Download Myofiber prestretch magnitude determines regional systolic function

Am J Physiol Heart Circ Physiol 305: H192–H202, 2013.
First published May 10, 2013; doi:10.1152/ajpheart.00186.2012.
Myofiber prestretch magnitude determines regional systolic function during
ectopic activation in the tachycardia-induced failing canine heart
Elliot J. Howard,1 Roy C. P. Kerckhoffs,1 Kevin P. Vincent,1 Adarsh Krishnamurthy,1
Christopher T. Villongco,1 Lawrence J. Mulligan,3 Andrew D. McCulloch,1 and Jeffrey H. Omens1,2
1
Department of Bioengineering, University of California San Diego, La Jolla, California; 2Department of Medicine,
University of California San Diego, La Jolla, California; and 3Therapy Delivery Systems/Leads Research, Medtronic,
Mounds View, Minnesota
Submitted 6 March 2012; accepted in final form 9 May 2013
epicardial pacing; fiber strain; heart failure; prestretch; wall thickening
ectopic ventricular pacing results in dyssynchronous electrical activation, giving rise to an altered sequence of
contraction, depressed pump function, and chronic ventricular
remodeling (27, 40). Badke and coworkers (4) first described the
effects of ectopic activation on regional mechanics in normal
hearts. During ventricular epicardial pacing, early shortening
(prior to aortic valve opening) occurs near the LV pacing site,
whereas late-activated regions lengthen or “prestretch” during
early systole. The magnitude of prestretch increases with local
activation time (7), resulting in an increase in peak magnitude of
fiber shortening in the late-activated regions (9, 18), with implications for subsequent long-term remodeling of the tissue. Proposed mechanisms for increased systolic fiber prestretch in lateactivated regions involve both mechanical deformation imposed
by adjacent early contracting regions and increased intracavity
pressure at the time of local electrical activation (7). A recent
computational study found that fiber prestretch resulted from a
spatial variation in local fiber stiffness and the governing requirement of force equilibrium in the presence of a dyssynchronous
activation sequence (19). Enhanced shortening function in late
activated tissue may be a result of length-dependent activation due
to longer fiber lengths (18, 28, 30).
In heart failure, the complex alterations in tissue mechanics
and regional muscle fiber function may alter the effects and
implications of dyssynchronous electrical activation. Investigating mechanical prestretch in the failing heart may provide
mechanistic insight into the role of length-dependent fiber
function in the early- and late-activated regions. Therefore, the
aim of the present study was to quantify fiber prestretch in a
canine model of dyssynchronous heart failure and investigate
possible mechanisms for increased local strains in late-activated tissue. Specifically, we hypothesize that in the failing
heart 1) the peak magnitude of fiber prestretch is proportional
to the amount of early-activated tissue; 2) end-systolic fiber
shortening and wall thickening increase in proportion to prestretch magnitude as seen in the normal heart; and 3) lengthdependent fiber stress generation is a mechanism of the strain
variation in early- and late-activated tissue. To address these,
we implemented a canine model of dyssynchronous heart
failure with implanted markers and x-ray imaging to measure
regional transmural strains in early- and late-activated tissue
and used a dog-specific finite-element model of the failing
heart to further elucidate potential mechanisms for changes in
local fiber function due to altered electrical activation.
IN THE NORMAL HEART,
Address for reprint requests and other correspondence: J. H. Omens, Dept.
of Medicine, Mail Code 0613-J, Univ. of California, San Diego, 9500 Gilman
Dr., La Jolla, CA 92093-0613 (e-mail: [email protected]).
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MATERIALS AND METHODS
All animal studies were performed according to the National Institutes
of Health “Guide for the Care and Use of Laboratory Animals.” Experimental protocols were submitted to and approved by the Animal Subjects Committee of the University of California, San Diego (UCSD),
which is accredited by the American Association for Accreditation of
Laboratory Animal Care.
Tachycardia-induced heart failure protocol. We implemented a
previously established canine model of tachycardia-induced heart
failure and myocardial infarction (6, 15) in five adult mongrel dogs
(19 –26 kg). Under sterile conditions and a surgical plane of anesthesia, a minimally invasive left thoracotomy was performed. Arterial
pressure was monitored throughout the surgery by placing a small
catheter, attached to a fluid-filled pressure transducer, into a side branch
of the right femoral artery. Bipolar epicardial leads (CAPSURE EPI,
model no. 4968, Medtronic, Minneapolis, MN) were sewn onto the
right ventricular apical epicardium and routed to a programmable
pacemaker capable of rates above 180 beats/min (INSYNC III, model
0363-6135/13 Copyright © 2013 the American Physiological Society
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Howard EJ, Kerckhoffs RC, Vincent KP, Krishnamurthy A,
Villongco CT, Mulligan LJ, McCulloch AD, Omens JH. Myofiber
prestretch magnitude determines regional systolic function during
ectopic activation in the tachycardia-induced failing canine heart. Am
J Physiol Heart Circ Physiol 305: H192–H202, 2013. First published
May 10, 2013; doi:10.1152/ajpheart.00186.2012.—Electrical dyssynchrony leads to prestretch in late-activated regions and alters the
sequence of mechanical contraction, although prestretch and its mechanisms are not well defined in the failing heart. We hypothesized that
in heart failure, fiber prestretch magnitude increases with the amount
of early-activated tissue and results in increased end-systolic strains,
possibly due to length-dependent muscle properties. In five failing dog
hearts with scars, three-dimensional strains were measured at the
anterolateral left ventricle (LV). Prestretch magnitude was varied via
ventricular pacing at increasing distances from the measurement site
and was found to increase with activation time at various wall depths.
At the subepicardium, prestretch magnitude positively correlated with
the amount of early-activated tissue. At the subendocardium, local
end-systolic strains (fiber shortening, radial wall thickening) increased
proportionally to prestretch magnitude, resulting in greater mean
strain values in late-activated compared with early-activated tissue.
Increased fiber strains at end systole were accompanied by increases
in preejection fiber strain, shortening duration, and the onset of fiber
relengthening, which were all positively correlated with local activation time. In a dog-specific computational failing heart model, removal of length and velocity dependence on active fiber stress
generation, both separately and together, alter the correlations between local electrical activation time and timing of fiber strains but do
not primarily account for these relationships.
LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
Fig. 1. Location of implanted myocardial markers and epicardial pacing sites
in the canine left ventricle. Intramyocardial gold beads were implanted at the
anterolateral left ventricle, between diagonal branches of the left anterior
descending (LAD) artery. Surface epicardial beads were sewn at the entrance
of each transmural column and at the apex and base of the heart, defined by the
bifurcation of the LAD and circumflex (CCX) arteries. Bipolar pacing electrodes were positioned at the right ventricular apex (not shown) and at five left
ventricular epicardial sites: anterior apical (A), anterior basal (B), anterior
midventricle (C), lateral (D), and posterior basal near the coronary sinus (E).
