Clinical Outcomes of Cardiac Resynchronization with Epicardial Left Ventricular Lead LU CHEN, M.S.,* HAIXIA FU, M.D.,†,‡ VICTOR G. PRETORIUS, M.D.,§ DACHUN YANG, M.D.,‡ HEATHER J. WISTE, B.A.,¶ HONGTAO YUAN, M.D.,‡ GREGORY K. FELD, M.D.,* YONG-MEI CHA, M.D.,‡ and ULRIKA M. BIRGERSDOTTER-GREEN, M.D.* From the *Division of Cardiology, Department of Medicine, University of California, San Diego, California; †Department of Cardiovascular Diseases, Henan Provincial People’s Hospital, Zhengzhou University, Henan, China; ‡Department of Cardiovascular Diseases, Mayo Clinics, Rochester, Minnesota; §Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Diego, California; and ¶Department of Health Science Research, Mayo Clinics, Rochester, Minnesota
Background: Left ventricular (LV) pacing in cardiac resynchronization therapy (CRT) can be achieved via a transvenous or epicardial route. A surgically implanted epicardial LV (eLV) lead is used after a standard transvenous LV (tLV) lead implantation has failed. However, studies of clinical outcomes in patients with eLV leads and comparisons of outcome between tLV and eLV-CRT are sparse. Therefore, the purpose of this study is to compare clinical response between tLV-CRT and eLV-CRT, as well as to understand the differences within the eLV-CRT population. Methods: Forty-four patients received eLV-CRT following unsuccessful attempts of tLV-CRT implantation between 2002 and 2013 at the University of California, San Diego (UCSD) and Mayo Clinics. These patients were matched for age, gender, and etiology of cardiomyopathy in a 1:2 ratio with a cohort of patients who received tLV-CRT during the same time period. Results: During a mean follow-up of 57 months, similar clinical outcomes and survival rate were noted between tLV and eLV-CRT patients (all P > 0.05). Within the eLV-CRT group, dilated cardiomyopathy patients had significant improvement in New York Heart Association class and ejection fraction (both P < 0.05), while ischemic cardiomyopathy patients did not (both P > 0.05). eLV-CRT patients with nonanterior lead location had significantly improved survival (P < 0.001). There was also a trend for improved survival in those with nonapical lead location (P = 0.09). Conclusion: In this case-matched two-centered study, comparable improvements were noted in patients with tLV-CRT and eLV-CRT. Operators should target nonanterior and nonapical locations during eLVCRT implantation. Use of eLV-CRT should be considered a viable alternative for CRT candidates. (PACE 2015; 38:1201–1209) epicardial CRT, pacing, CHF, surgery
Disclosures: Lu Chen, Haixia Fu, Victor G. Pretorius, Dachun Yang, Heather J Wiste, Hongtao Yuan: no relationships/disclosures. Gregory K. Feld: Medtronic, Boston Scientific, St. Jude Medical, Biotronik, Biosense Webster; Fellowship Support: Medwaves, Permenova, stocks. Yong-Mei Cha: Medtronic, Research Grants. Ulrika Birgersdotter-Green: Boston Scientific, Medtronic, and St. Jude Medical; Consulting fee, Honoraria and Research Grant: Spectranetics, Consulting fee. Address for reprints: Ulrika Birgersdotter-Green, M.D., Division of Cardiology, Department of Medicine, University of California, San Diego, 9444 Medical Center Dr., M/C 7411, La Jolla, CA 92037. Fax: 858-657-5314; e-mail: [email protected] Received February 2, 2015; revised May 26, 2015; accepted July 5, 2015. doi: 10.1111/pace.12687
Introduction Cardiac resynchronization therapy (CRT) is used to manage patients with advanced congestive heart failure (CHF).1,2 The conventional method of pacing the left ventricle in CRT is achieved by using a transvenous left ventricular (tLV) lead introduced through the coronary sinus. However, coronary venous anatomy has great interpersonal variation, which may result in the inability to reach an acceptable and stable LV lead position. Despite technological and procedural improvement, cardiac venous anatomy still limits implantation of tLV in a small but significant number of patients.3,4 Even with successful engagement of the coronary sinus, often times operators are limited by the anatomy to choose a less optimal pacing site.5,6 Studies have now
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demonstrated that certain pacing sites may be more detrimental than beneficial.7–9 Free from coronary venous anatomical restriction, surgically implanted epicardial LV (eLV) leads give operators the freedom to choose the most optimal pacing site.1 Previous studies have demonstrated that the location of the tLV lead is an important factor affecting the response to CRT.10–15 The posterolateral LV wall is often targeted for tLV lead implantation, as it is often the latest area of activation of the LV.15 The optimal site for eLVCRT implantation has been explored with measurements of pressure-volume loop,16 site of latest LV activation,17 and depolarization interval.18 Differences in acute hemodynamic response were demonstrated. However, objective and long-term clinical follow-up in these patients are not available. Comparisons between the effectiveness of tLV and eLV-CRT have been evaluated in small, single-center studies,319–25 but intragroup stratification and comparisons within the eLV-CRT population were not available in those studies. Therefore, the purpose of this study is to compare the clinical response of patients with tLV and eLV-CRT, as well as investigate variables that may contribute to differences in response to eLVCRT. Methods Study Patients and CRT Procedures After approval was obtained from the Institutional Review Board for this retrospective study, a list of patients who received CRT implantation between January of 2002 and January of 2013 was generated from the electrophysiological procedure database at the University of California, San Diego (UCSD) and the Mayo Clinic. Of 1,406 medically optimized CHF patients who underwent CRT implantation, 44 had failed tLV-CRT implantation due to inability to cannulate the coronary sinus ostium or difficulties in obtaining a stable and acceptable lead location (18 from UCSD and 26 from the Mayo Clinic). These patients subsequently underwent implantation of an eLV lead using video-assisted thoracic surgery (n = 8), minithoracotomy (n = 16), or standard median sternotomy (n = 16). Of those who received standard thoracotomy, 12 received eLV-CRT as a part of another cardiac procedure. A total of four patients were excluded in the surgical analysis, due to unavailable operative reports (n = 2) or congenital heart defects (n = 2). The eLV-CRT group was matched to tLV-CRT recipients from the Mayo Clinic patient population in a 1:2 ratio, with matching criteria including age, gender, and etiology of cardiomyopathy.
