- Email: [email protected]
Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines With Heart Failure
Accepted Manuscript Title: Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines with Heart Failure Author: Qiong Qiu, Li Yang, Jing-ting Mai, Ying Yang, Yong Xie, Yang-xin Chen, Jing-feng Wang PII: DOI: Reference:
S1071-9164(17)30029-5 http://dx.doi.org/doi: 10.1016/j.cardfail.2017.01.007 YJCAF 3919
To appear in:
Journal of Cardiac Failure
Received date: Revised date: Accepted date:
6-4-2016 13-12-2016 9-1-2017
Please cite this article as: Qiong Qiu, Li Yang, Jing-ting Mai, Ying Yang, Yong Xie, Yang-xin Chen, Jing-feng Wang, Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines with Heart Failure, Journal of Cardiac Failure (2017), http://dx.doi.org/doi: 10.1016/j.cardfail.2017.01.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines with Heart Failure
Short titles: Acute effects of MSP in canines with heart failure
Qiong Qiu, PhD. 1,2,# , Li Yang, PhD.1,#, Jing-ting Mai, PhD.1,2,#, Ying Yang, PhD.1,2, Yong Xie, PhD.1,2, Yang-xin Chen, MD., PhD.1,2,*, Jing-feng Wang, MD.,PhD., FHRS1,2, *
1
Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen
University, 107 Yanjiang West Road, Guangzhou, China, 510120
2
Key Laboratory of Cardiac Electrophysiology and Arrhythmia in Guangdong
Province, 107 Yanjiang West Road, Guangzhou, China, 510120
#
These authors contributed equally to this work.
*Corresponding author:
E-mail: [email protected], [email protected] Telephone/fax number: +86-020-81332623 Mail address: 107 Yanjiang West Road, Guangzhou, China, 510120,
1
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E-mail address for all the authors:
Qiong Qiu: [email protected];
Li Yang: [email protected]
Jing-ting Mai: [email protected];
Ying Yang: [email protected]
Xie Yong: [email protected];
Yang-xin Chen: [email protected]
Jing-feng Wang: [email protected]
2
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Highlights
Multisite biventricular pacing is superior to biventricular pacing in reducing dyssynchrony.
Multisite biventricular pacing is superior to biventricular pacing in improving hemodynamics.
The pacing site-combination has a potential effect on multisite biventricular pacing response.
ABSTRACT
Background: Multisite biventricular pacing(MSP) has been proposed as an alternative strategy to improve the efficiency of conventional biventricular pacing(BVP), but its utility remains unclear. This study sought to investigate whether MSP induced better synchrony and hemodynamic effects in canines with heart failure.
Methods and Results: After 3 weeks’ rapid right ventricular pacing(RVP), 7 canines were sutured with 4 left ventricular(LV) leads on anterior, lateral, posterior and apical wall, and followed by MSP and BVP. Hemodynamic, ECG and echocardiographic parameters were measured. Dyssynchrony was assessed by tissue Doppler imaging for Yu-index (longitudinal direction) and speckle tracking imaging for the standard deviation of time to peak radial strains (SDε, radial direction). Compared with BVP, mean MSP reduced QRS width (P<0.05), Yu-index (25.3±1.9ms vs. 31.6±4.3ms, P=0.008), SDε(32.8±5.9ms vs. 37.3±7.9ms, P=0.032) 3
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and
LV
end-diastolic
pressure(LVEDP,
P<0.05).
The
optimal
pacing
site-combination improved QRS width, YU-index, SDε, LVEDP as well as dP/dtmax significantly (all P<0.05), but the worst MSP(with the smallest dP/dtmax) did not show any improvement to BVP.
Conclusions: MSP is superior to BVP in reducing dyssynchrony and improving hemodynamics. The pacing site-combination has a potential effect on MSP response.
Keywords: cardiac resynchronization therapy; multisite biventricular pacing; hemodynamic; mechanical dyssynchrony
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List of Abbreviations
BVP: biventricular pacing
CRT: cardiac resynchronization therapy
dP/dtmax: maximum derivative of left ventricular pressure
dP/dtmin: minimum derivative of left ventricular pressure
LBBB: left bundle branch block
LV: left ventricle
LVEDP: left ventricular end-diastolic pressure
LVESP: left ventricular end-systolic pressure
MSP: multisite biventricular pacing
RVP: right ventricular pacing
SDε: standard deviation of time to peak radial strains of 12 LV segments
STI: speckle tracking imaging
TDI: tissue Doppler imaging
TR-L: time difference between the onsets of the right and left ventricular ejecting
5
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Yu-index: standard deviation of time to peak systolic velocities of 12 LV segments
6
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INTRODUCTION
Cardiac resynchronization therapy (CRT) is a recommended treatment for patients with heart failure and wide QRS complex.1, 2Many large randomized trials have proved that CRT improves left ventricular (LV) function, reverses remodeling, and reduces heart failure hospitalization and mortality.3-8However, approximately 30-40% patients implanted with a single LV lead do not respond to CRT, even with further deterioration on heart function.1, 2Dyssynchrony after implantation, due to myocardial scar, suboptimal lead position and electric conduction variation, is one of the major reasons for CRT nonresponse.9, 10Therefore, Multisite biventricular pacing(MSP) has arisen as an alternative strategy to improve electrical resynchronization and increase the response rate. However, human data were limited by the technical difficulties and showed conflicting results.
11-14
Meanwhile, it remains unclear whether pacing sites
affects MSP response.
Mechanical dyssynchrony evaluation is essential for predicting CRT response. Radial strain analysis, derived from speckle tracking imaging(STI), has been used to measure radial cardiac movement.
15-19
After CRT, decreased standard derivation of
time to peak radial strains(SDε) is associated with better long term outcome. 20 Tissue Doppler imaging (TDI), with its high time-resolution and reproducibility, is one of the most commonly used methods to evaluate longitudinal dyssynchrony.21 The standard deviation of time to peak systolic velocities from 12 segments (Yu-index), remains as a widely utilized parameter in current CRT researches.22-25 The combination of STI 7
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with TDI can provide higher accuracy in predicting CRT response, and is better than either technique alone.26
Accordingly, we performed MSP(with different site-combinations) in the canines with heart failure, and compared them with biventricular pacing (BVP) in electrical-mechanical dyssynchrony and hemodynamic parameters. The purpose of this study was to assess whether MSP could induce additional improvement from BVP, and the influences of pacing positions on MSP response.
METHODS AND RESULTS
This study was approved by the Academic Administration Committee of Sun Yat-sen Memorial Hospital of Sun Yat-sen University. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Experimental Model
The experiments were performed on 9 canines with 8-10 months old and 12-15kg weight. Three weeks’ rapid RVP (230 beats/min) induced severe LV dysfunction and dyssynchrony.
27, 28
Then, anesthesia was inducted with the sodium pentobarbital (30
mg/kg intravenous) and maintained by the isoflurane (0.5 to 1% in O2/N2O [1:2]). Meanwhile, mechanical ventilation was continued with 10ml/kg tidal volume. Epicardial electrodes (Medtronic, epi 4965) were suture to four locations on the LV via midline thoracotomy, and connected to an implantable pulse generator (Medtronic, 8
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InSync Sentry 7289). According to MADIT-CRT study, the electrode locations included basal anterior, lateral, posterior walls and apex (figure 1)29. During MSP, a special Y adapter was used to connect 2 leads to one LV output.
