Multipoint left ventricular pacing improves acute hemodynamic response assessed with pressure-volume loops in cardiac resynchronization therapy patients

Multipoint left ventricular pacing improves acute hemodynamic response assessed with pressure-volume loops in cardiac resynchronization therapy patients Carlo Pappone, MD, PhD,* Žarko Ćalović, MD,* Gabriele Vicedomini, MD,* Amarild Cuko, MD,* Luke C. McSpadden, PhD,† Kyungmoo Ryu, PhD,† Enrico Romano, BEng,‡ Massimo Saviano, MD,* Mario Baldi, MD,* Alessia Pappone, MD,* Cristiano Ciaccio, MD,* Luigi Giannelli, MD,* Bogdan Ionescu, MD,* Andrea Petretta, MD,* Raffaele Vitale, MD,* Angelica Fundaliotis, MD,§ Luigi Tavazzi, MD,* Vincenzo Santinelli, MD* From the *Department of Arrhythmology, Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy, † St Jude Medical, Sylmar, California, ‡St Jude Medical, Milan, Italy, and §Clinical Cardiology, Università del Piemonte A. Avogadro, Novara, Italy. BACKGOUND Conventional cardiac resynchronization therapy (CRT) improves acute cardiac hemodynamics. OBJECTIVE To investigate if CRT with multipoint left ventricular (LV) pacing in a single coronary sinus branch (MultiPoint Pacing [MPP], St Jude Medical, Sylmar, CA) can offer further hemodynamic benefits to patients. METHODS Forty-four consecutive patients (80% men, New York Heart Association III, end-systolic volume 180 ⫾ 77 mL, ejection fraction 27% ⫾ 6%, and QRS duration 152 ⫾ 17 ms) receiving a CRT device implant (Unify Quadra MP or Quadra Assura MP and Quartet LV lead, St Jude Medical) underwent intraoperative assessment of LV hemodynamics by using a pressure-volume loop system (Inca, CD Leycom). A pacing protocol was performed, including 9 biventricular pacing interventions with conventional CRT (CONV) using distal and proximal LV electrodes and various MPP configurations. Each pacing intervention was performed twice in randomized order with right ventricular pacing (BASELINE) repeated after every intervention. RESULTS Evaluable recordings were obtained in 42 patients. Relative to BASELINE, the best MPP intervention significantly increased the rate of pressure change (dP/dtmax; 15.9% ⫾ 10.0% vs 13.5% ⫾ 8.8%; P o .001), stroke work (27.2% ⫾ 42.5% vs 19.4% ⫾ 32.2%; P ¼ .018), stroke volume (10.4% ⫾ 22.5% vs 4.1% ⫾ 13.1%; P ¼ .003), and ejection fraction (10.5% ⫾ 20.9%

Introduction Landmark clinical trials have demonstrated that cardiac resynchronization therapy (CRT) in patients with prolonged QRS duration and reduced ejection fraction (EF) can reverse This study was sponsored by St Jude Medical. Dr McSpadden, Dr Ryu, and Mr Romano are employees of St Jude Medical. Address reprint requests and correspondence: Dr Carlo Pappone, Department of Arrhythmology, Maria Cecilia Hospital, GVM Care & Research, Via Corriera, 1, 48010 Cotignola (RA), Italy. E-mail address: [email protected].

1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.

vs 5.3% ⫾ 13.2%; P ¼ .003) as compared with the best CONV intervention. Moreover, the best MPP intervention improved acute diastolic function, significantly decreasing dP/dtmin (13.5% ⫾ 10.2% vs 10.6% ⫾ 6.8%; P ¼ .011), relaxation time constant (7.5% ⫾ 9.0% vs 4.8% ⫾ 7.2%; P ¼ .012), and end-diastolic pressure (18.2% ⫾ 22.4% vs 8.7% ⫾ 21.4%; P o .001) as compared with the best CONV intervention. CONCLUSIONS CRT with MPP can significantly improve acute LV hemodynamic parameters assessed with pressure-volume loop measurements as compared with CONV. KEYWORDS Heart failure; Cardiac resynchronization therapy; Hemodynamics; Pressure-volume loops; MultiPoint Pacing ABBREVIATIONS AV ¼ atrioventricular; BiV ¼ biventricular; CONV ¼ conventional cardiac resynchronization therapy; CRT ¼ cardiac resynchronization therapy; CS ¼ coronary sinus; dP/dt ¼ rate of pressure change; EDP ¼ end-diastolic pressure; EF ¼ ejection fraction; LV ¼ left ventricle/ventricular; MPP ¼ MultiPoint Pacing; PNS ¼ phrenic nerve stimulation; PV ¼ pressure-volume; RV ¼ right ventricle/ventricular; SV ¼ stroke volume; SW ¼ stroke work; τ ¼ time constant of relaxation (Heart Rhythm 2014;0:1–8) rights reserved.

