© 1998 American Heart Association, Inc.
Original Contributions |
Myocardial Presynaptic and Postsynaptic Autonomic Dysfunction in Hypertrophic Cardiomyopathy
From the MRC Cyclotron Unit and Imperial College School of Medicine (D.D., C.G.R., A.A.L., F.H., P.G.C.), Hammersmith Hospital, London, UK, and the Department of Nuclear Medicine (M.S., O.S.), University of Münster (Germany).
Correspondence to Paolo G. Camici, MD, MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 ONN, UK. E-mail paolo{at}cu.rpms.ac.uk
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Abstract |
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Abstract—Although hypertrophic cardiomyopathy (HCM) is genetically determined, several other factors, including autonomic dysfunction, may play a role in the phenotypic expression. A recent study using positron emission tomography with [11C]CGP 12177 ([11C]CGP) demonstrated that ß-adrenoceptor (ßAR) density is reduced in HCM and is correlated with disease progression. This present study tested the hypothesis that this downregulation is associated with reduced catecholamine reuptake (uptake 1) by myocardial sympathetic nerve terminals leading to increased local norepinephrine concentration. Myocardial presynaptic catecholamine reuptake was assessed by measuring the volume of distribution (Vd) of the catecholamine analogue [11C]hydroxyephedrine ([11C]HED) in 9 unrelated HCM patients aged 45±15 years. The maximum number of binding sites (Bmax) for myocardial ßAR density was measured in 13 unrelated HCM patients aged 40±12 years using the nonselective ß blocker [11C]CGP. Six patients were studied with both [11C]HED and [11C]CGP. Comparison was made with two groups of healthy control subjects for each ligand ([11C]HED, n=10, aged 35±8 years; [11C]CGP, n=19, aged 44±16 years). Myocardial Vd of [11C]HED (33.4±4.3 mL/g tissue) and ßAR density (7.3±2.6 pmol/g tissue) were significantly reduced in HCM patients compared with control subjects (71.0±18.8 mL/g tissue, P<.001, and 10.2±2.9 pmol/g tissue, P=.008, respectively). These results are consistent with our hypothesis that myocardial ßAR downregulation in HCM is associated with an impaired uptake-1 mechanism and hence increased local catecholamine levels.
Key Words: cardiomyopathy, hypertrophic • autonomic dysfunction • catecholamines • beta adrenoceptors • positron emission tomography
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Introduction |
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Most cases of HCM are familial with an autosomal dominant pattern and mutation of genes that encode myocardial contractile proteins.1 2 3 4 Although this is the case in the majority of HCM patients, there is considerable variation in the clinical manifestations of the disease that may not be always evident in obligate carriers.5 6 It has been hypothesized that other factors could play a role in the phenotypic expression of this condition. Some clinical features of HCM, such as left ventricular hypercontractility, the propensity to tachyarrhythmias,7 and the positive therapeutic effect of ß blockers,8 suggest an involvement of the autonomic nervous system with increased sympathetic activity.
Accordingly, using the nonselective ß blocker [11C]CGP with PET, we have previously demonstrated9 that myocardial ßAR density is reduced in patients with HCM compared with normal control subjects. In addition, using the same technique, we have recently demonstrated that a negative correlation exists between the density of myocardial ßARs and left ventricular function in patients with HCM.10 Receptor downregulation is normally a reaction to increased agonist concentration in the target tissue. In principle, an increased tissue norepinephrine concentration could result from increased neurotransmitter release from the nerve terminals and/or from an impaired neurotransmitter reuptake into the nerve terminal (uptake 1). The latter process can be assessed noninvasively with PET using the catecholamine analogue [11C]HED.
We therefore tested the hypothesis that the downregulation of myocardial ßAR in HCM is associated with reduced catecholamine reuptake by the myocardial sympathetic nerve terminals using PET studies with [11C]HED and [11C]CGP in patients with HCM and in healthy control subjects.
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Materials and Methods |
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Study Population
Patients
Sixteen unrelated HCM patients, aged 43±14 years, of a total of 120 attending the Hammersmith Hospital were identified as suitable for study (Table 1
). All underwent
preliminary screening, which included full history and clinical
examination, ECG, and echocardiogram. Since treatment with ß blockers
is known to affect myocardial ßAR density, the main exclusion
criterion of the present study was a current or past history of
treatment with ß blockers. In addition, patients who had taken
amiodarone during the last year were excluded because of
questions about its sympatholytic activity. In all 16 patients, left
ventricular hypertrophy was asymmetrical and
most marked in the septum in all cases. All patients were clinically
stable, and none had current or past evidence of left
ventricular failure. Patients receiving the calcium channel
blocker verapamil did not take their medication for 24
hours preceding the PET scan.
