(Circulation. 2000;101:1552.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Abnormalities of Cardiac Sympathetic Innervation in Arrhythmogenic Right Ventricular Cardiomyopathy
Quantitative Assessment of Presynaptic Norepinephrine Reuptake and Postsynaptic ß-Adrenergic Receptor Density With Positron Emission Tomography
From the Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology and Institute for Arteriosclerosis Research (T.W., M.B., G.B.) and Department of Nuclear Medicine (MS, H.L., O.S.), Münster, Germany, and the Medical Research Council-Cyclotron Unit and Imperial College School of Medicine, Hammersmith Hospital (C.G.R., A.A.L, F.H., P.G.C.), London, UK.
Correspondence to Dr Thomas Wichter, Medizinische Klinik und Poliklinik, Innere Medizin C (Kardiologie und Angiologie), Westfälische Wilhelms Universität, D-48129 Münster, Germany. E-mail wichtet{at}uni-muenster.de
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Abstract |
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Background—The frequent provocation of ventricular tachycardia by stress or catecholamines and the efficacy of antiarrhythmic drugs with antiadrenergic properties suggest an involvement of the cardiac adrenergic system in arrhythmogenesis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Previous studies demonstrated abnormalities of the presynaptic uptake-1 assessed by 123I-MIBG–single-photon emission computed tomography.
Methods and Results—This study investigated neuronal reuptake of norepinephrine (uptake-1) and ß-adrenergic receptor density in 8 patients with ARVC and 29 age-matched control subjects. All subjects underwent positron emission tomography with the volume of distribution (Vd) of [11C]hydroxyephedrine (11C-HED) used to assess presynaptic norepinephrine reuptake, the maximum binding capacity (Bmax) of [11C]CGP-12177 (11C-CGP-12177) to assess postsynaptic ß-adrenergic receptor density, and [15O]H2O for quantification of myocardial blood flow. Patients with ARVC demonstrated a highly significant global reduction in postsynaptic ß-adrenergic receptor density compared with that in control subjects (Bmax of 11C-CGP-12177: 5.9±1.3 vs 10.2±2.9 pmol/g tissue, P<0.0007), whereas the presynaptic uptake-1 tended toward reduction only (Vd of 11C-HED: 59.1±25.2 vs 71.0±18.8 mL/g tissue, NS). There were no differences in myocardial blood flow between the groups, and plasma norepinephrine was within normal limits in patients and control subjects.
Conclusions—The findings demonstrate a significant reduction of myocardial ß-adrenergic receptor density in patients with ARVC. This may result from a secondary downregulation after increased local synaptic norepinephrine levels caused by increased firing rates of the efferent neurons or as the result of impaired presynaptic catecholamine reuptake. These findings give new insights into the pathophysiology of arrhythmogenesis in ARVC, with potential impact on diagnostic evaluation and therapeutic management.