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There were a total of 86 tLV-CRT patients included in the study, as only one match each was available for two young eLV-CRT patients with congenital heart disease. LV Lead Location In both tLV and eLV-CRT implantation, the LV lead was placed in the best possible position per operators’ clinical judgment. Using the same technique as our previous study,26 location of the LV lead was determined by reviewing 24 hours postoperative chest radiography (CXR) performed as a part of routine medical care (Fig. 1). Three experienced observers interpreted lead location of the eLV lead tip independently. PA-view CXR was used to determine LV lead location on the vertical axis. Possible sites included basal, middle, and apical locations. Left lateral-view CXR was used to determine lead location on horizontal axis, with possible locations including anterior, anterolateral, lateral, posterolateral, and posterior (Figs. 1A and B). Three patients were completely excluded from lead location section of the study due to congenital heart disease. Six patients were partially excluded due to inability to obtain lead location secondary to unavailable left lateral CXR. Study Follow-Up and Data Collection Study patients were followed by implanting electrophysiologists and heart failure specialists at each institution after CRT implantation. Demographic information, baseline characteristics, CHF medication, and perioperative complications were obtained from Electronic Medical Records and detailed in Table I. New York Heart Association (NYHA) class was obtained from inpatient and outpatient documentations provided by experienced heart failure attending physicians. Echocardiographic parameters were obtained from echocardiograms as a part of routine medical care, or from documentations provided by external referring cardiologists. Preoperative echocardiogram closest to the LV lead implantation date was used to obtain baseline parameters. At least two postoperative echocardiograms were collected from each patient: one echocardiogram closest to 3 months postimplantation, and the latest echocardiogram prior to data collection. implantable cardioverter-defibrillator (ICD) therapies were obtained from remote and/or inclinic interrogation data. Survival data were obtained from Electronic Medical Records or Social Security Death Index. Statistical Analysis Baseline characteristics and change measures were compared between groups using two-sample t-tests and χ 2 tests where appropriate. Changes
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Figure 1. Postoperative 2-view chest radiography in posterior-anterior orientation showing basal (B), mid (M), apical (A) zone of the left ventricle (A). Left-lateral chest radiography delineating anterior (A), anterolateral (AL), lateral (L), posterolateral (PL), and posterior (P) zone of the left ventricle (B). Arrows indicate the left ventricular lead tip in both figures.
Table I. Baseline Characteristics of CRT Patients Transvenous-LV CRT (n = 86)
Epicardial-LV CRT (n = 44)
Variable
n
Mean ± SD or n (%)
n
Mean ± SD or n (%)
P Value
Age (years) Males ICM CRT-D versus CRT-P QRS duration Chronic AF NYHA class LVEF (%) Digoxin β-Blockers ACEI/ARB Aldactone Diuretic Statins
86 86 86 86 84 84 84 81 85 85 85 85 56 37
64.4 ± 13.7 54 (62.8%) 42 (48.8%) 75 (87.2%) 168.1 ± 35.1 18 (21.4%) 2.95 ± 0.46 24.2 ± 8.4 41 (48.2%) 80 (94.1%) 69 (81.2%) 27 (31.8%) 48 (85.7%) 24 (64.9%)
44 44 44 44 39 44 41 39 44 44 44 44 44 44
63.3 ± 15.3 28 (63.6%) 22 (50.0%) 42 (95.5%) 175.7 ± 35.1 17 (38.6%) 2.95 ± 0.62 24.8 ± 9.1 19 (43.2%) 40 (90.9%) 34 (77.3%) 17 (38.6%) 36 (81.8%) 26 (59.1%)
– – – 0.14 0.26 0.04 0.99 0.73 0.59 0.50 0.60 0.44 0.60 0.59
Patients were matched by age, gender, and etiology of cardiomyopathy. ACEI = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CRT = cardiac resynchronization therapy; CRT-D = CRT-defibrillator; CRT-P = CRT-pacemaker; ICM = ischemic cardiomyopathy; LV = left ventricular; LVEF = LV ejection fraction; NYHA = New York Heart Association Functional class; SD = standard deviation.
from pre-CRT to post-CRT within a group were assessed using paired t-tests. Survival data were displayed using Kaplan-Meier curves and differences in survival between groups were tested with a log-rank test. All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA).
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Results Baseline Characteristics The baseline characteristics of the study cohort are shown in Table I. No significant differences were noted between tLV and eLVCRT patients with the exception of chronic atrial
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Table II. Comparison of Improvement from pre-CRT to post-CRT between tLV-CRT and eLV-CRT tLV CRT (N = 86) Variable
n
NYHA QRS duration LVEF LVEDD LVESD LVEDV LVESV LA size MR grade
48 50 48 41 24 41 24 27 41
eLV CRT (N = 44)
Mean ± SD −0.66 −11.32 8.33 −3.71 −5.21 −25.97 −26.26 0.48 −0.29
± ± ± ± ± ± ± ± ±
n
0.72 31.35 10.93 5.73 6.93 42.44 36.29 6.47 0.56
31 35 29 26 21 26 21 17 22
Mean ± SD −0.53 −9.66 5.10 −1.77 −3.76 −14.15 −24.07 1.53 −0.16
± ± ± ± ± ± ± ± ±
0.77 30.89 9.73 5.83 6.29 44.18 37.20 7.46 0.70
P Value 0.47 0.81 0.19 0.18 0.47 0.28 0.84 0.62 0.41
eLV = epicardial left ventricular; LA = left atrium; LVEDD = LV end-diastolic dimension; LVEDV = LV end-diastolic volume; LVESD = LV end-systolic dimension; LVESV = LV end-systolic volume; MR = mitral regurgitation; tLV = transvenous left ventricular. Other abbreviations as in Table I.
