0021-972X/00/00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 1
Printed in U.S.A.
Systemic Hypertension and Impaired Glucose Tolerance
Are Independently Correlated to the Severity of the
Acromegalic Cardiomyopathy*
ANNAMARIA COLAO, ROBERTO BALDELLI, PAOLO MARZULLO,
ELISABETTA FERRETTI, DIEGO FERONE, PATRIZIA GARGIULO,
MARIO PETRETTA, GUIDO TAMBURRANO, GAETANO LOMBARDI,
ANTONIO LIUZZI
AND
Departments of Molecular and Clinical Endocrinology and Oncology (A.C., P.M., D.F., G.L.) and
Internal Medicine I (M.P.), Federico II University of Naples; Department of Clinical Science, Section of
Endocrinology, University La Sapienza (R.B., E.F., P.G., G.T.), Rome; and Division of Endocrinology,
S. Giuseppe Hospital, IRCCS, Istituto Auxologico Italiano (A.L.), Verbania, Italy
ABSTRACT
Increased mortality from cardiovascular diseases has been reported in acromegaly. Our objective was to evaluate the impact of
glucose tolerance abnormalities and/or systemic hypertension in further worsening the acromegalic cardiomyopathy. The study design
was open transversal. The subjects studied were 130 consecutive
naive acromegalic patients (74 women and 56 men; age, 17– 80 yr).
Interventricular septum (IST) and left ventricular (LV) posterior wall
thickness (PWT), LV mass index (LVMi), maximal early to late diastolic flow velocity ratio (E/A), isovolumic relaxation time (IRT), and
LV ejection fraction (EF) were measured by echocardiography. The
results were analyzed in line with the presence of glucose tolerance
abnormalities (normal in 60, impaired in 38, diabetes mellitus in 32)
and the presence (in 46) or absence (in 84) of hypertension. Patients
with impaired glucose tolerance and diabetes mellitus had significantly higher age (P 5 0.01), and systolic (P 5 0.01) and diastolic (P 5
0.01) blood pressures and lower E/A (P 5 0.01) and EF (P 5 0.01) than
those with normal glucose tolerance. Disease duration, circulating
GH and insulin-like growth factor I (IGF-I) levels, IST, LVPWT,
LVMi, and IRT were similar in the 3 groups. Normotensive patients
had significantly lower age (P , 0.001), LVPWT (P , 0.001), IST (P 5
0.003), LVMi (P , 0.001), and IRT (P 5 0.02) and significantly higher
E/A (P , 0.001) and EF (P , 0.001) than hypertensive subjects.
Disease duration, circulating GH, and IGF-I levels were similar in the
2 groups.
Multiple regression analysis showed that systolic blood pressure
was the strongest predictor of LVMi (P 5 0.0004), followed by GH
levels (P 5 0.02), whereas diastolic blood pressure was the strongest
predictor of LVEF reduction (P , 0.0001), followed by glucose tolerance status (P 5 0.02). Age was the strongest predictor of both E/A
impairment (P , 0.0001) and IRT (P 5 0.01), followed by IGF-I levels
(P 5 0.02).
Compared to patients with uncomplicated acromegaly, those with
hypertension but without abnormalities of glucose tolerance had an
increased prevalence of LV hypertrophy (75% vs. 37.2%) as well as of
impaired diastolic (50% vs. 7.8%) and systolic function (18.7% vs.
3.9%), whereas patients with glucose tolerance abnormalities but
without hypertension had only an increased prevalence of impaired
diastolic (39.7%) and systolic function (31.7%). The subgroup of acromegalic patients suffering from hypertension and diabetes mellitus
had the highest prevalence of LV hypertrophy (84.6%), diastolic filling
abnormalities (69.2%), and impaired systolic function at rest (53.9%).
A careful cardiac investigation should thus be performed in all acromegalic patients showing these complications. (J Clin Endocrinol
Metab 85: 193–199, 2000)
A
cidents is not only due to systemic hypertension, coronary
artery disease, and arrhythmias, but also to a specific cardiomyopathy (6 –11). In recent years, consistent evidence has
been produced that chronic GH and insulin-like growth factor I (IGF-I) excess in acromegaly causes a specific derangement of cardiomyocytes (11–13) with an increased incidence
of their apoptosis (14). The most evident morphological alteration is the concentric biventricular hypertrophy (9),
which is indicated as the cause of progressive diastolic and
systolic impairment and may seriously hazard the patient’s
cardiac well-being. Although left ventricular (LV) hypertrophy has been reported to be consistently higher in hypertensive acromegalic patients than in normotensive ones,
small series of patients have been investigated (8 –11). On the
other hand, patients with uncomplicated acromegaly were
reported to have higher blood pressure values, both at rest
and at peak exercise, than age-matched controls (15). Both
left ventricular (LV) diastolic and systolic functions were
CROMEGALY is a pituitary disease featured by progressive bone and organ overgrowth, frequently accompanied by deranged cardiovascular, cerebrovascular,
and respiratory functions that influence the final outcome
and contribute to the premature death observed in this condition (1– 4). In the literature, cardiovascular accidents are
claimed to be the main cause of the increased mortality in
acromegaly (1–5). The poor prognosis for cardiovascular ac-
Received July 27, 1999. Revision received September 22, 1999.
