M.D., PH.D., MITSUAKI ITOH, M.D., KIMITAKE IMAMURA, M.D., ATSUSHI SUZUKI, M.D., TOMOYUKI NAKANISHI, M.D., SOICHIRO YAMASHITA, M.D., AKINORI MATSUMOTO, M.D., HIDEKAZU TANAKA, M.D., PH.D., and KEN-ICHI HIRATA, M.D., PH.D From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
Background: Cardiac resynchronization therapy (CRT) improves the survival rates of patients with heart failure, but 30–40% of them do not respond to CRT, partially because of the position of the left ventricular (LV) lead. The relationship between the electrical and mechanical activation of the left ventricle is unknown. The aim of this study was to compare the electrical and mechanical dyssynchrony. Methods: We inserted electrode catheters into the coronary sinus (CS) and venous branches of the CS during CRT implantations and constructed electroanatomical contact maps in 16 patients using the EnSite NavXTM system. Mechanical activation was evaluated by speckle-tracking echocardiography and the latest mechanical and electrical sites were compared. The degrees of the electrical and mechanical delays of the implanted LV lead were also compared. Results: The electroanatomical maps revealed that the latest electrical sites were anterior in one, anterolateral in five, lateral in eight, and posterolateral in two. Echocardiographic imaging revealed that the latest mechanical sites were anteroseptal in two, anterior in four, lateral in five, posterior in two, and inferior in three. The latest electrical and mechanical sites matched in only three patients. The degree of the local mechanical delay for the LV lead was significantly larger in the responders than nonresponders, whereas the local electrical delay did not differ. Conclusion: A discrepancy between the electrical and mechanical dyssynchrony might affect an adequate LV lead positioning. (PACE 2014; 37:576–584) cardiac resynchronization therapy, electrical delay, mechanical delay, dyssynchrony
Introduction Although the cardiac function and survival rates in patients with severe heart failure are improved by cardiac resynchronization therapy (CRT),1–4 30–40% of the patients are unresponsive.1 The determinants of the CRT
Conflicts of Interest: None. Financial support: None. Disclosures: None. Address for reprints: Akihiro Yoshida, M.D., PH.D., Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunokicho, Chuo-ku, Kobe 650-0017, Japan. Fax: 078-382-5859; e-mail: [email protected] Received July 14, 2013; revised September 27, 2013; accepted October 20, 2013. doi: 10.1111/pace.12326
response comprised factors that are related to the patients and devices. A nonambulatory New York Heart Association (NYHA) class IV, absent of dyssynchrony, myocardial scars, and atrial fibrillation or premature ventricular contractions are associated with an unfavorable response to CRT. The device factors include the left ventricular (LV) lead position, right ventricle (RV) lead position, atrioventricular and interventricular delay settings, and pacing ratios (%).5–12 In regard to the RV lead position, Kiuchi et al. reported the impact of the RV lead pacing site guided by electroanatomical mapping.11 Many investigations have studied optimal LV lead positioning. A subanalysis of the Multicenter Automatic Defibrillator Implantation Trial– Cardiac Resynchronization Therapy (MADITCRT) study found an association of the apical
©2013 Wiley Periodicals, Inc. 576
May 2014
PACE, Vol. 37
ELECTRICAL AND MECHANICAL DYSSYNCHRONY
Table I. Baseline Characteristics No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Mean
Age
Gender
Heart Disease
NYHA
QRS (ms)
RV Pace
LVEF (%)
LVEDV (mL)
LVESV (mL)
76 63 77 80 79 78 81 62 61 62 70 69 76 64 38 74 69 ± 11
M M M M M M M F M M M M M M M M
ICM ICM ICM ICM ICM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM Sarcoidosis
III II II II II III II II II II III II III II III II
173 215 125 170 154 156 160 151 126 160 190 152 182 190 220 180 169 ± 27
0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1
35 21 26 29 23 22 30 16 24 34 34 29 17 29 25 22 26 ± 6
160 280 167 159 229 204 207 169 156 155 190 109 212 203 254 237 190 ± 43
104 221 124 112 177 159 144 142 117 102 126 78 176 144 191 184 141 ± 38
DCM = dilated cardiomyopathy; ICM = ischemic cardiomyopathy; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; NYHA = New York Heart Association; RV = right ventricle.
region with an unfavorable outcome.13 A shorter QRS duration during LV pacing also predicts CRT responses.14 With respect to the mechanical dyssynchrony, pacing at the site of the latest mechanical activation results in a superior echocardiographic response and a better prognosis.15 A randomized, controlled trial comparing a targeted approach to the LV lead placement with standard levels of care found that using speckle-tracking echocardiography to target the LV lead placement yields a significantly improved response and clinical status and lower rates of death and hospitalization related to heart failure.16 On the other hand, concerning the electrical dyssynchrony, an electrical delay of the LV lead from the onset of QRS correlates with improved LV dP/dt over baseline and clinical outcome.17 However, Klemm et al. studied mechanical dyssynchrony in postinfarction patients with a narrow QRS complex and concluded that delayed local wall motion in the damaged myocardium is not associated with local electrical conduction delay.18 The relationship between electrical and mechanical dyssynchrony remains unknown and adjustments to these different modalities of intracardiac electrical activation and speckle-tracking echocardiography have not been examined. This study compares electrical and mechanical dyssynchrony.
PACE, Vol. 37
Methods Study Population We enrolled 16 patients (mean age, 69 ± 11 years; male, n = 15; and female, n = 1) who received CRT between May 2010 and January 2012. The indications for the CRT consisted of an NYHA class II or III, left ventricular ejection fraction (LVEF) of ≤35%, and QRS ≥120 ms, including necessary RV pacing. The underlying cardiac diseases were ischemic cardiomyopathy in five, dilated cardiomyopathy in 10, and cardiac sarcoidosis in one. Thirteen patients had new implants and three were upgraded from RV pacing (Table I). CRT Implantation and Mapping The preoperative anatomical information about the coronary sinus (CS) and its branching veins was obtained using enhanced computed tomography (CT). The leads used for the CRT were transvenously implanted. The RV lead was positioned in the RV apex and the right atrial lead in the right atrial appendage. A guiding catheter was inserted into the CS and occlusive venography was performed under fluoroscopy. A 5-Fr 10-pole electrode catheter was inserted into the CS and 1.6-Fr six-pole electrode catheter into each vein branching from the CS. The catheters and leads were connected to an EnSite
May 2014
577
FUJIWARA, ET AL.
left ventricular end-systolic volume (LVESV) were derived and the LVEF was calculated from the conventional apical two- and four-chamber images using the biplane Simpson’s technique. The mechanical activation was evaluated by 2D speckle-tracking radial strain echocardiography from routine grayscale mid-LV and base-LV shortaxis images as previously described.19 The LV wall was divided into six areas in the short-axis view. The latest mechanical site was compared with the latest electrical site. Responders were defined as those having a >15% reduction in the LVESV at 6 months after the CRT.
