Annals of Internal Medicine
5 September 2000 Volume 133 Number 5
Cardiac Sympathetic Denervation in Parkinson Disease
David S. Goldstein, MD, PhD; Courtney Holmes, CMT; Sheng-Ting Li, MD; Simon
Bruce, MD; Leo Verhagen Metman, MD; and Richard O. Cannon, MD
Ann Intern Med. 2000;133:338-347.
Orthostatic hypotension is common in Parkinson disease (1). Although earlier
studies implicated L-dopa treatment as the cause (2), more recent studies
have shown that orthostatic hypotension may result from deficient
cardiovascular reflexes that depend on release of the sympathetic
neurotransmitter norepinephrine in the heart and blood vessels (3-5). We
call this phenomenon "sympathetic neurocirculatory failure."
Several recent studies have reported decreased myocardial concentrations of
radioactivity after injection of the sympathoneural imaging agent123
I-metaiodobenzylguanidine (123 I-MIBG) in patients with Parkinson disease
(6-13). This finding is consistent with but does not prove cardiac
sympathetic denervation. In addition, studies have not specifically
considered the possible association between cardiac sympathetic denervation
and sympathetic neurocirculatory failure in Parkinson disease. Measures of
autonomic function have included blood pressure during tilt-table testing
(abnormalities of which can have several causes), heart rate responses to
the Valsalva maneuver (which are determined mainly by changes in
parasympathetic cholinergic outflow to the heart), or skin conductance or
sweating responses (which are determined mainly by alterations in
sympathetic cholinergic outflow to the skin). These measures may not allow
assessment of sympathetic noradrenergic function.
One way to detect sympathetic neurocirculatory failure in a patient with
orthostatic hypotension is by analyzing beat-to-beat blood pressure
associated with performance of the Valsalva maneuver (Figure 1 ). In
patients with sympathetic neurocirculatory failure, blood pressure decreases
progressively during phase II of the maneuver, whereas normally blood
pressure plateaus or increases at the end of phase II (phase II-L). In
patients with sympathetic neurocirculatory failure, phase IV blood pressure
increases slowly back to baseline after release of the maneuver, whereas
normally blood pressure "overshoots." These abnormalities are a direct
result of deficient cardiovascular reflexes that depend on sympathetically
mediated release of norepinephrine. In our study, we defined sympathetic
neurocirculatory failure as chronic, reproducible orthostatic hypotension
associated with abnormal blood pressure responses in both phase II-L and
phase IV of the Valsalva maneuver.
Previous studies also have not independently confirmed that a low myocardial
concentration of123 I-MIBG-derived radioactivity actually reflects cardiac
sympathetic denervation in Parkinson disease. Neurochemical findings
indicating decreased norepinephrine release, neuronal uptake, turnover, and
synthesis in the heart could provide such confirmation. In humans, 6-[18
F]fluorodopamine can be used to visualize cardiac sympathetic innervation by
positron emission tomographic (PET) scanning (14), which provides excellent
spatial and temporal resolution. Since 6-[18 F]fluorodopamine is a
catecholamine handled in the heart in a manner similar to the way in which
norepinephrine is handled (15), PET scanning may allow functional and
anatomic assessments of sympathetic cardiac innervation (16).
We used PET scanning after injection of 6-[18 F]fluorodopamine and
neurochemical measurements during cardiac catheterization to answer the
following questions: 1) What proportions of patients with Parkinson disease,
with or without sympathetic neurocirculatory failure, have decreased
myocardial 6-[18 F]fluorodopamine-derived radioactivity? 2) Does decreased
myocardial 6-[18 F]fluorodopamine-derived radioactivity in Parkinson disease
actually reflect cardiac sympathetic denervation, as identified by indices
of cardiac norepinephrine release, neuronal uptake, turnover, and synthesis?
3) Does the frequency of cardiac sympathetic denervation differ between
groups of patients with Parkinson disease who have sympathetic
neurocirculatory failure and those who do not? 4) Does cardiac sympathetic
denervation also occur in patients with multiple-system atrophy, a
progressive neurodegenerative disease of adults that features autonomic
dysfunction and has parkinsonian, cerebellar, or mixed forms (17) ? (The
diagnosis of multiple-system atrophy is clinical and, except for a typically
poor response to L-dopa treatment, can be difficult to distinguish from
Parkinson disease.) 5) Is cardiac sympathetic denervation in patients with
Parkinson disease related to L-dopa treatment or to disease duration or
severity?
