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Europace (2007) 9, 1163–1170
doi:10.1093/europace/eum218
Single-site ventricular and biventricular pacing:
investigation of latest depolarization strategy
Michael W. Kimmel1, Nicholas D. Skadsberg2, Charles L. Byrd3, David J. Wright4, Timothy G. Laske5,
and Paul A. Iaizzo6*
Received 30 April 2007; accepted after revision 3 September 2007; online publish-ahead-of-print 11 October 2007
KEYWORDS
Cardiac resynchronization
therapy;
Electrophysiology;
Haemodynamics;
Non-contact mapping
Aims Cardiac resynchronization therapy with biventricular pacing has proved beneficial in symptomatic
heart failure patients, yet the effects in patients with structurally normal hearts remain unknown. We
hypothesized that, in an acute swine model with normal anatomy and function, single-site right ventricular (RV) pacing would better preserve haemodynamic function and electrical activation compared to
biventricular pacing.
Methods Endocardial single-site pacing was performed in anesthetized swine (n ¼ 7) from the RV
septum and RV apex. Biventricular pacing was performed using an epicardial left ventricular (LV) lead
and a RV lead. High-resolution, non-contact mapping was employed to record LV activation sequences
simultaneously with haemodynamic data after 5 min of consistent capture.
Results All pacing interventions significantly prolonged QRS and total endocardial activation durations
(P , 0.05) compared to intrinsic activation. Biventricular pacing with the RV apex lead significantly
impaired LV systolic mechanics (dP/dtmax, max LV pressure; P , 0.05), and reduced LV relaxation to
the greatest extent (dP/dtmin, P ¼ ns). Right ventricular septal pacing conserved function better than
other pacing interventions (P ¼ ns) and elicited an intrinsic electrical activation sequence.
Conclusion In intact, synchronous hearts, acute biventricular pacing resulted in systolic dysfunction and
abnormal LV electrical activation.
Introduction
Heart failure (HF) affects over 22 million people worldwide
and more than 5 million individuals in the US alone and contributes to over 300 000 deaths annually.1,2 Despite advancements in HF therapy, developed resistance to pharmacologic
treatments remains a major concern for cardiologists
when treating late-stage HF patients.3,4 Device-based treatments such as cardiac resynchronization therapy (CRT) with
biventricular (BiV) pacing have been shown to contribute
considerably to improving the HF patient’s haemodynamic
performance, functional status, and survival probability.2,4–12
With the increased evidence of the long-term deleterious
effects of conventional right ventricular apical (RVA) pacing,
there has been a growing interest in the investigation of
alternative pacing sites that preserve haemodynamic
* Corresponding author. Tel: þ1 612 624 7912; fax: þ1 612 624 2002.
E-mail address: [email protected]
function and the sequence of ventricular activation. With
technologies such as robotic-assisted and minimally invasive
surgeries, there are also renewed efforts examining the
potential advantages of epicardial placement of left ventricular (LV) leads allowing the clinician almost unlimited
access to the entire LV anterior and lateral freewall.13,14
Advances in pacing therapies, specifically BiV pacing, have
resulted in significant acute haemodynamic benefits in
symptomatic HF patients when stimulating late activating (lateral) regions of the LV in hearts with substantial
intraventricular conduction delay.15–18 Again, pacing site
(LV lead) plays a critical role in determining the degree
of cardiac functional improvement and is believed to
be patient dependent as was shown recently by Lambiase
and coworkers.19–21 Through the use of high-resolution
non-contact mapping (NCM), Lambiase demonstrated that
‘anatomically optimally placed’ transvenous leads may in
fact be positioned within regions of slower conduction,
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2007.
For permissions please email: [email protected].
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1
Departments of Surgery and Biomedical Engineering, University of Minnesota, B172 Mayo, MMC 107, 420 Delaware Street SE,
Minneapolis, MN 55455, USA; 2Medtronic, Inc., 7000 Central Avenue NE, Minneapolis, MN 55432-3576, USA; 3Broward General
Medical Center, 1625 SE 3rd Avenue, Suite 610, Fort Lauderdale, FL 33316, USA; 4CardioThoracic Centre, Liverpool NHS Trust,
Thomas Drive, Liverpool L14 3PE, UK; 5Medtronic, Inc., 8299 Central Avenue NE, MS P120, Minneapolis, MN 55432, USA; and
6
Department of Surgery, University of Minnesota, B172 Mayo, MMC 107, 420 Delaware Street SE, Minneapolis, MN 55455, USA
1164
thereby prolonging LV depolarization and influencing LV
synchronization.
