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The effect of nifedipine on myocardial perfusion and metabolism in systemic sclerosis. A positron emission tomographic study

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198
THE EFFECT OF NIFEDIPINE ON
MYOCARDIAL PERFUSION AND METABOLISM IN
SYSTEMIC SCLEROSIS
A Positron Emission Tomographic Study
DENIS DUBOC, ANDRE KAHAN, BERNARD MAZIERE, CHRISTIAN LOC'H, CHRISTIAN CROUZEL,
CHARLES J. MENKES, BERNARD AMOR, GEORGES STRAUCH,
FRANCOIS GUERIN, and ANDRE SYROTA
We assessed the effect of nifedipine on myocardial perfusion and metabolism in 9 patients with systemic sclerosis, using positron emission tomography
with a perfusion tracer (potassium-38) and a metabolic
tracer (lSF-fluorodeoxyglucose["FDG]). Nifedipine, 20
mg 3 times daily for 1 week, induced a significant
increase in 38K myocardial uptake, a significant decrease in "FDG myocardial uptake, and a significant
increase in the myocardial 38K:1SFDGratio. These
results indicate that the increase in myocardial perfusion is associated with modifications in myocardial energy metabolism, which probably result from a beneficial anti-ischemic effect of nifedipine in patients with
systemic sclerosis.
Primary myocardial involvement is common in
systemic sclerosis (SSc; scleroderma) and accounts
for a substantial proportion of the mortality associated
with this disease (1-6). On histopathologic examination, the myocardium in SSc is characterized by
diffuse, patchy fibrosis that does not correlate with
narrowing of the large coronary arteries (1,2,7-9).
From the S . H. Frkderic Joliot, CEA, Orsay, and the
Departments of Cardiology and Rheumatology and the Institut de
Recherche ThCrapeutique et Pharmacologique Cliniques Eclimed,
HBpital Cochin, Paris, France.
Denis Duboc, MD; AndrC Kahan, MD; Bernard Maziere,
PhD; Christian Loc'h, PhD; Christian Crouzel, PhD; Charles J.
Menki?s, MD: Professor of Rheumatology; Bernard Amor, MD:
Professor of Rheumatology ; Georges Strauch, MD: Professor of
Therapeutics; FranCois GuCrin, MD: Professor of Cardiology;
AndrC Syrota, MD, PhD: Professor of Biophysics.
Address reprint requests to Andre Kahan, MD, Department
of Rheumatology, Hbpital Cochin, 27 rue du Faubourg SaintJacques, 75614 Paris Cedex 14, France.
Submitted for publication March 23, 1990; accepted in
revised form August 28, 1990.
Arthritis and Rheumatism, Vol. 34, No. 2 (February 1991)
There is increasing evidence that myocardial fibrosis
may result from a primary abnormality of the small
coronary vessels (1,3,10). Angina pectoris and myocardial infarction have occurred in scleroderma patients with normal coronary arteries (10).
Pathologic findings consistent with progression
from contraction band necrosis-a histologic lesion
seen in the setting of ischemic injury followed by
reperfusion-through replacement fibrosis have been
observed in the myocardium of scleroderma patients
(1,3). Concentric intimal hypertrophy, narrowing, fibrosis, and fibrinoid necrosis of intramural coronary
arteries and arterioles have been noted in some, but
not all, studies (1,9,11,12). These anatomic abnormalities are consistent with the findings of a strikingly
reduced coronary reserve in patients with SSc (11).
Furthermore, thallium-201 myocardial perfusion defects are a common finding in patients with this disorder, when the patient is at rest, after exercise, or after
exposure to cold (13-18). These scintigraphic myocardial abnormalities are reversible, at least in part, in the
short term after coronary artery vasodilation with
intravenous dipyridamole or oral administration of
nifedipine and nicardipine (14,16,19).
Evidence has also accumulated suggesting a
causal relationship between thallium-201 myocardial
perfusion abnormalities and left ventricular dysfunction in patients with SSc (13,15,20). A relationship
between the magnitude of the thallium perfusion defects seen after exercise and the left ventricular ejection fraction, as determined by radionuclide ventriculography, was demonstrated (13). In that trial, the
majority of patients with abnormal left ventricular
response to exercise had thallium perfusion defects,
whereas the majority of patients with normal findings
NIFEDIPINE AND MYOCARDIAL PERFUSION IN SSc
on thallium scans had normal left ventricular function,
both while at rest and during exercise (13). Transient
cold-induced segmental left ventricular abnormalities,
which may be related to the transient cold-induced
thallium perfusion defects (15), have also been observed in this disorder (15,20). Nifedipine and nicardipine may limit the severity of resting or cold-induced
segmental left ventricular dysfunction in SSc patients
(20,21).
