Download Anisotropic Reinforcement of Acute Anteroapical Infarcts Improves

Anisotropic Reinforcement of Acute Anteroapical Infarcts
Improves Pump Function
Gregory M. Fomovsky, PhD; Samantha A. Clark, BS; Katherine M. Parker, MS;
Gorav Ailawadi, MD; Jeffrey W. Holmes, MD, PhD
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Background—We hypothesize that a therapy that improves left ventricular (LV) pump function early after infarction should
decrease the need for compensation through sympathetic activation and dilation, thereby reducing the risk of developing
heart failure. The mechanical properties of healing myocardial infarcts are an important determinant of LV function,
yet improving function by altering infarct properties has proven unexpectedly difficult. Using a computational model,
we recently predicted that stiffening a large anterior infarct anisotropically (in only one direction) would improve LV
function, whereas isotropic stiffening, the focus of previous studies and therapies, would not. The goal of this study was
to test the novel strategy of anisotropic infarct reinforcement.
Methods and Results—We tested the effects of anisotropic infarct reinforcement in 10 open-chest dogs with large
anteroapical infarcts that depressed LV pump function. We measured regional mechanics, LV volumes, and cardiac
output at a range of preloads at baseline, 45 minutes after coronary ligation (ischemia), and 30 minutes later, after
surgical reinforcement in the longitudinal direction (anisotropic). Ischemia shifted the end-systolic pressure–volume
relationship and cardiac output curves rightward, decreasing cardiac output at matched end-diastolic pressure by 44%.
Anisotropic reinforcement significantly improved systolic function without impairing diastolic function, recovering half
the deficit in overall LV function.
Conclusions—We conclude that anisotropic reinforcement is a promising new approach to improving LV function after a
large myocardial infarction. (Circ Heart Fail. 2012;5:515-522.)
Key Words: cardiac output ◼ mechanics ◼ myocardial infarction ◼ surgery
E
ach year, over one million Americans experience a myocardial infarction (MI).1 Despite current therapies, the
risk of developing heart failure after MI remains substantial,
particularly for older patients and those with reduced left
ventricular (LV) function.1,2 After infarction, the mechanical
properties of healing myocardial infarcts are a critical determinant of both depression of pump function and LV remodeling,3 suggesting that it might be possible to improve pump
function and/or reduce adverse postinfarction remodeling by
manipulating infarct mechanical properties.
Depressed pump function and LV dilation both contribute
to the development of heart failure after infarction. Therefore,
improving pump function and limiting LV dilation are both
important therapeutic goals. These 2 effects are easily confused in studies that rely on ejection fraction as the primary
indicator of function, because reducing LV volumes increases
ejection fraction even if stroke volume does not change. By
contrast, studies that report cardiac output curves over a range
of filling pressures can separate effects on dilation and pump
function. Polymer injection, surgical reinforcement, and computational modeling studies that report cardiac output curves
consistently show that these approaches reduce or limit LV
dilation and subsequent functional deterioration but do not
improve LV pump function acutely.7,15,20,21 We therefore sought
to develop a complementary therapeutic approach that could
improve LV pump function early after a large MI.
Normal myocardium deforms in a complex 3-dimensional
pattern with each heartbeat,22–24 and healing myocardial
infarcts can be highly anisotropic (having different mechan­
ical properties in different directions).25,26 By contrast, current
strategies for therapeutically modifying infarct mechanical
Clinical Perspective on p 522
In fact, several novel postinfarction therapies that work
at least in part by modifying infarct mechanics are now in
development. Injecting polymers into the infarct has been
reported to improve heart function and/or reduce remodeling,4–7 as have altering metalloproteinase activity pharmacologically8–12 or through electric stimulation,13 application of
surgical devices and meshes originally designed to arrest
dilation in patients with advanced heart failure,14–16 and periinfarct pacing.17–19
Received September 23, 2011; accepted May 15, 2012.