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Control Subjects
Two groups of age- and sex-matched healthy control subjects were
studied to limit radiation exposure. Ten subjects (aged 35±8 years)
served as controls for [11C]HED, and a second group of 19
subjects (aged 44±16 years) served as controls for
[11C]CGP. All control subjects had no history of cardiac
disease, a low risk profile, and normal physical examination. All had
normal resting ECGs and negative exercise tests in response to a high
workload.
All subjects gave written informed consent to the protocol, which was approved by the Hammersmith Hospital Research Ethics Committee and the United Kingdom Administration of Radioactive Substances Advisory Committee (ARSAC).
Study Protocol
Myocardial ßAR density was derived from the maximum number of
binding sites (Bmax) obtained from the
[11C]CGP scan in 13 patients (aged 40±12 years), and
transporter-mediated neuronal catecholamine uptake was
determined by measuring the Vd of [11C]HED in
9 patients (aged 45±15 years). In 6 patients, both scans were
performed. Plasma catecholamines were measured at three
points during each study, and venous blood samples were taken with the
subject in the supine position at baseline (
30 minutes after the
insertion of the venous cannula) and at 30 and 60 minutes
thereafter.
PET
The [11C]CGP and [11C]HED PET scans
were performed with the subjects positioned on the bed of an ECAT
931–08/12 positron emission tomograph (Siemens/CTI Inc) with
simultaneous acquisition of 15 planes. First, a rectilinear
scan was performed using an external ring source filled with
68Ge. This scan was used to position the left ventricle as
close as possible to the center of the axial and transaxial fields of
view of the scanner. After final positioning, a 20-minute transmission
scan was performed, and the attenuation correction coefficients for
each line of response in the emission sinograms were calculated from
this scan. The transmission scan was followed by the measurement of
myocardial blood volume using inhaled oxygen-15–labeled carbon
monoxide (C15O) and 10 minutes later (to allow for decay of
radioactivity) by the measurement of myocardial blood flow by means of
oxygen-15–labeled water (H215O) as described
previously.11 The H215O scan was
also used to calculate tissue fraction, defined as the proportion of
tissue within a given ROI that is capable of rapidly exchanging
water.12 After another 10 minutes, either the
[11C]CGP or [11C]HED scan was carried out
as described below. Six HCM patients had both [11C]CGP
and [11C]HED scans performed on different days.
[11C]HED Scan
[11C]HED was prepared by direct
N-methylation of metaraminol with [11C]methyl
iodide in sulfoxide as previously reported.13 An
intravenous infusion of [11C]HED (350±24
MBq) was given over a 2-minute period. A 38-frame dynamic emission scan
of 65-minute duration was used to define the temporal distribution of
the tracer in the myocardium. This scan consisted of a 30-s
background frame before the infusion of [11C]HED,
followed by six 5-s frames, six 10-s frames, three 20-s frames, four
30-s frames, five 60-s frames, four 150-s frames, and nine 300-s
frames. Arterialized venous blood was sampled continuously
from the antecubital vein of a heated hand using a peristaltic
withdrawal pump, and the whole-blood radioactivity concentration was
monitored using a BGO detection system. In addition, typically, 10
blood samples were taken manually during the scan for the measurement
of plasma metabolite concentrations and whole blood–to–plasma
[11C]HED concentration ratios and to calibrate the
on-line detection system.14
[11C]CGP Scan
[11C]CGP was prepared as reported
previously.15 The measurement of myocardial ßAR density
was performed according to a double-injection protocol described by
Delforge et al16 and modified by us.9 Briefly,
the first dose of high specific activity [11C]CGP
(159±29 MBq, 5.7±2.3 µg) was infused intravenously over
2 minutes, followed 30 minutes later by a second low specific activity
injection (300±67 MBq, 28.6±5.8 µg) infused over 2 minutes. A
55-frame dynamic emission scan was used to measure the temporal and
spatial distribution of the tracer in vivo. During the 30-minute period
after the start of the first infusion, 24 time frames (eight 15-s, four
30-s, two 60-s, two 120-s, and eight 150-s frames) were acquired. The
second infusion was then given, and the scan was completed with another
group of 30 frames, analogous to the sequence after the first
injection, but extended by six 150-s frames. Venous blood was
continuously withdrawn and passed through a BGO counting system to
assess changes in [11C]CGP blood concentration with
time.14 This information was used to correct the
[11C]CGP scan for vascular activity. Five calibration
blood samples were taken manually during this period and assayed for
11C activity in a well counter, which was cross-calibrated
with the scanner.
