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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4271-4277
Copyright © 2007 by The Endocrine Society

Risk Factors for Development of Coronary Heart Disease in Patients with Acromegaly: A Five-Year Prospective Study

Fausto Bogazzi, Luigi Battolla, Cheti Spinelli, Giuseppe Rossi, Silvia Gavioli, Vitantonio Di Bello, Chiara Cosci, Chiara Sardella, Duccio Volterrani, Enrica Talini, Pasquale Pepe, Fabio Falaschi, Giuliano Mariani and Enio Martino

Department of Endocrinology and Metabolism (F.B., S.G., C.C., C.Sa., E.M.), Cardio-Thoracic Department (V.D.B., E.T.), University of Pisa, 56124 Pisa, Italy; Second Radiodiagnostic Unit (L.B., C.Sp., F.F.), Azienda Ospedaliera Pisana, 56124 Pisa, Italy; Unit of Epidemiology and Biostatistics (G.R., P.P.), Institute of Clinical Physiology, National Research Council (C.N.R.), 56100 Pisa, Italy; and Regional Center of Nuclear Medicine (D.V., G.M.), 56100 Pisa, Italy

Address all correspondence and requests for reprints to: Fausto Bogazzi, M.D., Department of Endocrinology and Metabolism, University of Pisa, Ospedale Cisanello, Via Paradisa 2, 56124, Pisa, Italy. E-mail: f.bogazzi{at}endoc.med.unipi.it or fbogazzi{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Data on coronary heart disease (CHD) are scanty and matter of argument in acromegalic patients.

Objective: The objective of this study was to evaluate risk factors for development of CHD and the occurrence of cardiac events in acromegalic patients during a 5-yr prospective study.

Design: Ten-year likelihood for CHD development was estimated by the Framingham scoring system (FS); patients were stratified as having low (FS < 10), intermediate (≥ 10 FS < 20), or high (FS ≥ 20) risk. Coronary artery calcium content was measured using the Agatston score (AS) in all patients; those with positive AS were submitted to myocardial single-photon emission computed tomography; cardiac events were recorded during a 5-yr follow-up period.

Patients: Fifty-two consecutive patients (31 women, mean age 52 ± 11 yr) with controlled or uncontrolled acromegaly were followed prospectively for 5 yr.

Results: Thirty-seven patients (71%) had low, 14 patients (27%) had intermediate, and one patient (2%) had high CHD risk. CHD risk was unrelated to acromegaly activity or the estimated duration of disease. Among patients with FS less than 10%, 24 had AS equal to 0, eight had AS of 1 or greater and less than 100, and five had AS 100 or greater and less than 300, respectively. Among patients with FS 10 or greater and less than 20%, nine had AS equal to 0, two had AS of one or greater and less than 100, one had AS of 100 or greater and less than 300, and two had AS of 300 or greater; a patient of the latter group, having AS of 400 or greater, increased his CHD risk from 11% to 20% or more. FS or AS did not differ in patients with controlled or uncontrolled acromegaly (P = 0.981). All patients with positive AS had no single photon emission computed tomography perfusion defects. During the 5-yr follow-up period no patient developed ischemic cardiac events.

Conclusions: CHD risk in acromegalic patients, predicted by FS as in nonacromegalic subjects, is low; AS might have adjunctive role only in a subset of patients. However, most patients have systemic complications of acromegaly, which participate in the assessment of global CHD risk.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ACROMEGALY IS DUE to chronic GH/IGF-I excess, sustained in the majority of patients by pituitary adenoma (1). Systemic complications of GH excess include peculiar acromegalic cardiomyopathy, typical features of which are concentric biventricular hypertrophy and impairment of diastolic function (2, 3, 4, 5, 6). The long-lasting diastolic dysfunction could lead to systolic impairment and finally to cardiac failure (7). The aforementioned cardiac abnormalities are due to GH excess, although hypertension, diabetes, and dyslipidemia, frequently present in acromegalic patients, may participate to derangement of heart function (2, 8). In contrast, diastolic function could improve and even reverse after successful treatment of acromegaly, mainly in young subjects with a short duration of active disease (9, 10, 11, 12, 13).