From the Departments of Biomedical Engineering (G.M.F., S.A.C., K.M.P., G.A., J.W.H.), Medicine (J.W.H.), and Surgery (G.A.) and the Robert M.
Berne Cardiovascular Research Center (J.W.H.), University of Virginia, Charlottesville, VA.
Correspondence to Jeffrey W. Holmes, MD, PhD, Associate Professor of Biomedical Engineering and Medicine, Box 800759, Health System, University
of Virginia, Charlottesville, VA 22908. E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
515
DOI: 10.1161/CIRCHEARTFAILURE.111.965731
516 Circ Heart Fail July 2012
properties provide isotropic reinforcement. We recently
reported that selectively increasing infarct stiffness in the
longitudinal direction improved predicted pump function
in a computational model of a canine heart with a large
anteroapical infarct, whereas isotropic or circumferential
reinforcement did not.27 In the present study, we tested this
prediction experimentally in 10 dogs with large, acute anteroapical infarcts and significant depression of pump function
by surgically reinforcing the infarct region in the longitudinal
direction.
Methods
Surgical Preparation and Instrumentation
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This study was approved by the University of Virginia Animal Care
and Use Committee. Twenty-two adult mongrel dogs of both sexes
(Covance Research Products, Denver, PA; body weight 23.3±3.6 kg)
were anesthetized with sodium pentobarbital (30 mg/kg intravenous
induction, 5 mg/kg-hr maintenance), intubated, and ventilated with
room air. A heating pad was used to maintain constant body temperature. A left thoracotomy was performed at the fifth intercostal space,
the pericardium was opened, and the heart suspended in a pericardial
cradle. A snare made of cloth umbilical tape was placed around the
inferior vena cava (IVC) to facilitate temporary IVC occlusion. The
left anterior descending artery (LAD) was isolated and ligation suture
was placed distal to the first diagonal.
A Millar pressure catheter (Mikro-Tip SPC-454D; Millar
Instruments, Houston, TX) was inserted through the left carotid artery
to measure left ventricular pressure. A catheter in the femoral artery
was connected to a fluid-filled Gould manometer to monitor arterial
pressure. An ultrasonic flow probe (A20; Transonic Systems, Ithaca,
NY) was placed around the ascending aorta to measure left ventricular stroke volume (SV). Ten sonomicrometer crystals (2T-36S-40-RS;
Sonometrics, London, Ontario, Canada) were inserted into the LV
midwall using a metal introducer. Six crystals were used to measure
changes in the 3 axes of the LV (Figure 1A): anteroposterior, septal–
lateral, and base-apex (BA). Four additional crystals were placed in
the anterior LV wall, in the region supplied by the LAD, to measure
regional strains.
Experimental Protocol
After instrumentation, 2 mg/kg propranolol and 0.2 mg/kg atropine
were administered to minimize reflex changes in heart rate and intrinsic myocardial contractility.28 Blockade was confirmed by test
injection of 2.5 μg/kg dobutamine. Baseline data were then recorded
while preload was varied by temporary IVC occlusion (baseline).
The LAD was ligated between the first and second diagonal
branches; arteries providing collateral flow to the lower two thirds
of the anterior wall were also ligated as needed to produce a large,
dyskinetic ischemic region. Lidocaine (10 mg intravenously) was
administered in 11 animals to control arrhythmias and defibrillation
was required in 7. Hemodynamic and sonomicrometry data were
recorded every 5 minutes after LAD occlusion. Forty-five minutes
after LAD ligation, acute ischemia data were recorded during IVC
occlusion (ischemia).
