Carcinoid heart disease: Current understanding and future directions Chirdeep Patel, MD, a Moses Mathur, MD, MSc, b Ricardo O. Escarcega, MD, b and Alfred A. Bove, MD, PhD b Philadelphia, PA
Carcinoid tumors are rare and aggressive malignancies. A multitude of vasoactive agents are central to the systemic effects of these tumors. The additional burden of cardiac dysfunction heralds a steep decline in quality of life and survival. Unfortunately, by the time carcinoid syndrome surfaces clinically, the likelihood of cardiac involvement is 50%. Although medical therapies such as somatostatin analogues may provide some symptom relief, they offer no mortality benefit. On the other hand, referral to surgery following early detection has shown increased survival. The prompt recognition of this disease is therefore of the utmost importance. (Am Heart J 2014;0:1-7.)
Carcinoid tumors are rare neuroendocrine malignancies that arise from neural crest amine precursor uptake decarboxylation cells. 1 Over the last decade, the incidence in white men and women was noted to be 2.47 and 2.58 per 100,000 population per year, respectively, 2 whereas the incidence in African American men and women was 4.48 and 3.98 per 100,000 population per year, respectively. 3 According to recent data, the greatest incidence of carcinoids is in the gastrointestinal tract (67.5%) and the bronchopulmonary system (25.3%). Within the gastrointestinal tract, most carcinoid tumors occur in the small intestine (41.8%), rectum (27.4%), and stomach (8.7%). 3 Approximately 50% of patients develop symptoms of the carcinoid syndrome in the course of the disease, manifested by episodes of vasomotor changes (flushing and hypo- or hypertension), diarrhea, and bronchospasm. Among those in whom carcinoid syndrome has developed, approximately 50% develop carcinoid heart disease (CHD), which typically causes abnormalities of the right side of the heart. 1 The purpose of this review is to give an overview of the cardiac manifestations of carcinoid tumors.
From the aDrexel University College of Medicine, Division of Cardiology, 245 N 15th St, MS 470, Philadelphia, PA, and bTemple University Hospital, Department of Medicine, Section of Cardiology, 3401 N Broad St, Philadelphia, PA. Submitted August 14, 2013; accepted March 17, 2014. Reprint requests: Moses Mathur, MD, MSc, Department of Medicine, Section of Cardiovascular Diseases, Suite 945, Zone C 3401 N Broad St, Temple University Hospital, Philadelphia, PA, 19140. E-mail: [email protected] http://dx.doi.org/10.1016/j.ahj.2014.03.018 0002-8703 © 2014, Mosby, Inc. All rights reserved.
Pathophysiology The characteristic symptoms of carcinoid syndrome are primarily exerted via a multitude of vasoactive hormones secreted from the primary tumor site. These include serotonin, histamine, bradykinin, tachykinins, prostaglandins, 5-hydroxytryptamine, 5-hydroxytryptophan, chromogranin-A, substance-P, neurotensin, pancreatic polypeptide neurokinin-A, motilin, and atrial natriuretic peptide (ANP). Tumors initially grow in the wall of the intestine and eventually extend beyond the wall into the lymphatic and vascular systems in their proximity. Hematogenous access allows for spread to the liver, lungs, heart, brain, bone, and skin. 4 Involvement of the liver eventually results in impaired hepatic ability to degrade these tumor products and initiation of symptoms. Once metastasized to the liver, the right heart is directly vulnerable to tumor-secreted vasoactive hormones via the inferior vena cava. As detailed below, vasoactive substancessuchas5-HT2B andothershavebeenimplicated in the pathogenesis of valve dysfunction. Carcinoid heart disease is classically characterized by plaque-like deposits of fibrous tissue on the endocardial surfaces of valve leaflets, subvalvular apparatus (chordae and papillary muscles), and cardiac chambers and occasionally within the intima of the pulmonary arteries and the aorta. 5 Simultaneous involvement of both of the right-sided valves (tricuspid and pulmonic) strongly suggests CHD as a likely diagnosis. Although the compositions of the plaques on both right-sided valves are similar, the functional consequences are different. In the pulmonic valve, the plaques deposit on the leaflets, leading to the adherence of pulmonic leaflets with the pulmonary arterial endocardium. Eventually, this leads to a mixture of valvular stenosis and regurgitation. In the tricuspid valve, regurgitation tends to be the predominant feature because the plaques often
2 Patel et al
involve the subvalvular apparatus. 6,7 Compared to the right side of the heart (affected in N90% of cases), the left side is rarely affected because of pulmonary deactivation of hormonal substances in the blood stream. 6 Patent foramen ovale appears to be more common in patients with carcinoid syndrome compared to the general population. Their prevalence has been reported to be as high as 41% in patients with carcinoid syndrome and up to 59% in those with CHD. 8 One series suggests that the prevalence of CHD is significantly higher in patients with patent foramen ovale (76%-88%). 9
