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Carcinoid Heart Disease: a Review

  • Neuroendocrine Neoplasms (NS Reed, Section Editor)
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Abstract

Purpose of Review

The development of carcinoid heart disease (CHD) is a fibrotic complication of neuroendocrine neoplasms (NEN) which is associated with a poor prognosis. This review aims to summarise the clinical features, investigations and management of this condition.

Recent Findings

CHD can affect up to 50% of NET patients with carcinoid syndrome. However, it is often not screened for appropriately and recognised late when patients become symptomatic. A screening strategy with biomarkers and multimodality imaging is necessary for early recognition. Management by an experienced multidisciplinary team with appropriate medical therapeutic strategies and where indicated surgical intervention is needed to optimise clinical outcomes.

Summary

CHD is a poor prognostic factor, but recently, outcomes have improved due to the multidisciplinary approach and centralised care of CHD-NET patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3:1335–42.

    Article  Google Scholar 

  2. Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128(6):1717–51.

    Article  Google Scholar 

  3. • Laskaratos FM, Rombouts K, Caplin M, et al. Neuroendocrine tumors and fibrosis: an unsolved mystery? Cancer. 2017;123(24):4770–90. https://doi.org/10.1002/cncr.31079This review article provides a comprehensive overview of the pathophysiology of fibrosis in neuroendocrine neoplasms.

    Article  PubMed  Google Scholar 

  4. Modlin IM, Shapiro MD, Kidd M. Carcinoid tumors and fibrosis: an association with no explanation. Am J Gastroenterol. 2004;99(12):2466–78. https://doi.org/10.1111/j.1572-0241.2004.40507.x.

    Article  PubMed  Google Scholar 

  5. Gustafsson BI, Hauso O, Drozdov I, et al. Carcinoid heart disease. Int J Cardiol. 2008;129(3):318–24. https://doi.org/10.1016/j.ijcard.2008.02.019.

    Article  CAS  PubMed  Google Scholar 

  6. Fox DJ, Khattar RS. Carcinoid heart disease: presentation, diagnosis, and management. Heart. 2004;90(10):1224–8. https://doi.org/10.1136/hrt.2004.040329.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Grozinsky-Glasberg S, Grossman AB, Gross DJ. Carcinoid Heart Disease: from pathophysiology to treatment--'something in the way it moves'. Neuroendocrinology. 2015;101(4):263–73. https://doi.org/10.1159/000381930.

    Article  CAS  PubMed  Google Scholar 

  8. •• Davar J, Connolly HM, Caplin ME, et al. Diagnosing and managing carcinoid heart disease in patients with neuroendocrine tumors: an expert statement. J Am Coll Cardiol. 2017;69:1288–304 This review is an expert statement that provides a comprehensive overview of the management of carcinoid heart disease.

    Article  Google Scholar 

  9. Møller JE, Pellikka PA, Bernheim AM, et al. Prognosis of carcinoid heart disease: analysis of 200 cases over two decades. Circulation. 2005;112:3320–7.

    Article  Google Scholar 

  10. Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson’s disease. Lancet Neurol. 2007;6(9):826–9. https://doi.org/10.1016/S1474-4422(07)70218-1.

    Article  CAS  PubMed  Google Scholar 

  11. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581–8. https://doi.org/10.1056/NEJM199708283370901.

    Article  CAS  PubMed  Google Scholar 

  12. Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord. 2004;19(6):656–62. https://doi.org/10.1002/mds.20201.

    Article  PubMed  Google Scholar 

  13. Mason JW, Billingham ME, Friedman JP. Methysergide-induced heart disease: a case of multivalvular and myocardial fibrosis. Circulation. 1977;56(5):889–90.

    Article  CAS  Google Scholar 

  14. Roth BL. Drugs and valvular heart disease. N Engl J Med. 2007;356(1):6–9. https://doi.org/10.1056/NEJMp068265.

    Article  CAS  PubMed  Google Scholar 

  15. Rothman RB, Baumann MH, Savage JE, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102(23):2836–41.

    Article  CAS  Google Scholar 

  16. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med. 2007;356(1):39–46. https://doi.org/10.1056/NEJMoa054830.

    Article  CAS  PubMed  Google Scholar 

  17. Fitzgerald LW, Burn TC, Brown BS, et al. Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000;57(1):75–81.

    CAS  PubMed  Google Scholar 

  18. Setola V, Hufeisen SJ, Grande-Allen KJ, et al. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol. 2003;63(6):1223–9. https://doi.org/10.1124/mol.63.6.1223.

    Article  CAS  PubMed  Google Scholar 

  19. Nebigil CG, Hickel P, Messaddeq N, et al. Ablation of serotonin 5-HT(2B) receptors in mice leads to abnormal cardiac structure and function. Circulation. 2001;103(24):2973–9.