Immediately after the ischemia recording, the ischemic region
was anisotropically reinforced by sewing a modified Dacron patch
(Hemashield Knitted Double Velour Fabric; Maquet Cardiovascular
LLC, Wayne, NJ) onto the epicardial surface of the heart over the
ischemic area (Figure 1). The patches, typically used for LV aneurysm resection and repair,29 were modified by creating longitudinally oriented slits that allowed virtually unrestricted circumferential
­deformation in ex vivo mechanical tests and were sewn to the epicardial surface under as much longitudinal tension as the surgeon
felt could be applied without risking tearing of the sutures from the
myocardium; this resulted in a remarkably consistent 11.4%±2.9%
reduction in longitudinal segment lengths in the center of the infarct.
After reinforcement, data were again acquired during IVC occlusion
(anisotropic, acquired 30.7±7.3 minutes after ischemia). At the end
Figure 1. A, Diagram of sonomicrometer and patch placement;
see text for details. B, Photograph of a modified Dacron patched
sewed to the epicardial surface of the left ventricle. Black line on
patch is aligned with the long axis of the LV; LAD occluder is visible near left edge of photograph. LV indicates left ventricle; LAD,
left anterior descending artery.
of the experiment, animals were euthanized with an overdose of pentobarbital and hearts were excised for confirmation and imaging of
sonomicrometer placement.
Data Analysis
Hemodynamic data were processed using the Sonometrics software,
SonoSoft, and custom Matlab software. To assess the state of LV
function at each experimental condition, measurements were averaged over 3 to 5 cardiac cycles at constant preload. To analyze the
response of the LV to preload changes, cycles covering the full range
of pressure variation during IVC occlusion were analyzed and the
resulting parameters fitted to obtain end-diastolic (EDPVR) and endsystolic (ESPVR) pressure–volume relationships as well as cardiac
output curves.
For each cardiac cycle, end-diastole was defined as the point immediately before the sharp increase in LV pressure and end-systole
was identified as the point of maximal elastance.30 LV volumes were
computed from anteroposterior, septal–lateral, and BA axis lengths,
assuming a truncated ellipsoidal geometry.30 Because sonomicrometers were located in the LV midwall, these volumes included both
cavity volume and approximately half the LV wall volume, which
is essentially constant over the cardiac cycle. Stroke volume was
computed by integrating the ascending aorta flow signal as described
and validated by Steingart, neglecting retrograde (coronary) flow.31
At baseline, SVs computed by subtracting sonomicrometer-derived
EDV and ESV values (SVsono) agreed with SV computed by integrating the ascending aorta flow signal (SVflow). During ischemia,
SVsono was less accurate due to systolic bulging of the ischemic
region. Therefore, we report here only SVflow and compute ESV as
EDV−SVflow.
Fomovsky et al Anisotropic Infarcts Reinforcement 517
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ESPVR, EDPVR, and cardiac output curves for each condition
were fitted and used to interpolate data for comparison at matched
pressures. The linear ESPVR was obtained by fitting a straight
line to ESP versus ESV data (mean±SD R2 for fits to data from
individual animals=0.78±0.23), the exponential EDPVR and cardiac output (CO) curves by fitting a straight line to ln(EDP) versus EDV or CO data (R2 0.90±0.09 for EDPVR, 0.88±0.12 for CO
curve). Interpolated volume and cardiac output values at matched
pressures were also averaged to construct mean EDPVR, ESPVR,
and CO curves. To assess changes in LV shape, we fitted ln(EDP)
versus end-diastole segment length curves and compared interpolated BA, anteroposterior, and septal–lateral dimensions at matched
pressures.
Regional strains were computed from ≥3 segment lengths measured by the 4 sonomicrometers in the center of the ischemic region. Postmortem photographs were used to construct unit vectors
describing the orientation of each crystal pair relative to the short
axis of the LV. Real-time segment lengths were used to compute
2-dimensional systolic regional strains reflecting circumferential
shortening/stretching, longitudinal shortening/stretching, and
shearing in the anterior midwall from end diastole to end systole.32
Segment lengths interpolated at matched pressures from linear
fits of ln(EDP) versus end-diastole segment length data were
used to compute remodeling strains reflecting changes in enddiastolic configuration across different states (baseline, ischemia,
anisotropic).