From hormones to heart damage The specific mechanism of cardiac plaque formation in carcinoid disease is not fully known. Animal studies have implicated the paraneoplastic effects of excess serotonin, bradykinin, tachykinin, connective tissue growth factor, and transforming growth factor-B. 10 Individually, bradykinin has been shown to induce endocardial injury; and some have postulated the fibrosis to be a healing response of the endocardium to the induced damage. 11 Others have shown tachykinin to be a proliferative agent for the endocardial fibroblasts that lead to plaque formation. Lastly, serotonin appears to play a significant role in stimulating fibroblast growth and fibrogenesis. In actuality, CHD likely results from the effects of all these factors combined. 10 In a 5,743-patient study, 20% of female and 12% of male users of fenfluramine were afflicted with moderate to severe valvular disease. Those exposed to the drug had a 7-fold increase in requiring valvular surgery. 12 Fenfluramine and its active metabolite, norfenfluramine, both stimulate serotonin receptors. The latter is a potent agonist of the 5-HT2B receptors, which are found in abundance on human cardiac valves. The proposed mechanism of damage to cardiac valves is via repeated stimulation of 5-HT2B receptors, leading to inappropriate valve cell division. 13,14 The ergoline dopamine agonists (pergolide, bromocriptine, and cabergoline) used to treat Parkinson disease have also been associated with the occurrence of similar valvular disease. 15 A recent metaanalysis showed valvulopathy in 22% of pergolide users and 34% of carbergoline users compared to only 4% of nonusers. 16 Diagnosis Clinical symptoms of carcinoid disease typically occur between the fifth and seventh decades of life. The classic presentation of diarrhea and flushing is present in 70% and 90% of patients, respectively. Bronchospasm and wheezing are far less common and are only present in 10% to 20% of patients. The vast majority of patients with CHD present with signs of right heart failure. In general, because tricuspid and pulmonic valve abnormalities are well tolerated, patients
American Heart Journal Month Year
tend to have vague symptoms of fatigue and dyspnea on exertion. 17,18 On examination, a palpable right ventricular impulse and presence of a new murmur may suggest cardiac involvement. The auscultatory findings can be subtle in early disease, as the murmurs of tricuspid and pulmonary valve disease may be difficult to detect because of the low pressure in the pulmonary circulation. Cardiac murmurs are audible in 90% of patients at the time of diagnosis. A CHD study investigating the frequency of murmurs (confirmed via echocardiography) found 77% to have a tricuspid regurgitation (TR) murmur, 32% with a pulmonic stenosis murmur, 31% with a pulmonic regurgitation murmur, and only 8% with no audible murmur. 6 Restricted heart rate variability and atrial fibrillation may also be present. 19,20 Jugular venous pressure examination is also important as an early, large v wave may be the first physical examination finding of significant TR. As valvular disease progresses, examination features become readily apparent with progressive peripheral edema, ascites, and pulsatile hepatomegaly. Left-sided valvular disease and left heart failure are rare. Symptoms of mitral or aortic valvular disease and associated heart failure are present in b10% of patients. 10 Excess serotonin plays a central role in most carcinoid tumors. It is broken down by monoamine oxidase and aldehyde dehydrogenase into 5-hydroxyindoleacetic acid (5-HIAA). As 5-HIAA is excreted in urine, its level in a 24-hour urine collection serves as a valuable laboratory test for carcinoid disease. Various studies have shown the sensitivity of 5-HIAA levels to be 75% to 100% and the specificity to be 88% to 100%. 10,21,22 Patients with CHD have been shown, on average, to have 2- to 4-fold higher values of serum serotonin, platelet serotonin, and urinary 5-HIAA excretion. 23 Interestingly, several investigators have linked elevated 5-HIAA levels to progression of CHD. This risk of progression is higher in those with the highest levels of 5-HIAA. 24,25 Additionally, higher urinary 5-HIAA levels are correlated with worse echocardiographic findings. 26 It is important to note that a diet high in tryptophanrich foods may falsely elevate 5-HIAA levels, potentially leading to false-positive results. Conversely, the anti-Parkinson drug levodopa may falsely lower urinary 5-HIAA levels. 1 Serotonin levels are also known to be elevated in the paraganglioma syndrome, which includes extraadrenal pheochromocytomas. Recent studies have focused on the prohormone Nterminal fragment of the brain natriuretic peptide (NTFBNP), which has been shown to have more diagnostic accuracy for CHD than ANP. 27 In addition, the role of NTFBNP in combination with chromogranin-A (CgA) (an established tumor marker for neuroendocrine tumors) 24,28,29 has also been studied. These authors found elevated plasma NTFBNP and CgA levels to be associated with CHD. Here, elevation in plasma levels of both CgA and NTFBNP was associated with greater mortality. 30