Table III. Length of Follow-Up, Expirations, and Follow-Up Interrogation, Medical Therapy of tLV and eLV-CRT Patients
Average length of follow-up (m) Last follow-up interrogation BiV pacing (%) Appropriate shock Inappropriate shock Last follow-up medical therapy Digoxin β-Blockers ACEI/ARB Antiarrhythmics Aldactone Diuretics Statins Expirations
tLV-CRT (n = 86)
eLV-CRT (n = 44)
P Value
55.3 ± 40.2
57.1 ± 39.5
0.81
98 ± 3.9 12 1
98 ± 5.7 7 3
0.56 0.80 0.11
34 71 57 14 29 58 49 36
14 36 26 12 10 28 19 16
0.45 1 0.45 0.17 0.23 0.70 0.14 0.58
BiV = biventricular. Other abbreviations as in previous tables.
fibrillation, which was more commonly seen in eLV-CRT patients (21% vs 39%, P = 0.04). All patients received standard pharmacological therapy for CHF as detailed in Table I. Comparison between tLV and eLV-CRT Following CRT implantation, comparable improvements were noted in patients who received tLV and eLV-CRT (all P > 0.05), as detailed in Table II. Mean follow-up duration was comparable between tLV and eLV-CRT (55.3 ± 40.2 months vs 57.1 ± 39.5 months, P = 0.81). Improvements
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in NYHA class ( –0.66 ± 0.72 vs –0.53 ± 0.77, P = 0.47), LV ejection fraction (LVEF; 8.33 ± 10.93% vs 5.10 ± 9.73%, P = 0.19), LV end-systolic dimension (LVESD; –5.21 ± 6.93 mm vs –3.76 ± 6.29 mm, P = 0.47) were not significantly different between tLVCRT and eLV-CRT patients. Follow-up medical regimen, percentage of biventricular pacing, survival rate, and appropriate and inappropriate ICD shock event rates were not significantly different between the two groups (all P > 0.05; Table III).
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Table IV. Length of Hospital Stay and Perioperative Complications in Patients Who Received tLV and eLV-CRT Implantation
Average post-op LOS (days) Major complications Cardiac Pulmonary Vascular Other major complications Minor complications Pulmonary Genitourinary Minor bleeds/hematoma Other minor complications
tLV-CRT (n = 86)
eLV-CRT (n = 32)
P Value
1.9 ± 0.3
3.4 ± 1.8
0.05; Table IV). Patients received postoperative echocardiogram at a median (interquartile range) time of 5.2 (2.5–7.6) months following successful CRT implantation. There were no significant
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Figure 2. Survival probability of eLV-CRT patients based on anterior versus nonanterior LV lead location. CRT = cardiac resynchronization therapy; eLV = epicardial left ventricular; LV = left ventricular.
differences in NYHA or echocardiographical changes between eLV patients with apical versus nonapical lead location and anterior versus nonanterior lead location (all P > 0.05). A total of 16 (39%) patients expired during the mean followup period of 57.1 months. No expiration occurred within 30 days of eLV-CRT implantation. Patients with anterior lead location have a significantly lower survival rate than those with nonanterior lead location (P < 0.001, Fig. 2). The survival rate
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Figure 3. Survival probability of eLV-CRT patients based on apical versus nonapical LV lead location. Abbreviations as in Figure 2.
was not significantly different for apical compared to nonapical LV lead location patients (P = 0.09, Fig. 3); however, there was a trend for lower survival in apical leads, especially after several years. Etiology of Cardiomyopathy and Clinical Outcome in eLV-CRT Table V shows changes in clinical and echocardiographic measures in the eLV-CRT patients by dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM). In DCM patients (n = 19), improvements were noted in NYHA functional class (3.0 ± 0.5 vs 2.3 ± 0.9, P = 0.002), LVEF (23.2 ± 9.5% vs 29.3 ± 15.3%, P = 0.03), and LVESD (55.7 ± 12.3 mm vs 51.8 ± 10.6 mm, P = 0.07). In ICM patients (n = 22), all of these parameters showed nonstatistical significant improvement from pre-CRT to postCRT (all P > 0.05). The magnitudes of change in the ICM patients were smaller compared to the DCM patients. Discussion eLV-CRT implantations account for a small but clinically important number of total CRT implantations. Between April 2010 and December 2011, eLV leads accounted for over 10% of de novo LV leads implanted in the United States, or 12% (13,333 of 107,409) of all LV leads registered to the National ICD Registry.27 eLV pacing as a method for cardiac resynchronization has evolved over many years and is an established surgical approach. Despite its widespread acceptance as an alternative method to the standard transvenous approach, our understanding of this group of eLV-CRT patients is limited. A limited number of small studies have investigated acute hemodynamic
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changes among eLV-CRT patients,16–18 all of which suggested that targeted approach results in better hemodynamic response immediately following CRT implantation. Small cohort studies comparing the differences among tLV and eLV CRT patients have found similar long-term clinical outcome, but slightly elevated perioperative risk associated with eLV-CRT implantation.3,19,21–24 Our study, to the best of the authors’ knowledge, is the first case-matched study to illustrate both the differences in clinical outcome between tLV and eLV CRT, and the differences among eLVCRT patients over the longest known follow-up period. Our results demonstrate that tLV and eLVCRT are both equally effective therapy for patients with advanced CHF. These findings are consistent with prior publications.3,19,20,22–24 As the optimal area for transvenous LV pacing has previously been demonstrated to be the mid-lateral LV wall, it reinforces the importance of placement of eLV leads in this area as well. Different surgical approaches are available to reach the left ventricle, but some (anterior thoracotomy) might limit access to this ideal area and should be avoided. Approaching the left ventricle from a posterior and lateral aspect requires a left side up, lateral position of the chest on the operating table. Single lung ventilation is required to allow collapse of the left lung so as to expose the lateral border of the left ventricle. A 4th intercostal mid-axillary minithoracotomy can provide direct visualization of the phrenic nerve and the ideal area on the mid-lateral LV wall. Some authors have reported the use of a video scope and/or robotic arms to minimize the incision size while still placing the lead in the ideal position. In our experience, the need for these modalities is minimal and the procedure can usually be performed through a single 4-cm minithoracotomy using direct vision. With this technique, we were able to limit postoperative hospital stay to 3.4 days and perioperative complication rate to that of tLVCRT implantations. Our earlier attempts of eLV-CRT were limited by surgical technique and our understanding at the time, which resulted in more anterior lead positions compared to the latter part of our study. The majority of anterior leads were placed prior to 2008. With recent development in surgical technique, as well as a more targeted approach, eLV leads are now consistently placed in a lateral or posterolateral site of LV. Our data support that targeting a nonanterior and nonapical site is associated with better survival, mirroring the result from larger tLV-CRT analysis.7,9,15 The authors speculate that our earlier attempts of analyzing long-term effectiveness of tLV-CRT versus eLV-CRT may be contaminated by the more
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Table V. Comparison of Improvement between DCM and ICM eLV-CRT Patients
N DCM (n = 19) QRS duration (ms) NYHA functional class EF (%) LVESD (mm) ICM (n = 22) QRS duration (ms) NYHA functional class EF (%) LVESD (mm)
Pre-CRT Mean ± SD
Post-CRT Mean ± SD
Change (Post-Pre) Mean ± SD
P Value
17 13 12 10
165.8 3.0 23.2 55.7
± ± ± ±
38.0 0.5 9.5 12.3
155.3 2.3 29.3 51.8
± ± ± ±
25.3 0.9 15.3 10.6
−10.5 −0.7 6.2 −3.9
± ± ± ±
21.2 0.6 8.3 6.1
0.06 0.002 0.026 0.07
15 16 16 10
184.0 2.8 27.2 55.5
± ± ± ±
34.1 0.7 10.5 10.1
177.9 2.4 30.1 52.7
± ± ± ±
21.5 0.9 10.3 8.9
−6.1 −0.4 2.9 −2.8
± ± ± ±
40.6 0.8 9.4 6.5
0.57 0.10 0.23 0.21
DCM = dilated cardiomyopathy; EF = ejection fraction; ICM = ischemic cardiomyopathy. Other abbreviations as in previous tables.
