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Cardiovascular Function in Acromegaly

School of Medicine, Keele University, Stoke-on-Trent, Staffordshire, ST4 7QB, United Kingdom

Correspondence: Address all correspondence and requests for reprints to: R. N. Clayton, M.D., Ph.D., School of Medicine, Keele University, Thornburrow Drive, Stoke-on-Trent, Staffordshire ST4 7QB, United Kingdom. E-mail: r.n.clayton{at}keele.ac.uk

	Abstract

Top Abstract I. Introduction—Increased... II. Cardiomyopathy in Acromegaly III. Functional Changes in... IV. Cardiac Dysrhythmias in... V. The Endothelium in... VI. Conclusions References

 
Even with modern treatment, acromegaly is associated with a 2- to 3-fold increase in mortality, mainly from vascular disease, which is probably a result of the long exposure of tissues to excess GH before diagnosis and treatment. There is accumulating evidence that effective treatment to lower serum GH levels to less than 1–2 ng/ml (glucose suppressed or random, respectively) and normalize IGF-I improves long-term outcome and survival. In addition to recognized cardiovascular risk factors of hypertension, type 2 diabetes mellitus, and dyslipidemia, there is accumulating evidence of specific structural and functional changes in the heart in acromegaly. Along with endothelial dysfunction, these changes may contribute to the increased mortality in this disease. There are specific structural changes in the myocardium with increased myocyte size and interstitial fibrosis of both ventricles. Left ventricular hypertrophy is common even in young patients with short duration of disease. Some of these structural changes can be reversed by effective treatment. Functionally, the main consequence of these changes is impaired left ventricular diastolic function, particularly when exercising, such that exercise tolerance is reduced. Diastolic function improves with treatment, but the effect on exercise tolerance is more variable, and more longitudinal data are required to assess the benefits. What scant data there are on rhythm changes suggest an increase in complex ventricular arrhythmias, possibly as a result of the disordered left ventricular architecture. The functional consequences of these changes are unclear, but they may provide a useful early marker for the ventricular remodeling that occurs in the acromegalic heart. Endothelial dysfunction, especially flow-mediated dilatation, is an early marker of atherosclerosis, and limited data imply that this is impaired in active acromegaly and can be improved with treatment. Similarly, early arterial structural changes, such as thickened intima media layer, appear more common in acromegalics, and there are hints that this may diminish with effective treatment, although more studies are required for a definite conclusion on this topic. In conclusion, impaired cardiac and endothelial structure and function in acromegaly are risk factors for vascular mortality and should be regarded as legitimate therapeutic targets in the overall management of this condition.

I. Introduction—Increased Mortality in Acromegaly

II. Cardiomyopathy in Acromegaly

III. Functional Changes in the Acromegalic Heart

IV. Cardiac Dysrhythmias in Acromegaly

V. The Endothelium in Acromegaly

VI. Conclusions

	I. Introduction—Increased Mortality in Acromegaly

Top Abstract I. Introduction—Increased... II. Cardiomyopathy in Acromegaly III. Functional Changes in... IV. Cardiac Dysrhythmias in... V. The Endothelium in... VI. Conclusions References

 
BEFORE THE INTRODUCTION of effective therapy for patients with acromegaly, about 80% of the patients died before the age of 60 from cardiovascular disease (CVD) (1). Even with modern treatment, retrospective surveys, commencing from as early as 1970 (2), have consistently shown that overall mortality is increased 2- to 3-fold in acromegalic patients compared with that of an age- and sex-matched general population, despite what was, for the time, deemed appropriate treatment (reviewed in Ref. 3).

The main causes of the increased mortality are vascular and respiratory diseases, with cancer deaths, perhaps surprisingly, not increased (Table 1). There is considerable heterogeneity between reports with respect to gender differences and distinction between cardio- and cerebrovascular deaths. Moreover, these data are only as accurate as the death certification coding and registration in each country. Notwithstanding these issues, the conclusion of overall significantly increased rate of vascular deaths is substantiated. Survival in the acromegalic population is predicted to be about 10 yr less than in the general population (2, 3, 4, 5, 6, 7, 8, 9, 10). When considering what might predict this increased mortality, Rajasoorya et al. (9) and Orme et al. (8) have shown that the duration of disease and serum GH level are independent predictors of overall mortality, especially the product of the GH level and estimated duration of acromegaly (9). One study (11) defined remission after transsphenoidal surgery on the basis of serum IGF-I levels. In those in whom this biochemical index was normalized, the mortality was no different from that of the general population, whereas, in those in whom IGF-I remained elevated, the standarized mortality rate was 1.8. However, a more recent larger prospective study from the United Kingdom (12) failed to demonstrate an independent predictive value of serum IGF-I on mortality, although serum GH level was a good predictor. In this context, not all actions of GH are IGF-I dependent, as direct GH effects have been demonstrated in many tissues (e.g., bone and gonads). For example, a recent in vitro study demonstrated GH effects on myocyte hypertrophy and altered cellular metabolism in cultured myocytes in the absence of any change in IGF-I mRNA, implying an IGF-I-independent action of GH (13).