American Heart Journal Volume 0, Number 0
Figure 1
Patel et al 3
may also be noted. Lastly, TTE may also help identify pericardial effusions that may result as a consequence of myocardial carcinoid metastases. 6,31,32 In the event of limited TTE study because of poor acoustic windows, CHD may be further characterized using 3-dimensional echocardiography. As demonstrated by Bhattacharyya et al, 33 3-dimensional echocardiography can enhance observation of tricuspid and pulmonic valve anatomy and function, as well as the ability to detect the involvement of chordae and papillary muscles. Advanced image processing tools, such as myocardial deformation analysis (“strain analysis”) via TTE speckletracking, have also been explored. In one study, right ventricular function, detected by strain analysis, was reduced in patients with CHD independent of tricuspid valve dysfunction. 34 This finding implies that cardiac fibrosis occurs in the mural myocardium as well as in the valvular endocardium. The fact that a reduction in right ventricular function was detectable by strain analysis prior to overt valvular damage suggests its possible role in identifying those carcinoid patients that may be at a higher risk for developing overt CHD. 34
Management Most patients diagnosed with CHD have advanced carcinoid disease. The cornerstone of therapy is medical treatment with somatostatin analogues (such as octreotide and lanreotide), as well as standard heart failure therapy. 35
Transthoracic echocardiogram of the tricuspid valve in CHD. A, Right ventricular inflow view demonstrating thickened and retracted anterior and posterior leaflets of the tricuspid valve, resulting in malcoaptation at end-systole. B, Color flow Doppler image showing severe TR as a result of malcoaptation. (RA = right atrium, RV = right ventricle, AL = anterior leaflet of the tricuspid valve, PL = posterior leaflet of the tricuspid valve).
On 2-dimensional transthoracic echocardiogram (TTE), an affected tricuspid valve typically appears thickened. With progression of disease, the leaflets become fixed and remain in half-open position, resulting in regurgitation with some degree of stenosis (Figure 1, A). Color flow Doppler and continuous wave Doppler interrogation may help further characterize the degree of TR (Figures 1, B and 2). Involvement of the pulmonic valve may also lead to thickened appearance with reduced movement. Doppler assessment is even more valuable because clear visualization of the pulmonic valve may be limited by a patient’s anatomy. As a consequence of valvular CHD, the right-sided cardiac chambers may become increasingly dilated and hypokinetic. Ventricular septal wall motion abnormalities
Medical therapy Octreotide is an 8–amino acid peptide that acts on somatostatin receptors to reduce the secretion of vasoactive peptides. 36 Lanreotide is a newer analogue whose pharmacokinetics offer less frequent administration. Treatment with octreotide has been associated with symptomatic improvement and reduced serum serotonin and urinary 5-HIAA levels. Stabilization of tumor growth following octreotide has been noted in approximately 50% of patients in duration ranging from 8 to 16 months, but tumor regression is extremely rare. 37 Unfortunately, a decrease in serotonin levels due to octreotide therapy has not been shown to prevent or decrease the incidence of CHD. In addition, treatment of carcinoid tumor resulting in the regression of valvular disease has not been proven. 38 Cytotoxic chemotherapy is of limited value in carcinoid patients. Multiple drugs, including dacarbazine, interferon-a, doxorubicin, and 5-fluorouracil, have failed to show a significant response. 39,40 Newer chemotherapeutic agents such as toptecan have also failed to show significant improvement. 41 Surgical intervention In the absence of metastatic disease, surgical resection of the primary site is curative. 42 When hepatic metastases are present, initial or delayed surgical debulking could be
4 Patel et al
American Heart Journal Month Year
Figure 2
Transthoracic echocardiogram assessment of the tricuspid valve by continuous wave Doppler. Assessment of the tricuspid regurgitant jet by continuous wave Doppler demonstrating elevated peak velocity, gradient, and triangular-shaped flow envelope, all consistent with severe TR.
