Accepted Manuscript Title: Biodegradable Versus Non-Biodegradable Cardiac Support Device for Treating Ischemic Cardiomyopathy in a Canine Heart Author: Mutsunori Kitahara, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Ayumi Shintani, Toshiaki Akita, Yoshiki Sawa PII: DOI: Reference:
S1043-0679(17)30034-5 http://dx.doi.org/doi: 10.1053/j.semtcvs.2017.01.016 YSTCS 943
To appear in:
Seminars in Thoracic and Cardiovascular Surgery
Please cite this article as: Mutsunori Kitahara, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Ayumi Shintani, Toshiaki Akita, Yoshiki Sawa, Biodegradable Versus Non-Biodegradable Cardiac Support Device for Treating Ischemic Cardiomyopathy in a Canine Heart, Seminars in Thoracic and Cardiovascular Surgery (2017), http://dx.doi.org/doi: 10.1053/j.semtcvs.2017.01.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Biodegradable versus Non-Biodegradable Cardiac Support Device for
2
Treating Ischemic Cardiomyopathy in a Canine Heart
3 4 Kitahara-Biodegradable Cardiac Support Device
5 6 7 8 9
Mutsunori Kitahara, MD, a Shigeru Miyagawa, MD, PhD, a Satsuki Fukushima, MD, PhD, a Atsuhiro Saito, a PhD, Ayumi Shintani, PhD, MPH, b Toshiaki Akita, MD, PhD, c Yoshiki Sawa, MD, PhD a
10
Department of Cardiovascular Surgery, a Osaka University Graduate School of Medicine,
11
Osaka, Japan
12
Department of Clinical Epidemiology and Biostatistics, b Osaka University Graduate School of
13
Medicine, Osaka, Japan
14
Department of Cardiovascular Surgery, c Kanazawa Medical University, Ishikawa, Japan
15 16
Correspondence to Professor Yoshiki Sawa, MD, PhD,
17
Department of Cardiovascular Surgery,
18
Osaka University Graduate School of Medicine,
19
565-0871, 2-2 Yamadaoka, Suita, Osaka, Japan.
20
Tel: +81668793154; Fax: +81668793163; E-mail:
[email protected]
21
FUNDING SOURCES
22
This work was supported by the New Energy and Industrial Technology Organization and the
23
JSPS Core-to-Core Program.
24
CONFLICT OF INTEREST
25
None.
26 27 28 29 30
Article word count (exclusive of abstract and references): 3560 Keywords: dog; cardiac support device
Page 1 of 22
31
Abbreviations
32
LV = left ventricular
33
MI = myocardial infarction
34
RV = right ventricle
35
MDCT = multi-detector computed tomography
36
LVEDV = left ventricular end-diastolic volume
37
LVESV = left ventricular end-systolic volume
38
LVEF = left ventricular ejection fraction
39
DcT = deceleration time
40
dp/dt = rate of change in pressure
41
Tau = time constant of relaxation
42
Ees = end-systolic elastance
43
EDPVR = end-diastolic pressure-volume relationship
44
PRSW = preload recruitable stroke work
2 Page 2 of 22
45
ABSTRACT
46
Objective: The clinical studies of the efficacy of the non-biodegradable Corcap device have
47
shown inconsistent findings, at least in part, because of device-related impairment of diastolic
48
cardiac function. We hypothesized that use of biodegradable material for the cardiac support
49
device could contribute to an improvement in the diastolic function of the failing heart.
50
Methods:
51
biodegradable
52
Twelve-month-old beagles underwent anterior coronary artery ligation. One week after,
53
beagles were randomly assigned for implantation of a biodegradable cardiac support device
54
(n = 7), non-biodegradable cardiac support device (n = 8) or sham operation (n = 8).
55
Results: Twelve weeks after coronary artery ligation, the biodegradable group showed a
56
significantly
57
non-biodegradable and the sham groups (40% ± 3.3%, 32% ± 2.5% and 29 ± 2.6%,
58
respectively). Of note, diastolic function, as assessed by Tau, -dp/dt min, and EDPVR in the
59
cardiac catheter, was significantly better in both left and right ventricles in the biodegradable
60
group than in the non-biodegradable group. Moreover, global end-systolic wall stress was
61
significantly lower in the two device groups than in the sham group (P < 0.03). Furthermore,
62
global end-diastolic wall stress was significantly less in the biodegradable device group than
63
in the non-biodegradable group (P < 0.02).
64
Conclusions: The cardiac support devices made of biodegradable material were more
65
effective in improving systolic function, with preservation of diastolic function in the canine
66
chronic infarct heart, than devices made of non-biodegradable material.
