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(Circulation. 1997;95:2130-2140.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Cardiac Denervation on Development of Heart Failure and Catecholamine Desensitization
From the New England Regional Primate Research Center (N.S., S.F.V., R.K.K., M.U., K.A., T.A.P.), Southborough, Mass; Allegheny University of the Health Sciences (S.F.V., R.K.K., K.A., T.A.P., R.P.S.), Pittsburgh, Pa; the Department of Medicine (S.F.V., R.K.K., D.E.V.), Harvard Medical School (N.S., S.F.V., Y.-T.S, R.K.K., B.G-M., M.U., K.A., I.M., T.A.P., D.E.V.), and Brigham & Women's Hospital (S.F.V., D.E.V.), Boston, Mass; and the Department of Pediatrics (D.E.V.), Massachusetts General Hospital, Boston.
Correspondence to Dorothy E. Vatner, MD, New England Regional Primate Research Center, One Pine Hill Dr, PO Box 9102, Southborough, MA 01772-9102.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background Two signatures of heart failure are activation of the sympathetic nervous system and catecholamine desensitization. However, whether or not the elimination of cardiac nerves affects either the progression of heart failure or catecholamine desensitization is not clear.
Methods and Results We studied 8 dogs with selective ventricular denervation (VD) (surgical technique) and 10 intact dogs, chronically instrumented for measurement of left ventricular (LV) and arterial pressures, LV dP/dt, LV internal diameter, and wall thickness before and after heart failure was induced by rapid pacing (240 bpm) for 3 to 4 weeks. VD was confirmed by the absence of reflex effects induced by intracardiac veratrine and depletion of tissue norepinephrine and by supersensitive responses to norepinephrine. During the development of heart failure, LV end-systolic and end-diastolic stresses and heart rate increased, while myocardial contractility, as reflected by LV dP/dt and mean velocity of circumferential fiber shortening corrected for heart rate (Vcfc), decreased in both intact and VD dogs. However, the increases in LV end-diastolic stress and decreases in LV dP/dt as well as the relationship between LV systolic stress and Vcfc in heart failure were less (P<.05) in VD dogs. The responses of LV dP/dt and heart rate to both isoproterenol and norepinephrine in intact dogs were reduced in heart failure. The physiological desensitization to the inotropic effects of isoproterenol and norepinephrine was less in dogs with VD (P<.05), but chronotropic responses were similar because atrial innervation remained intact. Plasma norepinephrine levels were not different in VD dogs (592±79 pg/mL) compared with intact dogs (576±81 pg/mL) in heart failure.
Conclusions Dogs with selective VD tolerated the development of heart failure better than intact dogs and demonstrated significantly less catecholamine desensitization. The latter indicates that intact ventricular innervation is required for physiological expression of catecholamine desensitization despite comparable elevation of plasma catecholamines during the development of heart failure.
Key Words: ventricular denervation • catecholamines • receptors, beta, adrenergic • heart failure • physiology
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Introduction |
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It is well known that the sympathetic nervous system is activated and circulating catecholamine levels are increased in heart failure.1 2 3 4 5 However, whether or not these compensatory mechanisms affect the progression of heart failure is controversial. Whereas some studies have suggested that compensatory sympathetic nerve activity could play a supportive role in heart failure,6 7 other studies have suggested the opposite, that ß-adrenergic receptor blockade is beneficial in heart failure.8 9 10 11 12 13
Catecholamine desensitization is another hallmark of heart failure.14 15 16 17 18 19 20 21 22 The trigger for catecholamine desensitization could be either increased circulating catecholamine levels,15 17 23 increased cardiac neural activity, or both. Both of these questions, ie, the role of cardiac nerves in the progression of heart failure and their role in catecholamine desensitization in heart failure, could be approached with the use of models of either surgical cardiac denervation or pharmacological therapy. The surgical technique does not have the disadvantage of complicating influences of chronic ß-adrenergic receptor blockade therapy.24 Moreover, when a model of selective VD is used, heart rate control remains intact.
