From the Krannert Institute of Cardiology (D.P.Z.), Department of
Medicine, Indiana University School of Medicine, and the Roudebush Veterans
Administration Medical Center, Indianapolis, Ind, and the University Hospital
Utrecht (A.E.), Heart Lung Institute, Department of Cardiology, Utrecht, The
Netherlands.
Correspondence to Douglas P. Zipes, MD, Krannert Institute of Cardiology, 1111 West 10th St, Indianapolis, IN 46202-4800.
Methods and Results—We measured the ventricular
effective refractory period (ERP) shortening in response to bilateral
ansae subclaviae stimulation and ERP lengthening induced by bilateral
vagal stimulation as markers of autonomic innervation before and after
RV myocardial infarction (RVMI) produced by coronary ligation
(n=28 dogs) or intracoronary latex injection (n=18 dogs) into a
marginal branch of the right coronary artery in open-chest
anesthetized dogs. In each dog, ERPs measured in viable
peri-infarct area at two RV outflow tract (RVOT) sites and two septal
and four lateral sites at the RV free wall after RVMI showed reduced or
absent ERP shortening during bilateral ansae subclaviae stimulation
laterally, septally, and at RVOT sites 3 hours after RVMI. ERP
shortening in response to infused norepinephrine was still
present. Bilateral vagal stimulation during background
norepinephrine infusion (0.10 to 0.25 µg/kg per minute)
lengthened the ERP at all test sites before latex injection. After
transmural RVMI, vagally induced ERP prolongation was attenuated or
lost at lateral, septal, and RVOT test sites.
Conclusions—RVMI causes sympathetic and vagal denervation at
viable sites at the RVOT, lateral, and, to a lesser extent, septal
sides of the viable peri-infarct area. Autonomic denervation in the
RVOT might contribute to the development of ventricular
tachyarrhythmias after the acute stage of myocardial
infarction involving the RV.
Transmural LV myocardial infarction in patients and dogs produces
afferent and efferent sympathetic and vagal denervation in viable
myocardium apical to the infarcted
area.10 11 12 13 14 15 Although the pattern of sympathetic
and vagal nerve projections to the RV is similar to that of the LV,
the efferent sympathetic nerve fibers to the RVOT are located not only
in the superficial subepicardium but also intramurally and in the
subendocardium.16 Therefore, we sought to assess
the effects of RVMI on efferent sympathetic and vagal innervation of
viable myocardium in the viable peri-infarct area in an
open-chest canine model.
Measurement of ERP
Neural Stimulation
Bilateral Vagal Stimulation
Experimental Design
After the experiment, the heart was fibrillated and excised with the
electrodes still in place. The RV was separated from the remainder of
the heart and cut in slices from base to apex. Each slice was rinsed in
cold tap water and placed in a solution of distilled water,
phosphate-buffered saline, and NBT (Sigma Chemical) at 37°C for 20
minutes. In viable myocytes, NBT is reduced to form a dark purple
diformazan precipitate with intracellular diaphorases that
use NADH or NADPH as electron donors. The infarcted tissue remains
unstained. With this method, we verified the electrode position with
respect to the infarction as well as the transmural nature of the
infarction. No data presented were obtained from electrode
sites located within the region of latex distribution or myocardial
infarction.
Data Analysis
Sites were considered to be completely vagally denervated if
bilateral VS prolonged ERP
The data in this study are expressed as mean±SEM. Both one-way
repeated measures ANOVA and Newman-Keuls comparisons were used to
compare the baseline ERPs and ERP response to sympathetic stimulation
or VS. Statistical significance was set at P<.05.