AoV, aortic valve; MV, mitral valve.
the center of the heart. Aortic flow was obtained with an ultrasonic
flow probe (model no. T208; Transonic Systems, Ithaca, NY). LV
volumes were measured with a conductance catheter (3) (Webster
Laboratories, Baldwin Park, CA) positioned in the LV cavity via the
left carotid artery. The conductance catheter was calibrated in vivo at
the end of the study with a bolus (2–5 ml) injection of hypertonic
saline solution (6 M NaCl). Arterial and aortic pressures were monitored with fluid-filled gauges positioned in the right femoral artery
and left subclavian artery, respectively. Lead II electrocardiogram was
recorded, along with local bipolar electrograms from nonpaced LV
electrodes. A custom epicardial sock, consisting of 128 unipolar
electrodes, was positioned on the heart to measure the electrical
sequence of activation during ventricular pacing. Additionally, as
described above, bipolar electrodes positioned at the subepicardium
and subendocardium were used to measure local activation times at
the subepicardium, midwall (interpolated), and subendocardium at the
strain measurement site.
Pacing protocol and signal analysis. Atrial, right ventricular apex,
and LV epicardial pacing were performed via stimulation of bipolar
electrodes with square-wave pulse generators (model no. SD9; Grass
Instruments, Quincy, MA). LV epicardial pacing sites were anterior
base, anterior apex, anterolateral midventricle, lateral midventricle,
and posterior base near the coronary sinus (Fig. 1). All electrodes
were positioned at least 1 cm from the posterolateral infarct. Pacing
parameters were held constant throughout the study at a frequency ⬎
120% of intrinsic rate, voltage ⬎ 110% threshold value, and AV delay
of 40 milliseconds. The 128-electrode amplifier was set to a gain of
20 –50⫻, and signal frequencies outside the desired range (2–200
kHz) were filtered from the recorded signals. Off-line signal analysis
was performed in custom software in MATLAB 7.10 (Mathworks,
Natick, MA). The time of the maximum derivative of electrode
voltage was used to define the time of local activation at each
electrode.
For all pacing runs, hemodynamic variables were collected after
steady-state conditions were reached (⬃2 min following the onset of
pacing). Maximum (LVPmax), end-diastolic (LVEDP), and end-systolic (LVESP) LV pressures were determined with the calibrated
micromanometer signal. Stroke volume (SV) was found by numerical
integration of the aortic flow signal between the interval of aortic
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no. 8042, Medtronic). Radiopaque gold markers (1–2 mm) were
implanted to study three-dimensional transmural mechanics in the
anterolateral LV wall, as described previously (2, 14, 39). An implantable pressure gauge (model no. TA11PA-C40, Data Sciences
International, St. Paul, MN) was inserted into the left atrial appendage
for noninvasive monitoring of left atrial pressure after surgery. The
left circumflex coronary artery was dissected, and a marginal branch
of the circumflex was permanently ligated with the distal ends embolized with multiple injections (4 – 8 ml) of microspheres (100- to
300-␮m diameter, Biospheres Medical, Rockland, MA). Posterolateral scars were allowed to heal for 5 wk, and high rate ventricular
pacing (220 –250 beats/min) was performed for an additional 5 wk,
resulting in a 10-wk period post initial surgery. The primary purpose
of using a chronic infarct model, combined with the tachycardiainduced heart failure protocol, was to accelerate the progression of
heart failure and reduce the potential for reverse remodeling once the
rapid pacing period had ended and animals returned to normal sinus
rhythm. The success of the combined infarct and rapid pacing model
has been previously demonstrated by others (15). Prior to the terminal
study, high-rate pacing was discontinued for 24 h. Cessation of
high-rate pacing was done primarily to ensure lower intrinsic sinus
rates at the terminal study to allow for AV sequential pacing within
normal rates. Left atrial pressure was recorded at the onset, bidaily
throughout the duration, and 24 h after the cessation of high-rate
pacing. Only animals with mean left atrial pressure values of 3– 4
times the value recorded at the onset of high-rate pacing, and displaying clinical signs of heart failure, were entered into the terminal
experimental study.
Surgical preparation at the terminal study. Acute ventricular pacing studies were performed ⬃10 wk after animals had been subjected
to posterolateral infarction and heart failure protocols, as described
above. Animals were induced at the terminal study with intravenous
propofol (4 – 6 mg/kg), intubated, and mechanically ventilated with a
mixture of isoflurane (2%) and medical-grade oxygen (2 l/min) to
achieve a surgical plane of anesthesia. To maintain a sustainable
hemodynamic state (e.g., systolic pressure greater than 75 mmHg
during intrinsic rhythm), inotropic support and supplemental analgesia
were provided intermittently during the study with dopamine (3–10
␮g·kg⫺1·min⫺1 iv) and buprenorphine (0.02– 0.05 mg/kg sc), respectively. After a medial sternotomy and left thoracotomy at the fifth
intercostal junction, the heart was positioned in a pericardial cradle.
Bipolar pacing wires were sewn to the left atrial appendage for atrial
pacing. Custom-made bipolar plunge electrodes (7) were positioned at
the right ventricular apex and at five LV epicardial sites (Fig. 1). The
bipolar electrodes were used for measuring local electrical activation
time when not connected to the external stimulator. Additionally, at
each LV epicardial pacing site, a bipolar recording electrode was
positioned on the LV endocardium. Ventricular activation was
achieved by atrioventricular (AV) sequential pacing of the left atrial
appendage and one of the epicardial bipolar electrodes with a fixed
AV delay of 40 ms.
Varying the local electrical activation time at the anterolateral LV.
To alter the local electrical activation time at the anterolateral wall,
ventricular pacing at multiple epicardial pacing sites, with increasing
distance from the strain measurement site, was performed. LV epicardial pacing near the measurement site (i.e., anterior apex, Fig. 1)
was used to induce early electrical activation, whereas remote sites
were used to produce longer electrical activation times at the measurement site. Thus ventricular pacing at multiple anatomical sites
was used to vary the electrical activation time and magnitude of
prestretch at the anterolateral LV.
Electrical and hemodynamic measurements. LV cavity pressure
and rate of change were monitored with a high-fidelity micromanometer (model P6; Konigsburg Instruments, Pasadena, CA) placed in the
LV lumen via puncture of the LV apex and closure with a purse-string
suture. The micromanometer was matched to a statically calibrated
fluid-filled pressure gauge, which was zeroed at a level approximate to
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LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
Defining fiber prestretch and timing parameters of fiber strain. The
magnitude of fiber prestretch was defined as the strain magnitude at
the first onset of fiber shortening, which corresponded to either a fiber
strain value of zero or greater. Briefly, fiber strain rate was computed
from the time course of fiber strain. The first zero crossing of fiber
strain rate was defined as the onset of fiber shortening. The onset of
fiber relengthening was then defined as the first zero crossing of fiber
strain rate during the interval between the onset of fiber shortening
and global ventricular stimulus of the next beat. In cases where
multiple phases of shortening and lengthening occurred (i.e., multiple
local minima/maxima), the earliest onsets of shortening and relengthening were used. Fiber shortening duration was defined as time
difference between the first onset of relengthening and first onset of
shortening. Results depicting the onset of fiber relengthening are
presented minus the local activation time to correct for intrinsic
dependence on the timing difference between the ventricular stimulus
pacing artifact (0 ms) and local subendocardial electrical activation
time.
