SpringerLink
Log in

Preclinical markers of atherosclerosis in acromegaly: a systematic review and meta-analysis

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Objective

Multiple studies investigated preclinical markers of peripheral vascular damage in acromegaly (ACRO) reporting discordant results. The aim of this study was to run a meta-analysis to examine whether intima media thickness (IMT), flow mediated dilation (FMD) and arterial pulse wave velocity (PWV) are affected in acromegalic patients and to assess the impact of effective treatment of growth hormone excess on these outcomes.

Study selection

Twenty-seven studies comparing ACRO vs control (CON) populations and active (ACT) vs inactive (INACT) ACRO were included in the meta-analysis.

Data synthesis

ACRO compared to CON have higher IMT (ES = 0.83, 95% C.I. 0.35–1.30), p = 0.001, impaired FMD (ES = − 1.59, 95% C.I. − 2.33 to − 0.85, p < 0.0001) and higher PWV (ES = 0.76 95% C.I. 0.37–1.16, p = 0.0001). When patients with ACT vs INACT disease were considered IMT was higher (ES = 0.43, 95% C.I. 0.02–0.84, p = 0.041) and FMD was impaired (ES = − 0.66, 95% C.I. − 1.28 to 0.04, p = 0.038) in ACT patients. Meta-regression analysis of studies comparing IMT in ACT vs INACT acromegalic patients showed a significant and inverse association between the effect size and the percent of hypertensive (p = 0.025) and diabetic (p = 0.041) patients.

Conclusions

IMT, FMD and arterial stiffness are impaired in acromegaly showing that these patients may be at increased risk of atherosclerosis. In patients with active disease these preclinical markers of atherosclerosis are worse compared to patients with inactive disease but the role of diabetes and hypertension is prevailing on growth hormone excess.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Melmed S (2009) Acromegaly pathogenesis and treatment. J Clin Invest 119:3189–3202

    Article  CAS  Google Scholar 

  2. Melmed S (2006) Medical progress: acromegaly. N Engl J Med 355:2558–2573

    Article  CAS  Google Scholar 

  3. Pivonello R, Auriemma RS, Grasso LF, Pivonello C, Simeoli C, Patalano R, Galdiero M, Colao A (2017) Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities. Pituitary 20:46–62

    Article  Google Scholar 

  4. Akutsu H, Kreutzer J, Wasmeier G, Ropers D, Rost C, Mohlig M, Wallaschofski H, Buchfelder M, Schofl C (2010) Acromegaly per se does not increase the risk for coronary artery disease. Eur J Endocrinol 162:879–886

    Article  CAS  Google Scholar 

  5. Mosca S, Paolillo S, Colao A, Bossone E, Cittadini A, Iudice FL, Parente A, Conte S, Rengo G, Leosco D, Trimarco B, Filardi PP (2013) Cardiovascular involvement in patients affected by acromegaly: an appraisal. Int J Cardiol 167:1712–1718

    Article  Google Scholar 

  6. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr (1999) Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340:14–22

    Article  Google Scholar 

  7. Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A (2015) Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis. J Am Heart Assoc 4:e002270

    Article  Google Scholar 

  8. Ben-Shlomo Y, Spears M, Boustred C, May M, Anderson SG, Benjamin EJ, Boutouyrie P, Cameron J, Chen CH, Cruickshank JK, Hwang SJ, Lakatta EG, Laurent S, Maldonado J, Mitchell G, Najjar S, Newman AB, Ohishi M, Pannier B, Pereira T, Vasan RS, Shokawa T, Sutton-Tyrell K, Verbeke F, Wang KL, Webb DJ, Willum Hansen T, Zoungas S (2014) Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol 63:636–646

    Article  Google Scholar 

  9. Hejtmancik MR, Bradfield JY, Herrmann GR (1950) Acromegaly and the heart: a clinical and pathologic study. Ann Intern Med 34:1445–1456

    Google Scholar 

  10. Goldberg MB, Lisser H (1942) Acromegaly: a consideration of its course and treatment. J Clin Endocrinol 2:477–501

    Article  Google Scholar 

  11. Lie JT, Grossman SJ (1980) Pathology of the heart in acromegaly: anatomic findings in 27 autopsied patients. Am Heart J 100:41–52

    Article  CAS  Google Scholar 

  12. Schöfl C, Petroff D, Tönjes A, Grussendorf M, Droste M, Stalla G, Jaursch-Hancke C, Störmann S, Schopohl J (2017) Incidence of myocardial infarction and stroke in acromegaly patients: results from the German Acromegaly Registry. Pituitary 20:635–642