To date, CRT has focused mainly on HF patients without
the indication for anti-bradycardia pacing; therefore, in
hearts with preserved conduction systems, the influence of
pacing site and BiV therapy on cardiac function and electrophysiologic performance remains unknown. To better understand the influence of ventricular activation sequence on
pump function, we employed high-resolution NCM to study
the LV endocardial activation sequence. To that end, we
tested the hypothesis that atrio-ventricular, single-site
pacing would acutely preserve haemodynamic function and
electrical activation better when compared with BiV
pacing in a normal swine model.
M.W. Kimmel et al.
Total endocardial activation durations (TAD), local activation durations (LAD), endocardial breakout(s) (BO), and
endocardial activation sequences were analysed for each
of several pacing configurations (see Pacing protocol). The
BO location was identified as the site on the LV endocardium
where depolarization first appeared. This was defined as the
instant where the time-derivative of the virtual unipolar
electrogram (dV/dt) was maximally negative (maximum
negative slope) at the BO location.35–40 The TAD was
defined as the interval from endocardial BO to the latest
observed LV electrical activation (based on virtual unipolar
electrogram recordings). The LAD was defined as the time
interval between pacing initiation and LV endocardial BO.
Methods
Overall experiment durations were on the order of 5–6 h.
This research protocol was reviewed and approved by the
University of Minnesota Institutional Animal Care and Use
Committee, and was designed to ensure the humane treatment of all animals as indicated by the ‘Guide for the
Care and Use of Laboratory Animals’ (NIH). All animals
(n ¼ 7; 80.8 + 7.3 kg) were initially anesthetized using midazolam (2–3 mg/kg) administered via an ear vein, then intubated and mechanically ventilated to allow administration
of isoflurane to maintain a surgical depth of anaesthesia
(.1.0 MAC).22 Catheter access to the right ventricle (RV)
and LV of the heart was achieved via incisions made in the
isolated external jugular veins and right common carotid
arteries, respectively. Separate Millar Mikro-Tipw pressure
catheters (5 French (Fr), MPC 500, Millar, Houston, TX,
USA) were inserted into each ventricle to allow for continuous assessment of ventricular pressures. The derivative of
the LV pressure signal was calculated during post-collection
data analysis. Maximum positive rate of pressure increase
(max þdP/dt) and maximum rate of pressure decrease
(max 2dP/dt) values were determined. A Swan-Ganz catheter (7.5 Fr, 93A-931H, American Edwards Laboratories,
Irvine, CA, USA) was also inserted via the jugular vein and
passed through the RV, placing the catheter’s distal end
within a lumen of the pulmonary artery, thus allowing monitoring of pulmonary artery and left atrial (wedge) pressures
as well as right atrial pressure. Baseline haemodynamic data
were recorded prior to performing a sternotomy. The pericardial fat was removed and the pericardium cut to form a
pericardial cradle. After the chest was opened, 7–9 piezoelectric sonomicrometry crystals (SonoMetrics, London,
ON, Canada) were individually implanted into the midmyocardium, arranged into pairs septally, anteriorly, and
laterally.23–26
Non-contact mapping protocol
Using methods similar to those previously published, NCM
(EnSite 3000, St Jude Medical, St Paul, MN, USA) was used
to record and analyse endocardial electrical activation
patterns in the LV.27–35 A 9 Fr multielectrode array was
inserted via the left coronary artery, and a 7 Fr steerable
electrophysiology catheter (Conductr MC 6022, Medtronic,
Inc., Minneapolis, MN, USA) was introduced via the left
carotid artery. Catheters were visualized using fluoroscopy
to monitor and verify position within the heart.