anteriorly placed eLV leads in our study. As a result, changes in NHYA class, echocardiographic parameters, survival rate, and ICD therapy were similar between tLV and eLV-CRT group in our study. We determined optimal eLV lead location based on anatomical approach by targeting the mid-lateral and postero-lateral LV free wall. This approach was validated by intraoperative electrical mapping.18 Our study has indicated a significantly higher survival rate in patients with nonanterior lead location. This supports the speculation from Koos et al., who found that more anteriorly placed eLV leads in eLV-CRT resulted in higher mortality risk and minimally improved functional capacity.21 Comparison of survival rates between apical and nonapical eLV lead location trended toward significance. In particular, a lower survival rate in the apical group was especially prominent after several years of follow-up. Detrimental effects of anterior7,9 and apical15 lead location have been well established in tLV-CRT. Our data suggest those suboptimal lead locations have the same detrimental effect on clinical outcomes of eLV-CRT as well. A recent meta-analysis pointed out similarities and differences between ICM and DCM patients with tLV-CRT.28 In their comparison of randomized clinical trials, DCM patients showed greater magnitude of improvements in all parameters including LVEF, LV end-systolic volume, 6-minute walk distance, and quality of life. Authors cited scar burden as the result of suboptimal improvement in ICM patients. Similarly, our data on eLV-CRT agree with the larger trials. Significant clinical responses were noted in DCM patients
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who received eLV-CRT. In eLV-CRT patients with ICM, modest improvements were noted in all clinical parameters, including improvements in NYHA class and EF. The response should therefore be considered clinically significant. The small patient population and scar burden likely limited the improvements from reaching statistical significance. Scar burden is associated with nonresponsiveness to tLV-CRT in ICM patients.29,30 Targeting viable myocardium in previous studies has shown better clinical outcomes in tLV-CRT patients.12,31 Therefore, the authors speculate that scar burden also played a role in eLV-CRT patients of this study. Epicardial implantation offers the freedom of maneuvering the LV lead without restriction of coronary sinus and cardiac venous anatomy. However, assessment of scar burden, whether preoperatively or perioperatively, is still necessary. One potential advantage of eLV-CRT implantation over tLV-CRT implantation is the possibility of visualizing viable myocardial tissue intraprocedurally. If seen, areas of scar can be avoided intraoperatively. It is possible that our earlier attempts with eLV-CRT were contaminated by lead placement on or near myocardial scars. This could help explain nonresponders to CRT therapy in eLV-CRT patients with ICM etiology. Similarly, responses to eLV-CRT are likely in patients with visible scars avoided intraoperatively. Pacing on or near myocardial scars may have prevented the response of ICM group from reaching statistical significance. Avoiding the scar in the latter part of our study likely resulted in the clinical improvement noted above.
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Limitations This study is limited by its retrospective nature. Analysis of acute hemodynamic response was not available for comparison to the previous studies. Postoperative chest x-ray is the best available tool in this study. However, it should be noted that two-dimensional representation of three-dimensional structures could result in inaccuracy in determining lead locations. Perioperative complication rate is largely dependent on the experience level of the surgical team. Complications associated especially with tLVCRT, such as coronary sinus dissection and lead dislodgement, were not analyzed. Furthermore, the number of eLV patients in this study was relatively small, especially when comparing differences within this group by lead location or DCM versus ICM. Larger prospective studies focused on targeted eLV lead placement to a nonanterior,
nonapical site with viable myocardium are needed to confirm our data. Conclusion Surgically implanted eLV-CRT offers the freedom from coronary venous anatomy and remains a viable alternative to tLV-CRT. Similar clinical outcomes were noted in patients with tLVCRT and eLV-CRT. Improved clinical response to eLV-CRT was noted in patients with DCM, and to a lesser degree, in patients with ICM. Better survival rate was noted in patients with nonanterior LV lead locations. Targeting of the LV lead to a nonanterior and nonapical position with viable myocardium should be considered during eLV-CRT implantation. Although tLV-CRT with optimally placed tLV lead is still the standard of care, operators should recognize the prospect for eLV-CRT referral, and provide the best possible care for those patients.
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22.
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24.
25. 26.
patients receiving cardiac resynchronization therapy. Am J Cardiol 2004; 94:59–63. Mair H, Sachweh J, Meuris B, Nollert G, Schmoeckel M, Schuetz A, Reichart B, et al. Surgical epicardial left ventricular lead versus coronary sinus lead placement in biventricular pacing. Eur J Cardiothorac Surg 2005; 27:235–242. Miller AL, Kramer DB, Lewis EF, Koplan B, Epstein LM, Tedrow U. Event-free survival following CRT with surgically implanted LV leads versus standard transvenous approach. Pacing Clin Electrophysiol 2011; 34:490–500. Patwala A, Woods P, Clements R, Albouaini K, Rao A, Goldspink D, Tan L-B, et al. A prospective longitudinal evaluation of the benefits of epicardial lead placement for cardiac resynchronization therapy. Europace 2009; 11:1323–1329. Quigley RL. A hybrid approach to cardiac resynchronization therapy. Ann Thorac Cardiovasc Surg 2011; 17:273– 276. Chen L, Tiongson JE, Obrzut S, McDaniel MB, Chang H-Y, Patel J, Friedman PJ, et al. Standard chest radiograph predicts left ventricular lead location in chronic resynchronization therapy patients more accurately than intraoperative fluoroscopy. J Interv Card Electrophysiol 2012; 35:323–330.
