Cardiovascular Consequences of Early-Onset Growth Hormone Excess

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The Journal of Clinical Endocrinology & Metabolism 87(7):3097–3104 Copyright © 2002 by The Endocrine Society

Cardiovascular Consequences of Early-Onset Growth Hormone Excess ANNAMARIA COLAO, LETIZIA SPINELLI, ALBERTO CUOCOLO, STEFANO SPIEZIA, ROSARIO PIVONELLO, CAROLINA DI SOMMA, DOMENICO BONADUCE, MARCO SALVATORE, GAETANO LOMBARDI

AND

Department of Molecular and Clinical Endocrinology and Oncology (A.Co., R.P., C.D.S., G.L.) and Internal Medicine I (L.S., D.B.), and Nuclear Medicine Center of the National Council of Research, Department of Biomorphological and Functional Sciences (A.Cu., M.S.) Federico II University, 80131 Naples, Italy; Operative and Echo-Guided Surgery Unit, S. Maria del Popolo degli Incurabili Hospital (S.S.) and Scientific Institute for Research and Care Neuromed (A.Cu., R.P.), 86077 Pozzilli, Italy Acromegaly has relevant effects on the cardiovascular system, but few data deal with the early effects of GH and IGF-I excess. To study the early stage of acromegalic cardiomyopathy and give indirect evidence of the mechanisms underlying GH and IGF-I action on the human heart, 25 patients with uncomplicated acromegaly [15 young subjects with short-term (5 yr) disease] and 25 sex- and age-matched controls were studied. Cardiovascular risk parameters were studied by standard methods; cardiac morphology by M-mode and Doppler echocardiography, cardiac function at rest and at peak exercise by equilibrium radionuclide angiography, and vascular disease at common carotid arteries by Doppler ultrasonography. In the patient group these measurements were repeated after 6 months of treatment with octreotide-LAR (20 – 40 mg, im, every 28 d). Glucose, glycosylated hemoglobin, insulin, low density lipoprotein cholesterol, triglycerides, and fibrinogen levels were higher, and high density lipoprotein cholesterol levels were lower in acromegalic patients than in controls. Resting blood pressure was similar in patients and controls, whereas heart rate at rest and systolic blood pressure at peak exercise were higher in the patients. The left ventricular mass index was higher in acromegalic patients than in controls (123.3 ⴞ 8.9 vs. 81.5 ⴞ 4.3 g/m2; P < 0.001); seven patients had left ventricular hypertrophy. Diastolic function was similar in the two groups. The ejection fraction at rest, but not at peak exercise, was significantly increased in the patients compared with controls. As

L

ONG-STANDING GH and IGF-I excess causes profound alterations of the cardiovascular system. The concentric hypertrophy of the left ventricle is the most common feature of the cardiac involvement of acromegaly, occurring in more than two thirds of patients at diagnosis (1). The left ventricular (LV) hypertrophy rate increases with aging because it is higher than 90% in elderly patients with a long disease duration (2, 3). The existence of a specific acromegalic cardiomyopathy is now accepted; however, the prevalence and entity of the impairment of cardiac function are higher in patients with disease compliAbbreviations: HDL, High density lipoprotein; IMT, intima media thickness; LDL, low density lipoprotein; LV, left ventricular; LVEF, left ventricular ejection fraction; ⌬LVEF, exercise-induced change in LVEF; LVM, left ventricular mass; LVMi, left ventricular mass index; OCT, octreotide; OCT-LAR, slow release form of octreotide; PER, peak ejection rate; PFR, peak filling rate.

a consequence the exercise-induced changes in the ejection fraction were lower in patients than controls (8.7 ⴞ 1.1% vs. 21.9 ⴞ 3.5%; P < 0.001). At common carotid ultrasonography, young patients with acromegaly had increased diastolic peak velocity and increased intima media thickness, even if neither patient nor controls had atherosclerotic plaques. Six months after OCT-LAR treatment, GH and IGF-I levels remarkably decreased in all patients; 8 (53.3%) achieved disease control. Insulin, total cholesterol, and fibrinogen levels reduced, whereas high density lipoprotein cholesterol levels increased. Both at rest and at peak exercise, heart rate significantly decreased, whereas systolic and diastolic blood pressures did not change. The left ventricular mass index was significantly reduced, but it was still higher than the control value (101.6 ⴞ 3.5 g/m2; P < 0.01). The left ventricular ejection fraction at rest was significantly reduced, but its response at peak exercise was increased (16.3 ⴞ 2.4%), becoming similar to the control value. At common carotids, the intima media thickness of right and left arteries was significantly reduced as was the diastolic peak velocity without any change in systolic peak velocity. Short-term GH excess, despite causing enhanced cardiac performance at rest, reduces cardiac performance on effort and impairs vascular morphology. These deleterious effects of early-onset acromegaly are ameliorated by suppressing GH/ IGF-I levels for 6 months. (J Clin Endocrinol Metab 87: 3097–3104, 2002)