    Article  CAS  Google Scholar 

  20. Nebigil CG, Jaffre F, Messaddeq N, et al. Overexpression of the serotonin 5-HT2B receptor in heart leads to abnormal mitochondrial function and cardiac hypertrophy. Circulation. 2003;107(25):3223–9. https://doi.org/10.1161/01.CIR.0000074224.57016.01.

    Article  CAS  PubMed  Google Scholar 

  21. Pena-Silva RA, Miller JD, Chu Y, Heistad DD. Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves. Am J Physiol Heart Circ Physiol. 2009;297(4):H1354–60. https://doi.org/10.1152/ajpheart.00570.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Miller JD, Chu Y, Brooks RM, et al. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol. 2008;52(10):843–50. https://doi.org/10.1016/j.jacc.2008.05.043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325–38. https://doi.org/10.1038/nrneph.2016.48.

    Article  CAS  PubMed  Google Scholar 

  24. Jian B, Xu J, Connolly J, et al. Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol. 2002;161(6):2111–21.

    Article  CAS  Google Scholar 

  25. Bhattacharyya S, Toumpanakis C, Caplin ME, Davar J. Analysis of 150 patients with carcinoid syndrome seen in a single year at one institution in the first decade of the twenty-first century. Am J Cardiol. 2008;101:378–81.

    Article  Google Scholar 

  26. Buchanan-Hughes A, Pashley A, Feuilly M, et al. Carcinoid heart disease: prognostic value of 5- hydroxyindoleacetic acid levels and impact on survival - a systematic literature review. Neuroendocrinology. 2020.

  27. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation. 1993;87(4):1188–96.

    Article  CAS  Google Scholar 

  28. De Jesus T, Luis SA, Ryu JH, et al. Carcinoid heart disease in patients with bronchopulmonary carcinoid. J Thorac Oncol. 2018;13:1602–5.

    Article  Google Scholar 

  29. Westberg G, Wangberg B, Ahlman H, et al. Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome. Br J Surg. 2001;88(6):865–72. https://doi.org/10.1046/j.0007-1323.2001.01798.x.

    Article  CAS  PubMed  Google Scholar 

  30. Denney WD, Kemp WE Jr, Anthony LB, et al. Echocardiographic and biochemical evaluation of the development and progression of carcinoid heart disease. J Am Coll Cardiol. 1998;32(4):1017–22.

    Article  CAS  Google Scholar 

  31. Moller JE, Connolly HM, Rubin J, et al. Factors associated with progression of carcinoid heart disease. N Engl J Med. 2003;348(11):1005–15. https://doi.org/10.1056/NEJMoa021451.

    Article  PubMed  Google Scholar 

  32. • Steeds RP, Sagar V, Shetty S, et al. Multidisciplinary team management of carcinoid heart disease. Endocr Connect. 2019;8:R184–r199 An interesting review article on the multidisciplinary management of carcinoid heart disease.

    Article  CAS  Google Scholar 

  33. • Spada F, Laskaratos F, Crona J, Oleinikov K, Zandee W, Lamarca A, Alonso Gordoa T, Frassoni S, Munir A, Liu M, Panero A, Öberg K. A retrospective multicentre evaluation of the outcomes and management of carcinoid heart disease in patients with advanced midgut NETs: a NET-CONNECT Descriptive Study. Neuroendocrinology 2020; 110. A multicentre study on clinical outcomes of patients with carcinoid heart disease over the last decade.

  34. Bhattacharyya S, Davar J, Dreyfus G, Caplin ME. Carcinoid heart disease. Circulation. 2007;116:2860–5.

    Article  Google Scholar 

  35. Hart EA, Meijs TA, Meijer RCA, et al. Carcinoid heart disease: a guide for screening and timing of surgical intervention. Neth Hear J. 2017;25:471–8.

    Article  CAS  Google Scholar 

  36. Ross EM, Roberts WC. The carcinoid syndrome: comparison of 21 necropsy subjects with carcinoid heart disease to 15 necropsy subjects without carcinoid heart disease. Am J Med. 1985;79(3):339–54.

    Article  CAS  Google Scholar 

  37. Himelman RB, Schiller NB. Clinical and echocardiographic comparison of patients with the carcinoid syndrome with and without carcinoid heart disease. Am J Cardiol. 1989;63(5):347–52.

    Article  CAS  Google Scholar 

  38. Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation. 1995;92(4):790–5.