considered. The delayed surgical approach is usually reserved for larger initial size tumors, in which case debulking may be attempted after hepatic artery ligation or embolization. 43,44 Hepatic cytoreductive surgery is associated with a higher mean survival rate and should be the preferred therapeutic strategy in operable patients. 45 Current recommendations suggest strong consideration for hepatic resection. Because of the high rate of recurrence after resection (84% at 5 years), surgical debulking is usually a palliative measure rather than a cure. 46
Indications for cardiac surgery The indications for cardiac surgery include progressive fatigue, significantly impaired exercise capacity, and progression of right ventricular failure. 47 Recent studies showing a decrease in mortality rates have expanded the role of surgery in the management of CHD. Although a retrospective study by Moller et al 35 showed a decrease in perioperative mortality from 25% in the 1980s to 9% between 1995 and 2000, studies conducted at other centers recently have shown higher perioperative mortality rates of 18% to 20%. 48,49 Infection, right heart failure, carcinoid crises, and coagulopathy represent the most common causes of perioperative mortality. 48 Most long-term complications are related to the tumor itself. Progression of carcinoid disease is the most common cause of mortality past 30 days after surgery. The other common causes of death include right ventricular failure and infection. 49
Limited data exist for the surgical management of patients with left-sided valvular disease. One study reported surgical treatment of 11 patients who underwent valvular replacement. Aortic valve regurgitation was present in 6 patients, 4 of these patients had aortic valve replacement, and 2 had valve repair. Mitral regurgitation was noted in 7 patients, 6 of whom underwent valve replacement and 1 repair. Among the 9 surgical survivors, 8 had functional improvement in their symptoms, leading to the conclusion that surgery (valvuloplasty or valve repair) should be considered in select patients with left-sided involvement. 50 Although recent studies have demonstrated no significant difference in survival between bioprostheses versus mechanical prostheses, an increase in the use of bioprosthetic valves has been noted. 51–53 Despite medically controlled levels of vasoactive agents, the life expectancy of patients with bioprosthetic valves is still unfortunately lower than that of the bioprosthetic valves themselves. In a study by Bhattacharyya et al, 49 9% (2 out of 22) of patients developed bioprosthesis degeneration during a 26-month median follow-up period. Notably, no patients required reoperation. The exact timetable for the expected deterioration of the bioprosthetics and need for reoperation is not well described. The choice of valve prosthesis should be individualized to patient’s preference, desires, symptoms, and prognosis. The advantages and disadvantages of both valve types should be thoroughly explained to the patient so that he or she is an integral part of the decision-making process.
American Heart Journal Volume 0, Number 0
Intraoperative management The intraoperative management of a patient undergoing surgery is complex and requires a knowledgeable anesthesiologist. Many common medications used during the induction of anesthesia are known to induce the carcinoid crisis. This may result in labile blood pressure with signs of extreme hypo- or hypertension, severe flushing, arrhythmias, and bronchoconstriction. 54 Drugs that are considered to trigger mediator release include opioids (particularly meperidine and morphine), neuromuscular blockers (atracurium, mivacurium, and d-tubocurarine), epinephrine, norepinephrine, dopamine, and isoproterenol. 55 Succinylcholine (mediator release) and thiopental (histamine release) have controversial relative contraindications. 56,57 More recently, anesthetic management of these patients has focused on preventing mediator release with the use of somatostatin analogues. Intraoperative octreotide has been shown to prevent crises during surgery. 56,58 It is therefore recommended that intravenous octreotide (50-100 μg/h) be started at least 2 hours before surgery, with continued infusion for 48 hours after surgery. Patients may also require subcutaneous octreotide, depending on previous somatostatin analog requirements and current control of carcinoid syndrome. 59 Invasive percutaneous therapy Balloon valvuloplasty has been performed to treat pulmonary or tricuspid valves, but the results of the outcomes are mixed. In selected patients, valvuloplasty has produced symptomatic improvement, although rapid recurrent symptoms have been observed as well. 60,61 Prognosis The prognosis of patient’s with carcinoid disease depends on the tumor size, site of origin, metastasis, histology, and presence of the carcinoid syndrome. Carcinoid tumors of less than 1 cm (particularly in the small bowel) have a more favorable prognosis. The rate of nodal and distant metastasis increases with size. Overall 5-year survival for carcinoid tumors of the appendix is 98%, gastric (types I/II) is 81%, rectum is 87%, small intestinal is 60%, colon is 62%, and gastric types III/IV is 33%. 4 Long-term survival is related to excessive urinary excretion of 5-HIAA of N500 μmol in 24 hours, but the main predictor of prognosis is the presence of severe structural and functional abnormalities of the tricuspid valve. 62 Plasma CgA is an independent predictor of prognosis. 63 Natriuretic peptides produced in response to increased wall tension by the atria and ventricles of the heart are also associated with CHD. Increased levels of ANP have been shown to predict a worse prognosis. 23 Involvement of the heart is associated with an increased risk of morbidity and a higher mortality. Pellikka et al 6 showed a reduction in 3-year survival rate
Patel et al 5
associated with the presence of cardiac involvement (31% vs 68%). Development and progression of CHD complicate the carcinoid syndrome and contribute to a worse prognosis. In patients with severe cardiac involvement and well-controlled systemic disease, valve replacement surgery is an effective treatment modality that can relieve intractable symptoms and contribute to improved outcomes. 7
Future directions As noted above, the elevated serum levels of NTFBNP and CgA have been associated with CHD. Further advancements in such neurohormone-based diagnostic techniques may be helpful in early detection. In addition, further developments in ultrasound-imaging based detection, such as strain analysis, could be helpful towards developing a routine screening scheme for CHD in patients with known carcinoid tumors. In addition, the better understanding of the molecular mechanisms underlying the progression of fibrosis in CHD would lead to the development of appropriate targets for targeted molecular therapy. In carcinoid tumors, overexpression of factors associated with promotion of tumor growth and angiogenesis, such as vascular endothelial growth factor and vascular endothelial growth factor receptor subtypes, has been observed. 64 Protein kinase inhibitors with activity targeted to tyrosine kinase receptors may play a role in the future. Another potential target for therapeutic agents may be the rapamycin (mTOR) pathway, as it represents a major regulatory component of energy utilization and proliferation. 65,66 One of the key limitations in developing targeted agents has been the inability to accurately identify targets in a particular tumor. The need to define cross talk between the pathways involved in growth-promoting signals and the integration of tumor microenvironment signaling is therefore a key requirement in developing more effective therapies.