Under fluoroscopic guidance, endocardial pacing leads were
fixed in the right atrial appendage (RAA-intrins; CapsureSense 4574, Medtronic, Inc.), RV apex (RVA; CapsureFix
Novus 5076, Medtronic, Inc.), and mid-RV septum (RVS;
CapsureFix Novus 5076, Medtronic, Inc.). The LV epicardial
lead (LV-epi; Streamline 6495, Medtronic, Inc.) was placed
at a high posterior-lateral location, which was chosen as
the site of latest endocardial LV depolarization as determined by NCM during RAA-intrinsic pacing. Baseline intrinsic
activation was elicited by pacing from the RAA-intrins lead,
and subsequently recorded.
Single-site ventricular pacing was performed (DDD,
140 bpm, 0.5 ms, 5V, 100 ms AV delay) randomly from each
location (Figure 1) with haemodynamic and NCM data collected after 5 min of consistent pacing. Biventricular
pacing was performed using either the RVS (RVS-BiV) or
the RVA (RVA-BiV) endocardial lead combined with the
LV-epi lead (Figure 1). Pacing (140 bpm, 0.5 ms, 7V) was
carried out randomly in both aforementioned BiV configurations and data were recorded following at least 5 min of
consistent capture. Capture was verified by ECG morphology
and haemodynamic analysis, and noted on NCM.
Statistical analysis
Repeated measures analysis of variance (ANOVA) was performed to determine the relative effects of pacing site or
mode on the resultant electrical and haemodynamic parameters. When significance was indicated by ANOVA, a
Fisher’s least squares post hoc test was performed, with a
P-value of ,0.05 being considered significant. All values
are reported as the mean+standard deviation. Comparisons
were made between RAA-paced intrinsic activation and each
of the various single-site and BiV pacing modes, and also
between the RV and BiV pacing modes.
Results
Electrophysiologic data
Mean baseline QRS duration was 47.5 + 5 ms and mean baseline endocardial TAD was 45.8 + 14 ms during RAA pacing
rhythm (n ¼ 7). All pacing interventions resulted in significantly longer TADs and QRS durations when compared to
those produced by intrinsic RAA pacing (P , 0.05; Table 1).
It should be noted that both BiV pacing combinations produced significantly shorter LAD and QRS durations compared
to their respective single-site counterparts (P , 0.05). Also,
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Pacing protocol
Single-site ventricular and biventricular pacing
1165
(Figure 2F). These two activation wavefronts also fused
quickly on the posterior surface, progressed to the apex,
around to the anterior surface, and then terminated
basally at the septum.
Haemodynamic data
when compared to each single-site and BiV pacing mode,
RVA pacing resulted in the longest TADs and QRS durations
(P , 0.05).
Figure 2 illustrates a typical isochronal activation map
generated by each pacing mode. Similar to RAA-intrinsic
pacing (Figure 2A), it was observed that RVS pacing
(Figure 2B) produced a focal LV BO located in the mid-septal
region of the LV endocardium that led to a single activation
wavefront that propagated across the inferior portion of the
LV and then traversed up the lateral wall. In contrast,
depolarization from RVA pacing (Figure 2C) initiated in the
apex of the LV and then travelled radially up the endocardium and terminated in the high basal region. The activation
generated by pacing from the LV-epi position (Figure 2D)
created a pattern opposite of that generated during RAA
and RVS pacing. Conversely, both BiV pacing interventions
elicited two near-simultaneous BO and their resulting
depolarization wavefronts quickly converged. Specifically,
RVS-BiV pacing produced a high-lateral BO, with the activation wavefront moving initially towards the anterior
surface, then down the lateral wall to the apex, and
finally up the septum to a basal-septal termination
(Figure 2E). Right ventricular apex biventricular pacing
resulted in two near-simultaneous BO, one high on the
posterior-lateral wall and the other at a low septal location
Regional cardiac mechanics
Regional LV dysfunction was seen in the pace-activated LV
myocardium as shown in Figure 4, especially during LV-epi
and BiV pacing. The lateral wall crystal pair (4:5) exhibited
the characteristic ‘hour glass’ shape (during LV-epi and both
BiV) indicative of negative external work, while the septal
crystal pair (3:6) showed a widened waveform (during
LV-epi and RVA-BiV) caused by increased external work relative to normal myocardium.