Estimation of the amount of early-activated tissue at the subepicardium. We used electrical activation times measured with a
128-electrode epicardial sock to create 2D epicardial isochronal maps
using a polar grid projection (i.e., Bulls-eye plot) which conserved
both the longitudinal and circumferential distribution of the electrodes. Briefly, dog-specific polar grids were defined from 3D polar
coordinates of the 128 epicardial electrodes, obtained with a 3D
digitization arm (Faro Instruments) in the postmortem heart. Local
electrical activation time (ATlocal) at the strain measurement site was
used to threshold regions of early electrical activation; specifically,
regions with an activation time less than or equal to ATlocal minus 10
ms were defined as earlier-activated tissue. Percent total area of the
threshold region was used as a measure of the amount of earlier
activated tissue. Thus earlier activated tissue was defined relative to
the time of electrical activation at the strain measurement site.
Histological measurement of mean fiber and sheet angle orientation. To minimize the distortion effects of dehydration and shrinkage
associated with paraffin embedding, histological measurements were
obtained in fresh perfusion-fixed tissue. A transmural block from the
anterolateral left ventricle, near the location of the implanted markers,
was carefully excised with block edges cut parallel to the locally
defined longitudinal, circumferential, and radial directions. Mean fiber
and sheet angle measurements were then made at 1-mm transmural
increments from epicardium to endocardium (1). In the case of
bimodal distributions of sheet angle, mean sheet angle was determined
by the circular average of the dominant sheet population, defined by
the number of measurements. Mean fiber and sheet angle distributions
in each animal were then corrected for geometric changes and variations in chamber pressure during fixation using the method of Takayama et al. (34). The main assumptions of the methods employed
for fiber angle measurement were 1) myofibers lie in a plane parallel
to the local epicardial tangent plane, and 2) transmural fiber orientation can be described by a mean fiber angle at each incremental depth.
Numerical simulations in a dog-specific computational model of
the failing heart. Left ventricular mechanics were simulated in a
dog-specific model of biventricular electromechanics, created using
one dog from the experiments. Further details of the modeling
methods can be found in the Supplemental Material available with the
online version of this article). Anatomical models of the right and left
ventricular geometry and fiber architecture were fitted to MRI and
DT-MRI data (21). The fiber architecture fit using DT-MRI data was
initialized with generic transmural fiber angles of ⫺60° to ⫹60°
(epicardial to endocardial), with 0° transverse and sheet angles
throughout the myocardial volume. The fit was penalized against
regions with poor quality DT-MRI measurements (e.g., the RV free
wall) to preserve the initialized fiber-sheet orientations in those
regions. The ventricles were described by a total of 128 tricubic
Hermite finite elements and 5,016 degrees of freedom. Each element
consisted of a 3 ⫻ 3 ⫻ 3 arrangement of integration points. The finite
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valve opening and closure, as determined by the zero crossing of the
flow signal. Forward ejection fraction (EF) was determined by dividing SV by the end-diastolic volume determined by the conductance
catheter. Numerical computation was performed off-line using custom
software in MATLAB.
At the end of the study, animals were euthanized by an overdose of
pentobarbital (100 mg/kg iv). Hearts were isolated in situ, perfused
with cardioplegia, and perfusion-fixed at zero LV pressure with
buffered glutaraldehyde (5%).
Additional pacing protocols, not described and out of scope, were
performed in all five of the animals presented in the current study.
Data collected from these out of scope protocols have been presented
previously (14). Changes in body weight, unloaded LV volume, EDP,
and other hemodynamic variables in the five animals of the present
study have been previously summarized elsewhere (14).
Obtaining 3D geometry and fiber architecture with MRI and
DTMRI. For one dog (dog 6), geometry and fiber architecture were
measured with magnetic resonance imaging (MRI) and diffusion
tensor magnetic resonance imaging (DTMRI) in the excised, postmortem heart fixed with an LV pressure of 0 mmHg. These highresolution data were used to create a dog-specific computational
model. The MRI and DTMRI protocols were performed on a General
Electric (GE) Discovery MR750 3.0T whole body imaging system
(GE Healthcare Waukesha, WI) at the Center for Functional MRI at
UCSD. Anatomical scans were performed with a 3D gradient echo
pulse sequence; parameters were optimized for signal to noise: echo
time (TE) ⫽ minimum, repetition time (TR) ⫽ 8.7 ms, flip angle ⫽
15°, and averages ⫽ 4. A field of view of 10.0 cm and data matrix of
256 ⫻ 256 were prescribed for an in-plane resolution of 391 ␮m; slice
thickness was 1.0 mm, resulting in 82 contiguous slices. DTMRI was
performed with a custom 3D fast spin echo pulse sequence (10).
DTMRI parameters were TE ⫽ minimum, TR ⫽ 500 ms, FOV ⫽ 10
cm and in-plane resolution of 128 ⫻ 128 slices or 781 ␮m, slice
thickness of 1.0 mm, and 12 diffusion encoded directions.
Three-dimensional coordinate reconstruction of implanted myocardial markers. Intramyocardial markers were imaged with a biplane
cineradiography system and digital images from the two X-ray views
were acquired at high temporal resolution (125 frames/s). After
allowing time to reach steady state during each pacing run, radiographic images were collected for multiple beats with respiration
suspended at end expiration. Two-dimensional marker coordinates
from each view were then corrected for spherical distortion (1) and
reconstructed into three-dimensional coordinates (25) in a cardiac
coordinate system defined by five reference markers (26).
Three-dimensional transmural fiber mechanics throughout the cardiac cycle. Nonhomogenous, three-dimensional Lagrangian strain
distributions across the anterolateral LV were computed throughout
one complete cardiac cycle for atrial and ventricular activations. A
time series of radiographic images, representing one complete cardiac
cycle, were arranged such that the first and last frames corresponded
to subsequent occurrences of the local ventricular pacing stimulus,
visible as artifacts on the ECG recording. Unless otherwise specified,
the reference configuration for strain calculation was the first frame in
the time series, corresponding to the 3D positions of implanted
markers at the time of the local ventricular pacing stimulus. Time
courses of six independent strain components defined in a cardiac
material coordinate system (circumferential, longitudinal, and radial)
were determined at three transmural depths: subepicardium (25%),
midwall (50%), and subendocardium (75%). At each wall depth, mean
fiber angle measurements were used to rotate cardiac strain components (circumferential, longitudinal, radial) into fiber material coordinates (fiber, cross-fiber, radial) as described previously (2). The
primary assumption was that fibers lie predominantly in planes parallel to the epicardial tangent plane. With this assumption, a reference
coordinate system with directions aligned to the fiber, cross-fiber, and
radial axes is defined by a rotation of the cardiac coordinates by the
mean fiber angle.
LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
Model fiber strains at the subendocardial anterior LV equator were
selected for comparison of experimental findings at a similar site.
