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Is the Acromegalic Cardiomyopathy Reversible? Effect of
5-Year Normalization of Growth Hormone and Insulin-
Like Growth Factor I Levels on Cardiac Performance*
ANNAMARIA COLAO, ALBERTO CUOCOLO, PAOLO MARZULLO,
EMANUELE NICOLAI, DIEGO FERONE, ANNA MARIA DELLA MORTE,
ROSARIO PIVONELLO, MARCO SALVATORE, AND GAETANO LOMBARDI
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
ABSTRACT
Acromegalic patients are considered to be exposed to a doubled
mortality rate, mostly for cardiovascular diseases. This open prospec-
tive study was designed to evaluate whether the impairment of car-
diac performance could be reversed by the long-term suppression of
GH and insulin-like growth factor I (IGF-I) levels.
Eighteen patients with active acromegaly were studied before and
5 yr after surgery, followed by sc octreotide in 11 patients. Disease
control (GH levels ⱕ1
g/L after glucose load or ⱕ2.5
g/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 frac-
tion (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 hyper-
secretion to restore a normal cardiac performance in acromegaly.
(J Clin Endocrinol Metab 86: 1551–1557, 2001)
ACROMEGALIC PATIENTS ARE considered to be ex-
posed to a doubled mortality rate, mostly for cardio-
vascular diseases (1– 6). In recent years, both GH and insulin-
like growth factor I (IGF-I) excess and deficiency have been
found associated with several changes of cardiac structure
and function (7, 8). In acromegaly, particularly, concentric
cardiac hypertrophy is a frequent clinical and instrumental
finding at diagnosis, even in young patients with short dis-
ease duration (9–11). As a consequence of this phenomenon,
an early impairment of the left ventricular (LV) diastolic
filling has been described (12–16), whereas systolic dysfunc-
tion may develop in later stages of untreated disease (7, 8).
Other cardiovascular and metabolic disorders, such as arte-
rial hypertension, coronary artery disease, ventricular
arrhythmias, diabetes mellitus, and thyroid disorders are
observed in some patients with acromegaly and can inde-
pendently worsen the acromegalic cardiomyopathy (17, 18),
which seems, however, to be a specific disease (19).
Whether the acromegalic cardiomyopathy might be re-
versed 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 (20–23) or lanreotide (24, 25). The decrease of
LVM was generally followed by an improvement of LV fill-
ing (20–25). Conversely, the LV systolic function, measured
as LV ejection fraction (LVEF) either by echocardiography
(20 –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 dem-
onstrated that patients achieving disease control after 1 yr
of treatment with sc octreotide had a significant improve-
ment 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 perfor-
Received May 23, 2000. Revision received August 15, 2000. Rerevision
received December 6, 2000. Accepted December 6, 2000.
Address correspondence and requests for reprints to: Annamaria
Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinol-
ogy and Oncology, Federico II University of Naples, via Sergio Pansini
5, 80131 Naples, Italy. E-mail: colao@unina.it.
* Partially supported by Grant 9906153187 from Ministero Universita´e
Ricerca Scientifica e Technologica (Rome, Italy).
0021-972X/01/$03.00/0 Vol. 86, No. 4
The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.
Copyright © 2001 by The Endocrine Society
1551
mance, 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 cardiomyopa-
thy during successful long-term treatment of the primary
disease. To address this issue, LV diastolic and systolic func-
tions 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 corre-
lated to the therapeutic success in terms of disease control,
currently accepted as fasting or glucose-suppressed GH 2.5
g/L per 1
g/L or greater, respectively, and IGF-I levels
were normalized for age (29, 30).
Patients and Methods
Patients
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 per-
fusion tomography. The diagnosis of acromegaly was based on high
serum GH levels during an 8-h time-course sampling, not suppressible
below 2
g/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.