cated by hypertension, diabetes mellitus, or thyrotoxicosis (4 – 6). Fragments of information are available on structural changes in the hearts in patients shortly exposed to GH hypersecretion. In young patients with acromegaly, subtle cardiac alterations, such as LV overgrowth in the absence of hypertension and impaired diastolic filling, have been reported (7, 8). In particular, in a small group of 10 patients with recent-onset (⬍5 yr) acromegaly Fazio et al. (9) recently demonstrated that short-term GH excess causes an increase in LV mass (LVM) with eccentric remodeling and normal diastolic function and high cardiac output state with reduction of systemic vascular resistance. These data are at variance with long-term disease, where diastolic dysfunction and impaired systolic function on effort have been well demonstrated (1). Besides its effects on the heart, direct or mediated by IGF-I, GH excess causes an overall increased cardiovascular risk with an

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increase in the intima media thickness (IMT) of the carotids (10, 11) that has never been investigated in early-onset acromegaly. Because recently the possibility of treating cardiac failure with GH has been considered despite controversial results (12– 15), cardiovascular data on early-onset acromegaly can be highly relevant in understanding the mechanisms of GH and IGF-I action on the human cardiovascular system. Experimental studies, both in vivo and in vitro, demonstrated LV hypertrophy with enhanced cardiac function after short-term GH excess (16 –20) similar to that reported in healthy subjects (21). The effects of chronic GH excess on the cardiovascular system have been largely investigated, whereas data on short-term acromegaly are still very limited. To better understand the early effects of GH and IGF-I excess on the cardiovascular system, we assessed cardiovascular risk parameters, cardiac morphology and function by Doppler echocardiography and radionuclide angiography, and morphology of common carotids, by Doppler ultrasonography, in patients with recent onset of acromegaly before and after 6 months of treatment with the slow release form of octreotide (OCT-LAR), compared with those in sex- and agematched healthy controls. Subjects and Methods Patients Among 98 patients with acromegaly undergoing cardiovascular screening to investigate the prevalence and severity of acromegalic cardiomyopathy, 25 de novo patients with active uncomplicated acromegaly (13 women and 12 men) selected on the basis of age 40 yr or less were enrolled in the study. Fifteen had an estimated disease duration of 5 yr or less (range, 1–5 yr; mean ⫾ sem, 3.4 ⫾ 0.3 yr), and 10 patients had an estimated disease duration more than 5 yr (range, 5.5–10 yr; mean ⫾ sem, 8.2 ⫾ 0.6 yr). The diagnosis of acromegaly was established by high mean serum GH levels during an 8-h time course not suppressible to less than 2 ␮g/liter after a 75-g oral glucose tolerance test and by high plasma IGF-I levels for age (22). The presumed duration of acromegaly was estimated by a comparison of patients’ photographs taken during a 1to 2-decade span with an interval of 1–5 yr and by interviews to date the onset of acral enlargement and facial disfigurement. As a control group, 25 healthy volunteers were studied, each of whom were sex- and agematched with 1 patient (13 women and 12 men; age range, 20 – 40 yr). 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 (Naples, Italy).