It has long been recognized that there is an increased prevalence of cardiovascular mortality risk factors in acromegaly including hypertension, non-insulin-dependent diabetes mellitus (NIDDM), dyslipidemia, abdominal adiposity, and peripheral insulin resistance (all features of the metabolic syndrome). More recently, endothelial dysfunction with impaired flow-mediated dilatation (FMD) and increased intima media thickness (IMT) has been demonstrated (see Section V). Both of these indices are now recognized surrogate markers of early vascular disease and predictors of ischemic heart disease (reviewed in Ref. 17). Moreover, lowering of serum GH significantly improves many of the aforementioned risk factors. But is there a specific effect of GH/IGF-I on the heart and cardiac function, in addition to the above-mentioned risk factors, that might contribute to morbidity and mortality in acromegaly?

This brief review will consider the specific effects of GH/IGF-I on cardiac structure and function and emerging evidence for endothelial dysfunction in acromegaly.

	II. Cardiomyopathy in Acromegaly

Top Abstract I. Introduction—Increased... II. Cardiomyopathy in Acromegaly III. Functional Changes in... IV. Cardiac Dysrhythmias in... V. The Endothelium in... VI. Conclusions References

 
There is now a considerable literature that suggests that there is a specific cardiomyopathy in acromegaly, resulting in structural and functional abnormalities that may be partially reversed by effective reduction in GH/IGF-I levels. This was reviewed several years ago by Sacca et al. (18) and more recently by Colao et al. (19). Thus, what follows is an abbreviated review of the main topics and any additional data since 2001.

Is there a specific pathological entity in acromegaly unrelated to hypertension/NIDDM/dyslipidemia? The answer appears to be yes. The ventricular walls are concentrically thickened due to a relative increase in myocyte size without enlargement of cardiac chambers. Moreover, biopsy and autopsy studies indicate that interstitial fibrosis (up to 8-fold higher than in biopsies from myocardium in mitral stenosis) is the main histological feature that gradually impairs architecture and function (20). The pattern of mononuclear cell infiltration resembles multifocal myocarditis without necrosis. It has been suggested that this results from a marked (450-fold) increase in apoptosis of myocytes (20). Myocyte apoptosis was positively related to duration of disease and inversely with ejection fraction (20). However, in adult rats, administration of exogenous GH and IGF-I induces cardiac hypertrophy without concomitant fibrosis (21). The absence of fibrosis in the animal experiment may be a feature of the relatively short-term exposure to high GH compared with the years of exposure often experienced by the heart in humans with acromegaly.

Clinically, cardiac hypertrophy involves both the left and right ventricles in 90% of older patients with long duration of disease (22, 23). But recent reports suggest that about 20% of young (<30 yr old) normotensive acromegalics have cardiac hypertrophy (24) and that structural changes can occur after short-term exposure to GH (25). Thus, in patients under 40 yr old with active acromegaly of 3–7 yr duration, 54% had echocardiographic evidence of left ventricular hypertrophy, with this figure rising to 72% in patients 41–60 yr old with disease duration of 5–15 yr (19). Thus, cardiac hypertrophy, without ventricular dilatation, is a common early feature of the disease. Generally, angiography does not reveal defects of the coronary vessels (20).

The question is then—can this be reversed by successful treatment? The answer appears to be, emphatically, yes. Structural changes in the heart are observed with successful lowering of GH/IGF-I levels, as reviewed by Colao et al. (19). Most of these studies were of short duration (2–12 months) and used somatostatin analogs. Nevertheless, echocardiography revealed a reduction in the increased left ventricular mass index (LVMi) in nearly all studies, although whether these values reached those of normal controls is unclear from the data presented. What is interesting is that the cardiac remodeling seems to occur quite quickly, in 3 months in some reports. Colao et al. (19) report that the reduction in LVMi occurs in patients of all ages, and that 50% of patients with cardiac hypertrophy regained normal LVMi, although the authors do not present the data. Furthermore, the same conclusion was reached in the longer follow-up study of Vianna et al. (26). The practical consequence of these observations is that restoring cardiac structure and function (see below) becomes an objective of treatment, along with the other classical indications.