Epidemiological studies have reported cardiovascular and cerebrovascular events as the leading cause of death in patients with acromegaly, relating it to serum GH and/or IGF-I levels (14, 15, 16) or previous external radiation therapy for pituitary adenomas (15). However, data on coronary heart disease (CHD) and atherosclerosis are scanty and mainly referred to pathological examination of old series of patients (17, 18, 19, 20). Myocardial hypertrophy and fibrosis, considered the typical pathological feature of acromegalic cardiomyopathy, have been reported in 90% and 50–75% of patients, respectively, although coronary artery involvement was not a rare event (17, 18, 19, 20). In one study, only moderate amount of atherosclerosis of the aorta was observed and the coronary were "patent throughout" (19); on the contrary, significant involvement of coronary arteries was present in half cases of a small series of patients (17). Among 27 patients with acromegaly submitted to necropsy, 11% had significant coronary artery disease, 15% had evidence of old myocardial infarction, and 24% had significant atherosclerosis of the abdominal aorta (20).

Increased intima-media thickness of the carotid arteries, evaluated by echography, was revealed in about 50% of patients, followed by normalization after disease control (11, 21). In addition, based on findings that patients without atherosclerosis had higher serum IGF-I levels than those with atherosclerosis, a protective role of high IGF-I has been suggested (21).

Recently, patients with acromegaly were evaluated for the risk of CHD through combination of the Framingham score (FS) and detection of coronary artery calcium (CAC) content by computed tomography. Overall, the authors reported that 41% patients with acromegaly were at risk for coronary atherosclerosis (22). However, longitudinal information on the study group was not available; thus, it is unknown whether the estimated risk for CHD would have clinical impact and predictive significance. In contrast, determination of CAC content is still controversial, and a very recent document of a panel of experts revealed its incremental values over conventional risk factors only in patients with intermediate FS (23). Thus, either longitudinal assessment of CHD risk and the incremental value of CAC determination are unknown in patients with acromegaly.

The aim of the study was: 1) to evaluate the risk factors for CHD in patients with acromegaly and the occurrence of major cardiac events during a 5-yr follow up period; and 2) to assess whether CAC measurement might have an adjunctive role in defining the cardiovascular risk in these patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study population

The study group consisted of 52 consecutive patients with acromegaly (31 women, 21 men; mean age 52 ± 11 yr) referred to the Department of Endocrinology of University of Pisa during the period of January to May 2002. Thirteen patients had untreated active acromegaly (AcroUNTR) (nine women, four men; mean age 49.5 ± 9.7 yr), 13 patients had acromegaly in remission after trans-sfenoidal adenomectomy (AcroREM) (nine women, four men; mean age 52.8 ± 11.7 yr), 15 patients had controlled disease under somatostatin analogs therapy (SMSa) (AcroSMSA-Contr) (nine women, six men; mean age 55 ± 12.4 yr), and 11 patients had acromegaly not controlled under SMSa (AcroSMSA-Uncontr) (four women, seven men; mean age 49 ± 7.8 yr).

Thirty patients had arterial hypertension: 13 patients were treated with calcium channel blockers, five were treated with ß-blockers, and seven with angiotensin receptor antagonists; five patients were not taking any treatment at the time of enrollment. Five patients had diabetes mellitus and eight patients had impaired glucose tolerance; all patients with diabetes mellitus or impaired glucose tolerance were in dietary treatment and with metformin (three patients). Twenty-three patients had hypercholesterolemia, of whom, 16 were under hydroxymethylglutaryl coenzyme A reductase inhibitors (see Results).

Diagnosis of acromegaly was made according to clinical and laboratory features, including increased serum IGF-I levels for the age and the lack of suppression of serum GH levels less than 1 mg/liter after a 75-g oral glucose tolerance test (OGTT) (24). Acromegaly was caused by a pituitary GH-secreting microadenoma in 18 cases (35%), or by a macroadenoma in 34 cases (65%). No subjects had a positive history for myocardial infarction. Control of acromegaly under SMSa treatment was achieved in the presence of normal serum IGF-I levels for age (24). Estimated duration of acromegaly was expressed in years and consisted in the time interval between the onset of symptoms (determined on the basis of history and by comparison of previous personal photographs of face and hands over the time, when available) and diagnosis of acromegaly. All patients included in the study, which was approved by the Internal Review Board, gave their written informed consent.

GH and IGF-I assay

Serum GH and IGF-I were measured by commercial kits. GH was measured by automated Advantage chemiluminescent GH assay, and IGF-I by the automated Advantage chemiluminescent IGF-I assay (Nichols Diagnostics, Bad Nauheim, Germany) as reported (25). Coefficients of variations were as follows: IGF-I: intraassay 9.5%, interassay 10.2%; GH: intraassay: 5.1%, interassay, 8.3%. Normal values in our laboratory are as follows: GH, 0–5 µg/liter; IGF-I, 182–780 µg/liter, 16–24 yr; 90–492 µg/liter, 25–50 yr; 71–290 µg/liter, more than 50 yr.