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2014 Heart Rhythm Society. All

the progression of heart failure and reduce mortality.1,2 However, up to 40% of the patients fail to clinically respond to conventional therapy.3 The concept of multisite left ventricular (LV) pacing from 2 different coronary sinus (CS) branches, first demonstrated in humans by Pappone et al4 to provide an acute improvement in LV hemodynamics, was presented in the Triple Resynchronization In Paced Heart Failure Patients (TRIPHF) study to improve LV reverse remodeling in atrial fibrillation (AF) patients as compared to conventional http://dx.doi.org/10.1016/j.hrthm.2013.11.023

2 biventricular (BiV) pacing.5 Despite the demonstrated benefits, the added technical complexities of introducing 2 LV leads can increase procedure duration and fluoroscopy exposure6 while decreasing implantation success rate.7 Initial evidence published by Thibault et al8 in a feasibility study of 21 patients suggested that BiV pacing with multipoint LV pacing in a single CS branch (MultiPoint Pacing [MPP], St Jude Medical, Sylmar, CA) with a quadripolar LV lead can improve LV dP/dtmax (maximum rate of pressure change). We hypothesized that MPP in CRT patients could offer further hemodynamic improvement throughout the cardiac cycle as assessed by pressurevolume (PV) loop analysis. In this study, MPP was achieved with a recently available pulse generator that can pace the right ventricle (RV) traditionally and the LV with up to 2 electrode pairs on a quadripolar LV lead with programmable delays.

Methods See the Online Supplement for additional details.

Participants The study included consecutive patients meeting the enrollment criteria between April and November 2012 at a single investigational center. The local ethics committee approved the study protocol, and all patients gave informed consent before participation. The investigation conformed with the principles outlined in the Declaration of Helsinki. Inclusion criteria were an approved indication for CRT by European Society of Cardiology / European Heart Rhythm Association guidelines (ESC/EHRA) guidelines9 and the ability to provide informed consent. Primary exclusion criteria were New York Heart Association class IV and myocardial infarction within 40 days before enrollment.

Device implant Patients underwent implant of a CRT device with the MPP function (Unify Quadra MP or Quadra Assura MP, St Jude Medical) under conscious sedation according to standard practice. A quadripolar LV lead (Quartet LV lead, St Jude Medical) was targeted to a lateral, anterolateral, or posterolateral branch of the CS. Capture thresholds in the final lead position were acquired during pacing from the 4 electrodes of the quadripolar LV lead (referred to as D1, M2, M3, and P4 from distal to proximal).

Hemodynamic measurements Hemodynamic parameters recorded with a PV loop system (Inca, CD Leycom, Zoetermeer, The Netherlands) during each test pacing intervention were averaged over 16 consecutive beats and expressed as a percent change relative to the mean of 2 adjacent BASELINE (DDD mode RV pacing) recordings to account for any drift. Each test intervention was performed twice in a randomized order and the percent change was averaged over both replicates of a single test intervention. All interventions were delivered for

Heart Rhythm, Vol 0, No 0, Month 2014 approximately 45 seconds at a rate of 5–15 beats/min above the patient’s intrinsic rate with a fixed atrioventricular (AV) delay of 100 ms to ensure consistent ventricular capture.