Local fiber strain, the time to the onset of fiber relengthening, and
fiber shortening duration were computed to determine the effects of
length and velocity dependence on active stress generation in regulating local fiber function during dyssynchrony.
Statistical analysis. All measurements are reported as means ⫾ SE.
Statistical analysis was performed in SigmaPlot 11 (SyStat Software,
San Jose, CA). A one-factor repeated-measures ANOVA was used to
determine the effect of pacing site on functional parameters (e.g.,
QRSd, dP/dtmax, end-systolic Eff). Post hoc comparisons between
pacing sites were performed with a Tukey’s test. For comparison of
mean values between two groups a two-tailed Student’s t-test was
used. Linear regression analysis was performed to investigate the
effects of activation time and peak fiber prestretch on strain magnitudes and timing parameters for experimental and numerical results.
In all cases, statistical significance was accepted for P ⬍ 0.05.
RESULTS
Electrical dyssynchrony impairs global hemodynamic function. The effects of pacing site on electrical and hemodynamic
parameters are summarized in Table 1. Compared with atrial
activation, QRS duration was increased (P ⬍ 0.05) and SV
reduced (P ⬍ 0.05) during ventricular pacing at all sites. LV
dP/dtmax was lowered (P ⬍ 0.05) in a majority of the ventricular pacing sites, compared with atrial activation. Changes in
body weight, unloaded left ventricular volume, and end-diastolic filling pressure resulting from 5 wk of tachycardiainduced heart failure and posterolateral scarring have been
previously reported in all of these animals (14). Peak systolic
pressure and LV dP/dtmin were unchanged for nearly all LV
epicardial pacing sites, but significantly reduced (P ⬍ 0.05) for
the RVA pacing site, compared with atrial activation. After
combining data from all ventricular pacing sites, QRS duration
Fig. 2. Dog-specific computational model of the
failing canine heart. A: 128 tricubic Hermite finite
elements were used to describe realistic geometry
obtained from one experimental animal (dog 6).
Anterior (left) and basal (right) views of the fiber
architecture fitted to DT-MRI measurements were
registered to the mesh using a log-Euclidean framework to interpolate the tensors (23). The 3-dimensional local fiber-sheet structure is visualized by the
shape, orientation, and color glyphs; the primary and
minor axes of the glyphs represent the fiber and
sheet-normal axes, respectively. The glyph color
redundantly encodes circumferential to longitudinal
(blue to red) fiber orientation to illustrate the smooth
fiber variation. B: ventricular pacing at 2 separate
locations resulted in opposite sequences of electrical
activation. Local activation times are rendered in
color at the subendocardial surface of the finiteelement model. During left ventricular anterior apical pacing (EARLY, left), subendocardial activation
was relatively uniform across the anterolateral apical
wall and occurred earlier compared with the septal
and right ventricular free walls. Pacing on the posterior basal left ventricle (LATE, right) resulted in
delayed activation at the anterolateral left ventricle.
A comparable anterolateral location (red dot) to the
experimental protocol was used to compare differences between early at late activation. Local electrical activation time at the mechanical site was 28 and
81 ms for EARLY and LATE, respectively. Circ,
circumferential; Long, longitudinal.
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element model is shown in Fig. 2A. The finite element model was
coupled to a three-element Windkessel model (17), and the Arts
model of sarcomere mechanics (24) governed the generation of active
fiber stress. Parameters of the baseline sarcomere mechanics model
were obtained by matching LV cavity pressures and strain time
courses between model and experiment. Passive material properties
were estimated by matching end-diastolic LV pressure between model
and experiment. Electrical activation times (Fig. 2B) during ventricular pacing were computed by an electrophysiology model (35) using
a more refined discretization of the ventricles with 25,600 tricubic
Hermit finite elements, 245,520 degrees of freedom, and a 4 ⫻ 4 ⫻ 4
arrangement of integration points. Conduction velocities were determined by matching subendocardium activation time at the location of
strain measurement and QRS duration between experiment and
model. Electrical activation times were then used to initiate active
stress development.
The baseline active stress model (BASE) consisted of a Hill relationship, which modeled the sarcomere as a passive element in parallel with
contractile and series elastic elements. Detailed mathematical descriptions of the active stress model and its dependence on sarcomere length
and shortening velocity are described elsewhere (24).
The BASE model was then modified in the following ways: 1)
active stress dependency on sarcomere shortening velocity was removed, thus resulting in a velocity independent (VI) model; 2) active
stress dependency on sarcomere length was removed (LI); and 3)
active stress dependency on both sarcomere length and shortening
velocity was removed, thus resulting in a length and velocity independent model (LVI).
A total of eight simulations were performed using two activation
sequences (i.e., 2 pacing locations were used for each of the 4 active
stress models). The ventricular pacing locations were the posterior
basal near coronary sinus (PCS) and the anterior apical site (AAPEX),
as in the experiments, which resulted in early activation and late
activation at the anterolateral LV, respectively. The multiscale model
was solved with the Continuity 6.4 package (http://www.continuity.
ucsd.edu).
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LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
Table 1. Electrical and hemodynamic parameters at steady-state during ventricular pacing
Pacing Site
RR, ms
QRSd, ms
LVEDP, mmHg
LVESP, mmHg
LVPmax, mmHg
dP/dtmax, mmHg/s
dP/dtmin, mmHg/s
SV, ml
ATRIAL
RVA
PCS
LAT
ABASE
AMID
AAPEX
485.7 ⫾ 13.1
485.1 ⫾ 13.0
485.1 ⫾ 14.5
484.4 ⫾ 15.1
484.9 ⫾ 15.1
484.7 ⫾ 13.4
485.1 ⫾ 13.2
53.1 ⫾ 4.8
124.3 ⫾ 8.7*
123.4 ⫾ 14.0*
132.1 ⫾ 17.9*
121.9 ⫾ 13.0*
131.6 ⫾ 13.5*
109.8 ⫾ 11.1*
14.6 ⫾ 0.9
13.4 ⫾ 0.5
13.1 ⫾ 0.5
12.6 ⫾ 1.1
13.1 ⫾ 0.6
13.3 ⫾ 0.7
13.6 ⫾ 0.7
64.3 ⫾ 7.9
51.4 ⫾ 6.9
52.7 ⫾ 6.7
55.5 ⫾ 5.5
48.9 ⫾ 2.3
53.3 ⫾ 4.7
52.9 ⫾ 5.5
93.9 ⫾ 6.3
78.6 ⫾ 7.3*
81.6 ⫾ 7.7
84.7 ⫾ 6.4
78 ⫾ 3.2
82.6 ⫾ 4.9
81.9 ⫾ 5.7
1,768 ⫾ 344
1,296 ⫾ 329*
1,382 ⫾ 314†
1,438 ⫾ 307
1,264 ⫾ 232*
1,317 ⫾ 181*
1,300 ⫾ 157*
⫺1,593 ⫾ 161
⫺1,100 ⫾ 210†
⫺1,177 ⫾ 159
⫺1,318 ⫾ 194
⫺1,147 ⫾ 74
⫺1,294 ⫾ 133
⫺1,300 ⫾ 144
9.0 ⫾ 1.5
6.6 ⫾ 1.0*
6.2 ⫾ 0.7*
6.5 ⫾ 0.7*
5.5 ⫾ 0.3*
6.2 ⫾ 0.6*
6.4 ⫾ 0.7*
Values are mean ⫾ SE (n ⫽ 5). RR, RR interval; QRSd, QRS duration; LVEDP, end-diastolic left ventricular pressure; LVESP, end- systolic left ventricular
pressure; LVPmax, maximum left ventricular pressure; dP/dtmax, maximum rate of pressure change; dP/dtmin, minimum rate of pressure change; SV, stroke
volume; RVA, right ventricular apex; PCS, posterior near coronary sinus; LAT, lateral; ABASE, anterior base; AMID, anterior mid-ventricle; AAPEX, anterior
apex (i.e., site of intramyocardial markers). *Ventricular pacing vs. Atrial (P ⬍ 0.05, one-way repeated-measures ANOVA with Tukey post hoc test).