Study Protocol
As we reported earlier30, 31, RVP was used to imitate dyssynchronic contraction. BVP was performed by pacing on right ventricular apex and LV basal lateral segment. MSP was performed by pacing on 2 LV leads and RVP, and with up to 6 different LV site-combinations: anterior+lateral walls, anterior+posterior walls, anterior wall+apex, lateral+posterior walls, lateral wall+apex, posterior wall+apex. The orders of pacing modes were randomized per dog. The pacing rate was set to 20 beats above the intrinsic heart rate to prevent intrinsic ventricular activation. The parameters were recorded after pacing for 5 minutes. With hemodynamic stabilized, LV pressure, electrocardiographic and echocardiographic data were recorded at end-expiration with 5cm H2O positive pressure.
Echocardiographic Measurements
Echocardiography was performed by a commercially available cardiac ultrasound system (Vivid I, GE Healthcare). S3 transducer was used with the depth of 8-10cm. Routine 2-dimensional images were recorded digitally in cine-loop format (5 cardiac cycles).TDI images were recorded from apical 2-, 3-, 4-chamber views with 100-120 frames/s. During STI, the frame rate was set to >50 frames/s. Both basal and middle 9
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parasternal short axis views were recorded. Pulse-wave Doppler images, from left and right ventricular outflow tracts, were also recorded.
All images were analyzed offline using EchoPac system (version 10.0; GE-Vingmed Ultrasound), and by an investigator blinded to the pacing modes. After recording the time of aortic valve opening and closing from pulse wave Doppler in left ventricular outflow tract, the systolic interval was marked automatically on Q-Analysis screen. With TDI, the regions of interest (about 4mm× 6mm) were placed on the basal and middle segments, and adjusted manually from frame to frame. Then, the time-velocity curves were constructed. The time intervals from QRS to peak systolic velocity were measured to calculate Yu-index.
With STI, a circular region of interest was traced on the endocardium. Then, the epicardial circle was generated automatically. The time-strain curves from basal and middle segments were generated (Figure 2), and SDε was calculated to evaluate radial dyssynchrony.20Inter-ventricular dyssynchrony was measured as the difference between LV and RV pre-ejection period (TR-L), measured from the QRS complex to the onsetsof aortic and pulmonic flow respectively. All parameters were averaged from 3 consecutive cardiac cycles. Both absolute value and relative changes to RVP were recorded.
10
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Hemodynamic and Electrocardiographic Measurements
Through left carotid artery, the catheter (5F, Cordis) was placed into LV chamber and connected to the cardiac function analyzer for real-time intra-ventricular pressure display. From pressure-time curves, the following parameters were measured: LV end-systolic pressure (LVESP), LV end-diastolic pressure (LVEDP), the maximum derivative of LV pressure (dP/dtmax) and the minimum derivative of LV pressure (dP/dtmin). QRS width was measured from electrocardiogram. All parameters were averaged from 5 consecutive cardiac cycles. Both absolute value and relative changes to RVP were recorded.
Inter- and Intra-observer Variability in TDI and STI
To assess inter- and intra-observer variability, two blinded investigators measured 10 randomly selected echocardiographic data, and one of them repeated the measurements 1 month later. The variability was expressed as the absolute difference divided by the mean value of the measurement. The inter- and intra-observer variabilities were 17±6% and 9±5% for the time to peak systolic velocity, 16±8% and 13±7% for the time to peak systolic strain.
Statistical Analysis
Mean MSP was calculated as the mean value of 6 pacing combinations. According to dP/dtmax, the best( with the largest dP/dtmax)and worst (with the smallest dP/dtmax) MSP were defined. Statistical analysis was performed by SPSS software (IBM SPSS 11
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statistics 22.0). All values were expressed as mean ± SD for normal distribution, otherwise as median (25th-75th). Repeated measure of variance analysis was used to compare different pacing modes. Greenhouse-Geisser correction was applied when sphericity assumption was violated. The relative improvement, calculated as the percentage changes to RVP, was compared between BVP and MSP. Paired sample Student t test was used in normal distribution data; otherwise Mann-Whitney U test was used. Significance was determined as P<0.05. The Bonferroni correction was applied in multiple comparisons.
RESULTS
Canine Model of Heart Failure with Dyssynchrony
Two canines were excluded from the study, one died of ventricular arrhythmia and another suffered from serious pericardial infection. In the remaining 7 canines, rapid RVP induced overt heart failure. At the end of 3 weeks’ RVP, LV ejection fraction (LVEF) decreased to 32.5±1.5%. Myocardial dyssynchrony was also present: QRS width from 43.7±12.2ms to 114.9±19.4ms (P<0.001), Yu-index from 14.5±4.5ms to 51.0±8.1ms (P<0.001), and SDε from 35.2±10.8ms to 51.6±7.6ms (P=0.010).
Effect of MSP on Dyssynchrony
Compared with RVP, mean MSP and BVP reduced Yu-index, SDε and TR-L significantly (all P<0.05, Table 1).
Compared with BVP, mean MSP significantly
improved SDε in absolute and relative values(both P<0.05，Table 1, Figure3). 12
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Regarding Yu-index, significant differences were found in absolute value(P<0.05, table 1). Relative changes of mean MSP was indeed better than BVP, but without statistical significance(P>0.05, Figure 3). There was no significant difference in TR-L between BVP and mean MSP(P>0.05).
Compared with RVP, both BVP and mean MSP reduced QRS width significantly (P<0.05, Table 1): mean MSP reduced QRS by 25.6±7.5%, which was larger than BVP did (20.0±5.5%, P=0.014, Figure 3).
Effect of MSP on Hemodynamics
Compared with RVP, mean MSP and BVP significantly increased LVESP, dP/dtmax and decreased dP/dtmin(all P<0.01), but only mean MSP significantly deceased LVEDP (P=0.040, table 1).
Compared with BVP, LVEDP was significantly lower in mean MSP (P=0.041, table 1). Mean MSP decreased LVEDP by 27.6% from RVP, which was significantly larger than BVP did (P=0.049，Figure 4). There were no significant differences in LVESP, dP/dtmax and dP/dtmin between BVP and mean MSP (all P>0.05, table 1). No significant correlations were found between the changes of dP/dtmax and Yu-index (r=-0.001, P=0.995) or SDε(r=0.142, P=0.329).
13
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Influence of LV Pacing Sites on MSP response
There were totally 42 MSPs in 7 canines, 25(59.5%) of them were superior to BVP. Among different pacing site-combinations, various combinations induced different dP/dt
max.
We observed the pacing sites with the largest (best MSP) and smallest
(worst MSP) dP/dtmax in each canine. The results showed the best sites varied among canines: 2 in anterior+lateral walls, 2 in anterior wall and apex, 2 in lateral wall and apex, and 1 in posterior wall and apex. But anterior+ posterior and lateral+ posterior wall pacing could not induce largest dP/dtmax in every canine. Meanwhile, most canines
showed
smallest
dP/dtmax
with
lateral+posterior
(3
canines)
or
anterior+posterior (2 canines) pacing.