Accordingly, to achieve these goals, we compared the effects of pacing-induced heart failure in intact, conscious dogs and dogs with selective surgical VD. This study had four components: (1) documentation of completeness of VD, (2) documentation of denervation supersensitivity to the sympathetic neurotransmitter NE, (3) determination of whether dogs with VD fare better hemodynamically during the development of heart failure, and (4) determination of the mechanism of catecholamine desensitization in heart failure, ie, whether it involved cardiac nerves or circulating catecholamine levels.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Instrumentation
Thirty adult mongrel dogs of either sex weighing 20 to 30 kg each were anesthetized with halothane (0.5 to 1.5 vol%) and ventilated with a Harvard respirator after induction with thiamylal sodium (10 to 15 mg/kg IV). A left thoracotomy was performed through the fourth intercostal space by use of a sterile technique. In 15 dogs, surgical VD was performed.25 A solid-state miniature pressure gauge (model 22, Königsberg Instruments, Inc) was implanted in the LV through the apex. Tygon catheters (Norton Elastic and Synthetic Division) were implanted in the descending thoracic aorta and left atrial appendage. Piezoelectric ultrasonic dimension crystals were implanted on opposing anterior and posterior endocardial surfaces of the LV to measure the LV internal diameter and on opposing endocardial and epicardial surfaces to measure wall thickness. A screw-in type of pacing lead was attached to the RV free wall, and left atrial pacing electrodes were implanted. Catheters and leads were externalized, and the thoracotomy was closed. The chest was evacuated. Each dog was treated with 1 g of cephalothin for 10 days after surgery. In 15 dogs, the same instrumentation was implanted without VD (intact group). All dogs tolerated the operation. Two intact dogs and 3 VD dogs were euthanatized due to infection or bleeding within the first postoperative month before pacing was initiated. Animals used in this study were maintained in accordance with guidelines of the Committee on Animals of the Harvard Medical School and the Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services publication No. NIH 83-23, revised 1985).
Experimental Measurements
Experiments were initiated 2 to 3 weeks after recovery from
surgical instrumentation, when the dogs were healthy, ie, body
temperature, blood cell count, and chemistry were within normal limits.
Hemodynamic measurements were recorded with the
dogs fully awake, lying quietly on their right side. The fluid-filled
catheters in the aorta and left atrium were connected to strain-gauge
manometers (Statham Instruments) for the measurement of
arterial and atrial pressures. LV pressure was measured
with a solid-state miniature pressure gauge and calibrated in vivo
against the measurement of systolic arterial and
left atrial pressures. LV wall thickness and internal diameter were
measured with an ultrasonic transit-time dimension gauge. A
cardiotachometer triggered by the pressure pulse provided instantaneous
and continuous records of heart rate. The position of all catheters
and crystals was confirmed after euthanasia.
Experimental Protocol
Eighteen dogs (intact dogs, n=10; VD dogs, n=8) were studied in
the control state and 1 day, 1 week, and 3 to 4 weeks after pacing, ie,
as heart failure developed. An additional 7 dogs (intact dogs, n=3; VD
dogs, n=4) were studied as controls over the same time period without
inducing heart failure. There were four components involved in this
study: (1) documentation of completeness of VD, (2) documentation of
denervation supersensitivity, (3) determination of the effects of VD on
the progression of heart failure, and (4) determination of the effects
of VD on expression of catecholamine desensitization during
the development of heart failure.
Tests of Adequacy of Denervation Procedure
1. Electrical stimulation of cardiac nerves at surgery: VD was
confirmed by the elimination of both the ECG and positive inotropic
responses of the left ansa subclavia and thoracic vagi and positive
inotropic responses of the right ansa subclavia by electrical
stimulation (10 to 20 Hz, 5.0 ms, 5 to 10 V).
2. Reflex stimulation of cardiac nerves in conscious dogs: In 10 intact and 8 VD dogs, the responses to nitroglycerin (5 µg/kg IV), phenylephrine (5 µg/kg IV), and intracardiac (left atrial) veratrine alkaloid (5 µg/kg), which stimulates ventricular nerves, were tested 2 to 3 weeks after surgery.