†Ventricular pacing vs. Atrial (P ⬍ 0.10, one-way repeated measures ANOVA with Tukey post hoc test). No statistically significant differences were present
among ventricular pacing sites.
Table 2. Average fiber and sheet angle values at three
transmural depths in the anterolateral LV
Wall Depth
Fiber Angle0
Sheet Angle0
Sub-Epi
Mid
Sub-Endo
⫺7.45 ⫾ 3.13
34.8 ⫾ 3.48
73.5 ⫾ 5.50
⫺37.8 ⫾ 1.47
⫺50.5 ⫾ 2.20
⫺59.1 ⫾ 5.94
Values are mean ⫾ SE. Sub-Epi, subepicardium (25% wall depth); Mid,
midwall (50% wall depth); Sub-Endo, subendocardium (75% wall depth).
End-systolic fiber and radial strain magnitudes increase
with prestretch magnitude. Fiber (Fig. 5A) and radial (Fig. 5B)
strain throughout the cardiac cycle are shown for one animal
during epicardial pacing at the LV anterior apex and LV
posterior. Epicardial pacing at the LV anterior apex produced
early-activated (EARLY) tissue at the measurement site,
whereas epicardial pacing at the LV posterior resulted in
late-activated (LATE) tissue at the measurement site. LV
pressure time course and the time of end systole (dotted black
line) are superimposed onto the strain time courses to illustrate
timing differences, relative to global hemodynamic events, in
fiber shortening (negative strain) and radial wall thickening
(positive strain) between EARLY (Fig. 5, A and B; top) and
LATE (Fig. 5, A and B; bottom). During EARLY activation,
local fibers shortened prior to end diastole, reached peak
shortening near aortic valve opening and were stretched
throughout most of the ejection phase, resulting in fiber strain
values near zero at end systole, whereas with LATE activation,
fiber stretch (i.e., positive strain) occurred during early systole,
followed by shortening throughout ejection, and peak shortening occurred near end systole. Additionally, with EARLY
activation the wall thickening occurred prior to aortic valve
opening, whereas with LATE activation the majority of wall
thickening occurred after aortic valve opening and was maximum near end systole, thus contributing to systolic ejection.
The effect of prestretch magnitude on end-systolic fiber shortening and wall thickening at the subendocardium is presented
in Fig. 6. Both strain components were strongly correlated with
the magnitude of fiber prestretch, with significant slopes. Mean
values of end-systolic fiber shortening (Fig. 6A, right) and wall
thickening (Fig. 6B, right) were significantly greater in LATE
compared with EARLY activated tissue at the subendocardium. Regression data for all strain components and at three
transmural depths are provided in Supplemental Material available online with this article.
Preejection magnitude and timing parameters of fiber strain
increase proportionally to local electrical activation time. To
test for differences in fiber length due to variations in local
electrical activation time, fiber strain, referenced to end-diastole during atrial activation, at the time of local depolarization
and aortic valve opening were determined, and results are
shown in Fig. 7. Fiber strain at both the time of local electrical
activation (r ⫽ 0.38) and aortic valve opening (r ⫽ 0.44) were
positively correlated with local electrical activation time, and
both slopes were significantly different from zero. At the
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increased by 133.6 ⫾ 5.8% (P ⬍ 0.001) compared with atrial
activation, and LVPmax, dP/dtmax, dP/dtmin, and SV were reduced, compared with atrial activation, by 12.0 ⫾ 1.7% (P ⬍
0.01), 27.7 ⫾ 7.0% (P ⬍ 0.05), 22.3 ⫾ 3.6% (P ⬍ 0.01), and
20.0 ⫾ 5.1% (P ⬍ 0.05), respectively.
Transmural marker positions, LV wall geometry, and local
fiber-sheet orientations. The centroid of the epicardial surface
markers was located at a distance of 66.1 ⫾ 5.4% of the
apex-base length referenced from the base bead. The deepest
bead of the transmural array spanned 77.4 ⫾ 5.8% of the local
wall thickness. Ex vivo wall thickness near the markers was
11.7 ⫾ 0.4 mm in the perfusion-fixed geometric configuration
at a LV intracavity pressure of 0 mmHg. Values of mean fiber
and sheet angle orientation at the subepicardium, midwall, and
subendocardium are given in Table 2.
Fiber prestretch increases proportionally to the amount of
early activated tissue. In all animals, ventricular activation at
six anatomical sites (Fig. 1) resulted in a variation of local
electrical activation time and fiber prestretch magnitude at the
anterolateral LV. Figure 3 shows epicardial isochronal electrical activation with a bullseye plot during ventricular pacing at
two sites for one representative animal (Fig. 3A). The ventricular pacing sites (red arrows) were LV anterior apex (Fig. 3A,
top) and LV posterior near the coronary sinus (Fig. 3A, bottom), producing substantial differences in local activation time
at the epicardium (0 vs. 95 ms) at the strain measurement site.
In all experiments, the magnitude of peak fiber prestretch at
subepicardium (r ⫽ 0.73, P ⬍ 0.01), midwall (r ⫽ 0.69, P ⬍
0.01), and subendocardium (r ⫽ 0.57, P ⬍ 0.01) increased
with activation time at the corresponding wall depth. Finally,
the magnitude of peak fiber prestretch (Fig. 4) at the subepicardium positively correlated (r ⫽ 0.74) with the amount of
early-activated tissue, as defined as percent total of the mapped
epicardium, with a slope significantly different from zero (P ⬍
0.001).
LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
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subendocardium, the onset of fiber relengthening (r ⫽ 0.67)
and fiber shortening duration (r ⫽ 0.68) were positively correlated with local electrical activation time, with a significant
slope (P ⬍ 0.001), as shown in Fig. 8.
Dog-specific model of prestretch. A computational approach
was used to examine the effects of fiber length and shortening
velocity in regulating the local response to alterations in local
activation time and fiber prestretch. Global LV hemodynamics
(Table 3) and local fiber and radial strain time courses (Fig. 9)
calculated in the baseline dog-specific model matched well
with those from the experiment.