Study protocol At study entry, all 50 subjects underwent measurements of systolic and diastolic blood pressure; heart rate; determinations of serum levels of IGF-I, total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, triglycerides, and fibrinogen; echocardiography; equilibrium radionuclide angiography; and carotid ultrasonography. Then in acromegalic patients, measurements of GH, IGF-I, total cholesterol, LDL and HDL cholesterol, triglycerides, glucose, glycosylated hemoglobin, insulin, and fibrinogen levels; echocardiography; equilibrium radionuclide angiography; and carotid ultrasonography were repeated after 6 months of treatment with OCT-LAR. In line with WHO criteria, hypertension was diagnosed when diastolic blood pressure values were above 90 mm Hg and was graded as mild when between 91–104 mm Hg, moderate when between 105–114 mm Hg, and severe when 115 mm Hg or higher (23). Diabetes mellitus was diagnosed when fasting blood glucose levels were more than 140 mg/dl in 2 consecutive determinations or 200 mg/dl or higher 2 h after oral glucose. Reduced glucose tolerance was diagnosed when blood glucose levels were 140 –200 mg/dl 2 h after oral glucose (24). Hypertriglyceridemia was diagnosed when triglycerides levels were above 250 mg/dl (25).

Colao et al. • Cardiovascular Risk in Early-Onset Acromegaly

Hypercholesterolemia was diagnosed when total cholesterol levels were more than 240 mg/dl (26).

Treatment protocol All patients received an acute test with sc OCT at the dose of 100 ␮g to investigate individual patient’s tolerance to the drug (27). OCT-LAR was initially administered im at a dose of 20 mg every 28 d for 3 months. According to previous studies (28, 29), during treatment the final GH level was calculated as the average value from at least three blood samples collected at 15-min intervals the day before the injection, and is reported as the nadir GH. At this time point, plasma IGF-I concentrations were assayed as a single sampling. To achieve GH/IGF-I normalization, after 3 months of treatment the dose of OCT-LAR was increased to 30 mg every 28 d in patients still having GH levels above 5 ␮g/liter and IGF-I values above the normal range for age. The dose increment was performed in 14 patients. Disease control after OCT-LAR treatment was considered when fasting GH values were 2.5 ␮g/liter or less together with IGF-I values within the normal range for age (30).

Echocardiography M-Mode, two-dimensional, and pulsed Doppler echocardiographies were performed with commercially available ultrasound systems (Sonos 2500, Hewlett-Packard Co., Andover, MA) using a 2.5-mHz transducer, during three to five consecutive cardiac cycles. 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 (31). The following measurements were recorded on M-mode tracing: interventricular septum thickness and posterior wall thickness, LVM calculation by the Devereux’s formula (32), according to the Penn convention with the following regression-corrected cube formula: LVM ⫽ 1.04[(interventricular septum thickness ⫹ LVID ⫹ PWT)3 ⫺ (LVID)3] ⫺ 14 g. LV hypertrophy was considered when LVM index (LVMi) was 135 g/m2 or more in men and 110 g/m2 or more in women. The records were made by one investigator (L.S.) blind with respect to controls or patients and the individual patient’s response to treatment.

Equilibrium radionuclide angiography The angiography study was performed as previously reported (28). Briefly, 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. 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 watts every 2 min until angina, limiting dyspnea, or fatigue developed. No patient developed high grade ventricular arrhythmias necessitating termination of exercise. The LV ejection fraction (LVEF) was computed on the basis of relative end-diastolic and end-systolic counts. Peak LV ejection and filling rates were also calculated after a Fourier expansion with four harmonics. The peak ejection rate (PER) was computed as the minimum negative peak before end-systole, and the peak filling rate (PFR) as the maximum positive peak after end-systole on the first derivative of the LV time-activity curve. Both PER and PFR were computed in LV counts per sec, normalized for the number of counts at end-diastole and expressed as end-diastolic volume per sec. Normal parameters were: LVEF at rest, 50% or more; exercise-induced changes in LVEF (⌬LVEF), increase to 5% or more of basal values; PFR, 2.5 end-diastolic volume/sec or higher. Angiography was performed before and 6 months after treatment with OCT-LAR.

Carotid ultrasonography Common and internal carotid arterial ultrasound imaging was carried out with a Vingmed Sound CMF 725 equipment (Horten, Norway) by means of a 7.5-MHz annular phased array transducer. Details on the technique were reported previously (10). Right and left carotid arteries were scanned longitudinally, 2.5 cm proximal and 1 cm distal to the bifurcation. When satisfactory B-mode imaging of the common carotid artery wall was achieved, M-mode images were taken for several cardiac cycles to obtain the best quality measurements of IMT. Quantitative and semiquantitative indexes were evaluated by echo-Doppler ultrasonog-


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raphy, placing the sample volume (set at 75% of lumen caliber) in the middle of the vessel lumen. Ultrasonography imaging studies were performed by one operator (S.S.) blind as to patient or control examination and patient’s response to treatment. The variability in the IMT measurement for our instrument was 0.03 mm. Flow indexes of both carotids were investigated by measuring blood systolic and diastolic peak velocities. The IMT was measured at the level of both common carotid arteries and was considered normal when less than 1 mm (33). The presence, location, and size of plaques were also evaluated at the level of common carotid arteries.

