The clinical presentation and management of carcinoid heart disease

International Journal of Cardiology 173 (2014) 29–32

Contents lists available at ScienceDirect

International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

The clinical presentation and management of carcinoid heart disease R. Dobson a,e,⁎, M.I. Burgess a,b, D.M. Pritchard c,d, D.J. Cuthbertson a,e a

Neuroendocrine Tumour Group, University Hospital Aintree, Lower Lane, Liverpool, L9 7AL, UK Department of Cardiology, University Hospital Aintree, Lower Lane, Liverpool, L9 7AL, UK c Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, L69 3GE, UK d Neuroendocrine Tumour Group, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK e Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, L69 3GA, UK b

a r t i c l e

i n f o

Article history: Received 13 September 2013 Received in revised form 14 February 2014 Accepted 22 February 2014 Available online 28 February 2014 Keywords: Carcinoid heart disease Valve surgery Management

a b s t r a c t Carcinoid heart disease is a major cause of morbidity and mortality in patients with metastatic neuroendocrine tumours (NETs). Although cases of carcinoid syndrome and severe carcinoid heart disease requiring urgent intervention are well described, many patients with significant carcinoid heart disease may have insidious symptoms or even be asymptomatic. As haemodynamically significant carcinoid heart disease may be clinically silent, specific and individualised considerations must be made as to the most appropriate clinical criteria and time point at which surgical valve replacement should be undertaken in patients with carcinoid heart disease. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Carcinoid heart disease (Hedinger syndrome) is a major cause of morbidity and mortality in patients with metastatic neuroendocrine tumours (NETs). These tumours are rare, occurring in 1.2–2.1 per 100,000 people [1], but approximately 50% of patients will develop carcinoid syndrome, of which 20–50% will develop carcinoid heart disease [2,3]. Carcinoid heart disease is mediated by vaso-active substances secreted by the tumours, including 5 hydroxytryptamine, (5-HT, serotonin), prostaglandins, histamine and tachykinins which lead to deposition of endocardial plaques composed of fibrous tissue [4]. The deposits occur primarily on the downstream side of the valve leaflets; i.e. on the ventricular aspect of the tricuspid valve and the pulmonary arterial side of the pulmonary valve [5]. The disease is characterised by retraction and fixation of predominantly the right-sided valve leaflets, leading to a combination of valvular regurgitation and stenosis (Fig. 1), which ultimately can progress to right heart failure [6]. The left side of the heart is relatively protected as the lungs filter the vaso-active peptides, inactivating them in the pulmonary circulation before they reach the left atrium. Therefore left sided disease is seen only in patients with bronchial carcinoid or patent foramen ovale or in those with poorly controlled, severe carcinoid syndrome that overwhelms the pulmonary degradative capacity [7].

⁎ Corresponding author at: Clinical Sciences Centre, Aintree University Hospital, Lower Lane, Liverpool, L9 7AL, UK. Tel.: +44 151 529 5917; fax: +44 151 529 5888. E-mail address: [email protected] (R. Dobson).

http://dx.doi.org/10.1016/j.ijcard.2014.02.037 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Valve surgery is the only definitive treatment option for patients with carcinoid heart disease, with contemporary studies now demonstrating significantly improved survival associated with valve replacement compared with studies in previous decades [8,9]. There is no clear consensus surrounding the indications for, and optimum timing of, surgical intervention in patients with carcinoid heart disease.

2. Pathophysiology of carcinoid heart disease The precise pathways responsible for the development of carcinoid heart disease are still uncertain and the disease is likely to be multifactorial. However, there is a strong body of evidence that serotonin is involved in the pathogenic process. Firstly, serotonergic drugs used in the treatment of obesity, migraine and Parkinsons's disease have been demonstrated to cause valvular fibrosis [10]. Secondly, long-term serotonin administration has been shown to induce valvular fibrosis in rats [11]. Thirdly, urinary 5-hydroxyindoleacetic acid (5-HIAA), which is indicative of the amount of serotonin production, is significantly higher in patients with carcinoid heart disease compared to those without cardiac involvement [4,12]. However more than 50% of patients with elevated circulating serotonin levels do not develop carcinoid heart disease [9] and other biochemical mediators, such as activin A [13] and connective tissue growth factor [14] have also been associated with the development of the disease. Distinct from carcinoid heart disease, the myocardium can also be affected by direct infiltration of the neuroendocrine tumour. Myocardial metastases occur in around 4% of patients with metastatic NETs [3]