Figure 1. Measurement of the percentage of the electrical delay = B/A × 100(%). The local electrical delay of the LV lead was calculated as the time between the onset of the QRS and local electrogram of the LV lead.
NavXTM system (St. Jude Medical, Minneapolis, MN, USA) and electroanatomical contact maps were constructed. The earliest and latest activation sites were visualized on each map and then the LV lead was positioned in a lateral or posterolateral vein. Other veins were selected if those positions were unavailable due to a high pacing threshold or diaphragmatic stimulation. Measuring the LV Lead Electrical Delay The local electrical delay of the LV lead was calculated as the time between the onset of the QRS on the surface electrocardiogram and the local electrogram of the LV lead. This delay was corrected for the baseline QRS by expressing it as a percentage of the baseline QRS duration (Fig. 1). Nomenclature of the CS Branches After occlusive venography, we named each part of the CS. We divided the CS in the left anterior oblique view into the posterior, posterolateral, lateral, anterolateral, and anterior areas and similarly described the distribution of the branches. The CS and coronary veins in the anterior oblique view were divided into basal (including the CS), middle, and apical areas (Fig. 2). Echocardiography Echocardiography was performed before the CRT implantation. Routine digital grayscale twodimensional (2D) images were acquired in standard apical and parasternal views. The left ventricular end-diastolic volume (LVEDV) and
578
Measuring the LV Lead Mechanical Delay The total LV mechanical activation time was defined as the time between the peak radial strain of the latest mechanical site and earliest mechanical site. The site where the LV lead was finally positioned was confirmed by comparing the angiographic and CT images as described later. The mechanical delay of the LV lead was calculated as the time between the peak radial strain of the earliest mechanical site and peak radial strain of the LV lead. This delay was corrected for the total mechanical activation time by expressing it as a percentage of the total mechanical activation time (Fig. 3). We then compared the clinical effects of the electrical and mechanical delays. Positional Relationship in Different Modalities A method to adjust the positional relationship between angiography and echocardiography has not been established. We matched the angiographic and echocardiographic findings based on the anatomical position of the coronary branches and papillary muscles determined by CT (Fig. 4). The posterolateral vein indicated by a red arrow in the angiogram was also recognized by CT. This CT image was sliced at the same angle as that with angiography. So the location of the posterolateral vein in the angiography and CT was identical. The papillary muscles were easily detected and indicated by red circles. The papillary muscles in the echocardiograms were located in a clockwise location compared with the CT images; therefore, the posterolateral vein was located in the posterior region. Because the echocardiographic beam was passed in an oblique direction, the constructed images were generally rotated clockwise. Statistical Analysis Continuous valuables are expressed as means ± standard deviation. Groups were compared using Student’s t-test. A P < 0.05 was considered statistically significant.
May 2014
PACE, Vol. 37
ELECTRICAL AND MECHANICAL DYSSYNCHRONY
Figure 2. Measurement of the percentage of mechanical delay = B/A × 100(%). (A) Total mechanical activation time defined as the time between the peak radial strain of the latest mechanical site and earliest mechanical site. (B) Mechanical delay of the left ventricular (LV) lead defined as the time between the peak radial strain of the earliest mechanical site and peak radial strain of the LV lead.
Figure 3. Nomenclature of the coronary sinus branches. A = anterior; AL = anterolateral; L = lateral; P = posterior; PL = posterolateral.
Results Baseline Characteristics
169 ± 27 ms, 26 ± 6%, 190 ± 43 mL, and 141 ± 38 mL, respectively.
Table I shows the baseline characteristics of the patients. Eleven and five patients had an NYHA class II and III, respectively. The mean QRS duration, LVEF, LVEDV, and LVESV values were
Electroanatomical Mapping Electroanatomical mapping was accomplished in all 16 patients, in whom occlusive
PACE, Vol. 37
May 2014
579
FUJIWARA, ET AL.
Figure 4. Positional relationship in the different modalities. The posterolateral vein viewed with angiography is found to be located in the posterior region with echocardiography.
Figure 5. Electroanatomical map of the coronary sinus and its branches in Patient No. 2. The red and white indicate the earliest activation site in the anterior vein. The purple and blue indicate the latest site in the middle of the lateral vein. LAO = left anterior oblique; RAO = right anterior oblique.
venography revealed 56 coronary vein branches, of which 49 (88%) could be mapped. Figure 5 shows a color map of the intracardiac electrical activation in sinus rhythm. The earliest and latest electrical sites were located in the apical region of the anterior vein and in the middle region of the lateral vein, respectively. Figure 6 shows the latest electrical sites in all patients. This figure is shown in a clockwise rotation to match the echocardiographic view. These sites were distributed anteriorly in one (basal),
580
anterolaterally in five (basal, n = 4; middle, n = 1), laterally in eight (basal, n = 5; middle n = 3), and posterolaterally in two (both basal). The latest electrical sites were thus distributed to the lateral or anterolateral regions in 13 (81%) of the 16 patients. Latest Mechanical Site Figure 7 shows the latest mechanical sites in all patients. The latest mechanical sites were distributed anteroseptally in two (basal and
May 2014
PACE, Vol. 37
ELECTRICAL AND MECHANICAL DYSSYNCHRONY
LV Lead Position The final LV lead positions were anterolateral in three (basal, n = 1; middle, n = 2), lateral in eight (basal n = 3; middle n = 5), and posterolateral in four (basal n = 1; middle n = 3). They were located at the latest electrical site in six (40%) patients (Nos. 2, 4, 5, 8, 13, and 15) and at the latest mechanical site in five (33%; Nos. 2, 3, 6, 13, and 14).
Figure 6. Locations of the latest electrical sites. The circled numbers refer to the patient numbers. The latest electrical sites are mainly distributed in the lateral area.