Statistical Analysis
The goal of this study was to test the model prediction that longitudinal reinforcement can mitigate acute depression of pump function
after a large anteroapical infarction. Because this hypothesis can only
be tested if pump function is depressed, we used depression of pump
function as reflected by a rightward shift in the ischemia CO curve as
an inclusion criterion for this study. Dogs with no shift in CO curve
during ischemia were excluded from further analysis. In the remaining animals, parameters with independent numeric values at each
state (baseline, ischemia, anisotropic) were analyzed by one-way
repeated-measures analysis of variance with Newman-Keuls post
hoc comparisons when the analysis of variance showed significant
variation among the groups. For parameters that were zero at baseline by definition such as remodeling strains and changes in volumes,
we tested the effect of ischemia using a one-sample t test against a
hypothetical mean of zero and the effect of anisotropic reinforcement by paired 2-tailed t test of anisotropic versus ischemia data.
A probability value <0.05 was used as the threshold for statistical
significance for all tests.
Results
A total of 22 dogs underwent LAD ligation for this study. Of
these, 10 animals showed a shift in the ventricular function
curve (CO versus end-diastolic pressure) 45 minutes after
LAD ligation and were included in the study. Of the remaining 12 animals, 3 died of ventricular fibrillation after LAD
ligation, 8 showed no shift in the ventricular function curve
after LAD ligation, and one was excluded due to failure of the
data acquisition system during the study.
Hemodynamics
Heart rate and maximum dP/dt did not vary during the study,
demonstrating effective blockade of sympathetic and parasympathetic reflex changes (Table). Because the animals
were unable to compensate for reduced pump function by
increasing heart rate or intrinsic contractility, they relied on
the Frank-Starling mechanism, maintaining SV and CO by
significantly increasing EDP and EDV.
Table. Hemodynamic Parameters
Parameter
Baseline
Ischemia
Anisotropic
EDP, mm Hg
11.3±4.3
17.3±6.1†
15.9±7.5
EDV,* mL
78.2±15.5
89.0±18.0†
82.2±16.2‡
ESP, mm Hg
96.1±14.8
94.7±14.3
92.2±9.7
ESV,* mL
62.7±13.5
75.0±17.7†
66.9±15.4‡
SV, mL
15.5±3.8
14.0±3.9
15.4±3.5
HR, beats/min
108±10
109±15
111±15
CO, L/min
1.69±0.51
1.54±0.54
1.70±0.44
Maximum dP/dt, mm|Hg/s
1227±337
1220±431
1342±249
Hemodynamic data from 10 dogs that showed a shift in cardiac output
curve 45 min after coronary ligation. Dogs were pretreated with propranolol
and atropine to prevent reflex changes in heart rate and intrinsic myocardial
contractility; by design, end-systolic pressure (ESP), heart rate (HR), and
maximum dP/dt did not vary significantly during the experiment. During
ischemia, animals compensated for reduced systolic function through the
Frank-Starling mechanism, increasing end-diastolic pressure (EDP) and volume
(EDV) to maintain stroke volume (SV) and cardiac output (CO) despite increased
end-systolic volume (ESV). Anisotropic surgical reinforcement significantly
reduced EDV and ESV.
*Midwall volumes include cavity volume and approximately half the left
ventricular wall volume.
†P<0.001 versus baseline.
‡P<0.001 versus ischemia.
Mechanics of Acute Ischemia and
Anisotropic Reinforcement
Figure 2 illustrates the impact of ischemia and anisotropic reinforcement on regional and global function in a single animal. At
baseline, pressure-segment length loops indicated active contraction in the anterior wall (Figure 2A–B). Hemodynamic data
acquired during IVC occlusion produced the expected exponential EDPVR, linear end-ESPVR, and relatively steep working portion of the CO curve (Figure 2C–D). Forty-five minutes
after LAD ligation, pressure-segment loops indicated passive
lengthening rather than active contraction, the ESPVR was
shifted rightward, and the ventricular function curve was shifted
down and to the right with a >50% reduction in cardiac output
at matched EDP. Anisotropic surgical reinforcement selectively
reduced longitudinal segment lengths (Figure 2A), shifted the
ESPVR back to the left without affecting the EDPVR, and
reversed approximately half the shift in the CO curve.