Cardiac evaluation and determination of the Framingham risk score at 10 yr

Smoking habit, systolic and diastolic blood pressure, baseline serum glucose, total cholesterol, HDL cholesterol, and triglycerides were evaluated in all patients at booking.

Systolic and diastolic blood pressure was measured; basal electrocardiogram (ECG) and 2-dimensional color doppler echocardiograph evaluation were performed as previously reported in detail (12). No patients had a history of coronary artery disease, neither showed symptoms or signs of cardiac heart failure. Left ventricular (LV) mass (LVM), left ventricular mass index (LVMi), and ejection fraction (EF) were determined as reported (12). LV hypertrophy was defined when LVMi was 125 g/m2 or greater in men and 110 mg/m2 or greater in women (12). LV systolic dysfunction was defined when EF was less than 50%.

Hypertension was defined when systolic pressure was 140 or greater and/or diastolic pressure was 90 or greater (or on antihypertensive drugs); diabetes was diagnosed when fasting glucose was greater than 126 mg/dl at two consecutive measurements or when, 2 h after the OGTT, glucose was 200 mg/dl or greater; impaired glucose tolerance was defined when glucose was between 126–200 mg/dl 2 h after OGTT with an additional value of more than 200 mg/dl between 0–2 h after glucose load; and hypercholesterolemia was defined as when total cholesterol levels were 200 mg/dl or greater (5.17 mmol/liter), according to the National Cholesterol Education Program Adult Treatment Panel III guidelines (26). The 10-yr likelihood for development of coronary events was estimated using the multivariate scoring system of the Framingham Heart Study (23, 26).

Occurrence of cardiac ischemic events (myocardial infarction, angina pectoris) was evaluated by physical examination and interview every 6 months during the follow-up period.

Cardiac computed tomography (CT) scan and coronary calcium content

All patients underwent to CT CAC score with a retrospective ECG-triggered multidetector CT scanner (MDCT; Siemens 4-slice, Somatom Volume Zoom; Siemens, New York, NY), which is an unenhanced technique. Patients were in a supine position, and the scan volume was defined from the coronal scout view to include hearth completely.

The fixed scanning parameters were 4.0 x 2.5 mm collimation, 120 kV, and 0.5 sec per rotation time. Images were reconstructed with a 3-mm section thickness, slice interval 1.5 mm, 512 x 512 pixel matrix, 130–160 mm field of view, and medium smooth kernel.

The images were acquired during a single breath hold inspiration of about 20 sec and then were reconstructed and analyzed for CAC content using the Agatston algorithm (27), the equivalent mass (mgCaHA) and the global volume (mm3) in the left main artery, left anterior descendent artery, left circumflex artery, and right coronary artery.

The Agatston score (AS) quantifies the deposits of calcium in the coronary arteries and is calculated by multiplying the sum of the areas of each calcified lesion with a weighted CT attenuation score that depends on the maximal CT attenuation of the lesion in terms of Hounsfield Unit. AS was stratified as 0, 1–100 or greater, 101–300 or greater, and greater than 300. Normal values for AS are less than 50 until 60 yr and less than 300 over 60 yr (27). For the purpose of the present study, 52 normal subjects (without known endocrine or cardiac disease) of similar age and sex distribution were used as controls.

Single photon emission computed tomography (SPECT)

All patients with positive CAC score underwent a myocardial perfusion SPECT study according to an exercise stress and rest protocol as reported (28) About 1 h after the iv administration of 740 MBq of 99Tc-Tetrofosmin under resting conditions, SPECT images were acquired by using a dual detector {gamma} camera (Optima NT ELGEMS) equipped with low emission high resolution collimators.

Statistical analysis

Data were expressed as mean ± SD for quantitative variables and as absolute frequency and percentage for qualitative variables. Relationship between two qualitative variables was analyzed by the two-side Fisher’s exact test. Comparison among groups for quantitative variables was performed by ANOVA. When a quantitative variable was not normally distributed or variances were not homogenous, a log transformation was used. A Welch-ANOVA and a nonparametric test, Wilcoxon test, or Kruskal-Wallis test were also performed. A P value < 0.05 was considered as significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Clinical and biochemical findings of the study group are shown in Table 1Go. Thirty patients had arterial hypertension, five had diabetes, eight had impaired glucose tolerance, and 23 had hypercholesterolemia. Mean serum GH and IGF-I concentrations were higher in AcroUNTR and AcroSMSA-Uncontrthan in AcroREM or AcroSMSA-Contr (Table 1Go, P < 0.0001). After enrollment in the study, patients with untreated comorbidities received appropriate treatments: five patients with hypertension were treated with angiotensin receptor antagonists, two patients with diabetes were treated with metformin, and seven patients with hypercholesterolemia received bezafibrate (n = 1) or hydroxymethylglutaryl coenzyme A reductase inhibitors (n = 6).