Study protocol
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 mea-
surements, and electrocardiogram were performed in all patients. Hy-
pertension 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 treat-
ment, 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 oct-
reotide 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. Radio-
nuclide 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 eleva-
tion 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
TABLE 1. Hormone levels and hemodynamic and functional parameters measured at rest and at peak exercise by equilibrium
radionuclide angiography in healthy controls and patients with uncomplicated acromegaly
Parameters Controls (n ⫽36) Patients (n ⫽18) P
Range Mean ⫾SEM Range Mean ⫾SEM
Age (yr) 23–60 38.7 ⫾1.9 18–65 40.1 ⫾2.7
Serum GH levels (
g/L)
a
0.1–1.2 0.4 ⫾0.03 8–130 43.9 ⫾9 0.0001
Plasma IGF-I levels (
g/L) 130–333 230.3 ⫾9.2 350–850 600.7 ⫾36.4 0.0001
Heart rate (bpm)
At rest 48–96 73.9 ⫾2.0 60–105 79.4 ⫾2.9 0.5
During exercise 95–191 140.7 ⫾3.5 103–168 135.4 ⫾4.7 0.6
Systolic blood pressure (mm Hg)
At rest 100–135 121.4 ⫾1.2 90–150 121.1 ⫾3.6 1
During exercise 130–200 165.0 ⫾3.1 130–210 175.0 ⫾5.6 0.6
Diastolic blood pressure (mm Hg)
At rest 60–90 79.3 ⫾1.2 60–90 76.4 ⫾2.4 0.5
During exercise 80–120 100.0 ⫾2.2 75–140 97.2 ⫾3.3 0.3
Ejection fraction (%)
At rest 50–78 61.6 ⫾1.0 46–76 58.7 ⫾1.7 0.4
During exercise 56–95 72.5 ⫾1.5 37–75 56.1 ⫾2.4 0.001
⌬(%) 0–50.7 17.8 ⫾2.2 24–11.1 –4.9 ⫾2.6 0.001
PER (EDV/sec) 2.1–5.5 3.6 ⫾0.1 2.4–4.5 3.6 ⫾0.1 1
PFR (EDV/sec) 1.6– 4.1 2.8 ⫾0.1 1.2–4.9 3.1 ⫾0.2 0.6
PFR (SV/sec) 2.8–6.8 4.5 ⫾0.1 2.1–9.7 5.1 ⫾0.4 0.7
PFR/PER 0.4–1.1 0.7 ⫾0.02 0.4–1.2 0.8 ⫾0.05 0.05
Exercise duration 6–12 9.4 ⫾0.2 6–8 6.9 ⫾0.2 0.001
Exercise potency 75–125 100.0 ⫾2.8 50–125 80.0 ⫾3.7 0.001
a
GH values are the mean of a 6-h blood sampling. The normal GH value was ⱕ2.5
g/L. The normal IGF-I range in 20- to 30-, 31- to 40-,
41- to 50-, and over-50-yr-old subjects was 110–502, 100–494, 100 –303, and 78–258
g/L, respectively. Normal blood pressure DBP ⱕ90 mm
Hg. The normal PFR was ⱖ2.5 EDV/sec. The normal ejection fraction at rest was ⬎50% and the normal response of the ejection fraction at peak
exercise was ⬎5% of resting values.
1552 COLAO ET AL. JCE&M•2001
Vol. 86 •No. 4
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 per-
formed 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 mo-
tion 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 angio-
graphy studies were performed using a standard commercial software
system (General Electric). Indices of LV function were derived by com-
puter analysis of the background corrected time-activity curve, as re-
ported 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 advan-
tage of being background independent. LV diastolic filling was consid-
ered 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
g/L; 1
g/L corresponds to 3 mU/L. The intra- and
interassay coefficients of variation (CV) were 4.5% and 7.9%, respec-
tively. Plasma IGF-I was measured by IRMA after ethanol extraction
using Diagnostic Systems Laboratories kits (Webster, TX). The sensi-
tivity of the assay was 0.8
g/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 ttest 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%.
Results
At study entry, acromegalic patients had a lower LVEF at
peak exercise and LVEF exercise-induced changes, exercise
duration, and capacity than controls (Table 1). 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 ⫾9to2.6⫾1.5
g/L; P⬍0.0001) and IGF-I levels (from 600.7 ⫾36.4 to
316.9 ⫾46.8
g/L; P⬍0.0001) were significantly reduced
compared with baseline, but only 13 patients achieved dis-
ease 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
g/L by glucose
load. Six of the remaining 13 patients achieved disease con-
trol under increasing doses of octreotide during the first year
of treatment. In 5 patients, octreotide treatment did not in-
duce disease control during the 5-yr follow-up, but it sig-
nificantly 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 sig-
nificant 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 pres-
sure, diastolic filling, and exercise duration and capacity.