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27. Kremers MS, Hammill SC, Berul CI, Koutras C, Curtis JS, Wang Y, Beachy J, et al. The National ICD Registry Report: Version 2.1 including leads and pediatrics for years 2010 and 2011. Heart Rhythm 2013; 10:e59–e65. 28. Chen Y, Duan C, Liu F, Shen S, Chen P, Bin J. Impact of etiology on the outcomes in heart failure patients treated with cardiac resynchronization therapy: A meta-analysis. PloS One 2014; 9:e94614. 29. Wong JA, Yee R, Stirrat J, Scholl D, Krahn AD, Gula LJ, Skanes AC, et al. Influence of pacing site characteristics on response to cardiac resynchronization therapy. Circ Cardiovasc Imaging 2013; 6:542–550. 30. Bose A, Kandala J, Upadhyay GA, Riedl L, Ahmado I, Padmanabhan R, Gewirtz H, et al. Impact of myocardial viability and left ventricular lead location on clinical outcome in cardiac resynchronization therapy recipients with ischemic cardiomyopathy. J Cardiovasc Electrophysiol 2014; 25:507–513. 31. De Roest GJ, Wu L, de Cock CC, Hendriks ML, Delnoy PPHM, van Rossum AC, Allaart CP. Scar tissue-guided left ventricular lead placement for cardiac resynchronization therapy in patients with ischemic cardiomyopathy: An acute pressure-volume loop study. Am Heart J 2014; 167:537–545.
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Background: Left ventricular (LV) pacing in cardiac resynchronization therapy (CRT) can be achieved via a transvenous or epicardial route. A surgically implanted epicardial LV (eLV) lead is used after a standard transvenous LV (tLV) lead implantation has failed. However, studies of clinical outcomes in patients with eLV leads and comparisons of outcome between tLV and eLV-CRT are sparse. Therefore, the purpose of this study is to compare clinical response between tLV-CRT and eLV-CRT, as well as to understand the differences within the eLV-CRT population. Methods: Forty-four patients received eLV-CRT following unsuccessful attempts of tLV-CRT implantation between 2002 and 2013 at the University of California, San Diego (UCSD) and Mayo Clinics. These patients were matched for age, gender, and etiology of cardiomyopathy in a 1:2 ratio with a cohort of patients who received tLV-CRT during the same time period. Results: During a mean follow-up of 57 months, similar clinical outcomes and survival rate were noted between tLV and eLV-CRT patients (all P > 0.05). Within the eLV-CRT group, dilated cardiomyopathy patients had significant improvement in New York Heart Association class and ejection fraction (both P < 0.05), while ischemic cardiomyopathy patients did not (both P > 0.05). eLV-CRT patients with nonanterior lead location had significantly improved survival (P < 0.001). There was also a trend for improved survival in those with nonapical lead location (P = 0.09). Conclusion: In this case-matched two-centered study, comparable improvements were noted in patients with tLV-CRT and eLV-CRT. Operators should target nonanterior and nonapical locations during eLVCRT implantation. Use of eLV-CRT should be considered a viable alternative for CRT candidates. (PACE 2015; 38:1201–1209) epicardial CRT, pacing, CHF, surgery
Disclosures: Lu Chen, Haixia Fu, Victor G. Pretorius, Dachun Yang, Heather J Wiste, Hongtao Yuan: no relationships/disclosures. Gregory K. Feld: Medtronic, Boston Scientific, St. Jude Medical, Biotronik, Biosense Webster; Fellowship Support: Medwaves, Permenova, stocks. Yong-Mei Cha: Medtronic, Research Grants. Ulrika Birgersdotter-Green: Boston Scientific, Medtronic, and St. Jude Medical; Consulting fee, Honoraria and Research Grant: Spectranetics, Consulting fee. Address for reprints: Ulrika Birgersdotter-Green, M.D., Division of Cardiology, Department of Medicine, University of California, San Diego, 9444 Medical Center Dr., M/C 7411, La Jolla, CA 92037. Fax: 858-657-5314; e-mail: [email protected] Received February 2, 2015; revised May 26, 2015; accepted July 5, 2015. doi: 10.1111/pace.12687
Introduction Cardiac resynchronization therapy (CRT) is used to manage patients with advanced congestive heart failure (CHF).1,2 The conventional method of pacing the left ventricle in CRT is achieved by using a transvenous left ventricular (tLV) lead introduced through the coronary sinus. However, coronary venous anatomy has great interpersonal variation, which may result in the inability to reach an acceptable and stable LV lead position. Despite technological and procedural improvement, cardiac venous anatomy still limits implantation of tLV in a small but significant number of patients.3,4 Even with successful engagement of the coronary sinus, often times operators are limited by the anatomy to choose a less optimal pacing site.5,6 Studies have now
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demonstrated that certain pacing sites may be more detrimental than beneficial.7–9 Free from coronary venous anatomical restriction, surgically implanted epicardial LV (eLV) leads give operators the freedom to choose the most optimal pacing site.1 Previous studies have demonstrated that the location of the tLV lead is an important factor affecting the response to CRT.10–15 The posterolateral LV wall is often targeted for tLV lead implantation, as it is often the latest area of activation of the LV.15 The optimal site for eLVCRT implantation has been explored with measurements of pressure-volume loop,16 site of latest LV activation,17 and depolarization interval.18 Differences in acute hemodynamic response were demonstrated. However, objective and long-term clinical follow-up in these patients are not available. Comparisons between the effectiveness of tLV and eLV-CRT have been evaluated in small, single-center studies,319–25 but intragroup stratification and comparisons within the eLV-CRT population were not available in those studies. Therefore, the purpose of this study is to compare the clinical response of patients with tLV and eLV-CRT, as well as investigate variables that may contribute to differences in response to eLVCRT. Methods Study Patients and CRT Procedures After approval was obtained from the Institutional Review Board for this retrospective study, a list of patients who received CRT implantation between January of 2002 and January of 2013 was generated from the electrophysiological procedure database at the University of California, San Diego (UCSD) and the Mayo Clinic. Of 1,406 medically optimized CHF patients who underwent CRT implantation, 44 had failed tLV-CRT implantation due to inability to cannulate the coronary sinus ostium or difficulties in obtaining a stable and acceptable lead location (18 from UCSD and 26 from the Mayo Clinic). These patients subsequently underwent implantation of an eLV lead using video-assisted thoracic surgery (n = 8), minithoracotomy (n = 16), or standard median sternotomy (n = 16). Of those who received standard thoracotomy, 12 received eLV-CRT as a part of another cardiac procedure. A total of four patients were excluded in the surgical analysis, due to unavailable operative reports (n = 2) or congenital heart defects (n = 2). The eLV-CRT group was matched to tLV-CRT recipients from the Mayo Clinic patient population in a 1:2 ratio, with matching criteria including age, gender, and etiology of cardiomyopathy.
