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Original Studies |
Department of Molecular and Clinical Endocrinology and Oncology (An.C., P.M., D.F., G.L.), Nuclear Medicine Center of the National Council of Research, Department of Biomorphological and Functional Sciences (Al.C., E.N., A.M.D.M., M.S.) and Department of Internal Medicine (M.P.), Federico II University of Naples, 80131 Napoli, Italy
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 Napoli, Italy. E-mail: colao{at}unina.it
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients and controls were divided in two groups, on the basis of age below and above 40 yr. Circulating GH and insulin-like growth factor-I levels were significantly increased in patients, compared with controls, but were similar in the two groups of patients.
At peak exercise, the systolic blood pressure was significantly higher
in elderly patients (P < 0.001), whereas diastolic
blood pressure was significantly higher in young patients than in
age-matched controls (P < 0.01). Heart rate at
peak exercise was significantly higher in young than in elderly
patients and controls (P < 0.01), without any
evidence of arrhythmia in both groups. The left ventricular ejection
fraction at rest was normal (>50%) in all but 2 patients and in all
controls. The left ventricular ejection fraction at peak exercise was
significantly decreased in elderly, compared with young, patients
(P < 0.01) and in age-matched controls
(P < 0.001). A normal response of the left
ventricular ejection fraction to exercise was found in 12 of 40
patients (30%) and in 28 of 32 controls (87.5%) (
2,
5.764; P < 0.01). Exercise-induced changes in left
ventricular ejection fraction were significantly decreased in young
(+5.2 ± 4.4% vs. +21.3 ± 3.4%,
P < 0.005) and elderly patients (-10.2 ±
2.8% vs. +13.7 ± 2.7%, P <
0.0001), as compared with age-matched controls. The peak rate of left
ventricular filling was significantly higher in young, than in elderly,
patients whether peak filling rate was normalized to end-diastolic
volume (P < 0.001), or stroke volume
(P < 0.0001), or expressed as the ratio of peak
filling rate to peak ejection rate (P < 0.001).
The peak rate of left ventricular filling was significantly decreased
in elderly patients, compared with young patients and age-matched
controls, whether peak filling rate was normalized to end-diastolic
volume (P < 0.01), or stroke volume
(P < 0.005), or expressed as the ratio of peak
filling rate to peak ejection rate (P <
0.001).
In the patient group, the left ventricular ejection fraction at peak exercise was significantly correlated with age (r = -0.33, P < 0.05), estimated disease duration (r = -0.34, P < 0.05), exercise-induced changes of the left ventricular ejection fraction (r = 0.34, P < 0.05), and the peak rate of left ventricular filling, whether peak filling rate was normalized to end-diastolic volume (r = 0.33, P < 0.05). Age and estimated disease duration were both significantly correlated with the peak rate of left ventricular filling, whether peak filling rate was normalized to end-diastolic volume (r = 0.55, P < 0.001 and r = -0.49, P < 0.001, respectively), or stroke volume (r = 0.5, P < 0.001 and r = -0.57, P < 0.001, respectively), or expressed as the ratio of peak filling rate to peak ejection rate (r = 0.56, P < 0.0001 and r = -0.52, P < 0.001, respectively). In the control group, the left ventricular ejection fraction at peak exercise was significantly correlated with the left ventricular ejection fraction at rest (r = 0.54, P < 0.01), exercise-induced changes of the left ventricular ejection fraction (r = 0.57, P < 0.001), but neither with age nor peak rate of left ventricular filling at all measurements.