Thus, the myocardial lesion in SSc may be a
manifestation of focal ischemic injury resulting from
functional or structural vascular disease. However, as
suggested in studies of the cardiomyopathy of the
Syrian hamster (22), a metabolic abnormality of myocardial cells may have a role in these small coronary
artery abnormalities, and may account for at least
some of the findings in previous trials. To further
investigate these 2 possible pathogenetic mechanisms,
we assessed myocardial perfusion and metabolism,
using positron emission tomography (PET) with a
perfusion tracer (potassium-38) and a metabolic tracer
("F-fluorodeoxyglucose [ "FDG]), in patients with
SSc who were treated for 1 week with nifedipine.
PATIENTS AND METHODS
Patients. Nine SSc patients (7 women and 2 men)
with diffuse scleroderma were studied. All patients fulfilled
the American Rheumatism Association preliminary criteria
for the classification of SSc (23). The mean ? SEM age of the
patients was 50 k 2 years, and the mean ? SEM duration of
disease was 11 ? 3 years. Patients were excluded if they had
significant pulmonary involvement (forced vital capacity
[FVC] or carbon monoxide diffusing capacity [DLco] 4 0 %
of the predicted normal value) or renal involvement (serum
creatinine concentration > 106 pmoles/liter) or concomitant
diabetes mellitus. At the time of the study, none of the
patients was taking medication for cardiac or vascular disease. All patients gave informed consent for all procedures.
The following studies were performed in all patients: physical examination, electrocardiography, anteroposterior chest
radiography, 2-dimensional echocardiography, and pulmonary function testing (routine spirometry with FVC and
single-breath DLco).
Tracers and scanning procedures. PET studies (24)
were performed while the patient was at rest, on 2 occasions
1 week apart, once without and once with nifedipine treatment (20 mg 3 timedday for I week). For the scanning
images obtained after treatment with nifedipine, the last
20-mg dose was administered 60 minutes before the injection
of 38K (see below). A standardized carbohydrate-containing
breakfast (400 kcal, with 280 kcal derived from carbohydrates) was given 60 minutes before the injection of 38K.
The device used for PET (ECAT 11; Ortec, Oakridge,
TN) is a single-slice machine with a spatial resolution of 1.7
199
cm and a slice thickness of 1.9 cm. Each subject was
positioned within the positron scanner, and several transmission scans were collected at different chest levels by
means of a germanium-68 ring source to correct emission
data for 51 1-keV photon attenuation through the thorax. A
mid-left ventricular position was then selected for serial
transaxial emission tomography. The slice level was fixed in
relation to the detectors by a low-power laser beam and by
indelible ink marks on the patient's skin. Identical patient
positioning for all scanning procedures was accomplished by
carefully checking alignment of the laser beam and the
indelible ink marks on the skin.
After recording transmission images, 38K (4-7 mCi,
half-life 7.6 minutes) ( 2 5 ) was injected intravenously. Imaging began immediately after tracer administration. Ten
1-minute images of the heart were recorded over a period of
10 minutes.
Oral glucose (50 gm) was given 60 minutes before
administration of "FDG, to increase the ratio of exogenous
glucose to free fatty acid utilization (24). "FDG (4-6 mCi,
half-life 110 minutes) (24,26) was injected intravenously.
Forty-five minutes after administration of the tracer, 18FDG
images through the heart were recorded over a period of 10
minutes, at identical levels as those used for 38K imaging.
Each image was corrected for radioactive decay.
Three regions of interest (left ventricle, septum, and
lateral wall of left ventricle) were selected on the imaging
plane that crossed the ventricular myocardium. The results
of 3XKand "FDG imaging were expressed as the percentage
of injected dose/cm3 of left ventricular tissue. They were
compared for 38K myocardial uptake, "FDG myocardial
uptake, and the myocardial "K:I8FDG ratio, in the presence
and absence of nifedipine treatment, in the same zone of
interest. Assuming that 38K is essentially a tracer of myocardial blood flow (27,28) and that "FDG is essentially a
tracer of myocardial metabolism (26), the myocardial 38K:
"FDG ratio was useful in understanding the relationship
between myocardial perfusion and exogenous glucose extraction.
Statistical analysis. Differences between mean values
were analyzed by Student's t-test. Correlations between
quantitative variables were tested by means of simple linear
regression analysis. P values less than 0.05 were considered
significant.