Methods
The Intramural Research Board of the National Institute of Neurological
Disorders and Stroke approved the study protocol. All participants provided
written informed consent.
Participants
We included patients with Parkinson disease or multiple-system atrophy who
were studied at the National Institutes of Health Clinical Center in
Bethesda, Maryland. Twenty-nine patients had Parkinson disease, including 10
who were not receiving or had never received L-dopa. Twenty-four patients
had multiple-system atrophy, including 8 who were taking L-dopa at the time
of evaluation.
For comparison, we used 6-[18 F]fluorodopamine PET scan data and, in most
cases, cardiac neurochemical data from 7 patients with pure autonomic
failure (5 men, 2 women [mean age SE, 60 6 years]) and 33 controls. Of
these 33 controls, 22 had a history of neurocardiogenic syncope (4 men, 18
women [mean age, 35 3 years]) and 11 had a history of postural tachycardia
syndrome (1 man, 10 women [mean age, 42 4 years]). 6-[18 F]fluorodopamine
PET scan data were also obtained from 19 normal volunteers.
All patients with Parkinson disease were referred by neurologists or
movement disorder clinics and fulfilled accepted clinical criteria (18).
Parkinson disease was staged by using the Hoehn-Yahr classification. All
affected patients had bradykinesia, "cogwheel" rigidity, and one or more
additional parkinsonian features ("pill-roll tremor," stooped posture,
festinating gait, difficulty initiating movement, masklike face,
micrographia, or marked improvement in motor function during treatment with
L-dopa).
Patients with multiple-system atrophy had at least two parkinsonian features
but were not classified in terms of cerebellar, parkinsonian, or mixed
subtypes (17). All had gradually progressive parasympathetic failure
(manifested by impotence in men, urinary retention or incontinence,
constipation, or constant pulse rate) and had one or more additional
features of multiple-system atrophy (heat or cold intolerance and decreased
sweating, intention tremor or other evidence of cerebellar dysfunction,
slurred speech or a history of aspiration, or no or only slight improvement
during an adequate trial of L-dopa treatment).
Sympathetic neurocirculatory failure was defined as reproducible, chronic
orthostatic hypotension (decrease in diastolic pressure of at least 10 mm Hg
and in systolic pressure of at least 20 mm of Hg after 3 to 5 minutes of
standing), coupled with abnormal responses of beat-to-beat blood pressure
associated with the Valsalva maneuver (19). As noted previously, patients
with sympathetic neurocirculatory failure usually exhibit a progressive
decrease in blood pressure in phase II-L of the maneuver and an absence of a
pressure "overshoot" in phase IV after release of the maneuver.
Valsalva Maneuver
For the Valsalva maneuver, the patient lay supine with his or her head on a
pillow and blew into a plastic or rubber tube connected to a
sphygmomanometer, keeping a pressure of 30 mm Hg for 10 to 12 seconds. The
response of beat-to-beat blood pressure during phase II-L of the Valsalva
maneuver was considered to be normal if the diastolic and mean arterial
pressure increased before the end of the straining and abnormal if they
decreased. The response during phase IV was considered to be normal if the
systolic blood pressure increased progressively to a value exceeding the
baseline (measured just before the patient inhaled and then began straining)
and abnormal if the systolic pressure did not exceed the baseline.
Sympathetic Neuroimaging
Patients were positioned in a GE Advance scanner (General Electric,
Milwaukee, Wisconsin), with their thoraxes in the gantry. 6-[18
F]fluorodopamine (specific activity, 7.4 to 37 MBq/mmol; dose in most cases,
0.037 MBq) was dissolved in approximately 10 mL of normal saline and infused
intravenously at a constant rate for 3 minutes. Thoracic PET scanning was
performed for up to 3 hours. The tomographic data were divided into
intervals of 5 to 30 minutes. Data acquisition was not gated to the
electrocardiogram.
