Early Vascular Alterations in Acromegaly

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The Journal of Clinical Endocrinology & Metabolism 87(7):3174 –3179 Copyright © 2002 by The Endocrine Society

Early Vascular Alterations in Acromegaly GREGORIO BREVETTI, PAOLO MARZULLO, ANTONIO SILVESTRO, ROSARIO PIVONELLO, GABRIELLA OLIVA, CAROLINA DI SOMMA, GAETANO LOMBARDI, AND ANNAMARIA COLAO Departments of Medicine (G.B., A.S., G.O.) and Molecular and Clinical Endocrinology and Oncology (P.M., R.P., C.D., G.L., A.C.), University Federico II, 80131 Naples, Italy Acromegaly is associated with increased cardiovascular mortality; however, little is known about the early atherosclerotic changes occurring in such patients. Endothelial function, in the form of flow-mediated dilation (FMD) of the brachial artery, and intima-media thickness (IMT) of the carotid artery were measured by B-Mode ultrasound in: 1) 18 patients with active acromegaly; 2) 12 subjects cured from acromegaly; 3) 18 subjects without acromegaly, each of them matched to an acromegalic patients for age, sex, risk factors and treatments; and 4) 10 healthy subjects. Results are expressed as median plus (25th, 75th) percentile. In active acromegalic patients, FMD was 5.7 (3.9, 7.7)%, significantly lower than in both healthy subjects (P < 0.01) and matched

G

H AND IGF-I exert important effects on the heart and vascular system (1–3), and abnormal actions of these factors may result in disease states such as hypertension and atherosclerosis (3). Indeed, cardiovascular disease is a major cause of excessive morbidity and mortality in both hypopituitarism and acromegaly (4 – 6). The increased cardiovascular risk is generally attributed to the high prevalence of risk factors for atherosclerosis that characterizes either GH deficiency or excess (7–9). However, in both these conditions, vascular abnormalities may be present also in the absence of the classical risk factors (10, 11), thus suggesting that the increased atherosclerotic risk of these patients may be attributable, at least in part, to abnormal GH secretion itself. An early step in atherogenesis is the alteration of the normal properties of the endothelium, among which is the ability to release nitric oxide and induce vasodilation in response to physiological stimuli, such as increase in blood flow (12). Therefore, the reduction in endothelium-dependent FMD (flow-mediated dilation) is a marker of endothelial dysfunction, a generalized process, not necessarily confined to vascular bed with overt atherosclerosis. Actually, FMD is impaired in the brachial artery of patients with coronary (13) and peripheral arterial disease (14) and even of those with cardiovascular risk factors but without angiographically apparent disease (15). The latter finding suggests that reduced FMD may represent a measure of susceptibility to atheroma. A number of studies demonstrate that FMD is reduced in hypopituitary patients (11, 16, 17), who show also increased intima-media thickness (IMT) of the carotid arteries (10, 16, Abbreviations: CB, Carotid bifurcation; CCA, common carotid artery; CV, coefficient(s) of variation; FMD, flow-mediated dilation; IMT, intimamedia thickness; IRMA, immunoradiometric assay; NTG, nitroglycerin.

controls (P < 0.01). No difference between groups was observed for endothelium-independent vasodilation. Acromegalic patients had also higher IMT than healthy controls (P < 0.05), whereas no difference was observed with matched controls. In cured acromegalic patients, FMD was 9.2 (7.7, 10.5)%, significantly lower (P < 0.01) than in healthy controls but higher (P < 0.01) than in active patients. No difference in IMT was observed between active and cured patients. In conclusion, patients with acromegaly have functional and morphological vascular alteration that seems, at least in part, dependent on the GH excess itself. (J Clin Endocrinol Metab 87: 3174 –3179, 2002)