67
Abstract 247 words
Polyglycolic and
greater
acid
and
polyethyleneterephthalate
non-biodegradable
recovery
of
cardiac
support
echocardiographical
were
used
devices,
ejection
fraction
to
prepare
respectively.
than
the
68 69
3 Page 3 of 22
70
PERSPECTIVE STATEMENT
71
Cardiac support devices reduce diastolic wall stress, preventing progressive ventricular
72
remodeling. However, such devices may affect diastolic cardiac function. Devices made of
73
biodegradable material are more effective than non-biodegradable in improving systolic
74
function in the canine heart, with preservation of diastolic function, and could offer a superior
75
therapeutic alternative.
76 77
CENTRAL MESSAGE
78
Biodegradable cardiac support devices improve systolic function in the canine infarct heart,
79
while preserving diastolic function.
80
81 82
CENTRAL PICTURE W/LEGEND: figure 1A. The non-biodegradable (left) and
83
biodegradable (right) cardiac support device. 4 Page 4 of 22
84
INTRODUCTION
85
Left ventricular (LV) remodeling in myocardial infarction (MI) involves progressive dilatation of
86
the LV cavity and an increase in LV wall stress, leading to congestive heart failure.1, 2 The
87
ventricular constraint procedure is a non-transplant surgical treatment for heart failure, where
88
the entire epicardial surface is wrapped with a prosthetic material designed as a mesh
89
support sock that is fitted around the heart. This procedure has been shown to mechanically
90
reduce ventricular wall stress and prevent the progression of LV dilatation in preclinical
91
studies involving large animal models.3-7 Clinical studies of the Corcap device have reported
92
its beneficial effects on LV remodeling, including a significant reduction in LV volume and a
93
significant improvement in New York Heart Association functional class; however, no overall
94
survival benefit was found.7-8 These inconsistent results can partly be explained by the
95
non-biodegradable material used to wrap the ventricle, which can cause a chronic
96
foreign-body response, potentially leading to epicardial constraint that impairs the diastolic
97
function of the LV and the right ventricle (RV).
98 99
In contrast, in our group, we placed a device made from a biodegradable polyglycolic acid
100
over the entire LV and RV in a canine model of chronic MI and found that this biodegradable
101
material did not induce LV diastolic dysfunction associated with rigid fibrous tissue formation
102
around the device. However, the functional effects of the biodegradable device were not
103
directly compared to those of non-biodegradable device implantation.9 In the present study,
104
we tested our hypothesis that the use of biodegradable material for the ventricular constraint
105
procedure would contribute to greater functional benefits, diastolic function in particular, in
106
chronic MI, compared to devices made from non-biodegradable material.
107 108 109
METHODS
110
Animals (National Institutes of Health publication No. 85-23, revised 1996). The experimental
111
protocols were approved by the Ethics Review Committee for Animal Experimentation of
In this study, animal care complied with the Guide for the Care and Use of Laboratory
5 Page 5 of 22
112
Osaka University Graduate School of Medicine.
113 114
Anesthesia and Analgesia for Animals
115
Twenty-three beagles (Oriental Yeast, Co. Ltd.) weighing 9–11 kg were used in this study.
116
General anesthesia was induced by intramuscular injection of ketamine (10 mg/kg) and
117
xylazine (1 mg/kg), followed by endotracheal intubation; anesthesia was maintained by
118
intravenous propofol (2 mg/kg) and inhaled sevoflurane (1–2%). Meloxicam (0.2 mg/kg) and
119
cefazolin (30 mg/kg) were administered intramuscularly twice a day for 4 days, starting 1 day
120
before the procedure. After completion of the experiments, the animals were humanely killed
121
under general anesthesia, using an administration of intravenous potassium-based solution.9
122 123
Myocardial Infarction Induction
124
Under general anesthesia and electrocardiographic monitoring, intravenous lidocaine (10
125
mg/kg) was administered to prevent arrhythmias. A minimal left thoracotomy was performed
126
through the fifth intercostal space, and the heart was exposed by pericardiotomy. The left
127
anterior descending artery and the first and second diagonal coronary arteries were
128
permanently ligated, both proximally and distally, using 5-0 polypropylene sutures to produce
129
an anterior MI. After the layered closure, the animals were allowed to recover in individual
130
temperature controlled cages.
131 132
Design of the Cardiac Support Device
133
The cardiac support devices (0.9-1.1 g) were designed to cover the entire ventricular
134
myocardium and secure to the atrioventricular groove of the chronic MI canine heart, on the
135
basis
136
three-dimensional model was constructed, based on data derived from the contours of the
137
heart images, and a knitting machine then used the data to create a cardiac support device.