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  		TABLE 1. Clinical and biochemical features of groups of patients with acromegaly at study entry

 
Standard cardiac evaluation

All patients were asymptomatic for coronary artery disease and none had electrocardiography findings of CHD at resting, at study entry. Main echocardiographic parameters of the patients are shown in Table 1Go. Mean LVMi was 100 ± 29 g/m2. Fourteen patients (27%) had LV hypertrophy and the remaining patients had LV mass index within the normal range; LV hypertrophy was revealed in 36, 36, 14, and 14% of patients with AcroUNTR, AcroSMSA-Uncontr, AcroREM, and AcroSMSA-Contr, respectively (P = 0.166). All patients had normal LV systolic function (mean EF 67 ± 6%).

Ten-year likelihood for development of CHD

Likelihood for development of major CHD events was estimated by the multivariate scoring system of the Framingham Heart Study. Mean CHD risk at 10 yr was 8 ± 5%, ranging 0.19–20.3% in the whole study population (95% confidence interval limits 6.6–7.9%) without differences among groups (P = 0.981) (Fig. 1Go), even when adjusted for gender and hypertension (P = 0.908). Thirty-seven patients had low (FS < 10%), 14 patients had intermediate (FS between ≥10% and <20%), and one patient had high (FS ≥ 20%) risk for development of CHD. Patients with intermediate or high FS were equally distributed among the four groups (of acromegalic patients) as shown in Table 2Go[four AcroUNTR, three AcroREM, four AcroSMSA-Contr, four AcroSMSA-Uncontr (P = 0.756)]. CHD risk was not related to serum IGF-I concentrations (388.9 ± 280.6 and 390 ± 310.8 µg/liter for FS < 10% and 10% ≤ FS < 20%, respectively, ANOVA P = 0.985), or the estimated duration of disease (12.7 ± 6.0 and 16.1 ± 10.0 yr for FS < 10% and 10% ≤ FS < 20% respectively; ANOVA P = 0.255). As expected, CHD risk was independently associated to the pool of parameters included in the Framingham multiple scoring system (data not shown). The only patient with FS 20% or greater was not considered in the analysis.


Figure 1
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  		FIG. 1. Pretest estimating 10-yr risk of coronary artery disease (CHD) in each patient. Patients were grouped by activity of acromegaly and current treatment. Fourteen patients had FS between 10% or greater and less than 20% and one patient had FS 20% or greater. Patients with FS 10% or greater (intermediate and high risk for developing CHD) were equally distributed among the four groups of patients with acromegaly.

 

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  		TABLE 2. Distribution of 10-yr FS in acromegalic patients stratified according to the study groups

 
Determination of coronary calcium content

CAC content was determined in all patients and expressed as AS, the distribution of which did not differ among the study groups (P = 0.296) (Table 3Go, Fig. 2Go).


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  		TABLE 3. Distribution of calcium score in acromegalic patients stratified according to the study groups

 

Figure 2
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  		FIG. 2. CT scan imaging of representative patients with acromegaly. A and C, Diffuse calcified plaques in a patient with intermediate FS; B, limited calcified plaques in a patient with FS less than 10%; and D, absent calcified plaques in a patient with intermediate FS. LAD, Left anterior descendent artery; LM, left main artery; RCA, right coronary artery; CX, circumflex left artery.

 
Thirty-three patients had AS equal to 0, meaning that no calcified plaques were detected. Among them, 24 patients had FS less than 10%, and nine had FS between 10% or greater and less than 20%. Eleven patients had AS between 1 or greater and less than 100, eight of whom had FS less than 10%, two had FS between 10% or greater and less than 20%, and one having FS 20 or greater. Six patients had AS between 100 or greater and less than 300, five of whom with FS less than 10% and one with FS between 10% or greater and less than 20%. Finally, two patients had AS greater than 300, both having FS between 10% or greater and less than 20%. Distribution of AS classes among FS groups was not significantly different (P = 0.126, excluding the patient with FS ≥ 20% P = 0.192) (Table 4Go, Fig. 2Go).