18, 19), which is a morphological marker of early atherosclerosis (20). Conversely, very little information is available regarding the effect of acromegaly on vascular function (21, 22) and structure (23, 24). To assess whether GH excess is associated with early atherosclerotic alterations, we measured brachial artery FMD and carotid artery IMT in patients with active acromegaly. Furthermore, we studied a group of acromegalic patients in whom the therapeutic control of the disease had been achieved. Subjects and Methods Patients We studied 18 patients with active acromegaly and 12 patients in whom the control of acromegaly had been achieved by surgery, at least 5 yr before entering the study. All patients were recruited from the endocrine clinic. Acromegaly was diagnosed on the basis of high serum GH levels during an 8-h time course, not suppressible below 1 ␮g/liter after 75 g oral glucose load, and high IGF-I levels for age (25). Acromegaly was considered cured when safe hormone levels were achieved, i.e. fasting or glucose-suppressed GH levels were below 2.5 ␮g/liter and 1 ␮g/liter, respectively, together with normal IGF-I levels for age. Of the active acromegalic patients, 5 (28%) were current smokers (more than 10 cigarettes per day for at least 5 yr), 2 (11%) were affected by diabetes mellitus controlled by insulin, 4 (22%) were hypercholesterolemic (total cholesterol ⬎5.2 mm), 5 (28%) had hypertriglyceridemia (triglyceride concentration ⬎1.8 mm), and 5 (28%) were affected by hypertension well controlled by treatment with lysinopril (20 mg/d) (n ⫽ 2), atenolol (50 mg/d) (n ⫽ 1), or atenolol (50 mg/d) ⫹ enalapril (20 mg/d) (n ⫽ 2). No patient was consuming lipid-lowering drugs. Of the cured acromegalic patients, 3 (25%) were current smokers, 2 (17%) were affected by diabetes mellitus on treatment with a combination of metformin ⫹ glybenclamide, and 1 (8%) was hypertensive on treatment with atenolol (50 mg/d). None was affected by hyperlipidemia. None of the patients of both active and cured acromegalic groups referred symptoms related to coronary artery disease, cerebrovascular disease, or peripheral arterial disease.

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Controls Once the clinical characteristics of all the 18 active and 12 cured acromegalic patients were obtained, 3 control groups were recruited from 3 sources: out-patients attending our angiologic unit for venous insufficiency of the lower limbs, hospital staff, and their relatives. The first control group (healthy controls) consisted of 10 age-matched healthy subjects (mean age, 47 ⫾ 11; male/female, 6/4). None consumed drugs or were affected by conditions known to alter endothelial function or carotid IMT, with the exception of 1 subject who was smoker. The second control group (active acromegalic-matched controls) consisted of 18 subjects, each matched to an active acromegalic patient for age, sex, classic risk factors, and treatments. In particular, hyperlipemic control subjects were selected whose previous blood analyses showed plasma levels of cholesterol and triglycerides similar to those of hyperlipemic acromegalic patients. In addition, the difference between a control subject and the active acromegalic patient to whom he was matched had to be not greater than 0.39 mm for plasma cholesterol and 0.17 mm for plasma triglycerides. As in the patient group, none of the matched controls consumed hypolipemic drugs. With respect to diabetes mellitus and hypertension: because diabetic and hypertensive acromegalics were all on treatment, the criterion of matching was not that of choosing control subjects having similar plasma concentrations of glucose or similar levels of arterial pressure, but that of selecting subjects consuming the same drugs as acromegalics. Therefore, this control group comprised 2 diabetics on insulin treatment and 5 hypertensives, each of which consumed the same drug as that of an active acromegalic patient. As in the patient group, the active acromegalic-matched control comprised 5 smokers. The third control group (cured acromegalic-matched controls) included 12 subjects, each matched to an acromegalic cured patient. The matching procedure was the same as described above; and thus, as in the group of cured acromegalics, this control group comprised 3 smokers, 2 diabetics on treatment with a combination of metformin ⫹ glybenclamide, and 1 hypertensive consuming atenolol (50 mg/d). Of note, none of the subjects matched to active or cured acromegalic patients referred symptoms related to coronary artery disease, cerebrovascular disease, or peripheral arterial disease.

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variability for repeated measurements of resting arterial diameter is 0.01 ⫾ 0.02 mm.