138
The cardiac support device was knitted fabric made from 3-0 suture. The biodegradable and
139
non-biodegradable cardiac support devices were made from commercially available
of
data
obtained
from
multidetector
computed
tomography
(MDCT).
A
6 Page 6 of 22
140
polyglycolic acid and polyethyleneterephthalate suture, respectively (Nipro Corporation,
141
Figure 1A). Polyglycolic acid suture has a peak tensile strength of 19.4 ± 2.1 Newton (N),
142
while polyethyleneterephthalate suture has a peak tensile strength of 11.3 ± 1.5 N. In a rodent
143
model, it was found that the strength of the polyglycolic acid suture in vivo halved at 2 weeks
144
and was lost at 4 weeks, and the sutures were completely absorbed at 6 weeks.10, 11
145 146
Treatment of Cardiac Support Device Group
147
One week after coronary artery ligation, the animals were randomly assigned to one of 3
148
groups: biodegradable device group (n = 7), non-biodegradedable device group (n = 8), and
149
no-treatment (sham) group (n = 8). The heart was exposed via the re-thoracotomy through
150
the fifth intercostal space. The cardiac support device was placed as described previously. 3-5
151
The no-treatment group was subjected to the same procedures as the support device groups,
152
except for the device implantation (Figures 1B and C).
153 154
MDCT
155
Contrast electrocardiography-gated MDCT was performed using a 16-row MDCT scanner
156
(SOMATOM Emotion 16-Slice Configuration; Siemens) under general anesthesia. MDCT
157
was performed before infarction, and at 1 week (pre-treatment), 8 weeks, and 12 weeks after
158
MI. Four beagles which had tachycardia at MDCT were excluded from the analysis because
159
of compromised image quality (biodegradable group, n = 6; non-biodegradable group, n = 6;
160
no-treatment group, n = 7). MDCT was performed after intravenous injection of 30 mL of
161
non-ionic contrast medium (Iomeron; Bracco). All images were analyzed on a workstation
162
(AZE VirtualPlace Lexus64; AZE). The LV end-diastolic volume (LVEDV), LV end-systolic
163
volume (LVESV), and LV ejection fraction (LVEF) were obtained from the workstation.
164 165
Transthoracic Echocardiography
166
Transthoracic echocardiography was performed using a 3.0-MHz transducer (Altida; Toshiba
167
Medical Systems Corporation) under general anesthesia. Four beagles which had abnormal
7 Page 7 of 22
168
heart rhythms at echocardiography were excluded from the analysis (biodegradable group, n
169
= 6; non-biodegradable group, n = 6; no-treatment group, n = 7). Diastolic transmitral valvular
170
flow was evaluated using Doppler ultrasound. The following variables were measured: peak
171
flow velocity of early filling (E), peak flow velocity of atrial contraction (A), their ratio (E/A), and
172
the deceleration time (DcT) of early filling.
173 174
Cardiac Catheterization
175
Under general anesthesia, a 4-Fr pressure-volume catheter (CA-41063-PN; CD Leycom Co.)
176
was inserted into the LV through the ventricular apex via a left thoracotomy to measure
177
hemodynamic parameters and cardiac function. Then a pressure-volume catheter was
178
inserted into the RV via the left thoracotomy, according to the previous publication.12 Four
179
beagles were excluded from the analysis because of the conductance catheter failure
180
(biodegradable group, n = 6; non-biodegradable group, n = 7; no-treatment group, n = 6). The
181
catheter was connected to the pressure transducer controller and the conductance system
182
(Integral 3, Unique Medical Co. and Sentron pressure interface, CD Leycom Co.).13 Baseline
183
indices, including end-systolic pressure, end-diastolic pressure, the maximal rate of change
184
in pressure (dp/dt max), the minimal rate of change in pressure (-dp/dt min) and the time
185
constant of relaxation (Tau), were initially measured under stable conditions. Subsequently,
186
pressure-volume loops providing load-independent measures of the RV and LV function,
187
such as end-systolic elastance (Ees), end-diastolic pressure-volume relationship (EDPVR),
188
and preload recruitable stroke work (PRSW), were obtained by occluding the inferior vena
189
cava via the left thoracotomy.
190 191
Wall Stress Calculation
192
Each MDCT image was reconstructed from the long-axis cine-images, according to the
193
standardized LV segmentation, using a workstation (AZE VirtualPlace Lexus64; AZE). Each
194
long-axis cine-image was transferred to an off-line personal computer and LV wall stress was
195
evaluated using specifically developed software (YD Ltd.). The image with the smallest LV
8 Page 8 of 22
196
chamber area was selected as the end-systolic one, whereas the image with the largest LV
197
chamber was defined as the end-diastolic one. Papillary muscles were included in the LV
198
cavity. Local LV wall stress was calculated on the basis of the Janz equation: regional wall
199
stress = P × ΔAc / ΔAw, where P is LV end-systolic or end-diastolic pressure, and ΔAc and
200
ΔAw are the local-sectional areas of the LV cavity and local cross-sectional area of the LV
201
wall, respectively. Global LV wall stress was defined as the average of all regional values.