3. Measurement of cardiac tissue NE: After the physiological studies were completed, the animals were anesthetized with sodium pentobarbital (30 to 50 mg/kg IV), and at the time of euthanasia, LV tissue samples were removed immediately and placed in liquid nitrogen. Tissue NE levels were measured by a radioenzymatic assay.20
4. To determine whether the VD procedure was successful over the full time course of these experiments, both heart rate and mean arterial pressure responses to nitroglycerin, phenylephrine, and veratrine as well as inotropic responses to NE (0.05, 0.1, and 0.2 µg·kg-1·min-1 IV) were tested in three intact dogs and four VD dogs at 2, 3, and 8 to 9 weeks after surgical denervation.
Documentation of Denervation Supersensitivity
The 5-minute infusion of each dose of the sympathetic
neurotransmitter NE (0.05, 0.1, and 0.2
µg·kg-1·min-1
IV) was examined in 10 intact and 8 VD dogs. On a separate day,
5-minute infusions of NE (0.05, 0.1, and 0.2
µg·kg-1·min-1
IV) were studied in the presence of ganglionic blockade with
hexamethonium bromide (30 mg/kg IV) and methylatropine
bromide (0.1 mg/kg IV) in 8 intact and 6 VD dogs. Absence of reflex
heart rate changes in response to changes in arterial
pressure induced by phenylephrine (5 µg/kg IV) and
nitroglycerin (5 µg/kg IV) confirmed the adequacy of
ganglionic blockade.
Effects of VD on the Progression of Heart Failure
Hemodynamic measurements were made in the
control state in the absence and presence of ganglionic blockade, after
which rapid ventricular pacing was initiated at a rate of
240 bpm and controlled by use of a programmable pacemaker (model
EV4543, Pace Medical Inc), which was worn externally in a vest.
Additionally, in controls, the relationship between LV
end-systolic stress as an index of afterload and
Vcfc was examined by use of infusions of
phenylephrine (1, 2, and 5
µg·kg-1·min-1
IV) at a constant heart rate (150 bpm). Baseline
hemodynamics were recorded subsequently 1 day, 1
week, and 3 to 4 weeks after pacing, when heart failure was manifest.
Baseline hemodynamics were also recorded in the
absence and presence of ganglionic blockade. All data were collected
during normal sinus rhythm after a 30-minute stabilization period after
cessation of pacing. Plasma catecholamine samples were
taken in the control state and before the animals were killed and were
measured by a radioenzymatic assay.20
Effects of VD on Expression of Catecholamine
Desensitization During the Development of Heart Failure
Infusions of NE (0.05, 0.1, and 0.2
µg·kg-1·min-1
IV, each dose for 5 minutes) were repeated at 1 day, 1 week, and 3 to 4
weeks after induction of rapid pacing. The infusions of NE (0.05, 0.1,
and 0.2
µg·kg-1·min-1
IV) after ganglionic blockade plus atropine were also repeated at 3 to
4 weeks after pacing. All data were collected in sinus rhythm with the
pacemaker turned off except for selective experiments at a constant
heart rate (180 bpm) before and after heart failure. Infusions of ISO
(0.05, 0.1, 0.2, and 0.4
µg·kg-1·min-1
IV, each dose for 5 minutes) were also examined in both intact and VD
dogs before and after heart failure in the presence and absence of
ganglionic blockade, with and without heart rate held constant with
atrial pacing (240 bpm). During ISO infusions in the presence of
ganglionic blockade, mean arterial pressure was maintained
at baseline levels by use of phenylephrine infusions.
Data Analysis
Hemodynamic measurements were recorded on a
multichannel tape recorder (Honeywell) and played back on a
direct-writing oscillograph (Gould-Brush). LV, arterial,
and left atrial pressures, LV internal diameter, and wall-thickness
analog signals were digitized (500 Hz), and LV wall thickening, LV
diameter, LV fractional shortening, Vcfc, and LV wall
stress were calculated with the use of a computer-based (Data
Acquisition) system (Notocord System).
