Cardiac Rhythm Management
Articles Articles 2011 August

Hemodynamic Superiority of Dual-Site Left Ventricular Stimulation over Conventional Biventricular Stimulation in Heart Failure Patients

1IMRAN NIAZI, MD, 1JO ANN KIEMEN, APNP, 2PATRICK YONG, MS, 2MINDI NEWMAN, BS, 2JIANG DING, PhD, 2MICHAEL STUCKY, PhD, 2SHANTHA ARCOT-KRISHNAMURTHY, MS and 2NANCY YU, MS

1Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, WI
2Boston Scientific Corp, St. Paul, MN

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ABSTRACT. The left ventricle (LV) is excited from a single site with conventional biventricular pacing. We theorized that exciting the LV from two sites would improve intraventricular synchrony. Seven heart failure patients (NYHA Class III, QRS >150 ms, left bundle branch block) enrolled in the Milwaukee Multisite Acute CRT Study (MMACS) were analyzed. Two LV leads were placed in widely separated coronary sinus branches with one closer to the apical region (LVA) and the other near the basal region (LVB). Two right ventricular (RV) leads were positioned in the apex (RVA) and in the high septum (RVB). Short sequences of VDD stimulation were delivered in dual-site LV (LVA + LVB) and two biventricular (RVA + LVB, RVB + LVA) configurations with three atrioventricular (AV) delays (16%, 41%, 66% of intrinsic AV interval). For each patient, changes in LV + dP/dt from baseline were calculated for all AV delays and pacing configurations. The mean percentage increase of dP/dt with LVA + LVB was 16.2% ± 8% (p<0.05), which was significantly greater than that of RVA + LVB (10.4% ± 4%) and RVB + LVA (6% ± 5%). Cardiac resynchronization therapy (CRT) with simultaneous dual LV free-wall sites produced a significantly greater increase in dP/dt compared to biventricular CRT with a single LV site.

KEYWORDS. atrioventricular optimization, dP/dt, cardiac resynchronization therapy, heart failure, multisite left ventricular pacing.

The study was fully funded by Guidant Corp., now Boston Scientific Corp. With one exception, the non-MD authors were employees of Guidant at the time of the study. Jo Ann Kiemen, APNP, was study coordinator, and has no conflict of interest. Dr. Niazi reports he is a consultant for St. Jude Medical.
Manuscript received June 23, 2011, final version accepted July 8, 2011.

Address correspondence to: Imran Niazi, MD, 2801 W. Kinnickinnic River Parkway, #845, Milwaukee, WI 53215. E-mail: publishing24@aurora.org

Introduction

Cardiac resynchronization therapy (CRT) is widely accepted for treatment of patients with systolic heart failure, impaired left ventricular (LV) ejection fraction and electrical asynchrony. It improves systolic LV function, peak oxygen uptake, exercise tolerance and New York Heart Association (NYHA) Class1–5 and, over time, reverses the remodeling and neurohormonal changes accompanying heart failure.6–8 Large randomized trials also showed improved survival with CRT.9

Even so, a third of patients do not respond to CRT.1 There are several possible causes for this. CRT exerts its beneficial effects by more than one mechanism, but perhaps the most important contributing factor is restoration of intra-LV synchrony.2,10–13 Failure of biventricular (BIV) pacing to restore intra-LV synchrony is likely a major cause of patients failing to respond to CRT. Central to restoring intra-LV synchrony is the need for rapid and uniform electrical activation of the left ventricle. This is best accomplished by appropriate atrioventricular (AV) timing, such that there is activation of the left ventricle from multiple widely separate sites (via intrinsic conduction, transseptal conduction from the right ventricular (RV) pacing site and activation from the LV pacing site). It also is important that the LV stimulation site be in an optimal location to ensure rapid and uniform spread of electrical current throughout the left ventricle.

Some acute hemodynamic studies suggest that the mid-lateral wall of the left ventricle is the optimal pacing site,14 but other studies indicate that the optimal site may vary and be patient specific.15,16 Various methodologies to determine the optimal pacing site have been used, such as invasive measurement of dP/dt (rate and rise of LV pressure),17 mechanical asynchrony assessment by tissue Doppler18–23 or cardiac magnetic resonance imaging.24 All remain unproven or too cumbersome for routine clinical use.