At the subendocardial depth of the anterolateral wall, which
was similar to the experimental strain measurement location,
local electrical activation time for the two pacing sequences
were 28.0 and 81.9 ms, respectively. The timing of the onset of
fiber relengthening and fiber shortening duration were determined for the three model simulations (e.g., BASE, VI, LI, and
LVI) and compared with experimental results (Fig. 8). In the
BASE model both the onset of fiber relengthening (slope ⫽
1.27) and the duration of fiber shortening (slope ⫽ 0.93) were
positively correlated with local electrical activation time. Re-
moving length dependence from the active stress model had a
moderate effect on these relationships, reducing the slopes by
11% and 20%, respectively. Removing velocity dependence
reduced the magnitude of the slopes by 23% and 40%, respectively. Removing both length and velocity dependence on the
active stress showed a reduction in these relationships of 15%
and 37% compared with baseline. Thus removing the length
and velocity dependence of fiber shortening has a marginal
effect on the prestretch mechanics in the failing heart.
DISCUSSION
In the present study, we sought to investigate the mechanisms
for increased fiber prestretch in late-activated tissue, and the role
of fiber length change in determining local function in the dyssynchronous failing canine heart. We found that fiber prestretch at
the subepicardium increased proportionally to the amount of
earlier activated subepicardial tissue. Local end-systolic fiber
shortening and wall thickening were increased in the anterolateral
wall in proportion to the local electrical activation time and
magnitude of fiber prestretch. Increased end-systolic strain mag-
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Fig. 3. Varying local electrical activation time and
magnitude of fiber prestretch at the anterolateral left
ventricle (LV). LV wall mechanics were measured at
the anterolateral LV (solid black circles), and the
ventricular pacing site (red arrow) was varied to
produce a range of local electrical activation times
(Local AT) and fiber prestretch magnitude (Prestretch) at the strain measurement site. A: in one
representative animal (dog 9), electrical activation
times at the epicardium are illustrated using polar
isochronal electrical activation maps obtained during
ventricular pacing at 2 different anatomical sites using
an epicardial 128-electrode sock. Patch color represents linearly interpolated activation times recorded
by sock electrodes; color ranges from blue (0 ms) to
red (120 ms). Subepicardial anterior apical (EARLY,
top) and subepicardial posterior basal (LATE, bottom)
pacing resulted in 2 distinct electrical activation sequences, each producing a unique local subepicardial
electrical activation time (ATEPI) at the strain measurement site. B: at the strain measurement site, prestretch measured in all animals during ventricular
pacing at each site (i.e., 28 total data points) was
correlated with local AT for myofibers at the subepicardium (Sub-Epi Fibers, top), midwall (Mid Fibers,
middle), and subendocardium (Sub-Endo Fibers, bottom). For each transmural correlation, measurements
of fiber prestretch and local electrical activation time
were used for each corresponding wall depth (i.e.,
subepicardium, midwall, or subendocardium). Data
from EARLY (blue circles) and LATE (red triangles)
measured in the representative animal are indicated in
the regression plots. Prestretch, peak myofiber prestretch; Local AT, local electrical activation time;
POS, LV posterior; RV, right ventricle; ANT, LV
anterior; LAT, LV lateral. Sub-Epi, subepicardium
(25% depth); Midwall (50% depth); and Sub-Endo,
sub-endocardium (75% depth). r, correlation coefficient. *Slope different from zero (P ⬍ 0.01).
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LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
nitudes were attributed to altered timing of strain parameters,
which were sensitive to local electrical activation time. From these
experimental observations, we proposed that fiber length via
length-dependent activation was a primary determinant of strain
timing parameters in regions of late activation and prestretch.
Fig. 5. Differences in transmural fiber and radial strain time courses due to early and late electrical activation at the anterolateral left ventricle. Fiber strain (Eff;
A) and radial strain (E33; B) at 3 transmural depths (subepicardium, midwall, and subendocardium) of the anterolateral LV are plotted throughout the cardiac cycle
(in ms) for one representative animal (dog 9). Ventricular epicardial pacing at anterior apical (EARLY, top) and posterior basal (LATE, bottom) left ventricular
sites resulted in marked differences in subendocardial activation time (ATENDO), as well as end-systolic strain values. Time of end systole is denoted by the black
dotted line. LV pressure tracings are superimposed and synchronized with strain time courses. Reference time (0 ms) was the time of the local ventricular stimulus
artifact. Sub-Epi, subepicardium (25% depth); Mid, midwall (50% depth); Sub-Endo, sub-epicardium (75% depth).
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Fig. 4. Fiber prestretch magnitude increases with the amount of earlier
activated tissue at the subepicardium. Subepicardial peak fiber prestretch
(Sub-Epi Prestretch) was correlated with the amount of subepicardial earlieractivated tissue (Sub-Epi Early Tissue), defined as percent total of the epicardial tissue area. Earlier activated tissue was determined from polar epicardial
isochronal activation maps (see METHODS) in all animals during ventricular
pacing at each site (i.e., 28 total data points). Linear regression analysis
revealed a significant positive slope between Sub-Epi Prestretch and Sub-Epi
Early Tissue. Sub-Epi, sub-epicardium (25% depth); r, correlation coefficient.
*Slope different from zero (P ⬍ 0.001).
However, in a dog-specific computational model of the failing
heart, removing either or both fiber length and velocity dependence from active stress development had a small effect on the
timing parameters of fiber strain (e.g., onset of fiber relengthening,
fiber shortening duration), suggesting that the mechanism for
changes in local strains at sites with increased electrical activation
time is unlikely to be length- or velocity-dependent activation in
the failing heart.
Changes in global and local function with electrical dyssynchrony in normal hearts. In the presence of an abnormal
electrical conduction, such as left-bundle branch block or with
ectopic ventricular pacing, the spread of electrical activation is
markedly slowed and less uniform compared with normal sinus
rhythm (28, 37, 42). An altered sequence of electrical activation is associated with lower systolic blood pressures (27, 40)
reduced rates of LV pressure generation and relaxation (43),
and decreased LV stroke volume (9, 31). Additionally, the
temporal and spatial distribution of the magnitude of contraction is altered (4, 29, 38). Badke et al. (4) observed early
shortening (i.e., prior to aortic valve opening) and systolic
lengthening in regions near and remote to the site of ventricular
stimulus. Additional studies have shown that the onset of
mechanical activation (4, 41), and magnitude of ejection shortening (9, 18), increase with the local electrical activation time,
whereas Prinzen et al. (28) found that the interval between
local electrical activation time and onset of shortening was
nonuniform and increased in areas with greater delay in electrical activation time. Increased fiber shortening function at the
LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
subepicardial (9, 29) and mid wall (7) were previously observed in late-activated regions in normal canine hearts with
ectopic ventricular activation.
Timing and magnitude changes in local strains with electrical dyssynchrony in failing hearts. In the present study, we
found that fiber prestretch at the subepicardium increased
Fig. 7. Preejection subendocardial fiber strain increases proportionally with
local electrical activation time. The magnitude of subendocardial fiber strain
(Eff) at the time of local electrical activation (Local Activation) (A) and aortic
valve opening (B) were positively correlated with subendocardial electrical
activation time (AT) at the strain measurement site, suggesting longer subendocardial fiber lengths with increasing electrical activation time in lateactivated tissue compared with early-activated tissue. AT, electrical activation
time; Sub-Endo, sub-endocardium (75% depth); r, correlation coefficient.
