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Original Studies |
Departments of Endocrinology (R.B., G.I., G.M., B.C., G.T.), Internal Medicine (C.M., R.C.), and Experimental Medicine and Pathology (A.G.), University of Rome "La Sapienza", 00161 Rome, Italy; and Department of Experimental Medicine (E.F., M.-L.J.-R.), University of L’Aquila, L’Aquila, Italy
Address all correspondence and requests for reprints to: Roberto Baldelli, M.D., Clinica Medica II - Dipartimento di Endocrinologia, Università "La Sapienza", Viale del Policlinico, 00161 Rome, Italy.
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Abstract |
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Introduction |
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To avoid the inconvenience of multiple daily injections in long-term octreotide therapy, new SRIF analogs with slow-release (SR) formulations have been synthesized. Lanreotide (Ipsen Laboratories), an SR formulation of the SRIF analog BIM 23014 (18, 19, 20, 21) requiring an im injection every 10 to 14 days, has recently become available in Italy. The effects of SR-lanreotide on GH and IGF-I hypersecretion have been shown to be rather similar to those of octreotide (22). To our knowledge, no data concerning the influence of such a treatment on cardiac parameters in acromegaly are available to date. Thus, an open prospective study has been designed in order to evaluate the effects a 12-months treatment period in a series of 13 patients with persistent active disease after surgery. Ventricular structure and function have been studied by echo-Doppler examination at different time-points during the treatment period, including a short term evaluation after a single injection of SR-lanreotide.
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Materials and Methods |
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Thirteen patients with active acromegaly (four males, nine
females, 45.9 ± 16.3 yr old) were included in the study, the mean
duration of the disease being clinically evaluated about 12.1 ±
4.5 yr. None of them had overt diabetes, and three suffered from mild
hypertension, according to the definition of the World Health
Organization/International Society of Hypertension (23); the mean value
of three measurements was considered for each subject, and hypertension
was defined as systolic blood pressure (SBP) more than 140 mm Hg and/or
diastolic blood pressure more than 90 mm Hg. Acromegalic patients with
specific cardiac diseases (such as valvular dysfunction, ischemic heart
disease, primary cardiomyopathy, specific myocardial diseases, or
severe hypertension) were excluded from the study after a careful
patient’s interview, physical examination, 12-lead electrocardiogram,
chest x-ray, and complete echo-Doppler evaluation at baseline. The
individual characteristics of the selected patients are listed in Table 1
. In brief, all patients had been
previously operated on by a transphenoidal route, followed in two cases
by a transcranial route because of grossly invasive, giant adenomas at
the time of diagnosis. Seven patients had also received a conventional
postoperative radiotherapy 2.0 ± 1.9 yr before the study. Nine
patients had been previously treated for 2.6 ± 2.5 yr with
octreotide and/or cabergoline, which were withdrawn for at
least 6 weeks before they entered the study. The evolutivity of
the disease at the time of the study was attested by several random GH
levels more than 2.5 ng/mL, not suppressible less than 1 ng/mL after a
75-g glucose tolerance test, and accompanied by elevated age-corrected
IGF-I plasma levels. Evidence for residual pituitary adenoma tissue,
mainly intrasellar in most cases, was confirmed in all patients
by computerized tomography and/or nuclear magnetic resonance imaging.
In two patients, anterior pituitary dysfunction was adequately
compensated for by L-T4, cortisone acetate,
and/or gonadal steroids replacement therapy before entering the study.
All patients gave their informed consent to the study.
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All patients initially received SR-lanreotide (30 mg im) every 14 days over a 3-month period. In patients with persisting high levels of GH (>2.5 ng/mL) and/or elevated age-corrected IGF-I levels at the end of the first trimester, SR-lanreotide was subsequently administered every 10 days for the rest of the study period (n = 10). The time-points of the study were defined as follows: T0: pretreatment evaluation; T1: 10 days after the first im injection of 30 mg SR-lanreotide; T2: 14 days after the first im injection of 30 mg SR-lanreotide; T3: after 3 months of treatment (SR-lanreotide, 30 mg every 14 days); T4: after 6 months of treatment (SR-lanreotide, 30 mg every 10–14 days); and T5: after 12 months of treatment (SR-lanreotide, 30 mg every 10–14 days).