Discussion
At the present time, less symptomatic patients without significant systolic dysfunction and AV block who require pacing
support do not meet guidelines for CRT. As more patients
with a wider range of symptoms are implanted with BiV
systems and as patients are upgraded from dual to triple
chamber systems, the effects of BiV pacing in a heart
with preserved conduction need to be ascertained.41,42
Early implementation of CRT (NYHA functional class I or II)
has been suggested as a means to prevent disease progression11,17,43,44 and there is current investigation into
whether BiV is superior to conventional RV pacing in slowing
the progression of HF.45,46 Provided the ability of CRT to
reverse detrimental remodelling of the heart, pacing in a
more structurally normal heart becomes of interest.47–50
The current study demonstrated the utility of endocardial
electrical activation measurements, simultaneous with
recordings of haemodynamic and mechanical parameters,
to evaluate the sequelae of various pacing modes in an
intact swine heart.
Despite recently published reports focusing on the outcomes of CRT therapy, there remains a need to further
investigate the mechanisms underlying the outcomes
seen with CRT.2,51,52 Recently, Frias et al.53 performed
pacing in AV block canines and compared acute AV sequential pacing to atrio-biventricular pacing performed from
the RV (apex and outflow tract) and LV (apex and base).
It was demonstrated that QRS durations shortened and
LV performance improved with epicardial BiV pacing compared to standard single-site ventricular pacing. However,
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Figure 1 (A) Diagram of the normal intrinsic conduction system,
with its constituent parts labelled, depicting the natural electrical
activation progression beginning at the sino-atrial (SA) node, progressing through the atria, to the atrio-ventricular (AV) node,
through the bundle of His, down the bundle branches, and finally
passing through the Purkinje fibres before dissipating into the myocardium. The endocardial electrical BO (as observed using noncontact mapping) is shown by the blue circle. (B) Pacing lead
locations for the right atrial appendage (RAA-intrins), right ventricular septum (RVS), right ventricular apex (RVA), and left ventricular
epicardial (LV-epi) leads. Lead locations and combinations are
shown both in relation to the native conduction system, and also
in anatomic positions. All RV leads were implanted endocardially.
Intrinsic activation was elicited by pacing from the RAA-intrins.
Single-site pacing was performed from the RVA and RVS locations,
while BiV pacing included the addition of the LV-epi lead.
(Rendered anatomic image used with permission from Medtronic,
Inc., Minneapolis, MN, USA).
A summary of the haemodynamic parameters is also presented in Table 1. Compared to RAA-paced intrinsic LV
activation, RVA-BiV pacing was the only intervention that
demonstrated a significant reduction in the maximum generated LV pressure and LV max þdP/dt, both indicators of
systolic function (P , 0.05). No significant changes in systolic function were observed with either single-site pacing
from the RV. Minimum LV pressure (min LVP) and maximum
2dP/dt, indicators of diastolic function, were not significantly affected regardless of pacing intervention. It is
notable, however, that both systolic and diastolic function
tended to be impaired more with BiV pacing than with
single-site pacing, although these differences were not
statistically significant (Figure 3, P ¼ ns).
1166
M.W. Kimmel et al.