We hypothesized that simultaneously pacing two sites in the left ventricle would increase the chances of at least one site being “optimal.” Further, simultaneously stimulating two widely separated LV sites would simultaneously depolarize a larger portion of the left ventricle than stimulation of a single site; thus, dual-site LV pacing would be more akin to rapid depolarization of the entire left ventricle via the His–Purkinje system in the absence of conduction system disease. To test this hypothesis, we conducted a pilot study to determine whether it is clinically feasible to implant two LV leads, and to assess if dual-site LV stimulation would improve hemodynamic response compared with conventional BIV pacing.

Methods

This prospective, single-center study was approved by the Institutional Review Board at Aurora St. Luke's Medical Center, Milwaukee, WI. An investigational device exemption was obtained from the US Food and Drug Administration to allow use of a custom pacing and recording computer program (Flexstim II, Guidant Corp., St. Paul, MN).

Study population

After informed consent was obtained, 14 patients who met accepted criteria for a CRT-defibrillator (CRT-D) implant enrolled in this study. Study population demographics are detailed in Table 1.

Table 1: Patient demographics (n  =  14).

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Leads and catheters implantation

Standard operating procedures were used to implant a CRT-D; permanent leads were placed in the right atrial appendage, the right ventricular apex (RVA) and in a coronary sinus branch such that the lateral wall of the left ventricle was paced in a location closer to the apex (LVA) than the base. A temporary 5-French quadripolar pacing catheter was used to pace the high right ventricular septum (RVB), and an Easytrak (Boston Scientific Corp., Natick, MA) permanent LV lead was placed in either an anterolateral coronary sinus branch or the middle cardiac vein. This location was closer to the base (LVB) rather than the apex. Our intent was to pace two widely separated areas of the left ventricle. Figure 1a depicts the pacing sites.

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Figure 1: (a) Location of right and left ventricular pacing sites. The three pacing configurations: (b) LVA + LVB, (c) RVA + LVB, and (d) RVB + LVA. LVA: left ventricular mid-lateral/apical; LVB: left ventricular posterobasal; RVA: right ventricular apical region; RVB: right ventricular basal region (outflow tract).

Using a femoral approach, a 6-French pigtail catheter with a high-fidelity pressure sensor (Millar Instruments Inc., Houston, TX) was placed in the LV chamber. All leads and the pressure sensor were connected to the FlexStim II computer program, which controlled the pacing protocol and recorded the LV pressure, surface electrocardiogram and intracardiac electrograms on a beat-to-beat basis, during sinus rhythm as well as pacing.

The acute pacing protocol consisted of 30 beats of atrial-synchronous ventricular stimulation (VDD) in dual-site LV (LVA + LVB) and two standard BIV configurations, each employing both a single RV and a single LV lead. These configurations were RVA + LVB (RV apex + LV base) and RVB + LVA (RV base, i.e. septum + LV apex) (Figure 1b–d). Each configuration was tested at three AV delays, which were proportional (16%, 41%, and 66%) to each patient's intrinsic AV interval. The order of stimulation site–AV delay combination was random for each patient.

Data analysis

Data analysis was performed by observers blinded to pacing configuration and patient identity. Comparisons were made using paired Student's t-test. A value of p<0.05 was considered significant. Correlation was performed using Pearson's chi-square test.

Results

Coronary venous anatomy allowed dual-site LV lead placement in 12 patients. Figure 2 shows a representative patient. Adequate hemodynamic data could not be obtained in two patients because of frequent premature ventricular contractions, and in one patient because of displacement of the pigtail catheter out of the LV. In two additional patients, one of the RV or LV leads intermittently lost capture. Thus, complete data sets were obtained in seven patients.

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Figure 2: X-ray of the coronary sinus veins from a representative patient showing the location of a left ventricular (LV) lead with the tip electrode in the posterior-lateral apical area (LVA) and another lead with the tip electrode in the basal anterior-lateral region (LVB). Arrows point to right and left ventricular conductance catheters (Millar Instruments Inc., Houston, TX). RA: right atrium; RVA: right ventricular apical region; RVB: right ventricular basal region.

Electrical delay within the LV chamber

During sinus rhythm, analysis of intracardiac electrograms from each pacing site was used to assess the activation sequence of various regions of the two ventricles. LV activation was invariably later than RV activation (mean delay 78 ± 31 ms). The mid-lateral apical (LVA) region was later than the basal posterior (LVB) region by >15 ms in four patients. The reverse was true in one patient. In the remaining two patients, LVA and LVB were activated within 10 ms of each other.