Accepted September 29, 1999.
Address all 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 S. Pansini 5,
80131 Naples, Italy. E-mail: [email protected].
* This work was performed in cooperation with the Study Group on
Acromegaly of the Italian Society of Endocrinology and was partially
supported by Grant 9706151106 from MURST (Rome, Italy). This study
was presented in part at the 81st Annual Meeting of The Endocrine
Society, June 12–15, 1999, San Diego, California (Abstract OR 4 – 6).
193
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COLAO ET AL.
significantly impaired in patients compared to controls, with
an age-dependent worsening of the diastolic function (15).
The duration of heart exposure to chronically elevated GH
and IGF-I levels should also play a relevant role in determining the severity of cardiac abnormalities, as demonstrated by the inverse correlation between disease duration
and LV ejection fraction (EF) response at peak exercise in
uncomplicated acromegaly (15). However, young acromegalic patients estimated to have had the disease for longer
than 5 yr presented an increased LV mass index (LVMi) and
diastolic filling abnormalities (16, 17). In addition, acromegalic patients often present abnormal glucose tolerance,
which is associated with premature atherosclerosis and coronary artery disease (18, 19). Type 2 diabetes mellitus is
known to be a major independent risk factor for coronary
artery disease (18). Atherosclerosis accounts for about 80% of
all deaths from type 2 diabetes, of which approximately 75%
are due to coronary artery disease and the remaining 25% to
cerebrovascular or peripheral vascular accidents. Hypertension in these patients has a major impact on accelerating
atherosclerosis (18, 19). However, the impact of impaired
glucose tolerance or diabetes mellitus and/or systemic hypertension on cardiac morphology and function has been
poorly investigated to date.
The aim of this study was to evaluate the effects of chronic
GH and IGF-I excess alone or associated with abnormalities
of glucose tolerance (impaired glucose tolerance or diabetes
mellitus) and/or arterial hypertension on cardiac morphology and performance investigated by means of echocardiography.
Subjects and Methods
Patients
One hundred and thirty untreated acromegalic patients (74 women
and 56 men) consecutively admitted to the Department of Molecular and
Clinical Endocrinology and Oncology of the Federico II University of
Naples (Naples, Italy) and to the Department of Clinical Science of the
University La Sapienza (Rome, Italy) were included in the study after
their informed consent had been obtained. The mean ages of the patients
were 48.9 6 1.59 (mean 6 sem) and 47.2 6 2 yr in women and men,
respectively, with a range of 17– 80 and 24 –76 yr, respectively. The
protocol of the study was approved by the ethical committee of the
Federico II University of Naples. The diagnosis of acromegaly was made
on the basis of high serum GH levels (14.6 6 1.6 mg/L) during an 8-h
time course that were not suppressible below 2 mg/L after a 75-g oral
glucose tolerance test (oGTT) and high plasma IGF-I levels for age
(540.7 6 26.5 mg/L) (16). In patients with diabetes mellitus the oGTT was
not performed. The duration of acromegaly was estimated by comparing
patients’ photographs taken over 1–3 decades and by interviews to date
the onset of acral enlargement. We defined it as the interval between the
clinical onset and the time of treatment. In this series disease duration
ranged between 2– 40 yr (mean 6 sem, 11.2 6 0.6 yr).
Study design
Within 1 week from the admission for acromegaly, serum GH profile
(at least three blood samples at 30-min intervals), plasma IGF-I levels (in
two determinations), heart rate and blood pressure measurements, electrocardiogram, and echocardiogram were performed at study entry in
all patients. Blood pressure was measured in the right arm, with the
subject in a relaxed sitting position. The average of six measurements
(three taken by each of two examiners) with a mercury sphygmomanometer was used in all analysis. The fourth Korotkoff phase was considered as diastolic blood pressure (DBP). Hypertension was diagnosed
in the presence of DBP above 90 mm/Hg. When necessary, severity of
hypertension was classified on the basis of the WHO criteria as mild
when the DBP was between 91–104 mm Hg, moderate when the DBP
was between 105–114 mm Hg, and severe when the DBP was greater
than 115 mm Hg (20). The oGTT was performed by measuring blood
glucose every 30 min for 2 h after the oral administration of 75 g glucose
diluted in 250 ml saline solution. The diagnosis of diabetes mellitus or
impaired glucose tolerance was performed according to the following
criteria. Diabetes mellitus was diagnosed when fasting glucose was
above 126 mg/dL in two consecutive measurements or when 2 h after
the oGTT glucose was 200 mg/dl or more. Impaired glucose tolerance
was diagnosed when glucose was between 126 –200 mg/dL 2 h after the
oGTT with an additional measurement of 200 mg/dL or more between
0 –2 h after glucose load (21).