Figure 7. Locations of the latest mechanical sites. The circled numbers refer to the patient numbers. The latest mechanical sites are widely distributed.
middle, one each), anteriorly in four (basal and middle, two each), laterally in six (basal, n = 2; middle, n = 4), posteriorly in one (middle), and inferiorly in three (all middle). In contrast to the latest electrical sites, the latest mechanical sites were widely distributed. Comparison of the Latest Electrical and Mechanical Sites The latest electrical and mechanical sites were located in neighboring regions in six (38%) patients (Nos. 3, 7, 10, 14, 15, and 16), far apart in seven (44%; Nos. 4, 5, 6, 8, 9, 11, and 12), and matched only in three (19%; Nos. 1, 2, and 13). Thus, the electrical and mechanical dyssynchrony was generally discrepant.
PACE, Vol. 37
Clinical Follow-Up Because one patient died of pneumonia 5 months after the CRT implantation, we analyzed the clinical data from 15 patients. After 6 months of follow-up, 10 (66.7%) patients were responders and five (33.3%) were nonresponders. The LVESV decreased from 145 ± 40 mL to 106 ± 46 mL (P < 0.05) in all patients. The percentage of the local mechanical delay of the LV lead was significantly larger for responders than for nonresponders (93.1% ± 7.1% vs 76.5% ± 22.6%; P = 0.04), but that of the electrical delay did not significantly differ (79.2% ± 16.0% vs 69.0% ± 15.8%, P = 0.13; Fig. 8). Discussion We found that the latest electrical sites were located in the basal region of the lateral vein, and that the electrical and mechanical dyssynchrony was discrepant in 81% of patients. The mechanical dyssynchrony was larger in the responders than nonresponders. Rodriguez et al. and Fantoni et al. studied the LV endocardial activation using a 3D mapping system and found that the endocardial LV activation terminates in the basal posterior or posterolateral region.20,21 Here, we found the latest sites in the basal lateral or anterolateral areas, so they tended to be anterior rather than posterior. Endocardial and epicardial activation might differ, and simultaneous mapping of the endocardium and epicardium will clarify this notion. Anatomical coincidence is an important issue because electrical and mechanical activation is evaluated by different modalities. Positional relationships in different modalities have not been fully addressed in previous studies of lead positions and mechanical delays. Here, we confirmed an anatomical coincidence using CT and discovered that angiographic and echocardiographic images are not totally compatible. Echocardiographic images were rotated toward the clockwise direction relative to the angiographic images, as shown in Figure 4. Discussing the LV lead position determined using different modalities requires care.
May 2014
581
FUJIWARA, ET AL.
Figure 8. Percentage of the electrical and mechanical delays in responders and nonresponders. N = nonresponder; R = responder.
The PROSPECT trial described the limitations of evaluating the mechanical activation by tissue Doppler echocardiography.22 The same results were obtained in a subanalysis of the Japan Cardiac Resynchronization Therapy Registry Trial.23 However, the speckle-tracking echocardiographic analysis has recently provided a better predictive value.1519,24 This study used a radial strain analysis because the STAR study found that it could predict responders most precisely among the four types of strain measurements.25 We found that electrical and mechanical dyssynchrony were generally discrepant. There are some previous reports on electromechanical delays. Gurev et al. reported that an electromechanical delay was greater on the epicardium and base than on the endocardium and apex in a 3D electromechanical model of an intact rabbit heart.26 Badano et al. reported that about 40% of patients with heart failure and a narrow QRS have an intra LV electromechanical delay.27 The mechanism of the discrepancy between the electrical and mechanical dyssynchrony remains unknown. One possible mechanism is a transmural conduction delay. Whether or not the latest endocardial activation site and latest mechanical site are consistent is unknown. This issue will be resolved by simultaneously mapping the endocardium and epicardium for comparisons of the mechanical activation. Another possible mechanism is a disturbed electromechanical coupling. An electrically stim-
582
ulated heart releases calcium ions from intracellular stores through sarcomere activation and then the heart contracts. Many proteins such as plasmalemmal L-type calcium channels, Na/Ca exchangers, Na/H exchangers, ryanodine receptor channels, sarcoplasmic reticulum Ca adenosine triphosphatase, and phospholamban are related to excitation coupling.28,29 Experimental studies have shown that the myocardial contraction can alter the stretch-dependent regulation of ryanodine receptors and Na/H exchangers.30,31 Abnormalities of these proteins in the damaged myocardium might lead to a regional electromechanical delay. Our follow-up data indicated that the electrical delay at the site of the LV lead did not differ between responders and nonresponders, whereas the mechanical delay at the site of the LV lead was significantly larger in responders. These findings suggest that mechanical dyssynchrony is more important than electrical dyssynchrony for LV reverse remodeling. The present results support the findings of the TARGET study, which showed the usefulness of targeting the LV lead position by using speckle-tracking echocardiography.16 Study Limitations This study has some limitations. Electroanatomical maps were constructed through the coronary veins, so some areas could not be
May 2014
PACE, Vol. 37
ELECTRICAL AND MECHANICAL DYSSYNCHRONY
mapped because the electrode catheter could not be inserted into some veins or some areas did not contain any veins. Another limitation is that the mechanical activation was evaluated only by radial strain. However, radial strain is thought to be the most reliable method for deciding the most delayed mechanical site because the STAR study found that it is the most sensitive for predicting EF responses. Cardiac magnetic resonance imaging was not performed in this study, so we could not assess the distribution and extent of scar that might affect the electromechanical delay. This study was also limited by a small sample size. Whether the latest electrical or mechanical site is an adequate pacing site might
require a randomized study in a larger patient cohort. Conclusions Electroanatomical maps of the coronary veins could be constructed. The latest electrical sites were mainly in the lateral area, whereas the latest mechanical sites were distributed over a wide area. The latest electrical and mechanical sites matched in only 19% patients. A discrepancy between electrical and mechanical dyssynchrony might affect the adequate positioning of the LV leads. Mechanical dyssynchrony might be more important than electrical dyssynchrony for LV reverse remodeling.