The best MSP increased LVESP by 15.5%, dP/dtmax by 63.8% and decreased Yu-index by 58.0% from RVP. Compared with BVP, the best MSP not only induced more reduction in YU-index (-58.0±6.6% vs. -36.8±11.6%, P=0.006), SDε (-47.2±17.9% vs. -27.3±3.1%, P=0.030) and QRS width (P=0.043), but also improved LVEDP and dP/dtmax(P<0.05). However, there were no significant differences in LVESP, LVEDP, dP/dtmax or dP/dtmin between the worst MSP and BVP(all P>0.05). Also, no differences were found in Yu-index, SDε and QRS width (all P>0.05, Supplementary Figure 1). The worst MSP even decreased dP/dtmax from BVP in one canine.
14
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DISSUSION
CRT is a well-accepted therapy for patients with refractory heart failure and wide QRS complex, but the response rate has not yet been satisfactory. Hence, this study was designed to investigate whether MSP, a novel alternative pacing strategy, was better than conventional BVP. The major findings of this study were: 1)mean MSP acutely improved dyssynchrony (electrical and mechanical) and hemodynamics from baseline RVP, and was superior to conventional BVP;
2) Optimizing pacing
site-combination could improve synchrony and hemodynamic effects in MSP, but the sites differed among individuals .
Previous studies
Absence of CRT response is partly caused by suboptimal LV lead position and persistent mechanical dyssynchrony. Recently, MSP has been developed to increase the response rate by stimulating and capturing broader LV area. But the previous studies mainly observed its acute hemodynamic effects, and with conflicting results. A randomized crossover trial (TRIP-HF),
13
with 42 patients, showed that dual-vein
LV pacing yielded significant improvement in LVEF and LVESV at 3 months follow-up when compared to conventional BVP. Ginks et al found that dual-vein LV pacing increased LV dP/dtmax, but only significantly in patients with posterolateral scar.12 The recently introduced quadripolar lead simplifies MSP with one LV lead. Zanon et al32 reported that MSP with quadripolar lead yielded a small but consistent increase in hemodynamic response when comparing with BVP. However, Shetty et al 15
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did not find significant differences between MSP(dual or single quadripolar leads) and conventional CRT.33 Since optimized vector is essential for conventional CRT response, 34 the site-combination may also affect MSP improvement. Recently, Ploux et al examined the effects of multi-LV pacing(from 2 to 7 electrodes), and found that contractility improvement was limited to those with suboptimal single-LV pacing. 35
However, they performed pure LV pacing on canines without heart failure, which
was different from multi-LV+ RV pacing on failure heart.
Effects of MSP on mechanical dyssynchrony
Several studies have shown that asynchronous contraction leaded to major and asymmetric remodeling on ventricular walls. Re-coordinating contraction has profound effects on myocardium at molecular, cellular and structural levels, even reverses asymmetric remodeling to normal geometry.36-40Hence, immediate mechanical resynchronization after CRT is a predictor for better long-term outcome.15 Since cardiac motion is multidirectional and complicated, it is difficult to measure mechanical dyssynchrony accurately by single parameter. Combining radial with longitudinal indexes provides higher sensitivity and specificity in predicting long-term outcome after CRT.26
In the present study, we used Yu-index (derived from TDI) and SDε(derived from STI) to analyze myocardial dyssynchrony. As a result, MSP not only reduced QRS width, but also decreased Yu-index and SDε when compared to BVP. Moreover, MSP improved radial synchronization better than longitudinal one, as detected by Osca et 16
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al.
41
It demonstrates that MSP induces more synchronous electric conduction and
mechanical contraction. Such effects are associated with myocardial remodeling reversal, and fewer cardiac events in the long-term. 15, 18, 42, 43
Effects of MSP on hemodynamics
When the heart turns into asynchronous activation, it generates heterogeneity in segmental myocardial workload and changes the direction of regional blood flow (displacement of blood from early to late and back to early activation sites). It results in rightward shift of end-systolic pressure–volume relationship, decreasing stroke volume, and increasing LVEDP.
37
In our study, mean MSP decreased LVEDP,
dP/dtmin and increased LVESP, dP/dtmax when compared to RVP. Comparing to BVP, mean MSP significantly reduced LVEDP as well. MSP restores coordinate contraction and relaxation acutely, so LVEDP decreases.44 Moreover, lower LV filling pressure increases coronary blood flow, reverses ventricular remodeling and improves prognosis. 37
Influences of LV Pacing Sites in MSP
Pacing site-combination has potential influence on MSP response. The best MSP (with the largest dP/dtmax) was accompanied by more synchronous contraction and better hemodynamics. However, we found the best site-combination varied among animals. It was difficult to find a predictable site for all subjects, just as Zanon et al reported. 32On the contrary, the worst MSP(with the smallest dP/dtmax) was relatively 17
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fixed, and did not show any improvement to conventional BVP.
In patients with LBBB and RVP, an electric blocking line presents from the basal to the apical segment, and induces LV activation in U-shaped pattern.45, 46This line is individual special, and changes with pacing mode and electrode position. 46
45,
Therefore, MSP with different pacing positions has various effects on the
electrical conduction, mechanical dyssynchrony and relevant hemodynamics. It is worth mentioning that posterior +anterior/lateral pacing was not optimal site-combination in any canine, even deteriorated heart function. In our opinion, these 2 combinations should be avoided in clinical practice. The newly developed multiple-polar lead could provide more choices of pacing vectors,
47
the cardiologists
should choose the site-combination individually both during CRT implantation and at follow-up.
Study Limitations
Unavoidably, there were some limitations in this study. Firstly, we used rapid RV pacing canine model to imitate patients with heart failure and dyssynchrony. Although being kind of different from clinics, this model is still well accepted and widely used in CRT researches.48-50Secondly, we performed thoracic surgery to implant epicardial electrodes, which might cause myocardial injury to some degree. However, the object of this study was to compare the acute effects of MSP with other pacing modes. All the animals were studied under the same baseline condition. So the operation itself would interfere little with the results. Thirdly, we did not calculate the changes in LV 18
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end-systolic volume(LVESV) and LVEF from echocardiography, which might add to our finding. However, LVESV reflects chronic reverse remodeling and predict longer survivor only when measured at 3-12 months after CRT implantation.
51, 52
LVEF
might not be an accurate parameter to reflect real time pump function in tachycardia conditions. Nevertheless, invasive hemodynamic measurements, derived from left ventricular catheterization, are more accurate to reflect the real time cardiac function change, less affected by the volume status and heart rate variations, and therefore widely applied in acute CRT studies 42, 53Finally, the small sample size may be viewed as another limitation. However, the repeatability and consistency in this study was well enough to support the findings.
Conclusions
The present result indicates that MSP reduces dyssynchrony (electrical and mechanical) and improves hemodynamics in asynchronic heart failure, and is superior to BVP. LV pacing site-combination has a potential effect on MSP response. The optimal site-combination, which induces better hemodynamic effect and mechanical synchrony, differs among individuals. The suboptimal sites are mainly located on the posterior + anterior/lateral walls, and these sites should be avoided in clinical practice.
19
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Authors' contributions
QQ, JTM and LY executed the study and wrote the manuscript. YY participated in the animal study. YX analyzed data. JFW and YXC conceived the study, participated in its design and coordination, and helped to revise the manuscript.