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  		TABLE 4. Distribution of calcium score in acromegalic patients stratified according to the Framingham score system

 
AS was not related to serum IGF-I concentrations (ANOVA P = 0.303) or the estimated duration of disease (ANOVA P = 0.402). For AS equal to 0, AS 1 or greater and less than 100, AS 100 or greater and less than 300, and AS 300 or greater, IGF-I concentrations were 335.0 ± 243.7, 420.3 ± 285.9, 470.0 ± 306.3, and 792.5 ± 729.0 µg/liter, respectively, and the estimated duration of disease was 14.7 ± 7.8, 12.0 ± 6.1, 10.0 ± 3.8, and 16.5 ± 13.4 yr, respectively. AS was not associated with serum IGF-I concentrations (ANOVA P = 0.395), and the estimated duration of active disease (ANOVA P = 0.255), even though the two patients with AS 300 or greater were not included in the analysis.

Assessment of incremental value of CAC in the determination of global CHD risk

Among patients with FS less than10%, 24 had AS 0, eight had AS between 1 or greater and less than 100, and five had AS between 100 or greater and less than 300. Among patients with FS between 10% or greater and less than 20%, five had calcified plaques (two patients with AS between 1 or greater and less than 100, one with AS between 100 or greater and less than 300, and two with AS 300 or greater, one of the latter subset had AS greater than 400). According to the American College Foundation Clinical Expert Consensus Task Force (23), the patient with intermediary FS increased his CHD risk from 11% to 20% or greater after AS measurement. The patient with FS of 20 or greater had AS equal to 32.

Myocardial SPECT

All patients with positive AS were submitted to exercise stress SPECT to evaluate coronary artery reserve. Tests were negative (i.e. absent perfusion defects) in all examined patients.

Evaluation of major cardiac events during a 5-yr follow-up period

All patients were followed prospectively for 5 yr. Occurrence of major cardiovascular events was evaluated on clinical ground and interview every 6 months: no patients developed major cardiovascular events during the whole study period.

Relation between FS, additional value of AS, and occurrence of cardiac events at 5 yr

Overall, mean estimated risk for developing cardiovascular events in the whole study group was less than 1% per year; from a practical point, this means that two patients were expected to experience manifestation of CHD during the study period. The fact that no patient developed major events during the 5-yr follow-up period seems to be in agreement with the estimated risk using the FS. One patient with basal intermediate risk (FS 11%), having AS greater than 400, became at high risk (≥20% at 10 yr) for developing CHD. It is worth noting that the patient with pretest risk 20% or greater had AS 32 (i.e. normal for the age). No relationship was observed between FS and AS (P = 0.126).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Cardiac complications are frequent in patients with acromegaly, with hypertrophy and fibrosis considered the most common findings (2, 3, 4, 5, 6); on the opposite, data on coronary artery disease are scanty and a matter of argument. According to autoptic studies, myocardial fibrosis was revealed in 50–75% and hypertrophy in 90% of patients (17, 18, 19, 20). However, 15% patients had gross evidence of myocardial infarction and 27% had significant wall thickness of the small intramural branches of the coronary arteries unrelated to myocardial scar tissue (20). Other autoptic studies revealed aortic artery atherosclerosis in 50% of patients (17).

In vivo studies, using echography, reported increased intima-media thickness of carotid arteries in 50% patients with active acromegaly (11, 21), which normalized after medical control of disease activity (11). In addition, Otsuki et al. (21) found that patients without atherosclerotic changes of carotid arteries had plasma IGF-I concentrations higher than those with the atherosclerotic changes. The authors proposed a protective role of high IGF-I against atherosclerotic process, at least, in some acromegalic patients; the underlying mechanism might be regulation of local blood flow through an IGF-I mediated vascular production of endothelial nitric oxide (29). However, direct support to this hypothesis is not yet available.

A recent study using FS and CAC reported that 41% acromegalic patients were at risk for CHD, half of them having coronary artery calcifications (22). The study was observational, thus the predictive value of FS could not be verified. In addition, stratification of CHD risk by FS did not follow conventional rules, indicating 6% as a cutoff value, thus discriminating patients with low and intermediate risk. On the contrary, a consensus stratification of CHD risk based on FS identifies those having FS less than 10% as low-risk subjects, those having FS between 10% or greater and less than 20% as intermediate-risk, and those having FS 20% or greater as high risk (26). In fact, about 40% of patients classified as having intermediate risk in the study by Cannavò et al. (22) actually had FS less than 10, which more appropriately could be considered as having low risk for CHD.