Carotid artery study IMT of the carotid arteries was measured by a high resolution, Bmode ultrasound system, using a 7.5-MHz linear array transducer. Longitudinal views of the right and left common carotid arteries (CCAs) were taken 1 cm below the bifurcation. The right and left carotid bifurcations (CBs) were also viewed. IMT was the distance from the luminal surface of the first and the second echogenic line, measured on the posterior wall. For each of the four segments examined, three measurements were taken, and the mean was calculated. To quantify the carotid artery wall thickness, three measures were chosen: the mean of IMT of the CCAs, the mean of IMT of the CBs, and the maximum IMT of the four sites (max IMT). All scans were performed by the same experienced operator, whose intraobserver variability for repeated measurements of carotid IMT is 0.04 ⫾ 0.03 mm.

Biochemistry Total serum triglyceride, cholesterol, and high-density lipoprotein cholesterol concentrations were measured by commercially available kits. Serum GH levels were measured by immunoradiometric assay (IRMA) (HGH-CTK-IRMA; Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 ␮g/liter; 1 ␮g/liter corresponds to 2 mU/liter. The intraand interassay coefficients of variation (CV) were 4.5% and 7.9%, respectively. Plasma IGF-I was measured by IRMA, after ethanol extraction, using kits from Diagnostic Systems Laboratories, Inc. (Webster, TX). The sensitivity of the assay was 0.8 ␮g/liter. The normal IGF-I range in 20- to 30-, 31- to 40-, 41- to 50-, and 51- to 60-yr-old subjects was 110 – 450, 100 – 400, 100 –350, and 90 –300 ␮g/liter, respectively. The intraassay 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.

Study procedure Endothelial function study Endothelial function, as expressed by FMD, was measured by a validated, reproducible technique (26). Brachial artery diameter was measured from B-mode ultrasound images using a 7.5-MHz linear array transducer (Hewlett-Packard Co.). Flow velocity was measured with a pulsed Doppler signal at a 70-degree angle to the vessel, with the range gate (1.5 mm) in the artery center. The brachial artery was scanned in the antecubital fossa in a longitudinal fashion. When a satisfactory transducer position was found, the surface of the skin was marked, and the arm remained in the same position throughout the study. FMD was measured by determining the change in the diameter of the brachial artery after 60 sec of reactive hyperemia, relative to baseline measurements after deflation of a cuff, on the proximal portion of the arm, that had been inflated to 250 mm Hg for 5 min. The diameter was also measured before and 3 min after nitroglycerin (NTG) was administered, at a dose of 0.4 mg, by spray under the tongue. The response to NTG was used as a measure of endothelium-independent vasodilation. All images were coded and recorded on VHS videotape for subsequent blinded analysis. The arterial diameter was measured at a fixed distance from the anatomic markers. Measurements were taken from the anterior to the posterior interface between media and avventitia (M line) at end diastole, incident with the R wave on a continuously recorded electrocardiogram. Diameters of four cardiac cycles were analyzed for each scan, and measurements were averaged. The response of the vessel diameter to reactive hyperemia was expressed as percent change relative to the diameter just before cuff inflation. The response of the vessel diameter to NTG was expressed as percent change relative to the diameter just before drug administration. Blood flow was calculated by multiplying the velocity-time integral of the Doppler flow signal by heart rate and the cross-sectional area of the vessel. The increase in brachial blood flow was calculated as maximum flow recorded in the first 15 sec after cuff deflation and was expressed as percent change relative to the flow just before cuff inflation. Endothelial function study was performed by the same experienced operator, whose intraobserver

Studies were carried out in the morning, after an overnight fast, in a quiet room, at a constant temperature of 21 ⫾ 1 C. All subjects abstained from smoking and intake of caffeine-containing food or beverage for at least 12 h before the study. All drugs were discontinued for at least 18 h before the study. After the subjects lay quietly for 15 min, carotid artery ultrasound examination was performed, and then FMD was measured. After 15 min of rest, by which time the brachial artery diameter and flow had returned to baseline levels, NTG was administered, and the vasodilator response was measured 3 min later.