Key Words: cardiomyopathy • ventricular tachycardia • nervous system, autonomic • receptors, adrenergic, beta • tomography
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Introduction |
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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is frequent as an underlying disease in young patients with ventricular tachycardia (VT) and sudden death.1 2 3 These arrhythmias often occur during physical exercise or mental stress and may be provoked by intravenous catecholamine infusion during electrophysiological study (catecholamine sensitivity).4 5 In contrast, ventricular tachyarrhythmias are frequently suppressed by an antiarrhythmic drug regimen with antiadrenergic properties.5 6
The pathophysiological mechanisms of these observations in patients with ARVC are still under investigation. However, the clinical findings suggest an involvement of the cardiac sympathetic nervous system. Recently, abnormalities of the myocardial sympathetic function were demonstrated by reduced presynaptic uptake of [123I]meta-iodobenzylguanidine (123I-MIBG) with the use of single-photon emission computed tomography (SPECT).7
On the basis of these studies, we hypothesized that abnormalities of myocardial sympathetic function are present and may contribute to the arrhythmogenesis in ARVC. Reduced presynaptic uptake of radionuclide tracers may result from increased neuronal firing rates or impaired function of the presynaptic norepinephrine transporter (uptake-1). Either condition would result in elevated concentrations of synaptic norepinephrine that could lead to a subsequent downregulation of ß-adrenergic receptors on the postsynaptic membranes. To test this hypothesis, we assessed quantitatively the presynaptic uptake-1 and the postsynaptic ß-adrenergic receptor density in patients with ARVC with the use of positron emission tomography (PET) with the norepinephrine analogue [11C]hydroxyephedrine (11C-HED)8 and the ß-adrenergic receptor antagonist S-[11C]-CGP-12177 (11C-CGP-12177).9
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Methods |
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Subjects
Study Patients
Eight patients (4 men, 4 women; age 37±8 years, range 26 to 50; median 34 years) with ARVC and documented VT were investigated. ARVC was diagnosed according to the criteria proposed by an international study group on ARVC.10 The clinical characteristics of the study patients are summarized in Table 1
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Patient Selection
The main exclusion criteria of our study were signs or symptoms
of heart failure and a history of treatment with ß-blockers or other
drugs (including amiodarone) affecting the sympathetic nervous
system. Because of the potential influence on tracer uptake and/or
metabolism, patients after catheter ablation and those with
diabetes mellitus, pulmonary, renal, liver, or autoimmune
disease were also excluded from the study. In 1 case (patient 8), an
implantable cardioverter-defibrillator had been implanted subpectorally
by a transvenous approach. However, there was no interference of the
device with the field of view during the PET scans.
Control Groups
For the studies with 11C-HED and
[15O]H2O, the control
group consisted of 10 healthy volunteers (mean age 35±7
years, range 23 to 46, median 33 years). For the
11C-CGP-12177 scans, a control group of 19
subjects (mean age 44±16 years, range 21 to 65, median 45
years) was investigated. All control subjects had low-risk profiles,
normal examination results, resting 12-lead ECGs, and exercise tests.
No control subject was receiving drug treatment or had a history,
signs, or symptoms of diseases possibly affecting the sympathetic
nervous system.
Informed Consent
All patients and control subjects gave written informed consent
to the study protocol, which was approved by the Hammersmith Hospital
Research Ethics Committee and the United Kingdom Administration of
Radioactive Substances Advisory Committee.
Data Acquisition and Data Analysis
Cardiac presynaptic and postsynaptic sympathetic function was
assessed by dynamic PET (ECAT 931 to 08/12, Siemens/CTI), allowing the
simultaneous acquisition of 15 planes. Raw scan data were
stored on a MicroVax-II computer (Digital Equipment Corp) and
transferred to a SUN workstation for normalization, attenuation
correction, and reconstruction. The resulting images were further
analyzed as reported previously,11 with the use of
software developed under MatLab mathematical software packages (The
MathWorks Inc).
Study Protocol
In patients with ARVC, the measurement of cardiac presynaptic
and postsynaptic sympathetic functions was performed in the same
patient on 2 consecutive days. None of the patients or control subjects
had previously received ß-blockers. All subjects were off medication,
smoking, and caffeine-containing drinks for at least 36 hours.
Investigations were performed in the nonsedated resting state after
fasting for 
4 hours.
On the first day, PET scanning consisted of a transmission scan, a [15O]CO emission scan for blood volume, an 11C-HED dynamic emission scan for presynaptic uptake-1 function, and an [15O]H2O dynamic emission scan for resting myocardial blood flow (MBF). On the second day, transmission and [15O]CO emission scans were recorded in addition to an 11C-CGP-12177 dynamic emission scan for the assessment of postsynaptic ß-adrenergic receptor density.