Effect of Anisotropic Reinforcement on Regional
Mechanics and LV Shape
Remodeling strains in the center of the ischemic region
showed increased circumferential and longitudinal dimensions at a matched EDP of 12 mm Hg during ischemia
compared with baseline (Figure 3A). Anisotropic reinforcement reversed longitudinal remodeling (P<0.001 versus
ischemia) and modestly reduced circumferential remodeling
(P<0.01). Systolic strains were negative at baseline, indicating circumferential and longitudinal shortening during
contraction (Figure 3B). Acute ischemia abolished shortening in both directions (P<0.001 versus baseline), and
anisotropic reinforcement slightly increased systolic circumferential stretching without affecting longitudinal strain.
Globally, ischemia increased the BA dimension significantly
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Figure 2. Effect of ischemia and anisotropic reinforcement in a single animal.
A, B, Infarct region pressure-segment
length data. At baseline (black), loops
indicated active contraction in both the
longitudinal (A) and circumferential (B)
directions. During ischemia, both segments demonstrated passive stretch and
recoil along a single curve. Anisotropic
reinforcement reduced longitudinal segment length throughout the cardiac cycle.
C, Ischemia shifted the end-systolic pressure-volume relationship (ESPVR, closed
symbols) rightward and anisotropic reinforcement returned ESPVR toward baseline with little effect on the end-diastolic
relationship (EDPVR, open symbols). Note
that volumes are midwall volumes, including both cavity volume and approximately
half the LV wall volume. D, Cardiac output curves shifted down and to the right
with ischemia and returned toward baseline with anisotropic reinforcement. LV
indicates left ventricular.
(Figure 3C) but did not induce significant changes in either
short-axis dimension, whereas anisotropic reinforcement
restored BA length to baseline and increased the septal–
lateral dimension.
Effect of Anisotropic Reinforcement on Systolic
and Diastolic Function
Mean EDPVR and ESPVR curves showed clearly that
ischemia shifted the ESPVR rightward and anisotropic
reinforcement partially reversed this shift with little effect on
the EDPVR (Figure 4A). We quantified shifts in pressure–
volume behavior using volumes interpolated from individual
ESPVR and EDPVR curves at identical pressures for all
animals. As expected from the average curves, end-systolic
volume at a pressure of 85 mm Hg (ESV85) increased significantly with ischemia (Figure 4B), whereas end-diastolic
volume at a pressure of 12 mm Hg (EDV12) did not change.
Figure 3. Effect of ischemia and anisotropic reinforcement on regional strains
and LV dimensions. A, Remodeling
strains indicating changes in enddiastolic dimensions at a matched EDP of
12 mm Hg are zero at baseline by definition. Ischemia increased both circumferential and longitudinal dimensions
relative to baseline, whereas anisotropic
reinforcement dramatically reduced longitudinal remodeling. B, Systolic strains
indicating deformation from end diastole
to end-systole are negative at baseline,
indicating systolic shortening, and positive during ischemia, indicating systolic
stretching. C, Ischemia increased average
base-apex (BA) dimensions at a matched
end-diastolic pressure of 12 mm|Hg without significantly affecting anteroposterior
(AP) or septal–lateral (SL) dimensions.
Anisotropic reinforcement restored
BA to baseline and significantly increased
SL. *P<0.05 for comparison indicated.
LV indicates left ventricular; EDP,
end-diastolic pressure.
