This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, J. C. Articles by Davies, J. S. Search for Related Content PubMed PubMed Citation Articles by Smith, J. C. Articles by Davies, J. S.

The Effects of Depot Long-Acting Somatostatin Analog on Central Aortic Pressure and Arterial Stiffness in Acromegaly

Departments of Medicine (J.C.S., H.L., N.D., L.M.E., M.F.S., J.S.D.) and Cardiology (J.C.), University Hospital of Wales, Cardiff, CF4 4XN, Wales, United Kingdom

Address all correspondence and requests for reprints to: Dr. Jamie C. Smith, Department of Diabetes and Endocrinology, Old Building, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom. E-mail: jamie.smith{at}virgin.net.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Acromegaly is associated with increased cardiovascular risk. Although conventional risk factors such as glucose intolerance, hypertension, and dyslipidemia probably contribute, there may also be direct effects of GH/IGF-I excess on the vasculature. To study the effects of GH excess on the vasculature, we have assessed arterial stiffness in acromegalic subjects with and without active disease and have investigated the effects of Sandostatin LAR (OCT-LAR) on vascular function.

Sixteen normotensive subjects with acromegaly (10 males and 6 females) and 8 healthy controls were studied. Of the acromegalic subjects, eight had active disease (group A), and eight were cured (GH < 2.5 mU/liter; group B). The three groups were age, sex, and blood pressure matched. Group A subjects were restudied after 3 and 6 months of OCT-LAR therapy. Arterial stiffness was assessed by analyzing central arterial pressure waveforms derived from measured radial artery waveforms. This allowed determination of the augmentation of central pressure and the augmentation index. Lipids, glucose, and IGF-I were also measured.

Comparing the three groups (ANOVA; mean ± SD), the augmentation index was higher in group A (28 ± 12 vs. 12 ± 13%; P < 0.01) but not in group B (22 ± 7 vs. 12 ± 13%; P = 0.60), compared with controls. IGF-I was higher in group A (50.3 ± 21.2 nmol/liter; P < 0.01), compared with group B (22.5 ± 8.9 nmol/liter) and controls (19.5 ± 5.3 nmol/liter). On regression analysis, IGF-I concentration was identified as a strong independent predictor of the augmentation index (ß = 0.50; P = 0.007). There were no significant differences in aortic systolic pressure, aortic diastolic pressure, lipids, or glucose. Compared with baseline, OCT-LAR treatment resulted in a lowering of augmentation index at 3 months (20 ± 15 vs. 28 ± 12%; P < 0.05), but at 6 months (24 ± 16%; P = 0.21) there was no significant change. IGF-I was reduced from 50.3 ± 21.2 nmol/liter at baseline to 31.4 ± 13.2 nmol/liter at 3 months (P < 0.05) and 26.6 ± 15.8 nmol/liter at 6 months (P < 0.05).

In conclusion, acromegaly is associated with changes in the central arterial pressure waveform, suggesting large artery stiffening. This may have important implications for cardiac morphology and performance in acromegaly as well as increasing the susceptibility to atheromatous disease. Large artery stiffness is reduced in cured acromegaly and partially reversed after pharmacological treatment of active disease.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ATHEROSCLEROTIC CARDIOVASCULAR disease is largely responsible for the increased mortality associated with acromegaly (1, 2, 3). Although an increased prevalence of hypertension, glucose intolerance, and dyslipidemia probably contributes, evidence for cardiovascular abnormalities in uncomplicated acromegalics, in whom these coexisting risk factors are not present (4, 5, 6, 7), suggests a direct, deleterious effect of GH or IGF-I excess on the cardiovascular system.

Indeed, there is now increasing evidence for the involvement of the GH/IGF-I axis in the maintenance of cardiovascular homeostasis. Studies of GH-deficient hypopituitary adults have demonstrated impaired cardiac performance and vascular endothelial dysfunction, both of which are reversed by GH replacement (8, 9). In addition, suppression of GH excess with somatostatin analogs improves cardiac performance in acromegaly (10). Furthermore, epidemiological evidence suggests that subtle abnormalities of the GH/IGF-I axis may also play a causative role in the development of atherosclerotic disease (11).

Acromegaly has long been associated with detrimental changes to cardiac morphology and function. The development of concentric hypertrophy of the left ventricle in acromegaly, considered by many to relate to a specific acromegalic cardiomyopathy (12), may arise not only as a consequence of direct effects of GH/IGF-I on cardiomyocytes but also because of changes occurring in the structure and function of the peripheral vasculature.

