Vol. 276, Issue 3, H1103-H1106, March 1999
RAPID COMMUNICATION
Nicotine-modified postinfarction left ventricular remodeling
Francisco J.
Villarreal,
Derrick
Hong, and
Jeffrey
Omens
Department of Medicine, University of California, San Diego,
California, 92103
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ABSTRACT |
Cigarette smoking has been noted to impair
wound healing in tissues such as skin, bone, and gut. This study was
designed to examine whether nicotine adversely affects postinfarction
cardiac wound healing and remodeling in an experimental model of
myocardial infarction. For this purpose, two groups of rats were
studied. The control group received a simple bandage, and the nicotine group had a section (1.75 mg/day) of a nicotine patch attached on their
backs. After a 7-day treatment period, an anterior wall infarction was
induced. A bandage-free 7-day healing period followed, after which
hearts were isolated for mechanical tests. Nicotine-treated rats
developed significantly enlarged left ventricles with thin, infarcted
walls and a rightward shift in the passive pressure-volume relationship. Pressure-strain analysis also indicated possible changes
in the material properties of the wound for nicotine-treated rats. In
conclusion, nicotine has significant adverse effects on postinfarction
healing and left ventricular remodeling. These observations have
important clinical implications because of the enhanced risk for
development of heart failure.
wound healing; scarring; heart failure; cigarette smoke
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INTRODUCTION |
CIGARETTE SMOKING is one of the most important risk
factors for coronary artery disease and myocardial infarction (MI) (9). Subsequent to MI, rapid and efficienthealing and scarring must occur
for the patient to avoid cardiac rupture. In the absence of cardiac
rupture, impaired cardiac wound healing can lead to enhanced infarct
expansion and thus adversely modified cardiac remodeling (6). These
events increase the chances of development of ventricular dysfunction
and, ultimately, heart failure.
In 1977, Mosely and Finseth (3) first reported the impaired healing of
a hand wound in a cigarette smoker. Similar observations have been made
over the last 20 years in many tissues including skin, bone, mouth,
peptic ulcers, and others (8). The relationship between impaired tissue
wound healing and cigarette smoking has not been examined in
prospective clinical studies. The extent to which impaired wound
healing is noted to occur is such that smokers are commonly advised to
stop smoking before elective surgery or when recovering from trauma,
surgery, or disease (8). Cigarette smoke generates >4,000 toxins (9).
However, recent research has focused attention on the actions of
nicotine on wound healing (8).
Two properties of nicotine appear to be relevant to the issue of
impaired wound healing. The first property relates to the capacity of
nicotine to impair vascular function. Nicotine-impaired blood flow and
oxygenation in smokers appears to contribute significantly to a higher
degree of failure in plastic surgery procedures (3, 4). The second
property of nicotine relates to its capacity to inhibit the
proliferation of macrophages and fibroblasts (7, 10, 11). Scar tissue
development depends on fibroblast proliferation, migration, and
deposition of extracellular matrix proteins (2). Thus high plasma
levels of nicotine could reduce fibroblast proliferation and lead to
impaired wound healing.
Surprisingly, quantitative assessments of impaired wound healing in
smokers have not been sought in clinical or experimental studies in
organs such as the heart. The corroboration of such findings in the
infarcted healing human heart will have important clinical implications
related to the evaluation and treatment of patients who smoke. Thus the
objectives of the current study were to explore under controlled
experimental conditions the capacity of nicotine to adversely modify
global ventricular remodeling, as well as local (wound) ventricular
mechanics in the infarcted rat heart.
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MATERIALS AND METHODS |
Nicotine treatment.