Assays Serum GH levels were measured by immunoradiometric assay using commercially available kits (HGH-CTK-IRMA Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 ␮g/liter. The intra- and interassay coefficients of variation (CVs) were 4.5% and 7.9%, respectively. Plasma IGF-I was measured by immunoradiometric assay after ethanol extraction using Diagnostic Systems Laboratories, Inc., kits (Webster, TX). The normal range in 20- to 40-yr-old subjects is 110 – 450 ␮g/liter. The sensitivity of the assay is 0.8 ␮g/liter. The intraassay coefficients of variation were 3.4%, 3.0%, and 1.5% for the low, medium, and high points of the standard curve, respectively. The interassay coefficients of variation were 8.2%, 1.5%, and 3.7% for the low, medium, and high points of the standard curve. Fasting total, LDL, and HDL cholesterol; triglycerides; and fibrinogen levels were measured by standard procedures.

Statistical analysis Data are reported as the mean ⫾ sem. The statistical analysis was performed by means of the SPSS package (SPSS, Inc., Cary, NC). The effect of disease duration on cardiovascular parameters was analyzed in each group by the Wilcoxon matched pairs test. Comparison between patients and controls and between patients with disease duration 5 yr or less or more than 5 yr was performed by the Mann-Whitney test. The

correlation between disease duration, GH or IGF-I levels, and the cardiovascular parameters investigated was carried out by calculating the Spearman coefficient. Significance was set at 5%.

Results Basal evaluation

Age, sex distribution, total cholesterol levels, systolic and diastolic blood pressures at rest, and PFR, PER, LVEF at rest and at peak exercise were similar in the 25 patients and controls (Table 1). Although both patients and controls had normal values of cardiovascular risk parameters, glucose, glycosylated hemoglobin, insulin, LDL cholesterol, triglycerides, and fibrinogen levels were higher and HDL cholesterol levels were lower in acromegalic patients than in controls (Table 1). Heart rate at rest and systolic blood pressure at peak exercise were higher in the patients (Table 2). The LVMi was higher in acromegalic patients than in control subjects by approximately 30% (Table 1 and Fig. 1). Among the 25 patients, 15 patients (60%) had LV hypertrophy. LVEF at rest, but not at peak exercise, was significantly increased in the patients with disease duration of 5 yr or less compared with that in the controls (Table 2 and Fig. 2), but ⌬LVEF was lower in patients with disease duration of 5 yr or less and more than 5 yr than in controls (Fig. 2), as was exercise capacity and duration (Table 2). By common carotid ultrasonography increased IMT was found in the patients compared with the controls (Fig. 3), and 5 patients with disease duration more than 5 yr had IMT higher than normal, 2 of

TABLE 1. Demographic, endocrine, metabolic, and cardiac parameters in patients and controls at study entry

No. Women/men Mean age (yr) Fasting GH levels (␮g/liter) Plasma IGF-I levels (␮g/liter) Blood glucose levels (mg/dl) Glycosylated hemoglobin (%) Serum insulin levels (mU/liter) Total cholesterol levels (mg/dl) LDL-cholesterol levels (mg/dl) HDL-cholesterol levels (mg/dl) Serum triglycerides levels (mg/dl) Serum fibrinogen levels (mg/dl) Systolic blood pressure (mm Hg) At rest Exercise Diastolic blood pressure (mm Hg) At rest Exercise Heart rate (bpm) At rest Exercise LVM index (g/m2) PFR (EDV/sec) PER (EDV/sec) LVEF (%) At rest Exercise Exercise-induced changes Exercise duration (min) Exercise capacity (watts) Maximal Intima-media thickness (mm) EDV, End-diastolic volume.