In most patients, PET scanning was also used to delineate the left
ventricular myocardium and assess myocardial perfusion after administration
of the perfusion imaging agent13 N-ammonia. Intravenously injected13
N-ammonia exits the bloodstream rapidly and enters cells nonspecifically. A
few minutes after the injection, the concentration of13 N-ammonia-derived
radioactivity in the left ventricular myocardium exceeds that in the left
ventricular chamber, enabling visualization of the myocardium. Myocardial
tissue concentrations of13 N-ammonia-derived radioactivity depend on local
perfusion (20).
Neurochemical Testing
Patients underwent right-heart catheterization for measurements of
norepinephrine spillover into coronary sinus plasma and of venous-arterial
differences in plasma levels of dihydroxyphenylglycol (DHPG) and L-dopa.
After placement of arm and right internal jugular venous catheters (the
latter advanced into the coronary sinus), a tracer amount of [3
H]norepinephrine (levo- [2,5,6] [3 H]norepinephrine, New England Nuclear,
Boston, Massachusetts) was infused intravenously. Coronary sinus blood flow
was measured by thermodilution, and arterial and great cardiac venous or
coronary sinus blood was sampled after at least 20 minutes. Arterial and
cardiac venous plasma samples were assayed simultaneously for total and [3
H]-labeled norepinephrine, DHPG, and L-dopa (21).
Statistical Analysis
Cardiac images were analyzed as described elsewhere (22). Circular regions
of interest (diameters about half the width of the ventricular wall) were
created by using time-averaged images of single slices. Septal myocardial
concentrations of 6-[18 F]fluorodopamine-derived radioactivity were used
because the left ventricular free wall could not be identified with
certainty due to markedly decreased 6-[18 F]fluorodopamine-derived
radioactivity in many patients with sympathetic neurocirculatory failure.
During infusion of 6-[18 F]fluorodopamine, the concentration of 6-[18
F]fluorodopamine-derived radioactivity in the ventricular chambers exceeds
that in the interventricular septum, allowing identification of the septum
by negative contrast and placement of a septal region of interest.
Radioactivity concentrations, expressed in units of Bq/mL per MBq/kg of
injected 6-[18 F]fluorodopamine were measured for the scanning interval
between 5 and 10 minutes after initiation of the 3-minute infusion of 6-[18
F]fluorodopamine. Mean values for 6-[18 F]fluorodopamine-derived
radioactivity, cardiac norepinephrine spillover, and venous-arterial
differences in plasma levels of DHPG and L-dopa in the patient groups were
compared by analyses of variance or (if two compared groups) by
independent-means t-tests. Relationships between 6-[18
F]fluorodopamine-derived radioactivity and neurochemical measures were
assessed by linear and curvilinear (logarithmic) regression. A P value less
than 0.05 was considered statistically significant.
Results
We found no relationship between sympathetic neurocirculatory failure and
treatment with L-dopa (Table 1 ). Patients with Parkinson disease and
sympathetic neurocirculatory failure did not differ from patients with
Parkinson disease and no sympathetic neurocirculatory failure in mean
duration of Parkinson disease (6.2 2.1 years vs. 6.5 0.9 years,
respectively) or in stage of Parkinson disease, as indicated by Hoehn-Yahr
classification (2.4 0.5 vs. 1.9 0.2, respectively). Patients with
Parkinson disease and sympathetic neurocirculatory failure tended to be
older than patients with Parkinson disease and no sympathetic
neurocirculatory failure (70 3 years vs. 61 2 years, respectively) (t =
1.76; P = 0.09). The mean age of patients with multiple-system atrophy and
sympathetic neurocirculatory failure (59 2 years) did not differ from that
of patients with multiple-system atrophy and no sympathetic neurocirculatory
failure (62 3 years).
Valsalva Maneuver
By definition, all 26 patients with sympathetic neurocirculatory failure (9
with Parkinson disease and 17 with multiple-system atrophy) had abnormal
beat-to-beat blood pressure responses to the Valsalva maneuver (Table 2 ).
The same qualitative abnormalities occurred in both patient groups. Twenty
patients with Parkinson disease did not have sympathetic neurocirculatory
failure (because they did not have orthostatic hypotension) and performed a
technically adequate Valsalva maneuver. Of these, 12 had an abnormal
response of beat-to-beat blood pressure during phase II-L or phase IV and 2
had an abnormal response during both phases (Table 2 ). All volunteers had
normal blood pressure responses to the Valsalva maneuver, as did all
patients with multiple-system atrophy who did not have sympathetic
neurocirculatory failure and were able to perform a technically adequate
Valsalva maneuver.