A number of vascular abnormalities have been described in acromegaly, including preatherosclerotic changes of intima-media thickening in the common carotid arteries (7, 13, 14), reduced cutaneous vascular reactivity in small resistance vessels (6), and impaired flow-mediated dilation of the brachial artery (14). However, large arterial compliance and central hemodynamics have not previously been studied in acromegaly. Furthermore, the effects on large artery function of pharmacological suppression of the GH/IGF-I axis using somatostatin analogs are also unknown.

Healthy arteries are compliant structures capable of buffering the pressure changes that occur during the cardiac cycle. Energy is absorbed during systole and released during diastole, resulting in smooth peripheral blood flow and the maintenance of diastolic coronary perfusion. Antegrade arterial pressure waves are reflected back from the periphery, arriving in the central arteries after the central systolic pressure peak (15). However, as arteries stiffen, profound changes occur in the arterial pressure waveform. Pulse wave velocity increases, and this results in the reflected wave arriving earlier, thus adding to the central pressure wave to produce an augmented central systolic pressure (16). Elevated central pressure associated with reduced arterial compliance leads to the subsequent development of left ventricular hypertrophy (16, 17). It is therefore apparent that large artery stiffening, rather than merely being a marker for degenerative physical changes, has important hemodynamic consequences. Clear associations between arterial stiffening and the classical risk factors for atheroma, including age, smoking, hypercholesterolemia, and diabetes (17, 18, 19, 20, 21), have strengthened the concept that arterial stiffness is an important risk factor for the development of cardiovascular disease.

The aims of the present study were to assess arterial stiffness and central arterial hemodynamics in acromegalics with active and inactive disease and to examine the effects of treatment with Sandostatin LAR (OCT-LAR) on these parameters.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Sixteen patients (10 males and 6 females) with acromegaly were recruited from the endocrine clinic at the University Hospital of Wales and studied during a 6-month period. Informed written consent was obtained for each patient, and approval for the study was obtained from the local ethics committee. Acromegaly was diagnosed in keeping with typical clinical features, together with high-mean serum GH levels (from five measurements) during an 8-h time course, not suppressible less than 2 mU/liter after a 75-g oral glucose tolerance test, and by elevated IGF-I concentrations for age.

Patients were divided into two groups: those with active disease (group A), and those who had been cured (group B). Patients were considered cured if they were free of symptoms of active disease and repeatedly had fasting GH levels of less than 5 mU/liter, in association with IGF-I concentrations within the age- and sex-adjusted laboratory normal range. Patients in both groups were matched according to age, sex, and blood pressure. The characteristics of individual patients at entry to the study are shown in Table 1.

Study protocol

Measurements of vascular function and metabolic parameters (lipid profiles, glucose, IGF-I) were performed in all subjects at baseline. Patients with active disease (group A) then received treatment with the long-acting somatostatin analog (OCT-LAR; Novartis, Basel, Switzerland) at a starting dose of 10 mg, administered by monthly im injection. Two patients had previously received treatment with sc octreotide immediately before study entry. In these patients, a washout period of 1 month was applied before commencement of OCT-LAR. Dosage adjustments were made at 3 months according to symptom response and results of GH day profiles. Measurements of vascular function and metabolic parameters were repeated at 3 and 6 months after initiation of treatment.

Pulse wave analysis

Arterial stiffness and central aortic pressure were measured noninvasively by the technique of pulse wave analysis using the SphygmoCor apparatus (Version 6.01; AtCor, Sydney, Australia) as developed by O’Rourke and Gallagher (22). All measurements were taken from the radial artery at the wrist using a micromanometer (SPC-301; Millar Instruments, Houston, TX), applying the principle of applanation tonometry to flatten the artery by gentle pressure. Data were collected directly into a desktop computer and processed by the system software to allow accurate on-line recording of the radial artery waveform. The corresponding aortic pressure waveform can then be generated from an averaged radial artery waveform (derived from 20 sequentially recorded radial artery waveforms) using a validated transfer factor (22, 23, 24). Computerized analysis of the central waveform allows determination of the augmentation, the augmentation index, central aortic pressure, and the timing of wave reflection. The augmentation index is defined as the difference between the first and second peaks of the central arterial waveform, expressed as a percentage of the pulse pressure (22). The timing of the reflected wave, determined by calculating the time between the foot of the pressure wave and the inflection point, provides an estimation of aortic pulse wave velocity (25). Radial blood pressure was calibrated against brachial blood pressure, which was measured using conventional mercury sphygmomanometry. All subjects were studied in the fasting state. Two sequential measurements were taken on each subject, and from these the mean augmentation, augmentation index, timing of the reflected wave, and central aortic pressure were calculated. All measurements were performed by a single operator. Reproducibility of the augmentation index using the SphygmoCor apparatus was determined using methodology described elsewhere (26). The mean difference ± SD between repeated measurements of the augmentation index was 0.84 ± 4.0%.