	III. Functional Changes in the Acromegalic Heart

Top Abstract I. Introduction—Increased... II. Cardiomyopathy in Acromegaly III. Functional Changes in... IV. Cardiac Dysrhythmias in... V. The Endothelium in... VI. Conclusions References

 
Given the aforementioned structural changes in the heart in acromegaly, the question arises—are there concomitant functional changes and are they clinically relevant?

In a recent report, clinical symptoms and signs of heart failure were found in about 10% of newly diagnosed acromegalics (10 of 102 subjects). This was characterized by near-normal left ventricular systolic function and increased cardiac index, implying high output failure (27). In an older study (28), 7 of 256 patients had clinical evidence of heart failure, although overt left ventricular failure was only apparent in 2 patients (<1%). It is interesting that there are very limited prevalence data on clinically evident heart failure, although echocardiographic studies are more common. Most echocardiographic studies show normal left ventricular systolic function but impaired diastolic function as an early finding in acromegalic cardiomyopathy (reviewed in Ref. 19), which leads to impaired left ventricular filling. The prevalence of left ventricular diastolic dysfunction is approximately 30% in untreated subjects (29). The consequences of this are not so much at rest but on exercise, during which the ejection fraction is reduced, leading to reduced exercise tolerance. Using more sensitive equilibrium radionuclide angiography, impairment of ejection fraction after exercise was observed in 73% of patients (30) and in 40% of subjects under the age of 40 yr (31). Using the sensitive techniques of tissue Doppler imaging and TEI-index for assessment of global cardiac function, Herrmann et al. (32) demonstrated significant left ventricular diastolic dysfunction in active acromegaly with normal left ventricular mass. Moreover, diastolic dysfunction was related to disease activity in that the active group showed significantly impaired function compared with controls, whereas the well-controlled group (according to the criteria of Guistina et al., Ref. 14) were the same as controls. Importantly, these abnormalities were apparently correlated with disease duration, although the data in support of this statement are not shown. These results imply that early diastolic changes are reversible with successful treatment, but with the caveat that this was a cohort, not longitudinal, study. As in previous reports, there were no changes in parameters of left ventricular systolic function.

The next issue is whether cardiac function can be improved/restored to normal by effective lowering of GH/IGF-I in acromegaly. There have been several echocardiographic studies but with relatively small numbers of patients and short duration of treatment (2–12 months) (Ref. 19). Many of these studies used a somatostatin analog as the main treatment modality. The consensus seems to be clear: diastolic filling is improved, but the effect on ejection fraction and exercise tolerance is more variable. It is evident that improvement only occurs in those patients in whom the acromegaly is controlled. However, the definition of control varies somewhat between the studies, making true comparisons difficult. Moreover, selection bias could well confound some of the data interpretation, and a genuine randomized, controlled trial on the basis of intention to treat has never been performed. In the aforementioned studies, it is difficult to discern whether cardiac function returns to sex- and age-matched control values because of the short duration of some studies. In the most recent study addressing this question (26), 15 patients whose glucose tolerance test suppressed GH level was less than 2 ng/ml and who achieved normal or near-normal IGF-I values were assessed before and at a mean of 3.6 yr (range 1–6 yr) after pituitary surgery with or without radiotherapy. An advantage of this study was that none of the subjects had received a somatostatin analog, thereby eliminating any possibility of a confounding direct effect of these agents on the myocardium. Moreover, these patients were young, (mean age of 33 yr, range 19–55 yr), had no signs or symptoms of heart failure, and were neither hypertensive nor diabetic. As a group, diastolic function was reduced compared with controls and improved after successful treatment. However, it is not possible from the statistical analysis presented to be certain whether the posttreatment values were normal, although, for certain indices, this looks to be the case. Finally, in all the studies reviewed, there are little or no data on exercise tolerance before vs. after treatment, which is what matters to the patient.