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There were a total of 86 tLV-CRT patients included in the study, as only one match each was available for two young eLV-CRT patients with congenital heart disease. LV Lead Location In both tLV and eLV-CRT implantation, the LV lead was placed in the best possible position per operators’ clinical judgment. Using the same technique as our previous study,26 location of the LV lead was determined by reviewing 24 hours postoperative chest radiography (CXR) performed as a part of routine medical care (Fig. 1). Three experienced observers interpreted lead location of the eLV lead tip independently. PA-view CXR was used to determine LV lead location on the vertical axis. Possible sites included basal, middle, and apical locations. Left lateral-view CXR was used to determine lead location on horizontal axis, with possible locations including anterior, anterolateral, lateral, posterolateral, and posterior (Figs. 1A and B). Three patients were completely excluded from lead location section of the study due to congenital heart disease. Six patients were partially excluded due to inability to obtain lead location secondary to unavailable left lateral CXR. Study Follow-Up and Data Collection Study patients were followed by implanting electrophysiologists and heart failure specialists at each institution after CRT implantation. Demographic information, baseline characteristics, CHF medication, and perioperative complications were obtained from Electronic Medical Records and detailed in Table I. New York Heart Association (NYHA) class was obtained from inpatient and outpatient documentations provided by experienced heart failure attending physicians. Echocardiographic parameters were obtained from echocardiograms as a part of routine medical care, or from documentations provided by external referring cardiologists. Preoperative echocardiogram closest to the LV lead implantation date was used to obtain baseline parameters. At least two postoperative echocardiograms were collected from each patient: one echocardiogram closest to 3 months postimplantation, and the latest echocardiogram prior to data collection. implantable cardioverter-defibrillator (ICD) therapies were obtained from remote and/or inclinic interrogation data. Survival data were obtained from Electronic Medical Records or Social Security Death Index. Statistical Analysis Baseline characteristics and change measures were compared between groups using two-sample t-tests and χ 2 tests where appropriate. Changes
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Figure 1. Postoperative 2-view chest radiography in posterior-anterior orientation showing basal (B), mid (M), apical (A) zone of the left ventricle (A). Left-lateral chest radiography delineating anterior (A), anterolateral (AL), lateral (L), posterolateral (PL), and posterior (P) zone of the left ventricle (B). Arrows indicate the left ventricular lead tip in both figures.
Table I. Baseline Characteristics of CRT Patients Transvenous-LV CRT (n = 86)
Epicardial-LV CRT (n = 44)
Variable
n
Mean ± SD or n (%)
n
Mean ± SD or n (%)
P Value
Age (years) Males ICM CRT-D versus CRT-P QRS duration Chronic AF NYHA class LVEF (%) Digoxin β-Blockers ACEI/ARB Aldactone Diuretic Statins
86 86 86 86 84 84 84 81 85 85 85 85 56 37
64.4 ± 13.7 54 (62.8%) 42 (48.8%) 75 (87.2%) 168.1 ± 35.1 18 (21.4%) 2.95 ± 0.46 24.2 ± 8.4 41 (48.2%) 80 (94.1%) 69 (81.2%) 27 (31.8%) 48 (85.7%) 24 (64.9%)
44 44 44 44 39 44 41 39 44 44 44 44 44 44
63.3 ± 15.3 28 (63.6%) 22 (50.0%) 42 (95.5%) 175.7 ± 35.1 17 (38.6%) 2.95 ± 0.62 24.8 ± 9.1 19 (43.2%) 40 (90.9%) 34 (77.3%) 17 (38.6%) 36 (81.8%) 26 (59.1%)
– – – 0.14 0.26 0.04 0.99 0.73 0.59 0.50 0.60 0.44 0.60 0.59
Patients were matched by age, gender, and etiology of cardiomyopathy. ACEI = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CRT = cardiac resynchronization therapy; CRT-D = CRT-defibrillator; CRT-P = CRT-pacemaker; ICM = ischemic cardiomyopathy; LV = left ventricular; LVEF = LV ejection fraction; NYHA = New York Heart Association Functional class; SD = standard deviation.
from pre-CRT to post-CRT within a group were assessed using paired t-tests. Survival data were displayed using Kaplan-Meier curves and differences in survival between groups were tested with a log-rank test. All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA).
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Results Baseline Characteristics The baseline characteristics of the study cohort are shown in Table I. No significant differences were noted between tLV and eLVCRT patients with the exception of chronic atrial
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Table II. Comparison of Improvement from pre-CRT to post-CRT between tLV-CRT and eLV-CRT tLV CRT (N = 86) Variable
n
NYHA QRS duration LVEF LVEDD LVESD LVEDV LVESV LA size MR grade
48 50 48 41 24 41 24 27 41
eLV CRT (N = 44)
Mean ± SD −0.66 −11.32 8.33 −3.71 −5.21 −25.97 −26.26 0.48 −0.29
± ± ± ± ± ± ± ± ±
n
0.72 31.35 10.93 5.73 6.93 42.44 36.29 6.47 0.56
31 35 29 26 21 26 21 17 22
Mean ± SD −0.53 −9.66 5.10 −1.77 −3.76 −14.15 −24.07 1.53 −0.16
± ± ± ± ± ± ± ± ±
0.77 30.89 9.73 5.83 6.29 44.18 37.20 7.46 0.70
P Value 0.47 0.81 0.19 0.18 0.47 0.28 0.84 0.62 0.41
eLV = epicardial left ventricular; LA = left atrium; LVEDD = LV end-diastolic dimension; LVEDV = LV end-diastolic volume; LVESD = LV end-systolic dimension; LVESV = LV end-systolic volume; MR = mitral regurgitation; tLV = transvenous left ventricular. Other abbreviations as in Table I.