In conclusion, left ventricular performance is more frequently preserved in young patients with a short disease duration, although the left ventricular response to exercise was already reduced, as compared with controls. These results indicate that a careful investigation of diastolic and systolic function, by equilibrium radionuclide angiography, is advised in acromegalic patients at diagnosis, as it can be useful to reveal abnormalities in cardiac performance to be monitored during different treatments.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Another aspect that should not be disregarded is that, in normal subjects, relevant physiological changes in left ventricular function may occur as part of the aging process, so that the rate and extent of left ventricular filling is reduced (18, 19). However, no study has been reported, so far, in acromegalic patients to investigate whether cardiac function is modified in accordance with patients’ age as physiological response to aging. Therefore, this study was designed to evaluate the impact of acromegalic patients’ age and disease duration on cardiac performance. To address these issues, in a large series of rigorously selected patients with active acromegaly, but without evidence of other complications able to affect cardiac performance, left ventricular function at rest and during physical exercise was assessed by equilibrium radionuclide angiography.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Forty untreated acromegalic patients (19 women; 21 men; age
range, 18–67 yr) constituted the patient population. The patients were
selected among 77 patients on the basis of the absence of other
concomitant diseases, such as diabetes mellitus, coronary artery
diseases, long-standing hypertension, and hyperthyroidism, which could
affect cardiac function. Latent coronary artery disease was excluded
using exercise thallium-201 myocardial tomography. The diagnosis of
acromegaly was performed in keeping with high serum GH levels during an
8-hr time course, not suppressible below 2 µg/L after 75 g oral
glucose load and high plasma IGF-I levels for age (20). 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, and it was assumed
as the interval between the clinical onset and the time of treatment.
In the present series of patients, disease duration ranged between
4–30 yr. As a control group, 32 healthy volunteers, sex- and
age-matched with the patients (13 women; 19 men; age range, 23–62 yr)
were studied. All patients and controls gave their informed consent to
participate in this study, and the study protocol was approved by the
ethical committee of the Medical School of the University Federico II
of Naples. Twelve patients and 10 controls were smokers, and all had a
sedentary lifestyle. Patients and controls were divided in 2 groups, on
the basis of age below and above 40 yr (Table 1
). The threshold age of 40 yr was chosen
because of a significant increase of left ventricular mass without
alterations of diastolic and systolic function demonstrated by
echocardiography in patients below 40 yr of age (14). The preliminary
results of 10 out of 40 patients have been previously reported (21). At
the time of radionuclide angiography, 7 out of 40 patients were
occasionally found to have a diastolic blood pressure higher than 90 mm
Hg: hypertension was subsequently excluded by serial blood pressure
measurement during the subsequent follow-up, and no treatment for
hypertension was needed.
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In vivo labeling of red blood cells was performed
with 555 MBq (15 mCi) of 99mTc. Radionuclide angiography
was performed at rest and during dynamic physical exercise in the 45°
left anterior projection, with a 15° craniocaudal tilt, with the
patient in supine position. A small-field-of-view 
camera (Starcam
300 A/M, General Electric, Milwaukee, WI), equipped with a low-energy
all-purpose collimator, was used. Data were recorded at a rate of 30
frames/cardiac cycle for resting study and of 16 frames/cardiac cycle
for exercise study, on a dedicated computer system (General
Electric). At least 200,000 counts/frame were acquired. 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. No patient developed high-grade ventricular
arrhythmias necessitating termination of exercise. Heart rate and blood
pressure (by cuff sphygmomanometer) were monitored during exercise at
each stage.
Radionuclide angiography studies were analyzed using a standard commercial software system (General Electric). Left ventricular regions of interest were automatically drawn for each frame, and a background region of interest was also computer delineated on the end systolic frame. After background correction, a left ventricular time-activity curve was generated. Indexes of left ventricular function were derived by computer analysis of the background-corrected time-activity curve. Ejection fraction was computed on the basis of relative end-diastolic and end-systolic counts. Peak left ventricular ejection and filling rates were also calculated after a Fourier expansion with four harmonics. Peak ejection rate was computed as the minimum negative peak before end-systole and peak filling rate as the maximum positive peak after end-systole on the first derivative of the left ventricular time-activity curve. Both peak ejection rate and peak filling rate were computed in the left ventricular counts/sec, normalized for the number of counts at end-diastole and expressed as end-diastolic volume (EDV)/sec. When normalized for end-diastolic volume, both peak ejection rate and peak filling rate are influenced directly by the magnitude of the ejection fraction (22). 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 second (SV/sec) and as ratio of peak filling rate to peak ejection rate (23, 24). These two latter methods have the additional advantage of being background independent. Time-to-peak ejection rate was measured from the R wave, and time-to-peak filling rate was measured relative to end-systole (minimal volume on the time-activity curve).