References 1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Dusan ZK, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346:1845–1853. 2. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Luigi Tavazzi. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352:1539–1549. 3. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby R, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: The miracle ICD trial. J Am Med Assoc 2003; 289:2685– 2694. 4. McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, Dryden DM, Page R, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: A systematic review. J Am Med Assoc 2007; 297:2502–2514. 5. Doltra A, Vidal B, Silva E, Mont L, Tamborero D, Castel MA, Tolosana JM, et al. Comparison of hemodynamic versus dyssynchrony assessment for interventricular delay optimization with echocardiography in cardiac resynchronization therapy. Pacing Clin Electrophysiol 2011; 34:984–990. 6. Khan FZ, Virdee MS, Read PA, Pugh PJ, O’Halloran D, Fahey M, Elsik M, et al. Effect of low-amplitude two-dimensional radial strain at left ventricular pacing sites on response to cardiac resynchronization therapy. J Am Soc Echocardiogr 2010; 23:1168– 1176. 7. Tse HF, Lee KL, Wan SH, Yu Y, Hoersch W, Pastore J, Zhu Q, et al. Area of left ventricular regional conduction delay and preserved myocardium predict responses to cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2005; 16:690–695. 8. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, Djiane P, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 2002; 23:1780–1787. 9. Ellenbogen KA, Gold MR, Meyer TE, Fernndez Lozano I, Mittal S, Waggoner AD, Lemke B, et al. Primary results from the SmartDelay determined AV optimization: A comparison to other AV delay methods used in cardiac resynchronization therapy (Smart-AV) trial: A randomized trial comparing empirical, echocardiographyguided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010; 122:2660– 2668. 10. Koplan BA, Kaplan AJ, Weiner S, Jones PW, Seth M, Christman SA. Heart failure decompensation and all-cause mortality in relation to percent biventricular pacing in patients with heart failure: Is a goal of 100% biventricular pacing necessary? J Am Coll Cardiol 2009; 53:355–360. 11. Kiuchi K, Yoshida A, Fukuzawa K, Takano T, Kanda G, Takami K, Hirata K. Identification of the right ventricular pacing site for cardiac resynchronization therapy (CRT) guided by electroanatomical mapping (CARTO). Circ J 2007; 71:1599–1605. 12. Auricchio A, Prinzen FW. Non-responders to cardiac resynchronization therapy: The magnitude of the problem and the issues. Circ J 2011; 75:521–527.
PACE, Vol. 37
13. Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A, Barsheshet A, et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trialcardiac resynchronization therapy (MADIT-CRT) trial. Circulation 2011; 123:1159–1166. 14. Kobe J, Dechering DG, Rath B, Reinke F, Monnig G, Wasmer K, Eckardt L. Prospective evaluation of electrocardiographic parameters in cardiac resynchronization therapy: Detecting nonresponders by left ventricular pacing. Heart Rhythm 2012; 9:499–504. 15. Ypenburg C, van Bommel RJ, Delgado V, Mollema SA, Bleeker GB, Boersma E, Schalij MJ, et al. Optimal left ventricular lead position predicts reverse remodeling and survival after cardiac resynchronization therapy. J Am Coll Cardiol 2008; 52:1402– 1409. 16. Khan FZ, Virdee MS, Palmer CR, Pugh PJ, O’Halloran D, Read PA, Begley D, et al. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: The target study: A randomized, controlled trial. J Am Coll Cardiol 2012; 59:1509–1518. 17. Singh JP, Fan D, Heist EK, Alabiad CR, Taub C, Reddy V, Mansour M, et al. Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy. Heart Rhythm 2006; 3:1285– 1292. 18. Klemm HU, Krause KT, Ventura R, Schneider C, Aydin MA, Johnsen C, Boczor S, et al. Slow wall motion rather than electrical conduction delay underlies mechanical dyssynchrony in postinfarction patients with narrow QRS complex. J Cardiovasc Electrophysiol 2010; 21:70–77. 19. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J, 3rd. Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation 2006; 113:960–968. 20. Rodriguez LM, Timmermans C, Nabar A, Beatty G, Wellens HJ. Variable patterns of septal activation in patients with left bundle branch block and heart failure. J Cardiovasc Electrophysiol 2003; 14:135–141. 21. Fantoni C, Kawabata M, Massaro R, Regoli F, Raffa S, Arora V, Salerno-Uriarte JA, et al. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: A detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping system. J Cardiovasc Electrophysiol 2005; 16:112–119; discussion 120–111. 22. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, et al. Results of the predictors of response to CRT (prospect) trial. Circulation 2008; 117:2608–2616. 23. Seo Y, Ito H, Nakatani S, Takami M, Naito S, Shiga T, Ando K, et al. The role of echocardiography in predicting responders to cardiac resynchronization therapy. Circ J 2011; 75:1156– 1163. 24. Becker M, Kramann R, Franke A, Breithardt OA, Heussen N, Knackstedt C, Stellbrink C, et al. Impact of left ventricular lead position in cardiac resynchronization therapy on left ventricular remodelling. A circumferential strain analysis based on 2D echocardiography. Eur Heart J 2007; 28:1211–1220.
May 2014
583
FUJIWARA, ET AL. 25. Tanaka H, Nesser HJ, Buck T, Oyenuga O, Janosi RA, Winter S, Saba S, et al. Dyssynchrony by speckle-tracking echocardiography and response to cardiac resynchronization therapy: Results of the speckle tracking and resynchronization (STAR) study. Eur Heart J 2010; 31:1690–1700. 26. Gurev V, Constantino J, Rice JJ, Trayanova NA. Distribution of electromechanical delay in the heart: Insights from a threedimensional electromechanical model. Biophys J 2010; 99:745– 754. 27. Badano LP, Gaddi O, Peraldo C, Lupi G, Sitges M, Parthenakis F, Molteni S, et al. Left ventricular electromechanical delay in patients with heart failure and normal QRS duration and in patients with right and left bundle branch block. Europace 2007; 9:41–47. 28. Tenthorey D, de Ribaupierre Y, Kucera P, Raddatz E. Effects of verapamil and ryanodine on activity of the embryonic chick heart
584
during anoxia and reoxygenation. J Cardiovasc Pharmacol 1998; 31:195–202. 29. Turner MS, Bleasdale RA, Vinereanu D, Mumford CE, Paul V, Fraser AG, Frenneaux MP. Electrical and mechanical components of dyssynchrony in heart failure patients with normal QRS duration and left bundle-branch block: Impact of left and biventricular pacing. Circulation 2004; 109:2544–2549. 30. Petroff MG, Kim SH, Pepe S, Dessy C, Marban E, Balligand JL, Sollott SJ. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol 2001; 3:867–873. 31. Alvarez BV, Perez NG, Ennis IL, Camilion de Hurtado MC, Cingolani HE. Mechanisms underlying the increase in force and Ca(2+) transient that follow stretch of cardiac muscle: A possible explanation of the Anrep effect. Circ Res 1999; 85:716–722.