Conclusion Research has implicated the role of various vasoactive agents, particularly serotonin, in the deleterious effects of the carcinoid disease on the heart. Right heart failure associated with the valvular and endomyocardial fibrosis is associated with severe symptomatic functional limitations and survival decline. Early recognition and curative surgeries decrease the likelihood of CHD and confer an excellent prognosis. The innovative and multidisciplinary approach to the therapy of the disease has significantly improved outcomes, although cardiac surgery remains the only modality to benefit mortality. Advances in the fields of pathological research and biochemical engineering leading to targeted antifibrosis therapy combined with the liberal use of cardiac surgery are certain to improve patient outcomes.
6 Patel et al
Acknowledgements We would like to thank Dr Susan Wiegers, Dr Martin Keane, and Dr Pravin Patil for their help with the echocardiographic images presented in this article.
Disclosures Funding: No extramural funding was used to support this work. Conflict of interest: The authors report no conflict of interest.
References 1. Fox DJ, Khattar RS. Carcinoid heart disease: presentation, diagnosis, and management. Heart 2004;90(10):1224-8. 2. Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer 2001;92 (8):2204-10. 3. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97(4):934-59. 4. Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005;128(6):1717-51. 5. Pandya UH, Pellikka PA, Enriquez-Sarano M, et al. Metastatic carcinoid tumor to the heart: echocardiographic-pathologic study of 11 patients. J Am Coll Cardiol 2002;40(7):1328-32. 6. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993;87(4):1188-96. 7. Bernheim AM, Connolly HM, Hobday TJ, et al. Carcinoid heart disease. Prog Cardiovasc Dis 2007;49(6):439-51. 8. Mansencal N, Mitry E, Pilliere R, et al. Prevalence of patent foramen ovale and usefulness of percutaneous closure device in carcinoid heart disease. Am J Cardiol 2008;101(7):1035-8. 9. Mansencal N, Mitry E, Forissier JF, et al. Assessment of patent foramen ovale in carcinoid heart disease. Am Heart J 2006;15(5): 1129.e1-6. 10. Gustafsson BI, Hauso O, Drozdov I, et al. Carcinoid heart disease. Int J Cardiol 2008;129(3):318-24. 11. Oates JA, Melmon K, Sjoerdsma A, et al. Release of a kinin peptide in the carcinoid syndrome. Lancet 1964;1(7332):514-7. 12. Dahl CF, Allen MR, Urie PM, Hopkins PN. Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals. BMC Med 2008;6:34. [34-7015-6-34]. 13. 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. 14. 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. 15. Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease. Lancet Neurol 2007;6(9):826-9. 16. Simonis G, Fuhrmann JT, Strasser RH. Meta-analysis of heart valve abnormalities in Parkinson's disease patients treated with dopamine agonists. Mov Disord 2007;22(13):1936-42. 17. Caplin ME, Buscombe JR, Hilson AJ, et al. Carcinoid tumour. Lancet 1998;352(9130):799-805.