Patients with Parkinson disease and sympathetic neurocirculatory failure
tended to have smaller heart rate responses during phase II of the Valsalva
maneuver (5.6 1.6 beats/min) (Figure 1 ) than patients with Parkinson
disease who did not have sympathetic neurocirculatory failure (9.7 1.3
beats/min) (t = 1.8; P = 0.09). Heart rate responses during the Valsalva
maneuver did not distinguish patients with Parkinson disease and sympathetic
neurocirculatory failure from patients with multiple-system atrophy and
sympathetic neurocirculatory failure (data not shown).
Sympathetic Neuroimaging
Myocardial concentrations of 6-[18 F]fluorodopamine-derived radioactivity
varied highly significantly as a function of patient group (F = 26.3; P <
0.001). All 9 patients with Parkinson disease and sympathetic
neurocirculatory failure had markedly decreased septal myocardial
concentrations of 6-[18 F]fluorodopamine-derived radioactivity (2753 414
Bq/mL per MBq/kg) (Figure 2 ) compared with normal volunteers (9118 483
Bq/mL per MBq/kg) (t = 8.2; P < 0.001). Values among these patients were
similar to those in patients with pure autonomic failure (3814 778 Bq/mL
per MBq/kg). In contrast, all 24 patients with multiple-system atrophy had
normal myocardial concentrations of 6-[18 F]fluorodopamine-derived
radioactivity, regardless of the occurrence of sympathetic neurocirculatory
failure. The values were similar to those in patients with episodic or
persistent orthostatic intolerance. The difference in mean 6-[18
F]fluorodopamine-derived radioactivity between patients with Parkinson
disease and sympathetic neurocirculatory failure and patients with
multiple-system atrophy and sympathetic neurocirculatory failure (10 227
354 Bq/mL per MBq/kg) was also highly statistically significant (t = 13.0; P
< 0.001).
Among the 20 patients with Parkinson disease who did not have sympathetic
neurocirculatory failure, 11 had markedly decreased septal myocardial
concentrations of 6-[18 F]fluorodopamine-derived radioactivity (Figure 2 ).
The mean myocardial concentration of 6-[18 F]fluorodopamine-derived
radioactivity (5217 525 Bq/mL per MBq/kg) was less than that in patients
with multiple-system atrophy who did not have sympathetic neurocirculatory
failure (8724 653 Bq/mL per MBq/kg) (t = 3.6; P = 0.0013) and less than
normal (t = 5.5; P < 0.001). The mean septal myocardial concentration of
6-[18 F]fluorodopamine-derived radioactivity was significantly higher in
patients with Parkinson disease who did not have sympathetic
neurocirculatory failure than in those who did (t = 2.9; P = 0.007). The
mean age of patients with Parkinson disease and diffusely decreased
myocardial concentration of 6-[18 F]fluorodopamine-derived radioactivity (66
2 years) was significantly greater than that of the patients with localized
decreases in 6-[18 F]fluorodopamine-derived radioactivity (57 3 years) (t =
2.8; P = 0.01). Five of these 20 patients had decreased 6-[18
F]fluorodopamine-derived radioactivity that was localized to the left
ventricular apex or free wall, as judged from visual inspection of PET
scans. Therefore, only 4 patients with Parkinson disease had completely
normal 6-[18 F]fluorodopamine-derived radioactivity in all parts of the left
ventricular myocardium.
Cardiac Catheterization
All six patients with Parkinson disease and low myocardial concentrations of
6-[18 F]fluorodopamine-derived radioactivity who underwent right-heart
catheterization had markedly decreased cardiac extraction of [3
H]norepinephrine, norepinephrine spillover, and cardiac venous-arterial
increments in plasma levels of DHPG and L-dopa compared with patients who
had chronic orthostatic intolerance or multiple-system atrophy. The values
in patients with Parkinson disease and sympathetic neurocirculatory failure
were similar to those in patients with pure autonomic failure (Figures 3 and
4 ).