Male Sprague-Dawley rats weighing ~250 g had hair removed from their
backs via chemical depilation. The control group
(n = 6) received a section of a
bandage (Band-Aid) attached on their backs and changed daily for a
period of 7 days before infarction. The nicotine-treated group
(n = 6) had a section of a nicotine patch (Nicoderm) attached on their back underneath a larger piece of
bandage. The aim was to approximate nicotine levels to a serum concentration of 45 ng/ml. This concentration is comparable to blood
levels found in heavy-use human smokers (30 ng/ml) (12). The section of
the patches used in this study provided a dose of 1.75 mg/day. This
dose was selected following published data that indicate that such a
dosage regime generates average blood concentrations of 43 ng/ml in
rats of ~225-g weight (12). Patches were changed daily for 7 days.
All procedures were approved by the Institutional Animal Care and Use
Committee and conform to published NIH guidelines for animal research.
Surgical preparation.
Animals were anesthetized with ketamine (100 mg/kg) and xylazine (5 mg/kg) intramuscularly, intubated, and ventilated with room air. A left
thoracotomy was performed, the pericardium was opened, the heart was
exposed, and the left anterior descending coronary artery was occluded.
The chest was closed, and animals were allowed to recover for 7 days
without patches.
Terminal study.
The techniques for measuring passive mechanics in the rat heart have
been previously described (1, 5). Rats were anesthetized and
ventilated, and the heart was arrested with a modified hyperkalemic buffer solution. The isolated ventricles were vented, and a balloon was
inserted into the left ventricle (LV) and secured to the mitral annulus. To measure surface strain in these hearts, a set of markers was painted on the surface of the infarcted area of the LV. The positions of the markers were recorded on videotape during inflation of
the balloon to 25 mmHg. Simultaneous recordings of ventricular volume
were taken via analog-to-digital conversion on a personal computer.
Two-dimensional homogeneous passive myocardial strains were computed
with respect to a cardiac coordinate system [circumferential (E11), longitudinal
(E22) and in-plane shear strains
(E12)] referred to the
zero-pressure state. For each heart, strains were fit to polynomials as
functions of volume from which pressure-strain data were obtained.
Pressure-volume curves for each animal were fit to third-order
polynomials and averaged at the prescribed pressure loads.
The LV were sectioned into five short-axis rings. The section that most
clearly traversed the infarct area was selected for the following
measurements: anterior-posterior internal and external LV diameter,
septal-free wall internal and external LV diameter, LV anterior
(infarct) wall thickness, and posterior (normal) wall thickness. All
diameter and wall thickness measurements were made in triplicate with
NIH Image software and averaged. This same ring section as well as the
two adjacent rings were used to determine wound size by tracing the
pale infarct zone and total tissue area and calculating the percent
infarct area in each ring section.
Data analysis.
For the purposes of surgical procedures, data acquisition, and
analysis, the personnel involved were blinded as to the animal treatment received (i.e., sham treatment or nicotine). Statistical analysis was performed with either a Student's
t-test or repeated-measures ANOVA.
Results were considered to be statistically significant at
P 
0.05. All data are shown as means ± SD.
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RESULTS |
Assessment of ventricular remodeling.
Table 1 summarizes the results obtained
from morphometric measurements of control and nicotine-treated animals.
No differences were noted between the two groups in either heart or
animal weight at the time of surgery or after infarction (Table 1).
Significant increases were noted in the LV external and internal
septal-free wall and anterior-posterior diameters for the
nicotine-treated group. A significant shortening of the long axis of
the heart in nicotine-treated animals was also noted (i.e., cardiac
spheration). The infarcted anterior LV wall of nicotine-treated animals
was also significantly thinner versus controls with no differences in
noninfarcted posterior wall. Infarct size as derived from the morphometric assessment of wound size was comparable.
Ventricular mechanics.
Figure
1A shows
the average pressure-volume (P-V) curves
(n = 5 in control group caused by
incomplete intraventricular balloon unfolding in 1 animal) for the
inflation portion of the loading cycle. Volumes include the empty
balloon. There was a significant effect of nicotine treatment on the
volume. Thus the P-V curve in the nicotine-treated hearts is shifted to
the right with no apparent change in slope. The increase in unloaded
volume corresponds to the increase seen in the internal diameters. The
slopes at 5-mmHg pressure increments were not different by ANOVA (Fig.