Biochemical assays

Each subject was studied after an overnight fast with measurement of IGF-I, lipid profile, and plasma glucose. Total cholesterol and triglyceride concentrations were measured enzymatically using standard techniques. High-density lipoprotein (HDL) cholesterol was measured after precipitation of apolipoprotein B with phosphotungstate/magnesium. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedwald equation. IGF-I was measured after prior acid-ethanol extraction by polyethylene glycol-assisted second antibody RIA.

Statistical analyses

All statistical analyses were performed using SPSS for Windows (version 9.0; SPSS, Inc., Chicago, IL). Data are expressed as mean values ± SD. Statistical comparisons between groups were made using ANOVA. Post hoc analysis was then performed by pairwise multiple comparisons using the least significant difference test to determine which means differed. The relationship between variables was evaluated by stepwise multiple regression analysis. Within-group comparisons for treatment effects over time were performed using ANOVA, paired t tests, and the Wilcoxon test (nonparametric variables). A P value of less than 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline comparisons

Comparison of biochemical parameters and vascular function between the three groups (A, B, and C) is shown in Table 2. There were no differences in lipoprotein or glucose concentrations between the groups. IGF-I concentrations were significantly higher in the active disease group (group A; 50.3 ± 21.2 nmol/liter; P < 0.001) but did not differ between cured subjects (group B; 22.5 ± 8.9 nmol/liter) and healthy controls (group C; 19.5 ± 5.3 nmol/liter). Resting heart rate and peripheral brachial artery systolic and diastolic pressure were similar between groups. However, pulse wave analysis revealed differences in central hemodynamic indices. Group A subjects with active acromegaly had a higher augmentation of central arterial pressure (11 ± 5 mm Hg vs. 5 ± 6 mm Hg; P < 0.05) and a higher augmentation index (28 ± 12% vs. 12 ± 13%; P < 0.01), compared with healthy controls (Fig. 1). There were no significant differences in hemodynamic indices between cured subjects (group B) and healthy controls (group C).

View larger version (28K): [in this window] [in a new window]   Figure 1. Comparisons of augmentation index (AIx) and IGF-I between the three groups (mean ± SE). A, Active acromegaly; B, cured acromegaly. *, P < 0.01 in comparison with healthy controls.

In group A subjects, treatment with OCT-LAR resulted in a significant lowering of IGF-I, from 50.3 ± 21.2 nmol/liter at baseline to 31.4 ± 13.2 nmol/liter (P < 0.05) at 3 months and 26.6 ± 15.8 nmol/liter (P < 0.05) at 6 months. There were no significant effects on lipid profiles or glucose concentrations over the 6-month period. The effects of OCT-LAR on vascular function are shown in Table 4. Augmentation index was lowered significantly after 3 months of OCT-LAR treatment. However, this initial lowering of augmentation index was not sustained in statistical terms after 6 months of treatment (P = 0.21). There were no significant treatment effects on brachial artery pressure, central aortic pressure, or timing of wave reflection over the 6-month period.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

In contrast, individuals who had physical and biochemical evidence of cured disease had large artery function that did not differ significantly from that in healthy controls. Because patients in the study were normotensive and had normal glucose tolerance, these results suggest a direct deleterious effect of GH excess on large artery function. Suppression of GH/IGF-I activity with the somatostatin analog, OCT-LAR, resulted in an improvement in arterial stiffness after a 3-month period, as evidenced by a significant reduction in the augmentation index. However, this improvement was not sustained over a 6-month period.

Evaluating vascular function and cardiovascular risk in hypopituitary adults is complicated because of the heterogeneous nature of hypopituitarism. In the present study, it is possible that hormonal deficiencies contributed to the observed vascular abnormalities. Unphysiological corticosteroid replacement and inadequate sex hormone replacement may both play a role in increasing cardiovascular risk in hypopituitarism (27). In addition, untreated hypothyroidism is associated with detrimental changes to arterial function, although these changes are reversible after adequate thyroid hormone replacement (28). In the present study, all patients were adequately treated with L-thyroxine such that T₄ concentrations were maintained within the target laboratory range.