In the 9 dogs with RVMI produced by latex injection, 3 of the 17 RVOT
test sites exhibited complete sympathetic denervation as early as 20
minutes after latex injection. Nine of 17 RVOT test sites became
completely denervated 180 minutes after latex injection, but none of
the lateral and septal test sites did so (Fig 3
Dogs With Ligation of Marginal Branches of RCA
Eight dogs had transmural RV infarction as demonstrated with NBT
staining. Baseline ERPs of test sites are shown in Table 1
In another group of 5 dogs with ligation of marginal branches of RCA,
shortening of ERP in response to norepinephrine before and
3 hours after coronary occlusion was more pronounced at the
RVOT test sites than at lateral and septal sites (Fig 5
Vagal Denervation
Dogs With Ligation of Marginal Branches of RCA
The ERP data obtained from 5 dogs were excluded from statistical
analysis because dogs had no infarction or nontransmural
myocardial infarction and/or because dogs developed multiple
ventricular fibrillation episodes during refractory period
measurements during infusion of norepinephrine after
coronary ligation. Ventricular defibrillation was
accomplished promptly with the epicardial application of direct current
shocks (20 J), but because it has been previously
shown21 that defibrillating shocks significantly
affect neural responsiveness, these dogs were excluded from data
analysis.
In the remaining 7 dogs, 5 showed transmural myocardial infarction and
2 showed nontransmural myocardial infarction. Baseline ERPs of tested
sites are shown in Table 3
Sympathetic Denervation
Ito and Zipes16 have shown that the efferent
sympathetic fibers are located in the subepicardium and project to
the RV perpendicular to the right lateral AV groove or the LAD. The
sympathetic fibers to the RV myocardium near the RCA stem
predominantly from the right lateral AV groove. RV
myocardium close to the LAD receives sympathetic fibers
from both the right lateral AV groove and areas close to the LAD.
They16 also have shown that the sympathetic
innervation of the RVOT differs from the remainder of the RV and from
the LV. Efferent sympathetic fibers to the RVOT originate both from the
right lateral AV groove near the origin of the RCA and from areas near
the LAD. In the RVOT region, sympathetic fibers are located both in the
superficial subepicardium and deep myocardium.
RVOT Response to Norepinephrine
Vagal Denervation
Cause of Denervation
In this study, as in previous studies12 13 14 15 of LV
infarction, some RVOT test sites that were initially designated as
completely denervated by our arbitrary criteria subsequently showed
responses to neural stimulation that exceeded the complete denervation
cutoff value. Metabolic changes may play a
role,17 18 19 but the exact mechanism of this
phenomenon remains unexplained. Because little is known about the blood
supply to the cardiac nerve fibers, it is still unclear whether neural
denervation results because due to ischemia in the nerve
fibers, as in the contiguous myocardial fibers, or whether exposure to
certain substances in the ischemic environment through which
the axons pass causes functional denervation.18
Complete denervation of the nonischemic myocardium
situated at the RVOT side of the peri-infarct area is best explained by
the alteration of neurotransmission in the axons traveling through the
infarcted myocardium. The myocardial fibers located
septally and laterally receive innervation from nerve fibers traveling
along the LAD and left circumflex artery, which may explain the partial
denervation or attenuation of autonomic responses at these test sites.
Collateral blood flow to the septal and lateral sides of the infarction
may partially explain the absence of complete or partial denervation
after coronary ligation-induced infarction. Collateral blood
flow cannot account for the absence of complete denervation at the
lateral and septal test sites after RVMI produced by latex injection,
because latex embolizes collaterals and produces a transmural
myocardial infarction.
Consideration of the Experimental Model
We studied the autonomic changes up to 3 to 4 hours after
coronary occlusion. Earlier reports11 14
have demonstrated that histochemical changes indicative of autonomic
neural denervation take place within days. In the present study, no
histochemical studies were performed to confirm the functional
alterations in neural responsiveness; therefore, it might be more
accurate to refer to the autonomic alterations as neural dysfunction,
rather than as neural denervation, because we did not obtain
histochemical proof of the latter.
The criteria for denervation were arbitrary in the present study as
they have been used in previous studies.12 13 14 15 16 17 18 19 It
took
Myocardial blood flow was not determined in the present study. The
site of electrode placement with respect to the infarction was
determined with the use of NBT staining. This determination, in
addition to the fact that infusion of norepinephrine
shortened ERPs at the test sites, suggests that there were still
viable, functioning adrenergic receptors at the completely or partially
denervated test sites and that there appeared to be sufficient blood
flow to distribute the infused norepinephrine to these test
sites.
