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Original Studies |
Departments of Molecular and Clinical Endocrinology and Oncology (A.Co., P.M., D.F., G.L.) and Nuclear Medicine Center of the National Council of Research (C.N.R.), Department of Biomorphological and Functional Sciences (A.Cu., E.N., L.F., M.S.), Federico II University of Naples, Naples, Italy
Address all correspondence and requests for reprints: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, via S. Pansini 5, 80131 Naples, Italy. E-mail: rpivone{at}tin.it
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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OCT was initially given at a dose of 0.05–0.1 mg, 3 times daily, and the dose was subsequently increased to achieve GH/insulin-like growth factor I (IGF-I) normalization. Hormone normalization after treatment was considered when basal and/or oral glucose test-suppressed GH values were below 2.5 and 1 µg/L, respectively, and IGF-I values were within the normal range for age. To evaluate the response to OCT treatment in terms of cardiac performance, the 30 patients were divided into 2 groups on the basis of normalized (in 13 patients) or nonnormalized (in 17 patients) circulating GH and IGF-I levels.
At study entry, hypertension was found in 6 patients (20%), abnormal left ventricular diastolic filling was found in 12 patients (40%), and impaired left ventricular ejection fraction was found in 2 patients at rest (6.6%) and in 18 patients at peak exercise (60%). Before OCT treatment, exercise duration ranged from 6–10 min, and exercise workload ranged from 50–125 watts.
After 1-yr treatment with OCT, a significant decrease in circulating GH and IGF-I levels was achieved in all patients, but normalization was obtained only in 13 of 30 patients. In patients achieving circulating GH and IGF-I normalization after OCT treatment but not in those with persistently elevated hormone levels, a significant decrease in heart rate, both at rest (from 75.7 ± 3.3 to 66.5 ± 2.9 beats/min; P < 0.01) and after exercise (from 137.5 ± 4.9 to 123.7 ± 4.1 beats/min; P < 0.01), and a significant increase in left ventricular ejection fraction, both at rest (from 56.5 ± 1.8% to 66.5 ± 2.2%; P < 0.01) and after exercise (from 52.6 ± 2.4% to 67.1 ± 1.7%; P < 0.01), were found. In the 17 patients who had persistently high circulating GH and IGF-I levels after 1 yr of OCT treatment, left ventricular ejection fraction was unchanged at rest but was significantly reduced after exercise compared to the basal value (from 64.9 ± 2.4% to 57.2 ± 2.6%, P < 0.01); systolic blood pressure at rest was significantly increased (from 128.5 ± 4.9 to 141.2 ± 5.4 mm Hg; P < 0.05). In these 17 patients, the ejection fraction response to exercise was significantly impaired, mostly in those less than 40 yr of age (from 11.6 ± 3.2% to -0.3 ± 5.6%; P < 0.05). In particular, among 9 patients who had a normal response to exercise at study entry, 6 developed an abnormal response after 1 yr. Left ventricular diastolic filling was unchanged by OCT treatment in all patients. Exercise duration (only in young patients from 7.5 ± 0.5 to 9.3 ± 0.7 min; P < 0.05) and exercise workload (in all 13 patients from 80.8 ± 6.4 to 92.3 ± 5.9 watts; P < 0.05) were significantly increased in the group of patients with normalized GH and IGF levels, but not in the remaining 17 (from 7.6 ± 0.4 to 7.5 ± 0.4 min and from 89.9 ± 5.5 to 84.4 ± 4.5 watts, respectively).