Statistics
Data were expressed as mean±SE and were collected from the same
dogs before and after heart failure. Baseline
hemodynamics before and after heart failure were tested
by Student's t test. Baseline hemodynamics
before and 1 day, 1 week, and 3 to 4 weeks after the development of
heart failure in the two groups and responses to NE and ISO before and
after heart failure between both groups were tested statistically with
a repeated measures ANOVA procedure of Super ANOVA (Abacus Concepts).
Regression lines were compared by differences in both slopes and
elevations of the lines by use of the F test. A value of
P<.05 was considered indicative of a significant
difference.
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Results |
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Confirmation of VD
The completeness of VD was confirmed in three different ways. At surgery, electrical stimulation of cardiac nerves (left ansa subclavia) increased LV dP/dt by 86±14% before VD and did not increase LV dP/dt after VD. After recovery from surgery, in the intact group, phenylephrine (5 µg/kg IV) increased mean arterial pressure by 34±4 mm Hg and decreased heart rate reflexly by 28±5 bpm, whereas nitroglycerin (5 µg/kg IV) decreased mean arterial pressure by 14±1 mm Hg and increased heart rate by 47±8 bpm, and veratrine decreased mean arterial pressure by 25±8 mm Hg and heart rate by 38±9 bpm. In contrast, in the VD dogs, the responses to phenylephrine and nitroglycerin were similar, confirming the integrity of sinoaortic reflexes and sinoatrial nodal innervation. However, the responses of heart rate and mean arterial pressure to veratrine were abolished (Fig 1
),
confirming selective VD.
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Finally, at the time of euthanasia, LV and RV NE levels were 510±97
and 566±130 pg/mg wet wt, respectively, in intact sham dogs, whereas
in VD control shams, tissue NE levels were 1.7±0.1 and 1.8±0.2 pg/mg
wet wt, respectively. After heart failure, LV and RV NE levels were
significantly decreased in intact dogs (P<.05) compared
with sham intact dogs, ie, 137±28 and 152±33 pg/mg wet wt,
respectively. In VD dogs with heart failure, LV and RV NE levels were
similar to those in sham VD dogs, ie, 2.4±0.3 and 3.1±0.9 pg/mg wet
wt, respectively (Fig 2).
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P<.05 before and after heart
failure.
Denervation Supersensitivity Before Heart Failure
In intact dogs, NE (0.2
µg·kg-1·min-1)
increased LV dP/dt by 39±6% from 3098±237 mm Hg/s. In
contrast, in VD dogs, the same dose of NE increased LV dP/dt
significantly more, by 143±19% from 2404±56 mm Hg/s.
Dose-response relationships confirmed these individual effects (Fig 3,
left panel).
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) and VD
dogs (
), in the intact state (left) and in the presence of
ganglionic blockade (right). The increases in LV dP/dt were enhanced
significantly (P<.05) in VD dogs compared with intact dogs,
demonstrating denervation supersensitivity. *P<.05 for
difference in regression lines in intact and VD dogs.
In the presence of ganglionic blockade (Fig 3
, right panel), the
response of LV dP/dt to NE was still enhanced in VD dogs compared with
intact dogs, eg, during NE (0.2
µg·kg-1·min-1),
LV dP/dt was increased more (by 255±35%, from 2080±133
mm Hg/s) than in intact dogs (169±21%, from 2140±146 mm Hg/s)
(P<.05). Dose-response relationships confirmed these
individual effects.
Confirming the persistence of VD, both heart rate and mean arterial pressure responses to phenylephrine, nitroglycerin, and veratrine were not changed 2, 3, and 8 to 9 weeks after surgery in three intact dogs and four VD dogs. Furthermore, responses to NE (0.2 µg·kg-1·min-1) also were not changed, ie, supersensitive responses for LV dP/dt persisted (148±26% at 2 weeks, 147±27% at 3 weeks, and 155±29% at 8 to 9 weeks after surgery) in the four VD dogs.