*Slope different from zero (P ⬍ 0.05).
Fig. 8. Timing in subendocardial fiber strain parameters increases proportionally with local electrical activation time from experiments and a dog-specific
computational model. Fiber shortening duration (FSD; A) and the onset of fiber
relengthening (OFR; B) positively correlated with local electrical activation
time (AT) at the subendocardium in all experimental data (EXP, open circles,
left). Increased fiber shortening duration and onset of fiber relengthening likely
contribute to differences in end-systolic strains when local AT is altered at the
strain measurement site. A dog-specific computational model was developed
based on data collected in one animal, dog 6. Data from ventricular pacing at
two sites for dog 6 (closed circles) weres compared with EXP and model
simulations during pacing at identical sites (EXP-MODEL, right). In A,
compared with the baseline (BASE, squares) model, removal of velocity
dependence in fiber active stress generation (VI, diamonds) reduced the slope
by 40%; by 20% after removal of length dependence (LI, crosses); and by 37%
after removing both length and velocity dependence (LVI, triangles). In B,
compared with the BASE model, VI model reduced the slope by 23%; by 11%
in the LI model; and by 15% in the LVI model. Sub-Endo, sub-endocardium
(75% depth); FSD, fiber shortening duration; OFR, onset of fiber relengthening; EXP, all experimental data; EXP dog 6, experimental data for dog 6 at two
pacing sites; BASE, baseline active stress model; LI, length-independent active
stress model; VI, velocity-independent active stress model; LVI, length- and
velocity-independent active stress model; r, correlation coefficient. *Slope
different from zero (P ⬍ 0.001).
proportionally to the amount of earlier activated tissue at the
subepicardium, which provided further insights into the determinants of fiber prestretch. By prolonging local electrical
activation time, late-activated fibers may remain passive for a
longer duration of time and could be susceptible to stretching
due to early activated, stress-generating fibers. A previous
modeling study suggested that prestretch could be a result of a
regional imbalance of regional stiffness and the governing
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Fig. 6. End-systolic subendocardial fiber shortening and wall thickening increase
proportionally with fiber prestretch at the anterolateral left ventricle. A: endsystolic fiber shortening (negative fiber strain) at the subendocardium was correlated with the peak magnitude of fiber prestretch (Prestretch). B: subendocardial
wall thickening (positive radial strain) correlated with Prestretch. End-systolic
fiber shortening and wall thickening strain magnitudes at the subendocardium were
significantly increased for late-activated (LATE) compared with early-activated
(EARLY) tissue. Sub-Endo, sub-endocardium (75% depth); Eff, fiber strain; E33,
radial strain. r, correlation coefficient. *Slope different from zero (P ⬍ 0.05).
†P ⬍ 0.05, EARLY vs. LATE (Student’s t-test).
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LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
Table 3. Hemodynamic comparisons between experimental
and dog-specific computational model data
Pacing Site
AAPEX
EXP-Dog 6
MODEL
PCS
EXP-Dog 6
MODEL
LVEDP, mmHg
LVPmax, mmHg
LV dP/dtmax, mmHg/s
15
15
101
103
1,610
1,680
15
15
98
95
1,450
1,700
LVEDP, end-diastolic left ventricular pressure; LVPmax, maximum left
ventricular pressure; LV dP/dtmax; maximum rate of change of left ventricular
pressure; AAPEX, anterior apex; PCS, posterior basal near coronary sinus;
EXP, experiment; MODEL, dog-specific computational model.
Fig. 9. Subendocardial fiber and radial strain time courses from experiment and a dog-specific computational model. Fiber (A) and radial strains (B) measured
at the subendocardium of the anterolateral left ventricle are shown for one animal (EXP dog 6, left) and in a dog-specific computational model (MODEL, right)
of the same animal. Early activation with anterior apical pacing of the left ventricular subepicardium (EARLY-AAPEX, top) and late activation with posterior
basal near coronary sinus pacing (LATE-PCS, bottom) produced marked differences in fiber and radial strain time courses in experiment and a dog-specific
model. Note the qualitative agreement between experiment and baseline model strain values and quantitative agreement regarding onset of fiber shortening and
relengthening. EXP, experiment; AAPEX, anterior apical pacing; PCS, posterior basal near coronary sinus pacing.
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principle of force equilibrium (19), which would require spatial
variation of fiber length and stretching of late-activated fibers.
Our results on the effects of prestretch on local end-systolic
fiber and radial strain provide new insights into the role of
increased fiber prestretch in failing tissue with altered electrical
activation timing. Specifically, at the subendocardium, endsystolic fiber shortening and radial wall thickening strain values increased proportionally with fiber prestretch magnitude
and were significantly greater for late-activated tissue compared with early-activated tissue (Fig. 6). Our choice of using
fiber prestretch as an independent predictor of end-systolic
fiber shortening and wall thickening strains was based on the
inherit contractile nature of the myofilament. At the tissue
level, helical arrangement of myofibers, the transmural gradient in fiber orientation, and transmural differences in cellular
properties collectively result in complex, heterogeneous 3D
deformation. Thus factors that regulate fiber strain function
(e.g., length, shortening velocity) are likely to also determine
other strain values (e.g., radial strain, transverse shear strain).
Our findings support the hypothesis that increased magnitudes
of fiber prestretch result in greater magnitudes of systolic fiber
shortening and wall thickening at the subendocardium (Fig. 6),
as well as other normal and shear strains at various wall depths
(see online Supplemental Material).
We attributed differences in end-systolic strain magnitudes
between early- and late-activated tissue to differences in the timing
of strain parameters. Particularly with regard to fiber shortening, both
the onset of fiber relengthening and fiber shortening duration were
positively correlated with local activation time.
Role of fiber length and shortening velocity on fiber shortening
function. In failing hearts, we compared subendocardial preejection fiber strain at the times of local activation and aortic valve
opening during ventricular pacing at multiple sites using a common geometric reference, specifically atrial end diastole. At both
time points, we found that the magnitude of fiber strain positively
correlated with local activation time, and hence was greater in
regions with larger magnitudes of prestretch. In addition, the onset
of fiber relengthening and duration of fiber shortening were
prolonged with increasing local activation time (Fig. 8), which
could be a result of the increase in fiber length prior to local
activation. Additional studies, in isolated skeletal muscle fibers,
found that the magnitude and duration of force development were
increased with longer fiber length prior to stimulation, compared
with shorter lengths (11). It is generally thought that the increase
in force development is directly due to increased calcium sensitivity with increasing sarcomere length within physiological limits
(16), yet the exact mechanism by which increased sarcomere
length enhances calcium sensitivity is unclear. Additionally, active shortening decreases the amount of strong bound crossbridges (13, 32) and reduces the ability to generate force in a
process of shortening deactivation (22, 23). In late-activated
regions, the onset of fiber shortening was delayed and occurred
LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
dP/dtmax). We attributed this to interanimal variability in hemodynamic response to ventricular pacing at the various anatomical sites and possibly to the differences in inotropic support. Thus it is possible that grouping data based on common
anatomical sites may have masked intra-animal differences that
were present between pacing sites. Finally, there is much
clinical interest in the optimal placement of the left ventricular
lead during biventricular pacing, also referred to as cardiac
resynchronization therapy (CRT). The functional implications
of prestretch on CRT and lead placement are beyond the scope
of this study and warrant future studies, specifically utilizing
tools that can adequately give global assessments of local
function (e.g., MRI tracking) to correlate sites for optimal
pacing to baseline mechanical function (e.g., site of greatest
prestretch).