In conclusion, the results of the present study indicate that suppression of basal or glucose-suppressed GH levels below 2.5 or 1 µg/L, respectively, together with normalization of plasma IGF-I levels for 1 yr are followed by a significant improvement, but not complete normalization, of left ventricular ejection fraction either at rest or at peak exercise without significant changes in diastolic filling. By contrast, the persistence for 1 yr of elevated hormone levels caused a significant increase in systolic blood pressure and impaired cardiac performance. These data suggest that prolonged suppression of circulating GH and IGF-I levels could normalize cardiac performance and probably reverse the poor prognosis for cardiovascular disease in acromegaly.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The aim of the study was to investigate the effects of 1-yr treatment with OCT on left ventricular function in acromegaly. To address this issue, left ventricular diastolic and systolic functions were assessed at rest and during physical exercise in a large series of patients with active acromegaly before and after 1 yr of treatment with OCT. In addition, the changes in cardiac performance were correlated to the response to OCT treatment in terms of GH and IGF-I normalization.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thirty acromegalics constituted the patient population (15 women
and 15 men, age range, 18–65 yr). Latent coronary artery disease was
excluded using exercising thallium-201 myocardial tomography. The
diagnosis of acromegaly was performed in keeping with high serum GH
levels during an 8-h time course, not suppressible below 1 µg/L after
an oral glucose test (75 g) and high plasma IGF-I levels for age (18).
The presumed duration of acromegaly was assessed by comparison of
patients photographs taken during a 1- to 3-decade span and by
patient’s interviews to date the onset of acral enlargement. The
duration of disease was assumed to be the interval between the clinical
onset and the time of treatment. In the present series of patients,
disease duration ranged between 4–30 yr. All patients gave their
informed consent to participate in this study, and the study protocol
was approved by the ethical committee of the Medical School of Federico
II University of Naples. Twelve of 30 patients were smokers, and all
had a sedentary lifestyle. The clinical features of the patients
undergoing gated blood pool cardiac scintigraphy are shown in Table 1
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OCT was initially administered at a dose of 0.05–0.1 mg, three
times daily, in accordance with the patients’ individual compliance
(18), and the dose was subsequently increased to achieve GH/IGF-I
normalization (Table 1
). At study entry, plasma IGF-I levels were
assayed twice in a single sample, whereas the serum GH value was
calculated as the mean of a 6-h blood sampling (0800–1400 h, with
every 30 min sampling). During treatment, the final GH level was
calculated as the average value from at least three blood samples
collected at 15-min intervals 2 h after OCT administration. At
this time point, plasma IGF-I concentrations were assayed as single
sampling. Hormonal and clinical evaluations were carried out before
treatment, monthly for the first 3 months of treatment, and quarterly
during the first year of treatment. Hormone normalization after OCT
treatment was considered when basal and/or glucose-suppressed GH values
were below 2.5 and 1 µg/L, respectively, together with IGF-I values
within the normal range for age.
Gated blood pool cardiac scintigraphy
In vivo labeling of red blood cells was performed
with 555 megabecquerels (15 mCi) 99mTc. Radionuclide
angiography was performed at rest and during dynamic physical exercise
as previously described (9, 10). A small field of view 
-camera
(Starcam 300 A/M, General Electric, Milwaukee, WI) equipped with a low
energy all-purpose collimator was used. Exercise studies were performed
using a bicycle ergometer with a restraining harness to minimize
patient motion under the camera. Exercise loads were increased by 25
watts every 2 min until angina, limiting dyspnea, or fatigue developed.
Heart rate and blood pressure (by cuff sphygmomanometry) were monitored
during exercise at each stage. No patient developed high grade
ventricular arrhythmias necessitating termination of exercise.
Radionuclide angiography studies were performed using a standard
commercial software system (General Electric, Milwaukee, WI). Indexes
of left ventricular function were derived by computer analysis of the
background-corrected time-activity curve, as previously reported (9, 10). Both peak ejection rate and peak filling rate were computed in
left ventricular counts per s, normalized for the number of counts at
end diastole and expressed as end-diastolic volume per s. When
normalized for end-diastolic volume, both peak ejection rate and peak
filling rate are influenced directly by the magnitude of the ejection
fraction (19). To minimize this effect, we also analyzed peak filling
rate using two additional normalization methods: peak filling rate was
expressed relative to left ventricular stroke volume per s and as the
ratio of the peak filling rate to the peak ejection rate (20, 21).