American Heart Journal Month Year
18. Kaplan L. Endocrine tumors of the gastrointestinal tract and pancreas. In: Isselbacher K, Martin J, Braunwald E, eds. Harrison's principles and practices of internal medicine. 13th ed. New York: McGraw-Hill Inc; 1994. p. 1535-42. 19. Hoffmann J, Grimm W, Menz V, et al. Heart rate variability in carcinoid heart disease. Am J Cardiol 1999;83(1):128-31. [A9]. 20. Langer C, Piper C, Vogt J, et al. Atrial fibrillation in carcinoid heart disease: the role of serotonin. A review of the literature. Clin Res Cardiol 2007;96(2):114-8. 21. Kvols LK, Reubi JC. Metastatic carcinoid tumors and the malignant carcinoid syndrome. Acta Oncol 1993;32(2):197-201. 22. Feldman JM. Urinary serotonin in the diagnosis of carcinoid tumors. Clin Chem 1986;32(5):840-4. 23. 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. 24. 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. 25. Bhattacharyya S, Toumpanakis C, Chilkunda D, et al. Risk factors for the development and progression of carcinoid heart disease. Am J Cardiol 2011;107(8):1221-6. 26. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol 2005;89(3):151-60. 27. 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(7): 938-42. 28. Jensen EH, Kvols L, McLoughlin JM, et al. Biomarkers predict outcomes following cytoreductive surgery for hepatic metastases from functional carcinoid tumors. Ann Surg Oncol 2007;14(2):780-5. 29. Sondenaa K, Sen J, Heinle F, et al. Chromogranin A, a marker of the therapeutic success of resection of neuroendocrine liver metastases: preliminary report. World J Surg 2004;28(9):890-5. 30. 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(26):4293-9. 31. Moyssakis IE, Rallidis LS, Guida GF, Nihoyannopoulos PI. Incidence and evolution of carcinoid syndrome in the heart. J Heart Valve Dis 1997;6(6):625-30. 32. Howard RJ, Drobac M, Rider WD, et al. Carcinoid heart disease: diagnosis by two-dimensional echocardiography. Circulation 1982; 66(5):1059-65. 33. Bhattacharyya S, Toumpanakis C, Burke M, et al. Features of carcinoid heart disease identified by 2- and 3-dimensional echocardiography and cardiac MRI. Circ Cardiovasc Imaging 2010;3(1): 103-11. 34. Haugaa KH, Bergestuen DS, Sahakyan LG, et al. Evaluation of right ventricular dysfunction by myocardial strain echocardiography in patients with intestinal carcinoid disease. J Am Soc Echocardiogr 2011; 24(6):644-50. 35. Moller JE, Pellikka PA, Bernheim AM, et al. Prognosis of carcinoid heart disease: analysis of 200 cases over two decades. Circulation 2005;112(21):3320-7. 36. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999;17(2):600-6.
American Heart Journal Volume 0, Number 0
37. Eriksson B, Oberg K. Summing up 15 years of somatostatin analog therapy in neuroendocrine tumors: future outlook. Ann Oncol 1999;10(Suppl 2):S31-8. 38. Leong WL, Pasieka JL. Regression of metastatic carcinoid tumors with octreotide therapy: two case reports and a review of the literature. J Surg Oncol 2002;79(3):180-7. 39. Oberg K, Norheim I, Lundqvist G, Wide L. Cytotoxic treatment in patients with malignant carcinoid tumors. response to streptozocin– alone or in combination with 5-FU. Acta Oncol 1987;26(6):429-32. 40. Ritzel U, Leonhardt U, Stockmann F, Ramadori G. Treatment of metastasized midgut carcinoids with dacarbazine. Am J Gastroenterol 1995;90(4):627-31. 41. Ansell SM, Mahoney MR, Green EM, Rubin J. Topotecan in patients with advanced neuroendocrine tumors: a phase II study with significant hematologic toxicity. Am J Clin Oncol 2004;27(3):232-5. 42. Connolly HM, Nishimura RA, Smith HC, et al. Outcome of cardiac surgery for carcinoid heart disease. J Am Coll Cardiol 1995;25(2):410-6. 43. Eriksson BK, Larsson EG, Skogseid BM, et al. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer 1998;83(11):2293-301. 44. Brown KT, Koh BY, Brody LA, et al. Particle embolization of hepatic neuroendocrine metastases for control of pain and hormonal symptoms. J Vasc Interv Radiol 1999;10(4):397-403. 45. McEntee GP, Nagorney DM, Kvols LK, et al. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990;108(6):1091-6. 46. Sarmiento JM, Heywood G, Rubin J, et al. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003;197(1):29-37. 47. Connolly HM, Schaff HV, Mullany CJ, et al. Carcinoid heart disease: impact of pulmonary valve replacement in right ventricular function and remodeling. Circulation 2002;106(12 Suppl 1):I51-6. 48. Castillo JG, Filsoufi F, Rahmanian PB, et al. Early and late results of valvular surgery for carcinoid heart disease. J Am Coll Cardiol 2008; 51(15):1507-9. 49. Bhattacharyya S, Raja SG, Toumpanakis C, et al. Outcomes, risks and complications of cardiac surgery for carcinoid heart disease. Eur J Cardiothorac Surg 2011;40(1):168-72. 50. Connolly HM, Schaff HV, Mullany CJ, et al. Surgical management of left-sided carcinoid heart disease. Circulation 2001; 104(12 Suppl 1):I36-40. 51. Ridker PM, Chertow GM, Karlson EW, et al. Bioprosthetic tricuspid valve stenosis associated with extensive plaque deposition in carcinoid heart disease. Am Heart J 1991;121(6 Pt 1):1835-8.