May 2014
PACE, Vol. 37
Background: Cardiac resynchronization therapy (CRT) improves the survival rates of patients with heart failure, but 30–40% of them do not respond to CRT, partially because of the position of the left ventricular (LV) lead. The relationship between the electrical and mechanical activation of the left ventricle is unknown. The aim of this study was to compare the electrical and mechanical dyssynchrony. Methods: We inserted electrode catheters into the coronary sinus (CS) and venous branches of the CS during CRT implantations and constructed electroanatomical contact maps in 16 patients using the EnSite NavXTM system. Mechanical activation was evaluated by speckle-tracking echocardiography and the latest mechanical and electrical sites were compared. The degrees of the electrical and mechanical delays of the implanted LV lead were also compared. Results: The electroanatomical maps revealed that the latest electrical sites were anterior in one, anterolateral in five, lateral in eight, and posterolateral in two. Echocardiographic imaging revealed that the latest mechanical sites were anteroseptal in two, anterior in four, lateral in five, posterior in two, and inferior in three. The latest electrical and mechanical sites matched in only three patients. The degree of the local mechanical delay for the LV lead was significantly larger in the responders than nonresponders, whereas the local electrical delay did not differ. Conclusion: A discrepancy between the electrical and mechanical dyssynchrony might affect an adequate LV lead positioning. (PACE 2014; 37:576–584) cardiac resynchronization therapy, electrical delay, mechanical delay, dyssynchrony
Introduction Although the cardiac function and survival rates in patients with severe heart failure are improved by cardiac resynchronization therapy (CRT),1–4 30–40% of the patients are unresponsive.1 The determinants of the CRT
Conflicts of Interest: None. Financial support: None. Disclosures: None. Address for reprints: Akihiro Yoshida, M.D., PH.D., Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunokicho, Chuo-ku, Kobe 650-0017, Japan. Fax: 078-382-5859; e-mail: [email protected] Received July 14, 2013; revised September 27, 2013; accepted October 20, 2013. doi: 10.1111/pace.12326
response comprised factors that are related to the patients and devices. A nonambulatory New York Heart Association (NYHA) class IV, absent of dyssynchrony, myocardial scars, and atrial fibrillation or premature ventricular contractions are associated with an unfavorable response to CRT. The device factors include the left ventricular (LV) lead position, right ventricle (RV) lead position, atrioventricular and interventricular delay settings, and pacing ratios (%).5–12 In regard to the RV lead position, Kiuchi et al. reported the impact of the RV lead pacing site guided by electroanatomical mapping.11 Many investigations have studied optimal LV lead positioning. A subanalysis of the Multicenter Automatic Defibrillator Implantation Trial– Cardiac Resynchronization Therapy (MADITCRT) study found an association of the apical
©2013 Wiley Periodicals, Inc. 576
May 2014
PACE, Vol. 37
ELECTRICAL AND MECHANICAL DYSSYNCHRONY
Table I. Baseline Characteristics No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Mean
Age
Gender
Heart Disease
NYHA
QRS (ms)
RV Pace
LVEF (%)
LVEDV (mL)
LVESV (mL)
76 63 77 80 79 78 81 62 61 62 70 69 76 64 38 74 69 ± 11
M M M M M M M F M M M M M M M M
ICM ICM ICM ICM ICM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM Sarcoidosis
III II II II II III II II II II III II III II III II
173 215 125 170 154 156 160 151 126 160 190 152 182 190 220 180 169 ± 27
0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1
35 21 26 29 23 22 30 16 24 34 34 29 17 29 25 22 26 ± 6
160 280 167 159 229 204 207 169 156 155 190 109 212 203 254 237 190 ± 43
104 221 124 112 177 159 144 142 117 102 126 78 176 144 191 184 141 ± 38
DCM = dilated cardiomyopathy; ICM = ischemic cardiomyopathy; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; NYHA = New York Heart Association; RV = right ventricle.
region with an unfavorable outcome.13 A shorter QRS duration during LV pacing also predicts CRT responses.14 With respect to the mechanical dyssynchrony, pacing at the site of the latest mechanical activation results in a superior echocardiographic response and a better prognosis.15 A randomized, controlled trial comparing a targeted approach to the LV lead placement with standard levels of care found that using speckle-tracking echocardiography to target the LV lead placement yields a significantly improved response and clinical status and lower rates of death and hospitalization related to heart failure.16 On the other hand, concerning the electrical dyssynchrony, an electrical delay of the LV lead from the onset of QRS correlates with improved LV dP/dt over baseline and clinical outcome.17 However, Klemm et al. studied mechanical dyssynchrony in postinfarction patients with a narrow QRS complex and concluded that delayed local wall motion in the damaged myocardium is not associated with local electrical conduction delay.18 The relationship between electrical and mechanical dyssynchrony remains unknown and adjustments to these different modalities of intracardiac electrical activation and speckle-tracking echocardiography have not been examined. This study compares electrical and mechanical dyssynchrony.
PACE, Vol. 37
Methods Study Population We enrolled 16 patients (mean age, 69 ± 11 years; male, n = 15; and female, n = 1) who received CRT between May 2010 and January 2012. The indications for the CRT consisted of an NYHA class II or III, left ventricular ejection fraction (LVEF) of ≤35%, and QRS ≥120 ms, including necessary RV pacing. The underlying cardiac diseases were ischemic cardiomyopathy in five, dilated cardiomyopathy in 10, and cardiac sarcoidosis in one. Thirteen patients had new implants and three were upgraded from RV pacing (Table I). CRT Implantation and Mapping The preoperative anatomical information about the coronary sinus (CS) and its branching veins was obtained using enhanced computed tomography (CT). The leads used for the CRT were transvenously implanted. The RV lead was positioned in the RV apex and the right atrial lead in the right atrial appendage. A guiding catheter was inserted into the CS and occlusive venography was performed under fluoroscopy. A 5-Fr 10-pole electrode catheter was inserted into the CS and 1.6-Fr six-pole electrode catheter into each vein branching from the CS. The catheters and leads were connected to an EnSite
May 2014
577
FUJIWARA, ET AL.
left ventricular end-systolic volume (LVESV) were derived and the LVEF was calculated from the conventional apical two- and four-chamber images using the biplane Simpson’s technique. The mechanical activation was evaluated by 2D speckle-tracking radial strain echocardiography from routine grayscale mid-LV and base-LV shortaxis images as previously described.19 The LV wall was divided into six areas in the short-axis view. The latest mechanical site was compared with the latest electrical site. Responders were defined as those having a >15% reduction in the LVESV at 6 months after the CRT.