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Figure 4. Effect of ischemia and anisotropic reinforcement on
average pressure–volume curves. A, Ischemia shifted the endsystolic pressure–volume relationship (ESPVR, closed symbols)
rightward and anisotropic reinforcement returned ESPVR
toward baseline with little effect on the end-diastolic relationship
(EDPVR, open symbols). B, Comparing volumes interpolated at
matched pressures (dashed lines in A) showed no change in enddiastolic volume at 12 mm|Hg (EDV12) but a significant increase in
end-systolic volume at 85 mm|Hg (EDV85) with ischemia and significant reduction of EDV85 with anisotropic reinforcement. Note
that volumes are midwall volumes, including both cavity volume
and approximately half the LV wall volume. *P<0.05 for comparison indicated. LV indicates left ventricular.
Anisotropic reinforcement recovered more than half of the
change in ESV85 (P<0.01 versus ischemia) without affecting
EDV12.
Effect of Anisotropic Reinforcement on
Pump Function
A shift in CO curve during ischemia was an inclusion criterion for this study. Comparing the mean baseline and ischemia
curves, average CO at a matched EDP of 12 mm Hg dropped
44%, and a 50% increase in EDP to 18 mm Hg would have
been required to return to baseline CO (Figure 5A). Using
the baseline EDP in each individual animal and interpolating
to find CO at matched pressures in the other states confirmed a significant reduction in CO with ischemia (P<0.01;
Figure 5. Effect of ischemia and anisotropic reinforcement on
average cardiac output curves. A, Cardiac output curves shifted
down and to the right with ischemia and returned toward baseline with anisotropic reinforcement. B, Comparing cardiac output
interpolated at matched end-diastolic pressures (baseline EDP)
in each animal showed a significant drop in cardiac output with
ischemia and recovery of 50% of the deficit with anisotropic
reinforcement. *P<0.05 for comparison indicated.
Figure 5B). Anisotropic reinforcement recovered more than
half the deficit in CO (P<0.05).
Discussion
Acute myocardial infarcts stretch and bulge during systole,
wasting contractile energy expended by remaining noninfarcted myocardium and reducing overall pump function. The
changes are reflected in a rightward shift in both the ESPVR
and CO curve (Figures 4 and 5); for any level of preload,
the heart is able to generate less pressure and eject less SV.
Intuition suggests that stiffening these acute infarcts should
reduce systolic stretching of the infarct and improve function,
yet computational modeling and experimental studies have
consistently shown that although a stiffer infarct improves
systolic function, it also impairs diastolic function, shifting
not only the ESPVR, but also the EDPVR to the left. The systolic and diastolic effects offset, producing no net improvement in LV function.15,20,21,33
Until recently, such studies considered only isotropic
stiffening (increasing the stiffness equally in all directions).
However, the complex 3-dimensional nature of deformation in
the heart wall22–24 and the fact that healing myocardial infarcts
can be highly anisotropic in some animal models25,26 led us
to consider whether anisotropic stiffening or reinforcement
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might be a better strategy. We used a computational model to
ask what infarct mechanical properties would provide the best
pump function after a large anterior infarction and found that
the combination of high stiffness in the longitudinal direction
and low stiffness in the circumferential direction provided the
best predicted function.27 Infarct anisotropy appeared to circumvent the tradeoff between systolic and diastolic function,
improving systolic function with little impact on diastolic
function. In the present study, we tested this model prediction by surgically reinforcing acute anteroapical infarcts in
dogs with postinfarction depression of LV pump function.
We found that anisotropic reinforcement in these animals did
in fact improve systolic function with little effect on filling,
recovering half of the deficit in the CO curve associated with
acute ischemia. We conclude that anisotropic reinforcement
is a novel and promising approach to improving LV function
after a large MI.