The LVA–LVB and LVB–LVA intervals (during LVA and LVB pacing) were >25 ms in four patients (Table 2).

Table 2: Activation delay between LVA and LVB during LV pacing.

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Hemodynamic responses

The baseline dP/dt ranged from 427–952 mmHg/s. During VDD delivery at different AV delays and during different pacing configurations, the dP/dt change compared with intrinsic rhythm varied from −10% to 28%. The optimal AV interval was approximately 66% of the intrinsic AV interval in all patients and in all pacing configurations. No significant variations in intrinsic rhythm were observed during pacing in this patient population (typically intrinsic rhythm varied by no more than 5 bpm during the pacing procedure).

Impact of AV delay and pacing configuration

In the dual-site LV configuration, at the optimal AV interval, there was an average increase in dP/dt of 16.2% ± 8% (p<0.05), range 8–28%. This increase was significantly greater than that with the RVB + LVA configuration (Figure 3). RVB + LVA tended to produce a greater increase in dP/dt over baseline than RVA + LVB (10.4% ± 4% versus 6% ± 5%, p  =  NS). Note that during intrinsic rhythm, LVA was activated later than LVB in most patients (Table 2). The differences in hemodynamic response to pacing between RVB + LVA and RVA + LVB configurations seemed to correlate with the LVA–LVB delay during intrinsic rhythm, i.e. when LVA was depolarized significantly later than LVB, the LVA + RVB configuration tended to show greater hemodynamic response than LVB + RVA (Figure 4). Further, the differences in hemodynamic response between LVA + LVB and RVB + LVA tended to be greater when the LVA–LVB interval was longer (Figure 5).

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Figure 3: Change in average dP/dt (rate of rise of left ventricular pressure) with pacing compared to intrinsic sinus rhythm. Three pacing configurations (LVA + LVB, RVA + LVB, RVB + LVA) were plotted against three atrioventricular (AV) delays (AVD1, AVD2, AVD3). dP/dtmax increase with LVA + LVB was significantly greater than with RVA + LVB and RVB + LVA (p<0.05). LVA: left ventricular apical region; LVB: left ventricular basal region; RVA: right ventricular apical region; RVB: right ventricular basal region.


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Figure 4: Difference in the percentage of dP/dt (% dP/dt) increase between RVB + LVA and RVA + LVB at optimal atrioventricular intervals plotted against the differences in LVA–LVB activation time during intrinsic rhythm. Positive values in the y axis indicate that RVB + LVA is better than RVA + LVB, and positive values in the x axis indicate that LVA is later than LVB. LVA: left ventricular apical region; LVB: left ventricular basal region; RVA: right ventricular apical region; RVB: right ventricular basal region.


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Figure 5: Difference in percentage of dP/dt (% dP/dt) responses between LVA + LVB and RVB + LVA at optimal atrioventricular (AV) intervals plotted against the differences in LVA–LVB activation time; data obtained during RVB + LVA pacing at AV  =  16% intrinsic AV interval. Positive values in the y axis indicate that LVA + LVB is better than RVB + LVA. LVA: left ventricular apical region; LVB: left ventricular basal region; RVA: right ventricular apical region; RVB: right ventricular basal region.

Acute response rates with different pacing configurations

An acute (>5%) increase in dP/dtmax is considered a criterion for identifying an acute responder.2 By this criterion, all seven patients were acute responders with the dual-site LV configuration. One patient was classified a non-responder with the RVB + LVA configuration, and there was one non-responder and two borderline responders (dP/dtmax increase of 5%) with an RVA + LVB configuration.

Procedure time and complications

One patient with a previous history of diffuse atherosclerotic vascular disease suffered an ischemic stroke after the procedure. There were no other significant complications.

The mean procedure time was 182 ± 37 min. This included approximately 100 min for hemodynamic measurements and study-related procedures. Mean fluoroscopy time was 28 ± 13 min.

