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Original Studies |
Departments of Molecular and Clinical Endocrinology and Oncology (A.Co., P.M., D.F., R.P., G.L.) and Nuclear Medicine Center of the National Council of Research, Department of Biomorphological and Functional Sciences (A.Cu., E.N., A.M.D.M., M.S.), Federico II University of Naples, 80131 Naples, Italy; and Scientific Institute for Research and Care Neuromed (A.Cu., R.P.), 86077 Pozzilli, Italy
Address correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, via Sergio Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it * Partially supported by Grant 9906153187 from
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Eighteen patients with active acromegaly were studied before and 5 yr
after surgery, followed by sc octreotide in 11 patients. Disease
control (GH levels 
1 µg/L after glucose load or 2.5 µg/L after
fasting, respectively, together with normalized IGF-I levels for age)
was achieved in seven patients after surgery and in six patients after
0.3–0.6 mg/day sc octreotide. Five patients were not controlled during
the 5-yr follow-up. Cardiac performance at rest and at peak exercise
was assessed by equilibrium radionuclide angiography at study entry and
5 yr after surgery alone or plus octreotide. Thirty-six sex- and
age-matched healthy subjects served as controls.
At study entry, patients had a lower left ventricular ejection fraction
(LVEF) at peak exercise and LVEF exercise-induced changes, exercise
duration, and capacity than controls (P < 0.001).
After 5 yr of treatment, a significant decrease of resting heart rate
(P = 0.03) and a significant increase of LVEF at
peak exercise (P = 0.003) was found in patients
achieving disease control. LVEF response at peak exercise worsened in
none of the patients with controlled disease and in three patients with
uncontrolled disease (60%) (
2 = 5.5;
P = 0.02). Diastolic filling, exercise duration,
and workload did not significantly change during the 5-yr follow-up. No
difference was found between patients controlled by surgery alone or by
surgery plus octreotide.
This 5-yr prospective study demonstrated that the LVEF response at peak exercise improved in all patients achieving disease control, while it was worsened in 60% of uncontrolled ones. These results strengthen the need of a stable suppression of GH and IGF-I hypersecretion to restore a normal cardiac performance in acromegaly.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Whether the acromegalic cardiomyopathy might be reversed by achieving the biochemical control of the primary disease, is still controversial. A significant decrease of the LV mass (LVM) has been observed after long-term treatment with octreotide (20, 21, 22, 23) or lanreotide (24, 25). The decrease of LVM was generally followed by an improvement of LV filling (20, 21, 22, 23, 24, 25). Conversely, the LV systolic function, measured as LV ejection fraction (LVEF) either by echocardiography (20, 21, 22, 23, 24, 25) or by radionuclide angiography (26), was unchanged after long-term treatment of acromegaly, except in a few cases of overt heart failure (27).
However, if the hypothesis that the impairment of the cardiac performance was due to chronic GH and IGF-I excess is correct, then changes of cardiac function should be related to the efficacy of treatment. Recently, we demonstrated that patients achieving disease control after 1 yr of treatment with sc octreotide had a significant improvement of LVEF, both at rest and at peak exercise, whereas those with persistently uncontrolled disease had a further impairment of cardiac performance (28). These data are insinuative that the prolonged suppression of circulating GH and IGF-I levels might normalize the cardiac performance, thus helping in reversing the poor prognosis for cardiovascular disorders in acromegaly.
The aim of this open prospective study was to investigate the potential reversibility of the acromegalic cardiomyopathy during successful long-term treatment of the primary disease. To address this issue, LV diastolic and systolic functions were assessed at rest and at peak physical exercise by radionuclide angiography in patients with active acromegaly before and after 5 yr of treatment. Basal and posttreatment results were compared with those obtained in an appropriate control group. Changes of cardiac performance were correlated to the therapeutic success in terms of disease control, currently accepted as fasting or glucose-suppressed GH 2.5 µg/L per 1 µg/L or greater, respectively, and IGF-I levels were normalized for age (29, 30).
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Eighteen patients with uncomplicated acromegaly constituted the
patient population: nine women and nine men; age, 18–65 yr. Latent
coronary artery disease was excluded using exercise myocardial
perfusion tomography. The diagnosis of acromegaly was based on high
serum GH levels during an 8-h time-course sampling, not suppressible
below 2 µg/L after an oral glucose test (75 g), and high plasma IGF-I
levels for age (9, 29). The presumed duration of
acromegaly was assessed by comparison of a patient’s photographs taken
during a 1- to 3-decade span and by a patient’s interviews to date the
onset of acral enlargement; in the present series the estimated disease
duration ranged from 4–30 yr. As the control group, 36 healthy
volunteers sex- and age-matched with the patients (21 women and 15 men;
age, 20–60 yr) were studied. All patients and controls gave
their informed consent to participate in this study, approved by the
ethical committee of the Medical School of the Federico II University
of Naples. Five of 18 patients and 10 of the 36 controls were mild
smokers (<10 cigarettes per day), and all had a sedentary lifestyle.