Effects of Anisotropic Reinforcement
Globally, anisotropic reinforcement improved systolic function without impairing diastolic filling. Circumferential
systolic stretching in the infarct actually increased after
reinforcement, suggesting that simply reducing systolic
dyskinesis is not the primary mechanism for improved systolic function. Rather, our prior modeling study and current data suggest that anisotropic reinforcement reshapes
the heart at ED. Comparing remodeling strains and global
dimensions at matched EDP (Figures 3A and 3C), we found
that ischemia not only induced acute circumferential and
longitudinal expansion of the infarct, but also increased the
BA dimension of the LV significantly. Anisotropic reinforcement reversed longitudinal expansion in the infarct and
returned BA to baseline. Because reinforcement restricted
longitudinal expansion during diastole but did not reduce
diastolic volumes, we would expect increased stretching
along at least one other axis, and we in fact saw a significant increase in the end-diastolic septal–lateral dimension
after patch application. Therefore, anisotropic reinforcement
may increase preload in circumferentially oriented remote
myocardium. Additional studies are clearly required to better
understand the impact of anisotropic reinforcement on border
and remote myocardium as well as transmural variations
in regional strains after reinforcement (this study measured
­midwall strains).
Therapeutic Options After MI
After a large MI, sympathetic activation increases myocardial contractility and heart rate, and elevated filling pressures
increase diastolic volume and sarcomeric prestretch, enhancing contraction through the Frank-Starling mechanism.
Although sympathetic activation and LV dilation help preserve
CO acutely, they are also the initial steps in the pathogenesis
of heart failure. Standard postinfarction therapy therefore
includes β-blockers to counteract detrimental effects of
chronic sympathetic activation and angiotension-converting
enzyme inhibitors to slow LV remodeling.34 However, standard therapy tends to delay rather than prevent the development of failure, particularly in patients with large infarcts,
and the prognosis for patients with heart failure is bleak.35
Several groups have therefore explored more aggressive
approaches to preventing LV dilation, applying therapies
originally developed for heart failure immediately after
infarction to prevent LV dilation and functional deterioration
rather than waiting to address them until they occur. Gorman
and colleagues36 showed that early application of cardiac
support devices limits dilation and functional deterioration.
Several groups reported similar results with early postinfarction injection of polymers.4–7 Shuros et al19 adapted
biventricular pacing, originally developed for heart failure, to a strategy termed “peri-infarct pacing” for use early
after MI. By pre-exciting the border zone to reduce regional
stroke work, they were able to attenuate postinfarction LV
remodeling. Smalling and colleagues37,38 have even explored
the potential of LV unloading with LV assist devices and
aortic balloon pumps during initial reperfusion to decrease
infarct size.
These efforts all seek to limit LV dilation and remodeling earlier in the course of postinfarction healing but do
not provide immediate improvements in LV pump function. We sought to develop a complementary strategy for
improving LV function early after infarction. We hypothesize that a therapy that improves LV pump function early
after infarction should decrease the need for compensation through sympathetic activation and dilation, thereby
reducing the risk of developing heart failure. The present
study is exciting as a proof-of-concept that it is possible
to improve LV pump function immediately after infarction
by appropriately manipulating infarct mechanical properties. Chronic studies are required to determine whether this
acute improvement in pump function will in fact reduce
long-term dilation and development of heart failure. Our
approach shares the goal of improving LV pump function
early after infarction with regenerative approaches such as
stem cell injection that aim to restore functioning muscle
to the infarct region. However, much of the remodeling that
predisposes to heart failure occurs in the first few days,
whereas most regenerative approaches will require weeks
to fully implement. We therefore propose that mechanical
reinforcement early after infarction has significant potential not only as a standalone therapy, but also as an adjunct
to regenerative approaches.
Limitations
The goal of this study was to test the hypothesis that longitudinal reinforcement can improve depressed pump function
acutely in dogs with large anteroapical infarcts. Because sympathetic activation can temporarily compensate for depressed
pump function early after MI, we used pharmacological
blockade to prevent changes in heart rate and intrinsic myocardial contractility.28 This approach allowed us to recognize
and quantify changes in pump function through shifts in the
cardiac output curve; it also facilitated comparisons with
computational models, which typically hold intrinsic myocardial contractility and heart rate constant. However, additional studies are clearly required to test our hypothesis that
anisotropic reinforcement will alter postinfarction sympathetic activation and remodeling when neurohumoral reflexes
are intact.