Figure 1. Measurement of the percentage of the electrical delay = B/A × 100(%). The local electrical delay of the LV lead was calculated as the time between the onset of the QRS and local electrogram of the LV lead.
NavXTM system (St. Jude Medical, Minneapolis, MN, USA) and electroanatomical contact maps were constructed. The earliest and latest activation sites were visualized on each map and then the LV lead was positioned in a lateral or posterolateral vein. Other veins were selected if those positions were unavailable due to a high pacing threshold or diaphragmatic stimulation. Measuring the LV Lead Electrical Delay The local electrical delay of the LV lead was calculated as the time between the onset of the QRS on the surface electrocardiogram and the local electrogram of the LV lead. This delay was corrected for the baseline QRS by expressing it as a percentage of the baseline QRS duration (Fig. 1). Nomenclature of the CS Branches After occlusive venography, we named each part of the CS. We divided the CS in the left anterior oblique view into the posterior, posterolateral, lateral, anterolateral, and anterior areas and similarly described the distribution of the branches. The CS and coronary veins in the anterior oblique view were divided into basal (including the CS), middle, and apical areas (Fig. 2). Echocardiography Echocardiography was performed before the CRT implantation. Routine digital grayscale twodimensional (2D) images were acquired in standard apical and parasternal views. The left ventricular end-diastolic volume (LVEDV) and
578
Measuring the LV Lead Mechanical Delay The total LV mechanical activation time was defined as the time between the peak radial strain of the latest mechanical site and earliest mechanical site. The site where the LV lead was finally positioned was confirmed by comparing the angiographic and CT images as described later. The mechanical delay of the LV lead was calculated as the time between the peak radial strain of the earliest mechanical site and peak radial strain of the LV lead. This delay was corrected for the total mechanical activation time by expressing it as a percentage of the total mechanical activation time (Fig. 3). We then compared the clinical effects of the electrical and mechanical delays. Positional Relationship in Different Modalities A method to adjust the positional relationship between angiography and echocardiography has not been established. We matched the angiographic and echocardiographic findings based on the anatomical position of the coronary branches and papillary muscles determined by CT (Fig. 4). The posterolateral vein indicated by a red arrow in the angiogram was also recognized by CT. This CT image was sliced at the same angle as that with angiography. So the location of the posterolateral vein in the angiography and CT was identical. The papillary muscles were easily detected and indicated by red circles. The papillary muscles in the echocardiograms were located in a clockwise location compared with the CT images; therefore, the posterolateral vein was located in the posterior region. Because the echocardiographic beam was passed in an oblique direction, the constructed images were generally rotated clockwise. Statistical Analysis Continuous valuables are expressed as means ± standard deviation. Groups were compared using Student’s t-test. A P < 0.05 was considered statistically significant.
May 2014
PACE, Vol. 37
ELECTRICAL AND MECHANICAL DYSSYNCHRONY
Figure 2. Measurement of the percentage of mechanical delay = B/A × 100(%). (A) Total mechanical activation time defined as the time between the peak radial strain of the latest mechanical site and earliest mechanical site. (B) Mechanical delay of the left ventricular (LV) lead defined as the time between the peak radial strain of the earliest mechanical site and peak radial strain of the LV lead.
Figure 3. Nomenclature of the coronary sinus branches. A = anterior; AL = anterolateral; L = lateral; P = posterior; PL = posterolateral.
Results Baseline Characteristics
169 ± 27 ms, 26 ± 6%, 190 ± 43 mL, and 141 ± 38 mL, respectively.
Table I shows the baseline characteristics of the patients. Eleven and five patients had an NYHA class II and III, respectively. The mean QRS duration, LVEF, LVEDV, and LVESV values were
Electroanatomical Mapping Electroanatomical mapping was accomplished in all 16 patients, in whom occlusive
PACE, Vol. 37
May 2014
579
FUJIWARA, ET AL.
Figure 4. Positional relationship in the different modalities. The posterolateral vein viewed with angiography is found to be located in the posterior region with echocardiography.
Figure 5. Electroanatomical map of the coronary sinus and its branches in Patient No. 2. The red and white indicate the earliest activation site in the anterior vein. The purple and blue indicate the latest site in the middle of the lateral vein. LAO = left anterior oblique; RAO = right anterior oblique.
venography revealed 56 coronary vein branches, of which 49 (88%) could be mapped. Figure 5 shows a color map of the intracardiac electrical activation in sinus rhythm. The earliest and latest electrical sites were located in the apical region of the anterior vein and in the middle region of the lateral vein, respectively. Figure 6 shows the latest electrical sites in all patients. This figure is shown in a clockwise rotation to match the echocardiographic view. These sites were distributed anteriorly in one (basal),
580
anterolaterally in five (basal, n = 4; middle, n = 1), laterally in eight (basal, n = 5; middle n = 3), and posterolaterally in two (both basal). The latest electrical sites were thus distributed to the lateral or anterolateral regions in 13 (81%) of the 16 patients. Latest Mechanical Site Figure 7 shows the latest mechanical sites in all patients. The latest mechanical sites were distributed anteroseptally in two (basal and
May 2014
PACE, Vol. 37
ELECTRICAL AND MECHANICAL DYSSYNCHRONY
LV Lead Position The final LV lead positions were anterolateral in three (basal, n = 1; middle, n = 2), lateral in eight (basal n = 3; middle n = 5), and posterolateral in four (basal n = 1; middle n = 3). They were located at the latest electrical site in six (40%) patients (Nos. 2, 4, 5, 8, 13, and 15) and at the latest mechanical site in five (33%; Nos. 2, 3, 6, 13, and 14).
Figure 6. Locations of the latest electrical sites. The circled numbers refer to the patient numbers. The latest electrical sites are mainly distributed in the lateral area.