Assays
Circulating GH and IGF-I (after ethanol extraction) levels were assayed by immunoassays using commercially available kits. In our laboratory, the normal IGF-I range in adults (20–40 yr and 40–70 yr old) was 110–494 and 65–320 µg/L.
Statistical analysis
The statistical analysis was performed by means of a package using ANOVA (SPSS, Inc., Cary, NC). The effects of age and disease on systolic and diastolic parameters were analyzed with the two-way ANOVA, considering the main effects of the independent variance, age (<40 vs. >40 yr) and acromegaly (patients vs. controls) and the interaction between these two variables. The significance was set at 5%. Post hoc analysis was performed by means of paired and unpaired t tests, applying the Bonferroni’s correction. In this case, the significance was set at 1%. Stepwise multiple linear regression was performed to evaluate the relative importance of age, disease duration, GH, and IGF-I on systolic and diastolic parameters. Data are reported as mean ± SEM.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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).
The estimated duration of acromegaly was significantly longer in
patients older than 40 yr than in those younger than 40 yr (Table 1).
In controls, systolic blood pressure at rest was significantly
increased, compared with younger ones (P < 0.01). The
systolic blood pressure at peak exercise was significantly higher in
elderly patients than in age-matched controls (P <
0.001). Similarly, the diastolic blood pressure at peak exercise was
significantly increased in young patients, as compared with age-matched
controls (P < 0.01). The day of the study, mild
hypertension (diastolic blood pressure > 90 mm Hg) was
occasionally found in 2 out of 18 patients less than 40 yr old
(11.1%), in 5 out of 22 patients more than 40 yr old (22.7%), and in
none of the controls; stable hypertension was excluded by serial blood
pressure measurement during the subsequent follow-up. By contrast,
heart rate at peak exercise was significantly higher in young (compared
with elderly) patients and in young (compared with elderly) controls
(P < 0.01), without any evidence of arrhythmia in both
groups (data not shown). The left ventricular ejection fraction at rest
was similar in both the 2 groups of patients and controls: in
particular, the ejection fraction was normal (>50%) in all controls
and in 38 out of 40 patients. The resting ejection fraction was 47% in
1 young patient and 46% in 1 elderly patient. By contrast, the left
ventricular ejection fraction at peak exercise was markedly decreased
in elderly patients, as compared with young patients (P
< 0.001) and to age-matched controls (P < 0.001). The
normal increase (>5% of basal value) of the ejection fraction at peak
exercise was found in all controls and 11 patients (61.1%) less than
40 yr old, and in 12 out of 16 controls (75%) and only 1 out of 22
patients (4.5%) more than 40 yr old (2, 5.764;
P < 0.01). The exercise-induced changes in the left
ventricular ejection fraction were markedly different in young patients
and controls, as compared with elderly patients and controls (Fig. 1). The peak rate of left ventricular
filling was significantly decreased in elderly patients, as compared
with young patients and age-matched controls, whether the peak filling
rate was normalized to end-diastolic volume (P < 0.01)
or stroke volume (P < 0.005) or expressed as the ratio
of peak filling rate to peak ejection rate (P <
0.001). Young patients had the peak rate of left ventricular filling
significantly higher than in age-matched controls, whether the peak
filling rate was expressed as the ratio of peak filling rate to peak
ejection rate (P < 0.001). Finally, the exercise
duration was significantly lower in young and elderly patients than in
age-matched controls (P < 0.001 and P
< 0.01, respectively). The exercise capacity was significantly lower
only in young patients, than in controls (P <
0.001).