Latex was injected to embolize collaterals and produce a
transmural myocardial infarction in the present study as in
previous studies.12 13 14 15 16 Because of its inert
properties, it is not likely that latex itself interrupted both
sympathetic and vagal responses. Dogs with ligation of marginal
branches of RCA tended to have infarctions with less epicardial
involvement than did dogs with infarctions produced by
intracoronary latex injection. In the present study, vagal
and sympathetic denervations tended to occur more slowly after RVMI
produced by coronary ligation compared with after latex-induced
infarction. RVMI produced by ligation of marginal branches of the RCA
alone also interrupted both sympathetic and vagal responses; therefore,
autonomic denervation after latex-induced RVMI is very likely due to
the infarction and not to the latex.
Clinical Implications
The experimental RVMI model used in the present study differs from
the usual clinical setting. In the majority of patients with RVMI, the
RV is involved as an extension of LV infarction. In many cases, the RV
free wall is not involved in the infarction. Patients with acute RVMI
have acute RV dysfunction that can improve gradually to become almost
normal in time.21 22 23 These issues limit the
direct clinical applicability of the present study.
It has been shown that sympathetic denervation was arrhythmogenic in
dogs with LV myocardial infarction 4 to 22 days after
denervation.14 15 Although arrhythmia
induction was not tested in the present study, it is quite possible
that the heterogeneous development of sympathetic and vagal
denervation at the lateral, septal, and outflow tract sides of the RVMI
might contribute to the development of ventricular
tachyarrhythmias in the acute stage of infarction.
Received May 28, 1997;
revision received September 15, 1997;
accepted September 30, 1997.
2.
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Circulation. 1990;82:1095–1105.
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identification by hemodynamic measurements before and
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J Am Coll Cardiol. 1984;4:931–939.
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© 1998 American Heart Association, Inc.
Basic Science Reports
Right Ventricular Infarction Causes Heterogeneous Autonomic Denervation of the Viable Peri-infarct Area
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Because efferent
autonomic pathways to the right ventricle (RV) differ from the efferent
autonomic projections to the left ventricle (LV), we assessed the
effects of RV infarction on this innervation.
Key Words: infarction • ventricles • innervation
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Isolated RVMI
accounts for <3% of all cases of myocardial infarctions but is often
associated with considerable morbidity and
mortality.1 2 3 4 5 6 7 8 9 RVMI accompanies 30% to 50% of
inferior wall myocardial infarctions and, to a lesser
extent, posterior and anterior wall myocardial
infarctions1 2 3 4 5 6 7 8 9 and is a strong predictor of
arrhythmogenic, ischemic, and mechanical complications and high
in-hospital mortality in patients with acute inferior wall
myocardial infarction.1
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Surgical Preparation
Forty-six mongrel dogs of either sex weighing 20 to 25 kg were
initially anesthetized with pentobarbital sodium (30 mg/kg),
and anesthesia was maintained with 
-chloralose (10 mg/kg
per hour). The dogs were placed on a heating pad, intubated, and
ventilated with room air using a volume-cycled respirator (model 607,
Harvard Apparatus). Left femoral arterial blood
pressure was monitored, and normal saline was infused into the left
femoral vein at a rate of 100 to 200 mL/h to replace spontaneous fluid
losses. The chest was opened through a median sternotomy, and the heart
was suspended in a pericardial cradle. Depending on the
coronary anatomy, one or more proximal marginal
branches of the RCA were isolated for later occlusion. Two hook
electrodes made from Teflon-coated wires, insulated except for their
tips, were placed in myocardium at the RVOT side at the
septal side, and four electrodes were inserted at the lateral side of
the RV free wall (Fig 1
) for cathodal
unipolar stimulation; the anodal electrode was a 33-mm-diameter metal
disk placed in the abdominal wall. A bipolar plunge electrode in the RV
was used to record the ventricular responses induced by
extrastimuli. A thermistor (model 400, Yellow Springs Instrument) was
used to monitor epicardial temperature, which was maintained at 36°
to 38°C with an operating room table lamp and a heating pad. Data
acquisition began 40 minutes after placement of the plunge
electrodes.