Acknowledgements
We wish to thank for Kan Liu Ph.D, MD for his English editorial assistance. This study was partly supported by a grant from the National Natural Science Foundation of China (No. 81100101 and No. 81270212), Program for New Century Excellent Talents in University (NCET-13-0606), Guangdong Provincial Science & Technology Project (No. 2012B031800049) and Guangdong Province Natural Science Fund (No. S2013010014011).
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24. Faber L, Vlachojannis M, Oldenburg O, Hering D, Bogunovic N, Horstkotte D, et al. Long-term follow-up of cardiac resynchronization therapy: mechanical resynchronization and reverse left ventricular remodeling are predictive for long-term transplant-free survival. Int J Cardiovasc Imaging 2012; 28: 1341-50. DOI:10.1007/s10554-011-9946-7.
25. Gorcsan JR, Oyenuga O, Habib PJ, Tanaka H, Adelstein EC, Hara H, et al. Relationship of echocardiographic dyssynchrony to long-term survival after cardiac
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27. Kaab S, Nuss HB, Chiamvimonvat N, O'Rourke B, Pak PH, Kass DA, et al. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res 1996; 78: 262-73.
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29. Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A, et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation 2011; 123: 1159-66. DOI:10.1161/CIRCULATIONAHA. 110.000646.
30. Mai J, Wang F, Qiu Q, Tang B, Lin Y, Luo N, et al. Tachycardia pacing induces myocardial neovascularization and mobilizes circulating endothelial progenitor cells partly via SDF-1 pathway in canines. Heart Vessels 2016; 31: 230-40. DOI:10.1007/s00380-014-0613-5. 26
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31. Mai J, Hu Q, Xie Y, Su S, Qiu Q, Yuan W, et al. Dyssynchronous pacing triggers endothelial-mesenchymal transition through heterogeneity of mechanical stretch in a canine model. Circ J 2015; 79: 201-09. DOI:10.1253/circj.CJ-14-0721.
32. Zanon F, Baracca E, Pastore G, Marcantoni L, Fraccaro C, Lanza D, et al. Multipoint pacing by a left ventricular quadripolar lead improves the acute hemodynamic response to CRT compared with conventional biventricular pacing at any site. Heart Rhythm 2015; 12: 975-81. DOI:10.1016/j.hrthm.2015.01.034.
33. Shetty AK, Sohal M, Chen Z, Ginks MR, Bostock J, Amraoui S, et al. A comparison of left ventricular endocardial, multisite, and multipolar epicardial cardiac resynchronization: an acute haemodynamic and electroanatomical study. Europace 2014; 16: 873-79. DOI:10.1093/europace/eut420.
34. Asbach S, Hartmann M, Wengenmayer T, Graf E, Bode C, Biermann J. Vector selection of a quadripolar left ventricular pacing lead affects acute hemodynamic response to cardiac resynchronization therapy: a randomized cross-over trial. Plos One 2013; 8: e67235. DOI:10.1371/journal.pone.0067235.
35. Ploux S, Strik M, van Hunnik A, van Middendorp L, Kuiper M, Prinzen FW. Acute electrical and hemodynamic effects of multisite left ventricular pacing for cardiac resynchronization therapy in the dyssynchronous canine heart. Heart Rhythm 2014; 11: 119-25. DOI:10.1016/j.hrthm.2013.10.018.
36. Prinzen FW, Auricchio A. The "missing" link between acute hemodynamic effect 27
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37. Kirk JA, Kass DA. Electromechanical dyssynchrony and resynchronization of the failing heart. Circ Res 2013; 113: 765-76. DOI:10.1161/CIRCRESAHA. 113.300270.
38. Kirk JA, Holewinski RJ, Kooij V, Agnetti G, Tunin RS, Witayavanitkul N, et al. Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3beta. J Clin Invest 2014; 124: 129-38. DOI:10.1172/JCI69253.
39. Chakir K, Daya SK, Tunin RS, Helm RH, Byrne MJ, Dimaano VL, et al. Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization.
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41. Osca J, Alonso P, Cano O, Andres A, Miro V, Tello MJ, et al. The use of multisite left ventricular pacing via quadripolar lead improves acute haemodynamics and mechanical dyssynchrony assessed by radial strain speckle tracking:
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42. Bleeker GB, Mollema SA, Holman ER, Van de Veire N, Ypenburg C, Boersma E, et al. Left ventricular resynchronization is mandatory for response to cardiac resynchronization therapy: analysis in patients with echocardiographic evidence of left ventricular dyssynchrony at baseline. Circulation 2007; 116: 1440-48. DOI:10.1161/CIRCULATIONAHA.106.677005.
43. Haugaa KH, Marek JJ, Ahmed M, Ryo K, Adelstein EC, Schwartzman D, et al. Mechanical dyssynchrony after cardiac resynchronization therapy for severely symptomatic heart failure is associated with risk for ventricular arrhythmias. J Am Soc Echocardiogr 2014; 27: 872-79. DOI:10.1016/j.echo.2014.04.001.
44. Ukkonen H, Beanlands RS, Burwash IG, de Kemp RA, Nahmias C, Fallen E, et al. Effect of cardiac resynchronization on myocardial efficiency and regional oxidative metabolism. Circulation 2003; 107: 28-31. DOI: 10.1161/01.CIR. 0000047068.02226.95
45. Auricchio A, Fantoni C, Regoli F, Carbucicchio C, Goette A, Geller C, et al. Characterization of left ventricular activation in patients with heart failure and left bundle-branch
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46. Pratola C, Notarstefano P, Toselli T, Artale P, Squasi P, Baldo E, et al. Noncontact mapping of left ventricle during CRT implant. Pacing Clin Electrophysiol 2010; 33: 74-84. DOI:10.1111/j.1540-8159.2009.02578.x. 29
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47. Calo L, Martino A, de Ruvo E, Minati M, Fratini S, Rebecchi M, et al. Acute echocardiographic optimization of multiple stimulation configurations of cardiac resynchronization therapy through quadripolar left ventricular pacing: a tailored approach. Am Heart J 2014; 167: 546-54. DOI:10.1016/j.ahj.2013.12.028.
48. Helm RH, Byrne M, Helm PA, Daya SK, Osman NF, Tunin R, et al. Three-dimensional mapping of optimal left ventricular pacing site for cardiac resynchronization.
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49. Johnson L, Kim HK, Tanabe M, Gorcsan J, Schwartzman D, Shroff SG, et al. Differential effects of left ventricular pacing sites in an acute canine model of contraction dyssynchrony. Am J Physiol Heart Circ Physiol 2007; 293: H3046-55. DOI:10.1152/ajpheart.00728.2007.
50. Tops LF, Schalij MJ, Holman ER, van Erven L, van der Wall EE, Bax JJ. Right ventricular pacing can induce ventricular dyssynchrony in patients with atrial fibrillation after atrioventricular node ablation. J Am Coll Cardiol 2006; 48: 1642-48. DOI:10.1016/j.jacc.2006.05.072.
51. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the 30
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53. Tanaka H, Nesser HJ, Buck T, Oyenuga O, Janosi RA, Winter 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: 1690-700. DOI:10.1093/eurheartj/ehq213.