Fasting GH and IGF-I values and echo-Doppler studies were assessed at each time-point, with the exception of the echo-Doppler study, which was not performed at T1. To evaluate the possible contribution of previous radiotherapy on GH and IGF-I improvement throughout the study period, these parameters were also determined after 1 month withdrawal of SR-lanreotide in irradiated patients but were not statistically different from the prestudy values (8.9 ± 2.2 vs. 12.1 ± 4.0 ng/mL for GH, P = not significant; 552.8 ± 41.0 vs. 493.2 ± 52.0 ng/mL for IGF-I, P = not significant), indicating that GH/IGF-I decrease during the study period was mainly caused by SR-lanreotide treatment.
Thirteen healthy age- and sex-matched subjects were also studied as a control group.
Hormonal assays
Basal pituitary function was routinely assessed by measuring
fasting PRL, FT4, FT3, TSH, FSH, LH,
testosterone, and/or estradiol, cortisol, ACTH, and
dehydroepiandrosterone-sulfate by commercially available kits. Plasma
GH was determined by immunoradiometric assay (Biodata Diagnostics,
Rome, Italy), with a detection limit of 0.1 ng/mL; the inter- and
intraassay coefficients of variations ranged from 2.38–2.87 and from
2.17–2.54%, respectively. Plasma IGF-I was determined by RIA after
acid-ethanol extraction (BioChem ImmunoSystems, Italy);
inter-and intraassay coefficients of variation ranged from 5.9–7.1%
and from 3.4–5.4%, respectively. The following age-corrected IGF-I
were considered normal: 
483 ng/mL (20–30 yr), 397 ng/mL (31–40
yr), 306 ng/mL (41–50 yr), and 249 ng/mL (>50 yr).
M-B mode echo-Doppler studies
M-B mode echo-Doppler studies were carried out using a Vingmed CFM 800 Unit. The examination and the analysis of the results were performed by a single operator, who was unaware of the endocrinological status of the patient; the studies were conducted according to the American Society of Echocardiography directions and worldwide-used routine standards (24), as previously reported (25).
Briefly, left ventricular diameter and septal and posterior wall thickness were measured at end diastole and end systole, as defined by the electrocardiographic tracing. Left ventricular mass (LVM) was estimated using the anatomically validated formula of Devereux and Reicheck, according to the Penn convention (26, 27). The LVM index (LVMI) was determined by the ratio of LVM to body surface area. LVH was defined by LVMI exceeding 134 g/m2 in men and 110 g/m2 in women, respectively (27).
Left ventricular systolic function was evaluated by fractional shortening (FS), ejection fraction, stroke volume (SV), and left ventricular end-systolic stress (ESS). SV represents the difference between end-diastolic and end-systolic left ventricular volumes and was used to calculate the cardiac output (CO) according to the following formula: CO = heart rate (beats/min) x SV. In addition, two dynamic parameters were also considered: 1) left ventricular ESS (taking into account the systolic blood pressure at the time of the study) was calculated according to the formula of Reicheck: ESS (103 dynes/m2) = 0.334 x SBP x LVESD/PWST (1 + PWST/LVESD), where SBP is the systolic blood pressure, PWST is the posterior wall thickness, LVESD is the left ventricular end systolic diameter; and 2) the frequency-corrected mean velocity of circumferential fraction (MVCFc) was calculated using the following formula: MVCFc = FS/ETc, where ETc is the frequency, corrected for left ventricular ejection time, calculated using the formula: ETc = (ET)/R-R (interval from electrocardiogram).
Diastolic function was evaluated by the following pulsed Doppler echocardiographic parameters: 1) the isovolumetric relaxation time (IRT), an index of ventricular relaxation properties; and 2) early (E) and late (A) transmitral peak flow velocities, as well as E/A ratio, indicating the pattern of ventricular diastolic filling. IRT was measured by placing the doppler beam between the mitral and aortic valve junction and represents the interval between the end of aortic valve closure and onset of peak flow velocities and the mitral valve opening. E and A peak flow velocities and the E wave deceleration time were calculated in three to five consecutive cardiac cycles, showing reliable velocity profiles.
Statistical analysis
Unless otherwise specified, all data are presented as mean ± SEM. Differences concerning hormonal values and echocardiographic parameters at different time points of the study were compared by the Wilcoxon rank-test. The Mann-Whitney test was used for comparing patients, controls, and subgroups of patients. P < 0.05 was considered significant. Statistical analysis was made using a Statview 4.02 software for McIntosh.