202
Details of the logic and the validity of the software have been published previously.14
203 204
Histological Analysis
205
Paraffin-embedded transverse sections of the excised hearts were stained with routine
206
hematoxylin-eosin to assess the myocardial structure, with periodic acid-Schiff to measure
207
the short-axis diameter of the myocytes in the peri-infarct border zone, or with Masson’s
208
Trichrome to assess the extent of interstitial fibrosis in the peri-infarct border zone. The
209
sections were immunolabeled with anti-CD31 antibody (1:50 dilution; Abcam) to assess
210
capillary density, which was calculated as the number of positively stained capillary vessels in
211
randomly selected fields in the peri-infarct border zone. Myocyte diameter and capillary
212
density were measured in 10 different randomly selected fields using a Biorevo BZ-9000
213
fluorescence microscope (Keyence, Japan), and the percentage of fibrosis was calculated in
214
10 different randomly selected fields using MetaMorph software (Molecular Devices, Japan).
215 216
Statistical Analysis
217
All statistical analyses were performed using JMP software (JMP10; SAS institute Inc., Cary,
218
NC). Results are presented as the mean ± standard deviation. Within a group differences
219
were compared using the Wilcoxon signed-rank test and between-group differences were
220
compared using the Kruskal-Wallis test, followed by post-hoc pairwise Wilcoxon rank-sum
221
tests. Multiplicity in the pairwise comparisons was corrected by the Bonferroni procedure. A
222
two-sided significiance level of 0.05 was used for all statistical inferences.
9 Page 9 of 22
223
RESULTS
224
Procedure-Related Morbidity/Mortality and Gross Findings
225
In all, 23 animals were involved in this study. All 23 completed the study without unpredicted
226
procedure-related mortality/morbidity or any intolerable heart failure symptoms. All animals
227
consistently showed MI formation. The non-biodegradedable device covered both ventricles
228
and showed strong adhesion with the epicardial surface. In contrast, in the biodegradedable
229
device group, there were no residual traces of the device on the epicardial surface, apart from
230
granulomatous tissue, and no evidence of active inflammation (Figure 1). There were sparse
231
adhesive tissues in the pericardial space in the no-treatment group.
232 233
Predominant Improvement in LVEF with Biodegradable Device Implantation
234
The volume of the LV was serially assessed by MDCT. There were no significant differences
235
in either LVEDV or LVESV between the groups at any time points, but LVEDV and LVESV
236
tended to increase after MI induction in the no-treatment group (Figures 2A and B). The
237
delta-LVESV, the difference between the LVESV values recorded before the treatment and at
238
12 weeks after the MI induction, was significantly larger in the sham group than in the
239
non-biodegradable and the biodegradable groups. In contrast, the delta-LVEDV was
240
significantly larger in the sham and the biodegradable groups than that in the
241
non-biodegradable group (Figures 2C and D). As a result, the LVEF in the biodegradable
242
group was significantly greater at 8 and 12 weeks after the MI induction than before treatment.
243
On the other hand, the LVEF in the non-biodegradable and the non-treatment groups showed
244
no change at 8 and 12 weeks after the MI induction as compared to that recorded before
245
treatment (Figure 2E). The LVEF in the biodegradable group was thus significantly greater
246
than that in the non-biodegradable and the non-treatment groups.
247 248
Impaired Diastolic Function of the LV and the RV from the Non-Biodegradable Device
249
A pressure-volume catheter study was performed at 12 weeks after the MI induction. The
10 Page 10 of 22
250
systolic function of the LV, represented by Ees and dp/dt max, tended to be greater in the
251
biodegradable device group than in the other groups (Ees; P=0.04, dp/dt max; P=0.05,
252
Kruskal-Wallis test). However, there was no significant difference in these parameters
253
indicating systolic function for the RV (Figures 3A and B). The PRSW of the LV, but not the RV,
254
was significantly greater in the biodegradable device group than in the other groups in terms
255
(Figure 3F).