When the analysis was performed on the basis of treatment
efficacy, only in patients achieving disease control were heart
rate and systolic and diastolic blood pressure at rest signif-
icantly decreased and increased, respectively (Table 2). 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 uncon-
trolled 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 signif-
icantly improved in all and normalized in 5 (Fig. 1). Two
patients showing persistently high GH and IGF-I levels dur-
ing 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 re-
sponse 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).
At the end of follow-up, patients with controlled disease
REVERSIBILITY OF CARDIAC IMPAIRMENT IN ACROMEGALY 1553
had still a slightly but significantly lower LVEF at peak
exercise than sex- and age-matched controls (65.9 ⫾2.7 vs.
74.5 ⫾1.8%; P⬍0.01) without any difference in the exercise-
induced changes of LVEF (10.8 ⫾3.4 vs. 19.5 ⫾2.8%). In
addition, patients achieving disease control had significantly
lower heart rate (120.5 ⫾4.3 vs. 140.0 ⫾2.9 bpm; P⬍0.001),
and higher systolic (179.6 ⫾6.3 vs. 160.4 ⫾3.9 mm Hg; P⬍
0.01), but not diastolic, blood pressure at peak exercise than
controls. The parameters of LV filling were similar in con-
trolled patients and controls (Fig. 2). Similarly, exercise du-
ration (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).
Discussion
The most important finding of this study is that cardiac
performance improved in all patients achieving disease con-
trol during the 5-yr follow-up, and was normalized in 50%
of them. The LVEF response at peak exercise was further
impaired in 60% of the patients showing still slightly ele-
vated GH and IGF-I levels during the follow-up. However,
after 5 yr of disease control the LVEF at peak exercise was still
significantly lower in the patients than in healthy sex- and
age-matched controls.
The involvement of the heart in acromegaly has been rec-
ognized for over a century (38), and it has become progres-
sively clear that cardiac abnormalities can be considered as
major determinants of morbidity and reduction of life ex-
pectancy in this chronically developing disease (1–6). To
reduce the negative effects of chronic GH and IGF-I hyper-
secretion, 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
g/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 con-
trol 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 demon-
strated a significant decrease of LV hypertrophy following
successful surgery or somatostatin analog treatment (20–25).
LVM reduction was generally accompanied by an improve-
ment of the LV filling (20–25), 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 pa-
tients is still debated, because systolic function was reported
to be unaffected by GH/IGF-I suppression (20–25). How-
ever, all these studies investigated cardiac function by echo-
cardiography, 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
TABLE 2. Hormone levels hemodynamic and functional parameters measured at rest and at peak exercise by equilibrium radionuclide
angiography in patients with acromegaly after 5 years of surgery (patient 7) or octreotide treatment (patient 11)
Parameters Patients with controlled disease (n ⫽13) Patients with uncontrolled disease (n ⫽5)
Basal Treatment PBasal Treatment P
Age (yr) 34.7 ⫾2.7 48.4 ⫾8.6
Serum GH levels (
g/L) 40.2 ⫾9.6 1.5 ⫾0.3 0.002 53.1 ⫾22.2 5.5 ⫾0.7 0.09
Plasma IGF-I levels (
g/L) 619.0 ⫾44.4 373.4 ⫾30.8 ⬍0.001 553.2 ⫾64.3 430.0 ⫾147.3 0.4
Heart rate (bpm)
At rest 79.4 ⫾2.8 72.8 ⫾3.4 0.03 79.6 ⫾7.9 69.8 ⫾3.0 0.4