Pacing protocol Test and BASELINE pacing interventions were delivered by the implanted MPP-enabled CRT device in DDD mode (Table 1). Test pacing interventions consisted of conventional CRT (CONV) pacing from each of 2 single LV sites and with 2 MPP vector combinations. LV pacing vectors were selected from the 10 vectors available with the CRT devices used in this study (Online Supplemental Table 1). Any pacing vector resulting in phrenic nerve stimulation (PNS) or with high capture threshold Z3.5 V was not selected for the pacing protocol. The CONV interventions included 1 distal site (CONVDistal, D1 or M2 as cathode) and 1 proximal site (CONVProximal, M3 or P4 as cathode) paced simultaneously with the RV. If no pacing vector with M3 or P4 as cathode was available due to PNS or high capture threshold, a vector with M2 as cathode was selected for CONV-Proximal. The MPP interventions included 1 vector combination chosen to pace first from a distal electrode (LV1) and second from a proximal electrode (LV2) while maximizing anatomical separation of pacing sites (MPP-1 vector combination). Maximizing anatomical separation of pacing sites was defined as selecting 2 pacing vectors not having high capture threshold and not causing PNS with cathodes as far apart as possible along the quadripolar lead body. Another MPP vector combination was selected to pace first from a site of early electrical activation (LV1) and second from a site of late electrical activation (LV2) as measured from RV pacing to LV sensing at each of the 4 electrodes along the LV lead (MPP-2 vector combination). Combinations of tested LV1LV2 and LV2-RV delays are listed in Table 1. Capture at both pacing sites was verified by closely monitoring the surface electrocardiogram throughout the pacing protocol.

Statistical analysis All measurements were expressed as mean ⫾ SD. The best CONV and MPP configurations were defined for each patient per each PV loop parameter of interest as the intervention that produced the largest dP/dtmax, stroke work (SW), stroke volume (SV), EF, dP/dtmin, time constant of relaxation (τ), or end-diastolic pressure (EDP) change. Comparisons of different pacing interventions were made by using paired t tests. Comparisons of patient subgroups were made by using unpaired t tests. A P value of o.05 was considered significant. Correlations between PV loop parameters were quantified with Spearman’s ρ.

Results Study population Forty-four patients with baseline characteristics listed in Table 2 were enrolled and all patients successfully completed the implant and PV loop measurement procedures. Example

Pappone et al Table 1

Multipoint LV Pacing Improves Hemodynamic Response

3

Pacing protocol test interventions and hemodynamic results

Vector description* Intervention (all pacing in DDD mode) Pacing mode: CONV, LV þ RV simultaneous 1 CONV-Distal (D1 or M2 as LV cathode) 2 CONV-Proximal (M3 or P4 as LV cathode) Pacing mode: MPP, LV1- LV2- RV 3 MPP-1 Apical (LV1) - Basal (LV2) (defined as LV1 cathode more 4 distal than LV2 cathode) 5 6 7 8 MPP-2 Early (LV1) - Late (LV2) (defined based on electrical 9 delay from RV pacing to LV sensing)

No. of Best Mean Mean LV1-LV2 LV2-RV patients dP/dtmax ⫾ SD dP/dtmax, SW ⫾ SD Best SW, delay (ms) delay (ms) tested (mm Hg/s) n (%) (L  mm Hg) n (%) –

–

42

877 ⫾ 168

18 (43%)

5.4 ⫾ 2.7 23 (55%)

–

–

42

878 ⫾ 172

24 (57%)

5.2 ⫾ 2.6 19 (45%)

5 20 40 5 5 5 40

5 5 5 20 40 5 5

42 39 42 38 38 42 42

883 ⫾ 901 ⫾ 884 ⫾ 893 ⫾ 887 ⫾ 876 ⫾ 887 ⫾

7 (17%) 6 (15%) 10 (24%) 3 (8%) 4 (11%) 6 (14%) 6 (14%)

5.4 5.6 5.3 5.5 5.2 5.3 5.2

169 177 176 183 183 164 175

⫾ 2.8 ⫾ 2.9 ⫾ 2.8 ⫾ 2.8 ⫾ 2.7 ⫾ 2.6 ⫾ 2.7

7 (17%) 3 (8%) 5 (12%) 4 (11%) 5 (13%) 9 (21%) 9 (21%)

CONV ¼ conventional cardiac resynchronization therapy; dP/dt ¼ rate of pressure change; LV ¼ left ventricular; MPP ¼ MultiPoint Pacing; PNS ¼ phrenic nerve stimulation; RV ¼ right ventricular; SW ¼ stroke work. * Any vector with capture threshold Z3.5 V or causing PNS was excluded from the pacing protocol.

pressure recordings during BASELINE, MPP, and return to BASELINE are shown in Online Supplemental Figure 1. The Quartet quadripolar LV lead was placed in a lateral CS branch in 28 patients (64%) and in a nonlateral branch in 16 patients (36%; anterolateral: 10 [23%] patients and posterolateral: 6 [14%] patients).

time constraints, in 3 patients (7.1%) an abbreviated set of 6 BiV test pacing interventions were performed (Table 1, interventions 1–3, 5, 8, and 9) and in 1 patient (2.4%) 7 BiV test pacing interventions were performed (Table 1, interventions 1–5, 8, and 9).