Table 1 Haemodynamic and left ventricular electrical activation data measured for each pacing site and modea
max LVP (mmHg)
min LVP (mmHg)
max þdP/dt (mmHg/s)
max 2dP/dt (mmHg/s)
QRS (ms)
TAD (ms)
LAD (ms)
RAA-intrins
LV-epi
RVA
RVA-BiV
RVS
RVS-BiV
83.9 + 9.0
6.6 + 7.7
1272 + 285
21532 + 226
47.5 + 4.8
45.8 + 13.9
N/A
70.1 + 18.7
5.9 + 5.7
1077 + 194
21299 + 657
74.8 + 11.0*
58.3 + 3.7*
26.2 + 3.5
71.3 + 18.5
4.9 + 3.4
1077 + 135
21506 + 874
72.9 + 3.6***
63.2 + 7.6***
30.1 + 6.1**
62.6 + 23.1*
4.1 + 2.9
927 + 286*
21104 + 778
59.9 + 4.6*
52.7 + 6.3*
26.9 + 8.6
71.8 + 14.8
4.8 + 3.1
1101 + 177
21532 + 840
60.7 + 8.2***
52.1 + 10.4*
41.5 + 4.7**
69.6 + 15.2
4.8 + 3.1
1045 + 180
21232 + 679
56.3 + 7.9*
53.9 + 6.0*
23.5 + 4.7
Figure 2 Isochronal maps showing propagation of left ventricular (LV) endocardial electrical activation. In these images, colour corresponds
to relative activation time, with white representing the location of earliest electrical activity and blue or purple denoting the site of latest
recorded activity. These three-dimensional LV reconstructions are shown both in anterior/posterior (AP) and posterior/anterior (PA) orientations. Diagrams are included depicting the pacing site (‘burst’ symbol) and activation progression corresponding to the following pacing
locations: (A) right atrial appendage (RAA-intrins), (B) right ventricular septum (RVS), (C ) RV apex (RVA), (D) LV epicardial lead (LV-epi),
(E) RV septum biventricular (RVS-BiV), and (F) RV apex biventricular (RVA-BiV). Blue dots indicate BO locations on the LV endocardial
maps; green arrows signify normal fast conduction; solid red arrows indicate abnormal fast conduction; dashed red arrows indicate abnormal,
transmural slow conduction. Atrial pacing location is indicated by amber ‘burst’ symbol, with amber arrows signifying atrial activation. As
ventricular activation was examined in this study, atrial pacing was utilized in each case (except RAA pacing) to minimize the effects of intrinsic atrial activation on the ventricles.
it should be noted that, compared to humans, canines
have marked electrophysiological differences which
may limit translational relevance to the clinical arena;
specifically, Bowman and coworkers18,54 demonstrated
that the electrophysiological parameters of the swine
were more similar to those found in humans than those
from canines.
Electrophysiology
The current study employed NCM to record endocardial
electrical activation sequences during paced conditions
and demonstrated RVS pacing to elicit depolarization that
most closely mimicked the RAA-intrinsic waveform. Prinzen
et al.55 reported that LV function is more dependent on
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a
Haemodynamics and electrical timing values resulting from pacing at the right atrial appendage (RAA-intrins), left ventricular epicardial (LV-epi), right
ventricular apex (RVA), right ventricular apex biventricular (RVA-BiV), right ventricular septum (RVS), and right ventricular septum biventricular (RVS-BiV)
pacing. Maximum and minimum left ventricular pressures (LVP) are given in mmHg, positive and negative pressure-time derivatives (dP/dt) are in mmHg/s,
and electrical activation parameters [QRS duration (QRS), total activation duration (TAD), and local activation duration (LAD)] are in ms. All data are shown
as mean+SD [*P , 0.05 vs. RAA-intrins pacing, **P , 0.05 vs. corresponding BiV pair].
Single-site ventricular and biventricular pacing
1167
max LVP, max þdP/dt, and max 2dP/dt values. Specifically,
systolic performance was significantly impaired during both
RVA-BiV (P , 0.05) and RVS-BiV (P 0.10) pacing compared
to RAA-intrins pacing. This occurred even while QRS durations were at their shortest, highlighting the important
role mechanical synchrony plays in haemodynamic
performance.
Regional cardiac mechanics
Limitations
the sequence than the synchrony of electrical activation,
thereby highlighting the importance of such findings. The
LV activation maps generated during RAA-intrinsic pacing
paralleled the LV depolarization patterns found by Durrer
et al.56 using multiple intramural electrodes and was
similar to those reported by Cassidy et al.57
All pacing sites resulted in increased total activation durations. Myerburg et al. 58 determined that in the RV, electrical impulses can enter the Purkinje network from the lower
septum as well as certain locations in the RVOT. This
relationship is mirrored in the activation patterns recorded
in the present study – RVS pacing resulted in an LV pattern
that mimicked RAA-intrinsic pacing, while RVA pacing
caused an LV pattern that initiated at the apex. The same
relationship was reflected in overall ventricular activation
timing, in that pacing from the RVA lead resulted in a
longer TAD than did RVS pacing. This was likely due to transmural conduction across the septum that progressed more
slowly than that along the intrinsic conduction system.