Controls

Patients

P

25 13/12 30.6 ⫾ 1.2 0.8 ⫾ 0.06 303.4 ⫾ 11.3 92.9 ⫾ 2.6 2.5 ⫾ 0.2 9.5 ⫾ 0.4 186.3 ⫾ 3.5 90.2 ⫾ 5.1 59.8 ⫾ 2.6 94.2 ⫾ 6.4 227.8 ⫾ 7.9

25 13/12 31.2 ⫾ 1.2 43.8 ⫾ 6.6 772.0 ⫾ 34.8 111.6 ⫾ 4.3 4.7 ⫾ 0.1 24.2 ⫾ 2.3 199.6 ⫾ 8.3 120.5 ⫾ 6.9 43.9 ⫾ 1.6 143.7 ⫾ 14.5 370.0 ⫾ 12.6

1 1 0.4 ⬍0.001 ⬍0.001 0.002 ⬍0.001 ⬍0.001 0.1 ⬍0.001 ⬍0.001 0.017 ⬍0.001

119.4 ⫾ 1.5 144.4 ⫾ 2.7

120.0 ⫾ 1.9 168.0 ⫾ 4.0

74.8 ⫾ 1.0 91.0 ⫾ 2.2

78.0 ⫾ 1.8 96.6 ⫾ 2.0

0.4 0.2

77.8 ⫾ 1.2 142.8 ⫾ 3.3 86.1 ⫾ 2.7 3.10 ⫾ 0.11 3.18 ⫾ 0.12

84.9 ⫾ 1.2 148.2 ⫾ 2.6 131.2 ⫾ 3.3 3.37 ⫾ 0.15 3.35 ⫾ 0.12

⬍0.001 0.6 ⬍0.001 0.1 0.3

58.8 ⫾ 0.8 68.4 ⫾ 0.8 16.3 ⫾ 1.8 10.5 ⫾ 0.5 100.0 ⫾ 2.5 0.71 ⫾ 0.02

60.1 ⫾ 1.3 63.5 ⫾ 1.7 6.6 ⫾ 1.6 7.2 ⫾ 0.2 83.0 ⫾ 3.5 0.86 ⫾ 0.04

0.4 0.2 ⬍0.001 ⬍0.001 0.03 0.002

0.5 0.013

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TABLE 2. Endocrine, metabolic, and vascular parameters in the 25 patients, divided according with disease duration 5 yr or less or more than 5 yr, before and after 6 months of OCT-LAR treatment Patients with disease duration ⱕ5 yr

No. Fasting GH levels (␮g/liter) Plasma IGF-I levels (␮g/liter) Blood glucose levels (mg/liter) Glycosylated hemoglobin (%) Serum insulin levels (mg/liter) Total cholesterol levels (mg/dl) LDL-cholesterol levels (mg/dl) HDL-cholesterol levels (mg/dl) Serum triglycerides levels (mg/dl) Serum fibrinogen levels (mg/dl) Systolic peak velocity (cm/sec) Right Left Diastolic peak velocity (cm/sec) Right Left Intima-media thickness (mm) Right Left

Basal

LAR

15 42.6 ⫾ 8.5 759.5 ⫾ 45.4 111.1 ⫾ 5.3 4.7 ⫾ 0.1 22.6 ⫾ 2.9 200.5 ⫾ 10.9 103.8 ⫾ 4.6 47.1 ⫾ 1.7 125.3 ⫾ 8.7 370.7 ⫾ 16.8

15 5.2 ⫾ 1.4 427.5 ⫾ 25.7 104.1 ⫾ 6.2 5.0 ⫾ 0.2 8.2 ⫾ 0.9 179.9 ⫾ 5.1 104.9 ⫾ 4.6 50.2 ⫾ 2.2 92.6 ⫾ 6.1 286.7 ⫾ 16.5

84.1 ⫾ 6.8 80.5 ⫾ 5.6

82.9 ⫾ 5.4 83.3 ⫾ 5.5

32.5 ⫾ 3.4 32.5 ⫾ 3.1 0.75 ⫾ 0.03 0.75 ⫾ 0.03

P

Patients with disease duration ⬎5 yr

P

Basal

LAR

10 45.5 ⫾ 10.9 790.8 ⫾ 56.6 112.2 ⫾ 7.7 4.7 ⫾ 0.1 26.4 ⫾ 3.8 198.1 ⫾ 13.4 145.5 ⫾ 12.3 39.1 ⫾ 2.6 171.3 ⫾ 32.8 369.0 ⫾ 19.9