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Results |
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Mean pretreatment GH and IGF-I values were 10.1 ± 2.2 ng/mL
and 511.0 ± 33.0 ng/mL, respectively. The evolution of GH/IGF-I
levels throughout the study period is shown in Fig. 1, Fig. 2.
At the end of the study, mean plasma GH and IGF-I levels were 3.9
± 0.9 ng/mL (P < 0.005 vs. baseline; 7 of
13 patients with GH < 2.5 ng/mL) and 305.8 ± 34.2 ng/mL
(P < 0.05 vs. baseline, 8 of 13 patients
with normal age-corrected IGF-I), respectively.
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Data comparing acromegalic patients and controls are summarized in
Tables 2 and 3. Acromegalic patients showed
significantly higher LVM (P < 0.0005) and LVMI
(P < 0.0005), meeting the criteria for LVH in 10 cases
(2 males, 8 females), including 2 of the 3 hypertensive patients and 7
of the 9 patients previously treated with octreotide and/or
cabergoline.
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Short-term effects of SR-lanreotide on hemodynamic and echo-Doppler parameters
Blood pressure and heart rate were unchanged after a single injection of SR-lanreotide. A significant decrease in IVSDT, PWDT, and LVSV, together with a significant improvement of both LVM and LVMI (P < 0.05 for all parameters), was observed at T2. At the same time, a slight, but significant, decrease of both A wave and IRT were observed (P < 0.05 for both parameters), indicating a modest improvement of the left ventricular diastolic function, whereas systolic parameters were unchanged.
Evolution of hemodynamic and echo-Doppler parameters throughout the 12-month study period
Blood pressure and heart rate remained unchanged throughout the whole study period. Most echo-Doppler parameters continued to improve throughout the study period, although no more differences could be found between T4 and T5, indicating that the maximal cardiac effects were generally obtained after 6 months of treatment and sustained at 12 months. The decrease of both LVM and LVMI (P < 0.005 vs. baseline for both parameters at T3, T4, and T5) was accompanied by a significant reduction of IVSDT and PWDT, which were further decreased at T3 (P < 0.05 for both parameters), T4, and T5 (P < 0.05 and P < 0.005 at both time points, respectively). A significant reduction of left ventricular diastolic and systolic volumes (LVDV and LVSV) was also observed at T3 (P < 0.05 for both parameters), T4, and T5 (P < 0.05 and P < 0.005 at both time points, respectively). A significant decrease of both A-wave and IRT was observed at T3, T4, and T5 (P < 0.05 and P < 0.005 at each time point, respectively), indicating an improvement of the left ventricular diastolic function (i.e. the relaxation properties), which was also maximal at T4. In contrast, no significant reduction of left ventricular internal diameters was observed, with respect to pretreatment values.
Effects of SR-lanreotide on the LVM
Although LVM and LVMI were still higher in acromegalics than in controls at T5 (P < 0.001 for both parameters), 6 of 10 patients who met the criteria for LVH when they entered the study did not meet this criteria anymore at T5. Analysis of individual data revealed that, in this series, such a LVH reduction tended to be more frequent in younger patients, LVMI being normalized in 5 of 5 patients less than 45 yr old (100%) but in only 1 of 5 patients more than 45 yr old (20%). Accordingly, the mean age of patients who normalized LVMI was significantly lower that of patients who did not (mean ± SD; 38.0 ± 16.2 vs. 58.2 ± 3.3 yr, P < 0.05). The estimated duration of the disease was also significantly shorter in patients who normalized LVMI than in those who did not (mean ± SD; 8.8 ± 3.9 vs. 17.9 ± 3.9 yr, P < 0.02). In contrast, no significant difference could be found concerning pretreatment echo-Doppler parameters between both groups (data not shown). Neither could any significant difference be found between plasma GH and IGF-I levels at T0 and T5 between these two groups (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has long been recognized that cardiovascular involvement greatly contributes to the increased morbidity and mortality observed in acromegalics. However, the concept that GH/IGF-I hypersecretion is able to induce, by itself, a specific cardiomyopathy, has emerged more recently, supported by both in vivo and in vitro observations (4, 28). In particular, receptors for both GH (29) and IGF-I (30) are expressed by myocardial cells, and there is evidence that IGF-I is able to increase the size of cultured cardiomyocytes (31). In addition, cardiac abnormalities can be found in young normotensive acromegalics with normal glucose tolerance, who should represent a good human model for the study of precocious myocardial alterations almost caused by GH/IGF-I hypersecretion (25). During the past 15 yr, several reports on echo-Doppler and isotopic studies in acromegalics have been published, and a model of the natural history of acromegalic heart disease has been proposed by Saccà et al. (4). According to such a model, the early stage of the disease is characterized by functional abnormalities consisting of an hyperkinetic syndrome with an increased contractility and a high cardiac CO, followed by an intermediate stage characterized by a concentric biventricular myocardial hypertrophy associated with diastolic dysfunction at rest and systolic dysfunction on effort. Impaired cardiac performance is rare and appears only at the end stage of the disease. In the present series, the main echo-Doppler abnormalities observed before medical consisted of an increased LVMI associated with an impaired diastolic function, suggesting that most patients had an intermediate-staged cardiomyopathy. None had evidence of systolic dysfunction at rest. The baseline significant increase of SV and MVCFc observed in acromegalics, when compared with controls, could be a residual part of the hyperkinetic syndrome (32). In addition, the baseline-increased LVM could reflect the volume overload caused by the sodium and water retention induced by GH/IGF-I hypersecretion (33) and to the action of the renin-angiotensin system (4).