Acute pacing protocol

Best CONV and MPP interventions

Acute hemodynamic data from 2 patients (4.5%) were excluded from further analysis owing to frequently occurring preventricular contractions interfering with accurate hemodynamic measurements of paced beats. In 38 of the remaining 42 patients (90%), all 9 BiV test pacing interventions were performed as presented in Table 1. Owing to procedure

The best LV pacing intervention was patient specific and varied depending on the hemodynamic parameter used for the assessment (Table 1). With conventional BiV pacing, the distal LV site along the quadripolar lead (see Table 3 for selected CONV cathodes) was identified as the best site in 18 of 42 (43%) patients according to dP/dtmax and in 23 of 42 (55%) patients according to SW. There was not a significant difference in improvement relative to BASELINE with CRT at distal vs proximal sites along the quadripolar LV lead in dP/dtmax (distal: 12.2% ⫾ 9.0% [range 0.8% to 34.3%], proximal: 12.1% ⫾ 9.0% [range 0.7% to 38.2%]; P ¼ .80) or SW (distal: 13.8% ⫾ 31.4% [range 56.0% to 86.6%], proximal: 13.8% ⫾ 32.7% [range 50.0% to 98.1%]; P ¼ .99). The within-patient difference from distal to proximal CRT was 0.2% ⫾ 3.9% (range 8.6% to 10.5%) in dP/dtmax and 0.0% ⫾ 18.6% (range 91.9% to 33.9%) in SW. The best MPP intervention was found with the MPP-1 vector (maximized anatomical spacing with distal first and

Table 2

Baseline patient characteristics (N ¼ 44)

Characteristic

Value

Age (y) Sex Etiology NYHA functional class LV ejection fraction LV end-systolic volume (mL) QRS duration (ms) Pharmacological therapy

66 ⫾ 8 35 men (80%), 9 women (20%) 24 nonischemic (55%), 20 ischemic (45%) 44 class III (100%) 27% ⫾ 6% 180 ⫾ 77 152 ⫾ 17 39 diuretics (89%) 38 β-adrenergic receptor antagonists (86%) 35 antiplatelets (80%) 20 angiotensin-converting enzyme inhibitors (45%) 16 angiotensin receptor blockers (36%) 12 antiarrhythmic agents (27%) 7 anticoagulants (16%) 9 calcium channel blockers (20%) 4 cardiac glycosides (9%) 3 nitrates (7%)

LV ¼ left ventricular; NYHA ¼ New York Heart Association.

Table 3

CONV cathodes selected for the pacing protocol

CONV cathode selection (CONV-Distal/CONV-Proximal)

No. of patients

D1/P4 D1/M3 D1/M2 M2/P4 M2/M3

13 17 7 4 1

CONV ¼ conventional cardiac resynchronization therapy.

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Heart Rhythm, Vol 0, No 0, Month 2014

Table 4

MPP cathodes selected for the pacing protocol No. of patients

MPP cathode combinations (LV1 þ LV2)

MPP-1

MPP-2

D1 þ P4 P4 þ D1 D1 þ M3 M3 þ D1 D1 þ M2 M2 þ D1 M2 þ P4 P4 þ M2 M2 þ M3 M3 þ M2 M3 þ P4 P4 þ M3

17 0 14 0 7 0 3 0 1 0 0 0

3 3 4 5 6 9 2 3 4 2 0 1

(range 0.8% to 38.2%) with the best CONV intervention to 15.9% ⫾ 10.0% (range 0.8% to 39.4%) with the best MPP intervention (P o .001; Figure 2A). Similarly, the best MPP intervention significantly increased LV SW (27.2% ⫾ 42.5% [range 55.9% to 175.8%] vs 19.4% ⫾ 32.2% [range 49.9% to 98.1%]; P ¼ .018; Figure 2B), LV SV (10.4% ⫾ 22.5% [range 26.9% to 101.3%] vs 4.1% ⫾ 13.1% [range 23.8% to 35.0%]; P ¼ .003; Figure 2C), and LV EF (10.5% ⫾ 20.9% [range 22.0% to 87.0%] vs 5.3% ⫾ 13.2% [range 19.5% to 42.1%]; P ¼ .003; Figure 2D) as compared with the best CONV configuration. An increase from the best CONV intervention to the best MPP intervention was observed in 32 of 42 (76%) patients for LV dP/dtmax, 31 of 42 (74%) patients for LV SW, 32 of 42 (76%) patients for LV SV, and 31 of 42 (74%) patients for LV EF.