256 257
Diastolic function was assessed by cardiac catheterization. Tau, -dp/dt min, and EDPVR in
258
the LV showed greater improvement in the biodegradable device group than in the
259
non-biodegradable device group. This trend was also observed for the RV. Notably, Tau and
260
EDPVR in the RV showed a significant decrease in the no-treatment group in comparison
261
with the values observed in the non-biodegradable device group (Figures 3C-E). In addition,
262
diastolic function of the LV was serially evaluated using the Doppler transthoracic
263
echocardiography to measure the E/A ratio and DcT. The E/A ratio showed an increasing
264
trend after treatment in all the groups, with no significant difference between the groups at 12
265
weeks. However, recovery of the DcT was significantly greater in the biodegradable device
266
group than in the other groups. The DcT in the non-biodegradable group tended to be worse
267
than that in the no-treatment group at 12 weeks after MI induction (Table 1).
268 269
Reduction in Global End-Systolic/Diastolic Wall Stress by the Biodegradable Device
270
Global end-systolic/diastolic wall stresses of LV were assessed using the data obtained from
271
the MDCT and cardiac catheterization 12 weeks after the MI induction. Although there was no
272
significant difference in the LV end-systolic pressure between the groups, the LV end-diastolic
273
pressure was significantly lower in the biodegradable device group than in the other groups
274
(Figures 3G and H). Global end-systolic wall stress was significantly lower in the
275
non-biodegradable and the biodegradable groups than that in the no-treatment group (Figure
276
3I). In contrast, global end-diastolic wall stress was significantly lower in the biodegradable
277
device group than in the other groups (Figure 3J).
11 Page 11 of 22
278 279
Histological Evidence of Reverse of LV Remodeling after Device Implantation
280
Pathological cardiomyocyte hypertrophy and interstitial fibrosis in the border area 12 weeks
281
after infarction were assessed by periodic acid-Schiff and Masson’s trichrome staining,
282
respectively, to evaluate the degree of reversal of LV remodeling. The cardiomyocyte
283
diameter was significantly smaller in the infarct-border zone in the non-biodegradable and
284
biodegradable device groups than in the no-treatment groups. In addition, there was
285
significantly less interstitial fibrosis in the infarct-border zone of the non-biodegradable and
286
biodegradable device groups than in the no-treatment group (Figures 4A and B). Capillary
287
density in the infarct-border area, measured by immunostaining for CD31, was significantly
288
greater in the non-biodegradable and biodegradable device groups than in the no-treatment
289
group (Figure 4C).
290
12 Page 12 of 22
291
DISCUSSION
292
It is herein documented that the use of biodegradable material for cardiac support net devices
293
induced less granulomatous tissue formation around the ventricular surface, consequently
294
preserving diastolic LV and RV function, than the non-biodegradable material at 11 weeks
295
after the device implantation. In addition, systolic function, as assessed by MDCT and a
296
catheter study, was significantly improved by the implantation of the biodegradable device. In
297
contrast, the functional effects of the non-biodegradable device were inconsistent in this study.
298
Systolic function, represented by LVESV, LVEDP and global end-systolic wall stress, was
299
significantly better in the non-biodegradable device group than in the no-treatment group,
300
whereas systolic function, represented by LVEF, Ees, dp/dt max, or PRSW of the LV showed
301
no significant difference between the two groups. Notably, diastolic function of the RV,
302
represented by Tau and ESPVR, was worse in the non-biodegradable device group than in
303
the no-treatment group. Histologically, both devices led to a significant reduction in the
304
cardiomyocyte cell size and interstitial fibrosis and an increase in the capillary density, with no
305
significant difference between the two groups.
306 307
The beneficial effect of the non-biodegradable “Corcap”-type cardiac support device has
308
been well documented.3-7 However, it was not associated with a reduction in mortality. The
309
device has not yet been approved for clinical use, probably because the benefits of the
310
device were not sufficient for it to be of practical value in the real world.8 Another reason is
311
that it impairs diastolic function, mainly of the RV,15 so the positive effect of the device on LV
312
dimensions was not accompanied by an improvement in cardiac output.16,17 The degree of
313
adverse effect is dependent on the degree of constraint by the cardiac support device;
314
nevertheless, measuring or quantifying the amount of constraint applied is difficult if not
315
impossible.15 We hypothesized that biodegradable cardiac support devices, by inducing only
316
a temporary constraint effect, may contribute to functional recovery without adverse effects
317
on diastolic function.
13 Page 13 of 22
318 319
The polyglycolic acid used in the design of the biodegradable device is clinically attractive as
320
a biodegradable polymer, since its degradation product, glycolic acid, is a natural metabolite.
321
The degradation process involves the conversion of glycolic acid to carbon dioxide and water,
322
which are removed from the body via the respiratory system. In this study, we found no rigid
323
granulomatous tissue or inflammatory reaction over the cardiac surface 11 weeks after the
324
device implantation. In contrast, the polyethyleneterephthalate-based device induced thick
325
and rigid tissue over the cardiac surface, potentially impairing diastolic function. Although
326
further follow-up will be required to reinforce the specific evidence, polyglycolic acid was
327
found to preserve the diastolic function of the LV and the RV for 11 weeks after implantation.