CAC directly measures the amount of calcium deposits in the coronary arteries; thus, it could be considered index of coronary artery atherosclerosis (30, 31). However, a recent revision of the published data revealed that a positive calcium score does not increase CHD risk in subjects with low FS, as well as in those with high FS; thus, CAC determination does not seem useful in those categories of subjects (23). On the contrary, a recent consensus document drawn by a panel of experts indicated the incremental value of CAC only in patients with intermediate risk (i.e. FS ≥ 10% and < 20%) (23). In the latter group of patients, CAC is considered to have independent prognostic value over conventional cardiac risk factors (32, 33): an annual CHD rate of 0.4, 1.3, and 2.4% for score less than 100, between 100 or greater and 399, and 400 or greater, respectively, has been suggested (34, 35). Thus, a patient with intermediate risk and a CAC score 400 or greater would be expected to have an event rate superimposable to that of high-risk patients.

Data of the present study showed that the estimated risk for developing CHD in acromegalic patients was unrelated to disease activity or the estimated duration of acromegaly, linking it to common risk factors contributing to FS. Seventy-one percent of patients with acromegaly have a low risk and 29% have intermediate (27%) or high (2%) risk for developing CHD. FS was not influenced by acromegaly activity, and the supposed protective role of high serum IGF-I concentrations on atherosclerosis development (21) could not be supported by the present data. This could have been the case if a large proportion of acromegalic patients were found to be at high risk of developing CHD not occurring in those with high serum IGF-I. The scenario is far from that hypothesized because FS classes were similarly distributed among patients with active disease and in those with acromegaly in remission. In addition, no major cardiovascular events occurred during the 5-yr follow-up study, as expected on the estimated risk based on the Framingham algorithm. However, the limited study groups might underestimate the effects of acromegaly on CHD risk. The predictive value of FS was strengthened by negative SPECT in patients with positive AS, supporting integrity of myocardial perfusion; few data have been reported using perfusional SPECT in patients with acromegaly (36) suggesting perfusional defects not confirmed by angiography; however, SPECT was performed using 201-Thallium, which might have attenuation artifacts particularly in relation to gender, obesity, cardiac hypertrophy, or dilated cardiomyopathy (37, 38). On the opposite, our data fit with those of Metz et al. (39) suggesting a high negative predictive value of SPECT, performed using 99Tc-tetrofosmin.

In addition, our data are in agreement with those proposed by the recent report on the usefulness of calcium score (23). AS had incremental value in a patient among those with intermediate FS, as suggested by recent published data on nonacromegalic subjects (32, 33, 34).

In conclusion, our data suggest that acromegalic patients likely follow the criteria for development of CHD as assessed by the Framingham heart scoring. In contrast, as expected (1, 2), most patients of the present series had arterial hypertension, hypercholesterolemia, or diabetes associated to acromegaly, which take part in the assessment of CHD risk (2).


   Acknowledgments
 
We thank Prof. Aldo Pinchera (University of Pisa) for his continuous encouragement and advice.


   Footnotes
 
This work was partially supported by grants from the University of Pisa (Fondi d’Ateneo) and from Ministry of Education, University and Research (Rome, Italy) (to E.M.).

The authors have nothing to declare.

First Published Online September 4, 2007

Abbreviations: AcroREM, Patients with acromegaly in remission after pituitary adenomectomy; AcroSMSA-Contr, patients with active acromegaly controlled under somatostain analogs; AcroSMSA-Uncontr, patients with active acromegaly not controlled under somatostain analogs; AcroUNTR, patients with untreated active acromegaly; AS, Agatston score; CAC, coronary artery calcium; CHD, coronary heart disease; CT, computed tomography; ECG, electrocardiogram; EF, ejection fraction; FS, Framingham score; LV, left ventricular; LVM, LV mass; LVMi, LVM index; OGTT, oral glucose tolerance test; SMSa, somatostatin analogs therapy; SPECT, single photon emission computed tomography.

Received May 31, 2007.