PET Data Analysis
All sinograms were normalized, corrected for attenuation, and
then reconstructed to provide transaxial images with a spatial
resolution of 8.4-mm FWHM and a slice thickness of 6.6-mm FWHM. Data
acquisition and initial processing were performed using dedicated array
processors on a MicroVax II computer (Digital Equipment Corp). Images
were then transferred to a SUN workstation (SUN Microsystems Inc) and
further analyzed by dedicated software developed under the
MatLab mathematical software package (The MathWorks Inc). Images were
resliced by defining the heart axis in the vertical and horizontal
long-axis views. Thin short-axis slices perpendicular to the heart axis
were then constructed and displayed. To define the length of the heart,
the first (apical) and last (basal) slices containing left
ventricular myocardium were identified from
this series of short-axis slices. In order to have a fixed number of 12
slices for each study, a new slice thickness was determined by dividing
the heart length by twelve. The final set of short-axis slices was then
obtained by taking into account the new calculated slice thickness in
the reslicing process. In each of the resliced short-axis slices, inner
and outer myocardial borders were defined by manual tracing, and
additional lines through the anterior and inferior septum
were drawn on each slice. For the regional analysis, ROIs were
defined by dividing the left ventricular
myocardium into a 14-segment bull's-eye scheme as follows.
First, the myocardial area between the anterior and
inferior septal lines of the apical slice was defined as a
septal quadrant, and the remaining myocardium was divided
into anterior, lateral, and posterior quadrants. The
midventricular and basal slices were divided into five ROIs
each (ROIs 5 to 14) by further dividing the septal quadrant into equal
anterior and inferior ROIs. The ROIs from the 12 resliced
short-axis slices were then reduced in number by averaging the
corresponding regions in the apical (1–4), midventricular
(5–8), and basal (9–12) slices. In a further step, a whole-heart ROI
was created by averaging all pixels within the area between the outer
and inner traces for all 12 slices. These ROIs were then applied to all
emission images of the different scans.
Volume of Distribution of [11C]HED
The analysis of the myocardial time-activity curves was
based on the assessment of Vd using a single tissue
compartment model and least-squares nonlinear regression
analysis to provide influx and efflux rate constants
(K1 and K2,
respectively), where
Vd=K1/K2. A
correction was included to account for spillover of radioactivity
from arterial blood into the myocardium. The
input function was obtained jointly from the data obtained from the BGO
counting system (for times >15 minutes) and from an ROI situated over
the left atrium for time points between 0 and 15 minutes. This
combination was necessary because of a significant apparent loss of
[11C]HED from arterialized blood early in the
studies and the progressive increase in spillover from the
myocardial tissue into the left atrial ROI during the later phases of
the study. The part of the BGO curve representing the later
phase was used to correct for the spillover of radioactivity into
the left atrium. Plasma metabolite concentrations, determined using
HPLC, were used to provide the corrected plasma [11C]HED
input functions. The resulting values of Vd were regionally
corrected for partial volume and wall motion effects using the measured
values of tissue fraction (milliliters of exchangeable tissue per
milliliter of ROI, obtained from the H215O
scan).12 The values of Vd were then converted
from mL/mL tissue to mL/g tissue by dividing by 1.04 (myocardial tissue
density).12
Measurement of Myocardial ßAR Density
Myocardial time-activity curves were corrected for radioactive
decay and for vascular activity using the regional values of blood
volume and the radioactive concentration of blood samples taken
throughout the dynamic scan. The sections of the curve corresponding to
the two slow clearance phases, which represent the dissociation
of [11C]CGP bound to ßAR, were exponentially
extrapolated back to the start of the infusions. ßAR density was then
determined as the maximum number of available specific
[11C]CGP binding sites per gram of tissue
(Bmax) in the ROIs as reported previously.9 The
resulting values of myocardial ßAR density were then divided by 1.04
(myocardial tissue density) to convert from pmol/mL tissue to pmol/g
tissue.
Statistics
All measured values are expressed as mean±SD. Differences in
variances between data in the two studied groups were tested by
Levene's test for equality of variances. For statistical
analysis of differences in age, plasma
catecholamine levels, ROI size, global ßAR density,
global Vd of [11C]HED, and myocardial blood
flow between HCM patients and control subjects, two-tailed unpaired
t tests for equal/unequal variances were performed.
Correlation between the global ßAR density and Vd of
[11C]HED and between the PET studies and the
echocardiographic findings were tested using linear
regression analysis. The regional distribution of global ßAR
density and the Vd of [11C]HED was tested by
calculating COV over all 14 bull's-eye segments for each study.