328 329
This study also found that biodegradable devices were effective in improving systolic function.
330
LV systolic function, evaluated by PRSW, showed greater improvement in the biodegradable
331
device group than in the non-biodegradable device group. PRSW is the lord-independent
332
index of LV systolic function. Ees, another lord-independent index of systolic function, was
333
also greater in the biodegradable device group, although the difference did not reach
334
statistical significance. These data suggested the effectiveness of the biodegradable device
335
in improving systolic function. Previous studies have shown that the underlying mechanism of
336
restoration of cardiac support devices involves a reduction in ventricular wall stress and
337
myocardial stretch, which causes down-regulation of
338
neuroendocrine activity and a reduction in maladaptive gene expression.4, 5 It has also been
339
reported that cardiac support devices inhibit migration of the akinetic border zone into the
340
infarct by decreasing regional myocardial wall stress in the acute MI. 6 Myocytes were
341
substantially hypertrophied in response to the increased wall stress. Capillary number for
342
each cardiac myocyte might not be different among the three groups. For each working
343
myocyte, blood perfusion was increased in the two treatment groups as compared to the no
344
treatment group. In the present study, an increased capillary density and suppressed fibrosis
345
in the border zone were observed in both treatment groups, elucidating the effect of our
abnormally increased local
14 Page 14 of 22
346
unique cardiac support devices.
347
The other mechanism of restoration of damaged myocardium by the cardiac support device
348
involved decreasing regional myocardial wall stress in the acute MI. Global end-systolic wall
349
stress decreased significantly in both the non-biodegradable and biodegradable groups
350
compared to the no-treatment group. Although global end-systolic wall stress did not show a
351
significant difference between treatment groups 12 weeks after MI, global end-diastolic wall
352
stress was significantly lower
353
non-biodegradable device group. This result reflected the increased LV end-diastolic
354
pressure. The non-biodegradable device group showed significantly greater values of LV Tau
355
and EDPVR compared to the biodegradable device group. Increased Tau and EDPVR
356
represented increased ventricular chamber stiffness. These data suggested that the
357
increased LV end-diastolic pressure resulted from the epicardial constraint effect of the
358
cardiac support device. Previous studies have shown an increase in LV end-diastolic
359
pressure after the implantation of cardiac support devices.15 Our present study showed that a
360
cardiac support device made from the biodegradable material enhanced contractile function
361
and reversed remodeling without the tradeoff of impaired diastolic function in the chronic
362
period. Therefore, the biodegradable cardiac support device showed a greater recovery of
363
LVEF than the non-biodegradable device. The biodegradable cardiac support device
364
improved the cardiac function and alleviated ventricular remodeling.
in the biodegradable device group than in the
365 366
This study has several limitations. First, the follow-up period after the implantation was short.
367
However, there was no residual of biodegradedable material on the epicardial surface 11
368
weeks after device implantation, and the mechanical support effect of the device would have
369
been lost before complete material degradation at the end of this study, so remodeling may
370
remain suppressed even after complete degradation of the device. Our data support this
371
speculation, demonstrating a reduction in global wall stress of LV and histological finding with
372
no significant difference between the treatment groups. However, considering clinical
373
application, further experimental study would be valuable to predict long-term functional and
15 Page 15 of 22
374
pathological effects of this treatment for the patients having advanced cardiac failure, which
375
in general progresses over time. Second, the present study showed the effect of the
376
biodegradedable device in the acute phase of MI, so the effect on the ventricles in the chronic
377
phase, when remodeling has already occurred, remains unclear. Further studies are required
378
to assess the effect of this approach in chronic ischemic disease or non-ischemic dilated
379
cardiomyopathy. In addition, the optimal period of ventricular constraint was unknown.
380
Further studies are necessary to determine the optimal biodegradedable period. Third, the
381
structure and composition of the non-biodegradable devices used in this study were different
382
from those of the Corcap cardiac support device. In previous experimental studies, a
383
significant increase in LV end-diastolic pressure was not detected, so the adverse effect on
384
diastolic function might be exaggerated in the present study. Fourth, the variability in the
385
amount of constraint, which was dependent on the surgical procedure to adjust the device to
386
the heart, may have been a source of bias in this study. Finally, this study might be limited by
387
the small sample sizes, which potentially reduce the sharpness of statistical analysis, such as
388
Bonferroni method, causing less chance to draw statistical significance as seen in the data of
389
cardiac catheter study. However, overall, the sample size in this study would be sufficient to
390
draw the conclusion of the study, considering the limited number of experimental animal use.