Figure 7. Locations of the latest mechanical sites. The circled numbers refer to the patient numbers. The latest mechanical sites are widely distributed.
middle, one each), anteriorly in four (basal and middle, two each), laterally in six (basal, n = 2; middle, n = 4), posteriorly in one (middle), and inferiorly in three (all middle). In contrast to the latest electrical sites, the latest mechanical sites were widely distributed. Comparison of the Latest Electrical and Mechanical Sites The latest electrical and mechanical sites were located in neighboring regions in six (38%) patients (Nos. 3, 7, 10, 14, 15, and 16), far apart in seven (44%; Nos. 4, 5, 6, 8, 9, 11, and 12), and matched only in three (19%; Nos. 1, 2, and 13). Thus, the electrical and mechanical dyssynchrony was generally discrepant.
PACE, Vol. 37
Clinical Follow-Up Because one patient died of pneumonia 5 months after the CRT implantation, we analyzed the clinical data from 15 patients. After 6 months of follow-up, 10 (66.7%) patients were responders and five (33.3%) were nonresponders. The LVESV decreased from 145 ± 40 mL to 106 ± 46 mL (P < 0.05) in all patients. The percentage of the local mechanical delay of the LV lead was significantly larger for responders than for nonresponders (93.1% ± 7.1% vs 76.5% ± 22.6%; P = 0.04), but that of the electrical delay did not significantly differ (79.2% ± 16.0% vs 69.0% ± 15.8%, P = 0.13; Fig. 8). Discussion We found that the latest electrical sites were located in the basal region of the lateral vein, and that the electrical and mechanical dyssynchrony was discrepant in 81% of patients. The mechanical dyssynchrony was larger in the responders than nonresponders. Rodriguez et al. and Fantoni et al. studied the LV endocardial activation using a 3D mapping system and found that the endocardial LV activation terminates in the basal posterior or posterolateral region.20,21 Here, we found the latest sites in the basal lateral or anterolateral areas, so they tended to be anterior rather than posterior. Endocardial and epicardial activation might differ, and simultaneous mapping of the endocardium and epicardium will clarify this notion. Anatomical coincidence is an important issue because electrical and mechanical activation is evaluated by different modalities. Positional relationships in different modalities have not been fully addressed in previous studies of lead positions and mechanical delays. Here, we confirmed an anatomical coincidence using CT and discovered that angiographic and echocardiographic images are not totally compatible. Echocardiographic images were rotated toward the clockwise direction relative to the angiographic images, as shown in Figure 4. Discussing the LV lead position determined using different modalities requires care.
May 2014
581
FUJIWARA, ET AL.
Figure 8. Percentage of the electrical and mechanical delays in responders and nonresponders. N = nonresponder; R = responder.
The PROSPECT trial described the limitations of evaluating the mechanical activation by tissue Doppler echocardiography.22 The same results were obtained in a subanalysis of the Japan Cardiac Resynchronization Therapy Registry Trial.23 However, the speckle-tracking echocardiographic analysis has recently provided a better predictive value.1519,24 This study used a radial strain analysis because the STAR study found that it could predict responders most precisely among the four types of strain measurements.25 We found that electrical and mechanical dyssynchrony were generally discrepant. There are some previous reports on electromechanical delays. Gurev et al. reported that an electromechanical delay was greater on the epicardium and base than on the endocardium and apex in a 3D electromechanical model of an intact rabbit heart.26 Badano et al. reported that about 40% of patients with heart failure and a narrow QRS have an intra LV electromechanical delay.27 The mechanism of the discrepancy between the electrical and mechanical dyssynchrony remains unknown. One possible mechanism is a transmural conduction delay. Whether or not the latest endocardial activation site and latest mechanical site are consistent is unknown. This issue will be resolved by simultaneously mapping the endocardium and epicardium for comparisons of the mechanical activation. Another possible mechanism is a disturbed electromechanical coupling. An electrically stim-
582
ulated heart releases calcium ions from intracellular stores through sarcomere activation and then the heart contracts. Many proteins such as plasmalemmal L-type calcium channels, Na/Ca exchangers, Na/H exchangers, ryanodine receptor channels, sarcoplasmic reticulum Ca adenosine triphosphatase, and phospholamban are related to excitation coupling.28,29 Experimental studies have shown that the myocardial contraction can alter the stretch-dependent regulation of ryanodine receptors and Na/H exchangers.30,31 Abnormalities of these proteins in the damaged myocardium might lead to a regional electromechanical delay. Our follow-up data indicated that the electrical delay at the site of the LV lead did not differ between responders and nonresponders, whereas the mechanical delay at the site of the LV lead was significantly larger in responders. These findings suggest that mechanical dyssynchrony is more important than electrical dyssynchrony for LV reverse remodeling. The present results support the findings of the TARGET study, which showed the usefulness of targeting the LV lead position by using speckle-tracking echocardiography.16 Study Limitations This study has some limitations. Electroanatomical maps were constructed through the coronary veins, so some areas could not be
May 2014
PACE, Vol. 37
ELECTRICAL AND MECHANICAL DYSSYNCHRONY
mapped because the electrode catheter could not be inserted into some veins or some areas did not contain any veins. Another limitation is that the mechanical activation was evaluated only by radial strain. However, radial strain is thought to be the most reliable method for deciding the most delayed mechanical site because the STAR study found that it is the most sensitive for predicting EF responses. Cardiac magnetic resonance imaging was not performed in this study, so we could not assess the distribution and extent of scar that might affect the electromechanical delay. This study was also limited by a small sample size. Whether the latest electrical or mechanical site is an adequate pacing site might
require a randomized study in a larger patient cohort. Conclusions Electroanatomical maps of the coronary veins could be constructed. The latest electrical sites were mainly in the lateral area, whereas the latest mechanical sites were distributed over a wide area. The latest electrical and mechanical sites matched in only 19% patients. A discrepancy between electrical and mechanical dyssynchrony might affect the adequate positioning of the LV leads. Mechanical dyssynchrony might be more important than electrical dyssynchrony for LV reverse remodeling.