Clinical, endocrine, and cardiac data of patients and controls are
shown in Table 1
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At study entry, IGF-I levels were assayed twice in a single sample whereas the GH level was calculated as the mean of a 6-h blood sampling (0800–1400 h with 30-min sampling). Heart rate, blood pressure measurements, and electrocardiogram were performed in all patients. Hypertension was diagnosed in the presence of diastolic blood pressure greater than 90 mm Hg, in line with WHO criteria (31). Hormonal and clinical evaluations were carried out before treatment, monthly in the first 3 months of treatment, and quarterly during the first year of treatment, then yearly. During treatment, fasting GH level was calculated as the average value of at least three blood samples collected at 15-min intervals at 0800 h (in patients studied the first year after surgery alone) or 2 h after octreotide administration (in patients studied during octreotide treatment). However, in patients cured after surgery, the yearly evaluation of GH level was performed by calculating the mean of a 6-h blood sampling (0800–1400 h with 30-min sampling). At this time point, plasma IGF-I concentrations were assayed as single sampling. Radionuclide angiography was performed before treatment and after 1, 3, and 5 yr. In a subset of these patients, the results after the first year of follow-up have been previously reported (26, 28). The results of the 5-yr follow-up only were reported in this study.
Treatment protocol
All patients included in this study underwent surgical removal of the pituitary adenoma, producing a definitive cure in 7 of them. In the remaining 11, surgery allowed partial tumor removal. Persistent elevation of circulating GH and IGF-I levels led to start treatment with octreotide, initially administered at a dose of 0.05–0.1 mg three times daily in accordance with the individual patient’s tolerability (32), then increased to achieve disease control. Six octreotide-treated patients achieved disease control, whereas no effective and continuous disease control was obtained in the remaining five patients during the follow-up, despite transient increase of octreotide dosage up to 1.5 mg/day. This dose was no longer maintained during the follow-up because GH and IGF-I did not normalize. The maximal dose used in this study was 0.6 mg/day. All 18 patients had been treated with octreotide before surgery at doses of 0.3–0.45 mg/day for 3–6 months, as described previously (33).
Gated blood-pool cardiac scintigraphy
In vivo labeling of red blood cells was performed with 555 MBq (15 mCi) technetium-99m. Equilibrium radionuclide angiography was performed at rest and during dynamic physical exercise as previously described (15, 16, 28). A small field of view gamma 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 W every 2 min until angina, limiting dyspnea, or fatigue developed. Heart rate and blood pressure (by cuff sphygmomanometer) were monitored during exercise at each stage. No patient developed high-grade ventricular arrhythmia necessitating termination of exercise. Radionuclide angiography studies were performed using a standard commercial software system (General Electric). Indices of LV function were derived by computer analysis of the background corrected time-activity curve, as reported previously (15, 16, 28). Both peak ejection rate (PER) and peak filling rate (PFR) were computed in LV counts/sec, normalized for the number of counts at end-diastole and expressed as end-diastolic volume (EDV)/sec. When normalized for EDV, both PER and PFR are influenced directly by the magnitude of LVEF (34). To minimize this effect, we also analyzed the PFR using two additional normalization methods; it was expressed relative to the LV stroke volume and as the ratio between PFR and PER (35, 36). These two latter methods have the additional advantage of being background independent. LV diastolic filling was considered abnormal when the PFR was less than 2.5 EDV/sec, the LVEF was considered insufficient if less than 50% at rest and/or it increased less than 5% at peak exercise compared with resting condition (37). All of the examinations were performed by three independent observers (A.Cu., E.N., and A.M.D.M.) blind as to patient status.
Assays
Serum GH levels were measured by immunoradiometric assay (IRMA) (HGH-CTK-IRMA; Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/L; 1 µg/L corresponds to 3 mU/L. The intra- and interassay coefficients of variation (CV) were 4.5% and 7.9%, respectively. Plasma IGF-I was measured by IRMA after ethanol extraction using Diagnostic Systems Laboratories kits (Webster, TX). The sensitivity of the assay was 0.8 µg/L. The intra-assay CV were 3.4, 3.0, and 1.5% for the low, medium, and high points on the standard curve, respectively. The interassay CV were 8.2, 1.5, and 3.7% for the low, medium, and high points on the standard curve, respectively.