391 392
In conclusion, the cardiac support device made from biodegradable material was effective in
393
improving contractile function in the canine chronic infarct heart and appeared superior to the
394
device made from non-biodegradable material, especially with regard to the preservation of
395
diastolic function. These findings warrant further clinical studies to investigate the potential of
396
this device for treating ischemic cardiomyopathy.
397 398
ACKNOWLEDGMENTS
399
We thank Akima Harada, Shigeru Matsumi and Toshika Senba for providing us excellent
400
technical assistance.
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References
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Experimental observations and clinical implications. Circulation. 1990;81:1161–72.
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Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction:
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Alter P, Rupp H, Stoll F, Adams P, Figiel JH, Klose KJ, et al. Increased end diastolic
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wall stress precedes left ventricular hypertrophy in dilative heart failure-use of the
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volume-based wall stress index. Int J Cardiol. 2012;157:233-8.
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Chaudhry PA, Mishima T, Sharov VG, Hawkins J, Alferness C, Paone G, et al. Passive
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epicardial containment prevents ventricular remodeling in heart failure. Ann Thorac
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Sabbah HN, Sharov VG, Gupta RC, Mishra S, Rastogi S, Undrovinas AI, et al. Reversal
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of chronic molecular and cellular abnormalities due to heart failure by passive
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mechanical ventricular containment. Circ Res. 2003;93:1095-101.
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Blom AS, Mukherjee R, Pilla JJ, Lowry AS, Yarbrough WM, Mingoia JT, et al. Cardiac
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support device modifies left ventricular geometry and myocardial structure after
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myocardial infarction. Circulation. 2005;112:1274-83.
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Lembcke A, Dushe S, Dohmen PM, Hoffmann U, Wegner B, Kloeters C, et al. Early and
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late effects of passive epicardial constraint on left ventricular geometry: ellipsoidal
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re-shaping confirmed by electron-beam computed tomography. J Heart Lung
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Transplant. 2006;25:90-8.
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Mann DL, Acker MA, Jessup M, Sabbah HN, Starling RC, Kubo SH. Clinical evaluation
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of the CorCap Cardiac Support Device in patients with dilated cardiomyopathy. Ann
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Thorac Surg. 2007;84:1226–35
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Mann DL, Kubo SH, Sabbah HN, Starling RC, Jessup M, Oh JK, et al. Beneficial effects
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of the CorCap cardiac support device: five-year results from the Acorn Trial. J Thorac
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Cardiovasc Surg. 2012;143:1036–42.
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Kubota Y, Miyagawa S, Fukushima S, Saito A, Watabe H, Daimon T, et al. Impact of
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cardiac support device combined with slow-release prostacyclin agonist in a canine
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ischemic cardiomyopathy model. J Thorac Cardiovasc Surg. 2014;147:1081-7.
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materials. J Reprod Med. 1988;33:615-23.
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Gunatillake PA, Adhikari R. Biodegradable synthetic polymers for tissue engineering. Eur Cell Mater. 2003;5:1-16.
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Beauchamp PJ, Guzick DS, Held B, Schmidt WA. Histologic response to microsuture
12.
Bove T, Vandekerckhove K, Bouchez S, Wouters P, Somers P, Van Nooten G. Role of
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myocardial hypertrophy on acute and chronic right ventricular performance in relation to
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chronic volume overload in a porcine model: relevance for the surgical management of
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tetralogy of Fallot. J Thorac Cardiovasc Surg. 2014;147:1956–65.
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13. Saito S, Miyagawa S, Sakaguchi T, Imanishi Y, Iseoka H, Nishi H, et al. Myoblast sheet
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can prevent the impairment of cardiac diastolic function and late remodeling after left
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ventricular restoration in ischemic cardiomyopathy. Transplantation. 2012;93:1108-15.
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Shudo Y, Taniguchi K, Takeda K, Sakaguchi T, Matsue H, Izutani H, et al. Assessment
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of regional myocardial wall stress before and after surgical correction of functional
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ischaemic mitral regurgitation using multidetector computed tomography and novel
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software system. Eur J Cardiothorac Surg. 2010;38:163-70.
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Lee LS, Ghanta RK, Mokashi SA, Coelho-Filho O, Kwong RY, Bolman RM 3rd, et al.
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Ventricular restraint therapy for heart failure: the right ventricle is different from the left
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ventricle. J Thorac Cardiovasc Surg. 2010;139:1012–8.
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Lembcke A, Wiese TH, Dushe S, Hotz H, Enzweiler CN, Hamm B, et al. Effects of
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passive cardiac containment on left ventricular structure and function: verification by
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volume and flow measurements. J Heart Lung Transplant. 2004;23:11–9.