During the PET scans, blood pressure was monitored at 15-minute intervals. Heart rate and cardiac rhythm were monitored with continuous 12-lead ECG recording. Plasma norepinephrine was measured at the beginning and the end of each scanning procedure. Arterialized venous blood was sampled at a rate of 2.5 mL/min from the vein of a heated hand by means of a peristaltic withdrawal pump and a bismuth germanate (BGO) detection system for monitoring the input function.12 Additional blood samples were taken to calibrate the BGO detection system, measure whole blood/plasma ratios, and assay HED metabolites in plasma.
The left ventricle was centered in the scanner field of view by the use of a rectilinear scan recorded during the exposure of external germanium-68 ring sources. This was followed by a transmission scan of 20-minute duration for attenuation correction of subsequent emission data.
Myocardial Blood Volume
A blood volume scan was performed with the inhalation of
15O-labeled carbon monoxide
([15O]CO) delivered through a face mask at a
constant rate of 500 mL/min and a radioactive concentration of 3 MBq/mL
over 4 minutes. After 1 minute, to allow for tracer equilibration, a
6-minute emission scan was initiated, during which 4 venous blood
samples were taken to measure blood radioactivity. Myocardial blood
volume (mL/mL of region of interest, ROI) was calculated by relating
the regional concentration of radioactivity in the
[15O]CO scan to the mean concentration of
radioactivity in the blood samples (a value of 1.06 g/mL was assumed
for the density of blood). Extravascular tissue volume
(Vev, mL tissue/mL ROI) was calculated by
subtracting the blood volume image from the normalized transmission
scan.13
Myocardial Blood Flow
Resting MBF (in mL · min-1
· g-1) was measured after the administration
of an intravenous bolus (555 MBq) of
[15O]H2O and dynamic
emission scanning for 5.5 minutes.14 MBF was calculated
with the use of a single compartment model.13 14 The
perfusable tissue fraction (tf, mL exchangeable
tissue/mL ROI) was obtained from the
[15O]H2O scan data and
used to correct the 11C-HED scan information for
partial volume effects and to calculate the perfusable tissue index
(PTI=tf/Vev).13
Presynaptic Neuronal Catecholamine Reuptake
Presynaptic neuronal catecholamine reuptake was
measured by intravenous administration of the
norepinephrine analogue HED labeled with
11C. The uptake of 11C-HED
uptake was previously reported to correlate well with the activity of
the presynaptic norepinephrine.15
11C-HED was prepared on site by direct
N-methylation of metaraminol with
[11C]methyliodide in
sulfoxide.8 The compound was purified with the use of
high-performance liquid chromatography to
provide an isotonic buffered aqueous solution for injection with high
specific activity, resulting in low injectate levels of HED and
precursor (3.25±0.69 and 0.36±0.07 µg, respectively) and a
radiochemical purity >99.5%. 11C-HED (350±51
MBq) was infused intravenously over a period of 2 minutes.
A dynamic emission scan of 65-minute duration was recorded.
Uptake-1 was assessed by the volume of distribution (Vd) of 11C-HED with the use of a single tissue compartment model and least-squares nonlinear regression to provide rate constants for norepinephrine uptake (K1) and release (k2), where Vd=K1/k2. The arterial input function was obtained from the left atrium for the first 15 minutes after the start of infusion and from the BGO counting system afterward. This was necessary because of the net extraction of tracer from blood in the heated hand in the first phase and the low blood count rate and increasing myocardial spillover into the left atrial ROI later on. The later part of the BGO curve was used to correct for the spillover of radioactivity into the left atrium. Plasma metabolite concentrations were determined by high-performance liquid chromatography and used with the measured whole blood to plasma ratios to provide the plasma 11C-HED input curves. The resulting values of Vd (mL/mL ROI) were regionally corrected for partial volume and heart motion effects with the use of the measured values of perfused tissue fraction obtained from the MBF scan. To convert Vd from units of mL/mL to mL/g tissue, all values were divided by the density of myocardial tissue (1.04 g/mL tissue).