30

R. Dobson et al. / International Journal of Cardiology 173 (2014) 29–32

Fig. 1. Echocardiographic features of carcinoid heart disease: A. Dilated right heart, with thickened, retracted tricuspid valve leaflets. B. Colour flow Doppler revealing severe jet of tricuspid regurgitation filling a dilated right atrium. C. Continuous wave Doppler showing dense jet of tricuspid regurgitation.

but this may be an underestimation due to the limited resolution of traditional imaging modalities [15]. 3. Multi-modality imaging of carcinoid heart disease Echocardiography is the principal imaging modality used in the assessment of carcinoid heart disease, but other modalities are important, particularly in the quantification of the severity of disease. Cardiac magnetic resonance imaging (MRI) overcomes the issue of sub-optimal visualisation of the right-sided heart valves and has the advantage of enabling accurate quantification of regurgitant volumes and right ventricular ejection fraction [16,17]. This information is pivotal to the decision-making process for the long-term management of the patient. Carcinoid plaques can also be directly visualised using delayedenhancement imaging with gadolinium [18]. Positron emission tomography can also identify cardiac metastases using synthetic radiolabelled octreotide with radio-nuclide tracers such as 68gallium [19] and 18F-dihydroxy-phenyl-alanine [15]. 4. Impact of carcinoid heart disease on symptoms and survival Whilst the majority of patients with severe carcinoid heart disease will present with signs of right heart failure (dyspnoea and peripheral oedema) [1], it is important to note that a substantial proportion of patients with cardiac involvement have no signs or symptoms. Clinical assessment including New York Heart Association (NYHA) classification, and physical examination to identify cardiac murmurs or peripheral oedema are rarely sufficient, even with disease severe enough to warrant valve replacement [20]. There is no evidence that patients with NETs are predisposed to particular cardiac arrhythmias. Neuroendocrine tumours are slow-growing, with well-differentiated tumours (grade 1, proliferative index Ki67 b2%) conferring a median survival of 124 months [21] versus a significantly reduced survival of around 48 months in patients with concomitant carcinoid heart disease [22]. Carcinoid heart disease in conjunction with NYHA class III or IV symptoms has a particularly poor prognosis with a median survival of 11 months [23]. Age and severe tricuspid regurgitation are independent risk factors for death in patients with cardiac involvement [24]. Right sided heart failure caused by carcinoid heart disease is the commonest cause of death in this patient group (around 50%) [25] with tumour progression responsible for around 45% of deaths. These survival data provide further justification for routine cardiac screening of all patients with metastatic NETs and may provide a rationale for earlier and/or more aggressive intervention to prevent symptoms of right heart failure. At our centre all patients with hepatic metastases and/or carcinoid syndrome have annual transthoracic echocardiography to screen for carcinoid heart disease. With regard to the clinical course of cardiac involvement, high urinary 5HIAA levels are a predictor of progression of carcinoid heart disease [26]. This finding was corroborated by Bhattacharyya et al. [27] who demonstrated that a urinary 5HIAA level greater than 300 μmol/24 h and