Patients’ classification
According to the above-mentioned criteria, 84 patients were normotensive, 32 had mild hypertension, 12 had moderate hypertension and
2 had severe hypertension. Systolic blood pressures were 129.1 6 2.1 and
140.3 6 3.6 mm Hg, and diastolic blood pressures were 83.9 6 1.4 and
90.3 6 2 mm Hg in the normotensive and hypertensive groups, respectively. Fifteen patients with hypertension were untreated, 28 patients
were treated with angiotensin-converting enzyme inhibitors, two with
angiotensin-converting enzyme inhibitors plus diuretics, and 1 with
calcium antagonists. Sixty patients had normal glucose tolerance, 38 had
impaired glucose tolerance, and 32 had diabetes mellitus. All diabetic
patients were treated with oral hypoglycemic agents, except for 2 treated
with insulin. All patients presented with hypertension and/or glucose
tolerance abnormalities at diagnosis, with an estimated duration of these
complications of 2–10 yr. Considering both variables, 6 groups were
obtained, as shown in Table 1, which summarizes patients’ classification
and hormone profile at study entry.
Echocardiographic study
M-mode, two-dimensional, and pulsed Doppler echocardiographic
studies were performed with ultrasound systems (Apogee CX, Interspec, Inc., Ambler, PA; in Naples and in Rome) using a 3.5-MHz trans-
TABLE 1. Patients classification according to glucose tolerance and blood pressure levels
No. of patients
Age (yr)
Disease duration
Serum GH levels
(mg/L)
Plasma IGF-I levels
(mg/L)
a
b
Normal blood
pressure and
glucose
tolerance
Normal blood
pressure and
impaired glucose
tolerance
Normal blood
pressure and
diabetes
mellitus
Hypertension
and normal
glucose tolerance
Hypertension
and impaired
glucose
tolerance
48
39.9 6 2.2
9.7 6 0.9
15.4 6 3.4
19
46.6 6 3.2
9.6 6 1.2
19.8 6 6.3
16
55.5 6 3.7a
13.5 6 1.8
17.5 6 3.2
15
51.5 6 3.7a
13.3 6 1.6
13.4 6 7.4
18
52.3 6 2.7a
12.1 6 1.6
16.4 6 4.4
556.6 6 40.5
615.6 6 67.1
575.9 6 26.5
501.2 6 60.7
520.4 6 70.1
P , 0.01 vs. patients normotensive and with normal glucose tolerance.
P , 0.01 vs. patients normotensive and with impaired glucose tolerance.
Hypertension
and diabetes
mellitus
14
64.4 6 3.5a,b
12.7 6 1.9
24.5 6 4.9
579.9 6 73.1
P
,0.0001
NS
NS
NS
ACROMEGALIC CARDIOMYOPATHY
ducer during at least three consecutive cardiac cycles. The records were
made by investigators blind with respect to the presence of metabolic
abnormalities or arterial hypertension. All patients were studied in the
left lateral recumbent position after a 10-min resting period according
to the recommendations of the American Society of Echocardiography
(22). The following measurements were recorded on M-mode tracing:
interventricular septum (IST) and posterior wall thickness (LVPWT), the
frequency-normalized mean velocity of circumferential fiber shortening
end-diastolic and end-systolic volumes (EDV and ESV), and ejection
fraction (EF 5 EDV 2 ESV/EDV%), estimated according to the Quinones method (23). A normal LVEF was considered to be a value above
50%. The LV mass (LVM) was calculated using Devereux’s formula
according to Penn’s convention with the following regression-corrected
cube formula: LVM 5 1.04[(ISV 1 LVID 1 PWT)3 2 (LVID)3] 2 14 g.
LV hypertrophy was diagnosed when LVM values, corrected for body
surface area (LVMi), were 135 g/m2 or more in males and 110 g/m2 or
more in females. Doppler studies provided indexes of ventricular filling
that were derived from the mitral flow velocities curves, i.e. maximal
early diastolic flow velocity (E in centimeters per s), maximal late diastolic flow velocity (A in centimeters per s), the ratio between E and A
curves (E/A, normal value .1). The isovolumic relaxation time (IRT)
corrected for cardiac frequencies (in milliseconds) also served as an
index of LV filling.
Assays
Circulating GH and IGF-I levels were assayed by immunoassays
using commercially available kits. Fasting GH levels were considered
to be above normal when more than 2.5 mg/L. In our laboratories the
normal IGF-I ranges in 20- to 30-, 31- to 40-, 41- to 50-, and over
50-yr-old subjects were 110 –502, 100 – 494, 100 –303, and 78 –258
mg/L, respectively.
Statistical analysis
The statistical analysis was performed by means of the SPSS, Inc.