Effects of VD on Baseline Hemodynamics
Before heart failure, heart rate, LV systolic pressure,
mean arterial pressure, LV end-diastolic
pressure, fractional shortening, Vcfc, and
end-systolic and end-diastolic wall stresses were
not different between intact dogs (n=10) and VD dogs (n=8). However, LV
dP/dt was slightly (P<.05) lower in VD dogs (2576±142
mm Hg/s) than in intact dogs (2991±163 mm Hg/s). (See Table 1.)
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In the presence of ganglionic blockade, there were no significant hemodynamic differences between intact and VD dogs.
Effects of VD on Responses to Heart Failure
In intact conscious dogs, heart failure increased heart rate
(+29±4 bpm), LV end-diastolic pressure (+18.3±1.8
mm Hg), and end-systolic (+25.5±4.3 g/cm2) and
end-diastolic (+41.1±4.5 g/cm2) wall stresses,
whereas mean arterial pressure (-18±3 mm Hg), LV
dP/dt (-1486±178 mm Hg/s), fractional shortening
(-11.9±2.4%), and Vcfc (-0.59±0.12
s-1) decreased significantly. In VD dogs, the
decreases in LV dP/dt (-950±170 mm Hg/s) and increases in LV
end-diastolic pressure (+9.4±1.6 mm Hg/s) and wall
stress (+23.8±4.0 g/cm2) were significantly attenuated
(P<.05) as heart failure developed compared with responses
in intact dogs (Fig 4). Furthermore, the inverse
relation between Vcfc and LV end-systolic wall
stress was steeper in intact dogs as heart failure developed compared
with responses to an acute increase in afterload induced with
phenylephrine. Importantly, this relationship was better
maintained in VD dogs than in intact dogs (Fig 5). Heart
rate changes were similar between intact and VD dogs.
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In the presence of ganglionic blockade, the differences between intact and VD dogs appeared to be more pronounced, ie, in VD dogs, end-diastolic pressure (+8.7±1.4 mm Hg) and wall stress (+24.1±3.8 g/cm2) increased less during the development of heart failure than in intact dogs (+19.5±1.7 mm Hg and +49.0±4.2 g/cm2, respectively; P<.05). Similarly, LV dP/dt (-509±135 mm Hg/s), Vcfc (-0.13±0.08 s-1/2), and fractional shortening (-2.0±1.8%) tended to decrease to a lesser extent in VD dogs than they did in intact dogs as heart failure developed (-1106±163 mm Hg/s, -0.33±0.08 s-1/2, and -6.9±1.6%, respectively).
In intact dogs, plasma NE increased (to 576±81 from 223±18 pg/mL) and plasma EPI increased significantly (to 332±86 from 142±21 pg/mL; P<.05) during the development of heart failure. In VD dogs, baseline plasma NE and EPI levels were not different (NE, 219±43 pg/mL; EPI, 169±24 pg/mL), nor were the observed increases in plasma catecholamines (NE, 592±79 pg/mL; EPI, 344±60 pg/mL) different during the development of heart failure compared with intact dogs.
Despite the attenuated changes in LV geometry in VD dogs during the development of heart failure, there were no significant differences in LV plus septum weight/body weight among all groups, ie, LV plus septum weight/body weight was 5.1±0.1 g/kg in intact dogs without heart failure, 4.9±0.3 g/kg in intact dogs with heart failure, 5.1±0.2 g/kg in VD dogs without heart failure, and 4.8±0.3 g/kg in VD dogs with heart failure.
Effects of VD on Responses to ISO in Heart Failure
Chronotropic Effects of ISO
In controls, the heart rate responses to ISO (0.4
µg·kg-1·min-1)
increased significantly (P<.05) and similarly in both
intact dogs (+103±15% from 104±3 bpm) and VD dogs (+100±10% from
104±6 bpm). After the development of heart failure, the heart rate
response to ISO was attenuated similarly and significantly in both
groups (intact, +33±6%; VD, +32±7%) (Table 2).
Similar chronotropic desensitization to ISO was observed in the
presence of ganglionic blockade for both groups (Table 2). Taken
together, these heart rate data indicate that desensitization to the
ß-adrenergic agonist ISO occurred to a similar extent in the atria of
both intact and VD dogs, in which cardiac innervation was intact. (See
Figs 6 and 7.)