As arteries stiffen, profound changes occur to the arterial pressure waveform as a result of structural and functional changes to both large and small arteries. Large artery stiffening results in an increase in the speed of wave travel, and functional changes in smaller arteries at peripheral reflectance sites enhance reflection of the wave. Stiffening throughout the vascular tree therefore results in early return of the reflected wave, together with increased amplitude of the returning wave, both of which contribute to an augmented central systolic pressure (16).

The mitogenic effects of GH excess on cardiomyocytes have been extensively investigated and undoubtedly explain a major component of the abnormal cardiac structure and function observed in acromegaly (12). However, because the heart is a pump, its function needs to be considered in the context of maintaining cardiac output via the vascular tree. Thus, cardiac performance is determined not only by local ventricular mechanical factors but also by the opposition to contraction imposed by the vascular tree against which the heart must pump. Our observations in normotensive acromegalics of elevated aortic peak systolic pressure resulting from enhanced wave reflection are similar to those described in other conditions that are associated with large artery stiffening, including systemic hypertension, diabetes, and aging itself (16). Indeed, myocardial hypertrophy with increased contractile mass constitutes one of the principle compensatory mechanisms whereby the heart adapts to a chronically increased afterload (29). However, in acromegaly the situation is complex because GH exerts a potent hypertrophic stimulus on left ventricular mass leading to increased wall thickness (4, 5). Thus, despite reduced large arterial compliance and elevated central pressure, left ventricular wall stress is actually reduced. The relative contribution of arterial stiffening in the genesis of the observed cardiac abnormalities in acromegaly is unclear at present.

There has been relatively little study of vascular structure and function in acromegaly. A previous study of carotid intima-media thickening comparing acromegalics with controls matched for cardiovascular risk factors showed intima-media thickness to be more pronounced in controls (30), suggesting an antiatherogenic effect of GH excess. However, in contrast, other studies have reported both structural and functional vascular abnormalities in acromegaly. Increased intima-media thickening has been demonstrated in acromegalics with both active (13, 14) and cured disease (13). Brevetti et al. (14) also demonstrated that flow-mediated dilation of the brachial artery was significantly impaired in patients with active disease compared with those with cured acromegaly. In addition, endothelium-dependent dilation of small cutaneous vessels was reduced in a group of 10 normotensive acromegalics compared with matched controls (6).

Although stiffening of the vascular tree is determined to a large extent by irreversible, structural changes such as those that occur with aging (31), the mechanical properties of large arteries are also regulated by vasoactive mediators. Indeed, we and others have recently shown that nitric oxide (NO), in part, regulates large arterial stiffness (32, 33). Our present findings in acromegaly of altered central arterial pressure waveforms associated with arterial stiffening may therefore arise due to impaired release of endothelium-derived NO, as demonstrated in other disease states including diabetes (34) and GH deficiency (9). Our observations that arterial stiffness is reduced in cured acromegalics and partially reduced in patients with active disease after suppression of the GH/IGF-I axis with OCT-LAR further supports the notion that arterial compliance in acromegaly is modulated, at least in part, by functional factors.

Because conventional risk factors, including dyslipidemia, glucose intolerance, and hypertension have been controlled for in the present study, a direct effect of GH excess on vascular physiology may be responsible for the observed findings. Our observation that IGF-I concentration was independently predictive of augmentation index further supports this hypothesis. IGF-I is known to have vasoregulatory properties that are linked directly with the L-arginine/NO pathway. Endothelial cells possess binding sites for IGF-I, and in vitro studies in animal models have identified IGF-I as an endothelium-dependent vasodilator (35, 36). In humans, the vasodilating effects of IGF-I in the forearm circulation can be blocked by L-N^G-monomethylarginine (37), suggesting that IGF-I-mediated vasodilatation occurs via an NO-dependent mechanism. Furthermore, in the low IGF-I state of adult GHD, restoration of physiological levels of IGF-I results in an improvement of NO bioavailability and vascular reactivity (9, 38). Intuitively, increased levels of IGF-I in acromegaly might therefore be expected to produce an increase in arterial compliance via an NO-mediated effect. The fact that the opposite seems to occur suggests that other mechanistic factors are likely to be responsible for vascular abnormalities in acromegaly. Further study will be required to elucidate these mechanisms.