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Figure 1. Heart viewed from the right anterolateral aspect.
, Sites of electrode placement; shaded area, region of infarction.
Ao indicates aorta; SVC, superior vena cava; IVC, inferior
vena cava; RA, right atrium; OT, outflow tract; S, septal; L, lateral;
LMA, left main coronary artery; LCx, left circumflex
coronary artery; and LA, left atrium.
The ERPs were determined with the extrastimulus technique using
a programmable stimulator (Krannert Medical Engineering) as reported
previously.11 12 13 14 15 16 17 18 19 20 The ERP, determined to the
nearest 1 ms, was defined as the longest
S1S2 interval at which
S2 failed to produce a ventricular
response. The ERPs were determined in triplicate and averaged.
Bilateral Ansae Subclaviae Stimulation
The ansae subclaviae were isolated as they exited from the
stellate ganglia, doubly ligated, and cut. Shielded bipolar electrodes
were placed on the right and left anterior and posterior ansae
subclaviae and connected to a programmable nerve stimulator (Pulsar 4;
Frederick Haer). Stimuli were rectangular 4-ms pulses delivered at a
frequency of 2 to 4 Hz and 3 to 4 V. Ansae SS intensity was increased
until a 10 to 30 mm Hg increase in mean systemic
arterial blood pressure was produced. Determination of the
refractory period was started 2 minutes after the onset of neural
stimulation. After the experiment norepinephrine was
infused at dosages of 0.20 to 0.25 µg/kg per min, and ERPs were
remeasured. The conditions of neural stimulation were kept constant in
each experiment.
Two Teflon-coated wire electrodes were embedded in the cardiac
end of each vagal nerve. Rectangular pulses of 4-ms duration were
delivered at a frequency of 20 Hz and 0.1 V greater than that required
to produce asystole for the right vagal nerve and asystole or complete
AV block for the left vagal nerve. Effects of VS were determined during
intravenous infusion of norepinephrine at rates
of 0.10 to 0.25 µg/kg per minute to achieve a constant background of
sympathetic tone as reported previously.17 The
amount of norepinephrine infused was kept constant in each
experiment. ERP measured during norepinephrine infusion
served as control for determination of vagal effects on RV
refractoriness.
Baseline ERP values were obtained at control state, during SS,
and during norepinephrine infusion (0.20 to 0.25 µg/kg
per minute). Ten minutes after the baseline ERP values were obtained,
coronary occlusion was performed by latex injection or
coronary ligation. In the group of dogs that underwent latex
injection (n=18), the isolated marginal branch was cannulated with a
PE-50 catheter, and 0.5 mL latex solution was injected to produce
transmural RVMI as in previous studies on LV myocardial
infarctions.12 13 14 15 In 23 dogs, depending on the
coronary anatomy, one or more marginal branches of the
RCA were ligated in a one-stage manner to produce transmural or
nontransmural infarction. ERPs were then determined at 20, 60, 120, and
180 minutes after coronary occlusion. It took 
15 to 20
minutes to determine the ERPs during each session; the data
presented at 20 minutes, for example, were obtained at 20 to 40
minutes after coronary occlusion. In an additional 5 dogs, we
examined the ERP responses to norepinephrine infusion
before and 3 hours after infarction produced by coronary artery
ligation.
As reported previously,11 12 13 14 15 16 17 18 19 20 sites were
considered completely sympathetically denervated if stimulation of
bilateral ansae subclaviae shortened the ERP 
9 ms before
coronary occlusion but 
2 ms after coronary occlusion.