Statistical analysis
Data are reported as mean ± SEM. Student’s
t test for paired data (to evaluate the effect of treatment
in individual patients), ANOVA (to evaluate the effect of treatments in
the patients groups in line with treatment efficacy and to compare
patients and controls), and 2 test were used
where appropriate. Spearman’s rank correlation test was used to
analyze the correlation between the patients’ age and gain in the
exercise-induced changes of ejection fraction. The significance was set
at 5%.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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). In particular, 6 patients (33.3%)
and 10 controls (27.8%) had abnormal PFR, 2 patients (11.1%) and 1
control (2.8%) had impaired LVEF at rest, whereas 14 patients (77.8%)
and 5 controls (13.9%) (2 = 18.8;
P < 0.0001) had abnormal LVEF response at peak
exercise.
At the 5-yr follow-up, both GH (from 43.9 ± 9 to 2.6 ± 1.5
µg/L; P < 0.0001) and IGF-I levels (from 600.7
± 36.4 to 316.9 ± 46.8 µg/L; P < 0.0001) were
significantly reduced compared with baseline, but only 13 patients
achieved disease control. Seven of these patients were cured by surgery
alone, five within the first year and the remaining two during the
second year after surgery. In the latter patients, octreotide therapy
was not started because IGF-I levels were only slightly elevated during
the first year after surgery, and GH levels were suppressed between 1
and 2 µg/L by glucose load. Six of the remaining 13 patients achieved
disease control under increasing doses of octreotide during the first
year of treatment. In 5 patients, octreotide treatment did not induce
disease control during the 5-yr follow-up, but it significantly
decreased GH and IGF-I levels (Table 2).
Two elderly not-controlled patients showed fluctuations of GH and IGF-I
levels into the normal range, indicating a partial control of the
disease. No age difference was found between the groups of patients
achieving or not achieving disease control, but a trend toward an older
age in uncontrolled patients was found (Table 2). At the 5-yr
follow-up, a significant decrease of resting heart rate (from 79.4
± 2.9 to 72.0 ± 2.6 beats per minute (bpm);
P = 0.04), a significant increase of LVEF at peak
exercise (from 56.1 ± 2.4 to 64.1 ± 2.6%;
P = 0.004), and a percent change after exercise (from
-4.9 ± 2.6 to 6.9 ± 3.2%; P = 0.001) was
found in the whole series. Conversely, no difference was found in blood
pressure, diastolic filling, and exercise duration and capacity.
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). No change of heart rate and
systolic and diastolic blood pressure was found at peak exercise. The
LVEF at rest was unchanged both in patients with and in those without
disease control (Table 2). LVEF at rest normalized in the patient with
disease control, whereas it was still abnormal in the patient with poor
controlled disease. LVEF at peak exercise and its exercise-induced
changes were significantly increased only in the patients achieving
disease control (P = 0.003 and P <
0.001, respectively; Table 2), both after surgery and after surgery
plus octreotide (Fig. 1). By contrast,
patients with uncontrolled disease showed a trend toward a further
impairment of exercise-induced changes of LVEF (Fig. 1 and Table 2).
Among the 14 patients with LVEF failure at peak exercise, 10 achieved
disease control during the follow-up; LVEF significantly improved in
all and normalized in 5 (Fig. 1). Two patients showing persistently
high GH and IGF-I levels during the follow-up had LVEF improvement at
peak exercise, whereas the remaining three patients (60%) impaired
their LVEF at peak exercise (Fig. 1). The worsening of LVEF
response at peak exercise was significantly associated with
uncontrolled disease (2 = 5.5;
P = 0.02). The LV diastolic filling, except for a
decrease of PFR in controlled patients (P = 0.03), PER,
exercise duration, and workload, did not significantly change during
the 5-yr follow-up in all patients (Table 2). No difference was found
in the parameters of cardiac function between patients controlled after
surgery alone or after surgery plus octreotide (Fig. 2).