While the LAD was longer for RVS pacing than RVA, once LV
BO occurred, the chamber depolarized quicker, indicating
preferential conduction.
Study limitations include not optimizing the interventricular
(V–V) pacing interval, pacing at a high, non-physiologic rate,
and not studying the influence of pacing site in a chronic
swine model. Simultaneous pacing at each lead location
was performed during BiV pacing rather than optimizing
the V–V timing, likely generating increased interventricular
mechanical dyssynchrony. However, it has been reported
that the majority of the improvement in CRT patients
is attributed to the simple implementation of pacing,
rather than optimization of V–V timing.65–69 By consistently
pacing from the RAA in each situation, the pacing rate and
AV delay were controlled to preclude the native rate from
interfering with paced activation, as well as to prevent retrograde atrial activation.70 Native AV intervals ranged from
150 to 200 ms, and while a paced heart rate of 140 bpm is
not considered optimal from a cardiac performance standpoint, this rate was necessary due to the elevated native
heart rate of the swine during the study. Future studies
are merited to investigate the effect of pacing rates, as
well as A–V and V–V intervals. Before a direct application
to the clinical setting can be ascertained, chronic animal
studies need to be performed to elucidate whether or not
these mechanisms are similar in the chronically paced heart.
Haemodynamics
Conclusion
A trend for greater impairment of haemodynamic performance was associated with BiV pacing, as shown by decreased
The results of this study suggest that acute BiV pacing in a
structurally normal heart both prolongs LV endocardial
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Figure 3 (A) Comparison of maximum positive change in left ventricular (LV) pressure generated during single-site (RAA-intrins,
LV-epi, RVA, RVS) and biventricular (RVA-BiV, RVS-BiV) pacing
modes (asterisk – P,0.05 vs. RAA-intrins pacing). (B) Comparison
of maximum negative change in LV pressure generated during singlesite (RAA-intrins, LV-epi, RVA, RVS) and biventricular (RVA-BiV,
RVS-BiV) pacing modes (RAA-intrins, right atrial appendage;
LV-epi, left ventricular epicardial; RVA, right ventricular apex;
RVA-BiV, right ventricular apex biventricular; RVS, right ventricular
septum; RVS-BiV, right ventricular septum biventricular).
Similar to published work, local dysfunction was observed in LV
regions near the pacing sites59,60 as demonstrated by regional
pressure-length loops shown in Figure 4. Prinzen et al.61
demonstrated in canines that total myocardial work is
reduced by 50% in early-activated regions and increased by
50% in late-activated regions, as compared with normal electrical activation. This can be seen in the characteristic ‘hourglass’ shape of the lateral crystal pair trace (4:5) during LV-epi
and both BiV pacing modes, and in the wide septal crystal pair
trace (3:6) during LV-epi and RVA-BiV pacing.
It stands to reason that in a healthy heart, any disruption
or change in the electrical activation would result in suboptimal performance. As was found by Tyers,62 the greater the
departure from intrinsic activation, the worse the haemodynamic performance. Specifically, BiV pacing is a greater
departure from native excitation when compared to singlesite pacing, and should correspondingly impair function to a
greater degree. Epicardial pacing effectively reverses this,
further contributing to an abnormal activation sequence,
especially in healthy myocardium.63 Similar to research published by Faris et al.,64 caution needs to be taken in deriving
direct clinical application from the results of the present
study, as healthy hearts were used.
1168
M.W. Kimmel et al.
activation and induces systolic haemodynamic dysfunction,
regardless of anatomic location of the RV pacing lead.
Single-site pacing of the RV or LV within an otherwise
healthy heart will likewise compromise haemodynamic performance. With the goal of maintaining a physiologic-like
activation sequence and minimizing regional dysfunction,
it is believed that pacing from a lead placed on the RV
septum best maintains normal cardiac function in structurally normal hearts.
Conflict of interest: M.W.K., N.D.S., and T.G.L. are employees and
shareholders of Medtronic, Inc.
Funding
Funding was provided by Medtronic, Inc. (basic research
contract), and the Institute for Engineering in Medicine
and Department of Surgery, University of Minnesota.
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