Test sites were considered partially sympathetically denervated if the
ERP shortening induced by bilateral SS was attenuated 60% after
coronary occlusion. In 3 sites of dogs receiving latex
injection and 2 sites of dogs receiving coronary ligation, SS
during the 3 hours after infarction shortened ERP 2 ms on one
occasion and 3 to 6 ms on one or more different occasions, indicating
some oscillation around the cutoff value. These sites were
considered to be completely sympathetically denervated. Three sites
with <9-ms shortening of ERP before coronary occlusion were
excluded from the study because of possibly insufficient effects of
SS. 3 ms before coronary artery
occlusion but 1 ms after coronary occlusion. Test sites were
considered partially vagally denervated if the ERP prolongation
produced by bilateral VS was reduced 60% after coronary
occlusion. In 3 sites of dogs receiving latex injection and 1 site of
dogs receiving coronary ligation, VS during the 3 hours after
infarction lengthened ERP 1 ms on one occasion and 2 to 3 ms on one
or more different occasions, representing some variations
around the cutoff value. These sites were considered to be completely
vagally denervated. Four test sites with <3-ms prolongation of ERP
before coronary occlusion were excluded from the
analysis because of possibly insufficient effects of VS.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Sympathetic Denervation
Dogs With Latex Injection of a Marginal Branch of RCA
In all 9 dogs that received latex injection into a marginal branch
of the RCA, transmural myocardial infarction was demonstrated with NBT
staining, and complete sympathetic denervation was achieved in at least
one RVOT site in each dog over a period of 3 hours. Baseline ERPs of RV
test sites are shown in Table 1. The
cumulative rate of complete and partial sympathetic denervation of the
test sites is shown in Fig 2. In this
figure, the results of complete and partial sympathetic denervation in
latex-induced infarctions and ligation-induced infarctions are
combined, and the insert shows the relative distribution of these
changes.
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Table 1. Changes in Baseline ERP in Sympathetic Denervation
Experiments
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Figure 2. Complete and partial sympathetic denervation at
the viable peri-infarct area of the transmural infarction produced by
intracoronary latex injection and by ligation of marginal
branches of the RCA. Solid line indicates the cumulative percentage of
completely sympathetically denervated RVOT test sites on ordinate as a
function of time; dotted line, data from the lateral, septal, and RVOT
test sites that exhibited partial denervation; numbers, total number of
completely or partially denervated test sites and (in parentheses)
number of test sites that showed shortening of ERP of 2 ms during
bilateral SS at the moment of determination; C, control before
coronary occlusion. The diagram of the heart visualizes with a
gray gradient the extent of the denervation in the viable peri-infarct
area. See text for details.). Three of the 8 RVOT test sites
without complete denervation, 5 of the 18 septal sites, and 19 of the
36 lateral test sites became partially denervated (ie, ERP shortening
induced by bilateral SS was attenuated 60% after coronary
occlusion) 180 minutes after latex injection (Fig 3). Shortening of ERP
in response to norepinephrine was present at all sites
(Fig 3), except for 1 RVOT test site that was located in the infarct
area. This latter site was excluded from the data analysis.
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Figure 3. Shortening of ERP induced by bilateral SS at
lateral, septal, and RVOT test sites before and after
intracoronary latex injection. Top, Sympathetically induced ERP
shortening at lateral and septal sites was attenuated 20 to 60 minutes
after coronary occlusion and declined further thereafter. Nine
RVOT test sites exhibited an ERP shortening to SS of 2 ms on one or
more occasions after latex injection and were therefore regarded as
completely sympathetically denervated (Den(+)). The pattern of
attenuated sympathetic response was also seen at the RVOT test sites
without complete denervation (bottom left) and with complete
denervation (bottom right). ERP shortening during SS was plotted over
time (minutes), starting before coronary occlusion. NE
indicates ERP response to norepinephrine infusion 200
minutes after infarction.
The number of ligated marginal branches supplying the lateral RV
free wall depended on the coronary anatomy of the dog
(average, 2.4±0.3 ligations; n=11 dogs). Three dogs in the
coronary ligation group that developed a nontransmural
myocardial infarction as demonstrated by NBT staining showed no
sympathetic denervation. These dogs demonstrated relatively constant
ERP values over the 3-hour test period and are used as time
controls (Table 2). Their data are not
included in Fig 2
.
