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(Circulation. 1997;96:3416-3422.)
© 1997 American Heart Association, Inc.
Articles |
Increased Myocardial Muscarinic Receptor Density in Idiopathic Dilated Cardiomyopathy
An In Vivo PET Study
From Service de Medecine Nucléaire, Hopital Bichat, Paris (D.L.G., N.D.); Service de Cardiologie, Hopital Beaujon, Paris (A.C.-S.); and Service Hospitalier Frederic Joliot, Département de Recherche Médicale, DSV-CEA, Orsay, France (J.D., A.S., P.M.).
Correspondence to Dominique Le Guludec, Service de Médecine Nucléaire, Hôpital Bichat, 46 rue Henri Huchard, 75018 Paris, France.
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Abstract |
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Background Congestive heart failure is associated with decreased stimulated myocardial adenylate cyclase activity, increased Gi-binding protein, attenuated parasympathetic tone, and increased modulation of ß-adrenergic inotropic left ventricular stimulation by parasympathetic agonists. Despite these abnormalities, changes in the density or affinity of ventricular muscarinic receptors have not been demonstrated in patients.
Methods and Results The density and affinity constants of myocardial muscarinic receptors were evaluated noninvasively by means of positron emission tomography with 11C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, in 20 patients with congestive heart failure due to idiopathic dilated cardiomyopathy (mean left ventricular ejection fraction, 22±9%) and compared with values in 12 normal subjects. The mean receptor concentration was significantly higher in patients than in control subjects (B'max, 34.5±8.9 versus 25±7.7 pmol/mL, P<.005), with no changes in affinity constants. The change in heart rate after injection of 0.6 mg of cold MQNB was lower in patients than in control subjects (34±20% versus 55±36%, P<.05), and receptor density correlated negatively with maximal heart rate in the patients (r=.45, P<.05).
Conclusions Congestive heart failure is associated with an upregulation of myocardial muscarinic receptors. This may be an adaptive mechanism to ß-agonist stimulation and should increase the number of potential targets for pharmacological intervention.
Key Words: receptors • heart failure • nervous system, autonomic
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Introduction |
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Congestive heart failure is associated with a marked imbalance of the autonomic nervous system. This includes an increase in sympathetic drive, downregulation of left ventricular ß-adrenoreceptors, and selective loss of the myocardial contractile response to ß-adrenergic stimulation.1 2 3 Cardiac parasympathetic control in patients with chronic heart failure is less well documented, even though the role of the parasympathetic system is increasingly suspected in heart disease and in the events that characterize its outcome, especially sudden death.4 5 6 7 8 Several lines of evidence suggest that the parasympathetic receptor-effector system is altered in heart failure. A chronic attenuation of cardiac vagal tone has been inferred from studies of heart rate variability in patients with cardiomyopathy.9 10 11 12 13 This attenuation of parasympathetic tone evolves early in the course of ventricular dysfunction in animal models.14 Parasympathetic agonists restore tonic and reflex vagal activity.15 16 17 18 19 In the myocardium, increased modulation of ß-adrenergic inotropic left ventricular stimulation by parasympathetic agonists has recently been demonstrated in experimental heart failure as well as in patients with congestive heart failure.20 21 22 A reduction in GTP-stimulated adenylate cyclase activity and an increase in the amount or functional activity of Gi
regulatory protein have been
reported in animals and humans.23 24 25 26 27 These data suggest
that either the density or affinity of receptors coupling with the
inhibitory guanine nucleotide–binding protein,
which include muscarinic receptors (MR), is altered in the failing
myocardium. The status of MR in the failing heart is controversial. Decreased MR density and specific loss of high-affinity agonist binding have been found in a canine model of cardiac failure secondary to pressure-overload hypertrophy.23 However, in dogs with nonischemic, pacing-induced heart failure, Vatner et al27 recently found an upregulation of MR, together with increased Gi levels and greater inotropic inhibition by acetylcholine. In the only available human study, MR density was found unchanged with an in vitro binding assay in explanted hearts.24
The need for invasive endomyocardial biopsies to obtain samples large enough for in vitro binding measurements has hindered the evaluation of MR in earlier stages of the disease and precluded any comparison with normal subjects. Positron emission tomography (PET), using 11C-methylquinuclidinyl benzilate (MQNB), a highly specific hydrophilic antagonist, as ligand can be used in humans for noninvasive quantification of left ventricular MR with a mathematical model based on a multi-injection protocol.28 29 30 The aim of this study was to compare myocardial MR density and affinity constants in patients with chronic idiopathic heart failure due to idiopathic dilated cardiomyopathy with values in normal subjects.