Discussion

This was the first study assessing the acute hemodynamic effect of dual-site LV pacing in comparison to conventional (single-site LV) BIV pacing using invasive LV pressure monitoring. It demonstrated that dual-site LV pacing at an optimal AV interval produced a greater acute hemodynamic response than the two single LV-single RV site configurations; concordant results were obtained in a previous study that employed triple-site (RV + 2LV) pacing but assessed hemodynamics using echocardiography,15 and have been confirmed by a subsequent study that has been reported in preliminary fashion.25 Another study conducted by Padeletti et al.26 showed discordant results. Padeletti's study differed from this study in several important respects. It compared triple-site pacing (two LV leads plus RV apical lead) to standard CRT, whereas this study compared dual-site LV-only pacing to standard CRT. Further, one of the two LV leads paced as the anode in Padeletti's study, whereas both LV leads in this study were cathodes. In Padeletti's study, atrial-overdrive pacing was used, whereas this study employed atrial-sensed pacing. Padeletti et al. used a conductance catheter to assess LV performance; we used a high-fidelity system (pressure sensor catheter (Millar Instruments Inc.) and the Flexstim II (Guidant Corp.)), which has been validated in several prior trials by other investigators.2,14,27,28 These differences may account for the differing results obtained by Padeletti et al.

The acute responder rate of 100% with dual-site LV stimulation was greater than has been reported with conventional CRT employing a single RV and a single LV site; indeed, one non-responder and two borderline responders with BIV pacing configurations using a single LV site became acute responders with dual-site LV pacing. Kocovic et al.25 showed similar clinical results in patients who received a second LV lead after failing to respond to conventional CRT.

Support for the clinical superiority of multisite LV stimulation is also obtained from the mid-term results of an ongoing study of triple-site pacing,29 which demonstrated a 96% clinical response rate and improved LV reverse remodeling compared with conventional BIV pacing.

These results can be explained by the lack of uniform electrical conduction in diseased myocardium. Zones of slow conduction and anatomic block impede rapid transmyocardial transmission of electrical impulses. Areas of functional block can develop depending upon the pacing site.30,31 The variation in LVA–LVB conduction times during intrinsic and paced rhythms supports this concept (Table 2).

Our results also suggest that conduction delay or functional block played an important role in determining the optimal LV pacing site; the LVA site was activated significantly later than the LVB in most patients. Pacing the electrically latest site provides the best response to CRT;14 our study confirmed this finding since the pacing configuration using LVA (i.e. RVB + LVA) provided a superior hemodynamic response (Figure 4). Cases with greater LVA–LVB delay showed greater hemodynamic improvement with dual-site LV pacing compared with RVB + LVA (Figure 5). An increased LVA–LVB conduction time suggested that either one of the LV leads paced in a zone of conduction or there was anatomic or functional block between the two LV pacing sites. In either case, rapid and uniform depolarization of the LV was impeded. By pacing two separate LV sites, we ensured that (a) stimulation was accomplished on either side of the conduction block and/or (b) at least one of the LV pacing sites did not lie in a zone of slow conduction.

Clinical implications

Our study showed that it is clinically feasible to place two separate LV leads via the coronary venous system during a CRT-D implant safely and within a clinically reasonable time in the majority of patients. Dual-site LV stimulation provided greater acute hemodynamic benefit than conventional CRT, and patients who failed to respond with conventional CRT pacing configurations did respond to dual-site LV pacing. If the acute results we obtained are confirmed by randomized long-term studies, we speculate that multisite LV stimulation may become accepted therapy, possibly using a single multipolar lead positioned appropriately in the coronary venous system. Triple Resynchronization In Paced Heart Failure Patients (TRIP HF), a small randomized study, explored the clinical impact of triple-site pacing in patients with atrial fibrillation. Although the primary end point was not met, there was a significant increase in LV ejection fraction with triple-site pacing compared with conventional CRT.32

Limitations

Due to time constraints, not all combinations of BIV stimulations were fully investigated (e.g. RVA + LVA, RVB + LVB). Because of the complexity of the study, complete data sets were obtained only in a limited number of patients. Finally, this study focused on acute hemodynamic response; it remains to be seen if this CRT modality will improve clinical outcome.

Acknowledgment

The authors gratefully acknowledge Barbara Danek, Joe Grundle and Katie Klein for editorial preparation of the manuscript and Brian Miller and Brian Schurrer for their help in preparing illustrations.