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Table 2. Changes in ERP Induced by SS in Five Dogs With
Nontransmural RVMI . In 1 of the
8 dogs with transmural myocardial infarction, no complete sympathetic
denervation was achieved at any RVOT test site. In the remaining 7
dogs, complete sympathetic denervation occurred in at least 1 RVOT test
site. In 1 of the 7 dogs, ventricular fibrillation was
induced during ERP measurement 20 minutes after coronary
ligation. Data obtained after the application of defibrillation DC
shock (20 J) were excluded from the analysis. Complete
sympathetic denervation occurred at 7 of the 14 RVOT test sites 180
minutes after coronary occlusion (Fig 4). Partial denervation (ie, ERP
shortening induced by bilateral SS attenuated 60% after
coronary occlusion) occurred at 15 of the 32 lateral test sites
180 minutes after coronary ligation. At the remaining 7 RVOT
and 16 septal test sites, responses to SS were slightly attenuated over
time (Fig 4). Two RVOT test sites located in the infarct zone as
demonstrated by NBT staining did not show a shortening of ERP in
response to norepinephrine 180 minutes after
coronary occlusion and consequently were not included in the
data analysis.
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Figure 4. Shortening of ERP induced by SS in 8 dogs with
transmural myocardial infarction produced by ligation of marginal
branches of the RCA. Seven RVOT sites exhibited complete sympathetic
denervation. For format and abbreviations, see Fig 3 .). In these dogs, the ERPs were
determined during bilateral SS and then during
norepinephrine infusion before coronary occlusion
and 3 hours after coronary occlusion. Four RVOT test sites
showed complete denervation and 5 RVOT test sites did not exhibit
complete denervation 3 hours after coronary occlusion. There
were no differences in ERP responses to bilateral SS or
norepinephrine infusion between RVOT sites with and without
complete sympathetic denervation.
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Figure 5. Shortening of ERP in response to
norepinephrine (NE) infusion before and 3 hours after
coronary occlusion (CO). ERP shortening at the RVOT sites was
more marked compared with lateral and septal sites
(P<.005). The difference in ERP response to infused NE
between RVOT test sites with and without complete denervation was not
statistically significant (P=NS).
Dogs With Latex Injection of a Marginal Branch of RCA
In 9 dogs receiving intracoronary latex injection, 3 of
the 36 lateral sites and 1 of the 18 RVOT sites were involved in
myocardial infarction; therefore, data from these sites were excluded.
Baseline ERP of test sites are shown in Table 3. Cumulative rate of complete and
partial vagal denervation after latex- and ligation-induced infarctions
are shown in Fig 6. In the 9 dogs with
RVMI produced by latex injection, as early as 20 minutes after
coronary occlusion, 3 RVOT test sites exhibited complete vagal
denervation. Complete vagal denervation was achieved in 11 of 17 RVOT
test sites 3 hours after latex injection (Fig 7). Partial vagal denervation occurred at
17 of the 33 lateral sites, 7 of the 16 septal sites, and 2 of the 6
RVOT test sites without complete denervation over a period of 3 hours.
Lengthening of the refractory period in response to bilateral VS was
significantly attenuated after coronary occlusion over a period
of 3 hours at all test sites (Fig 7).
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Table 3. Changes in Baseline ERP During
Norepinephrine Infusion in Vagal Denervation Experiments
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Figure 6. Cumulative percentage of completely vagally
denervated RVOT sites and partially denervated lateral, septal, and
RVOT test sites after latex- and ligation-induced RVMI in the same
manner as in Fig 2 . Insert shows the distribution of these changes. See
text for details.
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Figure 7. Lengthening of ERP induced by VS in 9 dogs with
transmural myocardial infarction produced by latex injection into a
marginal branch of the RCA. In 11 test sites at the RVOT side of the
infarction, ERP prolongation in response to VS was 1 ms on one or
more occasions after coronary occlusion and according to our
criteria these sites were designated as completely denervated (Den).