(Cary, NC) package. Data are reported as the mean 6 sem. The effect of
hypertension (analysis performed on two groups) on cardiac structural
and functional parameters was analyzed by means of the unpaired
Student’s t test. The effect of glucose tolerance alone (analysis performed
on three groups) and combined with hypertension (analysis performed
on six groups) on cardiac structural and functional parameters was
evaluated by ANOVA . The significance was set at 5%. Post-hoc analysis
was performed by unpaired t test, applying Bonferroni’s correction. The
stepwise multiple linear regression was performed to evaluate the relative importance of age, disease duration, GH and IGF-I levels, systolic
blood pressure (SBP), DBP, and the presence or absence of glucose
tolerance abnormalities in structural (IST, LVPWT, LVMi) and functional parameters (E/A, IRT, EF).
195
Results
No difference was found in age, disease duration, serum
GH and IGF-I levels, IST, LVPWT, IRT, E/A, and LVEF,
except for a mild, insignificant increase in LVMi (133.1 6 7.7
vs. 119.1 6 4.1 g/m2; P 5 0.053), between acromegalic men
and women (data not shown).
Acromegalic cardiomyopathy and abnormalities of glucose
tolerance (Table 2)
Age was significantly higher in patients with diabetes
mellitus than in those with normal and impaired glucose
tolerance (P 5 0.01). Both SBP and DBP values were significantly higher in patients with impaired glucose tolerance
and diabetes mellitus than in those with normal glucose
tolerance (P 5 0.01). IST and LVMi were similar in the three
groups, but LVPWT was significantly higher in patients with
diabetes mellitus than in those with normal or impaired
glucose tolerance (P 5 0.01). In patients with diabetes mellitus, E/A was significantly lower than in those with normal
glucose tolerance (P 5 0.01), and LVEF was significantly
lower in patients with impaired glucose tolerance and diabetes mellitus than in those with normal glucose tolerance
(P 5 0.01). No difference was found in circulating GH and
IGF-I levels and disease duration among the three groups.
Acromegalic cardiomyopathy and hypertension (Table 3)
In hypertensive patients, age (P , 0.001), IST (P 5 0.003),
LVPWT (P , 0.001), LVMi (P , 0.001), and IRT (P 5 0.02)
were significantly higher, whereas E/A (P , 0.001) and LVEF
(P , 0.001) were significantly lower than in normotensive
patients. No difference was found in disease duration and
circulating GH and IGF-I levels between normotensive and
hypertensive patients. No difference was found in LVMi
(157.1 6 3.5 vs. 133.8 6 10.7 g/m2), E/A (1.06 6 0.04 vs. 1.03 6
0.06), and LVEF (56.1 6 1.9% vs. 51.6 6 3.6%) between patients with mild hypertension and those with moderate/
severe hypertension. No difference was found in LVMi
(146.1 6 18.2 vs. 146.5 6 7.4 g/m2) between patients treated
for hypertension and those not treated.
In this study LV hypertrophy was observed in 66 pa-
TABLE 2. Effect of glucose tolerance abnormalities on structural and functional cardiac parameters
No. of patients
Age (yr)
Disease duration (yr)
Serum GH levels (mg/L)
Plasma IGF-I levels (mg/L)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Interventricular septum thickness (mm)
Left ventricular posterior wall thickness (mm)
Left ventricular mass index (g/m2)
E/A
Isovolumic relaxation time (ms)
Left ventricular ejection fraction (%)
a
b
Normal glucose
tolerance
Impaired glucose
tolerance
Diabetes
mellitus
60
41.3 6 1.7
10.7 6 0.8
14.9 6 3.2
544.3 6 34.6
127.1 6 2.2
82.9 6 1.5
10.1 6 0.3
9.9 6 0.2
120.6 6 6.9
1.26 6 0.04
112.0 6 3.0
64.1 6 1.5
38
49.9 6 2.3a
10.8 6 1
17.3 6 3.8
572.3 6 48.5
140.5 6 3.7a
92.3 6 2.0a
11.1 6 0.2
9.8 6 0.3
122.6 6 6.8
1.19 6 0.05
108.1 6 3.2
56.8 6 1.8a
32
59.3 6 2.5b
13.3 6 1.3
21.1 6 2.8
584.6 6 38.8
153.7 6 3.9a
94.2 6 2.2a
11.1 6 0.4
10.8 6 0.4b
139.5 6 8.2
1.04 6 0.04a
116.1 6 6.3
55.0 6 2.1a
P
,0.001
NS
NS
NS
,0.001
,0.001
NS
,0.05
NS
,0.01
NS
,0.001
P , 0.01 vs. patients normotensive and with normal glucose tolerance.
P , 0.01 vs. patients normotensive and with normal glucose tolerance and vs. patients normotensive and with impaired glucose tolerance.