    Article  Google Scholar 

  13. Colao A, Spinelli L, Cuocolo A, Spiezia S, Bonaduce D, Salvatore M, Lombardi G (2002) Cardiovascular consequences of early-onset growth hormone excess. J Clin Endocrinol Metab 87:3097–3104

    Article  CAS  Google Scholar 

  14. Colao A, Marzullo P, Lombardi G (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

    Article  CAS  Google Scholar 

  15. Kršek M, Prázný M, Marek J, Škrha J, Justova V, Lacinova Z (2002) The relationship between serum levels of insulin-like growth factor-I and its binding proteins and microvascular function in acromegalic patients. Growth Horm IGF Res 12:54–59

    Article  Google Scholar 

  16. 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 54:791–796

    Article  CAS  Google Scholar 

  17. 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 54:515–524

    Article  CAS  Google Scholar 

  18. 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

    Article  CAS  Google Scholar 

  19. Galoiu S, Jurcut¸ R, Vlădaia A, Florian A, Purice M, Popescu BA, Ginghina˘ C, Coculescu M (2012) Structural and functional changes of carotid wall properties in patients with acromegaly are not restored after 1 year of GH/IGF1 normalization. Exp Clin Endocrinol Diabetes 120:238–243

    Article  CAS  Google Scholar 

  20. Irving RJ, Carson MN, Webb DJ, Walker BR (2002) Peripheral vascular structure and function in men with contrasting GH levels. J Clin Endocrinol Metab 87:3309–3314

    Article  CAS  Google Scholar 

  21. Matsuda Y, Kawate H, Matsuzaki C, Sakamoto R, Abe I, Shibue K, Kohno M, Adachi M, Ohnaka K, Nomura M, Takayanagi R (2013) Reduced arterial stiffness in patients with acromegaly: noninvasive assessment by the cardio-ankle vascular index (CAVI). Endocr J 60:29–36

    Article  CAS  Google Scholar 

  22. Ozkan H, Celik O, Hatipoglu E, Kantarci F, Kadioglu P (2012) Procalcitonin can be used as a marker of premature atherosclerosis in acromegaly. Pituitary 15:358–364

    Article  CAS  Google Scholar 

  23. Topaloglu O, Sayki Arslan M, Turak O, Ginis Z, Sahin M, Cebeci M, Ucan B, Cakir E, Karbek B, Ozbek M, Cakal E, Delibasi T (2014) Three noninvasive methods in the evaluation of subclinical cardiovascular disease in patients with acromegaly: epicardial fat thickness, aortic stiffness and serum cell adhesion molecules. Clin Endocrinol 80:726–734

    Article  CAS  Google Scholar 

  24. Topsakal S, Akin F, Turgut S, Yaylali GF, Herek D, Ayada C (2015) Relationship of apelin, procalcitonin, and fetuin. A concentrations with carotid intima-media thickness in acromegaly. Ann Clin Biochem 52:456–461

    Article  CAS  Google Scholar 

  25. Turgut S, Topsakal S, Ata MT, Herek D, Akın F, Özkan S, Turgut G (2016) Leptin receptor gene polymorphism may affect subclinical atherosclerosis in patients with acromegaly. Avicenna J Med Biotechnol 8:145–150

    PubMed  PubMed Central  Google Scholar 

  26. Akgul E, Tokgozoglu SL, Erbas T, Kabakci G, Aytemir K, Haznedaroglu I, Oto A, Kes SS (2010) Evaluation of the impact of treatment on endothelial function and cardiac performance in acromegaly. Echocardiography 27:990–996

    Article  Google Scholar 

  27. Baykan M, Erem C, Gedikli Ö, Hacıhasanoglu A, Erdogan T, Kocak M, Kaplan Ş, Korkmaz L, Çelik S (2009) Impairment in flow-mediated vasodilatation of the brachial artery in acromegaly. Med Princ Pract 18:228–232

    Article  Google Scholar 

  28. Boysan SN, Kantarci F, Celik O, Mihmanli I, Gazioglu N, Kadioglu P (2012) Atherosclerotic risk factors and premature atherosclerosis in acromegaly before and after 48 months of octreotide-LAR treatment. Angiology 63:522–527

    Article  CAS  Google Scholar 

  29. Cansu GB, Yılmaz N, Yanıkoğlu A, Özdem S, Yıldırım AB, Süleymanlar S, Altunbaş HA (2017) Assessment of diastolic dysfunction, arterial stiffness and carotid intima media thickness in patients with acromegaly. Endocr Pract 23:536–545