more than 3 flushing episodes per day are independent predictors of the development or progression of carcinoid heart disease. 5. Guidelines for management of carcinoid heart disease Consensus European Neuroendocrine Tumor Society (ENETs) guidelines state that annual echocardiography is mandatory as part of the routine surveillance of patients with carcinoid heart disease [28]. However, current American and European guidelines do not address the issue of how to best manage patients with asymptomatic or minimally symptomatic carcinoid heart disease [29–32]. Advanced carcinoid heart disease is easy to identify on a transthoracic echocardiogram; however, in the early stages of the disease, the diagnosis can be challenging. Subtle thickening of the tricuspid valve leaflets and subvalvular apparatus, with mild tricuspid regurgitation may be a nonspecific finding and it is for this reason that patients should be screened in a serial fashion, with comparisons made to previous echocardiograms. Echocardiography is the gold standard for the detection of carcinoid heart disease and should be performed by an echo-sonographer with personal experience of at least 200 examinations per year [33]. A variety of biomarkers have been identified for the presence and severity of carcinoid heart disease. The most useful to date is N-terminal pro-brain natriuretic peptide (NT-proBNP) which is recommended in the UK & Ireland Neuroendocrine Tumour Society (UKINETS) guidelines [34] as a screening tool for carcinoid heart disease (level of evidence 1b) in patients with midgut NETs, with or without hepatic metastases, and all patients with the carcinoid syndrome. Chromogranin A has also been shown to be a sensitive marker for cardiac involvement in patients with NETs [35]. As therapeutic options and therefore prognosis, for patients with NETs improve, an awareness of how to best identify and manage carcinoid heart disease, and the optimal time point to consider valve replacement become increasingly important. 6. Medical and surgical interventions for carcinoid heart disease Carcinoid heart disease is a rare, complex disease, and should be managed in a specialist centre, with multi-disciplinary team input from oncologists, cardiologists, endocrinologists, gastroenterologists and surgeons (colorectal, hepatobiliary and cardiothoracic) [5]. A holistic approach is essential in the management of patients with carcinoid heart disease, reflecting the patient's preferred treatment option, the cardiac manifestations of the tumour, and the effect of any cardiac disease on the management of the underlying NET. There is no current evidence to suggest that medical interventions such as somatostatin analogues, hepatic artery embolisation or systemic chemotherapy have a beneficial effect on the progression of valvular disease [26] and bacterial endocarditis prophylaxis is not indicated in patients with carcinoid heart disease [36]. General measures to treat right heart failure, such as the use of loop diuretics and fluid and salt restriction may improve symptoms of oedema. However these measures can be deleterious in advanced right ventricular failure due to depletion of intravascular volume further reducing cardiac output, leading to

R. Dobson et al. / International Journal of Cardiology 173 (2014) 29–32

fatigue and breathlessness [6]. Digoxin is believed to improve right ventricular contractility but there are limited data on its use in patients with pure right heart failure [4]. The best supporting evidence that surgical resection of the underlying tumour retards or prevents carcinoid heart disease comes from Bernheim et al., who demonstrated that hepatic resection of metastases in patients with cardiac involvement was associated with decreased cardiac progression and improved prognosis [37]. However, valve surgery is the only definitive treatment option for those with severe carcinoid heart disease; improving both quality of life and overall survival [22,38]. Patients with carcinoid heart disease represent a high-risk surgical and anesthetic group due to their potential perioperative hemodynamic lability, characterised by flushing, bronchospasm, cardiac arrhythmias and profound peripheral vasodilatation and hypotension (carcinoid crisis) [39]. Furthermore, the distinction between this and reduced cardiac output due to right ventricular dysfunction also poses a challenge for the anesthetist. Acute renal failure is a common, yet difficult to predict post-operative complication, occurring in 22% of patients in one study [40]. An increased risk of bleeding during hepatic resection due to raised venous pressures is another important consideration. The peri-operative use of an octreotide infusion reduces the risk of hypotension and carcinoid crisis [41]. Valve repair, although preferable, is not usually possible due to the degree of leaflet restriction causing post-repair stenosis [1]. The decision regarding which valve prosthesis to implant is complex. Mechanical prostheses were previously recommended because of fear of premature degeneration of the bio-prosthesis due to active carcinoid disease [42]. However bio-prosthetic valves have the advantage of not requiring long term anticoagulation, making subsequent surgical procedures (e.g. hepatic artery embolisation or cytoreductive surgery) less complicated [38]. As peri-operative mortality rates improve and patients are living longer following their valvular surgery, it is clear that decisions regarding which type of prosthesis to implant must be made on individual case-by-case basis. Connolly et al. advocate tricuspid and pulmonary valve replacement with symptomatic carcinoid heart disease affecting both valves following their observation that patients with competent pulmonary valves have a smoother postoperative recovery than patients with a tricuspid valve replacement and pulmonary valvectomy [43]. The authors of this study found that pulmonary valve replacement also has an important impact on post-operative right ventricular size. More recently successful balloon pulmonary valvuloplasty has been described for a patient with carcinoid heart disease causing pulmonary stenosis, who was not suitable for surgery [44]. This may be a useful option for the frailer patient with a high surgical risk, although rapid relapse of symptoms following balloon valvuloplasty has limited its clinical application [7]. 7. Indications for valve surgery Due to the small numbers of patients with carcinoid heart disease, the optimum timing of surgical intervention is unclear with no current consensus regarding the indications for valve surgery. Previously only patients with progressive symptoms despite optimal medical therapy have been considered suitable for valve replacement. However, as moderate to severe right ventricular dilatation and tricuspid regurgitation (with or without symptoms) are associated with an increased risk of death [22,24] and as peri-operative mortality rates decrease, we advocate that patients are referred to a cardiothoracic surgeon early in their disease course, even with the mildest of symptoms. A less contentious indication for valve replacement, which is advocated in the ENETS consensus guidelines [31], is patients with severe carcinoid heart disease, even in the absence of symptoms, with resectable liver metastases [1]. Carcinoid heart disease may be associated with markedly elevated post-sinusoidal pressures causing a pulsatile liver, thereby precluding safe hepatic resection [45]. At our institution the indications for referral to a cardiac surgeon are symptoms of right ventricular failure, a