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), estimated disease duration (r =
-0.34, P < 0.05), exercise-induced changes of the
left ventricular ejection fraction (r = 0.34, P <
0.05), and the peak rate of left ventricular filling, whether the peak
filling rate was normalized to end-diastolic volume (r = 0.33,
P < 0.05). Age and estimated disease duration (Fig. 3) were both significantly correlated
with the peak rate of left ventricular filling, whether the peak
filling rate was normalized to end-diastolic volume (r = 0.55,
P < 0.001 and r = -0.49, P <
0.001, respectively), or stroke volume (r = 0.5, P
< 0.001 and r = -0.57, P < 0.001,
respectively), or expressed as the ratio of peak filling rate to peak
ejection rate (r = 0.56, P < 0.0001 and r =
-0.52, P < 0.001, respectively). In the control
group, the left ventricular ejection fraction response at peak exercise
was significantly correlated with the left ventricular ejection
fraction response at rest (r = 0.54, P < 0.01),
exercise-induced changes of the left ventricular ejection fraction
(r = 0.57, P < 0.001), but neither with age nor
with the peak rate of left ventricular filling, at all measurements. At
the multiple regression analysis, disease duration was the strongest
predictor of ejection fraction at peak exercise, whereas the patient’s
age was the strongest predictor of the peak rate of the left
ventricular filling. The results of the multiple regression analysis
are shown in Table 2.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the present study, we demonstrated that cardiac function is still
preserved in young patients, less than 40 yr old, although being
significantly reduced as compared with age-matched controls. The
majority of patients (61.1%) and all controls of the young group had a
normal ejection fraction at rest, with a normal response to exercise.
By contrast, in patients more than 40 yr old, both systolic and
diastolic function of the left ventricle were significantly impaired.
None of them, except one, had a greater than 5% increase in the left
ventricular ejection fraction after exercise, so that the response of
the left ventricular ejection fraction to exercise was significantly
associated with acromegaly (2, 7.936; P
< 0.005). A significant impairment of left ventricular diastolic
filling was observed in elderly patients, as compared with young
patients and with age-matched controls. In the whole patient group, the
estimated disease duration was significantly and directly correlated
with age, but significantly and inversely correlated with left
ventricular ejection fraction response at peak exercise and with peak
rate of left ventricular filling, whether the peak filling rate was
normalized to end-diastolic volume, or stroke volume, or expressed as
the ratio of peak filling rate to peak ejection rate.
Patients’ age and disease duration were closely correlated, but from the multivariate analysis and the comparison with controls, it seemed that the estimated disease duration was the strongest predictor in determining the impaired cardiac performance in acromegaly. Thus, from the results of the present study, it emerged that the younger the age and the shorter the disease duration, the more frequently preserved the cardiac function. However, it was evident that cardiac performance was already impaired in young patients, who presented with a preserved diastolic function, when compared with age-matched healthy controls. These results seem to be relevant not only in understanding the pathophysiology of acromegalic cardiomyopathy but also in evaluating the cardiac effects of any treatment able to suppress circulating GH and IGF-I levels. In fact, although a significant decrease of left ventricular mass was described by echocardiography following octreotide administration (27, 28, 29), no significant improvement of left ventricular ejection fraction was observed by equilibrium radionuclide angiography (21). The lack of a significant improvement of systolic function following treatments able to suppress GH and IGF-I levels might be attributable to a different pretreatment cardiac performance in individual patients. In fact, a notable improvement was reported after octreotide treatment in patients with heart failure (30). It should be also considered that, when the effect of octreotide on cardiac performance was evaluated separately for patients achieving normalization of GH (<2.5 µg/L) and IGF-I and those who had not, a significant improvement in the response to exercise of the left ventricular ejection fraction was detected only in the former group (31). A significant increase in the ejection fraction at peak exercise was observed after 1 yr of octreotide treatment, either in young or in elderly patients achieving normalization of hormone levels, although elderly patients presented with a more severe impairment of systolic function at baseline (31).
In conclusion, the early impairment in cardiac performance indicates the necessity for a precocious diagnosis of acromegaly. A careful investigation of diastolic and systolic function, by equilibrium radionuclide angiography, should be included in the workup of acromegalic patients (32), because it can be useful to reveal abnormalities in cardiac performance to be monitored during different treatments.
Received June 15, 1998.
Revised November 30, 1998.
Revised January 28, 1999.
Accepted February 1, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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) between age and ejection fraction at rest
(top) and at peak exercise (bottom).