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Methods |
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Study Population
Patients
We studied 20 men (age, 52±14 years) with chronic congestive heart failure related to idiopathic dilated cardiomyopathy. Criteria for inclusion were symptoms of congestive heart failure (New York Heart Association functional class II to IV) for >6 months; left ventricular radionuclide ejection fraction of
45%; and no recognized cause for
the disease. Valve disease and coronary artery disease
(narrowing >50% of the lumen artery) were ruled out in all patients
by coronary angiography and left ventricular
angiography <6 months before the PET study. Patients with diabetes
mellitus or severe systemic hypertension were also excluded. An
echocardiographic study was performed during the week
of the PET study to evaluate wall thickness and left
ventricular function. A cardiopulmonary stress test
was also performed in all but class IV patients to estimate the peak
exercise oxygen consumption and the anaerobic threshold.
All the patients were clinically stable for at least 1 week before the
PET study. Ongoing treatments comprised
angiotensin-converting enzyme inhibitors
(n=12), diuretics (n=18), digoxin (n=17), and nitrates (n=6).
None of the patients was taking ß-blockers.
Control Subjects
The control group consisted of 12 healthy men (mean age, 43±10
years). They had normal clinical, ECG, and
echocardiographic examinations, and none was taking
medication. The study protocol was approved by the ethics committee of
our institution, and written informed consent was obtained from each
subject.
PET Protocol
Preparation of 11C-MQNB and Data Acquisition
MQNB was labeled with 11C by methylation of QNB with
11C-methyl iodide. Labeled material had a specific
radioactivity ranging from 12 to 80 GBq/µmol at the time of the first
injection. PET studies were performed with a time-of-flight assisted
positron camera.31 Transmission scans were performed with
a rotating 68Ge source and used for subsequent attenuation
corrections. Emission data were recorded in list mode, starting
with the first injection of 11C-MQNB until the end of the
experiment. Sixty-two sequential images, using one of the seven
cross-sections, were reconstructed according to the specific
experimental protocol used. Calibration was checked every week with a
cylindrical phantom containing a uniform source of
68Ge.
Experimental Protocol
The PET study included three injections of 11C-MQNB
and/or MQNB. At the beginning of the experiment, 
370 MBq of
11C-MQNB was injected intravenously. Thirty
minutes later, 0.3 mg of unlabeled ligand was injected
intravenously (displacement). Sixty minutes later, a
mixture of labeled (300 MBq) and unlabeled MQNB (0.3 mg), in the
same syringe, was administered (coinjection). The overall study lasted
90 minutes.
The acquisition protocol was conducted early in the morning after an overnight fast. Arterial pressure was measured before and every 2 minutes after each injection. The heart rate was continuously monitored during the acquisition as well as 30 minutes before and 60 minutes after the PET scan, and the ECG was recorded every minute for 10 minutes after each injection and then every 5 minutes.
PET Data Analysis
Two to three consecutive slices were analyzed.
Myocardial regions of interest were manually drawn on the 10-minute
images (Fig 1
). For each myocardial
slice, four regions of interest were drawn, one encompassing the entire
left ventricular myocardium and three segmental
regions (septal, anterior, and lateral). The input function was
obtained from a region of interest drawn manually within the left
ventricular cavity on the largest slice.29
List-mode acquisition allowed time-of-flight confidence–weighed
reconstruction of 10-second images during the first 2 minutes after
labeled ligand injection and longer-duration images (up to 5 minutes)
when radioactivity decreased. 11C-MQNB time-activity curves
were generated for each individual region of interest after correction
for 11C decay and were expressed as pmol/mL after
dividing by specific radioactivity measured at time
0.28
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Myocardial wall thickness was carefully measured by means of M-mode echocardiography according to standard recommendations and by the same observer in all patients; PET data were corrected for losses in count recovery due to the small thickness of the heart wall compared with the spatial resolution of the PET system. The correction was performed in each myocardial region of interest with the use of a recovery factor measured experimentally on a heart phantom with the same PET system. For the global region of interest, a mean thickness was used in case of small differences in wall thickness.29 Spillover from blood cavity to myocardium was accounted for by use of a vascular fraction (Fv) in the fitting procedure.29
Ligand-Receptor Model
The compartmental model used in this study has been described
elsewhere.28 29 Briefly, it was a nonequilibrium,
nonlinear, two-step model: transport of the ligand from the blood to a
free ligand compartment and a classic ligand-receptor interaction.
The model parameters characterizing the ligand-receptor interactions were similar to those used in in vitro studies, ie, the concentration of available receptors (B'max) and the equilibrium dissociation constant Kd (ratio of the dissociation rate constant k-1 to the association rate constant k+1). In addition, the experimental data were used to determine the fraction of extravascular fluid in which MQNB—a very hydrophilic ligand—interacts with the receptors (denoted by VR).