Statistical analysis Data were tested for normality using the Shapiro-Wilkins test; and, because brachial artery FMD and carotid artery IMT were not normally distributed, nonparametric statistical tests were used throughout. Groups were compared using the two-tailed Mann-Whitney U test, and correlations between variables were calculated using Spearman rank correlations. Skewed data are expressed as median plus (25th, 75th) percentiles; normally distributed data are given as mean ⫾ sd.

Results Patient characteristics

Table 1 reports characteristics of active acromegalic patients and active acromegalic-matched controls. Characteristics of cured acromegalic patients and cured acromegalicmatched controls are reported in Table 2. Brachial artery FMD

Baseline values of brachial artery diameter and blood flow did not differ between patients and matched controls (Tables 1 and 2). Conversely, FMD was significantly lower in active

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TABLE 1. Clinical and hemodynamic characteristics of active acromegalic patients and active acromegalics matched controls

Age (yr) Male/female GH (␮g/liter) IGF-I (␮g/liter) Smokers Total cholesterolemia (mM) Hypercholesterolemics (n ⫽ 4) Nonhypercholesterolemics (n ⫽ 14) Triglyceridemia (mmol/liter) Hypertrigliceridemics (n ⫽ 5) Nonhypertriglyceridemics (n ⫽ 13) Glycemia (mg/dl) Diabetics (n ⫽ 2) Nondiabetics (n ⫽ 16)a Systolic arterial pressure (mm Hg) Hypertensives (n ⫽ 5) Normotensives (n ⫽ 13)b Diastolic arterial pressure (mm Hg) Hypertensives (n ⫽ 5) Normotensives (n ⫽ 13)b Brachial artery diameter (mm) Brachial artery blood flow (ml/min) a b

Active acromegalics (n ⫽ 18)

Matched controls (n ⫽ 18)

45 ⫾ 11 10/8 15.4 ⫾ 12.2 643 ⫾ 154 5 (28%)

48 ⫾ 15 10/8 1.0 ⫾ 0.9 236 ⫾ 54 5 (28%)

5.9 ⫾ 0.4 4.4 ⫾ 0.4

5.7 ⫾ 0.5 4.1 ⫾ 0.6

2.5 ⫾ 0.4 1.3 ⫾ 0.5

2.7 ⫾ 0.5 1.1 ⫾ 04

155 ⫾ 58 98 ⫾ 20

135 ⫾ 47 90 ⫾ 25

137 ⫾ 7 124 ⫾ 10

134 ⫾ 10 119 ⫾ 9

90 ⫾ 6 80 ⫾ 5 4.03 ⫾ 0.9 161 ⫾ 42

87 ⫾ 5 75 ⫾ 5 4.06 ⫾ 1.1 175 ⫾ 55

P ⬍ 0.01 P ⬍ 0.01

Plasma glucose ⬍120 mg/dl. Systolic blood pressure ⱕ140 mm Hg, diastolic blood pressure ⱕ90 mm Hg.

TABLE 2. Clinical and hemodynamic characteristics of cured acromegalic patients and cured acromegalics matched controls Cured acromegalics (n ⫽ 12)

Matched controls (n ⫽ 12)

50 ⫾ 10 8/4 0.62 ⫾ 0.27 114 ⫾ 30 3 (25%)

49 ⫾ 15 8/4 0.6 ⫾ 0.8 198 ⫾ 46 3 (25%)

4.1 ⫾ 0.4

3.9 ⫾ 0.5

1.0 ⫾ 0.2

1.2 ⫾ 0.3

91 ⫾ 14 89 ⫾ 9

106 ⫾ 15 83 ⫾ 9

Age (yr) Male/female GH (␮g/liter) IGF-I (␮g/liter) Smokers Total cholesterolemia (mM) Hypercholesterolemics (n ⫽ 0) Nonhypercholesterolemics (n ⫽ 12) Triglyceridemia (mmol/liter) Hypertrigliceridemics (n ⫽ 0) Nonhypertriglyceridemics (n ⫽ 12) Glycemia (mg/dl) Diabetics (n ⫽ 2) Nondiabetics (n ⫽ 10)a Systolic arterial pressure (mm Hg) Hypertensives (n ⫽ 1) Normotensives (n ⫽ 11)b Diastolic arterial pressure (mm Hg) Hypertensives (n ⫽ 1) Normotensives (n ⫽ 11)b Brachial artery diameter (mm) Brachial artery blood flow (ml/min) a b