31

requirement for hepatic surgery, progressive right ventricular dilatation or decline in right ventricular function. 8. Risks of valve replacement for carcinoid heart disease The first cardiac valve surgery for carcinoid heart disease was performed in 1963, with an unacceptably high peri-operative mortality rate of 20–50% [7]. Peri-operative mortality rates following valve replacement range widely in the literature but have improved in recent years (Table 1). Weingarten quoted an overall 13% peri-operative mortality rate in their review of one hundred patients undergoing valve surgery for carcinoid heart disease between 1985 and 2003 [46]. This rate decreased from 28% to 6% over the 18-year period. A similar rate of 18% was quoted by Castillo in 2008 [41]. More recently Mokhles reported a 5% peri-operative mortality rate in their series of 19 patients undergoing valve replacement [8]. With regard to long-term follow-up, their group demonstrated a 71% and 43% survival rate at 1 and 5 years respectively. The improved survival of patients with carcinoid heart disease in recent years may reflect the increasing surgical experience in this field, and better peri-operative management of the patient with Octreotide. In a multivariate analysis of 10 year all cause mortality in patients with carcinoid heart disease Moller demonstrated a hazard ratio of 0.48 (p b 0.001) for cardiac surgery [22]. There are no data on the influence of patient age and co-morbidities on the outcome of valvular surgery for carcinoid heart disease; however, extrapolating from data on valve surgery in general [47], these factors increase peri-operative risk and must be considered before making the decision to operate. 9. Carcinoid heart disease in the asymptomatic patient As previously stated, there is a lack of guidance on the management of patients with carcinoid heart disease who are asymptomatic. Clinical decisions surrounding treatment options for these patients are difficult and should take into account multiple factors such as the patient's wishes, age, co-morbidities, tumour volume, presence of loco-regional or distant metastases and the need for surgical tumour resection. 10. Areas for future research A prospective multi-national registry of patients with carcinoid heart disease undergoing referral to cardio-thoracic surgeons and consideration of valve surgery, detailing their clinical characteristics, surgical interventions and outcome would facilitate the development of evidence-based guidelines for carcinoid heart disease, an important component of NET care. Moreover, data on the progression of carcinoid heart disease are needed to build upon the small numbers of studies in this area [26,27] to enable evidence-based guidelines for the management of patients with asymptomatic or minimally symptomatic carcinoid heart disease. 11. Conclusion Echocardiographic screening for carcinoid heart disease in patients with metastatic NETs, including those with no symptoms is pivotal in the determination of the most appropriate medical and surgical treatment. The management of carcinoid heart disease must be individualised for each patient. Although the optimum timing of valvular surgical intervention remains unclear, we recommend early referral of patients with carcinoid heart disease to a cardiothoracic surgeon to ensure that patients with advanced disease are not disadvantaged by late decisions to operate. Grants/fellowships supporting the paper Investigator initiated research fund awarded to DJC by Ipsen Limited.

32

R. Dobson et al. / International Journal of Cardiology 173 (2014) 29–32

Table 1 Surgical outcomes for valve replacement in carcinoid heart disease. Author; year, type of study

Number of patients

30 day peri-operative mortality

Long term survival

Connolly; 1995 [23] Observational cohort study Robiolio; 1995 [9] Retrospective study Castillo; 2008 [41] Retrospective study Bhattacharyya; 2011 [38] Observational cohort study Mokhles; 2011 [8] Retrospective study

26

35%

40% 2 year survival

8

63%

38% 2 year survival

11

18%

100% at median 21 months (4–75)

22

18%

19

5%

56% 1 44% 2 71% 1 43% 5

Disclosure statement RD, MIB & DMP have nothing to declare. DJC was awarded the research fund stated above.