MPP ¼ MultiPoint Pacing.

Improvement in acute diastolic function

proximal second) in 30 of 42 (71%) patients by dP/dtmax and in 24 of 42 (57%) patients by SW while the remaining patients experienced better hemodynamic response with the MPP-2 vector (see Table 4 for selected MPP cathode combinations). The difference in improvement relative to BASELINE between the best MPP-1 vector combination and the best MPP-2 vector combination was significant for dP/dtmax (MPP-1: 15.5% ⫾ 10.0% [range 0.8% to 39.4%], MPP-2: 14.2% ⫾ 9.4% [range 1.0% to 38.1%]; P ¼ .002) but not for SW (MPP-1: 23.5% ⫾ 41.6% [range 58.6% to 167.4%], MPP-2: 22.9% ⫾ 43.0% [range 55.9% to 175.8%]; P ¼ .78). The within-patient difference from MPP-1 to MPP-2 was 1.3% ⫾ 2.5% (range 2.9% to 8.4%) in dP/dtmax and 0.6% ⫾ 13.4% (range 63.7% to 32.6%) in SW. MPP pacing with the minimum LV1-LV2 delay (5 ms) was better than the longest LV1-LV2 delay (40 ms) in 24 of 42 (57%) patients by dP/dtmax (best 5 ms delay: 15.0% ⫾ 9.9% [range 0.8% to 39.4%], best 40 ms delay: 14.4% ⫾ 9.2% [range 0.2% to 34.4%]; P ¼ .23) and in 25 of 42 (60%) patients by SW (best 5 ms delay: 23.2% ⫾ 40.8% [range 55.9% to 165.6%], best 40 ms delay: 20.3% ⫾ 45.8% [range 77.5% to 175.8%]; P ¼ .23). The within-patient difference from MPP with the minimum LV1-LV2 delay to the longest LV1-LV2 delay was 0.5% ⫾ 2.7% (range 7.6% to 8.0%) in dP/dtmax and 2.9% ⫾ 15.2% (range 63.7% to 32.5%) in SW.

The best MPP configuration improved LV dP/dtmax relative to BASELINE by 3.0% ⫾ 4.2% as compared with the best CONV configuration in ischemic patients. This improvement was not significantly different from the improvement in nonischemic patients (1.9% ⫾ 2.3%; P ¼ .27; Figure 4A). Furthermore, improvements in LV SW, LV SV, and LV EF with the best MPP configuration compared with the best CONV configuration were not significantly different regardless of etiology (SW: 5.9% ⫾ 27% ischemic vs 9.6% ⫾ 15% nonischemic; P ¼ .57; Figure 4B; SV: 5.6% ⫾ 11% ischemic vs 6.9% ⫾ 14% nonischemic; P ¼ .74; Figure 4C; EF: 4.7% ⫾ 9.0% ischemic vs 5.6% ⫾ 12% nonischemic; P ¼ .78; Figure 4D).

Improvement in acute hemodynamic response with MPP

Dependence of hemodynamic response on LV lead position

PV loop expansion occurred during the best MPP intervention relative to the best CONV intervention in representative ischemic (Figure 1A) and nonischemic (Figures 1B–1D) patients. Typically, the separation of the MPP loop from the CONV loop began at end systole and was maintained throughout the relaxation and filling phases of diastole (Figures 1A–1C). In other patients, the separation began at end diastole and continued through systole (Figure 1D). Averaged over all patients, LV dP/dtmax significantly increased (relative to BASELINE) from 13.5% ⫾ 8.8%

PV loop expansion with MPP was observed in patients with lateral (Figures 1A, 1B, and 1D) and nonlateral (Figure 1C) LV lead positions. The hemodynamic improvement with the best MPP configuration compared with the best CONV configuration was not significantly different for lateral vs nonlateral LV lead positions for dP/dtmax (lateral: 2.8% ⫾ 3.5%; nonlateral: 1.7% ⫾ 3.0%; P ¼ .31), SW (lateral: 7.5% ⫾ 19%; nonlateral: 8.5% ⫾ 24%; P ¼ .88), SV (lateral: 6.2% ⫾ 15%; nonlateral: 6.5% ⫾ 6.7%; P ¼ .93), or EF (lateral: 4.4% ⫾ 13%; nonlateral: 6.6% ⫾ 6.9%; P ¼ .52).