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Inotropic Effects of ISO
In the control state, the LV dP/dt response to ISO (0.4
µg·kg-1·min-1)
increased significantly (P<.05) in both intact (+165±15%
from 3128±212 mm Hg/s) and VD (+205±19% from 2469±92
mm Hg/s) dogs. After the development of heart failure, the LV dP/dt
response to ISO was attenuated significantly (P<.05) in the
intact dogs (+72±10% from 1529±74 mm Hg/s) compared with VD
dogs in which the ISO response was preserved (+198±23% from
1555±60 mm Hg/s) (Table 2; Fig 8).
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To be certain that differences in heart rate responses did not
contribute to the differential inotropic responses between intact and
VD dogs, the response to ISO (0.4
µg·kg-1·min-1)
was compared with heart rate held constant by atrial pacing at 240 bpm.
In intact dogs, ISO (0.4
µg·kg-1·min-1,
n=10) increased LV dP/dt by 151±13% from 3081±340 mm Hg/s
before the development of heart failure, whereas the LV dP/dt response
to ISO was significantly less (+68±10% from 1756±139 mm Hg/s;
P<.05) after the development of heart failure. In contrast,
in VD dogs, ISO (0.4
µg·kg-1·min-1,
n=7) increased LV dP/dt similarly before and after heart failure
(before, 184±24%; after, 180±25%) (Fig 9). The
presence of ganglionic blockade did not further alter the pattern or
the magnitude of desensitization in either intact or VD dogs (Table 2).
Thus, selective VD prevented the development of desensitization to the
inotropic effects of the ß-adrenergic receptor agonist ISO.
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Effects of VD on Responses to NE in Heart Failure
Chronotropic Effects of NE
Heart rate decreased significantly (P<.05) by
15±2% from 99±4 bpm in response to NE (0.2
µg·kg-1·min-1)
in intact dogs. In VD dogs, the chronotropic effects of NE were not
different compared with those in intact dogs, ie, -12±3% from 101±6
bpm. After the development of heart failure, NE decreased heart rate
significantly less in both intact and VD dogs.
In the presence of ganglionic blockade, NE (0.2 µg·kg-1·min-1) increased heart rate by 27±8% in intact dogs before heart failure, and after heart failure, the increase in heart rate was less (4±2%; P<.05). In VD dogs, NE (0.2 µg·kg-1·min-1) increased heart rate by 30±9% before heart failure. After heart failure, the increase in heart rate in response to NE was less (12±4%; P<.05). These values were not different from those in intact dogs, suggesting that desensitization during the development of heart failure occurred similarly in the atria of both intact and VD dogs, in which cardiac innervation was intact.
Inotropic Effects of NE
In intact dogs, NE (0.2
µg·kg-1·min-1)
increased LV dP/dt by 39±6% from 3098±237 mm Hg/s. After the
development of heart failure, the LV dP/dt response to NE was
desensitized significantly, ie, NE increased LV dP/dt significantly
less (P<.05) by 24±5% from 1460±80 mm Hg/s. In
contrast, the LV dP/dt responses to NE (0.2
µg·kg-1·min-1)
were not desensitized after the development of heart failure in VD
dogs. NE increased LV dP/dt by 143±19%, from 2404±56 mm Hg/s
before heart failure. After heart failure, NE increased LV dP/dt by
136±20% from 1586±72 mm Hg/s (Fig 10). These
responses were not different before and after the development of heart
failure (Table 3).
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To be certain that differences in heart rate responses did not
contribute to the differential inotropic responses between intact and
VD dogs, the response to NE (0.2
µg·kg-1·min-1)
was compared with heart rate held constant with ventricular
pacing at 180 bpm. In intact dogs, NE (0.2
µg·kg-1·min-1,
n=10) increased LV dP/dt by 68±12% from 2642±211 mm Hg/s
before the development of heart failure, whereas the LV dP/dt response
to NE was significantly decreased (+38±4% from 1218±54
mm Hg/s; P<.05) after the development of heart failure. In
contrast, in VD dogs, NE (0.2
µg·kg-1·min-1,
n=7) increased LV dP/dt similarly before and after heart failure
(before, 187±19%; after, 176±15%) (Fig 11).