1B), and this was also true when the
absolute volumes were normalized to the unloaded, zero-pressure volume.
Thus nicotine treatment did not appear to modify overall compliance of
the ventricle, although the shift in unloaded volume together with
comparable slopes could imply a decrease in overall tissue compliance.
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Fig. 1.
A: average passive left ventricular
(LV) pressure-volume (P-V) relationships for nicotine-treated
(n = 6) and control
(n = 5) infarcted hearts. Two-way
ANOVA indicates significant effect of treatment on pressure
(P < 0.011; i.e., right shifted).
Interactive effect of treatment on P-V relationship was not
significant. B: average slopes of LV
P-V relationships for nicotine-treated
(n = 6) and control
(n = 5) infarcted hearts. Nicotine
treatment did not cause a significant change in slope (i.e.,
compliance) of P-V relationship at any pressure.
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To examine differences in tissue mechanics in the infarcted area
independent of LV geometry, epicardial strains were computed as
functions of pressure (Fig. 2). Positive
strains indicate segment lengthening. ANOVA showed a significant effect
of treatment on the strain-pressure relationship for both
E11 and
E22 within the infarct;
E12 was not different. As can be
observed, E11 tended to decrease
with nicotine treatment, whereas
E22 increased substantially.
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Fig. 2.
Two-dimensional LV epicardial strains in infarcted area as functions of
inflation pressure. There was a significant effect of treatment on
pressure-strain relationship for both circumferential
(E11;
P = 0.012) and longitudinal
(E22;
P = 0.001) strains. Shear strains
(E12) were not different. Thus
function in infarcted wall appears to be altered by nicotine
treatment.
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|
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DISCUSSION |
After MI in surviving patients, a process of wound healing begins in
the affected tissue. The extent and efficacy of postinfarction healing
greatly influences the ensuing process of cardiac remodeling (6).
Adversely affected cardiac remodeling parameters such as progressive
cardiac enlargement are known to correlate closely with the development
of heart failure or death. Although the association between cigarette
smoking and delayed or impaired wound healing has been recognized in
clinical fields such as surgery (4), there are no carefully controlled
studies that examine the effects of cigarette smoking on postinfarction
wound healing and ventricular remodeling. The purpose of the current
study was to assess the effects of nicotine, an important derivative of
cigarette smoke, on wound healing and remodeling after infarction in
rats. Results from the current study indicate that the application of
transdermal nicotine before MI in rats generates important and adverse
modifications to various LV remodeling parameters 7 days after MI.
Elevation of nicotine levels induced an enlargement of the LV cavity,
thinning of the infarcted wall, and a more spherically shaped LV
(shortened long axis). These geometric changes were accompanied by
changes in the passive mechanics of the LV as evidenced by a
right-shifted P-V relationship and a change in wound (i.e., developing
scar) two-dimensional pressure strain characteristics, independent of wound size.
Thus results from this study provide initial evidence for the adverse
effects of nicotine on postinfarction LV healing and remodeling. Future
studies should examine the mechanism of action of nicotine on tissue
wound healing and long-term consequences that follow these
observations, in particular those that follow myocardial infarction.
Ultimately, large clinical studies will be needed to establish the
consequences of MI in humans who are using tobacco or nicotine
products. The establishment of impaired scarring in humans might also
lead to reassessment of current accepted postinfarction therapy in
patients who smoke.
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ACKNOWLEDGEMENTS |
This study was supported by National Heart, Lung, and Blood
Institute Grant HL-03160 to F. Villarreal.
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FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: F. J. Villarreal, UCSD Med. Ctr., 200 West Arbor St., San Diego, CA 92103-8412.
Received 7 October 1998; accepted in final form 3 December 1998.
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Am J Physiol Heart Circ Physiol 276(3):H1103-H1106
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Abstract
Introduction