Plasma Norepinephrine Assay
Before starting the PET study, venous blood was drawn at
baseline, after a 30-minute rest period in the supine position. Plasma
norepinephrine concentrations were determined by
radioenzymatic assay.32
Statistical Analysis
All values are expressed as mean±SD. Data were compared by
Student's paired and unpaired t tests. Correlation
coefficients, assuming linear regression, were calculated for paired
variables. A value of P<.05 was considered
statistically significant.
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Results |
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Patient Characteristics
The mean age of the patients was not significantly different from that of the control subjects (52±14 years; range, 17 to 69 versus 43±10; range, 28 to 59). Four of the 20 patients were graded stage IV in the New York Heart Association classification, 10 stage III, and 6 stage II. All were in sinus rhythm, with a basal heart rate significantly higher than the control subjects (80±18 versus 64±10 bpm, P<.01). The mean left ventricular ejection fraction was 22±9% (range, 10% to 45%) (Table 1
). Peak exercise oxygen consumption in
class II and III patients ranged between 19.4 and 24.9 mL/min per
kilogram (mean, 19±4), with an anaerobic threshold of
12.8±4.7 mL/min per kilogram on average.
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Mean echographic end-diastolic wall thickness was thinner in patients than in control subjects (8.4±1 versus 9.7±0.9 mm, P<.005). There was no significant difference in regional wall thicknesses, and the maximal individual difference between wall thickness did not exceed 1 mm.
PET Receptor Quantification
The dynamic time-activity curve was similar in patients and
control subjects. After the first tracer injection, the myocardial
concentration increased rapidly, then remained constant until the
displacement. The displacement of 11C-MQNB by unlabeled
MQNB resulted in a decrease in myocardial radioactivity. Coinjection of
labeled and unlabeled MQNB produced a second increase in radioactivity,
immediately followed by a decrease (Fig 2).
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The mean receptor concentration (B'max) in the
patients was 34.5±8.9 pmol/mL, a value significantly higher
than in control subjects (25±7.7 pmol/mL, P<.005)
(Fig 3). The equilibrium dissociation
constant Kd was not significantly different between
patients and control subjects (Table 2).
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In the patients, the respective receptor concentrations were not significantly different in the septal, anterior, and lateral regions (36.5±9, 33.2±10, and 34.5±11 pmol/mL, respectively).
Correlations of MR With Clinical and Laboratory Variables
The basal heart rate was significantly higher in patients than in
control subjects (80±18 versus 64±10, P<.01). The maximal
heart rate during the procedure was always reached 6 to 8 minutes after
the coinjection (ie, after 0.6 mg of cold MQNB, an equivalent of
atropine). The percentage of change in heart rate was significantly
lower in patients than in control subjects (34±20% versus 55±36%,
P<.05) (Table 3). Moreover,
there was a weak negative correlation between maximal heart rate and
the individual density of MR in the patients (r=.45,
P<.05) (Fig 4). Resting
plasma norepinephrine concentrations were higher in
patients than in control subjects (663±246 versus 420±350
pg/mL, P<.05). No correlation was found between MR
density and the left ventricular ejection fraction or the
norepinephrine concentration in the patients.
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Discussion |
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This is the first study reporting an increase in myocardial muscarinic receptors in patients with chronic heart failure due to idiopathic dilated cardiomyopathy.
Role of Ventricular MR in the Normal and Failing
Heart
Histochemical and immunohistochemical methods and PET studies with
tracers binding to vesicular acetylcholine transporters of cholinergic
neurons have demonstrated preganglionic and postganglionic
parasympathetic innervation of the ventricles.33 34 35
The effects of the parasympathetic system on the inotropic modulation of nonfailing left ventricular myocardium have been shown in animals as well as in humans. The parasympathetic system acts through muscarinic cholinergic inhibition of ß-adrenergic cardiac responsiveness but has no significant effect on left ventricular inotropism in baseline conditions.23 27 36 37 38 39 Acetylcholine decreases the contractile response of isolated myocytes to sympathetic agonists.26 In dogs, vagal stimulation strongly attenuates the dobutamine-stimulated inotropic response (left ventricular peak positive dP/dt) and the maximal velocity of contractile elements.39 In humans with no cardiac disease, Stratton et al38 reported enhanced adrenaline- and noradrenaline-induced inotropic stimulation after parasympathetic blockade by atropine. Landzberg et al21 showed that acetylcholine reduced the intracoronary dobutamine–induced increase in left ventricular peak positive dP/dt by 66% and that this effect was reversed by atropine. Koglin et al,40 using M-mode echocardiography, also showed that the positive inotropic response to continuous infusion of isoproterenol was significantly reduced by the muscarinic cholinergic agonist carbachol. These studies confirmed the myocardial m-cholinergic receptor–mediated effects on in vivo sympathetic-induced changes in contractility in normal subjects.