31
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Figure Legend
Figure 1
The anterior, lateral and posterior electrodes were sutured on the basal segments near the anterior interventricular vein, posterior-lateral branch of the coronary vein and middle cardiac vein, respectively; the apical electrode was sutured on the lateral apical myocardium.
Figure 2
Time to peak radial strain curves from (A) right ventricular pacing(RVP), (B) biventricular pacing(BVP), (C)best multisite biventricular pacing(MSP) and (D) worst MSP in a canine.
Figure 3
Comparison of electrical-mechanical dyssynchrony between mean multisite biventricular pacing(MSP) and biventricular pacing (BVP). All values were expressed as the relative changes to RVP. SDε, standard deviation of the time to peak systolic strains from 12 segments; Yu-index, standard deviation of the time to peak systolic velocities from 12 segments.. *, compared with BVP, P<0.05 32
Page 32 of 35
Figure 4
Comparison of hemodynamic parameters between mean MSP and BVP. All values were expressed as the relative changes to RVP. dP/dtmax, maximum derivatives of left ventricular pressure; dP/dtmin, minimum derivatives of left ventricular pressure; LVESP, left ventricular end-systolic pressure; LVEDP, left ventricular end-diastolic pressure. The bars represented median(inter-quartile range).*, compared with BVP, P<0.05.
Supplementary Figure 1
A, dP/dtmax in best/worst MSPs from each canines; B, hemodynamic parameters in best/worst MSPs and BVP; C, electrical and mechanical dyssynchrony in best/worst MSPs and BVP. The data were expressed as the relative changes to RVP. *, P<0.05 when compared with BVP; #, P<0.05 when compared with best MSP. B, median (inter-quartile range), C, mean± SD.
33
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Table 1. Comparison of dyssynchrony and hemodynamic parameters in RVP, BVP and mean MSP
RVP
BVP
mean MSP
BVP vs. mean MSP (P value)
YU-index(ms)
51.0 ±8.1
31.6 ±4.3 *
25.3 ±1.9 *
0.008
SDε(ms)
51.6 ±7.6
37.7 ±7.9*
32.8 ±5.9 *
0.032
TR-L (ms)
41.7±5.6
24.8±9.7*
21.9±8.7*
0.752
QRS width(ms)
119.1
0.038 95.0 ±13.4 *
87.9 ±14.7 *
81.2 ±7.9
91.0 ±9.3 *
90.3 ±3.2 *
0.852
1432.9
1890.0
2025.0
0.181
±362.2
±439.8 *
±386.1 *
LVEDP(mmHg)
8.8 ±1.6
8.2 ±1.1
6.3 ±1.3 *
0.041
dP/dtmin(mmHg/s)
-1364.3
-1690.0
-1782.0
0.474
±151.5
±274.2*
±404.7*
±19.4 LVESP(mmHg) dP/dtmax(mmHg/s)
Data were expressed as mean ± SD.*, P<0.05 when compared with RVP.
BVP, biventricular pacing; dP/dtmax, maximum derivative of left ventricular pressure; dP/dtmin, minimum derivative of left ventricular pressure; LVESP, left ventricular end-systolic pressure; LVEDP, left ventricular end-diastolic pressure; MSP, multisite biventricular pacing; RVP, right ventricular pacing; SDε, standard deviation of the 34
Page 34 of 35
time to peak systolic strains from 12 segments; TR-L: the time difference between the onsets of the right and left ventricular ejecting; Yu-index, standard deviation of the time to peak systolic velocities from 12 segments.
35
Page 35 of 35
S1071-9164(17)30029-5 http://dx.doi.org/doi: 10.1016/j.cardfail.2017.01.007 YJCAF 3919
To appear in:
Journal of Cardiac Failure
Received date: Revised date: Accepted date:
6-4-2016 13-12-2016 9-1-2017
Please cite this article as: Qiong Qiu, Li Yang, Jing-ting Mai, Ying Yang, Yong Xie, Yang-xin Chen, Jing-feng Wang, Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines with Heart Failure, Journal of Cardiac Failure (2017), http://dx.doi.org/doi: 10.1016/j.cardfail.2017.01.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines with Heart Failure
Short titles: Acute effects of MSP in canines with heart failure
Qiong Qiu, PhD. 1,2,# , Li Yang, PhD.1,#, Jing-ting Mai, PhD.1,2,#, Ying Yang, PhD.1,2, Yong Xie, PhD.1,2, Yang-xin Chen, MD., PhD.1,2,*, Jing-feng Wang, MD.,PhD., FHRS1,2, *
1
Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen
University, 107 Yanjiang West Road, Guangzhou, China, 510120
2
Key Laboratory of Cardiac Electrophysiology and Arrhythmia in Guangdong
Province, 107 Yanjiang West Road, Guangzhou, China, 510120
#
These authors contributed equally to this work.
*Corresponding author:
E-mail: [email protected], [email protected] Telephone/fax number: +86-020-81332623 Mail address: 107 Yanjiang West Road, Guangzhou, China, 510120,
1
Page 1 of 35
E-mail address for all the authors:
Qiong Qiu: [email protected];
Li Yang: [email protected]
Jing-ting Mai: [email protected];
Ying Yang: [email protected]
Xie Yong: [email protected];
Yang-xin Chen: [email protected]
Jing-feng Wang: [email protected]
2
Page 2 of 35
Highlights
Multisite biventricular pacing is superior to biventricular pacing in reducing dyssynchrony.
Multisite biventricular pacing is superior to biventricular pacing in improving hemodynamics.
The pacing site-combination has a potential effect on multisite biventricular pacing response.
ABSTRACT
Background: Multisite biventricular pacing(MSP) has been proposed as an alternative strategy to improve the efficiency of conventional biventricular pacing(BVP), but its utility remains unclear. This study sought to investigate whether MSP induced better synchrony and hemodynamic effects in canines with heart failure.
Methods and Results: After 3 weeks’ rapid right ventricular pacing(RVP), 7 canines were sutured with 4 left ventricular(LV) leads on anterior, lateral, posterior and apical wall, and followed by MSP and BVP. Hemodynamic, ECG and echocardiographic parameters were measured. Dyssynchrony was assessed by tissue Doppler imaging for Yu-index (longitudinal direction) and speckle tracking imaging for the standard deviation of time to peak radial strains (SDε, radial direction). Compared with BVP, mean MSP reduced QRS width (P<0.05), Yu-index (25.3±1.9ms vs. 31.6±4.3ms, P=0.008), SDε(32.8±5.9ms vs. 37.3±7.9ms, P=0.032) 3
Page 3 of 35
and
LV
end-diastolic
pressure(LVEDP,
P<0.05).
The
optimal
pacing
site-combination improved QRS width, YU-index, SDε, LVEDP as well as dP/dtmax significantly (all P<0.05), but the worst MSP(with the smallest dP/dtmax) did not show any improvement to BVP.
Conclusions: MSP is superior to BVP in reducing dyssynchrony and improving hemodynamics. The pacing site-combination has a potential effect on MSP response.