	IV. Cardiac Dysrhythmias in Acromegaly

Top Abstract I. Introduction—Increased... II. Cardiomyopathy in Acromegaly III. Functional Changes in... IV. Cardiac Dysrhythmias in... V. The Endothelium in... VI. Conclusions References

 
There are very few data on the prevalence and severity of cardiac dysrhythmias in acromegaly (28, 33). Recently, Kahaly et al. (34) studied 32 acromegalics and compared them with 50 controls without heart disease. Both the severity and frequency of ventricular dysrhythmias were significantly higher in acromegalics compared with controls. Specifically, 48% of acromegalics compared with 12% of controls had complex ventricular arrhythmias. The frequency of ventricular premature complexes increased with duration of acromegaly, and the severity of arrhythmia correlated with left ventricular mass but not with GH levels. The increase in ventricular arrhythmias is perhaps not unexpected, considering the remodeling of the left ventricle that occurs. The functional consequences of the ventricular arrhythmias was not reported, however. There was no increase in the frequency of supraventricular arrhythmias.

Another study investigated late potentials in a signal-averaged electrocardiogram as a predictor of ventricular dysrhythmias (35). These late potentials are frequently seen in patients after myocardial infarction and are predictors of arrhythmic events (36). Disorganized and asynchronous electrical activity is thought to arise from areas of surviving muscle at the border of the infarct. Such areas are separated from each other by fibrous tissue, thereby creating a disorganized and disconnected network of myofibrils. This architecture is not dissimilar from that observed histologically in the acromegalic heart, in which there are areas of hypertrophied myocytes separated by fibrosis and cellular infiltration. In the study by Herrmann et al. (35), late potentials were detected in 9 of 16 (56%) patients with active acromegaly vs. 2 of 32 (6%) well-controlled patients (P = 0.001; the IGF-I level normal for age and glucose-suppressed GH is <1 ng/ml). When active and well-controlled acromegalics together were compared with controls, 26% vs. 0% had late potentials, but there was no separate statistical analysis of the well-controlled acromegalics vs. controls. Inspection of their data, however, would seem to indicate no difference, implying that well-controlled acromegalics were normal with respect to these variables. No association was found between presence of late potentials and LVMi. None of the acromegalics studied had clinical symptoms or signs of coronary artery disease when studied. On exercise electrocardiogram, 3 of 16 in the active acromegaly group and 4 of 32 in the well-controlled group had complex ventricular dysrhythmias (probability values were not significant) (Ref. 35), and these did not correlate with late potentials, perhaps questioning the pathological relevance of the latter. None had significant ST-segment changes on exercise electrocardiogram. Based on the aforementioned results, the authors (35) speculate that presence of late potentials may be a sensitive and early indicator of myocardial remodeling in acromegaly.

In neither of these two studies were any longitudinal within-patient data obtained to determine whether treatment changed the electrophysiological abnormalities. If these are related to altered left ventricular structure/histology, as surmised in the reports, the extent to which the changes are reversible would depend upon how the myocardial architecture changes with treatment. However, earlier studies (28, 33) showed that arrhythmias were as frequent before as after treatment of acromegaly, implying that fibrous tissue infiltration had resulted in permanent irreversible scarring. However, the extent of reduction in GH/IGF-I in these studies is unclear and probably did not meet modern criteria for safe levels. Thus, it seems prudent to include noninvasive electrocardiographic monitoring in longitudinal prospective studies of treatment outcomes.

	V. The Endothelium in Acromegaly

Top Abstract I. Introduction—Increased... II. Cardiomyopathy in Acromegaly III. Functional Changes in... IV. Cardiac Dysrhythmias in... V. The Endothelium in... VI. Conclusions References

 
The endothelium is highly active metabolically and plays a key role in vascular homeostasis through the release of a variety of autocrine and paracrine substances. The healthy endothelium, particularly endothelium-derived nitric oxide (NO), not only modulates the tone of the underlying vascular smooth muscle but also inhibits several proatherogenic processes, including monocyte and platelet adhesion, oxidation of low-density lipoproteins, synthesis of inflammatory cytokines, smooth muscle proliferation and migration, and platelet aggregation, thus exhibiting important antiatherogenic effects. It also has an antithrombotic and fibrinolytic function (37). The key mediator of these functions is NO (reviewed in Ref. 38). Endothelial cell dysfunction is the initiating event in the development of atherosclerosis (39), and assessment of endothelial function by different methods has emerged as a tool for detection of evidence of preclinical CVD (40).