Differences in COV between HCM patients and control subjects were then
tested by two-tailed t tests for equal/unequal variances. A
value of P<.05 was considered to be statistically
significant.
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Results |
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Heart rate and blood pressure at baseline were not significantly different between HCM patients and control subjects, and there was no significant change in these parameters during both the [11C]HED and [11C]CGP scans, confirming no pharmacological effect of the tracers (Table 2
). Baseline plasma
catecholamines were similar in patients and control
subjects (norepinephrine, 2.84±2.9 versus 1.77±1.2
nmol/L, P=.28; epinephrine, 0.22±0.1 nmol/L versus
0.31±0.2 nmol/L, P=.26). There were no significant changes
in the plasma catecholamine levels measured in the samples
obtained after injection of either [11C]HED or
[11C]CGP.
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Myocardial Blood Flow
Average left ventricular blood flow was comparable in
patients and control subjects (0.92±0.19 versus 1.00±0.21 mL ·
min-1 · g-1, respectively;
P=.26), and there were no differences in the different
cardiac regions in patients or control subjects.
Volume of Distribution of [11C]HED
In patients with HCM, the myocardial Vd of
[11C]HED was 33.4±14.3 compared with 71.0±18.8 mL/g
(P<.001) in control subjects (Fig 1). The COV of the regional
Vd over the 14-segment bull's-eye scheme was not
significantly different between HCM patients and control subjects (COV,
21.8±7.3% versus 17.0±4.1%, respectively; P=.09). In HCM
there was a significant correlation (r=.76,
P=.017) between left ventricular shortening and
myocardial Vd of [11C]HED.
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Myocardial ßAR Density
Global ßAR density was significantly lower in the patients
(7.3±2.6 pmol/g tissue) compared with the control subjects (10.2±2.9
pmol/g tissue, P=.008) (Fig 2). Regional analysis showed no
significant difference in tracer distribution throughout the 14 ROIs
both in HCM patients and in control subjects (COV, 17.1±6.6% versus
18.7±7.1%; P=.51). In the six HCM patients studied with
both [11C]HED and [11C]CGP, there was no
significant correlation between myocardial Vd of
[11C]HED and ßAR density (r=.24,
P=NS).
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Discussion |
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The results of the present study confirm and extend previous observations that suggest a dysfunction of the myocardial autonomic nervous system in patients with HCM. As reported earlier, myocardial ßAR density is significantly reduced in HCM patients compared with control subjects.9 10 The degree of ßAR downregulation observed in the present study (
32%) is in good agreement with
previously reported results (35%) in patients with preserved left
ventricular function.9 The second and major finding of the present study is significant impairment of transporter-mediated neuronal uptake via the uptake-1 mechanism in patients with HCM. This is consistent with previous reports using single-photon emission tomography, where reduced myocardial fixation of an iodine-123–labeled marker, [123I]-metaiodobenzylguanidine, was demonstrated in HCM patients, who experienced increased washout of the catecholamine analogue from the myocardium.17 18 19 20 21 22 Furthermore, using labeled norepinephrine, with aortic and coronary sinus sampling, Brush et al23 found significantly reduced myocardial norepinephrine uptake in patients with HCM compared with control subjects (59±17% versus 79±13%).
The analysis of [11C]HED kinetics was extended beyond the simple assessment of tracer uptake to improve the accuracy and sensitivity of the measurement.24 25 26 A simple uptake measurement is time dependent because of the constantly changing myocardial concentration of [11C]HED after injection, and the rapid sequestration of the tracer by the uptake-1 transporter is flow-limited except for the most severe cases of uptake-1 malfunction.27 The Vd of the tracer (which is independent of time and blood flow) was therefore measured to overcome these limitations. The technique was additionally modified by including (1) subtraction of tracer spillover from the myocardium into the ventricular ROI in the estimation of arterial blood time-activity function, (2) correction for the substantial "grow in" of radioactive metabolites of [11C]HED in the circulating plasma, and (3) partial volume correction of the Vd using the measurement of tissue fraction.
An alternative interpretation of the reduced values of the Vd of the ligand could be that the hypertrophy and abnormal structure of the myocardium in HCM results in a relative reduction of the number of sympathetic nerve terminals per gram of tissue. We do not consider this explanation to be tenable because the reduction in Vd was associated with a much greater increase in the clearance of the tracer from the tissue in HCM patients compared with normal subjects. A reduction in nerve terminals alone would not result in an increase of the clearance of the tracer from tissue. In addition, the perfusable tissue index was similar in the patients and control subjects, and the changes in the Vd were not confined to the regions of maximal myocardial hypertrophy.