In addition to acute systolic improvement, BiV pacing with MPP improved acute diastolic function as assessed by –dP/dtmin, τ, and EDP (Figure 3). Relative to BASELINE, the best MPP configuration significantly decreased dP/dtmin (12.6% ⫾ 7.8% [range 37.7% to 3.8%] vs 10.6% ⫾ 6.8% [range 25.5% to 7.0%]; P o .001), τ (6.2% ⫾ 8.0% [range 25.9% to 13.2%] vs 4.8% ⫾ 7.2% [range 20.0% to 16.2%]; P ¼ .010), and EDP (18.2% ⫾ 22.4% [range 69.5% to 65.0%] vs 8.7% ⫾ 21.4% [range 56.7% to 62.2%]; P o .001) as compared with the best CONV configuration.

Dependence of hemodynamic response on etiology

Multipoint LV Pacing Improves Hemodynamic Response

LV Pressure (mmHg)

140

105

SW

49.1 % 70.3 %

dP/dt

10.2 % 13.5 %

70

35

0 150

175

200

Best Best CONV MPP

ischemic etiology lateral LV lead

200

225

LV Pressure (mmHg)

Pappone et al

non-ischemic etiology lateral LV lead

150

135

SW

25.4 % 41.7 %

dP/dt

3.2 % 4.0 %

45

155

180

180

Best Best CONV MPP

90

0 130

25.5 % 38.5 % 10.4 % 7.3 %

140

165

190

215

LV Volume (mL)

205

230

LV Pressure (mmHg)

LV Pressure (mmHg)

non-ischemic etiology anterolateral LV lead

SW dP/dt

50

LV Volume (mL) 180

Best Best CONV MPP

100

0 115

250

5

non-ischemic etiology lateral LV lead

135

Best Best CONV MPP SW

51.8 % 67.9 %

dP/dt

8.8 % 12.1 %

90

45

0 150

180

LV Volume (mL)

210

240

270

LV Volume (mL)

Best MPP Configuration

Best CONV Configuration

RV Only (DDD)

Figure 1 Representative PV loops. PV loops are shown during RV pacing (dashed gray line), the best CONV configuration (black solid line), and the best MPP configuration (solid green line) from representative (A) ischemic and (B–D) nonischemic patients. MPP resulted in the expansion of the PV loop in patients with both etiologies. The embedded tables show the percent increase in LV SW and LV dP/dtmax over BASELINE for the CONV and MPP configurations. CONV ¼ conventional cardiac resynchronization therapy; dP/dt ¼ rate of pressure change; LV ¼ left ventricular; MPP ¼ MultiPoint Pacing; PV ¼ pressurevolume; RV ¼ right ventricular; SW ¼ stroke work.

LV SW

LV dP/dtMax

% change from BASELINE

40

p < 0.001

80

p = 0.018

LV SV 40

p = 0.003

LV EF 40

30

60

30

30

20

40

20

20

10

20

10

10

0

0

Best CONV

Best MPP

0

Best CONV

Best MPP

p = 0.003

0

Best CONV

Best MPP

Best CONV

Best MPP

Figure 2 Improvement in acute hemodynamic parameters with MPP. Biventricular pacing with MPP resulted in significant improvement in (A) LV dP/dtmax, (B) LV SW, (C) LV SV, and (D) LV EF as compared with CONV. CONV ¼ conventional cardiac resynchronization therapy; dP/dt ¼ rate of pressure change; EF ¼ ejection fraction; LV ¼ left ventricular; MPP ¼ MultiPoint Pacing; SV ¼ stroke volume; SW ¼ stroke work.

6

Heart Rhythm, Vol 0, No 0, Month 2014 LV τ

LV -dP/dtMin

% change from BASELINE

0

Best CONV

Best MPP

0

Best CONV

LV EDP

Best MPP

0

-7

-5

-15

-14

-10

-30

-21

-15

-45

p < 0.001

-28

p = 0.010

Best CONV

Best MPP

p < 0.001

-60

-20

Figure 3 Improvement in diastolic function with MPP. The best MPP intervention significantly decreased (A) –dP/dtmin, (B) τ, and (C) EDP as compared with the best CONV intervention. CONV ¼ conventional cardiac resynchronization therapy; dP/dt ¼ rate of pressure change; EDP ¼ end-diastolic pressure; LV ¼ left ventricular; MPP ¼ MultiPoint Pacing; τ ¼ time constant of relaxation.