In conclusion, acromegalics without overt cardiovascular disease show alterations in central arterial pressure waveforms, which arise because of enhanced wave reflection associated with large artery stiffening. Altered central hemodynamics may have important implications for cardiac morphology and performance in acromegaly, as well as increasing the susceptibility to atheromatous disease. Observations that these changes are attenuated in cured acromegaly and are partially reversed after pharmacological suppression of the GH/IGF-I axis suggest a functional component to arterial stiffness related to a direct deleterious effect of GH excess on vascular function.

	Acknowledgments

 
We thank the Department of Biochemistry at the University Hospital of Wales for blood sample analysis.

	Footnotes

 
J.C. is supported by the British Heart Foundation.

Abbreviations: HDL, High-density lipoprotein; LDL, low-density lipoprotein; NO, nitric oxide.

Received November 7, 2002.

Accepted February 10, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Wright AD, Hill DM, Lowy C, Russell-Fraser T 1970 Mortality in acromegaly. Q J Med 153:1–16
2. 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]
3. Nabarro JDN 1987 Acromegaly. Clin Endocrinol (Oxf) 26:481–512[Medline]
4. Fazio S, Cittadini A, Sabatini D, Merola B, Colao AM, Biondi B, Lombardi G, Sacca L 1993 Evidence for biventricular involvement in acromegaly: a Doppler echocardiographic study. Eur Heart J 14:26–33[Abstract/Free Full Text]
5. Fazio S, Cittadini A, Biondi B, Palmieri EA, Riccio G, Bone F, Oliviero U, Sacca L 2000 Cardiovascular effects of short-term growth hormone hypersecretion. J Clin Endocrinol Metab 85:179–182[Abstract/Free Full Text]
6. Maison P, Demolis P, Young J, Schaison G, Giudicelli J-F, Chanson P 2000 Vascular reactivity in acromegalic patients: preliminary evidence for regional endothelial dysfunction and increased sympathetic vasoconstriction. Clin Endocrinol (Oxf) 53:445–451[CrossRef][Medline]
7. Colao A, Spinelli L, Cuocolo A, Spiezia S, Pivonello R, di Somma C, Bonaduce D, Salvatore M, Lombardi G 2002 Cardiovascular consequences of early-onset growth hormone excess. J Clin Endocrinol Metab 87:3097–3104[Abstract/Free Full Text]
8. Cittadini A, Cuocolo A, Merola B, Fazio S, Sabatini D, Nicolai E, Colao A, Longobardi S, Lombardi G, Sacca L 1994 Impaired cardiac performance in GH-deficient adults and its improvement after GH replacement. Am J Physiol 267:E219–E225
9. Smith JC, Evans LM, Wilkinson I, Goodfellow J, Cockcroft JR, Scanlon MF, Davies JS 2002 Effects of GH replacement on endothelial function and large-artery stiffness in GH-deficient adults: a randomized, double-blind, placebo-controlled study. Clin Endocrinol (Oxf) 56:493–501[CrossRef][Medline]
10. Merola B, Cittadini A, Colao A, Ferone D, Fazio S, Sabatini D, Biondi B, Sacca 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. Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T 2002 Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 106:939–944[Abstract/Free Full Text]
12. Sacca L, Cittadini A, Fazio S 1994 Growth hormone and the heart. Endocr Rev 15:555–573[Abstract]
13. Colao A, Spiezia S, Cerbone G, Pivonello R, Marzullo P, Ferone D, Di Somma C, Assanti AP, Lombardi G 2001 Increased arterial intima-media thickness by B-M mode echodoppler ultrasonography in acromegaly. Clin Endocrinol (Oxf) 54:515–524[CrossRef][Medline]
14. Brevetti G, Marzullo P, Silvestro A, Pivonello R, Oliva 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]
15. Karamanoglu M, Gallagher DE, Avolio AP, O’Rourke MF 1994 Functional origin of reflected pressure waves in a multibranched model of the human arterial system. Am J Physiol 267:H1681–H1688
16. O’Rourke MF, Kelly RP 1993 Wave reflection in the systemic circulation and its implications in ventricular function. J Hypertens 11:327–337[Medline]
17. Saba PS, Roman MJ, Pini R, Spitzer M, Ganau A, Devereux RB 1993 Relation of arterial pressure waveform to left ventricular and carotid anatomy in normotensive subjects. J Am Coll Cardiol 22:1873–1880[Abstract]