Keywords: cardiac resynchronization therapy; multisite biventricular pacing; hemodynamic; mechanical dyssynchrony
4
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List of Abbreviations
BVP: biventricular pacing
CRT: cardiac resynchronization therapy
dP/dtmax: maximum derivative of left ventricular pressure
dP/dtmin: minimum derivative of left ventricular pressure
LBBB: left bundle branch block
LV: left ventricle
LVEDP: left ventricular end-diastolic pressure
LVESP: left ventricular end-systolic pressure
MSP: multisite biventricular pacing
RVP: right ventricular pacing
SDε: standard deviation of time to peak radial strains of 12 LV segments
STI: speckle tracking imaging
TDI: tissue Doppler imaging
TR-L: time difference between the onsets of the right and left ventricular ejecting
5
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Yu-index: standard deviation of time to peak systolic velocities of 12 LV segments
6
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INTRODUCTION
Cardiac resynchronization therapy (CRT) is a recommended treatment for patients with heart failure and wide QRS complex.1, 2Many large randomized trials have proved that CRT improves left ventricular (LV) function, reverses remodeling, and reduces heart failure hospitalization and mortality.3-8However, approximately 30-40% patients implanted with a single LV lead do not respond to CRT, even with further deterioration on heart function.1, 2Dyssynchrony after implantation, due to myocardial scar, suboptimal lead position and electric conduction variation, is one of the major reasons for CRT nonresponse.9, 10Therefore, Multisite biventricular pacing(MSP) has arisen as an alternative strategy to improve electrical resynchronization and increase the response rate. However, human data were limited by the technical difficulties and showed conflicting results.
11-14
Meanwhile, it remains unclear whether pacing sites
affects MSP response.
Mechanical dyssynchrony evaluation is essential for predicting CRT response. Radial strain analysis, derived from speckle tracking imaging(STI), has been used to measure radial cardiac movement.
15-19
After CRT, decreased standard derivation of
time to peak radial strains(SDε) is associated with better long term outcome. 20 Tissue Doppler imaging (TDI), with its high time-resolution and reproducibility, is one of the most commonly used methods to evaluate longitudinal dyssynchrony.21 The standard deviation of time to peak systolic velocities from 12 segments (Yu-index), remains as a widely utilized parameter in current CRT researches.22-25 The combination of STI 7
Page 7 of 35
with TDI can provide higher accuracy in predicting CRT response, and is better than either technique alone.26
Accordingly, we performed MSP(with different site-combinations) in the canines with heart failure, and compared them with biventricular pacing (BVP) in electrical-mechanical dyssynchrony and hemodynamic parameters. The purpose of this study was to assess whether MSP could induce additional improvement from BVP, and the influences of pacing positions on MSP response.
METHODS AND RESULTS
This study was approved by the Academic Administration Committee of Sun Yat-sen Memorial Hospital of Sun Yat-sen University. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Experimental Model
The experiments were performed on 9 canines with 8-10 months old and 12-15kg weight. Three weeks’ rapid RVP (230 beats/min) induced severe LV dysfunction and dyssynchrony.
27, 28
Then, anesthesia was inducted with the sodium pentobarbital (30
mg/kg intravenous) and maintained by the isoflurane (0.5 to 1% in O2/N2O [1:2]). Meanwhile, mechanical ventilation was continued with 10ml/kg tidal volume. Epicardial electrodes (Medtronic, epi 4965) were suture to four locations on the LV via midline thoracotomy, and connected to an implantable pulse generator (Medtronic, 8
Page 8 of 35
InSync Sentry 7289). According to MADIT-CRT study, the electrode locations included basal anterior, lateral, posterior walls and apex (figure 1)29. During MSP, a special Y adapter was used to connect 2 leads to one LV output.
Study Protocol
As we reported earlier30, 31, RVP was used to imitate dyssynchronic contraction. BVP was performed by pacing on right ventricular apex and LV basal lateral segment. MSP was performed by pacing on 2 LV leads and RVP, and with up to 6 different LV site-combinations: anterior+lateral walls, anterior+posterior walls, anterior wall+apex, lateral+posterior walls, lateral wall+apex, posterior wall+apex. The orders of pacing modes were randomized per dog. The pacing rate was set to 20 beats above the intrinsic heart rate to prevent intrinsic ventricular activation. The parameters were recorded after pacing for 5 minutes. With hemodynamic stabilized, LV pressure, electrocardiographic and echocardiographic data were recorded at end-expiration with 5cm H2O positive pressure.
Echocardiographic Measurements
Echocardiography was performed by a commercially available cardiac ultrasound system (Vivid I, GE Healthcare). S3 transducer was used with the depth of 8-10cm. Routine 2-dimensional images were recorded digitally in cine-loop format (5 cardiac cycles).TDI images were recorded from apical 2-, 3-, 4-chamber views with 100-120 frames/s. During STI, the frame rate was set to >50 frames/s. Both basal and middle 9
Page 9 of 35
parasternal short axis views were recorded. Pulse-wave Doppler images, from left and right ventricular outflow tracts, were also recorded.
All images were analyzed offline using EchoPac system (version 10.0; GE-Vingmed Ultrasound), and by an investigator blinded to the pacing modes. After recording the time of aortic valve opening and closing from pulse wave Doppler in left ventricular outflow tract, the systolic interval was marked automatically on Q-Analysis screen. With TDI, the regions of interest (about 4mm× 6mm) were placed on the basal and middle segments, and adjusted manually from frame to frame. Then, the time-velocity curves were constructed. The time intervals from QRS to peak systolic velocity were measured to calculate Yu-index.
With STI, a circular region of interest was traced on the endocardium. Then, the epicardial circle was generated automatically. The time-strain curves from basal and middle segments were generated (Figure 2), and SDε was calculated to evaluate radial dyssynchrony.20Inter-ventricular dyssynchrony was measured as the difference between LV and RV pre-ejection period (TR-L), measured from the QRS complex to the onsetsof aortic and pulmonic flow respectively. All parameters were averaged from 3 consecutive cardiac cycles. Both absolute value and relative changes to RVP were recorded.
10
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Hemodynamic and Electrocardiographic Measurements
Through left carotid artery, the catheter (5F, Cordis) was placed into LV chamber and connected to the cardiac function analyzer for real-time intra-ventricular pressure display. From pressure-time curves, the following parameters were measured: LV end-systolic pressure (LVESP), LV end-diastolic pressure (LVEDP), the maximum derivative of LV pressure (dP/dtmax) and the minimum derivative of LV pressure (dP/dtmin). QRS width was measured from electrocardiogram. All parameters were averaged from 5 consecutive cardiac cycles. Both absolute value and relative changes to RVP were recorded.
Inter- and Intra-observer Variability in TDI and STI
To assess inter- and intra-observer variability, two blinded investigators measured 10 randomly selected echocardiographic data, and one of them repeated the measurements 1 month later. The variability was expressed as the absolute difference divided by the mean value of the measurement. The inter- and intra-observer variabilities were 17±6% and 9±5% for the time to peak systolic velocity, 16±8% and 13±7% for the time to peak systolic strain.
Statistical Analysis
Mean MSP was calculated as the mean value of 6 pacing combinations. According to dP/dtmax, the best( with the largest dP/dtmax)and worst (with the smallest dP/dtmax) MSP were defined. Statistical analysis was performed by SPSS software (IBM SPSS 11
Page 11 of 35
statistics 22.0). All values were expressed as mean ± SD for normal distribution, otherwise as median (25th-75th). Repeated measure of variance analysis was used to compare different pacing modes. Greenhouse-Geisser correction was applied when sphericity assumption was violated. The relative improvement, calculated as the percentage changes to RVP, was compared between BVP and MSP. Paired sample Student t test was used in normal distribution data; otherwise Mann-Whitney U test was used. Significance was determined as P<0.05. The Bonferroni correction was applied in multiple comparisons.