References

  1. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99:1567–1573.
  2. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation 1999;99:2993–3001.
  3. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853.
  4. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111–118.
  5. Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002;39:2026–2033.
  6. Saxon LA, De Marco T, Schafer J, Chatterjee K, Kumar UN, Foster E, VIGOR Congestive Heart Failure Investigators. Effects of long-term biventricular stimulation for resynchronization on echocardiographic measures of remodeling. Circulation 2002;105:1304–1310.
  7. Yu CM, Chau E, Sanderson JE, et al. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105:438–445.
  8. Stellbrink C, Breithardt OA, Franke A, et al. Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart failure and ventricular conduction disturbances. J Am Coll Cardiol 2001;38:1957–1965.
  9. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–2150.
  10. Auricchio A, Spinelli JC. Cardiac resynchronization for heart failure: present status. Congest Heart Fail 2000;6:325–329.
  11. Leclercq C, Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 2002;39:194–201.
  12. Leon AR, Greenberg JM, Kanuru N, et al. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol 2002;39:1258–1263.
  13. Auricchio A, Ding J, Spinelli JC, et al. Cardiac resynchronization therapy restores optimal atrioventricular mechanical timing in heart failure patients with ventricular conduction delay. J Am Coll Cardiol 2002;39:1163–1169.
  14. Butter C, Auricchio A, Stellbrink C, et al. Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients. Circulation 2001;104:3026–3029.
  15. Pappone C, Rosanio S, Oreto G, et al. Cardiac pacing in heart failure patients with left bundle branch block: impact of pacing site for optimizing left ventricular resynchronization. Ital Heart J 2000;1:464–469.
  16. Gold M, Auricchio A, Hummel JD, et al. Comparison of stimulation sites within left ventricular veins on the acute hemodynamic effects of cardiac resynchronization therapy. Heart Rhythm 2005;2:376–381.
  17. Yu Y, Auricchio A, Ding J, et al. Selection of heart failure patients for ventricular resynchronization therapy using normalized RV-LV pressure loop area. (abstract) J Card Fail 2000;6(Suppl 2):32.
  18. Breithardt OA, Stellbrink C, Kramer AP, et al. Echocardiographic quantification of left ventricular asynchrony predicts an acute hemodynamic benefit of cardiac resynchronization therapy. J Am Coll Cardiol 2002;40:536–545.
  19. Sogaard P, Egeblad H, Pedersen AK, et al. Sequential versus simultaneous biventricular resynchronization for severe heart failure: evaluation by tissue Doppler imaging. Circulation 2002;106:2078–2084.
  20. Penicka M, Bartunek J, De Bruyne B, et al. Circulation 2004;109:978–983.
  21. Gorscan J 3rd, Kanzaki H, Bazaz R, Dohi K, Schwartzman D. Usefulness of echocardiographic tissue synchronization imaging to predict acute response to cardiac resynchronization therapy. Am J Cardiol 2004;93:1178–1181.
  22. Bax JJ, Bleeker GB, Marwick TH, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44:1834–1840.
  23. Pitzalis MV, Iacoviello M, Romito R, et al. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol 2002;40:1615–1622.
  24. Helm RH, Byrne M, Helm PA, et al. Three-dimensional mapping of optimal left ventricular pacing site for cardiac resynchronization. Circulation 2007;115:953–961.
  25. Kocovic DZ, Britton NM, Heimann MD. Dual left ventricular leads in cardiac resynchronization therapy: long term follow-up. (abstract) Heart Rhythm 2007;4:S383.
  26. Padeletti L, Colella A, Michelucci A, et al. Dual-site left ventricular cardiac resynchronization therapy. Am J Cardiol 2008;102:1687–92.
  27. Auricchio A, Stellbrink C, Sack S, et al. The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol 1999;83(5B):130D–5D.
  28. Stellbrink C, Auricchio A, Butter C, et al. Pacing Therapies in Congestive Heart Failure II study. Am J Cardiol 2000;86(9A):138K–143K.
  29. Leclercq C, Gadler F, Kranig W, et al. A randomized comparison of triple-site versus dual-site ventricular stimulation in patients with congestive heart failure. J Am Coll Cardiol 2008;51:1455–1462.
  30. Lambiase PD, Rinaldi A, Hauck J, et al. Non-contact left ventricular endocardial mapping in cardiac resynchronization therapy. Heart 2004;90;44–51.
  31. Auricchio A, Fantoni C, Regoli F, et al. Characterization of left ventricular activation in patients with heart failure and left bundle-branch block. Circulation 2004;109:1133–1139.
  32. Lenarczyk R, Kowalski O, Kukulski T, et al. Mid-term outcomes of triple site vs. conventional cardiac resynchronization therapy: a preliminary study. Int J Cardiol 2009;133:87–94.

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