In experimental heart failure, there is evidence of an enhanced negative inotropic effect of acetylcholine. Vatner et al,27 using a dog model of pacing-induced heart failure, showed that acetylcholine reduced left ventricular peak positive dP/dt more after pacing-induced heart failure than before pacing despite lesser reductions in arterial pressure. Conversely, Böhm et al24 reported a marked reduction in positive inotropic responses to isoprenaline and milrinone in failing human hearts obtained during transplantation, but inhibition of this response by carbachol was not different in failing and nonfailing myocardium. However, Parker et al22 have recently shown an enhanced inhibition of dobutamine-stimulated inotropic responses by intracoronary infusion of acetylcholine in patients with cardiomyopathy: left ventricular peak positive dP/dt was reduced by 75% versus by only 35% in control subjects. The same group had previously reported that this indirect negative inotropic effect of the parasympathetic agonist was the same in patients with transplantation and control subjects,22 in keeping with the similar myocardial MR density in patients with transplantation and control subjects, as evaluated by PET.30 This lack of change in MR sensitivity or density after heart transplantation suggests that dual sympathetic and parasympathetic denervation may not have the same consequences on the receptor-effector system as decreased parasympathetic tone associated with increased sympathetic tone (encountered in chronic heart failure). Thus supersensitivity of the failing myocardium to parasympathetic agonists seems to be associated in vivo with reduced parasympathetic tone in patients with idiopathic dilated cardiomyopathy.
Changes at the Postreceptor Level in the Failing
Myocardium
Muscarinic agonists inhibit stimulated adenylate
cyclase activity, an effect involving MR interaction with the
inhibitory guanine nucleotide–binding protein
(Gi). Gi inactivates the catalytic
subunit of adenylate cyclase, thereby reducing
intracellular cAMP levels and exerting an
antiadrenergic effect.2 3 4
cAMP-mediated responses are one of the main targets of cholinergic
interaction in the ß-adrenergic–stimulated myocardium,
even if other mechanisms, such as regulation of protein
phosphorylation, may be involved.41 In the
failing human myocardium, depressed basal and guanine
nucleotide–stimulated adenylate cyclase
activity was found, associated with increased Gi binding
protein levels or functional activity.2 25 27 42 43 44 This
increase in Gi was functionally relevant in idiopathic
but not ischemic cardiomyopathy. In human
idiopathic cardiomyopathic tissue, pertussis toxin
labeling has shown a 36% increase in Gi levels, associated
with enhanced inhibition of adenylate cyclase activation by
Gpp Nhp.42 In dogs with pacing-induced heart failure, an
increased Gi2 level in sarcolemmal membrane
preparations was found, with a parallel increase in dose-responses to
carbachol inhibition of stimulated adenylate cyclase
activity; acetylcholine induced a more pronounced decrease in left
ventricular peak positive dP/dt in dogs after
pacing-induced heart failure than at baseline.27 This
suggests that the increased Gi in heart failure has a
significant role in regulating adenylate cyclase and
myocardial contractility and that an enhanced site
number or agonist affinity of receptors coupling to the
inhibitory guanine nucleotide–binding protein
may be involved.
Changes in MR Density or Affinity in Chronic Heart Failure
Studies of MR density and affinity in congestive heart failure are
rare and uncongruent. In particular, differences are observed between
animal and human studies. MR density changes can be induced in isolated
cells, with downregulation of MR by agonist exposure and upregulation
by antagonist exposure.36 44 45 46 MR
upregulation after long-term exposure to the parasympathetic
antagonist atropine was demonstrated in mouse
cortical neurons.45 Such changes in myocardial MR density
after pharmacological intervention can be evidenced by PET with
11C-MQNB. In dogs treated with an irreversible
acetylcholinesterase inhibitor, a similar downregulation of
myocardial MR was observed with the use of 11C-MQNB and
3H-MQNB.35
A significant reduction in myocardial MR was reported in a model of chronic pressure overload in dogs, with no changes in affinity constants.23 Conversely, in a dog model of pacing-induced heart failure, a 23% increase in MR density was found in antagonist and agonist binding experiments, with no change in affinity constants, associated with a 55% elevation of Gi levels.27 Another group reported a 53% increase in MR in a similar model with the hydrophilic ligand 3H-N-methyl-scopolamine.47 Fu et al,48 using a rat model of ischemic heart failure, showed that the depressed, stimulated adenylate cyclase activity was associated with changes in MR affinity rather than density, with low-affinity and super high-affinity forms of receptors instead of low- and high-affinity forms.
