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Original Studies |
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
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: colao{at}unina.it
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Abstract |
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Multiple regression analysis showed that systolic blood pressure was the strongest predictor of LVMi (P = 0.0004), followed by GH levels (P = 0.02), whereas diastolic blood pressure was the strongest predictor of LVEF reduction (P < 0.0001), followed by glucose tolerance status (P = 0.02). Age was the strongest predictor of both E/A impairment (P < 0.0001) and IRT (P = 0.01), followed by IGF-I levels (P = 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.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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.
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Subjects and Methods |
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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 ± 1.59 (mean ± SEM) and 47.2 ± 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 ± 1.6 µg/L) during an 8-h time course that were not suppressible below 2 µg/L after a 75-g oral glucose tolerance test (oGTT) and high plasma IGF-I levels for age (540.7 ± 26.5 µg/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 ± SEM, 11.2 ± 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
± 2.1 and 140.3 ± 3.6 mm Hg, and diastolic blood pressures were
83.9 ± 1.4 and 90.3 ± 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.
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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 transducer 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 = EDV - 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 = 1.04[(ISV + LVID + PWT)3 - (LVID)3] - 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 µg/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 µg/L, respectively.
Statistical analysis
The statistical analysis was performed by means of the SPSS, Inc. (Cary, NC) package. Data are reported as the mean ± 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).
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Results |
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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 = 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 = 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 = 0.01). In patients with diabetes mellitus, E/A was significantly lower than in those with normal glucose tolerance (P = 0.01), and LVEF was significantly lower in patients with impaired glucose tolerance and diabetes mellitus than in those with normal glucose tolerance (P = 0.01). No difference was found in circulating GH and IGF-I levels and disease duration among the three groups.
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)In hypertensive patients, age (P < 0.001), IST (P = 0.003), LVPWT (P < 0.001), LVMi (P < 0.001), and IRT (P = 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 ± 3.5 vs. 133.8 ± 10.7 g/m2), E/A (1.06 ± 0.04 vs. 1.03 ± 0.06), and LVEF (56.1 ± 1.9% vs. 51.6 ± 3.6%) between patients with mild hypertension and those with moderate/severe hypertension. No difference was found in LVMi (146.1 ± 18.2 vs. 146.5 ± 7.4 g/m2) between patients treated for hypertension and those not treated.
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). 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 = 3.33; P = 0.01) and was higher
(P = 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 = 3.87; P = 0.005), and it was lower
(P = 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 = 6.79; P = 0.0001) and
was lower (P = 0.01) in hypertensive patients, with and
without glucose tolerance abnormalities, than in normotensive subjects
(Fig. 4).
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At linear correlation, LVMi was directly correlated with age (r = 0.297; P < 0.001), GH (r = 0.221; P = 0.01), and IGF-I (r = 0.206; P = 0.03) levels; SBP (r = 0.348; P < 0.001); and DBP (r = 0.304; P < 0.001). The LVEF was inversely correlated with age (r = -0.260; P = 0.005), GH levels (r = -0.186; P = 0.04), SBP (r = -0.406; P < 0.001), DBP (r = -0.526; P < 0.001), and glucose tolerance status (r = -0.388; P < 0.001). E/A was significantly inversely correlated with age (r = -0.593; P < 0.001), disease duration (r = -0.215; P = 0.03), SBP (r = -0.477; P < 0.001), DBP (r = -0.381; P < 0.001), and glucose tolerance status (r = -0.335; P < 0.001).
The multiple regression analysis (Table 4)
showed that SBP was the strongest predictor of LVMi (t
= 3.7; P < 0.001), followed by GH levels
(t = 2.2; P = 0.02), whereas DBP was
the strongest predictor of EF (t = -6;
P < 0.0001), followed by glucose tolerance
(t = -2.2; P = 0.02). Age was the
strongest predictor of both the E/A ratio (t = -6.5;
P < 0.0001) and IRT (t = 2.5;
P = 0.01), followed by IGF-I levels for the latter
parameter (t = 2.2; P = 0.02).
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Discussion |
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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 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, 28, 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 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, 33, 34, 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.
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Footnotes |
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Received July 27, 1999.
Revised September 22, 1999.
Accepted September 29, 1999.
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