Patel et al 7
52. Thorburn CW, Morgan JJ, Shanahan MX, Chang VP. Long-term results of tricuspid valve replacement and the problem of prosthetic valve thrombosis. Am J Cardiol 1983;51(7):1128-32. 53. Schoen FJ, Hausner RJ, Howell JF, et al. Porcine heterograft valve replacement in carcinoid heart disease. J Thorac Cardiovasc Surg 1981;81(1):100-5. 54. Vaughan DJ, Brunner MD. Anesthesia for patients with carcinoid syndrome. Int Anesthesiol Clin 1997;35(4):129-42. 55. Ockert DB, White RD. Anesthetic management of patients with carcinoid heart disease undergoing cardiac surgery: two case reports and a review of previous experience. J Cardiothorac Anesth 1988; 2(5):658-65. 56. Claure RE, Drover DD, Haddow GR, et al. Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management. Can J Anaesth 2000;47(4):334-7. 57. Stoelting R, ed. Pharmacology and physiology in anesthetic practice. 3rd ed. Philadelphia: J.B. Lippincott-Raven Co.; 1999. 58. Marsh HM, Martin Jr JK, Kvols LK, et al. Carcinoid crisis during anesthesia: successful treatment with a somatostatin analogue. Anesthesiology 1987;66(1):89-91. 59. Bhattacharyya S, Davar J, Dreyfus G, Caplin ME. Carcinoid heart disease. Circulation 2007;116(24):2860-5. 60. Onate A, Alcibar J, Inguanzo R, et al. Balloon dilation of tricuspid and pulmonary valves in carcinoid heart disease. Tex Heart Inst J 1993;20(2):115-9. 61. Grant SC, Scarffe JH, Levy RD, Brooks NH. Failure of balloon dilatation of the pulmonary valve in carcinoid pulmonary stenosis. Br Heart J 1992;67(6):450-3. 62. 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. 63. Moran CA, Suster S, Coppola D, Wick MR. Neuroendocrine carcinomas of the lung: a critical analysis. Am J Clin Pathol 2009;131(2):206-21. 64. Silva SR, Bowen KA, Rychahou PG, et al. VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis. Int J Cancer 2011;128(5):1045-56. 65. Bago-Horvath Z, Sieghart W, Grusch M, et al. Synergistic effects of erlotinib and everolimus on bronchial carcinoids and large-cell neuroendocrine carcinomas with activated EGFR/AKT/mTOR pathway. Neuroendocrinology 2012;96(3):228-37. 66. Leung R, Lang B, Wong H, et al. Advances in the systemic treatment of neuroendocrine tumors in the era of molecular therapy. Anticancer Agents Med Chem 2013;13(3):382-8.
Carcinoid tumors are rare and aggressive malignancies. A multitude of vasoactive agents are central to the systemic effects of these tumors. The additional burden of cardiac dysfunction heralds a steep decline in quality of life and survival. Unfortunately, by the time carcinoid syndrome surfaces clinically, the likelihood of cardiac involvement is 50%. Although medical therapies such as somatostatin analogues may provide some symptom relief, they offer no mortality benefit. On the other hand, referral to surgery following early detection has shown increased survival. The prompt recognition of this disease is therefore of the utmost importance. (Am Heart J 2014;0:1-7.)
Carcinoid tumors are rare neuroendocrine malignancies that arise from neural crest amine precursor uptake decarboxylation cells. 1 Over the last decade, the incidence in white men and women was noted to be 2.47 and 2.58 per 100,000 population per year, respectively, 2 whereas the incidence in African American men and women was 4.48 and 3.98 per 100,000 population per year, respectively. 3 According to recent data, the greatest incidence of carcinoids is in the gastrointestinal tract (67.5%) and the bronchopulmonary system (25.3%). Within the gastrointestinal tract, most carcinoid tumors occur in the small intestine (41.8%), rectum (27.4%), and stomach (8.7%). 3 Approximately 50% of patients develop symptoms of the carcinoid syndrome in the course of the disease, manifested by episodes of vasomotor changes (flushing and hypo- or hypertension), diarrhea, and bronchospasm. Among those in whom carcinoid syndrome has developed, approximately 50% develop carcinoid heart disease (CHD), which typically causes abnormalities of the right side of the heart. 1 The purpose of this review is to give an overview of the cardiac manifestations of carcinoid tumors.