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In the presence of ganglionic blockade, NE (0.2
µg·kg-1·min-1)
increased LV dP/dt by 169±21% from 2140±146 mm Hg/s in intact
dogs before the development of heart failure, whereas the LV dP/dt
response to NE was attenuated significantly (+50±7% from
1141±101 mm Hg/s; P<.05) after the development of
heart failure. In contrast, the LV dP/dt response to NE was not
desensitized after the development of heart failure in VD dogs. NE (0.2
µg·kg-1·min-1)
increased LV dP/dt by 255±35% from 2080±133 mm Hg/s before the
development of heart failure and by 226±26% from 1648±17
mm Hg/s after the development of heart failure (Table 3).
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Discussion |
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There are two unique features to the current investigation: (1) the use of an animal model with selective VD to study the role of cardiac nerves on the progression of experimental heart failure and (2) the use of this model to study mechanisms of catecholamine desensitization in heart failure. There were two major findings. First, the elimination of ventricular nerves attenuated the decline of cardiac function during the progression of heart failure. Second, we demonstrated that cardiac nerves, rather than circulating catecholamines, were responsible for physiological desensitization to sympathomimetic amines during the development of heart failure.
The approach used in the current investigation was different from prior studies in that selective VD was used to interrupt neural traffic, as opposed to pharmacological blockers. Selective VD did not exert major effects on baseline cardiac function. One reason is that heart rate and atrial function were not disturbed because atrial innervation remained intact. Second, in healthy, conscious dogs, baseline sympathetic tone is relatively low. Therefore, it was not surprising that selectively interrupting the ventricular cardiac nerves did not exert a major effect on baseline cardiac function.
The first major finding of the current investigation is that dogs with
selective VD tolerated the development of heart failure better than
control animals with intact nerves that were subjected to the chronic
rapid-pacing stimulus. In support of this concept, increases in LV
end-diastolic pressure and wall stress and decreases in
myocardial contractility in VD dogs were less as heart
failure developed than they were in intact dogs. However, chronotropic
changes were similar because, as noted above, atrial innervation
remained intact. The protective effects of VD were even more apparent
in the presence of ganglionic blockade (Table 1). Under these
conditions, atrial function, eg, heart rate, did not change with
induction of heart failure, but decreases in LV dP/dt and
Vcfc and increases in LV end-diastolic pressure
and stress were clearly less in VD dogs. One other study26
examined the effects of total cardiac denervation in the response to
heart failure but failed to demonstrate improvement. There are four
major differences between that study and the present study: (1) the
use of selective VD versus total cardiac denervation; (2) direct
measurements of preload, afterload, and myocardial
contractility in the current study, which may be more
precise than those obtained by echocardiography;
(3) the current study was conducted in the presence of ganglionic
blockade, in which differences between VD and intact dogs were even
more apparent; and (4) the current investigation was conducted in awake
animals, whereas echocardiographic studies generally
require sedation, which could affect both cardiac loading conditions as
well as contractility.26
Of critical importance in studies involving cardiac denervation is documentation that the denervation is complete and persistent. To this end, completeness of denervation was confirmed initially at the time of surgery by observing the abolition of effects of electric stimulation of sympathetic nerves. At the time that experiments were conducted in the conscious animals, arterial baroreflex responses elicited by phenylephrine and nitroglycerin confirmed that baroreflex control of heart rate remained intact. However, stimulation of ventricular receptors with veratrine alkaloids demonstrated that reflex hypotension and bradycardia were not observed in dogs with VD. After the end of the experiments, demonstration of depletion of tissue norepinephrine further confirmed denervation. Finally, a separate group of animals with VD was studied for 2 months, ie, the time period for all protocols to be completed in the dogs with heart failure. In these animals, supersensitivity to NE, a signature of denervation, was observed without abatement during the entire 2-month observation period.