Accepted August 29, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Melmed S 2006 Medical progress: acromegaly. N Engl J Med 355:2558–2573[Free Full Text]
  2. Colao AM, Ferone D, Marzullo P, Lombardi G 2004 Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 25:102–152[Abstract/Free Full Text]
  3. Sacca’ L, Cittadini A, Fazio S 1994 Growth hormone and the heart. Endocr Rev 15:555–573[CrossRef][Medline]
  4. Ciulla M, Arosio M, Barelli MV, Paliotti R, Porretti S, Valentini P, Tortora G, Buonamici V, Moraschi A, Capiello V, Magrini F 1999 Blood-pressure independent cardiac hypertrophy in acromegalic patients. J Hypert 17:1965–1969[CrossRef][Medline]
  5. Clayton RN 2003 Cardiovascular function in acromegaly. Endocr Rev 24:272–277[Abstract/Free Full Text]
  6. Colao AM, Marzullo P, Di Somma C, Lombardi G 2001 Growth hormone and the heart. Clin Endocrinol (Oxf) 54:137–154[CrossRef][Medline]
  7. Fazio S, Cittadini A, Cuocilo A, Merola B, Sabatini D, Colao AM, Biondi B, Lombardi G, Saccà L 1994 Impaired cardiac performance is a distinct feature of uncomplicated acromegaly. J Clin Endocrinol Metab 79:441–446[Abstract]
  8. Minniti G, Jaffrain-Rea ML, Moroni C, Balzelli R, Ferretti E, Cassone R, Gulino A, Tamburrano G 1998 Echocardiographic evidence for a direct effect of GH/IGF-I hypersecretion on cardiac mass and function in young acromegalics. Clin Endocrinol (Oxf) 49:101–106[CrossRef][Medline]
  9. Colao AM, Marzullo P, Cuocilo A, Spinelli L, Pivonello R, Bonaduce D, Salvatore M, Lombardi G 2003 Reversal of acromegalic cardiomyopathy in young but not in middle-aged patients after 12 months of treatment with the depot long-acting somatostatin analogue octreotide. Clin Endocrinol (Oxf) 58:176–196
  10. Merola B, Cittadini A, Colao AM, Ferone D, Fazio S, Sabatini D, Biondi B, Saccà L, Lombardi G 1993 Chronic treatment with the somatostatin analog octreotide improves cardiac abnormalities in acromegaly. J Clin Endocrinol Metab 77:790–793[Abstract]
  11. Colao A, Marzullo P, Lombardi G, the Multicenter Italian Study Group on Lanreotide 2002 Effect of a six-month treatment with lanreotide on cardiovascular risk factors and arterial intima-media thickness in patients with acromegaly. Eur J Endocrinol 146:303–309[Abstract]
  12. Bogazzi F, Di Bello V, Palagi C, Delle Donne MG, Di Cori A, Gavioli S, Talini E, Cosci C, Sardella C, Brogioni S, Mariani M, Martino E 2005 Improvement of intrinsic myocardial contractility and cardiac fibrosis degree in acromegalic patients treated with somatostatin analogues: a prospective study. Clin Endocrinol (Oxf) 62:590–596[CrossRef][Medline]
  13. Pivonello R, Galderisi M, Auriemma RS, De Martino MC, Galdiero M, Ciccarelli A, D’Errico A, Kourides I, Barman P, Lombardi G, Colao A 2007 Treatment with GH receptor antagonist in acromegaly: effect on cardiac structure and performance. J Clin Endocrinol Metab 92:476–482[Abstract/Free Full Text]
  14. Orme SM, McNally RJQ, Catwright RA, Belchetz PE 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 83:2730–2734[Abstract/Free Full Text]
  15. Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS 2004 Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. J Clin Endocrinol Metab 89:1613–1617[Abstract/Free Full Text]
  16. Kauppinen-Makelin R, Sane T, Reunanen A, Valimaki MJ, Kiskanen L, Markkanen H, Lottyniemi E, Ebelig T, Jaatinen P, Laine H, Nuutila P, Salmela P, Salmi J, Stenman UH, Viikari J, Voutinalainen E 2005 A nationwide survey of mortality in acromegaly. J Clin Endocrinol Metab 90:4081–4086[Abstract/Free Full Text]
  17. Courville C, Mason VR 1938 The heart in acromegaly. Arch Intern Med 61:704–713[Abstract/Free Full Text]
  18. Goldberg MB, Lisser H 1942 Acromegaly: a consideration of its course and treatment. Report of four cases with autopsies. J Clin Endocrinol 2:477–501
  19. Hejtmancik MR, Bradfield JY, Herrmann GR 1950 Acromegaly and heart: a clinical and pathologic study. Ann Intern Med 34:1445–1456
  20. Lie JT, Grossman SJ 1980 Pathology of the heart in acromegaly: anatomic findings in 27 autopsied patients. Am Heart J 100:41–52[CrossRef][Medline]
  21. Otsuki M, Kasamaya S, Hiroyasu Y, Saito H, Sumitani S, Kouhara H, Saito Y, Ohnishi T, Arita N 2001 Characterization of premature atherosclerosis of carotid arteries in acromegalic patients. Clin Endocrinol (Oxf) 54:791–796[CrossRef][Medline]