These two latter methods have the additional advantage of being
background independent. To evaluate the response to OCT treatment in
terms of cardiac performance, the 30 patients were divided into two
groups on the basis of suppression of GH levels below 2.5 µg/L in
basal conditions and/or below 1 µg/L after an oral glucose test
together with plasma IGF-I normalization for age (Table 2). The results of OCT treatment were
also evaluated in patients grouped in accordance of age below and above
40 yr because of the physiological decline of the diastolic function
with aging (22). The threshold age of 40 yr was chosen on the basis of
a previous study that demonstrated the presence of a significant
increase in left ventricular mass without alterations of systolic
function, assessed by echo cardiography, in patients less than 40 yr of
age (12).
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Serum GH levels were assayed by RIA using commercial kits. The sensitivity of the assay was 0.2 µg/L. The intra- and interassay coefficients of variation (CVs) were 4.5% and 7.9%, respectively. Plasma IGF-I was measured after ethanol extraction by immunoradiometric assay using commercial kits. In our laboratory the normal IGF-I ranges in adults aged 20–40 and 40–70 yr were 110–494 and 65–320 µg/L, respectively. The sensitivity of the assay was 0.8 µg/L. The intraassay CVs were 3.4%, 3.0%, and 1.5% for low, medium, and high points of the standard curve, respectively. The interassay CVs were 8.2%, 1.5%, and 3.7% for low, medium, and high points of the standard curve.
Statistical analysis
Data are reported as the mean ± SEM. Student’s t test for paired data and ANOVA followed by Newman-Keuls test were used where appropriate. The significance was set at 5%.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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).
In the whole group of patients before OCT treatment, exercise duration
ranged from 6–10 min (7.5 ± 0.3 min), and exercise workload
ranged from 50–125 watts (83.8 ± 4.2 watts).
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), but
suppression of basal (patients 2, 3, 10, 12–14, 19, 20, and 26; Table 1) or glucose-induced (patients 8, 16, 28, and 30; Table 1) GH levels
below 2.5 or 1 µg/L, respectively, together with plasma IGF-I
normalization for age was obtained in only 13 of 30 patients (no. 2, 3,
8, 10, 12–14, 16, 19, 20, 26, 28, and 30; Table 1). A significant
decrease in heart rate, both at rest and after exercise, was found in
patients achieving hormone normalization after OCT treatment, but not
in those with persistently elevated hormone levels (Table 2). A
significant improvement of left ventricular ejection fraction, both at
rest and after exercise, was found in the 13 patients with GH and IGF-I
level normalization, but not in the remaining 17 patients (Table 2).
Overall, the response to exercise was normalized in 5 of 18 patients.
The individual data for plasma IGF-I levels and exercise-induced change
in ejection fraction before and after OCT treatment in the 13 patients
with hormone normalization and in the 17 patients with high hormone
levels are shown in Figs. 2 and 3, respectively. In the 17 patients who
had persistently high circulating GH and IGF-I levels after 1 yr of OCT
treatment, left ventricular ejection fraction was unchanged at rest but
was significantly reduced after exercise compared to the basal value
(Table 2); systolic blood pressure at rest was significantly increased
(Table 2). In these 17 patients, the ejection fraction response to
exercise was significantly impaired mostly in those less than 40 yr of
age (from 11.6 ± 3.2% to -0.3 ± 5.6%; P
< 0.05; Fig. 1). In particular, among 9 patients who had a normal
response to exercise at study entry, 6 developed an abnormal response
after 1 yr (Fig. 3). One patient (no. 27, Table 1) could not be
subjected to exercise due to a severe impairment of hypertension
(180/110 mm Hg) at the 1-yr follow-up. Left ventricular diastolic
filling was unchanged by OCT treatment in all patients (Table 2).