In the human failing heart, Böhm et al24 found no changes in either MR density or affinity constants in patients with dilated cardiomyopathy, using in vitro binding studies with triated QNB, despite their observations on adenylate cyclase activity and Gi. These findings disagree with our observation that MR are upregulated in idiopathic dilated cardiomyopathy patients. This apparent discrepancy may have several explanations, such as the preparation of membranes (which can alter receptor properties), the different accessibility of receptor sites to tracers in the intact organ and in homogenates, the persistence of vagal tone in vivo, and potential effects of halothane anesthesia, which affects Gi proteins in the failing myocardium.49
However, the main difference between PET and in vitro studies may lie in the binding ligand used. MQNB is a hydrophilic ligand that binds only to externalized MR, in contrast to the lipophilic ligand QNB, which binds to both externalized and internalized receptors of the three subtypes. The physiological response to muscarinic stimulation in the heart requires agonist interaction with receptors on the cell surface; this means that the receptor number measured in cell homogenates may not reflect the actual number of receptors on intact cells capable of agonist binding. Indeed, the changes in MR density after preexposure to agonist varied according to the tracer used: lipophylic as H3-QNB, or hydrophylic as H3-MS or MQNB.46 50
Whether or not increased Gi levels in the failing heart depend only on alterations in the MR pathway is uncertain. Other myocardial receptors coupling to Gi, such as A1-adenosine receptors, may be involved.51 Marquetant et al52 showed that chronic ß-blockade downregulated both M2-MR and A1-adenosine receptors in rat cardiac membranes. However, despite the proven distribution of A1-adenosine receptors in the human ventricle,51 the study by Koglin et al40 failed to show any effect of adenosine on ß-adrenergic inotropic stimulation in normal subjects, contrasting with the significant effect of the muscarinic agonist carbachol.
Limitations of the Study
A main limitation is the method of partial volume effect
correction and the use of ungated PET. The absolute quantitative
tissue-labeled concentration had to be corrected, given the low
ventricular wall thickness together with the limited
spatial resolution of PET, by use of a recovery coefficient based on
M-mode echocardiography. Only the
end-diastolic thickness was used, whereas PET
parameters were averaged throughout the cardiac cycle, as
gated PET does not seem feasible in receptor imaging studies. This
results in a partial volume–related underestimation of the true tissue
tracer concentration because of a decline in average wall thickness due
to a loss of systolic wall thickening in
cardiomyopathic patients. Thus the
B'max of receptors, which is divided by the
recovery factor, was probably underestimated in the patients compared
with the control subjects, and the difference between the two groups is
probably larger than that found here. This affects individual data and
may account for the overlap of B'max values
between the patients and control subjects. Unfortunately, in this
noninvasive study, the relationship between MR density and left
ventricular inotropism was not evaluated, and no
conclusions can be drawn as to the functional importance of the
increased externalized fraction of MR for contractile
responsiveness.
Finally, drug interference with MR cannot be ruled out because medical therapy was not discontinued before this investigation. Most patients were receiving digoxin and angiotensin-converting enzyme inhibitors, both of which improve baroreflex function, possibly interfering with MR receptors and the adenylate cyclase system.53 54
Clinical Implications
Several recent studies have emphasized the consequences of
impaired cardiac parasympathetic control in patients with heart
failure, which may contribute to an increased risk of
death.4 5 6 7 8 Studies of conscious animals and patients have
shown significant protection from ventricular fibrillation
by muscarinic agonists.5 15 Preliminary data suggest a
beneficial effect of chronic muscarinic agonist administration in
congestive heart failure patients.55 Increased MR density
and activity may be an adaptive mechanism by which sustained
ß-agonist stimulation is turned off, thereby attenuating myocardial
metabolic demands and its detrimental consequences such as
ischemia and arrhythmia. Whether an increase in
parasympathetic tone would be beneficial for patients with congestive
heart failure remains to be determined, but an increased myocardial MR
density should offer more potential targets for endogenous
or exogenous agonists as well as physical intervention.
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Acknowledgments |
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We thank the cyclotron and radiochemistry staff of the Service Hospitalier Frederic Joliot (C. Crouzel, D. Fournier, and B. Maziere) and the computing group (B. Secher, V. Frouin, and R. Rougetet) for their technical assistance.
Received March 7, 1997; revision received July 7, 1997; accepted July 21, 1997.
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