Previous clinical studies of catecholamine reuptake using [11C]HED have relied on a relatively crude kinetic analysis of the studies with terms such as retention, retention fraction, and retention index being used to describe the regional myocardial concentration of this tracer after normalization to the area under the arterial blood time-activity curve (derived from an ROI over the left ventricle). This analysis is sufficient for clinical studies in which there is gross disturbance or loss of sympathetic nerve terminals, but because we anticipated relatively subtle changes in HCM, a new analysis was developed. Animal models13 28 and studies in the isolated rat heart27 have defined the behavior of [11C]HED, particularly in response to blockade of the uptake-1 transporter with desipramine and differing concentrations of norepinephrine. Similar studies are not feasible in humans, but we feel that the sympathomimetic [11C]HED provides a surrogate model of norepinephrine reuptake by the sympathetic nerve terminal.
The regional analysis performed in the present study indicates that the abnormalities of sympathetic innervation are relatively homogeneous throughout the left ventricular myocardium. This observation is in keeping with the demonstration that other key features of this disease, eg, the distribution of some pathological changes,29 diastolic function abnormalities,30 and coronary vasodilator reserve,31 do not necessarily match the geography of macroscopic hypertrophy. From a pathophysiological point of view, these studies strengthen the hypothesis that the increased local neurotransmitter concentration in the synaptic cleft is associated with a chronic reduction in catecholamine reuptake and contributes to myocardial ßAR downregulation in HCM, although we could not find any relationship between ßAR and [11C]HED Vd in the 6 patients who underwent both studies. Similar results have been reported in idiopathic dilated cardiomyopathy, in which myocardial ßAR downregulation has been demonstrated using [11C]CGP and PET.32 However, studies of myocardial norepinephrine concentration in biopsy specimens have yielded conflicting results; the mean norepinephrine concentration in HCM was normal although substantially elevated in 2 patients, whereas in patients with dilated cardiomyopathy, myocardial norepinephrine concentration was reduced.33 Although the arteriovenous difference of norepinephrine is significantly higher in HCM patients than in control subjects, cardiac production of dihydroxyphenylglycol is reduced for a given amount of norepinephrine spillover, suggesting reduced neuronal uptake of norepinephrine.23 Furthermore, inhibition of neuronal uptake by desipramine augmented the cardiac response to administered norepinephrine and prolonged the response to sympathetic stimulation.
Unlike patients with congestive heart failure, no significant increase in circulating catecholamines was found in patients with HCM in this or other studies,9 10 32 despite the demonstration of myocardial ßAR downregulation. This supports the model proposed by Bristow et al,34 suggesting that increases in local neurotransmitter concentrations rather than circulating catecholamine levels are probably responsible for myocardial ßAR downregulation in HCM.
The ligand used for quantification of ßARs in the present study is a radiolabeled nonselective ß blocker, [11C]CGP. Human myocardium contains a relatively high proportion of the ß2 ßAR subtype (14% to 40% of the total ßAR population), with the downregulation that occurs in the failing ventricle being almost entirely due to reduction in the ß1 subtype. Although we did not perform selective measurements, we consider it reasonable to assume that the reduction in ßAR density as indicated by [11C]CGP binding reflects a reduction in the number of available receptors of the ß1 subtype. The relative importance of the ßAR subtypes in HCM is unknown, but we10 have previously demonstrated a significant positive correlation between left ventricular function (as assessed by echocardiography) and myocardial ßAR density in a group of HCM patients with and without heart failure. In addition, only those patients with HCM undergoing no treatment or treatment with verapamil alone were eligible for the present study, and they represent those with less symptomatic limitation. Because no relationship has been demonstrated between symptoms, phenotype, and prognosis, it is unlikely that the present study describes an abnormality that is not present in those patients receiving treatment for more significant symptomatic limitations or dysrhythmias.
Conclusions
The present study is the first to show noninvasively and
quantitatively that norepinephrine reuptake by the cardiac
sympathetic neurons is abnormal in HCM. These findings offer an
explanation for the global reduction in ßAR, with insufficient
spillover of norepinephrine to elevate the plasma
norepinephrine concentration. Further studies are needed to
ascertain whether these changes in the cardiac sympathetic system
relate to the variable phenotype and prognosis seen within
pedigrees with the same mutation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We are grateful to all staff of the MRC Cyclotron Unit involved in this study, especially the members of the radiochemistry section for production of the radiopharmaceuticals, the radiographers for performing the studies, and the blood laboratory group for on-line blood and metabolite analysis. We are especially grateful to Daniella Muallem for help with the data analysis of the HED scans.
Received May 19, 1997; accepted October 1, 1997.
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