Table III. Length of Follow-Up, Expirations, and Follow-Up Interrogation, Medical Therapy of tLV and eLV-CRT Patients
Average length of follow-up (m) Last follow-up interrogation BiV pacing (%) Appropriate shock Inappropriate shock Last follow-up medical therapy Digoxin β-Blockers ACEI/ARB Antiarrhythmics Aldactone Diuretics Statins Expirations
tLV-CRT (n = 86)
eLV-CRT (n = 44)
P Value
55.3 ± 40.2
57.1 ± 39.5
0.81
98 ± 3.9 12 1
98 ± 5.7 7 3
0.56 0.80 0.11
34 71 57 14 29 58 49 36
14 36 26 12 10 28 19 16
0.45 1 0.45 0.17 0.23 0.70 0.14 0.58
BiV = biventricular. Other abbreviations as in previous tables.
fibrillation, which was more commonly seen in eLV-CRT patients (21% vs 39%, P = 0.04). All patients received standard pharmacological therapy for CHF as detailed in Table I. Comparison between tLV and eLV-CRT Following CRT implantation, comparable improvements were noted in patients who received tLV and eLV-CRT (all P > 0.05), as detailed in Table II. Mean follow-up duration was comparable between tLV and eLV-CRT (55.3 ± 40.2 months vs 57.1 ± 39.5 months, P = 0.81). Improvements
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in NYHA class ( –0.66 ± 0.72 vs –0.53 ± 0.77, P = 0.47), LV ejection fraction (LVEF; 8.33 ± 10.93% vs 5.10 ± 9.73%, P = 0.19), LV end-systolic dimension (LVESD; –5.21 ± 6.93 mm vs –3.76 ± 6.29 mm, P = 0.47) were not significantly different between tLVCRT and eLV-CRT patients. Follow-up medical regimen, percentage of biventricular pacing, survival rate, and appropriate and inappropriate ICD shock event rates were not significantly different between the two groups (all P > 0.05; Table III).
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Table IV. Length of Hospital Stay and Perioperative Complications in Patients Who Received tLV and eLV-CRT Implantation
Average post-op LOS (days) Major complications Cardiac Pulmonary Vascular Other major complications Minor complications Pulmonary Genitourinary Minor bleeds/hematoma Other minor complications
tLV-CRT (n = 86)
eLV-CRT (n = 32)
P Value
1.9 ± 0.3
3.4 ± 1.8
0.05; Table IV). Patients received postoperative echocardiogram at a median (interquartile range) time of 5.2 (2.5–7.6) months following successful CRT implantation. There were no significant
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Figure 2. Survival probability of eLV-CRT patients based on anterior versus nonanterior LV lead location. CRT = cardiac resynchronization therapy; eLV = epicardial left ventricular; LV = left ventricular.
differences in NYHA or echocardiographical changes between eLV patients with apical versus nonapical lead location and anterior versus nonanterior lead location (all P > 0.05). A total of 16 (39%) patients expired during the mean followup period of 57.1 months. No expiration occurred within 30 days of eLV-CRT implantation. Patients with anterior lead location have a significantly lower survival rate than those with nonanterior lead location (P < 0.001, Fig. 2). The survival rate
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Figure 3. Survival probability of eLV-CRT patients based on apical versus nonapical LV lead location. Abbreviations as in Figure 2.
was not significantly different for apical compared to nonapical LV lead location patients (P = 0.09, Fig. 3); however, there was a trend for lower survival in apical leads, especially after several years. Etiology of Cardiomyopathy and Clinical Outcome in eLV-CRT Table V shows changes in clinical and echocardiographic measures in the eLV-CRT patients by dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM). In DCM patients (n = 19), improvements were noted in NYHA functional class (3.0 ± 0.5 vs 2.3 ± 0.9, P = 0.002), LVEF (23.2 ± 9.5% vs 29.3 ± 15.3%, P = 0.03), and LVESD (55.7 ± 12.3 mm vs 51.8 ± 10.6 mm, P = 0.07). In ICM patients (n = 22), all of these parameters showed nonstatistical significant improvement from pre-CRT to postCRT (all P > 0.05). The magnitudes of change in the ICM patients were smaller compared to the DCM patients. Discussion eLV-CRT implantations account for a small but clinically important number of total CRT implantations. Between April 2010 and December 2011, eLV leads accounted for over 10% of de novo LV leads implanted in the United States, or 12% (13,333 of 107,409) of all LV leads registered to the National ICD Registry.27 eLV pacing as a method for cardiac resynchronization has evolved over many years and is an established surgical approach. Despite its widespread acceptance as an alternative method to the standard transvenous approach, our understanding of this group of eLV-CRT patients is limited. A limited number of small studies have investigated acute hemodynamic
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changes among eLV-CRT patients,16–18 all of which suggested that targeted approach results in better hemodynamic response immediately following CRT implantation. Small cohort studies comparing the differences among tLV and eLV CRT patients have found similar long-term clinical outcome, but slightly elevated perioperative risk associated with eLV-CRT implantation.3,19,21–24 Our study, to the best of the authors’ knowledge, is the first case-matched study to illustrate both the differences in clinical outcome between tLV and eLV CRT, and the differences among eLVCRT patients over the longest known follow-up period. Our results demonstrate that tLV and eLVCRT are both equally effective therapy for patients with advanced CHF. These findings are consistent with prior publications.3,19,20,22–24 As the optimal area for transvenous LV pacing has previously been demonstrated to be the mid-lateral LV wall, it reinforces the importance of placement of eLV leads in this area as well. Different surgical approaches are available to reach the left ventricle, but some (anterior thoracotomy) might limit access to this ideal area and should be avoided. Approaching the left ventricle from a posterior and lateral aspect requires a left side up, lateral position of the chest on the operating table. Single lung ventilation is required to allow collapse of the left lung so as to expose the lateral border of the left ventricle. A 4th intercostal mid-axillary minithoracotomy can provide direct visualization of the phrenic nerve and the ideal area on the mid-lateral LV wall. Some authors have reported the use of a video scope and/or robotic arms to minimize the incision size while still placing the lead in the ideal position. In our experience, the need for these modalities is minimal and the procedure can usually be performed through a single 4-cm minithoracotomy using direct vision. With this technique, we were able to limit postoperative hospital stay to 3.4 days and perioperative complication rate to that of tLVCRT implantations. Our earlier attempts of eLV-CRT were limited by surgical technique and our understanding at the time, which resulted in more anterior lead positions compared to the latter part of our study. The majority of anterior leads were placed prior to 2008. With recent development in surgical technique, as well as a more targeted approach, eLV leads are now consistently placed in a lateral or posterolateral site of LV. Our data support that targeting a nonanterior and nonapical site is associated with better survival, mirroring the result from larger tLV-CRT analysis.7,9,15 The authors speculate that our earlier attempts of analyzing long-term effectiveness of tLV-CRT versus eLV-CRT may be contaminated by the more