References 1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Dusan ZK, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346:1845–1853. 2. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Luigi Tavazzi. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352:1539–1549. 3. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby R, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: The miracle ICD trial. J Am Med Assoc 2003; 289:2685– 2694. 4. McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, Dryden DM, Page R, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: A systematic review. J Am Med Assoc 2007; 297:2502–2514. 5. Doltra A, Vidal B, Silva E, Mont L, Tamborero D, Castel MA, Tolosana JM, et al. Comparison of hemodynamic versus dyssynchrony assessment for interventricular delay optimization with echocardiography in cardiac resynchronization therapy. Pacing Clin Electrophysiol 2011; 34:984–990. 6. Khan FZ, Virdee MS, Read PA, Pugh PJ, O’Halloran D, Fahey M, Elsik M, et al. Effect of low-amplitude two-dimensional radial strain at left ventricular pacing sites on response to cardiac resynchronization therapy. J Am Soc Echocardiogr 2010; 23:1168– 1176. 7. Tse HF, Lee KL, Wan SH, Yu Y, Hoersch W, Pastore J, Zhu Q, et al. Area of left ventricular regional conduction delay and preserved myocardium predict responses to cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2005; 16:690–695. 8. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, Djiane P, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 2002; 23:1780–1787. 9. Ellenbogen KA, Gold MR, Meyer TE, Fernndez Lozano I, Mittal S, Waggoner AD, Lemke B, et al. Primary results from the SmartDelay determined AV optimization: A comparison to other AV delay methods used in cardiac resynchronization therapy (Smart-AV) trial: A randomized trial comparing empirical, echocardiographyguided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010; 122:2660– 2668. 10. Koplan BA, Kaplan AJ, Weiner S, Jones PW, Seth M, Christman SA. Heart failure decompensation and all-cause mortality in relation to percent biventricular pacing in patients with heart failure: Is a goal of 100% biventricular pacing necessary? J Am Coll Cardiol 2009; 53:355–360. 11. Kiuchi K, Yoshida A, Fukuzawa K, Takano T, Kanda G, Takami K, Hirata K. Identification of the right ventricular pacing site for cardiac resynchronization therapy (CRT) guided by electroanatomical mapping (CARTO). Circ J 2007; 71:1599–1605. 12. Auricchio A, Prinzen FW. Non-responders to cardiac resynchronization therapy: The magnitude of the problem and the issues. Circ J 2011; 75:521–527.
PACE, Vol. 37
13. Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A, Barsheshet A, et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trialcardiac resynchronization therapy (MADIT-CRT) trial. Circulation 2011; 123:1159–1166. 14. Kobe J, Dechering DG, Rath B, Reinke F, Monnig G, Wasmer K, Eckardt L. Prospective evaluation of electrocardiographic parameters in cardiac resynchronization therapy: Detecting nonresponders by left ventricular pacing. Heart Rhythm 2012; 9:499–504. 15. Ypenburg C, van Bommel RJ, Delgado V, Mollema SA, Bleeker GB, Boersma E, Schalij MJ, et al. Optimal left ventricular lead position predicts reverse remodeling and survival after cardiac resynchronization therapy. J Am Coll Cardiol 2008; 52:1402– 1409. 16. Khan FZ, Virdee MS, Palmer CR, Pugh PJ, O’Halloran D, Read PA, Begley D, et al. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: The target study: A randomized, controlled trial. J Am Coll Cardiol 2012; 59:1509–1518. 17. Singh JP, Fan D, Heist EK, Alabiad CR, Taub C, Reddy V, Mansour M, et al. Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy. Heart Rhythm 2006; 3:1285– 1292. 18. Klemm HU, Krause KT, Ventura R, Schneider C, Aydin MA, Johnsen C, Boczor S, et al. Slow wall motion rather than electrical conduction delay underlies mechanical dyssynchrony in postinfarction patients with narrow QRS complex. J Cardiovasc Electrophysiol 2010; 21:70–77. 19. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J, 3rd. Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation 2006; 113:960–968. 20. Rodriguez LM, Timmermans C, Nabar A, Beatty G, Wellens HJ. Variable patterns of septal activation in patients with left bundle branch block and heart failure. J Cardiovasc Electrophysiol 2003; 14:135–141. 21. Fantoni C, Kawabata M, Massaro R, Regoli F, Raffa S, Arora V, Salerno-Uriarte JA, et al. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: A detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping system. J Cardiovasc Electrophysiol 2005; 16:112–119; discussion 120–111. 22. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, et al. Results of the predictors of response to CRT (prospect) trial. Circulation 2008; 117:2608–2616. 23. Seo Y, Ito H, Nakatani S, Takami M, Naito S, Shiga T, Ando K, et al. The role of echocardiography in predicting responders to cardiac resynchronization therapy. Circ J 2011; 75:1156– 1163. 24. Becker M, Kramann R, Franke A, Breithardt OA, Heussen N, Knackstedt C, Stellbrink C, et al. Impact of left ventricular lead position in cardiac resynchronization therapy on left ventricular remodelling. A circumferential strain analysis based on 2D echocardiography. Eur Heart J 2007; 28:1211–1220.
May 2014
583
FUJIWARA, ET AL. 25. Tanaka H, Nesser HJ, Buck T, Oyenuga O, Janosi RA, Winter S, Saba S, et al. Dyssynchrony by speckle-tracking echocardiography and response to cardiac resynchronization therapy: Results of the speckle tracking and resynchronization (STAR) study. Eur Heart J 2010; 31:1690–1700. 26. Gurev V, Constantino J, Rice JJ, Trayanova NA. Distribution of electromechanical delay in the heart: Insights from a threedimensional electromechanical model. Biophys J 2010; 99:745– 754. 27. Badano LP, Gaddi O, Peraldo C, Lupi G, Sitges M, Parthenakis F, Molteni S, et al. Left ventricular electromechanical delay in patients with heart failure and normal QRS duration and in patients with right and left bundle branch block. Europace 2007; 9:41–47. 28. Tenthorey D, de Ribaupierre Y, Kucera P, Raddatz E. Effects of verapamil and ryanodine on activity of the embryonic chick heart
584
during anoxia and reoxygenation. J Cardiovasc Pharmacol 1998; 31:195–202. 29. Turner MS, Bleasdale RA, Vinereanu D, Mumford CE, Paul V, Fraser AG, Frenneaux MP. Electrical and mechanical components of dyssynchrony in heart failure patients with normal QRS duration and left bundle-branch block: Impact of left and biventricular pacing. Circulation 2004; 109:2544–2549. 30. Petroff MG, Kim SH, Pepe S, Dessy C, Marban E, Balligand JL, Sollott SJ. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol 2001; 3:867–873. 31. Alvarez BV, Perez NG, Ennis IL, Camilion de Hurtado MC, Cingolani HE. Mechanisms underlying the increase in force and Ca(2+) transient that follow stretch of cardiac muscle: A possible explanation of the Anrep effect. Circ Res 1999; 85:716–722.
May 2014
PACE, Vol. 37