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TABLE 3. Effect of hypertension on structural and functional cardiac parameters
No. of patients
Age (yr)
Disease duration (yr)
Serum GH levels (mg/L)
Plasma IGF-I levels (mg/L)
Interventricular septum thickness (mm)
Left ventricular posterior wall thickness (mm)
Left ventricular mass index (g/m2)
E/A
Isovolumic relaxation time (ms)
Left ventricular ejection fraction (%)
Normotensive
patients
Hypertensive
patients
84
43.9 6 1.7
10.4 6 0.7
16.5 6 2.5
572.9 6 28.8
10.3 6 0.2
9.7 6 0.2
114.0 6 3.9
1.25 6 0.04
108.7 6 2.8
63.5 6 1.1
46
55.4 6 1.9
12.7 6 0.9
18.6 6 3.0
529.8 6 40.3
11.6 6 0.2
11.0 6 0.3
146.3 6 9.5
1.06 6 0.03
117.6 6 3.4
53.5 6 1.7
P
,0.001
NS
NS
NS
0.003
,0.001
,0.001
,0.001
0.02
,0.001
FIG. 1. Prevalence of LV hypertrophy, diastolic filling abnormalities (measured as E/A ,1) and impairment of systolic function (measured as
LVEF ,50%) in the 130 patients divided into 6 groups on the basis of the absence of hypertension and glucose tolerance abnormalities (NT-NGT),
the absence of hypertension and impaired glucose tolerance (NT-IGT), the absence of hypertension and diabetes mellitus (NT-DM), hypertension
and normal glucose tolerance (HT-NGT), hypertension and impaired glucose tolerance (HT-IGT), and hypertension and diabetes mellitus
(HT-DM).
tients (50.8%), impaired diastolic filling was found in 37
(28.5%), and an insufficient LVEF was measured in 25
patients (19.2%). The prevalence of LV hypertrophy, impaired E/A, and inadequate LVEF was higher in patients
with glucose tolerance abnormalities and/or hypertension
(Fig. 1). All 14 patients with hypertension and diabetes
mellitus had 1 or more pathological findings at echocardiography. When both glucose tolerance abnormalities
and hypertension were considered together, LVMi was
significantly different among groups (F 5 3.33; P 5 0.01)
and was higher (P 5 0.01) in hypertensive patients than in
normotensive subjects with both normal and impaired
glucose tolerance (Fig. 2). Similarly, E/A was significantly
different (F 5 3.87; P 5 0.005), and it was lower (P 5 0.01)
in patients with hypertension and diabetes mellitus than
in normotensive subjects even in presence of impaired
glucose tolerance (Fig. 3). The LVEF was significantly different (F 5 6.79; P 5 0.0001) and was lower (P 5 0.01) in
hypertensive patients, with and without glucose tolerance
abnormalities, than in normotensive subjects (Fig. 4).
Correlation study
At linear correlation, LVMi was directly correlated with
age (r 5 0.297; P , 0.001), GH (r 5 0.221; P 5 0.01), and IGF-I
(r 5 0.206; P 5 0.03) levels; SBP (r 5 0.348; P , 0.001); and
DBP (r 5 0.304; P , 0.001). The LVEF was inversely correlated with age (r 5 20.260; P 5 0.005), GH levels (r 5 20.186;
P 5 0.04), SBP (r 5 20.406; P , 0.001), DBP (r 5 20.526; P ,
0.001), and glucose tolerance status (r 5 20.388; P , 0.001).
ACROMEGALIC CARDIOMYOPATHY
FIG. 2. LVMi shown as individual data and the mean 6 SEM in the
six groups of patients. NT-NGT, No hypertension and normal glucose
tolerance; NT-IGT, no hypertension and impaired glucose tolerance;
NT-DM, no hypertension and diabetes mellitus; HT-NGT, hypertension and normal glucose tolerance; HT-IGT, hypertension and impaired glucose tolerance; HT-DM, hypertension and diabetes mellitus. *, P , 0.01 vs. NT-NGT and NT-IDG groups.
197
FIG. 3. Maximal early to late diastolic flow velocity ratio (E/A), shown
as individual data and the mean 6 SEM in the dic groups of patients.
NT-NGT, No hypertension and normal glucose tolerance; NT-IGT, no
hypertension and impaired glucose tolerance; NT-DM, no hypertension and diabetes mellitus; HT-NGT, hypertension and normal glucose tolerance; HT-IGT, hypertension and impaired glucose tolerance;
HT-DM, hypertension and diabetes mellitus. *, P , 0.01 vs. NT-NGT
and NT-IDG groups.
E/A was significantly inversely correlated with age (r 5
20.593; P , 0.001), disease duration (r 5 20.215; P 5 0.03),
SBP (r 5 20.477; P , 0.001), DBP (r 5 20.381; P , 0.001), and
glucose tolerance status (r 5 20.335; P , 0.001).
The multiple regression analysis (Table 4) showed that SBP
was the strongest predictor of LVMi (t 5 3.7; P , 0.001),
followed by GH levels (t 5 2.2; P 5 0.02), whereas DBP was
the strongest predictor of EF (t 5 26; P , 0.0001), followed
by glucose tolerance (t 5 22.2; P 5 0.02). Age was the
strongest predictor of both the E/A ratio (t 5 26.5; P ,
0.0001) and IRT (t 5 2.5; P 5 0.01), followed by IGF-I levels
for the latter parameter (t 5 2.2; P 5 0.02).