10 4.8 ⫾ 1.2 414.7 ⫾ 35.6 105.0 ⫾ 9.2 5.1 ⫾ 0.2 8.9 ⫾ 1.3 177.1 ⫾ 6.6 130.7 ⫾ 7.4 48.5 ⫾ 3.7 103.9 ⫾ 18.8 280.0 ⫾ 21.3

1 0.003 0.001 0.2 0.07 0.005 0.1 0.2 0.001 0.02 ⬍0.001

0.8 0.5

98.0 ⫾ 8.9 82.1 ⫾ 6.7

81.0 ⫾ 7.4 83.3 ⫾ 6.8

0.3 0.7

34.0 ⫾ 3.7 35.4 ⫾ 2.8

0.4 0.2

30.4 ⫾ 4.3 28.6 ⫾ 3.4

32.7 ⫾ 4.5 33.5 ⫾ 3.4

0.4 0.2

0.66 ⫾ 0.03 0.68 ⫾ 0.02

0.001 0.008

0.86 ⫾ 0.08 0.87 ⫾ 0.08

0.70 ⫾ 0.06 0.76 ⫾ 0.06

0.004 0.01

1 0.002 ⬍0.001 0.08 0.07 ⬍0.001 0.03 0.9 0.03 0.0007 ⬍0.001

FIG. 1. LVMi in 25 controls and in 15 patients with presumed duration of acromegaly of 5 yr or less and more than 5 yr at study entry. *, P ⬍ 0.001 vs. both patients groups. Superscript graph shows the mean ⫾ SE LVMi in both patients groups before and after 6 months of OCT-LAR treatment compared with controls.

them with clear atherosclerotic plaques. Disease duration, but not GH and IGF-I levels, was significantly correlated with LDL cholesterol levels (r ⫽ 0.51; P ⫽ 0.008), systolic blood pressure at rest (r ⫽ ⫺0.44; P ⫽ 0.002), LVEF at rest (Fig. 4) and at peak exercise (r ⫽ ⫺0.65; P ⫽ 0.0005), ⌬LVEF (Fig. 4), exercise duration (r ⫽ ⫺0.45; P ⫽ 0.02), and maximal carotid IMT (Fig. 4). Effect of 6-month suppression of GH/IGF-I levels

After 6 months of OCT-LAR treatment, GH and IGF-I levels were remarkably reduced in all patients (Table 2); 8 (53.3%) with disease duration of 5 yr or less and 5 (50%) with disease duration more than 5 yr achieved disease control.

Total cholesterol (only in patients with disease duration ⱕ5 yr), insulin, triglycerides, and fibrinogen levels significantly decreased after treatment; glucose and glycosylated hemoglobin levels did not change; whereas HDL cholesterol levels increased (Table 2). Only in patients with disease duration of 5 yr or less was heart rate significantly decreased both at rest and at peak exercise, whereas systolic and diastolic blood pressures did not change in either group. LVMi was significantly reduced in both groups, but it was still higher than the control value (P ⬍ 0.01; Fig. 1). PER increased in both groups, LVEF at rest decreased in patients with disease duration of 5 yr or less and increased in those with disease duration more than 5 yr (Table 3). ⌬LVEF increased only in



FIG. 2. LVEF at rest in 25 controls and in 15 patients with presumed duration of acromegaly of 5 yr or less and more than 5 yr at study entry. Superscript graph shows the mean ⫾ SE ⌬LVEF in 25 controls and in 15 patients with presumed duration of acromegaly of 5 yr or less and more than 5 yr at study entry. *, P ⬍ 0.001 vs. both patients groups.

FIG. 3. Maximal IMT measured by ultrasonography at the common carotid arteries in 25 controls and in 15 patients with presumed duration of acromegaly of 5 yr or less and more than 5 yr at study entry. *, P ⬍ 0.001 vs. both patients groups. Superscript graph shows the mean ⫾ SE maximal IMT in both patients groups before and after 6 months of OCT-LAR treatment compared with controls.

patients with disease duration of 5 yr or less, whereas exercise duration increased in both groups (Table 3). At common carotids, IMT of right and left arteries significantly decreased after treatment without any change in systolic and diastolic peak velocities. Disease duration, but not GH and IGF-I levels, was still significantly correlated with LVEF at peak exercise (r ⫽ ⫺0.6; P ⫽ 0.001), ⌬LVEF (r ⫽ ⫺0.6; P ⫽ 0.001), and exercise duration (r ⫽ ⫺0.45; P ⫽ 0.02).