120 124 ⫾ 4

130 120 ⫾ 7

80 78 ⫾ 6 3.98 ⫾ 1.0 123 ⫾ 35

75 80 ⫾ 5 4.01 ⫾ 1.2 147 ⫾ 58

Plasma glucose ⬍120 mg/dl. Systolic blood pressure ⱕ140 mm Hg, diastolic blood pressure ⱕ90 mm Hg.

acromegalic patients than in controls (Fig. 1). Actually, in the patient group, FMD was 5.7 (3.9, 7.7)%; whereas it was 13.0 (12.0, 15.7)% (P ⬍ 0.001) in healthy controls and 10.8 (9.6, 12.2)% (P ⬍ 0.001) in the control group matched to the active patients for age, sex, risk factors, and therapy. The corresponding values for non-endothelium-dependent, NTGmediated vasodilation were 16.2 (11.9, 18.3)%, 14.6 (10.9, 17.7)%, and 15.3 (11.4, 17.9)%. As shown in Fig. 1, in patients cured from acromegaly, FMD was 9.2 (7.7, 10.5)%, a value significantly lower than that in healthy controls (P ⬍ 0.001) and in cured acromegalic-matched controls (P ⬍ 0.05), in whom it was 11.4 (10.1, 13.4)%. Noteworthy, in cured acro-

megalic patients, FMD was significantly higher than in active acromegalic patients (Fig. 1). Carotid artery IMT

Table 3 shows mean IMT of CCAs and CBs, and max IMT. In active acromegalic patients, all these three measures were similar to those in active acromegalic-matched controls but significantly higher than in healthy subjects. Similar results were observed for cured acromegalic patients. No difference in IMT was observed between active acromegalics and cured patients. A significant relationship between maximum IMT



FIG. 1. Boxes showing median values (⽧) and interquartile ranges of FMD in the study population. Active, Active acromegalics; Active MC, active acromegalic-matched controls; Cured, cured acromegalics; Cured MC, cured acromegalic-matched controls; *, lower than in healthy subjects (P ⬍ 0.01); §, lower than in active MC (P ⬍ 0.01); #, lower than in cured (P ⬍ 0.01); †, lower than in healthy subjects (P ⬍ 0.05); ‡, lower than in cured MC (P ⬍ 0.05). TABLE 3. Intima media thickness (IMT) of the carotid artery in patients and controls Mean IMT (mm) CCAs

Healthy subjects Active acromegaly Matched controls Patients Cured from acromegaly Matched controls Patients a b

Mean IMT (mm) CBs

0.45 (0.40, 0.57)

Max IMT (mm)

0.53 (0.45, 0.70)

0.58 (0.51, 0.73)

a

0.68 (0.48, 0.87) 0.79 (0.65, 0.93)b

a

0.76 (0.57, 1.13) 0.90 (0.74, 1.10)b

0.83 (0.66, 1.29)a 0.97 (0.80, 1.28)b

0.78 (0.52, 0.88)b 0.78 (0.63, 1.00)b

0.87 (0.60, 1.07)b 1.06 (0.72, 1.30)b

0.95 (0.75, 1.23)b 1.23 (0.83, 1.45)b

Higher than in healthy subjects, P ⬍ 0.05. Higher than in healthy subjects, P ⬍ 0.01.

and FMD was found both in active (r ⫽ ⫺0.47, P ⬍ 0.05) and cured acromegalics (r ⫽ ⫺0.58, P ⬍ 0.05). Mean IMT of CCAs and CBs did not correlate with FMD. Discussion