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Table V. Comparison of Improvement between DCM and ICM eLV-CRT Patients
N DCM (n = 19) QRS duration (ms) NYHA functional class EF (%) LVESD (mm) ICM (n = 22) QRS duration (ms) NYHA functional class EF (%) LVESD (mm)
Pre-CRT Mean ± SD
Post-CRT Mean ± SD
Change (Post-Pre) Mean ± SD
P Value
17 13 12 10
165.8 3.0 23.2 55.7
± ± ± ±
38.0 0.5 9.5 12.3
155.3 2.3 29.3 51.8
± ± ± ±
25.3 0.9 15.3 10.6
−10.5 −0.7 6.2 −3.9
± ± ± ±
21.2 0.6 8.3 6.1
0.06 0.002 0.026 0.07
15 16 16 10
184.0 2.8 27.2 55.5
± ± ± ±
34.1 0.7 10.5 10.1
177.9 2.4 30.1 52.7
± ± ± ±
21.5 0.9 10.3 8.9
−6.1 −0.4 2.9 −2.8
± ± ± ±
40.6 0.8 9.4 6.5
0.57 0.10 0.23 0.21
DCM = dilated cardiomyopathy; EF = ejection fraction; ICM = ischemic cardiomyopathy. Other abbreviations as in previous tables.
anteriorly placed eLV leads in our study. As a result, changes in NHYA class, echocardiographic parameters, survival rate, and ICD therapy were similar between tLV and eLV-CRT group in our study. We determined optimal eLV lead location based on anatomical approach by targeting the mid-lateral and postero-lateral LV free wall. This approach was validated by intraoperative electrical mapping.18 Our study has indicated a significantly higher survival rate in patients with nonanterior lead location. This supports the speculation from Koos et al., who found that more anteriorly placed eLV leads in eLV-CRT resulted in higher mortality risk and minimally improved functional capacity.21 Comparison of survival rates between apical and nonapical eLV lead location trended toward significance. In particular, a lower survival rate in the apical group was especially prominent after several years of follow-up. Detrimental effects of anterior7,9 and apical15 lead location have been well established in tLV-CRT. Our data suggest those suboptimal lead locations have the same detrimental effect on clinical outcomes of eLV-CRT as well. A recent meta-analysis pointed out similarities and differences between ICM and DCM patients with tLV-CRT.28 In their comparison of randomized clinical trials, DCM patients showed greater magnitude of improvements in all parameters including LVEF, LV end-systolic volume, 6-minute walk distance, and quality of life. Authors cited scar burden as the result of suboptimal improvement in ICM patients. Similarly, our data on eLV-CRT agree with the larger trials. Significant clinical responses were noted in DCM patients
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who received eLV-CRT. In eLV-CRT patients with ICM, modest improvements were noted in all clinical parameters, including improvements in NYHA class and EF. The response should therefore be considered clinically significant. The small patient population and scar burden likely limited the improvements from reaching statistical significance. Scar burden is associated with nonresponsiveness to tLV-CRT in ICM patients.29,30 Targeting viable myocardium in previous studies has shown better clinical outcomes in tLV-CRT patients.12,31 Therefore, the authors speculate that scar burden also played a role in eLV-CRT patients of this study. Epicardial implantation offers the freedom of maneuvering the LV lead without restriction of coronary sinus and cardiac venous anatomy. However, assessment of scar burden, whether preoperatively or perioperatively, is still necessary. One potential advantage of eLV-CRT implantation over tLV-CRT implantation is the possibility of visualizing viable myocardial tissue intraprocedurally. If seen, areas of scar can be avoided intraoperatively. It is possible that our earlier attempts with eLV-CRT were contaminated by lead placement on or near myocardial scars. This could help explain nonresponders to CRT therapy in eLV-CRT patients with ICM etiology. Similarly, responses to eLV-CRT are likely in patients with visible scars avoided intraoperatively. Pacing on or near myocardial scars may have prevented the response of ICM group from reaching statistical significance. Avoiding the scar in the latter part of our study likely resulted in the clinical improvement noted above.
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Limitations This study is limited by its retrospective nature. Analysis of acute hemodynamic response was not available for comparison to the previous studies. Postoperative chest x-ray is the best available tool in this study. However, it should be noted that two-dimensional representation of three-dimensional structures could result in inaccuracy in determining lead locations. Perioperative complication rate is largely dependent on the experience level of the surgical team. Complications associated especially with tLVCRT, such as coronary sinus dissection and lead dislodgement, were not analyzed. Furthermore, the number of eLV patients in this study was relatively small, especially when comparing differences within this group by lead location or DCM versus ICM. Larger prospective studies focused on targeted eLV lead placement to a nonanterior,
nonapical site with viable myocardium are needed to confirm our data. Conclusion Surgically implanted eLV-CRT offers the freedom from coronary venous anatomy and remains a viable alternative to tLV-CRT. Similar clinical outcomes were noted in patients with tLVCRT and eLV-CRT. Improved clinical response to eLV-CRT was noted in patients with DCM, and to a lesser degree, in patients with ICM. Better survival rate was noted in patients with nonanterior LV lead locations. Targeting of the LV lead to a nonanterior and nonapical position with viable myocardium should be considered during eLV-CRT implantation. Although tLV-CRT with optimally placed tLV lead is still the standard of care, operators should recognize the prospect for eLV-CRT referral, and provide the best possible care for those patients.
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