    Article  CAS  Google Scholar 

  39. Zuetenhorst JM, Bonfrer JM, Korse CM, et al. Carcinoid heart disease: the role of urinary 5-hydroxyindoleacetic acid excretion and plasma levels of atrial natriuretic peptide, transforming growth factor-beta and fibroblast growth factor. Cancer. 2003;97(7):1609–15. https://doi.org/10.1002/cncr.11226.

    Article  CAS  PubMed  Google Scholar 

  40. Bhattacharyya S, Toumpanakis C, Chilkunda D, et al. Risk factors for the development and progression of carcinoid heart disease. Am J Cardiol. 2011;107:1221–6.

    Article  Google Scholar 

  41. Bhattacharyya S, Toumpanakis C, Caplin ME, Davar J. Usefulness of N-terminal pro-brain natriuretic peptide as a biomarker of the presence of carcinoid heart disease. Am J Cardiol. 2008;102:938–42.

    Article  CAS  Google Scholar 

  42. Dobson R, Burgess MI, Valle JW, et al. Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality. Br J Cancer. 2014;111:1703–9.

    Article  CAS  Google Scholar 

  43. Kidd M, Bodei L, Modlin IM. Chromogranin A: any relevance in neuroendocrine tumors? Curr Opin Endocrinol Diabetes Obes. 2016;23:28–37.

    Article  CAS  Google Scholar 

  44. Korse CM, Taal BG, de Groot CA, et al. Chromogranin-A and N-terminal pro-brain natriuretic peptide: an excellent pair of biomarkers for diagnostics in patients with neuroendocrine tumor. J Clin Oncol. 2009;27:4293–9.

    Article  CAS  Google Scholar 

  45. Bergestuen DS, Edvardsen T, Aakhus S, et al. Activin A in carcinoid heart disease: a possible role in diagnosis and pathogenesis. Neuroendocrinology. 2010;92(3):168–77. https://doi.org/10.1159/000318014.

    Article  CAS  PubMed  Google Scholar 

  46. Agha AM, Lopez-Mattei J, Donisan T, et al. Multimodality imaging in carcinoid heart disease. Open Heart. 2019;6:e001060.

    Article  Google Scholar 

  47. • Davar J LO, Caplin M, Toumpanakis C. Features of carcinoid heart disease identified by cardiac computed tomography. J Cardiovasc Comp Tomogr 2020; In press. A recent study on the role of cardiac CT as an imaging modality for the diagnosis and management of carcinoid heart disease.

  48. Askew JW, Connolly HM. Carcinoid valve disease. Curr Treat Options Cardiovasc Med. 2013;15:544–55.

    Article  Google Scholar 

  49. Laskaratos FM, Caplin M. Treatment challenges in and outside a network setting: gastrointestinal neuroendocrine tumours. Eur J Surg Oncol. 2019;45(1):52–9. https://doi.org/10.1016/j.ejso.2018.03.012.

    Article  PubMed  Google Scholar 

  50. Joish VN, Perez-Olle R, Lapuerta P, et al. Burden of carcinoid heart disease in patients with carcinoid syndrome initiating somatostatin analogues. Clin Ther. 2019;41:1716–1723.e1712.

    Article  Google Scholar 

  51. Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–33.

    Article  Google Scholar 

  52. Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–63.

    Article  CAS  Google Scholar 

  53. Pavel M, Gross DJ, Benavent M, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial. Endocr Relat Cancer. 2018;25:309–22.

    Article  CAS  Google Scholar 

  54. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125–35.

    Article  CAS  Google Scholar 

  55. Strosberg J, Wolin E, Chasen B, et al. Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with (177)Lu-dotatate in the phase III NETTER-1 trial. J Clin Oncol. 2018;36:2578–84.

    Article  CAS  Google Scholar 

  56. Davis LM, Nicou N, Martin W, et al. Timing of peptide receptor radiotargeted therapy in relation to cardiac valve surgery for carcinoid heart disease in patients with neuroendocrine metastases and cardiac syndrome. A single-centre study from a centre of excellence. Nucl Med Commun. 2020;41:575–81.

    Article  Google Scholar 

  57. Veen KM, Quanjel TJM, Mokhles MM, et al. Tricuspid valve replacement: an appraisal of 45 years of experience. Interact Cardiovasc Thorac Surg. 2020;30:896–903.

    Article  Google Scholar 

  58. Nguyen A, Schaff HV, Abel MD, et al. Improving outcome of valve replacement for carcinoid heart disease. J Thorac Cardiovasc Surg. 2019;158:99–107.e102.

    Article  Google Scholar 

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Correspondence to Christos Toumpanakis.

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Laskaratos, FM., Davar, J. & Toumpanakis, C. Carcinoid Heart Disease: a Review. Curr Oncol Rep 23, 48 (2021). https://doi.org/10.1007/s11912-021-01031-z

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