Postsynaptic ß-Adrenergic Receptor Density
The postsynaptic myocardial ß-adrenergic receptor density was
measured with the use of the S-enantiomer of the
nonselective hydrophilic ß-adrenergic receptor antagonist
CGP-12177
(4-[3'-t-butylamino-2'-hydroxypropoxy]-benzimidazol-2 to
1), which was asymmetrically synthesized and labeled with
11C on site.9 Studies
evaluating the accuracy and reproducibility of
11C-CGP-12177 and PET for the quantification of
ß-adrenergic receptor density showed excellent
results.16 17 After initial rectilinear, transmission, and
blood volume ([15O]CO) scanning, measurement of
myocardial ß-adrenergic receptor density was performed according to a
modification of the double-injection method previously reported in
detail.18 19 During a dynamic emission scan, a first dose
of 11C-CGP-12177 with high specific activity
(170±10 MBq, 4.2±0.4 µg cold CGP-12177) was infused
intravenously over a 2-minute period. Thirty minutes later,
a second dose with low specific activity (348±20 MBq, 22.8±2.1 µg
cold CGP-12177) was infused over a period of 2 minutes.
ß-Adrenergic receptor density was calculated by measurement of the maximal specific binding capacity (Bmax, pmol/g) of the ß-adrenergic receptor antagonist 11C-CGP-12177. The 2 sections of the curve corresponding to the slow clearance of tracer from tissue, which represent the dissociation of 11C-CGP-12177 bound to ß-adrenergic receptors after each injection, were exponentially extrapolated on the y-axis back to the start of each infusion. Bmax was calculated with the use of a modification of the equation described by Delforge et al18 to take account of the molar content of CGP-12177 in both injections.19 Time-activity curves were corrected for decay and spillover of radioactivity from blood to the myocardium by use of the blood volume image and the blood time-activity curves. Bmax was corrected for the partial volume effect by normalization to the regional values of extravascular tissue volume (Vev, mL tissue/mL ROI) obtained from the blood volume and transmission scans. To convert Bmax from units of pmol/mL tissue to pmol/g tissue, all values were divided by the density of myocardial tissue (1.04 g/mL tissue).
Statistical Analysis
Results are expressed as mean±SD. After testing for the
equality of variances (Levene test, SPSS), the Student’s t
test was used for the comparison between groups for the values of
Vd of 11C-HED,
Bmax of 11C-CGP-12177, MBF,
tissue indexes, hemodynamic parameters, and
plasma catecholamine levels. The coefficient of variation
was used to test for regional differences of left
ventricular distribution of 11C-HED
and 11C-CGP-12177. A value of P=0.05
was considered significant.
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Results |
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The results of presynaptic and postsynaptic sympathetic functions with quantitative PET scanning in patients with ARVC are summarized in Figure 1
and Table 2.
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Hemodynamic Parameters
In patients and control subjects, heart rate and blood pressure
were normal at baseline and during the scans without significant
differences between the groups. A 12-lead ECG recording
confirmed the absence of complex ventricular
arrhythmias during the PET scans in all patients and control
subjects.
Plasma Norepinephrine
In patients with ARVC, plasma norepinephrine
concentrations were within normal limits, were not different from the
control group (1.23±0.23 vs 1.42±0.71 nmol/L; NS), and remained
constant during the scans. There was no correlation between plasma
norepinephrine concentrations and presynaptic neuronal
catecholamine reuptake (11C-HED) or
postsynaptic ß-adrenergic receptor density
(11C-CGP-12177).
Myocardial Blood Flow
In patients with ARVC, global MBF at rest (1.01±0.25 vs
0.97±0.25 mL · min-1 · g
tissue-1; NS) and the perfusable tissue index
(0.94±0.06 vs 0.94±0.09; NS) were normal and not different when
compared with that in control subjects. No regional differences were
observed in either group.
Myocardial Sympathetic Function
Global Vd of HED was reduced by 17% in ARVC
patients compared with control subjects (59±25 vs 71±19 mL/g tissue),
which was, however, not statistically significant (P=0.22).