During exercise 136.5 ⫾5.7 120.5 ⫾4.3 0.07 132.4 ⫾8.5 131.6 ⫾6.7 0.9
Systolic blood pressure (mm Hg)
At rest 117.3 ⫾3.7 129.6 ⫾4.1 0.01 131.0 ⫾7.8 128.0 ⫾9.6 0.9
During exercise 170.0 ⫾6.7 179.6 ⫾6.3 0.3 188.0 ⫾8.6 180.0 ⫾13.8 0.6
Diastolic blood pressure (mm Hg)
At rest 75.4 ⫾2.7 82.5 ⫾2.1 0.01 79.0 ⫾5.1 84.0 ⫾4.0 0.3
During exercise 96.9 ⫾4.3 103.5 ⫾4.4 0.3 98.0 ⫾4.9 98.0 ⫾8.0 1.0
Ejection fraction (%)
At rest 59.5 ⫾2.2 60.1 ⫾2.6 0.2 56.6 ⫾3.0 60.4 ⫾3.6 0.2
During exercise 55.8 ⫾2.9 65.9 ⫾2.7 0.003 56.8 ⫾4.9 59.2 ⫾6.2 0.6
⌬(%) – 6.5 ⫾3.4 10.8 ⫾3.4 ⬍0.001 –0.7 ⫾3.8 –3.1 ⫾5.8 0.6
PER (EDV/sec) 3.6 ⫾0.2 3.6 ⫾0.2 0.8 3.4 ⫾0.3 3.4 ⫾0.3 0.6
PFR (EDV/sec) 3.2 ⫾0.3 2.6 ⫾0.2 0.03 2.5 ⫾0.6 2.8 ⫾0.4 0.4
PFR (SV/sec) 5.6 ⫾0.6 4.5 ⫾0.4 0.06 4.3 ⫾0.8 3.6 ⫾0.6 0.6
PFR/PER 0.9 ⫾0.06 0.7 ⫾0.06 0.09 0.7 ⫾0.1 0.8 ⫾0.08 0.3
Exercise duration 7.1 ⫾0.3 7.1 ⫾0.5 1 6.4 ⫾0.4 7.4 ⫾0.6 0.9
Exercise potency 80.0 ⫾4.8 82.7 ⫾7.6 0.2 80.0 ⫾5.0 80.0 ⫾5.0 0.3
Patients were sub-grouped on the basis of disease control evaluated by suppression of circulating GH levels (ⱖ2.5 or 1
g/L fasting or after
oral glucose test, respectively) and normalization of IGF-I levels for age. GH values are the mean of at least three samples. The normal GH
range was ⱕ7.5 mU/L. The normal IGF-I range in 20- to 30-, 31- to 40-, 41- to 50-, and over-50-yr-old subjects was 110–502, 100–494, 100 –303,
and 78–258
g/L, respectively. The normal blood pressure was DBP ⱕ90 mm Hg. The normal PFR was ⱖ2.5 EDV/sec. The normal ejection
fraction at rest was ⬎50% and the normal response of the ejection fraction at peak exercise was ⬎5% of resting values.
1554 COLAO ET AL. JCE&M•2001
Vol. 86 •No. 4
equilibrium radionuclide angiography, we found no signif-
icant 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, persis-
tent 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 pro-
gression of the cardiomyopathy.
This long-term prospective study was designed to verify
the potential reversibility of cardiac impairment character-
izing 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, re-
ported 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 signif-
icant 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 signif-
icantly 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
FIG. 1. Plasma IGF-I levels (left) and
exercise-induced changes of LVEF
(right) in patients achieving disease
control after surgery (top) or after sur-
gery plus octreotide (middle) and in
those presenting elevated GH and
IGF-I levels during the 5-yr follow-up
(bottom).
REVERSIBILITY OF CARDIAC IMPAIRMENT IN ACROMEGALY 1555
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 con-
trast with previous data of short-term follow-ups (28), no im-
provement 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 af-
fected with primary hypertrophic cardiomyopathy (46, 47) or
on heart rate via the conduction system (48), seems to be ex-
cluded 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.
Acknowledgments
We are indebted to A. Giaccio, medical student at the Department of
Molecular and Clinical Endocrinology and Oncology, Federico II Uni-
versity of Naples, for help in taking care of acromegalic patients.
FIG. 2. LVEF at rest (top left) and at
peak exercise (middle left), exercise-
induced changes of LVEF (bottom left),
PFR measured as EDV (top right),
stroke volume (middle right) and as the
ratio between PFR and PER (bottom
right) in patients achieving disease con-
trol after surgery or octreotide com-
pared with sex- and age-matched con-
trols. ⴱ,P⬍0.01 vs. baseline.
1556 COLAO ET AL. JCE&M•2001
Vol. 86 •No. 4
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