Obesity and insulin resistance are associated with blunted endothelium-dependent, but not endothelium-independent, vasodilation (41), with failure of hyperinsulinemia to augment endothelium-dependent vasodilation (42). This indicates that obesity is associated with endothelial dysfunction and endothelial resistance to the enhancing effect of insulin on endothelium-dependent vasodilation. Endothelial dysfunction might therefore contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects, such as those with acromegaly. Insulin resistance has been proposed as a central metabolic basis for the clustering of risk factors in the multiple cardiovascular risk syndrome (syndrome X). However, Pinkney et al. (43) have argued that the central problem may be endothelial dysfunction rather than insulin resistance. In resistance vessels, the endothelium regulates blood flow and blood pressure through the production of powerful vasoactive substances such as NO, endothelin-1, and thromboxane A2 (44).

Studies of endothelial function in acromegaly are scarce, although there are several reports of hemodynamic abnormalities and disordered cardiovascular function in acromegaly. Chanson et al. (45) demonstrated reduced brachial artery blood flow with significantly higher forearm vascular resistance in acromegalic patients compared with matched control subjects. This is in contrast to the previously reported increased renal blood flow and glomerular hyperfiltration (46) and increased functional liver plasma flow (47) and could imply heterogeneity in the distribution of cardiac output in acromegaly (48). Defective brachial artery dilation in response to increased blood flow might account for the increased forearm vascular resistance and might represent underlying endothelial dysfunction.

Recently, Maison et al. (49) reported impaired endothelium-dependent vasodilation in acromegalic patients together with exaggerated sympathetic-mediated vasoconstrictor response. To what extent the peripheral insulin resistance of acromegaly contributes to this and what contribution is made by high GH/IGF-I levels is unclear. FMD of the brachial artery was significantly lower in acromegalics than in healthy and risk-factor-matched controls (by 64% and 47%, respectively) (Ref. 50). However, in cured acromegalics, FMD was significantly higher than in noncured acromegalics, although it was still lower than in the healthy and risk-factor-matched controls. Non-endothelium-dependent brachial artery dilatation was similar in all groups. These results suggest a partially reversible effect of GH/IGF-I on this important aspect of endothelial function. A prospective within-subject study is essential to confirm this conclusion. If confirmed, this would be an important additional consideration for advocating aggressive lowering of GH/IGF-I levels to reduce the risk of CVD morbidity/mortality. To date, there are no studies on soluble endothelial cell markers in acromegaly. Thus, additional studies are needed that directly investigate endothelial function in acromegaly.

With respect to possible endothelium-dependent structural changes in acromegaly, two studies (50, 51) have shown increased IMT in the carotid arteries. In performing comparisons between acromegalics and controls, it is important to match the controls for similar vascular risk factors. Thus, when Brevetti et al. (50) compared IMT in the common carotid artery with healthy controls, they showed a similar increase that disappeared when matched to a control population with similar vascular risk factors. Furthermore, cured acromegalics did not show a lower IMT than noncured acromegalics, although this was a cohort comparison rather than a within-subject longitudinal comparison of pre- and posttreatment measures. In a subsequent study, Colao et al. (52) suggested a trend toward decrease in IMT after disease control for 6 months with a somatostatin analog. In contrast, Otsuki et al. (53) found that IMT was lower in acromegalic than nonacromegalic controls matched for risk factors. These studies would, therefore, suggest that any IMT change in acromegaly is more likely secondary to the increased prevalence of CVD risk factors (hypertension/NIDDM/dyslipidemia) rather than GH/IGF-I excess per se. Nevertheless, the evidence, albeit indirect, indicates that GH status in acromegaly does influence the endothelium either directly via endothelial IGF-I receptors, or indirectly through effects on hypertension, body composition, and lipid metabolism.