    Article  Google Scholar 

  30. Kartal I, Oflaz H, Pamukc¸u B, Meric M, Aral F, Ozbey N, Alagol F (2010) Investigation of early atherosclerotic changes in acromegalic patients. Int J Clin Pract 64:39–44

    Article  CAS  Google Scholar 

  31. Mullan RJ, Flynn DN, Carlberg B, Tleyjeh IM, Kamath CC, LaBella ML, Erwin PJ, Guyatt GH, Montori VM (2009) Systematic reviewers commonly contact study authors but do so with limited rigor. J Clin Epidemiol 62:138–142

    Article  Google Scholar 

  32. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097

    Article  Google Scholar 

  33. Bolanowski M, Kaluzny M, Daroszewski J, Szuba A (2006) Flow mediated dilatation and svcam concentration as the markers of endothelial dysfunction in patients with acromegaly. Endocrine Abstracts. Program of the 8th European Congress of Endocrinology incorporating the British Endocrine Societies, Glasgow, UK, (Abstract 11 P402)

  34. Ferrau F, Romanello G, Squadrito S, Carerj S, Nipote C, Iudicello R, Trimarchi F, Cannavo S (2008) Systemic comorbidities induce early vascular alterations in patients with active acromegaly Program of the 10th European Congress of Endocrinology of the European Society of Endocrinology, Berlin, Germany, (Abstract 16 P455)

  35. Karaca Z, Dogan H, Ismailogullari S, Kalay N, Tanriverdi F, Unluhizarci K, Caglar AS, Kelestimur F (2016) Cardiovascular effects of obstructive sleep apnea syndrome (OSAS) on acromegaly. Endocrine Abstract. Program of the 18th European Congress of Endocrinology of the Endocrine Society of Endocrinology. Munich, Germany, (Abstract 41 EP919)

  36. De Martino MC, Auriemma RS, Brevetti G, Vitale G, SchianoV Galdiero M, Grasso L, Lombardi G, Colao A, Pivonello R (2010) The treatment with growth hormone receptor antagonist in acromegaly: effect on vascular structure and function in patients resistant to somatostatin analogues. J Endocrinol Invest 33:663–670

    Article  Google Scholar 

  37. Jurcut R, Găloiu S, Florian A, Vlădaia A, Ioniţă OR, Amzulescu MS, Baciu I, Popescu BA, Coculescu M, Ginghina C (2014) Quantifying subtle changes in cardiovascular mechanics in acromegaly: a Doppler myocardial imaging study. J Endocrinol Invest 37:1081–1090

    Article  CAS  Google Scholar 

  38. Lin E, Wexler TL, Nachtigall L, Tritos N, Swearingen B, Hemphill L, Loeffler J, Bille BMK, Klibanski A, Miller KK (2012) Effects of growth hormone deficiency on body composition and biomarkers of cardiovascular risk after definitive therapy for acromegaly. Clin Endocrinol 77:430–438

    Article  CAS  Google Scholar 

  39. Paisley AN, Banerjee M, Rezai M, Schofield RE, Balakrishnannair S, Herbert A, Lawrance JA, Trainer PJ, Cruickshank JK (2011) Changes in arterial stiffness but not carotid intimal thickness in acromegaly. J Clin Endocrinol Metab 96:1486–1492

    Article  CAS  Google Scholar 

  40. Unübol M, Güney E, Türe M, Eryılmaz U (2014) Mean platelet volume and arterial stiffness in patients with acromegaly. Anadolu Kardiyol Derg 14:456–463

    Article  Google Scholar 

  41. Yaron M, Izkhakov E, Sack J, Azzam I, Osher E, Tordjman K, Stern N, Greenman Y (2016) Arterial properties in acromegaly: relation to disease activity and associated cardiovascular risk factors. Pituitary 19:322–331

    Article  CAS  Google Scholar 

  42. Sharma MD, Nguyen AV, Brown S, Robbins RJ (2017) Cardiovascular disease in acromegaly. Methodist Debakey Cardiovasc J 13:64–67

    Article  Google Scholar 

  43. Berg C, Petersenn S, Lahner H, Herrmann BL, Buchfelder M, Droste M, Stalla GK, Strasburger CJ, Roggenbuck U, Lehmann N, Moebus S, Jockel KH, Mohlenkamp S, Erbel R, Saller B, Mann K (2010) Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J Clin Endocrinol Metab 95:3648–3656

    Article  CAS  Google Scholar 

  44. Carmichael JD, Broder MS, Cherepanov D, Chang E, Mamelak A, Said Q, Neary MP, Bonert V (2017) The association between biochemical control and cardiovascular risk factors in acromegaly. BMC Endocr Disord 17:15–20