Among all patients, the concentration of 6-[18 F]fluorodopamine-derived
radioactivity had a linearly positive correlation with the extraction
fraction of [3 H]norepinephrine (r = 0.74; P < 0.001) (Figure 3 ), a
curvilinearly positive correlation with cardiac norepinephrine spillover (r
= 0.59 for the relationship with the logarithm of norepinephrine spillover;
P < 0.001), and a curvilinearly positive correlation with the cardiac
venous-arterial differences in plasma levels of DHPG and L-dopa (Figure 4 ).
We found a linearly positive correlation between the venous-arterial
differences in plasma levels of DHPG and L-dopa (r = 0.80; P < 0.001).
Mean total-body norepinephrine spillover (that is, the appearance rate of
norepinephrine in arterial plasma) in patients with Parkinson disease and
sympathetic neurocirculatory failure (4.61 1.56 nmol/min) did not differ
significantly from that in patients with multiple-system atrophy and
sympathetic neurocirculatory failure (2.95 0.34 nmol/min) and tended to
exceed that in patients with pure autonomic failure (0.87 0.24 nmol/min) (t
= 2.1; P = 0.06).
Discussion
In our study, patients with Parkinson disease who had sympathetic
neurocirculatory failure, as detected by chronic orthostatic hypotension and
abnormal beat-to-beat blood pressure responses to the Valsalva maneuver, all
had markedly decreased 6-[18 F]fluorodopamine-derived radioactivity. In
addition, half of patients who did not have sympathetic neurocirculatory
failure had diffusely decreased concentrations of 6-[18
F]fluorodopamine-derived radioactivity in the left ventricular myocardium.
Therefore, a low myocardial concentration of 6-[18 F]fluorodopamine-derived
radioactivity was typical in most patients with Parkinson disease and in all
patients with Parkinson disease who had sympathetic neurocirculatory
failure.
The neurochemical findings from right-heart catheterization indicated that
in patients with Parkinson disease, low myocardial concentrations of 6-[18
F]fluorodopamine-derived radioactivity reflect loss of functional
sympathetic nerve terminals. All patients with Parkinson disease who had low
myocardial concentrations of 6-[18 F]fluorodopamine-derived radioactivity
and underwent right-heart catheterization had markedly decreased cardiac
extraction of circulating [3 H]norepinephrine. This extraction depends
mainly on neuronal uptake by way of the membrane norepinephrine transporter
(23). All of these patients had a markedly decreased estimated rate of entry
of endogenous norepinephrine into the cardiac venous plasma (cardiac
norepinephrine spillover). Cardiac norepinephrine spillover depends on
release of norepinephrine from local sympathetic nerves (24). All of these
patients had virtual absence of a venous-arterial increment in plasma levels
of DHPG. Under resting conditions, this increment mainly reflects turnover
of norepinephrine stored in vesicles in sympathetic nerves (25). Finally,
all of these patients had virtual absence of a venous-arterial increment in
plasma levels of endogenous L-dopa. This increment mainly reflects
biosynthesis of norepinephrine in sympathetic nerves (26, 27). We believe
that these results, which indicated decreased neuronal uptake, release,
turnover, and synthesis of norepinephrine, can be explained only by loss of
functional cardiac sympathetic nerve terminals.
Four patients with Parkinson disease had discontinued L-dopa treatment at
the time of evaluation, and 6 had never taken L-dopa. Moreover, all 8
patients with multiple-system atrophy who were taking L-dopa at the time of
evaluation had normal myocardial 6-[18 F]fluorodopamine-derived
radioactivity. These findings exclude L-dopa treatment as an explanation for
cardiac sympathetic denervation in Parkinson disease.
Because the mean duration and clinical stage of Parkinson disease in
patients with sympathetic neurocirculatory failure did not differ from those
in patients without sympathetic neurocirculatory failure, cardiac
sympathetic denervation in Parkinson disease does not seem to be restricted
to severe cases or to occur as a late consequence of the disease. In our
study, several patients first came to clinical attention for symptoms and
signs of autonomic failure; symptoms and signs of Parkinson disease became
evident only years later. Nevertheless, because this was a cross-sectional
and not a longitudinal study, our results do not exclude the possibility
that patients with cardiac sympathetic denervation but without orthostatic
hypotension eventually develop clinically overt sympathetic neurocirculatory
failure.