	VI. Conclusions

Top Abstract I. Introduction—Increased... II. Cardiomyopathy in Acromegaly III. Functional Changes in... IV. Cardiac Dysrhythmias in... V. The Endothelium in... VI. Conclusions References

 
What seems to emerge from the longitudinal studies is a definite benefit to cardiac structure and function of reducing GH/IGF-I levels to normal/near normal. However, additional long-term studies are required to establish how this translates into clinical benefit and possible reduction in mortality from vascular disease. One word of caution is required. It is evident that hypopituitarism is associated with increased mortality from vascular disease and cardiac structural and functional abnormalities not dissimilar from those seen in acromegaly (see Refs. 18 and 19 for reviews). Whether this is caused by the GH deficiency present in the majority of these patients or is related to other aspects of hypopituitarism is much debated. Nevertheless, some patients with acromegaly develop hypopituitarism and even GH deficiency as a result of their treatment. Therefore, the question arises of how much GH/IGF-I is required to maintain normal cardiac structure and function? It is therefore prudent to try and avoid overtreatment of acromegaly. In this context, medical treatments with somatostatin analogs and GH receptor antagonists offer the prospect of more fine-tuning of GH/IGF-I reduction than does pituitary surgery or radiotherapy and so in the future might provide the answer(s) to this important question. Moreover, specific and selective suppression of GH/IGF-I is achievable with these treatment modalities, thereby avoiding the complication of other hormone insufficiency. Similar remarks also apply to endothelial function. The future prospects for reducing/eliminating the excess mortality from CVD in acromegaly are encouraging. But, as with all other complications, these prospects are critically dependent on early diagnosis before changes induced by chronic GH/IGF-I excess become irreversible.

	Footnotes

 
Abbreviations: CVD, Cardiovascular disease; FMD, flow-mediated dilatation; IMT, intima media thickness; LVMi, left ventricular mass index; NIDDM, non-insulin-dependent diabetes mellitus; NO, nitric oxide.

	References

Top Abstract I. Introduction—Increased... II. Cardiomyopathy in Acromegaly III. Functional Changes in... IV. Cardiac Dysrhythmias in... V. The Endothelium in... VI. Conclusions References

 