Modeling limitations. The Arts active stress model used in the
dog-specific model does not include the mechanics of shortening
deactivation. Removal of velocity and length dependence did
change the relation between local activation time and fiber shortening duration, but did not completely eliminate it. Therefore,
shortening deactivation may be one mechanism responsible for
the remaining effects on the latter relation, and was not implemented in the current model. Mitral regurgitation may have
occurred in the dilated failing dog hearts, although we do not have
any direct measurement to support this. Such regurgitation could
affect the ventricular pressure, but was not part of the model used
here. Another possible effect that was not taken into account is a
difference in regional electromechanical delay due to the rate of
change of ventricular pressure (33).
Conclusions. In the present study with dyssynchronous failing
hearts, local end-systolic fiber shortening and wall thickening
strains were found to increase in proportion to the magnitude of
fiber prestretch, primarily at the subendocardium. Additionally, at
the subepicardium, fiber prestretch magnitude increased with
greater amounts of early-activated tissue, suggesting that prestretch is determined in part by early shortening near the pacing
site. Overall, these findings suggest that even with depressed
length-dependent activation, the effects of prestretch on local fiber
function in the dyssynchronous failing canine heart are similar to
those previously found in the normal heart.
ACKNOWLEDGMENTS
We are grateful to Drs. James Covell and Bruce Ito for their support with
the surgical preparation and fruitful discussions. We also thank Dr. Morton
Printz for supplying us with the implantable left atrial pressure transducers and
telemetric monitoring system. We are particularly indebted to Dr. Irina Ellrott,
DVM, without whose surgical and veterinary skills these difficult chronic heart
failure preparations would not have been possible.
GRANTS
This study was supported by a University of California Discovery Grant
ITL06-10159 (A. D. McCulloch) that was cosponsored by Medtronic. Additional support was provided National Institutes of Health (NIH) Grants HL46345 (A. D. McCulloch), RR-08605 (A. D. McCulloch), HL-096544 (A. D.
McCulloch), and HL-32583 (J. H. Omens), and by National Science Foundation Graduate Fellowship DGE-1144086 (K. P. Vincent)
DISCLOSURES
L. J. Mulligan is an employee of Medtronic. Primary funding for this study
was provided by a University of California Discovery Grant ITL06-10159
(A.D. McCulloch) that was cosponsored by Medtronic. Medtronic provided
implantable electrodes, programmable pacemakers, surgical and interrogatory
accessories, and technical support.
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against greater systolic pressure (Fig. 5). Thus differences in the
onset of fiber relengthening and shortening duration could also be
explained by processes involving shortening deactivation, which
would be exaggerated in early-activated regions that presumably
shorten at greater velocities due to low intracavity pressure prior
to global ventricular ejection.
Insights from a computational model on the mechanisms
regulating the effect of prestretch on local strains differences
between early and late activated tissue. Length dependence of
force development (36), rate of fiber shortening (8, 12), afterload (9), cross-bridge cycling kinetics (5), and mechanoelectric
feedback (20) are likely to contribute to the differences in
magnitude and timing of local stain values in the failing heart.
To probe potential mechanisms for changes in strain timing
parameters, we developed a dog-specific computational model
based upon in vivo hemodynamic data, high-resolution biventricular geometry and fiber architecture, and similar anatomical
pacing and strain measurement sites. In our baseline model
simulations, in which active stress development depended on
fiber length and shortening velocity, differences in strain timing parameters (e.g., shortening duration, and onset of relengthening) between early and late activation were similar to
experimental results (Fig. 8). Removing length and/or velocity
dependence had a marginal effect on this difference. While
factors other than hemodynamics, activation time, fiber length,
and shortening velocity were not included in the active stress
model, the results suggest that other mechanisms are likely
involved in the effects of prestretch on local systolic function.
Experimental limitations. In the present study we measured
local function in the anterolateral left ventricles of open-chest,
anesthetized failing canine hearts at steady-state during ventricular ectopic pacing. Thus our findings characterize the acute
response to alterations in local activation time and prestretch in
the chronic failing canine heart and may not represent the
mechanical response in closed-chest, conscious animals. During the terminal pacing study, inotropic support was provided
intravenously to maintain a sustainable hemodynamic state. As
a result, myocardial contractility and the dynamics of activation and relaxation may have been altered. We suspect that
inotropic support was likely to have a small effect on the
regional mechanical function, but we did not quantitatively
verify these differences. Three-dimensional strains were measured in vivo with a defined cardiac coordinate system; postmortem dissections in the fixed excised heart were used to
define a local material coordinate system. Histological data on
the mean fiber angle at the strain measurement site was used to
define a strain coordinate system with one of the axes aligned
to the long axis of the fiber. The primary assumption in this
methodology is that fibers lay in plane parallel to the epicardial
tangent plane thus allowing for a simple in-plane rotation of the
cardiac coordinates. Thus out-of-plane contributions to fiber
strain would be unaccounted for in the current method. Additionally, the possibility for local distortion in the region of
strain measurement due to fixation at low LV cavity pressures
could be a potential source of error; however, to minimize this
error we corrected for deformations that occurred due to
fixation and cavity pressure change by calculating a fiber angle
change resulting from a deformation from the fixed lowpressure state to the in vivo end-diastolic state. We did not
find a statistical effect of left ventricular pacing site on global
hemodynamic loading (e.g., EDP) and function (LVPmax,
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LOCAL FIBER FUNCTION IN DYSSYNCHRONOUS FAILING HEARTS
AUTHOR CONTRIBUTIONS
Author contributions: E.J.H., R.C.K., L.J.M., A.D.M., and J.H.O. conception and design of research; E.J.H., R.C.K., and J.H.O. performed experiments;
E.J.H., R.C.K., K.P.V., A.K., C.T.V., A.D.M., and J.H.O. analyzed data;
E.J.H., R.C.K., K.P.V., A.K., C.T.V., A.D.M., and J.H.O. interpreted results of
experiments; E.J.H., K.P.V., A.K., and C.T.V. prepared figures; E.J.H. drafted
manuscript; E.J.H., R.C.K., K.P.V., A.D.M., and J.H.O. edited and revised
manuscript; E.J.H., R.C.K., K.P.V., A.K., C.T.V., L.J.M., A.D.M., and J.H.O.
approved final version of manuscript.
20.
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