None of the RVOT test sites exhibited spontaneous restoration of the
ERP response toward baseline values at more than one consecutive ERP
measurement episode. ERP lengthening in response to bilateral VS was
significantly attenuated after coronary occlusion over a period
of 3 hours at all test sites. ERP prolongation during VS is plotted
over time (minutes). For format and abbreviations, see Fig 3.
The number of marginal branches ligated was dependent on the
coronary anatomy of the dog (average, 2.2±0.5
ligations; 12 dogs). The difference in the number of ligated marginal
branches of the RCA between the vagal denervation group and sympathetic
denervation group was not statistically significant
(P=NS). . The cumulative rate of complete and partial
vagal denervation after coronary ligation is shown in Fig 6.
Complete vagal denervation occurred at RVOT test sites but not at
lateral or septal test sites. Seven of the 13 RVOT sites showed
complete vagal denervation over a period of 3 hours (Fig 8). Partial vagal denervation was
achieved at 11 of the 26 lateral test sites. The ERP lengthening in
response to bilateral VS was markedly attenuated at the lateral test
sites (n=26) and RVOT sites that showed complete vagal denervation,
whereas it was slightly reduced at the septal test sites (n=12) and
RVOT test sites (n=6) without denervation (Fig 8).
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Figure 8. Lengthening of ERP induced by VS in 7 dogs with
RVMI (5 transmural and 2 nontransmural) produced by coronary
ligation. For format and abbreviations, see Fig 3 . See text for
details.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Major Findings
RVMI produced by intracoronary latex injection or ligation
of marginal branches of the RCA caused selective complete sympathetic
and vagal denervation in the viable peri-infarct area at the RVOT side
of the infarction. After latex-induced infarction, partial sympathetic
and vagal denervation occurred at the lateral, RVOT, and septal sides
of the infarction. After ligation-induced infarction, partial
denervation was observed only at the lateral side of the infarction,
and the autonomic responsiveness at the septal and RVOT sites without
denervation was attenuated. This pattern of denervation after RVMI
differs from that after LV infarction. The shortening of ERP at the
RVOT test sites produced by norepinephrine infusion, but
not by bilateral SS, was more pronounced before and 3 hours after
coronary occlusion compared with septal and lateral test
sites.
In the present study, we observed selective complete efferent
sympathetic denervation at viable test sites located at the RVOT side
of the infarction. Partial denervation occurred at the lateral, septal,
and RVOT sides of the infarction produced by latex injection. The
shortening of ERPs in response to bilateral SS after latex-induced RV
infarction was attenuated at the RVOT, lateral, and septal sites
without apparent complete denervation. However, the septal and lateral
sites exhibited less attenuation in shortening of ERPs during bilateral
SS after coronary ligation-induced RVMI (Figs 3 and 4). This
pattern of denervation in the viable peri-infarct zone after RVMI
differs from that after LV infarction. Barber et
al11 have shown that bilateral SS in dogs after
LV myocardial infarction shortened the ERPs at sites basal to the
infarction. However, approximately one third of the tested sites
located apical to, but not within, the zone of infarction no longer
responded to SS after LV infarction.11
Interestingly, in the present study, we observed a more
pronounced ERP shortening to a standard concentration of
norepinephrine infusion at the RVOT test sites compared
with that at septal and lateral test sites. This latter observation is
not due to denervation supersensitivity (ie, chronically denervated
sympathetically denervated myocardium becoming
supersensitive to the effects of infused catecholamines).
The explanation might be a higher density of ß-adrenergic receptors
or a higher sensitivity of these receptors for
catecholamines in this region. However, the exact mechanism
must be delineated in future studies. Denervation supersensitivity was
not noted in the present study, probably because of the short time
course of the experiments.14 15
The pattern of vagal denervation was similar to that of
sympathetic denervation. Functional denervation occurred
heterogeneously and gradually over a period of 3 hours
after coronary occlusion. Ito and Zipes16
have shown that the functional efferent vagal pathways to the RV are
located superficially at the right lateral AV groove and then dive into
the myocardium at 10 to 15 mm from the AV groove, when
all vagal fibers become intramural. RV myocardium near the
RCA receives vagal fibers mainly from the right lateral AV groove,
whereas myocardium near the LAD receives vagal innervation
both from the right lateral AV groove and from regions near the LAD.