Global maximum binding capacity (Bmax) for
CGP-12177 was reduced by 42% in ARVC compared with control subjects
(5.9±1.3 vs 10.2±2.9 pmol/g tissue), which was highly significant
(P<0.0007). There was no correlation between presynaptic
and postsynaptic function in each patient (r=0.39; NS). No
statistical differences were detected in regional presynaptic
11C-HED uptake or postsynaptic ß-adrenergic
receptor density in either group. A clear regional reduction of
11C-HED uptake was present in 4 patients with
ARVC (Figure 2).
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Discussion |
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The present study used quantitative PET to further elucidate the nature of previously suggested sympathetic dysinnervation and investigated for the first time in vivo both the presynaptic (11C-HED) and postsynaptic (11C-CGP-12177) adrenergic function in patients with ARVC. The results provide clear evidence of abnormal sympathetic myocardial innervation in patients with ARVC and demonstrate a severe and highly significant reduction of postsynaptic ß-adrenergic receptor density (Bmax of 11C-CGP-12177) that has not been investigated in ARVC before our studies. Although abnormalities of the presynaptic function (Vd of 11C-HED) were not significant in the limited number of patients included in the present study, the results confirm and extend our previous observations by radionuclide studies performed with 123I-MIBG-SPECT, which consistently demonstrated regional reduction of transporter-mediated neuronal catecholamine reuptake (uptake-1) in ARVC.7
Potential Mechanisms of Sympathetic Dysinnervation in ARVC
Hypoperfusion
Myocardial hypoperfusion with reduced tracer uptake can be
excluded as a mechanism of sympathetic dysinnervation in ARVC because
the distribution volume (Vd) for
11C-HED, being the ratio of influx and efflux
rates, is independent of changes in MBF. In addition, coronary
angiography as well as MBF
([15O]H2O-PET) were
normal in all patients with
ARVC.
Denervation
In ARVC, myocardial atrophy and fibrofatty replacement progresses
from the subepicardium toward the subendocardium.1 2 3
Because sympathetic nerve fibers travel in the subepicardium, localized
presynaptic sympathetic denervation may occur early in the course of
the disease process before functional abnormalities become
apparent.2 7
However, the findings of the present study do not support the presence of such a denervation process underlying sympathetic dysinnervation in ARVC. Analysis of the tracer clearance rate from the myocardium revealed substantially higher blood flow–corrected k2 values (ie, k2/MBF) for the 4 subjects who had a reduced Vd for 11C-HED (subjects 1, 4, 6, and 7), whereas this parameter was normal for the 4 subjects with normal or high values of Vd. The blood flow–corrected uptake values (K1/MBF) were normal for both of these subgroups. These findings strongly support a reduced uptake-1 to release ratio and argue against a loss of neurons. Moreover, the finding of normal values of perfusable tissue index in these patients would not be consistent with an increase in adipose or fibrous tissue.
Increased Sympathetic Activity
High levels of circulating plasma catecholamines have
been suggested as a potential mechanism for the diffuse reduction of
presynaptic tracer uptake (123I-MIBG,
11C-HED), acceleration of tracer washout, and
subsequent downregulation of postsynaptic ß-adrenergic receptor
density in patients with heart failure or
pheochromocytoma.20 21 However, in patients with ARVC, the
present study and other reports22 have shown that
plasma catecholamines are not elevated. These findings
suggest that increased synaptic norepinephrine confined to
the heart23 or enhanced myocardial sensitivity to
catecholamines rather than elevated plasma levels may be
responsible for increased sympathetic activity of the
myocardium in ARVC. Increased norepinephrine
concentrations in the synaptic cleft may result either from increased
presynaptic release (firing rates of efferent sympathetic nerve fibers)
or from decreased synaptic clearance (uptake-1) of
norepinephrine. Subsequently, this would result in some
degree of competitive inhibition of intraneuronal tracer reuptake
(Vd for 11C-HED) and in a
downregulation of postsynaptic ß-adrenergic receptor density
(Bmax for 11C-CGP-12177),
thus providing the most convincing hypothesis for sympathetic
dysinnervation in ARVC patients as reported in the present
study.