References [1] Raja SG, Bhattacharyya S, Davar J, Dreyfus GD. Surgery for carcinoid heart disease: current outcomes, concerns and controversies. Future Cardiol 2010;6(5):647–55. [2] Bhattacharyya S, Toumpanakis C, Caplin ME, Davar J. Usefulness of N-terminal ProBrain Natriuretic Peptide as a biomarker of the presence of carcinoid heart disease. Am J Cardiol 2008;102:938–42. [3] Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease: clinical and echocardiographic spectrum in 74 patients. Circulation 1993;87:1188–96. [4] Fox DJ, Khattar RS. Carcinoid heart disease: presentation, diagnosis and management. Heart 2004;90:1224–8. [5] Palaniswamy C, Frishman WH, Aronow WS. Carcinoid heart disease. Cardiol Rev 2012;20:167–76. [6] Bernheim AM, Connolly HM, Hobday TJ, Abel MD, Pellikka PA. Carcinoid heart disease. Prog Cardiovasc Dis 2007;49(6):439–51. [7] Gustafsson BI, Hauso O, Drozdov I, Kidd M, Modlin IM. Carcinoid heart disease. Int J Cardiol 2008;129(3):318–24. [8] Mokhles P, van Herwerden LA, de Jong PL, et al. Carcinoid heart disease: outcomes after surgical valve replacement. Eur J Cardiothorac Surg 2012;41(6):1278–83. [9] Robiolio PA, Rigolin VH, Harrison JK, et al. Predictors of outcome of tricuspid valve replacement in carcinoid heart disease. Am J Cardiol 1995;75:485–8. [10] Bhattacharyya S, Schapira AH, Mikhailidis DP, Davar J. Drug-induced fibrotic valvular heart disease. Lancet 2009;374:577–85. [11] Gustafsson BI, Tommeras K, Nordrum I, et al. Long-term serotonin administration induces heart valve disease in rats. Circulation 2005;111(12):1517–22. [12] Zuetenhorst JM, Bonfrer JMGM, Korse CM, Bakker R, van Tinteren H, Taal BG. 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;97:1609–15. [13] 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. [14] Bergestuen DS, Gravning J, Haugaa KH, et al. Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors. BMC Cancer 2010;10:6. [15] Fiebrich HB, Brouwers AH, Links TP, de Vries EGE. Myocardial metastases of carcinoid visualized by 18F-dihydroxy-phenyl-alanine positron emission tomography. Circulation 2008;118:1602–4. [16] Franzen D, Boldt A, Raute-Kreinsen U, Koerfer R, Erdmann E. Magnetic resonance imaging of carcinoid heart disease. Clin Cardiol 2009;32:E92–3. [17] Klobucic M, Paar MH, Padovan RS, Vincelj J, Fila B. New images in carcinoid heart disease. Cardiovasc J Afr 2012;23:e8-10. [18] Moerman V, Dewilde D, Hermans K. Carcinoid heart disease: typical findings on echocardiography and cardiac magnetic resonance imaging. Acta Cardiol 2012;67:245–8. [19] Bhattacharrya S, Toumpanakis C, Burke M, Taylor AM, Caplin ME, Davar J. Features of carcinoid heart disease identified by 2-and 3-dimensional echocardiography and cardiac MRI. Circulation 2010;3:103–11. [20] 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(3):378–81. [21] Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26(18):3063–72. [22] Moller JE, Pellikka PA, Bernheim AM, Schaff HV, Rubin J, Connolly HM. Prognosis of carcinoid heart disease: analysis of 200 cases over two decades. Circulation 2005;112(21):3320–7. [23] Connolly HM, Nishimura RA, Smith HC, Pellikka PA, Mullany CJ, Kvols LK. Outcome of cardiac surgery for carcinoid heart disease. J Am Coll Cardiol 1995;25:410–6.