RESULTS
Canine Model of Heart Failure with Dyssynchrony
Two canines were excluded from the study, one died of ventricular arrhythmia and another suffered from serious pericardial infection. In the remaining 7 canines, rapid RVP induced overt heart failure. At the end of 3 weeks’ RVP, LV ejection fraction (LVEF) decreased to 32.5±1.5%. Myocardial dyssynchrony was also present: QRS width from 43.7±12.2ms to 114.9±19.4ms (P<0.001), Yu-index from 14.5±4.5ms to 51.0±8.1ms (P<0.001), and SDε from 35.2±10.8ms to 51.6±7.6ms (P=0.010).
Effect of MSP on Dyssynchrony
Compared with RVP, mean MSP and BVP reduced Yu-index, SDε and TR-L significantly (all P<0.05, Table 1).
Compared with BVP, mean MSP significantly
improved SDε in absolute and relative values(both P<0.05，Table 1, Figure3). 12
Page 12 of 35
Regarding Yu-index, significant differences were found in absolute value(P<0.05, table 1). Relative changes of mean MSP was indeed better than BVP, but without statistical significance(P>0.05, Figure 3). There was no significant difference in TR-L between BVP and mean MSP(P>0.05).
Compared with RVP, both BVP and mean MSP reduced QRS width significantly (P<0.05, Table 1): mean MSP reduced QRS by 25.6±7.5%, which was larger than BVP did (20.0±5.5%, P=0.014, Figure 3).
Effect of MSP on Hemodynamics
Compared with RVP, mean MSP and BVP significantly increased LVESP, dP/dtmax and decreased dP/dtmin(all P<0.01), but only mean MSP significantly deceased LVEDP (P=0.040, table 1).
Compared with BVP, LVEDP was significantly lower in mean MSP (P=0.041, table 1). Mean MSP decreased LVEDP by 27.6% from RVP, which was significantly larger than BVP did (P=0.049，Figure 4). There were no significant differences in LVESP, dP/dtmax and dP/dtmin between BVP and mean MSP (all P>0.05, table 1). No significant correlations were found between the changes of dP/dtmax and Yu-index (r=-0.001, P=0.995) or SDε(r=0.142, P=0.329).
13
Page 13 of 35
Influence of LV Pacing Sites on MSP response
There were totally 42 MSPs in 7 canines, 25(59.5%) of them were superior to BVP. Among different pacing site-combinations, various combinations induced different dP/dt
max.
We observed the pacing sites with the largest (best MSP) and smallest
(worst MSP) dP/dtmax in each canine. The results showed the best sites varied among canines: 2 in anterior+lateral walls, 2 in anterior wall and apex, 2 in lateral wall and apex, and 1 in posterior wall and apex. But anterior+ posterior and lateral+ posterior wall pacing could not induce largest dP/dtmax in every canine. Meanwhile, most canines
showed
smallest
dP/dtmax
with
lateral+posterior
(3
canines)
or
anterior+posterior (2 canines) pacing.
The best MSP increased LVESP by 15.5%, dP/dtmax by 63.8% and decreased Yu-index by 58.0% from RVP. Compared with BVP, the best MSP not only induced more reduction in YU-index (-58.0±6.6% vs. -36.8±11.6%, P=0.006), SDε (-47.2±17.9% vs. -27.3±3.1%, P=0.030) and QRS width (P=0.043), but also improved LVEDP and dP/dtmax(P<0.05). However, there were no significant differences in LVESP, LVEDP, dP/dtmax or dP/dtmin between the worst MSP and BVP(all P>0.05). Also, no differences were found in Yu-index, SDε and QRS width (all P>0.05, Supplementary Figure 1). The worst MSP even decreased dP/dtmax from BVP in one canine.
14
Page 14 of 35
DISSUSION
CRT is a well-accepted therapy for patients with refractory heart failure and wide QRS complex, but the response rate has not yet been satisfactory. Hence, this study was designed to investigate whether MSP, a novel alternative pacing strategy, was better than conventional BVP. The major findings of this study were: 1)mean MSP acutely improved dyssynchrony (electrical and mechanical) and hemodynamics from baseline RVP, and was superior to conventional BVP;
2) Optimizing pacing
site-combination could improve synchrony and hemodynamic effects in MSP, but the sites differed among individuals .
Previous studies
Absence of CRT response is partly caused by suboptimal LV lead position and persistent mechanical dyssynchrony. Recently, MSP has been developed to increase the response rate by stimulating and capturing broader LV area. But the previous studies mainly observed its acute hemodynamic effects, and with conflicting results. A randomized crossover trial (TRIP-HF),
13
with 42 patients, showed that dual-vein
LV pacing yielded significant improvement in LVEF and LVESV at 3 months follow-up when compared to conventional BVP. Ginks et al found that dual-vein LV pacing increased LV dP/dtmax, but only significantly in patients with posterolateral scar.12 The recently introduced quadripolar lead simplifies MSP with one LV lead. Zanon et al32 reported that MSP with quadripolar lead yielded a small but consistent increase in hemodynamic response when comparing with BVP. However, Shetty et al 15
Page 15 of 35
did not find significant differences between MSP(dual or single quadripolar leads) and conventional CRT.33 Since optimized vector is essential for conventional CRT response, 34 the site-combination may also affect MSP improvement. Recently, Ploux et al examined the effects of multi-LV pacing(from 2 to 7 electrodes), and found that contractility improvement was limited to those with suboptimal single-LV pacing. 35
However, they performed pure LV pacing on canines without heart failure, which
was different from multi-LV+ RV pacing on failure heart.
Effects of MSP on mechanical dyssynchrony
Several studies have shown that asynchronous contraction leaded to major and asymmetric remodeling on ventricular walls. Re-coordinating contraction has profound effects on myocardium at molecular, cellular and structural levels, even reverses asymmetric remodeling to normal geometry.36-40Hence, immediate mechanical resynchronization after CRT is a predictor for better long-term outcome.15 Since cardiac motion is multidirectional and complicated, it is difficult to measure mechanical dyssynchrony accurately by single parameter. Combining radial with longitudinal indexes provides higher sensitivity and specificity in predicting long-term outcome after CRT.26
In the present study, we used Yu-index (derived from TDI) and SDε(derived from STI) to analyze myocardial dyssynchrony. As a result, MSP not only reduced QRS width, but also decreased Yu-index and SDε when compared to BVP. Moreover, MSP improved radial synchronization better than longitudinal one, as detected by Osca et 16
Page 16 of 35
al.
41
It demonstrates that MSP induces more synchronous electric conduction and
mechanical contraction. Such effects are associated with myocardial remodeling reversal, and fewer cardiac events in the long-term. 15, 18, 42, 43
Effects of MSP on hemodynamics
When the heart turns into asynchronous activation, it generates heterogeneity in segmental myocardial workload and changes the direction of regional blood flow (displacement of blood from early to late and back to early activation sites). It results in rightward shift of end-systolic pressure–volume relationship, decreasing stroke volume, and increasing LVEDP.