Discussion
The results of this study demonstrate that acromegalic
patients suffering from hypertension and diabetes mellitus
had a more severe impairment of cardiac performance than
those without hypertension and with normal tolerance to
glucose. Compared to patients with uncomplicated acromegaly, those with hypertension but without abnormalities of
glucose tolerance had an increased prevalence of LV hypertrophy (75% vs. 37.2%) as well as of impaired diastolic (50%
vs. 7.8%) and systolic function (18.7% vs. 3.9%), whereas
patients with glucose tolerance abnormalities but without
hypertension had only an increased prevalence of impaired
diastolic (39.7%) and systolic function (31.7%). The subgroup
of acromegalic patients suffering from hypertension and diabetes mellitus had the highest prevalence of LV hypertrophy (84.6%), diastolic filling abnormalities (69.2%), and impaired systolic function at rest (53.9%).
Recent evidence demonstrated that GH and IGF-I are important in the regulation of cardiac development and myocardial growth. GH acts on the heart both directly and via
IGF-I production. In fact, it has been demonstrated that rats
whose pituitary gland has been surgically removed respond
to GH administration with an increase in cardiac IGF-I content (24) and messenger ribonucleic acid (mRNA) expression
FIG. 4. LVEF, shown as individual data and the mean 6 SEM in the
six groups of patients. NT-NGT, No hypertension and normal glucose
tolerance; NT-IGT, no hypertension and impaired glucose tolerance;
NT-DM, no hypertension and diabetes mellitus; HT-NGT, hypertension and normal glucose tolerance; HT-IGT, hypertension and impaired glucose tolerance; HT-DM, hypertension and diabetes mellitus. *, P , 0.01 vs. NT-NGT group.
in a dose-dependent manner (25). IGF-I causes hypertrophy
of cultured rat cardiomyocytes by acting on these cells
through specific receptors (26). However, the increase in
systemic blood pressure is known to be a potent cardiac
hypertropic factor. After pressure overload secondary to
banding of the ascending aorta, aorto-caval shunt, or experimental renal hypertension, increased IGF-I mRNA content
was found in rat myocardium (25, 27–29). Increased IGF-I
produces increased mRNA levels of sarcomeric proteins,
including myosin light chain-2 and troponin (26). Besides the
hypertropic effect, GH and IGF-I have a direct effect on
myocardial contractility. Increased contractility was shown
in preparations of cardiac tissue from animal models with
chronic GH excess (30), probably due to increased calcium
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TABLE 4. Results of multivariate regression analysis
Independent variables
Left ventricular mass index
E/A
IRT
Left ventricular ejection fraction
Dependent variables
B
SE-B
Systolic blood pressure
GH levels
Age
Age
IGF-I levels
Diastolic blood pressure
Glucose tolerance
0.731
0.506
20.010
0.427
20.022
20.467
22.947
0.198
0.229
0.001
0.171
0.009
0.077
1.313
95% Confidence
interval of B
0.33
0.051
20.013
0.877
20.042
20.622
25.556
1.124
0.961
20.007
0.767
20.002
20.312
20.337
b
t
P
0.348
0.204
20.592
0.243
20.215
20.526
20.210
3.696
2.209
26.503
2.497
22.257
26.000
22.243
,0.001
0.02
,0.0001
0.01
0.02
,0.0001
0.02
B, Regression coefficient; b, standardized regression coefficient.
responsiveness of myofilaments (31). This experimental evidence supports the rather constant finding in acromegalic
patients of cardiomegaly, which appears to be disproportionate compared to the increase in size of other internal body
organs (32). LV hypertrophy occurred in about one third of
the patients without any evidence of hypertension or glucose
tolerance abnormalities and in the majority of those with
hypertension both with (64.7% and 84.6%) and without (75%)
the concomitant presence of impaired glucose tolerance or
diabetes mellitus. Mild to moderate-severe hypertension was
diagnosed in 35.4% of the patients enrolled in this study. The
values of SBP were the strongest predictor of LVMi, followed
by GH levels. This confirms that hypertension is the major
determinant of LV hypertrophy in acromegalic as in healthy
subjects and suggests a direct involvement of hormonal excess in the acromegalic cardiomegaly. LV hypertrophy can be
reversed by suppression of GH and IGF-I levels with octreotide and lanreotide in acromegaly (5, 16, 32–35). However,
the finding of an increased prevalence of LV hypertrophy in
patients with hypertension indicates the need for an optimal
control of hypertension together with adequate suppression
of GH and IGF-I levels to reduce LVM. Disease duration was
not correlated to the extent of LV hypertrophy, probably
because in these patients hypertension could accelerate myocardial hypertrophy.