An important issue is to determine the reversibility of cardiac abnormalities, along with GH/IGF-I reduction or normalization. There is now accumulating evidence that myocardial hypertrophy can be rapidly improved by octreotide: a significant reduction in LVM, IVSDT, and PWDT can be observed after a short-term octreotide treatment, in acromegalics with LVH (14); and this improvement is sustained at 6 months (13, 16) and 12 months (28) of treatment. Improvement of subclinical diastolic dysfunction has also been reported after 6 months of octreotide treatment (15, 16), a finding in agreement with the correlation found between LVH and diastolic dysfunction in these patients (34). In contrast, the effect of GH/IGF-I normalization on systolic performance when impaired is still controversial and may occur later (28, 35); it is difficult to decide to what extent the rapid hemodynamic improvement, observed after octreotide treatment in acromegalics with end-stage disease (36), reflects a specific improvement in the acromegalic cardiomyopathy or a significant reduction in volume overload. To our knowledge, this is the first study reporting the effects of an SR formulation of a SRIF analog, SR-lanreotide, on LVMI and diastolic relaxation properties in acromegaly. SR formulations have the advantage of avoiding the fluctuations in GH concentrations that may occur throughout the day with conventional octreotide treatment and allowing a better compliance to the treatment. A good indication is represented by patients with ongoing disease after surgery, in whom long-term control of the disease should be achieved by medical treatment, radiotherapy, or both.
It is interesting to note that some improvement in ventricular mass and left ventricular relaxation properties could be observed after a single injection of SR-lanreotide. This improvement was reinforced after 3 months of the same drug dose, whereas the subsequent improvement observed between the 3rd and 6th months of treatment is likely to reflect the increase of the SR-lanreotide dose in a large subset of patients. Thereafter, the improvement of LVMI and diastolic relaxation properties was sustained until the 12th month of treatment, whereas systolic parameters remained grossly unchanged throughout the study. These findings are in agreement with previous data reported in octreotide-treated patients (16).
A significant subset of patients with LVH before treatment did not continue to meet the criteria for LVH after SR-lanreotide treatment (6/10). Because LVH is arbitrarily defined by LVMI exceeding a conventional cut-off value, this does not mean that all these patients had their LVM really normalized. In fact, the mean LVM and LVMI were still significantly above control values at the end of the treatment period. However, a significant reduction of LVMI can be used as a criteria for the identification of patients with a reversible acromegalic cardiomyopathy. Interestingly, all but one of these patients were less than 45 yr old, a finding that is likely to reflect the fact that young patients usually have a shorter exposure to GH/IGF-I hypersecretion (25) and a lower incidence of hypertension (37).
We conclude that SR-lanreotide is able to induce a significant improvement of LVMI and diastolic function in acromegalic patients with postsurgical persisting disease. Determining whether such beneficial effects will improve the life expectancy of these patients should deserve further long-term studies.
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Acknowledgments |
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Footnotes |
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Received July 28, 1998.
Revised October 20, 1998.
Accepted October 26, 1998.
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) and IGF-I (
) plasma levels,
before and during SR-lanreotide treatment (*, P <
0.05; **, P < 0.005 vs. baseline),
in a series of 13 acromegalic patients with postoperative ongoing
disease.
) and in
13 acromegalic patients at baseline (•) and during SR-lanreotide
treatment (