RESULTS
Clinical findings. All of the patients had Raynaud's phenomenon. None of them had a history of
systemic hypertension or a blood pressure higher than
140/90 mm Hg during the evaluation. None had congestive heart failure or cardiac enlargement (documented by standard chest radiography). Three patients
had chest pain consistent with angina pectoris. Electrocardiography results were normal in 8 patients and
showed T wave inversion in 1 patient. Echocardiography results were normal in all patients; in particular,
none had symmetric or asymmetric hypertrophy of the
DUBOC ET AL
200
Table 1. Results of positron emission tomographic studies of myocardial perfusion and metabolism in 9 patients with systemic sclerosis at
baseline and after treatment with nifedipine*
~~
Left ventricle
Baseline
38K
I'FDG
"K: IXFDGratio
6.97 2 0.61
0.83 t 0.09
9.61 k 1.62
Septum
After
nifedipine
8.33
0.69
13.37
Lateral wall
of left ventricle
2
2
2
0.49t
0.06t
2.48t
* "K and '8F-fluorodeoxyglucose (18FDG) values are the mean
t P < 0.05 versus baseline, by Student's paired t-test.
Baseline
7.27
0.83
9.70
f
f
?
0.63
0.09
1.44
After
nifedipine
8.58
0.68
14.24
f 0.43t
f 0.06t
f
2.65t
Baseline
6.69 f 0.65
0.83 f 0.10
9.61 2 1.86
After
nifedipine
8.08
0.71
12.57
f
f
2
0.57t
0.06
2.34t
2 SEM percentage of injected dose ( x I0+')/cm3 of left ventricular tissue.
myocardium. Three patients had previously undergone coronary angiography, with normal results.
Chest radiographs showed normal findings in 4
patients and mildly abnormal interstitial markings in 5.
Findings of pulmonary function studies were normal in
I patient. Three patients had mild or moderate restrictive lung disease (FVC 5 0 4 0 % of predicted), and 5
other patients had an isolated decrease in the DLco
(5680% of predicted). The mean t SEM Po, was 78
i 2 mm Hg (range 70-87). No patient had either
physical findings of severe pulmonary hypertension or
electrocardiographic evidence of right ventricular hypertrophy. All patients had normal serum creatinine
concentrations (mean t SEM 80 t 4 pmoles/liter).
PET results. The results of PET studies before
and after treatment with nifedipine are shown in Table
1. In the absence of treatment with nifedipine, the 38K
and "FDG values in the septum and the lateral wall of
the left ventricle did not differ significantly. After
nifedipine treatment, myocardial uptake of 38K was
significantly increased in the left ventricle, as well as in
the septum and the lateral wall, compared with baseline values. In contrast, myocardial uptake of 18FDG
was significantly decreased in the left ventricle and the
septum, compared with baseline. There was also a
decrease in myocardial uptake of "FDG in the lateral
wall after treatment with nifedipine; however, although this decrease was of the same order of magnitude as that seen in the septum, it did not reach
statistical significance. The myocardial 38K:I8FDG rawas
increased in the left
the
septum, and the lateral wall after treatment with
nifedipine, compared with the ratio at baseline.
PET images of a representative patient with
ssc are shown in ~i~~~~ 1. The individual values of
38K myocardia1 uptake and
uptake
in the left Ventricle for the 9 patients are shown in
Figure 2. No correlation was found between the re-
sults of PET and either patient age, disease duration,
pulmonary function test results (FVC, DLco, Po,),
hemodynamic data (systolic and diastolic blood pressure, heart rate, systolic pressure-heart rate product),
or glycemia.
Adverse effects of nifedipine. Nifedipine was
well tolerated by most of the patients in the study.
There were no significant differences in the mean
SEM heart rate (78 & 3 beatdminute versus 79 t 4
beatsiminute), systolic blood pressure (126 2 4 mm Hg
*
Figure 1. positron emission tomographic images o f a m,d-left "entricular slice in a representative patient with systemic sclerosis,
showing 3'K myocardial uptake at baseline (upper left), 38K myocardial uptake after treatment with nifedipine (lower left), I'Ffluorodeoxyglucose (I'FDG)
myocardial uptake at baseline (upper
right), and "FDG myocardial uptake after treatment with nifedipine
(lower right). An increase in 38K myocardial uptake and a decrease
in ''FDG myocardial uptake are Seen after treatment with nifedipine.