Concordance of dP/dtmax, SW, and SV measurements The changes in SW and SV relative to BASELINE with different MPP and CONV interventions were positively correlated with mean correlation coefficient ρ ¼ .53 ⫾ .35 (Online Supplemental Table 2). In contrast, correlation coefficients between SW and dP/dtmax varied between .75 and .87 with mean .14 ⫾ .46. Similarly, SV vs dP/dtmax correlation coefficients varied between .73 and .88 with mean .01 ⫾ .45.

Discussion In this study, we demonstrate for the first time that CRT with MPP results in a significant improvement in acute systolic and diastolic hemodynamic function. While previous studies have demonstrated improvement in only dP/dtmax with MPP in a single CS branch in patients8 or in a biophysical

12

LV dP/dt Max

54

percentage point increase from CONV to MPP

p = ns

model,10 no study has previously examined the effect of MPP on hemodynamics over the full cardiac cycle with PV loop analysis. Interestingly, we identified that in addition to the improvement in cardiac contractility with MPP as previously described, MPP can offer further benefit to diastolic LV function as well. In contrast to prior studies of multipoint LV pacing using 2 LV leads in different CS branches showing implant success rates of 62%,7 80%,11 86%,5 or 92%,6 we achieved implant success in all 44 of 44 (100%) patients in our study. These findings could have important implications for improving CRT patient outcomes.

Hemodynamic parameter improvement The 2.4%–7.9% improvement in LV dP/dtmax, SW, SV, and EF observed during BiV pacing with MPP compared with conventional CRT supports the hypothesis that pacing from

LV SW

30

LV SV

30

p = ns

p = ns

p = ns

8

36

20

20

4

18

10

10

0

0

0

0

Ischemic (N = 19)

LV EF

Non-ischemic (N = 23)

Figure 4 Similar acute hemodynamic response to MPP in ischemic and nonischemic patients. The improvement in (A) LV dP/dtmax, (B) LV SW, (C) LV SV, and (D) LV EF with MPP relative to CONV was similar in ischemic (black bars) and nonischemic (white bars) patients. CONV ¼ conventional cardiac resynchronization therapy; dP/dt ¼ rate of pressure change; EF ¼ ejection fraction; LV ¼ left ventricular; MPP ¼ MultiPoint Pacing; SV ¼ stroke volume; SW ¼ stroke work.

Pappone et al

Multipoint LV Pacing Improves Hemodynamic Response

multipoint LV sites can further augment the well-described systolic benefits of CRT, likely by better synchronizing LV contraction and/or recruiting additional LV myocardial tissue. The acute hemodynamic measurements in our study were performed during a rigorous pacing protocol with test configurations repeated and performed in a randomized order and with return to baseline pacing after every test configuration. A similar rigorous protocol was used previously by Thibault et al,8 whose findings suggested that the use of such a pacing protocol can identify true changes in LV function during various pacing interventions. In addition to systolic changes in LV function, we observed improvement in diastolic function characterized by –dP/dtmin, τ, and EDP. Previous studies of the effect of CRT on LV diastolic function are mixed, but improvement has been demonstrated particularly in CRT responders and nonischemic patients.12 Our results suggest that MPP may confer further improvement to response beyond conventional CRT by affecting LV relaxation.

MPP vector combination and delay selection Determining the optimal pacing vector and interventricular delay can be a challenge with conventional CRT. With MPP, the addition of a second LV pulse with another programmable delay results in even more programming options. In this study, we evaluated 2 methods of MPP vector combination selection and multiple delay combinations. In this patient cohort, an empiric method of selecting MPP pacing vectors based on maximizing anatomical spacing between LV1 and LV2 cathodes resulted in the best dP/dtmax and SW response more often than an electrical delay–based selection method. Moreover, pacing with 5-ms LV1-LV2 delay produced the best dP/dtmax and SW response more often than pacing with 40-ms LV1-LV2 delay.