  22. Cannavò S, Almoto B, Cavalli G, Squadrito S, Romanello G, Vigo MT, Fiumara F, Benvenga S, Trimarchi F 2006 Acromegaly and coronaric disease: an integrated evaluation of conventional coronary risk factors and coronary calcifications detected by computed tomography. J Clin Endocrinol Metab 91:3766–3772[Abstract/Free Full Text]
  23. Greenland P, Bonow RO, Eisenberg MJ, Grundy SM, Lauer MS, Post WS, Raggi P, Redberg RF, Rodgers GP, Shaw LJ, Taylor AJ, Weintraub WS 2007 Clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain. Circulation 115:402–426[Free Full Text]
  24. Colao A, Martino E, Cappabianca P, Cozzi R, Scanarini M, Ghigo E, A.L.I.C.E. Study Group 2006 First-line therapy of acromegaly: a statement of the A.L.I.C.E. (acromegaly primary medical treatment learning and improvement with continuous medical education) Study Group. J Endocrinol Invest 29:1017–1020[Medline]
  25. Manetti L, Lupi I, Morselli LL, Albertini S, Cosottini M, Grasso L, Genovesi M, Pinna G, Mariotti S, Bogazzi F, Bartalena L, Martino E 2007 Prevalence and functional significance of antipituitary antibodies in patients with autoimmune and non-autoimmune thyroid diseases. J Clin Endocrinol Metab 92:2176–2181[Abstract/Free Full Text]
  26. Grundy SM, Cleeman JI, Merz NB, Brewer HB, Clark LT, Hunnighake DB, Pasternak RC, Smith SC, Stone NJ 2004 Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation 110:227–239[Abstract/Free Full Text]
  27. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte Jr M, Detrano R 1990 Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15:827–832[Abstract]
  28. Petronio AS, Rovai D, Musumeci G, Baglini R, Nardi C, Libruno U, Palagi C, Volterrani D, Mariani M 2003 Effects of abciximab on microvascular integrity and left ventricular functional recovery in patients with acute infarction treated by primary coronary angioplasty. Eur Heart J 24:67–76[Abstract/Free Full Text]
  29. Delafontaine P, Lou H, Alexander RW 1991 Regulation of insulin-like growth factor 1 messenger RNA levels in vascular smooth muscle cells. Hypertension 18:742–747[Abstract/Free Full Text]
  30. Budoff MJ, Achebach S, Blumenthal RS, Carr JJ, Goldin JG, Greenland P, Guerci AD, Lima JAC, Rader DJ, Rubin GD, Shaw LJ, Wiegers SE 2006 Assessment of coronary artery disease by cardiac computed tomography: a statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 114:1761–1791[Free Full Text]
  31. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS 1995 Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 92:2157–2162[Abstract/Free Full Text]
  32. Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD 2005 Coronary calcification, coronary disease risk factor, C-reactive protein, and atherosclerotic cardiovascular disease event: the St. Francis Heart Study. J Am Coll Cardiol 46:158–165[Abstract/Free Full Text]
  33. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC 2004 Coronary artery calcium score combined with Framinghan score for risk prediction in asymptomatic individuals. JAMA 291:210–215[Abstract/Free Full Text]
  34. Redberg RF, Vogel RA, Criqui MH, Herrington DM, Lima JA, Roman MJ 2003 34th Bethesda Conference: Task force #3—What is the spectrum of current and emerging techniques for the noninvasive measurement of atherosclerosis? J Am Coll Cardiol 41:1886–1898[Free Full Text]
  35. Third report of the National Cholesterol Education Program (NCEP) 2002 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–3421[Free Full Text]
  36. Herrmann BL, Brandt-Mainz K, Saller B, Bruch C, Wieneke H, Kugler C, Ferdin S, Hahn S, Erbel R, Bockisch A, Mann K 2003 Myocardial perfusion abnormalities in patients with active acromegaly. Horm Metab Res 35:183–188[CrossRef][Medline]
  37. Kapur A, Latus KA, Davies G, Dhawan RT, Eastick S, Jarritt PH, Roussakis G, Young MC, Anagnostopoulos C, Bomanji J, Costa DC, Pennell DJ, Prvulovich EM, Ell PJ, Underwood SR 2002 A comparison of three radionuclide myocardial perfusion tracers in clinical practice: the ROBUST study. Eur J Nucl Med Mol Imaging 29:1608–1616[CrossRef][Medline]
  38. Taillefer R, DePuey EG, Udelson JE, Beller GA, Latour Y, Reeves F 1997 Comparative diagnostic accuracy of Tl-201 and Tc-99m sestamibi SPECT imaging (perfusion and ECG-gated SPECT) in detecting coronary artery disease in women. J Am Coll Cardiol 29:69–77[Abstract]
  39. Metz LD, Beattie M, Hom R, Redberg RF, Grady D, Fleischmann KE 2007 The prognostic value of normal exercise myocardial perfusion imaging and exercise echocardiography: a meta-analysis. J Am Coll Cardiol 49:227–237[Abstract/Free Full Text]




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