Vagal fibers to the RVOT are located deep in the
myocardium, and the innervation pattern does not differ
from the remainder of the RV. Our findings are compatible with the
latter study, showing that transmural and nontransmural myocardial
infarction causes complete vagal denervation at the RVOT side of the
infarction. Vagal denervation at the RVOT side of the peri-infarct zone
might be due to innervation of this area, with nerve fibers
projecting mainly from the RCA and traveling through the infarcted
myocardium. The innervation of lateral and septal sides
stems from both the RCA and left coronary artery and thus
exhibit partial denervation, but not complete elimination, of vagally
induced ERP prolongation at these test sites after infarction.
Vagal and sympathetic responses became lost or attenuated at the
RVOT test sites and became attenuated at the lateral and septal test
sites only within 20 minutes after coronary occlusion, with
additional sites losing responsiveness over time. The time course of
denervation is concordant with that of previous
studies.12 The reason for selective complete
denervation at the RVOT side of the peri-infarct zone might be
innervation of this area with nerve fibers projecting mainly from
the RCA and traveling through the infarcted tissue. The lateral and
septal sides apparently receive nerve fibers from the regions of both
RCA and left coronary artery, which might explain the partial
denervation or attenuation, but not complete elimination, of autonomic
responsiveness of refractoriness at these test sites.
Previous studies14 15 have shown that in the
canine heart 4 to 21 days after transmural myocardial infarction or
dissection of the AV groove, elimination of responses in ERP to
sympathetic stimulation or VS are accompanied by the biochemical
evidence of denervation of sympathetic or vagal fibers. In the
present study, because only a limited number of sites were sampled,
more extensive denervation may exist than suggested by the data
presented. 15 minutes to determine the duration of ERPs both in the
control state and during nerve stimulation. Although it is possible
that minor changes in ERP might occur during these 15 minutes, this did
not seem to be an important source of error. Tables 1 through 3 show
that the baseline ERPs were stable during the experiments. It is
unlikely that electrotonic interactions between infarcted and
noninfarcted areas took place; however, we cannot totally exclude this
possibility.
Zehender et al1 have shown in their series
of 200 patients with acute inferior wall myocardial
infarctions that more than half had RV involvement. Those patients had
a risk of dying in the hospital seven to eight times that for patients
with acute inferior wall myocardial infarctions who did not
have evidence of RV involvement. They1 have also
shown that the poor outcome in their patients could not be explained on
the basis of more severe damage to the LV in these patients. Yusuf et
al3 have suggested that the poor outcome in
patients with inferior wall myocardial infarction with RV
involvement may be due to an increase in serious
ventricular arrhythmias, advanced AV block, and
cardiac rupture.
Selected Abbreviations and Acronyms
AV
=
atrioventricular
ERP
=
effective refractory period
LAD
=
left anterior descending coronary artery
LV
=
left ventricle, ventricular
NBT
=
nitro blue tetrazolium
RCA
=
right coronary artery
RV
=
right ventricle, ventricular
RVMI
=
right ventricular myocardial infarction
RVOT
=
right ventricular outflow tract
SS
=
ansae subclaviae stimulation
VS
=
vagal stimulation
Acknowledgments
This study was supported in part by the Herman C. Krannert Fund
and by grant HL-52323 from the National Heart, Lung, and Blood
Institute of the National Institutes of Health. Dr Elvan was the
recipient of research fellowship grant R95006 from the Dutch Heart
Foundation (The Hague, The Netherlands).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Zehender M, Kasper W, Kauder E, Schontaler M,
Geibel A, Olschewski M, Just H. Right ventricular
infarction as an independent predictor of prognosis after acute
inferior myocardial infarction. N Engl J
Med. 1993;328:981–988.
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