However, due to the significant increase in the ejection fraction, the
peak filling rate, measured as stroke volume per s, was significantly
decreased in patients with hormone normalization after OCT treatment
(Table 2). Finally, exercise duration (only in young patients from
7.5 ± 0.5 to 9.3 ± 0.7 min; P < 0.05) and
exercise workload (in all 13 patients from 80.8 ± 6.4 to
92.3 ± 5.9 watts; P < 0.05) were significantly
increased in the group of patients with normalized GH and IGF-I levels,
but not in the remaining 17 (from 7.6 ± 0.4 to 7.5 ± 0.4
min and from 89.9 ± 5.5 to 84.4 ± 4.5 watts,
respectively).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The results of the present study clearly show that cardiac performance was significantly improved in patients achieving normalization of circulating GH (<2.5 µg/L in basal conditions or 1 µg/L after an oral glucose test) and IGF-I levels for age, but not in those with persistence of elevated hormone levels. It should be noted that in patients with high GH and IGF-I levels followed for 1 yr, cardiac systolic performance, evaluated as left ventricular ejection fraction during exercise, was significantly impaired in the large majority of them. Although in only 3 of 13 patients who achieved GH levels below 2.5 µg/L and normal IGF-I levels for age after 1 yr of OCT treatment, the left ventricular ejection fraction response to exercise was normalized, and a trend toward an improvement was observed in the large majority of patients. These findings suggest that a longer period of treatment is necessary to completely recover the impaired cardiac performance. In a previous study we did not find any increase in the ejection fraction of 11 acromegalic patients treated for 1–2 yr with OCT (17). It should be mentioned that in this small group of patients the results were not analyzed in line with GH and IGF-I normalization (17).
OCT treatment produced changes in hemodynamic parameters that could affect cardiac performance: in fact, resting and peak exercise heart rate were significantly reduced in cured patients, whereas resting systolic blood pressure was significantly increased in noncured patients. These data are of clinical relevance because hypertension and arrhythmia together with diabetes mellitus are considered the major complications affecting cardiac performance and, probably, mortality for cardiac disorders in acromegalic patients (6, 7, 8, 23, 24, 25). In the present series, blood pressure was unchanged in patients with suppressed GH levels and normalized IGF-I levels, in partial disagreement with previous data (30). In accordance with an improved physical performance, both exercise duration and exercise workload were significantly increased in cured patients achieving circulating GH and IGF-I normalization after OCT treatment. Similar data were reported in a smaller group of patients subjected to treadmill exercise treated with OCT for 1 yr (31). In addition, from the results of the present study it emerged that young patients had a more preserved left ventricular systolic function than elderly ones. Impairment of diastolic function was more evident in young than in aged patients, as in the elderly, diastolic function is known to decline physiologically (22). On the other hand, the unsuccessful normalization of circulating GH and IGF-I levels was followed by further impairment of left ventricular ejection fraction during exercise, which was more evident in young patients and can be regarded as a progression of cardiomyopathy.
In conclusion, the results of the present study indicate that the suppression of GH levels below 2.5 or 1 µg/L in the basal condition or after an oral glucose test together with normalization of plasma IGF-I levels for 1 yr is followed by a significant improvement, but not complete normalization, of left ventricular ejection fraction both at rest and at peak exercise without significant changes in diastolic filling. By contrast, the persistence for 1 yr of elevated hormone levels caused a significant increase in systolic blood pressure and impaired cardiac performance. These data suggest that the prolonged suppression of circulating GH and IGF-I levels could normalize cardiac performance and probably reverse the poor prognosis for cardiovascular disease in acromegaly. Whether a complete normalization of hemodynamic and cardiac parameters is achievable in all patients or only in those with shorter disease duration when structural and/or morphological changes are not definitive is unknown. However, from the data reported in the present study it seems that left ventricular function can be significantly improved in elderly patients with a presumed long disease duration provided that hormone normalization is prolonged and sustained.
Received July 23, 1998.
Revised September 15, 1998.
Accepted September 18, 1998.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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