Discussion

The most relevant finding of the current study is the demonstration of the profound impact played by acromegaly, even in its early stage (⬍5 yr) on cardiovascular risk parameters, cardiac morphology and function, and vascular morphology. The characteristics of cardiovascular abnormalities associated with short-term acromegaly are partially different those found in patients with long-standing disease, even

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FIG. 4. Results of correlation analysis in the 25 patients at study entry: disease duration vs. maximal IMT (max IMT; top left) vs. LVEF at rest (top right) and ⌬LVEF (bottom).

among patients of the same age. In particular, similar to patients with long-standing disease (reviewed in Ref. 1), young patients with early-onset acromegaly have an unfavorable lipid and glucose profile, LV hypertrophy, and increased IMT of common carotids, but, in contrast, they have no alteration of diastolic function, enhanced cardiac performance at rest, or evidence of clear-cut atherosclerotic plaques. Interestingly, despite the increased cardiac performance at rest young patients with early-onset acromegaly have a profound decrease in exercise capacity and duration, leading to a decrease in cardiac performance on effort. The natural history of acromegalic heart disease was postulated by Sacca` et al. (34) to develop through three main phases: 1) an early stage characterized by a hyperkinetic syndrome, with increased cardiac output and decreased peripheral vascular resistance; 2) an intermediate stage associated with biventricular hypertrophy, impaired diastolic filling, and abnormal response to physical exercise; and 3) a late stage ending in cardiac dilatation and congestive heart failure. Because the diagnosis of acromegaly is often delayed [8 –10 yr from disease beginning (22)], the early stage acromegalic cardiomyopathy has yet to be clarified. Among ap-

proximately 100 patients with acromegaly specifically investigated in our department for cardiomyopathy, 15 were selected due to early diagnosis and absence of other concomitant diseases and were compared with 10 patients of the same age but with longer disease duration. We found that early stage acromegalic cardiomyopathy is associated with a hyperkinetic syndrome, LV hypertrophy, and no evidence of diastolic dysfunction, in agreement with previous findings of Minniti et al. (8) and Fazio et al. (9). However, we first demonstrated that the impairment of cardiac performance on effort is already present in the early stage of the disease, at partial variance with the Sacca` hypothesis (34). Furthermore, an initial atherosclerotic process was shown by the increase in IMT of common carotid in accordance with the clear-cut insulin-resistant state and unfavorable lipid profile of these patients. It should be noted that patients below 40 yr of age but with a longer than 5-yr history of acromegaly have LV hypertrophy, depressed systolic function, and increased carotid IMT similarly to middle-aged patients (1). Besides contributing to understanding of the development of the acromegalic cardiovascular disease, our data add helpful information about the mechanisms of GH action on the



TABLE 3. Results of echocardiography and equilibrium radionuclide angiography in the 25 patients, divided according to disease duration 5 yr or less or more than 5 yr, before and after 6 months of OCT-LAR treatment Patients with disease duration ⱕ5 yr

No. Systolic blood pressure (mm Hg) At rest Exercise Diastolic blood pressure (mm Hg) At rest Exercise Heart rate (bpm) At rest Exercise LVM index (g/m2) PFR (EDV/s) PER (EDV/s) LVEF (%) At rest Exercise Exercise-induced changes Exercise duration (min) Exercise capacity (watts)