In our study, all patients with Parkinson disease and sympathetic
neurocirculatory failure had markedly decreased septal myocardial 6-[18
F]fluorodopamine-derived radioactivity, and approximately 50% of patients
with Parkinson disease who did not have sympathetic neurocirculatory failure
nevertheless had decreased septal radioactivity. Decreased myocardial 6-[18
F]fluorodopamine-derived radioactivity may therefore be a more sensitive
test for loss of sympathetic terminal innervation in Parkinson disease than
clinical physiologic changes.
Although studies using123 I-MIBG have shown a remarkably high frequency of
decreased myocardial123 I-MIBG-derived radioactivity in patients with
Parkinson disease, the studies have disagreed about associations of
decreased123 I-MIBG-derived radioactivity with the duration or severity of
Parkinson disease or with coexistent autonomic failure. For example, Takatsu
and colleagues (13) noted decreased123 I-MIBG-derived radioactivity
independent of Hoehn-Yahr classification, disease duration, or orthostatic
hypotension. Orimo and coworkers (9) found that decreased myocardial123
I-MIBG-derived radioactivity tended to worsen as Parkinson disease
progressed: Only approximately 50% of patients with stage I disease had
decreased123 I-MIBG-derived radioactivity, and all patients with autonomic
dysfunction were in stages III, IV, or V. Braune and colleagues (28) noted
decreased myocardial123 I-MIBG-derived radioactivity independent of the
duration or severity of autonomic or parkinsonian symptoms. Yoshita (6)
reported decreased myocardial123 I-MIBG-derived radioactivity independent of
disease severity or L-dopa treatment. In our study, we found that decreased
6-[18 F]fluorodopamine-derived radioactivity was not associated with disease
severity or duration or with L-dopa treatment but was associated with
sympathetic neurocirculatory failure.
Patients with sympathetic neurocirculatory failure in the setting of
Parkinson disease, pure autonomic failure, or multiple-system atrophy shared
the same abnormal beat-to-beat blood pressure responses to the Valsalva
maneuver; however, only the first two groups had evidence of cardiac
sympathetic denervation. Therefore, the occurrence of sympathetic
neurocirculatory failure does not imply cardiac sympathetic denervation.
Conversely, because patients with evidence of diffuse cardiac sympathetic
denervation did not always have abnormal blood pressure responses to the
Valsalva maneuver, the occurrence of cardiac sympathetic denervation does
not imply sympathetic neurocirculatory failure.
In our study, all patients with Parkinson disease and sympathetic
neurocirculatory failure had evidence of cardiac sympathetic denervation,
and all patients with multiple-system atrophy and sympathetic
neurocirculatory failure had evidence of normal cardiac sympathetic
innervation. These findings suggest that sympathetic neurocirculatory
failure in patients with Parkinson disease may result from a process that
involves loss of sympathetic terminal innervation. In contrast, sympathetic
neurocirculatory failure in patients who have multiple-system atrophy may
result from a process that involves abnormal reflexive regulation of
sympathetic neuronal outflows to intact terminals.
Total-body norepinephrine spillover in patients with Parkinson disease and
sympathetic neurocirculatory failure exceeded that in patients with pure
autonomic failure. Both groups, however, had low myocardial 6-[18
F]fluorodopamine-derived radioactivity. Because pure autonomic failure is
thought to be associated with diffuse loss of sympathetic terminal
innervation, our findings suggest that sympathetic denervation may be
cardioselective in Parkinson disease.
Sympathetic denervation, at least in the heart, seems to be characteristic
of most patients with Parkinson disease. Therefore, the disease may reflect
an abnormality of catecholamine function not only in the brain but also in
the periphery. Many reports have supported the notion that in Parkinson
disease, loss of nigrostriatal dopamine cells results in some way from
oxidative or neurotoxic injury (29-36). The high rate of oxidative
deamination of norepinephrine that takes place in cardiac sympathetic nerves
(25) may help to explain cardioselectivity of sympathetic denervation in
Parkinson disease. For further consideration of this hypothesis, such
cardioselectivity must be verified by neurochemical and neuroimaging
approaches applied in different body organs. In addition, clinical methods
must be developed to detect and quantify injury from oxidative deamination
of catecholamines. Our results suggest that only Parkinson disease, not
multiple-system atrophy, is associated with loss of sympathetic terminal
innervation. This possible etiopathologic distinction might prove clinically
useful in the differential diagnosis of these conditions.
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