The extent to which different models of denervation demonstrate supersensitivity remains controversial. Because this topic has not been examined in a model of selective VD, it was important to investigate it as part of the present study. Denervation supersensitivity is mainly caused by lack of neural uptake mechanisms for the neurotransmitter NE.27 Second, loss of baroreflex buffering of cardiac function plays a role.27 Third, postsynaptic supersensitivity mechanisms are also involved.27 For these reasons, supersensitivity to NE was most significant because with NE, several mechanisms, ie, lack of neural uptake, baroreflex buffering, and postsynaptic mechanisms, all play a role. After ganglionic blockade, the supersensitivity was still present but less apparent.
The second major goal of the current investigation was the determination of the mechanism of catecholamine desensitization in heart failure. It has not been clear whether the chronically elevated circulating catecholamines are responsible for the catecholamine desensitization, which is another hallmark of heart failure. If circulating catecholamines were the predominant stimulus, then desensitization should not have been attenuated in the animals with VD. Heart failure induced classic catecholamine desensitization to inotropic responses induced by both ISO and NE in intact dogs, both in the presence and absence of ganglionic blockade. However, this was not observed in dogs with VD. In contrast, chronotropic responses induced by both ISO and NE were desensitized similarly in intact dogs and dogs with VD, again confirming the presence of intact atrial innervation. Because chronotropic changes were similar in both groups, it was not surprising that additional experiments conducted with heart rate held constant by electrical pacing confirmed the inotropic desensitization to ISO and NE in intact dogs with heart failure and the lack of desensitization in VD dogs with heart failure.
Therefore, because desensitization was significantly prevented with the development of heart failure in VD dogs, it suggests that NE released from neurons, rather than circulating catecholamines, is the dominant trigger. In support of this are studies showing a much higher concentration of NE in the synaptic cleft than occurs in the systemic circulation.28 Moreover, administration of catecholamines to mimic the rise in plasma NE and EPI observed in heart failure has surprisingly little effect on cardiac function in normal animals.29 These observations in combination suggest that high concentrations of catecholamines are required to initiate desensitization mechanisms, which can be achieved by neural stimulation but not by the levels of circulating catecholamines generally observed in heart failure.
It might be argued that the reason that VD dogs failed to demonstrate
catecholamine desensitization was simply that the severity
of heart failure was less. To address this point, it must be noted that
catecholamine desensitization is apparent at 1 day of
pacing30 and decreases further with 1 week of pacing and
then with 3 to 4 weeks of pacing. Hemodynamic
impairment in terms of decreases in LV dP/dt and increases in LV
end-diastolic pressure were similar in the intact dogs at 1
week and the VD group at 3 to 4 weeks (Fig 4; Table 3), yet as noted
above, catecholamine desensitization was clearly apparent
after 1 day of pacing in intact dogs30 but was not evident
after 3 to 4 weeks of pacing in VD dogs (Figs 8 and 10).
In summary, cardiac nerves play a critical role in the progression of
heart failure. As noted above, cardiac nerves mediate
catecholamine desensitization. We might then speculate that
desensitization mechanisms are potentially protective and that
continued sympathetic stimulation might be deleterious in the
progression of heart failure. Thus, although cardiac nerves may play an
important role in the response to stress, in the chronic setting, these
compensatory mechanisms may actually exacerbate the condition of
cardiac dysfunction. In support of this concept are the current
experiments in dogs with VD, which tolerated the development of heart
failure better as evidenced by less severe hemodynamic
perturbations. Further evidence can be extrapolated from recent
experiments in our laboratory with a transgenic mouse model with
overexpressed Gs
, in which chronically enhanced
sympathetic stimulation during the life of the animals resulted in a
picture of cardiomyopathy.31 32
Whether these concepts are unique to the specific models studied or can
be extrapolated to human heart failure remains to be determined.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Sato is the recipient of the Samuel A. Levine Fellowship grant from the American Heart Association, Massachusetts Affiliate. Dr Shannon is the recipient of a Clinician-Scientist Award from the American Heart Association. This study was supported in part by USPHS grants HL-38070, HL-33107, HL-37404, and RR-00168.
Received July 29, 1996; revision received November 13, 1996; accepted November 25, 1996.
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References |
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