Basal

LAR

15

15

119.0 ⫾ 2.5 170.0 ⫾ 5.1

118.3 ⫾ 2.8 168.0 ⫾ 4.5

77.0 ⫾ 2.4 96.3 ⫾ 2.5

Patients with disease duration ⬎5 yr Basal

P

10

10

0.9 0.8

121.5 ⫾ 3.0 165.0 ⫾ 6.7

115.5 ⫾ 2.8 167.0 ⫾ 5.6

0.2 0.8

77.3 ⫾ 2.7 93.5 ⫾ 2.3

0.9 0.3

79.5 ⫾ 2.8 97.0 ⫾ 3.7

77.5 ⫾ 3.3 91.2 ⫾ 3.2

0.4 0.2

86.8 ⫾ 1.0 152.3 ⫾ 2.6 128.9 ⫾ 4.6 3.5 ⫾ 0.2 3.5 ⫾ 0.1

78.0 ⫾ 1.9 133.9 ⫾ 2.3 104.4 ⫾ 3.3 3.4 ⫾ 0.2 4.1 ⫾ 0.2

0.002 ⬍0.001 ⬍0.001 0.6 0.04

82.1 ⫾ 2.4 142.2 ⫾ 4.8 134.6 ⫾ 4.4 3.2 ⫾ 0.2 3.1 ⫾ 0.2

78.5 ⫾ 2.4 135.0 ⫾ 1.0 113.9 ⫾ 5.4 3.7 ⫾ 0.2 4.2 ⫾ 0.2

0.06 0.2 ⬍0.001 0.07 0.009

63.6 ⫾ 1.0 67.9 ⫾ 1.0 8.7 ⫾ 1.1 7.5 ⫾ 0.3 86.7 ⫾ 5.4

59.9 ⫾ 0.8 69.6 ⫾ 1.5 16.3 ⫾ 2.4 9.1 ⫾ 0.3 95.0 ⫾ 5.0

0.008 0.3 0.003 0.002 0.2

54.9 ⫾ 2.1 56.9 ⫾ 3.0 3.4 ⫾ 3.4 6.8 ⫾ 0.2 77.5 ⫾ 2.5

60.7 ⫾ 1.7 63.7 ⫾ 1.8 4.7 ⫾ 2.0 8.4 ⫾ 0.4 90.0 ⫾ 5.5

0.04 0.05 0.7 0.008 0.09

human heart. Recently, GH was postulated to be useful in treating heart failure based on several experimental trials in humans (12–15). From the current data, one of the potential beneficial effects of short-term GH excess is to induce hypertrophy and enhance cardiac function. In a similar cohort of patients studied by echocardiography, Fazio et al. (9) suggested that in early-onset acromegaly the sodium retention and volume expansion induced by GH excess (35, 36) combined with reduction of peripheral vascular resistance are prevalent, giving a net result of the direct trophic actions of GH/IGF-I (increasing mostly parietal thickness) combined with the increased preload (increasing mostly cavity dimension). In agreement with Fazio et al. (9), but in disagreement with Minniti et al. (8), we found a normal peak filling rate in our patients. However, no study has reported cardiac performance on effort or vascular status in early-onset acromegaly, two aspects mandatory to elucidate the potential use of GH in heart disease. We found impaired cardiac performance at peak exercise with initial alterations of vascular wall in our patients, thus pointing out the limits of GH treatment at high doses in heart disease. We also investigated the reversibility of cardiovascular alterations after GH/IGF-I suppression by OCT-LAR, one of the drugs currently used to successfully treat acromegaly in approximately two thirds of patients (37, 38). Similarly to previous findings we found decreases in insulin, triglycerides, and fibrinogen levels and in LVMi and IMT at common carotids together with increases in HDL cholesterol levels and exercise duration in patients with shorter and those with longer disease duration. However, heart rate decreased, and LVEF at rest and ⌬LVEF increased only in patients with shorter disease duration. A direct cardiac effect of OCT on cardiac mass, as shown in patients with primary hypertrophic cardiomyopathy (39, 40), or on heart rate via the conduction system (41) can be hypothesized. However, in a previous study we found similar results in a cohort of patients cured by surgery alone (42). This study was not designed to investigate the difference between patients

P

LAR

achieving or not achieving disease control; however, in a recent study including only patients achieving disease control, we found a better response in reversing acromegalic cardiomyopathy in young than in middle-aged patients (43). Because cardiovascular alterations in young patients with short disease duration seem to be milder than those in patients with longer disease duration, to reverse and/or arrest cardiovascular disease is likely to be easier in young patients with early-onset disease who are less likely to develop complications able to maintain cardiovascular disease independently from GH/ IGF-I excess. In conclusion, short-term GH excess, despite causing enhanced cardiac performance at rest, reduces cardiac performance on effort and impairs vascular morphology. These deleterious effects of early-onset acromegaly are reversed by suppression of GH/IGF-I levels for 6 months after pharmacotherapy. Acknowledgments Received December 10, 2001. Accepted March 7, 2002. 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 supported in part by Grant 7492 from Regione Campania.

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