year survival year survival year survival year survival

[24] Westberg G, Wanberg B, Ahlman H, Bergh CH, Beckman-Suurkula M, Caidahl K. Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome. Br J Surg 2001;88:865–72. [25] 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;79:339–54. [26] Moller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors associated with progression of carcinoid heart disease. N Engl J Med 2003;348:1005–15. [27] Bhattacharyya S, Toumpanakis C, Chilkunda D, Caplin ME, Davar J. Risk factors for the development and progression of carcinoid heart disease. Am J Cardiol 2011;107:1221–6. [28] Eriksson B, Kloppel G, Krenning E, et al. Consensus guidelines for the management of patients with digestive neuroendocrine tumors—well-differentiated jejunal-ileal tumor/carcinoma. Neuroendocrinology 2008;87:8–19. [29] Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guidelines for the diagnosis and management of neuroendocrine tumors. Pancreas 2010;39:753–66. [30] Caplin M, Sundin A, Nillson O, et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms. Neuroendocrinology 2012;95:88–97. [31] Pape UF, Perren A, Niederle B, et al. ENETS consensus guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology 2012;95:135–56. [32] Kunz PL, Reidy-Lagunes D, Anthony LB, et al. NANETS consensus guidelines for the management and treatment of neuroendocrine tumours. Pancreas 2013;42:557–77. [33] Plockinger U, Gustafsson B, Ivan D, Szpak W, Davar J. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: echocardiography. Neuroendocrinology 2009;90:190–3. [34] Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2012;61:6–32. [35] Korse CM, Taal BG, de Groot CA, Bakker RH, Bonfrer JMG. Chromogranin A and Nterminal Pro-brain Natriuretic Peptide: an excellent pair of biomarkers for diagnostics in patients with neuroendocrine tumor. J Clin Oncol 2009;27:4293–9. [36] Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA guideline update on valvular heart disease: focused update on infective endocarditits. J Am Coll Cardiol 2008;52:676–85. [37] Bernheim AM, Connolly HM, Rubin J, et al. Role of hepatic resection for patients with carcinoid heart disease. Mayo Clin Proc 2008;83(2):143–50. [38] Bhattacharayya S, Raja SG, Toumpanakis C, Caplin ME, Dreyfus GD, Davar J. Outcomes, risks and complications of cardiac surgery for carcinoid heart disease. Eur J Cardiothorac Surg 2011;40:168–72. [39] Castillo JG, Silvay G, Solis J. Current concepts in diagnosis and perioperative management of carcinoid heart disease. Semin Cardiothorac Vasc Anesth 2013;17(3):212–23. [40] Regner KR, Connolly HM, Schaff HV, Albright RC. Acute renal failure after cardiac surgery for carcinoid heart disease: incidence, risk factors, and prognosis. Am J Kidney Dis 2005;45(5):826–32. [41] Castillo JG, Filsoufi F, Adams DH, Raikhelkar J, Zaku B, Fischer GW. Management of patients undergoing multivalvular surgery for carcinoid heart disease; the role of the anaesthetist. Br J Anaesth 2008;101:618–26. [42] Connolly HM, Pellikka PA. Carcinoid heart disease. Curr Cardiol Rep 2006;8:96–101. [43] Connolly HM, Schaff HV, Mullany CJ, Abel MD, Pellikka PA. Carcinoid heart disease: impact of pulmonary valve replacement in right ventricular function and remodeling. Circulation 2002;106:I-51–6. [44] Carrilo-Ferreira P, Silva D, Almeida AG, et al. Carcinoid heart disease: outcome after balloon valvuloplasty. Can J Cardiol 2013;29:751.e7–9. [45] Lillegard JB, Fisher JE, McKenzie TJ, et al. Hepatic resection for the carcinoid syndrome in patients with severe carcinoid heart disease: does valve replacement permit safe hepatic resection? J Am Coll Surg 2011;213:130–8. [46] Weingarten TN, Abel MD, Connolly HM, Schroeder DR, Schaff HV. Intraoperative management of patients with carcinoid heart disease having valvular surgery: a review of one hundred consecutive cases. Anesth Analg 2007;105:1192–9. [47] Jamieson WRE, Edwards FH, Schwartz M, Bero JW, Clark RE, Grover FL. Risk stratification for cardiac valve replacement. national cardiac surgery database. Ann Thorac Surg 1999;67:943–51.