Recent in vitro studies in adult rat cardiac myocytes reported norepinephrine-stimulated apoptosis mediated by ß-adrenergic stimulation of intracellular cAMP and subsequent activation of protein kinase A, which increased calcium influx, thus inducing apoptotic cell death.24 In patients with ARVC, increased synaptic concentrations of norepinephrine therefore may not only increase the propensity to ventricular tachyarrhythmias but may contribute to the progression of myocardial atrophy mediated by apoptotic cell death, which recently has been discussed as a pathogenetic mechanism in ARVC.25
Sympathetic Dysinnervation and Arrhythmogenesis
An imbalance of the sympathetic tone is considered to increase the
propensity to develop ventricular arrhythmias in
various cardiac diseases and conditions. Increased sympathetic activity
with abnormal adrenergic stimulation of the myocardium may
result from increased norepinephrine concentrations in the
synaptic cleft, which may be modulated by physical exercise or
exogenous exposure to catecholamines. This may cause
changes of cellular cAMP production and protein
phosphorylation,26 which may affect the
spatial heterogeneity of calcium transients and
subsequently increase the dispersion of repolarization and enhance the
propensity for ventricular
tachyarrhythmias. Frequent stimulation of postsynaptic
ß-adrenergic receptors may subsequently lead to downregulation of
ß-adrenergic receptor density (Figure 3). These mechanisms may (in
part) be reversible by antiadrenergic drugs
(ß-blockade). Therefore, the results of the present study are in
line with previous investigations that proved good clinical efficacy of
ß-blockers in combination with class-III antiarrhythmic agents for
the treatment of ventricular
tachyarrhythmias in patients with
ARVC.5 6
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Study Limitations
Although the number of patients investigated in the present
study is small, they represent a carefully selected and
well-characterized cohort. The diagnosis of ARVC was made on the basis
of detailed noninvasive and invasive investigations, and only patients
without previous treatment with ß-blockers were included.
Because of the limited spatial resolution of the PET scanner, it was not possible to perform accurate quantitative measurements in the thin right ventricular wall. Improvement of spatial resolution by the use of ECG gating was not possible because quantification of presynaptic and postsynaptic measurements requires dynamic PET scanning with acquisition of short time frames.
Regional abnormalities of presynaptic adrenergic function were not as extensive as previously reported in studies using 123I-MIBG SPECT7 and were found in only 4 patients with ARVC in the present study. This may be explained by patient selection, which was not based on the results of preceding 123I-MIBG scanning but rather on the absence of previous treatment with antiadrenergic drugs. Additional reasons may include the limited number of patients investigated in the present study and differences in tracer characteristics between 123I-MIBG and 11C-HED.
The catecholamine concentration in the synaptic cleft and the firing activity of the efferent sympathetic nerves were not measured directly. Therefore, although a causal interrelation between high synaptic norepinephrine concentrations and downregulated ß-adrenergic receptor density is a probable and suitable explanation, it remains hypothetic.
Conclusions
The results of the present study provide convincing evidence
of abnormal sympathetic myocardial innervation in ARVC with significant
reduction of postsynaptic ß-adrenergic density. These findings not
only give new insights in the arrhythmogenesis of ARVC but may have
therapeutic implications, because pharmacological interventions
resulting in a normalization of synaptic norepinephrine
concentrations and postsynaptic ß-adrenergic receptor density in the
heart might reduce the propensity for ventricular
tachyarrhythmias and sudden death in patients with
ARVC.
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Acknowledgments |
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This study was supported in part by grants (Wi 1214/1-1, Le 999/1-1) from the Deutsche Forschungsgemeinschaft, Bonn, Germany.
Received May 4, 1999; revision received October 15, 1999; accepted November 5, 1999.
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