Similarly to hypertension, glucose tolerance abnormalities
are likely to play a relevant role in further impairing cardiac
performance in acromegaly. In our series, glucose tolerance
abnormalities were diagnosed in approximately half of the
patients (53.8%), and overt diabetes mellitus was present in
32 of them (24.6%). Type 2 diabetes mellitus is known to be
a major independent risk factor for coronary artery disease
(18). Although the earlier onset and accelerated course of
atherosclerosis in type 2 diabetic patients are considered to
be multifactorial, hyperglycemia itself together with abnormalities in lipoprotein metabolism and increased propensity
to oxidative damage are thought to accelerate vascular damage (18). In these patients a hypercoagulable state occurs due
to enhanced coagulation with decreased fibrinolysis, platelet
hyperaggregability, and endothelial dysfunction (18). Hypertension has a major impact on the accelerated atherosclerosis of diabetic patients (19). From the results of this study
it emerged that 31 of 32 patients with hypertension and
impaired glucose tolerance or diabetes mellitus had 1 or
more cardiac abnormalities. In detail, 24 patients had LV
hypertrophy, 17 had reduced E/A, and 15 had inadequate
EF. E/A and IRT, considered to be diastolic filling parameters, were significantly correlated with age, in line with a
previous observation in healthy subjects (35) and in patients
with uncomplicated acromegaly (15). Diastolic filling was
also inversely correlated with IGF-I levels, which suggests a
direct role of hormone excess not only in the altered cardiac
structure but also in the impairment of diastolic function. In
addition, the multiple regression analysis demonstrated that
DBP and glucose tolerance were the strongest predictors of
EF. When diastolic filling (E/A) and systolic function (EF)
were investigated by analyzing the data for the 130 patients
separately according to the presence of one or more complications, the prevalence of a clear-cut functional impairment appeared to increase in the complicated disease.
In conclusion, the results of this study demonstrated that
acromegalic patients suffering from hypertension and diabetes mellitus have a more severe impairment of cardiac
performance than those without hypertension and with normal tolerance to glucose. The cardiac involvement in acromegaly has been recognized for over a century (36). The
results of this study, however, indicate that a clear-cut impairment of diastolic and systolic functions occurred in more
than half of the acromegalic patients suffering from hypertension and glucose tolerance abnormalities. This finding
strengthens the need to carefully monitor cardiac performance in acromegalic patients. Optimal control of hyperglycemia and hypertension together with the suppression of
GH and normalization of IGF-I levels are needed to reverse
the cardiovascular risk of acromegalic patients.
References
1. Nabarro JDN. 1987 Acromegaly. Clin Endocrinol (Oxf). 26:481–512.
2. Wright AD, Hill DM, Lowy C, Russell Fraser T. 1970 Mortality in acromegaly.
Q J Med. 153:1–16.
3. Bengtsson B, Eden S, Ernest I, Oden A, Sjogren B. 1988 Epidemiology and
long term survival in acromegaly. Acta Med Scand. 223:327–335.
4. Orme SM, McNally RJQ, Cartwright RA, Belchetz PE. 1998 Mortality and
cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol
Metab. 83:2730 –2734.
5. Colao A, Lombardi G. 1998 Growth-hormone and prolactin excess. Lancet.
352:1455–1461.
6. Pepine CJ, Aloia J. 1970 Heart muscle disease in acromegaly. Am J Med.
48:530 –534.
7. Savage DD, Henry WL, Eastman RC, Rorer JS, Gorden P. 1979 Echocardiographic assessment of cardiac anatomy and function in acromegalic patient.
Am J Med. 67:823– 828.
8. Morvan D, Komajda M, Grimaldi A, Turpin G, Grosgogeat Y. 1991 Cardiac
hypertrophy and function in asymptomatic acromegaly. Eur Heart J.
12:666 – 672.
9. Fazio S, Cittadini A, Sabatini D, et al. 1993 Evidence for biventricular involvement in acromegaly: a Doppler echocardiographic study. Eur Heart J.
14:26 –33.
10. Bertoni PD, Morandi G. 1987 Impaired left ventricular diastolic function in
acromegaly: an echocardiographic study. Acta Cardiol. 42:1–10.
11. Rodrigues EA, Caruana MP, Lahiri A, Nabarro JDN, Jacobs HS, Raftery EB.
ACROMEGALIC CARDIOMYOPATHY
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
1989 Subclinical cardiac dysfunction in acromegaly: evidence for a specific
disease of heart muscle. Br Heart J. 62:185–194.
Deleted in proof.
López-Velasco R, Escobar-Morreale HF, Vega B, et al. 1997 Cardiac involvement in acromegaly: specific myocardiopathy or consequence of systemic
hypertension. J Clin Endocrinol Metab. 82:1047–1053.
Frustaci A, Chimenti C, Setoguchi M, et al. 1999 Cell death in acromegalic
cardiomyopathy. Circulation. 99:1426 –1434.