    Article  Google Scholar 

  45. Lorenz MW, Polak JF, Kavousi M, Mathiesen EB, Völzke H, Tuomainen TP, Kiechl S (2012) Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet 379:2053–2062

    Article  Google Scholar 

  46. Raitakari OT, Celermajer DS (2000) Flow-mediated dilatation. Br J Clin Pharmacol 50:397–404

    Article  CAS  Google Scholar 

  47. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE (1992) Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:1111–1115

    Article  CAS  Google Scholar 

  48. Neunteufl T, Heher S, Katzenschlager R, Wölfl G, Kostner K, Maurer G, Weidinger F (2000) Late prognostic value of flow-mediated dilatation in the brachial artery of patients with chest pain. Am J Cardiol 86:207–210

    Article  CAS  Google Scholar 

  49. Townsend RR (2017) Arterial stiffness: recommendations and standardization. Pulse 4(Suppl 1):3–7

    PubMed  Google Scholar 

  50. Nabarro JDN (1987) Acromegaly. Clin Endocrinol 26:481–512

    Article  CAS  Google Scholar 

  51. Moroni C, Jaffrain-Rea ML, Esposito V, Santoro A, Affricano C, Cantore G, Tamburrano G, Cassone R (2001) Marked improvement in cardiovascular function after successful transsphenoidal surgery in acromegalic patients. Clin Endocrinol 55:307–313

    Article  Google Scholar 

  52. Colao A, Ferone D, Marzullo P, Cappabianca P, Cirillo S, Boerlin V, Lancranjan I, Lombardi G (2001) Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly. J Clin Endocrinol Metab 86:2779–2786

    CAS  PubMed  Google Scholar 

  53. Souadjian JV, Schirger A (1967) Hypertension in acromegaly. Am J Med Sci 254:629–633

    Article  CAS  Google Scholar 

  54. Maffei P, Sicolo N, Plebani M (1999) Lipoprotein(a) in acromegaly. Ann Intern Med 130:537–538

    Article  CAS  Google Scholar 

  55. Ragonese M, Alibrandi A, Di Bella G, Salamone I, Puglisi S, Cotta OR, Torre ML, Ferrau F, Ruggeri RM, Trimarchi F, Cannavo S (2014) Cardiovascular events in acromegaly: distinct role of Agatston and Framingham score in the 5-year prediction. Endocrine 47:206–212

    CAS  PubMed  Google Scholar 

  56. Bogazzi F, Battolla L, Spinelli C, Rossi G, Gavioli S, Di Bello V, Cosci C, Sardella C, Volterrani D, Talini E, Pepe P, Falaschi F, Mariani G, Martino E (2007) Risk factors for development of coronary heart disease in patients with acromegaly: a five-year prospective study. J Clin Endocrinol Metab 92:4271–4277

    Article  CAS  Google Scholar 

  57. Cannavo S, Almoto B, Cavalli G, Squadrito S, Romanello G, Vigo MT, Fiumara F, Benvenga S, Trimarchi F (2006) Acromegaly and coronary disease: an integrated evaluation of conventional coronary risk factors and coronary calcifications detected by computed tomography. J Clin Endocrinol Metab 91:3766–3772

    Article  CAS  Google Scholar 

  58. Herrmann BL, Severing M, Schmermund A, Berg C, Budde T, Erbel R, Mann K (2009) Impact of disease duration on coronary calcification in patients with acromegaly. Exp Clin Endocrinol Diabetes 117:417–422

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the University of Padova (ex-60% 2014 to C.P.).

Author information

Authors and Affiliations

  1. Department of Medicine, DIMED, Internal Medicine 3, University of Padua, Via Giustiniani 2, 35128, Padova, Italy

    Matteo Parolin, Francesca Dassie, Chiara Martini, Roberto Mioni, Lucia Russo, Francesco Fallo, Marco Rossato, Roberto Vettor, Pietro Maffei & Claudio Pagano

Authors
  1. Matteo Parolin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesca Dassie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roberto Mioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lucia Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francesco Fallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marco Rossato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Roberto Vettor
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pietro Maffei
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Claudio Pagano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pietro Maffei.

Ethics declarations

Conflict of interest

Pietro Maffei received unrestricted grants from Novartis, Pfizer and Ipsen and has been member of Novartis, Italfarmaco, Pfizer and Ipsen advisory board.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parolin, M., Dassie, F., Martini, C. et al. Preclinical markers of atherosclerosis in acromegaly: a systematic review and meta-analysis. Pituitary 21, 653–662 (2018). https://doi.org/10.1007/s11102-018-0911-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-018-0911-5

Keywords

Search

Navigation