18. Arnett DK, Evans GW, Riley WA 1994 Arterial stiffness: a new cardiovascular risk factor. Am J Epidemiol 140:669–682[Free Full Text]
19. Glasser SP, Arnett DK, McVeigh GE, Finkelstein SM, Bank AJ, Morgan DJ, Cohn JN 1997 Vascular compliance and cardiovascular disease: a risk factor or a marker? Am J Hypertens 10:1175–1189[CrossRef][Medline]
20. Wilkinson IB, MacCullum H, Rooijmans DF, Murray GD, Cockcroft JR, McKnight JA, Webb DJ 2000 Increased augmentation index and systolic stress in subjects with type 1 diabetes mellitus. Q J Med 93:441–448
21. Wilkinson IB, Prasad K, Hall IR, Thomas A, MacCallum H, Webb DJ, Frenneaux MP, Cockcroft JR 2002 Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia. J Am Coll Cardiol 39:1005–1011[Abstract/Free Full Text]
22. O’Rourke MF, Gallagher DE 1996 Pulse wave analysis. J Hypertens 14(Suppl 5):S147–S157
23. Karamanoglu M, O’Rourke MF, Avolio AP, Kelly RP 1993 An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. Eur Heart J 14:160–167[Abstract/Free Full Text]
24. Pauca AL, O’Rourke MF, Kon KD 2001 Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension 38:932–937[Abstract/Free Full Text]
25. Murgo JP, Westerhof N, Giolma JP, Altobelli SA 1980 Aortic input impedance in normal man: relationship to pressure waveforms. Circulation 62:105–116[Free Full Text]
26. Wilkinson IB, Fuchs SA, Jansen IM, Spratt JC, Murray GD, Cockcroft JR, Webb DJ 1998 Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis. J Hypertens 16:2079–2084[CrossRef][Medline]
27. Tomlinson JW, Holden N, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM 2001 Association between premature mortality and hypopituitarism. Lancet 357:425–431[CrossRef][Medline]
28. Obuobie K, Smith J, Evans LM, John R, Davies JS, Lazarus JH 2002 Increased central arterial stiffness in hypothyroidism. J Clin Endocrinol Metab 87:4662–4666[Abstract/Free Full Text]
29. Grossman W, Jones D, McLaurin LP 1975 Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56–64
30. Otsuki M, Kasayama S, Yamamoto H, Saito H, Sumitani S, Kauhara H, Saitah Y, Ohnighi T, Arita N 2001 Characterization of premature atherosclerosis of carotid arteries in acromegalic patients. Clin Endocrinol (Oxf) 54:791–796[CrossRef][Medline]
31. O’Rourke MF 1999 Wave travel and reflection in the arterial system. J Hypertens 17(Suppl):S45–S47
32. Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, Ganz P 2001 Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 38:1049–1053[Abstract/Free Full Text]
33. Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft JR 2002 Nitric oxide regulates local arterial distensibility in vivo. Circulation 105:213–217[Abstract/Free Full Text]
34. Goodfellow J, Ramsey MW, Luddington LA, Jones CJ, Coates PA, Dunstan F, Lewis MJ, Owens DR, Henderson AH 1996 Endothelium and inelastic arteries: an early marker of vascular dysfunction in non-insulin dependent diabetes. Br Med J 312:744–745[Free Full Text]
35. Haylor J, Singh I, el Nahas AM 1991 Nitric oxide inhibitor prevents vasodilation by insulin-like growth factor 1. Kidney Int 39:333–335[Medline]
36. Wu HY, Yue CJ, Chyu KY, Hsueh WA, Chan TM 1994 Endothelial-dependent vascular effects of insulin and insulin-like growth factor 1 in the perfused rat mesenteric artery and aortic ring. Diabetes 43:1027–1032[Abstract]
37. Fryburg DA 1996 N^G-monomethyl-L-arginine inhibits the blood flow but not the insulin-like response of forearm muscle to IGF-I. Possible role of nitric oxide in muscle protein synthesis. J Clin Invest 97:1319–1328[Medline]
38. Boger RH, Skamira C, Bode-Buger SM, Brabant G, von zur Muhlen A, Frolich JC 1996 Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind, placebo-controlled study. J Clin Invest 98:2706–2713[Medline]

This article has been cited by other articles:

				J. J. Puder, S. Nilavar, K. D. Post, and P. U. Freda Relationship between Disease-Related Morbidity and Biochemical Markers of Activity in Patients with Acromegaly J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 1972 - 1978. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, J. C. Articles by Davies, J. S. Search for Related Content PubMed PubMed Citation Articles by Smith, J. C. Articles by Davies, J. S.