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Computational and experimental studies have consistently
found that isotropic infarct reinforcement or stiffening does
not improve LV function acutely,7,15,20,21 whereas our data
show that anisotropic reinforcement does improve LV function acutely in this animal model. We did not compare isotropic against anisotropic reinforcement in this study; additional
studies would be needed to test definitively whether anisotropic reinforcement improves acute LV function more than
isotropic reinforcement. In addition, for this proof-of-concept
study, we reinforced the infarct by sewing a modified Dacron
patch to the epicardial surface. Clinically, sewing a modified
or specially manufactured patch to the epicardial surface could
be feasible in the subset of patients who undergo surgical
revascularization early after infarction, but developing a minimally invasive approach to anisotropic reinforcement would
extend its potential use to a much larger patient population.
Approximately one third of the animals entering this study
were excluded because there was no evidence of altered pump
function after infarction. Some of this variability among animals was likely due to variations in infarct size. Ligating the
same artery in the same place can produce a wide range of
infarct sizes in different dogs due to an extensive and variable network of coronary collaterals. Although we ligated
collaterals where apparent, it is likely that infarct size varied substantially among animals and that animals with small
infarcts showed less depression of pump function. In addition,
although changes in other hemodynamic parameters with
ischemia were similar between the included and excluded
groups, dP/dt increased significantly only in the excluded
group, suggesting that pharmacological blockade might have
been incomplete in some of these animals.
Conclusions
In summary, we tested the model prediction that longitudinal reinforcement of acute canine anteroapical infarcts can
acutely improve depressed LV pump function. Anisotropic
reinforcement improved systolic function without impairing
filling, restoring half the deficit in the CO curve associated
with acute ischemia. We conclude that anisotropic reinforcement is a novel and promising approach to improving LV
function after a large MI. The next step in the development of
this potential therapy is to conduct chronic animal studies to
evaluate the impact of anisotropic reinforcement on LV function, remodeling, and the development of heart failure.
Acknowledgments
We acknowledge the surgical assistance of N. Craig Goodman.
Sources of Funding
Supported by the University of Virginia Coulter Translational
Research Program (G.A., J.W.H.) and National Institutes of Health/
National Heart, Lung and Blood Institute R01 HL-075639 (J.W.H.).
Disclosures
None.
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CLINICAL PERSPECTIVE
After myocardial infarction, both depressed pump function and gradual dilation and remodeling of the left ventricle contribute to the development of heart failure. Although it seems logical that mechanically reinforcing the healing infarct should
improve pump function, multiple studies have found that mechanical therapies such as surgical reinforcement and polymer
injection can prevent dilation but do not directly improve pump function. Typically, stiffening the infarct improves systolic
function but impairs filling, producing no net benefit on cardiac output. Importantly, these prior studies used methods that
stiffen or reinforce the infarct similarly in all directions (isotropically). In the current study, we tested a new approach—
reinforcing infarcts in only one direction (anisotropically)—in dogs with large anteroapical infarcts and found that anisotropic reinforcement can improve systolic function without impairing filling, significantly enhancing cardiac output curves.
Long-term studies are now needed to determine whether anisotropic reinforcement early after infarction improves pump
function enough to reduce the subsequent risk of heart failure.
Anisotropic Reinforcement of Acute Anteroapical Infarcts Improves Pump Function
Gregory M. Fomovsky, Samantha A. Clark, Katherine M. Parker, Gorav Ailawadi and Jeffrey
W. Holmes
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Circ Heart Fail. 2012;5:515-522; originally published online June 4, 2012;
doi: 10.1161/CIRCHEARTFAILURE.111.965731
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