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Olsson A, Bredin F, Franco-Cereceda A. Echocardiographic findings using tissue
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velocity imaging following passive containment surgery with the Acorn CorCap cardiac
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support device. Eur J Cardiothorac Surg. 2005;28:448–53.
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Pilla JJ, Blom AS, Brockman DJ, Ferrari VA, Yuan Q, Acker MA. Passive ventricular
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constraint to improve left ventricular function and mechanics in an ovine model of heart
455
failure secondary to acute myocardial infarction. J Thorac Cardiovasc Surg.
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2003;126:1467–76.
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Figure Legends
460
Figure 1. Implantation of the cardiac support device. (A) Macroscopic view of the
461
non-biodegradable cardiac support device (left) and biodegradable cardiac support device
462
(right). (B) The implanted cardiac support device wraps around the entire ventricle. (C) Study
463
protocol of experiment and assessment of cardiac function and histological analysis. Cardiac
464
support device at 12 weeks after myocardial infarction (MI). Representative photographic
465
images of the heart after implantation of the non-biodegradable device (D) and biodegradable
466
device (F). Representative photographic images of the heart (Masson’s Trichrome staining)
467
with the implanted non-biodegradable device (E) and biodegradable device (G).
468
Representative hematoxylin and eosin staining of the epicardium. (H) The white arrow points
469
to the non-biodegradable device. (I) The black arrow points to the granulomatous tissue
470
formed because of the presence of the degradable device; there is no evidence of active
471
inflammation.
472 473
Figure 2. Multi-detector computed tomography analysis. (A) Changes in left ventricular
474
end-systolic volume (LVESV). (B) Changes in left ventricular end-diastolic volume (LVEDV).
475
(C) The variation in LVESV from pre-treatment to 12 weeks (ΔLVESV). (D) The variation in
476
LVEDV from pre-treatment to 12 weeks (ΔLVEDV). (E) Changes in left ventricular ejection
477
fraction (LVEF). No treatment is denoted by a solid line, non-biodegradable device is denoted
478
by a dotted line, and biodegradable device is denoted by a dashed/dotted line. *P < .02
479
versus corresponding no treatment, †P < .02 versus corresponding non-biodegradable device,
480
‡
P < .03 versus LVEF at pre-treatment.
481 482
Figure 3. Cardiac catheterization data and global left ventricular wall stress. (A) Ees,
483
end-systolic elastance (P = .04, Kruskal-Wallis test). (B) dp/dt max, the maximal rate of
484
change in pressure (P = .05, Kruskal-Wallis test). (C) Tau, the time constant of relaxation. (D)
485
-dp/dt min, the minimal rate of change in pressure. (E) EDPVR, end-diastolic
20 Page 20 of 22
486
pressure-volume relationship. (F) PRSW, preload recruitable stroke work. (G) LVESP, left
487
ventricular end-systolic pressure. (H) LVEDP, left ventricular end-diastolic pressure, (I)
488
Global end-systolic wall stress, and (J) Global end-diastolic wall stress. RV, right ventricle; LV,
489
left ventricle.
490 491
Figure 4. Histological evaluation at 12 weeks after MI. (A) Myocyte short-axis diameter in the
492
border zones; cardiomyocyte hypertrophy is significantly lower in the treatment groups than
493
in the no-treatment group. (B) Interstitial fibrosis in the border zones; Masson’s Trichrome
494
staining shows significantly less interstitial fibrosis in the treatment groups than in the
495
no-treatment group. (C) Capillary density in the border zones; capillary density is more
496
enhanced in the treatment groups than in the no-treatment group.
497
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498
TABLE. Echocardiography findings of diastolic transmitral valvular flow
Pre-MI
Pre-treatment (1 week)
Post-treatmt (12 weeks)
No-treatment (n=7)
1.64 ± 0.12
1.39 ± 0.11
2.10 ± 0.19
Non-biodegradable device (n=6)
1.68 ± 0.24
1.50 ± 0.19
1.86 ± 0.19
biodegradable device (n=6)
1.71 ± 0.30
1.53 ± 0.15
2.07 ± 0.06
No-treatment (n=7)
107 ± 21.9
68.8 ± 12.7
88.3 ± 13.5*
Non-biodegradable device (n=6)
102 ± 18.4
77.2 ± 8.10
71.0 ± 10.2*
biodegradable device (n=6)
101 ± 9.7*
70.4 ± 11.0
106 ± 9.7†
E/A
DcT (ms)
499
Table Legend
500
Data are represented as mean ± standard deviation. *P < .05 versus pre-MI, †P < .05 versus
501
corresponding non-biodegradable device.
502
MI; myocardial infarction, E/A; E/A ratio, DcT; deceleration time of early filling
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