Etiology dependence of acute hemodynamic benefits Compared with nonischemic patients, patients with ischemic heart disease show less improvement in EF, less LV reverse remodeling, and poorer response rate to CRT13–15 likely owing to the presence of substantial nonfunctional myocardial scar tissue and delivery of pacing at nonoptimal sites in regions of scar.16 Conceivably, MPP may offer further benefit to ischemic patients relative to conventional CRT by engaging additional adjacent viable tissue and normalizing propagation patterns around the scar tissue. In support of such a hypothesis, we observed similar improvement in dP/dtmax, SW, SV, and EF regardless of the etiology, suggesting that ischemic patients derived similar acute hemodynamic benefit from MPP as nonischemic patients. Although the present study was not properly powered to resolve differences between these subgroups, if confirmed in a larger population this finding implies MPP could be valuable to treat patients with ischemic heart disease, who traditionally have poorer response to CRT.

7

The relationship of acute response to long-term response Conflicting results have been reported on the relationship between acute improvement in hemodynamic parameters and long-term response to CRT. Although a study of 32 patients by Duckett et al17 showed high predictive value of an acute increase in invasive LV dP/dtmax 410% over baseline, a recent study of 285 patients by Bogaard et al18 reported no relationship between acute dP/dtmax increase and reverse remodeling, supporting the findings of other smaller studies.19,20 Another recent study pointed to a 420% increase in SW as a potential parameter and cutoff for predicting long-term reverse remodeling.21 In our study, the expected response rate based on these published dP/dtmax (410%) and SW (420%) cutoffs was 30 of 42 (71%) for dP/dtmax and 19 of 42 (45%) for SW with the best MPP intervention and was 29 of 42 (69%) for dP/ dtmax and 16 of 42 (38%) with the best CONV intervention. Follow-up results from this study and other studies will shed more light on the relationship between acute hemodynamic improvement and long-term response.

PV loop parameter concordance A previous PV loop study has shown a discordant relationship between SW and dP/dtmax improvement relative to baseline in 34 patients during a single tested BiV pacing intervention.22 In our study, we demonstrate that within an individual patient, changes in these 2 acute parameters (dP/dtmax and SW) are often poorly correlated with one another during an acute pacing protocol using numerous different pacing interventions. In our study, only 14 of 42 (33%) patients had any BiV pacing intervention that met both the dP/dtmax (410%) and SW (420%) published response cutoffs. PV loop measurements have the potential to help individualize CRT optimally based on acute hemodynamic improvement, but additional studies are needed to understand the relationship between hemodynamic parameters and the relationship between acute and long-term response.

Study limitations This study suffers from the known limitations of PV loop measurements by using the conductance catheter method. Specifically, while the integrated solid-state transducer provides robust pressure measurements, accurate volume measurements depend on careful catheter placement along the long axis of the LV with the distal tip in the apex. It is assumed that the LV chamber is cylindrical with walls contracting uniformly toward the central axis, an assumption that, especially in heart failure patients with dilated and dyssynchronously contracting hearts, may not be valid. Nevertheless, in all 44 patients, we were able to achieve satisfactory catheter placement as assessed by using fluoroscopy and PV loop morphology. Owing to the risk of additional procedure time for the acute pacing protocol during implantation, AV delay and VV delay were not optimized in our pacing protocol and not all

8 pacing vectors or vector combinations were tested. A short and standardized AV delay of 100 ms was used in all patients and in all pacing interventions (MPP, CONV, and BASELINE) to ensure ventricular capture. Although differences in AV synchrony at different LV pacing sites may have affected hemodynamic output, it is unlikely that the small corrections to AV delay required to compensate would have significantly altered our conclusions.23 CONV interventions were performed with simultaneous BiV pacing since this is considered standard programming with CRT. Finally, as this was an acute feasibility study including a small number of patients and the multiple pacing modes used constrained the duration of each stimulation period, our results should be confirmed in a larger population.

Conclusions Acute hemodynamic measurements of LV dP/dtmax, SW, SV, and EF demonstrated that BiV pacing with multipoint LV pacing improves systolic LV function compared with conventional CRT. Importantly, we observed a nonsignificant difference between systolic improvement in ischemic patients, who typically have poor CRT response, and in nonischemic patients. Furthermore, ventricular relaxation improved with MPP, as indicated by decrease in –dP/dtmin, τ, and EDP relative to CONV. The implications of this finding on the effects of CRT on patient outcomes may be valuable and important. Long-term follow-up and outcomes from these patients will help confirm these findings and determine to what extent alterations in diastolic performance affect CRT response.

Appendix Supplementary data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2013.11.023.

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