Colao A, Cuocolo A, Marzullo P, et al. 1999 Impact of patient’s age and disease
duration on cardiac performance in acromegaly: a radionuclide angiography
study. J Clin Endocrinol Metab. 84:1518 –1523.
Colao A, Merola B, Ferone D, Lombardi G. 1997 Acromegaly. J Clin Endocrinol Metab. 82:2777–2781.
Minniti G, Jaffrain-Rea Ml, Moroni C, et al. 1998 Echocardiographic evidence
for a direct effect of GH/IGF-I hypersecretion on cardiac mass and function
in young acromegalics. Clin Endocrinol (Oxf). 49:101–106.
Calles-Escandon J, Garcia-Rubi E, Mirza S, Mortensen A. 1999 Type 2 diabetes: one disease, multiple cardiovascular risk factors. Coronary Artery Dis.
10:23–30.
Gorelick PB, Sacco RL, Smith DB, et al. 1999 Prevention of first stroke: a
review of guidelines and a multidisciplinary consensus statement from the
National Stroke Association. JAMA. 281:1112–1120.
WHO. 1996 Hypertension control. Report of a WHO expert committee. WHO
Tech Rep Ser. 862:1– 83.
The DECODE study group on behalf of the European Diabetes Epidemiology Group. 1999 Glucose tolerance and mortality: comparison of WHO and
American Diabetes Association diagnostic criteria. Lancet. 354:617– 621.
Sahn DJ, De Maria A, Kissio J, Weyman A. 1978 The committee on M-mode
standardization of the American Society of Echocardiography. Recommendations regarding quantification in M-mode echocardiography: results of a survey of echocardiography measurements. Circulation. 58:1072–1083.
Quinones MA, Waggoner AD, Reduto LA, et al. 1981 A new simplified and
accurate method for determining ejection fraction with two-dimensional echocardiography. Circulation. 64:744 –753.
Flyvbjerg A, Jorgensen KD, Marshall SM, Orskov, H. 1991 Inhibitory effect
of octreotide on growth hormone-induced IGF-I generation and organ growth
in hypophysectomized rats. Am J Physiol. 260:E568 –E574.
Isgaard J, Nilsson A, Vickman K, Isaksson OGP. 1989 Growth hormone
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
199
regulates the level of insulin-like growth factor-I mRNA in rats skeletal muscle.
J Endocrinol. 120:107–112.
Ito H, Hiroe M, Hirata Y, et al. 1993 Insulin-like growth factor-I induces
hypertrophy with enhanced expression of muscle specific genes in cultured rat
cardiomyocytes. Circulation. 87:1715–1721.
Hanson MC, Kenneth AF, Alexander RV, Delafontaine P. 1993 Induction of
cardiac insulin-like growth factor-I gene expression in pressure overload hypertrophy. Am J Med Sci. 306:69 –74.
Wahlander H, Isgaard J, Jennische E, Friberg P. 1992 Left ventricular insulinlike growth factor-I increases in early renal hypertension. Hypertension.
19:25–32.
Reiss K, Meggs LG, Li P, Olivetti G, Capasso JM, Anversa P. 1994 Upregulation of IGF-I, IGF-I receptor and late growth-related genes in ventricular
myocytes after infarction in rats. J Cell Physiol. 158:160 –168.
Timsit J, Riou B, Bertherat J, et al. 1990 Effects of chronic growth hormone
hypersecretion on intrinsic contractility, energetics, isomyosin pattern, and
myosin adenosine triphosphatase activity of rat left ventricle. J Clin Invest.
86:507–515.
Stromer H, Cittadini A, Douglas PS, Morgan JP. 1996 Exogenously administered growth hormone and insulin-like growth factor-1 alter intracellular
Ca21 handling and enhance cardiac performance. In vitro evaluation in the
isolated isovolumic buffer-perfused rat heart. Circ Res. 62:285–288.
Saccà L, Cittadini A, Fazio S. 1994 Growth hormone and the heart. Endocr Rev.
15:555–573.
Merola B, Cittadini A, Colao A, et al. 1993 Chronic treatment with the somatostatin analog octreotide improves cardiac abnormalities in acromegaly.
J Clin Endocrinol Metab. 77:790 –793.
Baldelli R, Ferretti E, Jaffrain-Rea ML, et al. 1999 Cardiac effects of lanreotide,
a slow release somatostatin analog, in acromegalic patients. J Clin Endocrinol
Metab. 84:575–532.
Hradec J. Kral J, Janota T, et al. 1999 Regression of acromegalic left ventricular
hypertrophy after lanreotide (a slow-release somatostatin analog). Am J Cardiol 83:1506 –1509.
Bonow RO, Vitale DF, Bacharach SL, Maron BJ, Green MV. 1988 Effects of
aging on asynchronous left ventricular regional function and global ventricular
filling in normal human subjects. J Am Coll Cardiol. 11:50 –58.
Huchard H. 1895 Anatomie pathologique, lesions et trouble cardiovasculaires
de l’acromegalie. J Practiciens. 9:249 –250.