37
In our study, mean MSP decreased LVEDP,
dP/dtmin and increased LVESP, dP/dtmax when compared to RVP. Comparing to BVP, mean MSP significantly reduced LVEDP as well. MSP restores coordinate contraction and relaxation acutely, so LVEDP decreases.44 Moreover, lower LV filling pressure increases coronary blood flow, reverses ventricular remodeling and improves prognosis. 37
Influences of LV Pacing Sites in MSP
Pacing site-combination has potential influence on MSP response. The best MSP (with the largest dP/dtmax) was accompanied by more synchronous contraction and better hemodynamics. However, we found the best site-combination varied among animals. It was difficult to find a predictable site for all subjects, just as Zanon et al reported. 32On the contrary, the worst MSP(with the smallest dP/dtmax) was relatively 17
Page 17 of 35
fixed, and did not show any improvement to conventional BVP.
In patients with LBBB and RVP, an electric blocking line presents from the basal to the apical segment, and induces LV activation in U-shaped pattern.45, 46This line is individual special, and changes with pacing mode and electrode position. 46
45,
Therefore, MSP with different pacing positions has various effects on the
electrical conduction, mechanical dyssynchrony and relevant hemodynamics. It is worth mentioning that posterior +anterior/lateral pacing was not optimal site-combination in any canine, even deteriorated heart function. In our opinion, these 2 combinations should be avoided in clinical practice. The newly developed multiple-polar lead could provide more choices of pacing vectors,
47
the cardiologists
should choose the site-combination individually both during CRT implantation and at follow-up.
Study Limitations
Unavoidably, there were some limitations in this study. Firstly, we used rapid RV pacing canine model to imitate patients with heart failure and dyssynchrony. Although being kind of different from clinics, this model is still well accepted and widely used in CRT researches.48-50Secondly, we performed thoracic surgery to implant epicardial electrodes, which might cause myocardial injury to some degree. However, the object of this study was to compare the acute effects of MSP with other pacing modes. All the animals were studied under the same baseline condition. So the operation itself would interfere little with the results. Thirdly, we did not calculate the changes in LV 18
Page 18 of 35
end-systolic volume(LVESV) and LVEF from echocardiography, which might add to our finding. However, LVESV reflects chronic reverse remodeling and predict longer survivor only when measured at 3-12 months after CRT implantation.
51, 52
LVEF
might not be an accurate parameter to reflect real time pump function in tachycardia conditions. Nevertheless, invasive hemodynamic measurements, derived from left ventricular catheterization, are more accurate to reflect the real time cardiac function change, less affected by the volume status and heart rate variations, and therefore widely applied in acute CRT studies 42, 53Finally, the small sample size may be viewed as another limitation. However, the repeatability and consistency in this study was well enough to support the findings.
Conclusions
The present result indicates that MSP reduces dyssynchrony (electrical and mechanical) and improves hemodynamics in asynchronic heart failure, and is superior to BVP. LV pacing site-combination has a potential effect on MSP response. The optimal site-combination, which induces better hemodynamic effect and mechanical synchrony, differs among individuals. The suboptimal sites are mainly located on the posterior + anterior/lateral walls, and these sites should be avoided in clinical practice.
19
Page 19 of 35
Authors' contributions
QQ, JTM and LY executed the study and wrote the manuscript. YY participated in the animal study. YX analyzed data. JFW and YXC conceived the study, participated in its design and coordination, and helped to revise the manuscript.
Acknowledgements
We wish to thank for Kan Liu Ph.D, MD for his English editorial assistance. This study was partly supported by a grant from the National Natural Science Foundation of China (No. 81100101 and No. 81270212), Program for New Century Excellent Talents in University (NCET-13-0606), Guangdong Provincial Science & Technology Project (No. 2012B031800049) and Guangdong Province Natural Science Fund (No. S2013010014011).
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Figure Legend
Figure 1
The anterior, lateral and posterior electrodes were sutured on the basal segments near the anterior interventricular vein, posterior-lateral branch of the coronary vein and middle cardiac vein, respectively; the apical electrode was sutured on the lateral apical myocardium.
Figure 2
Time to peak radial strain curves from (A) right ventricular pacing(RVP), (B) biventricular pacing(BVP), (C)best multisite biventricular pacing(MSP) and (D) worst MSP in a canine.
Figure 3
Comparison of electrical-mechanical dyssynchrony between mean multisite biventricular pacing(MSP) and biventricular pacing (BVP). All values were expressed as the relative changes to RVP. SDε, standard deviation of the time to peak systolic strains from 12 segments; Yu-index, standard deviation of the time to peak systolic velocities from 12 segments.. *, compared with BVP, P<0.05 32
Page 32 of 35
Figure 4
Comparison of hemodynamic parameters between mean MSP and BVP. All values were expressed as the relative changes to RVP. dP/dtmax, maximum derivatives of left ventricular pressure; dP/dtmin, minimum derivatives of left ventricular pressure; LVESP, left ventricular end-systolic pressure; LVEDP, left ventricular end-diastolic pressure. The bars represented median(inter-quartile range).*, compared with BVP, P<0.05.
Supplementary Figure 1
A, dP/dtmax in best/worst MSPs from each canines; B, hemodynamic parameters in best/worst MSPs and BVP; C, electrical and mechanical dyssynchrony in best/worst MSPs and BVP. The data were expressed as the relative changes to RVP. *, P<0.05 when compared with BVP; #, P<0.05 when compared with best MSP. B, median (inter-quartile range), C, mean± SD.
33
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Table 1. Comparison of dyssynchrony and hemodynamic parameters in RVP, BVP and mean MSP
RVP
BVP
mean MSP
BVP vs. mean MSP (P value)
YU-index(ms)
51.0 ±8.1
31.6 ±4.3 *
25.3 ±1.9 *
0.008
SDε(ms)
51.6 ±7.6
37.7 ±7.9*
32.8 ±5.9 *
0.032
TR-L (ms)
41.7±5.6
24.8±9.7*
21.9±8.7*
0.752
QRS width(ms)
119.1
0.038 95.0 ±13.4 *
87.9 ±14.7 *
81.2 ±7.9
91.0 ±9.3 *
90.3 ±3.2 *
0.852
1432.9
1890.0
2025.0
0.181
±362.2
±439.8 *
±386.1 *
LVEDP(mmHg)
8.8 ±1.6
8.2 ±1.1
6.3 ±1.3 *
0.041
dP/dtmin(mmHg/s)
-1364.3
-1690.0
-1782.0
0.474
±151.5
±274.2*
±404.7*
±19.4 LVESP(mmHg) dP/dtmax(mmHg/s)
Data were expressed as mean ± SD.*, P<0.05 when compared with RVP.
BVP, biventricular pacing; dP/dtmax, maximum derivative of left ventricular pressure; dP/dtmin, minimum derivative of left ventricular pressure; LVESP, left ventricular end-systolic pressure; LVEDP, left ventricular end-diastolic pressure; MSP, multisite biventricular pacing; RVP, right ventricular pacing; SDε, standard deviation of the 34
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time to peak systolic strains from 12 segments; TR-L: the time difference between the onsets of the right and left ventricular ejecting; Yu-index, standard deviation of the time to peak systolic velocities from 12 segments.
35
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