1. Corville C, Mason WR 1938 The heart in acromegaly. Arch Intern Med 61:704–713
2. Wright AD, Hill DM, Lowy C, Fraser TR 1970 Mortality in acromegaly. Q J Med 39:1–16
3. Clayton RN 1997 New developments in the management of acromegaly. Should we achieve an absolute biochemical cure? J Endocrinol 155(Suppl 1S):23–29
4. Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R 1980 Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol (Oxf) 12:71–79[Medline]
5. Bates AS, Van’t Hoff W, Jones JM, Clayton RN 1993 An audit of outcome of treatment in acromegaly. Q J Med 86:293–299
6. Bengtsson B-A, Eden S, Ernest I, Oden A, Sjogren B 1988 Epidemiology and long-term survival in acromegaly. Acta Med Scand 223:327–335[Medline]
7. Nabarro JDN 1987 Acromegaly. Clin Endocrinol (Oxf) 26:481–512[Medline]
8. Orme SM, McNally RJQ, Cartwright 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]
9. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson AK 1994 Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 41:95–102[Medline]
10. Beauregard C, Truong U, Hardy J, Serri O 2003 Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf) 58:86–91[CrossRef][Medline]
11. Swearingen B, Barker II FG, Katznelson L, Biller BM, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT 1998 Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 83:3419–3426[Abstract/Free Full Text]
12. Ayuk J, Clayton RN, Sheppard MC, Stewart PM, Bates AS, Cerebrovascular mortality in acromegaly is increased by the use of external radiotherapy and is not predicted by elevated serum IGF-1. Program of the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, 2003 (Abstract)
13. Lu C, Schwartzbauer G, Sperling MA, Devaskar SU, Thamotharan S, Robbins PD, McTiernan CF, Liu JL, Jiang J, Frank SJ, Menon RK 2001 Demonstration of direct effects of growth hormone on neonatal cardiomyocytes. J Biol Chem 276:22892–22900[Abstract/Free Full Text]
14. Guistina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S 2000 Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 85:526–529[Abstract/Free Full Text]
15. Melmed S, Casanueva FF, Cavagnini F, Chanson P, Frohman L, Grossman A, Ho K, Kleinberg D, Lamberts S, Laws E, Lombardi G, Vance ML, Von Werder K, Wass J, Guistina A 2002 Guidelines for acromegaly management. J Clin Endocrinol Metab 87:4054–4058[Free Full Text]
16. Celniker AC, Chen AB, Wert RM, Sherman BM 1989 Variability in the quantitation of circulating growth hormone using commercial immunoassays. J Clin Endocrinol Metab 68:469–476[Abstract]
17. Abdu TAM, Elhadd T, Pfeifer M, Clayton RN 2001 Endothelial dysfunction in endocrine disease. Trends Endocrinol Metab 12: 257–265
18. Sacca L, Cittadini A, Fazio S 1994 Growth hormone and the heart. Endocr Rev 15:555–573[Abstract]
19. Colao A, Marzullo P, Di Somma C, Lombardi G 2001 Growth hormone and the heart. Clin Endocrinol (Oxf) 54:137–154[CrossRef][Medline]
20. Frustaci A, Chimenti C, Setoguchi M, Guerra S, Corsello S, Crea F, Leri A, Kajstura J, Anversa P, Maseri A 1999 Cell death in acromegalic cardiomyopathy. Circulation 99:1426–1434[Medline]
21. Cittadini A, Stromer H, Katz SE, Clark R, Moses AC, Morgan JP, Douglas PS 1996 Differential cardiac effects of growth hormone and IGF-1 in the rat. A combined in vivo and in vitro evaluation. Circulation 93:800–809[Medline]
22. Lie JT 1980 Pathology of the heart in acromegaly; anatomic findings in 27 autopsied patients. Am Heart J 100:41–52[CrossRef][Medline]
23. Morvan D, Komajada M, Grimaldi A, Turpin G, Grosgogeat Y 1991 Cardiac function and hypertrophy and function in asymptomatic acromegaly. Eur Heart J 12:666–672
24. Minniti G, Jaffrain-Rea ML, Moroni C, Baldelli R, Ferretti E, Cassone R, Gulino A, Tamburrano G 1998 Echocardiographic evidence for a direct effect of GH/IGF-1 hypersecretion on cardiac mass and function in young acromegalics. Clin Endocrinol (Oxf) 49:101–106[CrossRef][Medline]
25. Fazio S, Cittadini A, Biondi B, Palmeiri BA, Riccio G, Bone F, Olivero U, Sacca L 2000 Cardiovascular effects of short-term growth hormone hypersecretion. J Clin Endocrinol Metab 85:179–182[Abstract/Free Full Text]
26. Vianna CB, Vieira MLC, Mady C, Liberman B, Durazzo AES, Knoepfelmacher M, Salgado LR, Ramires JAF 2002 Treatment of acromegaly improves myocardial abnormalities Am. Heart J 143:873–876
27. Damjanovics SS, Neskovic AN, Petakov MS, Popovic V, Vujisic B, Petrovic M, Nikolic-Djurovic M, Simic M, Pekic S, Marinkovic J 2002 High output heart failure in patients with newly diagnosed acromegaly. Am J Med 112:610–616[CrossRef][Medline]
28. Hayward RP, Emanuel RW, Nabarro JDN 1987 Acromegalic heart disease: influence of treatment of acromegaly on the heart. Q J Med 62:41–58
29. Colao A, Baldelli R, Marzullo P, Ferretti E, Ferone D, Gargiulo P, Petretta M, Tamburrano G, Lombardi G, Liuzzi A 2000 Systemic hypertension and impaired glucose tolerance are independently correlated to the severity of acromegalic cardiomyopathy. J Clin Endocrinol Metab 85:193–199[Abstract/Free Full Text]