NIFEDIPINE AND MYOCARDIAL PERFUSION IN SSc
2
A
\
0.3
c
B
D
Figure 2. Results of positron emission tomographic studies of the
left ventricle in 9 patients with systemic sclerosis, showing levels of
38K myocardial uptake at baseline (A) and after treatment with
nifedipine (B), and levels of '8F-fluorodeoxyglucose ("FDG) myocardial uptake at baseline (C) and after treatment with nifedipine
(D). Values are the percentage of injected dose ( X 10+2)/cm3of left
ventricular tissue.
versus 121 _t 4 mm Hg), or diastolic blood pressure (81
t 4 mm Hg versus 80 ? 3 mm Hg) before and after
treatment with nifedipine. The systolic pressure-heart
rate product did not differ significantly before and after
treatment with nifedipine (mean SEM 98 6 versus
None of the
94 k 5 beatdminute . mm Hg X
patients had chest pain or electrocardiographic
changes after treatment with nifedipine. No arrhythmias were observed. Glycemia, which was determined
just before administration of I8FDG, did not differ
significantly before and after treatment with nifedipine
(6.9 k 0.2 mmoles/liter versus 7.0 ? 0.2 mmoledliter).
Two patients reported mild symptoms (headache and
flushing). However, these adverse effects did not require
specific treatment or modification of the protocol.
*
*
DISCUSSION
The results of the present study demonstrate
that nifedipine (60 mg/day for 1 week) induces a
20 1
significant increase in 38K myocardial uptake, a significant decrease in 18FDG myocardial uptake, and a
significant increase in the myocardial 38K:I8FDG ratio
in patients with SSc. Assuming that 38K is primarily a
perfusion tracer (27,28), these data are consistent with
those of previous studies demonstrating improvement
in thallium-201 myocardial perfusion after short-term
oral administration of the calcium channel blockers
nifedipine and nicardipine (14,19). Nifedipine is a
potent dilator of coronary arteries. In patients with
coronary artery disease, it decreases smooth muscle
tone in the coronary arteries, thereby reducing coronary vascular resistance and increasing coronary
blood flow; it also increases blood flow through coronary collateral vessels (29-32). Since 6 of our 9 patients did not have coronary angiography performed, it
is possible that some of the defects in 38K myocardial
uptake could have been related to proximal atherosclerotic coronary disease. However, proximal coronary
disease could account for only a minority of these
defects in the present SSc population, which is composed mainly of women without known risk factors
( I S , 6).
The mechanism by which nifedipine improved
38K myocardial uptake in our patients cannot be
determined from the present results. However, the
data are consistent with the hypothesis that defects in
the myocardial uptake of 38K may be due, at least in
part, to vasospasm of the small coronary arteries,
which may be improved after coronary artery vasodilation with nifedipine. This hypothesis is also supported by findings of previous studies (10,13-19).
Several mechanisms could account for the simultaneous nifedipine-induced decrease in 18FDG
myocardial uptake. A decrease in cardiac work is
unlikely, since the modifications in systolic blood
pressure and heart rate were minimal, and there was
no significant change in the systolic pressure-heart
rate product. A decrease in circulating hormones such
as insulin, an increase in free fatty acids, or a direct
effect on transmembranous glucose transport could
decrease "FDG myocardial uptake. The action of
nifedipine on myocardial metabolism therefore remains controversial. Findings in some, but not all,
studies suggest an absence of beneficial modification
of myocardial oxygen consumption and myocardial
lactate extraction during rest, in animals and in patients with angina (33-35). Glucose homeostasis and
hormonal responses after oral glucose loading are not
influenced by nifedipine after short-term treatment in
DUBOC ET AL
202
nondiabetic patients (36-38). Thus, although the above
hypotheses cannot be excluded, they seem unlikely.
In conclusion, the findings of the present study,
demonstrating the concomitant increase in 38K myocardial uptake and decrease in "FDG myocardial
uptake after nifedipine treatment in patients with systemic sclerosis, are consistent with a nifedipineassociated beneficial effect on myocardial perfusion
and a decrease in exogenous glucose utilization, probably resulting from an improvement in myocardial
oxidative metabolism. Two hypotheses could account
for these findings. A primary metabolic abnormality in
the scleroderma myocardial cell could induce myocardial perfusion dysfunction, as previously suggested in
studies of the cardiomyopathy of the Syrian hamster
(22). Alternatively, a primary dysfunction of small
coronary arteries could induce ischemic abnormalities
of myocardial metabolism, which could be improved,
at least in part, by treatment with nifedipine. Further
investigation is needed to elucidate the mechanism of
action of this agent in myocardial abnormalities in
ssc.
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