Impaired FMD and increased IMT represent, respectively, the earliest functional and structural vascular changes in atherogenesis. Both are associated with classical cardiovascular risk factors (16, 27) and thus have been advocated as measures of susceptibility to atheroma. This study demonstrates that, compared with healthy subjects, acromegalic patients, who are at high risk to develop cardiovascular complications (3), have reduced brachial artery FMD and increased carotid artery IMT. The alteration in vascular reactivity does not reflect an unspecific incapacity to vasodilate, but is dependent on endothelial dysfunction. Actually, no difference between groups was observed for endothelium-independent, NTG-mediated dilation. The mechanisms by which acromegaly induces functional and morphological changes in major arteries remain to be clarified. Acromegaly is associated with a cluster of risk

factors (3), each of them able to induce vascular damage. In the present study, we selected two control groups (one formed by healthy subjects, the other consisting of subjects each matched to an acromegalic patient for age, sex, smoking habit, hypertension, diabetes mellitus, hyperlipidemia, and pharmacological treatments. The latter group had greater carotid IMT and lower brachial artery FMD than the former, thus confirming the atherogenic potential of cardiovascular risk factors. Patients with active acromegaly had similar IMT but lower FMD than active acromegalic-matched controls. This suggests that GH excess itself plays a role in generating endothelial dysfunction; elevated levels of GH/IGF-I could have direct, detrimental effects on the vascular wall. IGFs are potent mitogens for vascular smooth muscle cells (28), and constant infusion of IGF-I further stimulates vascular smooth muscle cell proliferation in the intima-media of rat aorta after balloon catheter injury (29). Furthermore, treatment with IGF-I increases the transcription and the consequent expression of intercellular adhesion molecule-1 (30). Increased expression of adhesion molecules is a typical feature of endothelial dysfunction (31). On the other hand, IGF-I increases

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nitric oxide production by vascular endothelial cells (32), and GH treatment improves endothelial function and reduces carotid artery IMT in hypopituitary patients (11, 17, 20). In contrast with the hypothesis that in acromegaly, GH/ IGF-I excess may be responsible for vascular alterations, are the results by Otsuki et al. (24), who found that the carotid artery IMT in 21 acromegalic patients was lower than in 42 nonacromegalics matched to the patients for sex, age, and risk factors. This would imply that GH/IGF-I excess exerts antiatherogenic effects. However, in that study, it was not reported whether matched controls had symptomatic atherosclerotic vascular diseases, which were absent in the patient population. Moreover, no information was given about the antihypertensive and hypolipemic treatments that have been shown to reduce carotid artery IMT (33, 34). Therefore, it cannot be excluded that the greater IMT observed by Otsuki et al. (24) in matched controls was attributable to the fact that they had a more pronounced atherosclerotic profile and/or a less effective therapeutic regimen than acromegalic patients. It is noteworthy that, in the present study, active acromegalics and matched controls did not have symptomatic atherosclerotic diseases and consumed the same drugs at the same dosages. In patients cured from acromegaly, brachial artery FMD was significantly greater than in active acromegalic patients, who had a more pronounced atherosclerotic risk profile, and it was lower than in cured acromegalic-matched controls. This indicates that endothelial dysfunction is, at least partially, reversible and suggests that GH/IGF-I excess itself is associated with vascular abnormality. In contrast, GH/IGF-I suppression was apparently ineffective in reducing carotid artery IMT, as previously reported (23). That study and the present one, however, were designed as open, transversal studies. More recently, a prospective study demonstrated a trend toward a decrease in IMT in a group of acromegalics achieving disease control after Lanreotide treatment (35). However, longer, prospective trials of time-course evolution of IMT in treated acromegalic patients are needed to assess the reversibility of this structural alteration and to better define the role played by GH and IGF-I excess in atherogenesis. Acknowledgments Received October 2, 2001. Accepted March 25, 2002. Address all correspondence and requests for reprints to: Gregorio Brevetti, M.D., Via G. Iannelli, 45/A, 80131 Napoli, Italy. E-mail: [email protected].

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