30. Fazio S, Cittadini A, Cuocolo A, Merola B, Sabatini D, Colao A, Biondi B, Lombardi G, Sacca L 1994 Impaired cardiac performance is a distinct feature of uncomplicated acromegaly. J Clin Endocrinol Metab 79:441–446[Abstract]
31. Colao A, Cuocolo A, Mazullo P, Nicolai E, Ferone D, Della Morte A, Salvatore M, Lombardi G 1999 Impact of patient’s age and disease duration on cardiac performance in acromegaly: a radionuclide angiography study. J Clin Endocrinol Metab 84:1518–1523[Abstract/Free Full Text]
32. Herrmann BL, Bruch C, Saller B, Bartel T, Ferdin S, Erbel R, Mann K 2002 Acromegaly: evidence for a direct relation between disease activity and cardiac dysfunction in patients without ventricular hypertrophy. Clin Endocrinol (Oxf) 56:595–602[CrossRef][Medline]
33. Rodrigues EA, Caruana MP, Lahiri A, Nabarro JDN, Jacobs HS, Raftery EB 1989 Subclinical cardiac dysfunction in acromegaly: evidence for a specific disease of heart muscle. Br Heart J 62:185–194[Abstract/Free Full Text]
34. Kahaly G, Olshausen KV, Mohr-Kahaly S, Erbel R, Boor S, Beyer J, Meyer J 1992 Arrhythmia profile in acromegaly. Eur Heart J 13:51–56[Abstract/Free Full Text]
35. Herrmann BL, Bruch C, Saller B, Ferdin S, Dagres N, Ose C, Erbel R, Mann S 2001 Occurrence of ventricular late potentials in patients with active acromegaly. Clin Endocrinol (Oxf) 55:201–207[CrossRef][Medline]
36. Koser LM, Cheriparambil KM, Schifter DR, Saul BI, Reddy CV 2000 Clinical significance of variability of ventricular late potentials detected before discharge in patients after myocardial infarction. Am Heart J 139:134–141[Medline]
37. Tribe RM, Poston L 1996 Oxidative stress and lipid in diabetes: a role in endothelium vasodilator dysfunction? Vasc Med 1:195–206[Medline]
38. Radomski MW, Salas E 1995 Nitric oxide—biological mediator, modulator and factor of injury: its role in the pathogenesis of atherosclerosis. Atherosclerosis 118(Suppl):569–580
39. Ross R 1999 Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126[Free Full Text]
40. Anderson TJ 1999 Assessment and treatment of endothelial dysfunction in humans. J Am Coll Cardiol 34:631–638[Free Full Text]
41. Arcaro G, Zamboni M, Rossi L, Turcato E, Covi G, Armellini F, Bosello O, Lechi A 1999 Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity. Int J Obes Relat Metab Disord 23:936–942[CrossRef][Medline]
42. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD 1996 Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 11:2601–2610
43. Pinkney JH, Stehouwer CD, Coppack SW, Yudkin JS 1997 Endothelial dysfunction: cause of insulin resistance syndrome. Diabetes 46(Suppl 2):S9–S13
44. Vane JR, Anggard EE, Botting RM 1990 Regulatory functions of vascular endothelium. N Engl J Med 323:27–36[Medline]
45. Chanson P, Megnien JL, del Pino M, Coirault C, Merli I, Houdouin L, Harris AG, Levenson J, LeCarpentier Y, Simon A, Chemla D 1998 Decreased regional blood flow in patients with acromegaly. Clin Endocrinol (Oxf) 49:725–731[CrossRef][Medline]
46. Dullaart RP, Meijer S, Marbach P, Sluiter WJ 1992 Effect of somatostatin analogue Octreotide on renal haemodynamics and albuminuria in acromegalic patients. Eur J Clin Invest 22:494–502[Medline]
47. Avagnina P, Martini M, Terzolo M, Sansoe G, Peretti P, Tinivella M, Pia A, Molino G, Angeli A 1996 Assessment of functional liver mass and plasma flow in acromegaly before and after long term treatment with octreotide. Metabolism 45:109–113
48. Evans LM, Davies JS 1998 Heterogeneous haemodynamics in acromegaly: evidence of endothelial dysfunction? Clin Endocrinol (Oxf) 49:711–712[CrossRef][Medline]
49. Maison P, Demolis P, Young J, Schaison G, Guidicelli JF, Chanson P 2000 Vascular reactivity in acromegalic patients: preliminary evidence for regional endothelial dysfunction and increased sympathetic vasoconstruction. Clin Endocrinol (Oxf) 53:445–451[CrossRef][Medline]
50. Brevetti G, Marzullo P, Silvestro A, Pivonello R, Olvia G, Di Somma C, Lombardi G, Colao A 2002 Early vascular alterations in acromegaly. J Clin Endocrinol Metab 87:3174–3179[Abstract/Free Full Text]
51. Colao A, Spiezia S, Cerbone G, Pivanello R, Marzullo P, Ferone D, Di Somma D, Assanti AP, Lombardi G 2001 Increased intima-media thickness by B-M mode echo-Doppler ultrasonography in acromegaly. Clin Endocrinol (Oxf) 54:515–524[CrossRef][Medline]
52. Colao A, Marzullo P, Lombardi G, and the Multicenter Italian Study on Lanreotide 2002 Effect of six months treatment with lanreotide on cardiovascular risk factors and arterial intima-media thickness in patients with acromegaly. Eur J Endocrinol 146:303–309[Abstract]
53. Otsuki M, Kasayama S, Yamamoto H, Saito H, Sumitani S, Kauhara H, Saitah Y, Ohnighi T, Arita N 2001 Characterisation of premature atherosclerosis of carotid arteries in acromegalic patients. Clin Endocrinol (Oxf) 54:791–796[CrossRef][Medline]

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