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). Similarly, exercise duration
(7.1 ± 0.5 vs. 9.1 ± 0.2 min, P
< 0.001) and capacity (82.7 ± 7.6 vs. 100.0 ±
3.1 W, P < 0.01) remained significantly lower in
patients than in controls. As a whole, no correlation was found between the patients’ age and the gain in LVEF at peak exercise (r = -2.38; P = 0.2).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The involvement of the heart in acromegaly has been recognized for over a century (38), and it has become progressively clear that cardiac abnormalities can be considered as major determinants of morbidity and reduction of life expectancy in this chronically developing disease (1, 2, 3, 4, 5, 6). To reduce the negative effects of chronic GH and IGF-I hypersecretion, hormone levels should be constantly suppressed. Recent surveys studying mortality in acromegalic patients reported a significant decrease of the standard mortality rate when a suppression of GH levels below 2.5 µg/L was achieved (3, 4). Although no extensive study has accurately ascertained any correlation between the mortality rate in acromegaly and IGF-I levels, due to the relatively recent introduction of this assay, some consensus exists that IGF-I should be lowered to the appropriate age range (6, 39, 40). Aside from the well known beneficial effects of disease control induced by surgery or pharmacotherapy on most clinical signs and symptoms (29, 41, 42), the effect of GH and IGF-I suppression on the acromegalic cardiomyopathy has been less extensively investigated. Several studies have demonstrated a significant decrease of LV hypertrophy following successful surgery or somatostatin analog treatment (20, 21, 22, 23, 24, 25). LVM reduction was generally accompanied by an improvement of the LV filling (20, 21, 22, 23, 24, 25), the abnormality of which is known to precede that of systolic function when the primary disease is left untreated.
Whether the successful suppression of hormone levels is followed by a consequent improvement not only of cardiac hypertrophy but also of cardiac function in acromegalic patients is still debated, because systolic function was reported to be unaffected by GH/IGF-I suppression (20, 21, 22, 23, 24, 25). However, all these studies investigated cardiac function by echocardiography, which is affected by two major limitations, the intra and interobserver variability and the poor sensitivity, due to the assumptions necessary to calculate the LVEF (43). However, even using a more sensitive technique, such as the equilibrium radionuclide angiography, we found no significant LVEF improvement after 12–24 months of treatment with sc octreotide (26). When the analysis of the results was performed in line with treatment effectiveness, a significant improvement of cardiac performance was observed only in patients achieving disease control (28). Interestingly, persistent disease activity led to a further impairment of LVEF response at peak exercise after 1 yr of unsuccessful octreotide treatment (28). Altogether, these data claimed the need for a strong and prolonged hormone suppression to stop the progression of the cardiomyopathy.
This long-term prospective study was designed to verify the potential reversibility of cardiac impairment characterizing acromegaly. Our results clearly demonstrated that all 13 patients achieving disease control after 5 yr of treatment either with surgery alone or combined with octreotide, reported improvement of cardiac performance, and restoration of a normal LVEF response at peak exercise was obtained in half of them. By contrast, among the five patients presenting moderately elevated GH and IGF-I levels during the follow-up, the LVEF response at peak exercise was clearly impaired in 60%. In the entire group, the parameters of diastolic filling were not significantly modified during the 5-yr follow-up and were similar to controls.
The treatment of acromegaly is also followed by some change in the hemodynamic parameters, which could affect cardiac performance per se. In fact, a significant reduction in heart rate at rest and at peak exercise in controlled patients and a significant increase in resting systolic blood pressure in uncontrolled patients have been previously observed after 1 yr of treatment with octreotide (28). The results of the present study confirmed that in controlled patients heart rate at rest was significantly decreased. In addition, heart rate at peak exercise was significantly reduced compared with control. Conversely, systolic and diastolic blood pressure at rest were significantly increased in controlled but not in uncontrolled patients. Whether the long-term suppression of IGF-I is followed by an increase of the vascular resistance nitric oxide mediated (44, 45), and thus causes the increase in blood pressure in patients with disease control, cannot be ruled out. However, a similar pathogenetic mechanism has been claimed to explain the increase in blood pressure occurring in patients with GH deficiency (45). In contrast with previous data of short-term follow-ups (28), no improvement in physical performance, both exercise duration and exercise workload, was observed in this study. A direct cardiac effect of octreotide, as shown on cardiac mass in patients affected with primary hypertrophic cardiomyopathy (46, 47) or on heart rate via the conduction system (48), seems to be excluded by the evidence that the results were similar in patients controlled by surgery and in those controlled by octreotide.
In conclusion, the results of this open 5-yr prospective study indicate that the effective suppression of GH levels together with the age-adjusted normalization of plasma IGF-I levels after surgery or surgery plus pharmacotherapy with octreotide is followed by a significant improvement of cardiac performance in all patients, and by total recovery in half cases. The majority of patients still presenting with mildly elevated GH and IGF-I along the follow-up had a significant impairment of cardiac performance. These data strongly suggest that the suppression of GH and IGF-I to age-corrected normal limits is mandatory to improve or, at least arrest, the acromegalic cardiomyopathy. The increase in blood pressure after long-term GH and IGF-I control was unexpected and it cannot be ruled out whether it was a consequence of hormone suppression.
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Acknowledgments |
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Received May 23, 2000.
Revised August 15, 2000.
Revised December 6, 2000.
Accepted December 6, 2000.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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