From the aDrexel University College of Medicine, Division of Cardiology, 245 N 15th St, MS 470, Philadelphia, PA, and bTemple University Hospital, Department of Medicine, Section of Cardiology, 3401 N Broad St, Philadelphia, PA. Submitted August 14, 2013; accepted March 17, 2014. Reprint requests: Moses Mathur, MD, MSc, Department of Medicine, Section of Cardiovascular Diseases, Suite 945, Zone C 3401 N Broad St, Temple University Hospital, Philadelphia, PA, 19140. E-mail: [email protected] http://dx.doi.org/10.1016/j.ahj.2014.03.018 0002-8703 © 2014, Mosby, Inc. All rights reserved.
Pathophysiology The characteristic symptoms of carcinoid syndrome are primarily exerted via a multitude of vasoactive hormones secreted from the primary tumor site. These include serotonin, histamine, bradykinin, tachykinins, prostaglandins, 5-hydroxytryptamine, 5-hydroxytryptophan, chromogranin-A, substance-P, neurotensin, pancreatic polypeptide neurokinin-A, motilin, and atrial natriuretic peptide (ANP). Tumors initially grow in the wall of the intestine and eventually extend beyond the wall into the lymphatic and vascular systems in their proximity. Hematogenous access allows for spread to the liver, lungs, heart, brain, bone, and skin. 4 Involvement of the liver eventually results in impaired hepatic ability to degrade these tumor products and initiation of symptoms. Once metastasized to the liver, the right heart is directly vulnerable to tumor-secreted vasoactive hormones via the inferior vena cava. As detailed below, vasoactive substancessuchas5-HT2B andothershavebeenimplicated in the pathogenesis of valve dysfunction. Carcinoid heart disease is classically characterized by plaque-like deposits of fibrous tissue on the endocardial surfaces of valve leaflets, subvalvular apparatus (chordae and papillary muscles), and cardiac chambers and occasionally within the intima of the pulmonary arteries and the aorta. 5 Simultaneous involvement of both of the right-sided valves (tricuspid and pulmonic) strongly suggests CHD as a likely diagnosis. Although the compositions of the plaques on both right-sided valves are similar, the functional consequences are different. In the pulmonic valve, the plaques deposit on the leaflets, leading to the adherence of pulmonic leaflets with the pulmonary arterial endocardium. Eventually, this leads to a mixture of valvular stenosis and regurgitation. In the tricuspid valve, regurgitation tends to be the predominant feature because the plaques often
2 Patel et al
involve the subvalvular apparatus. 6,7 Compared to the right side of the heart (affected in N90% of cases), the left side is rarely affected because of pulmonary deactivation of hormonal substances in the blood stream. 6 Patent foramen ovale appears to be more common in patients with carcinoid syndrome compared to the general population. Their prevalence has been reported to be as high as 41% in patients with carcinoid syndrome and up to 59% in those with CHD. 8 One series suggests that the prevalence of CHD is significantly higher in patients with patent foramen ovale (76%-88%). 9
From hormones to heart damage The specific mechanism of cardiac plaque formation in carcinoid disease is not fully known. Animal studies have implicated the paraneoplastic effects of excess serotonin, bradykinin, tachykinin, connective tissue growth factor, and transforming growth factor-B. 10 Individually, bradykinin has been shown to induce endocardial injury; and some have postulated the fibrosis to be a healing response of the endocardium to the induced damage. 11 Others have shown tachykinin to be a proliferative agent for the endocardial fibroblasts that lead to plaque formation. Lastly, serotonin appears to play a significant role in stimulating fibroblast growth and fibrogenesis. In actuality, CHD likely results from the effects of all these factors combined. 10 In a 5,743-patient study, 20% of female and 12% of male users of fenfluramine were afflicted with moderate to severe valvular disease. Those exposed to the drug had a 7-fold increase in requiring valvular surgery. 12 Fenfluramine and its active metabolite, norfenfluramine, both stimulate serotonin receptors. The latter is a potent agonist of the 5-HT2B receptors, which are found in abundance on human cardiac valves. The proposed mechanism of damage to cardiac valves is via repeated stimulation of 5-HT2B receptors, leading to inappropriate valve cell division. 13,14 The ergoline dopamine agonists (pergolide, bromocriptine, and cabergoline) used to treat Parkinson disease have also been associated with the occurrence of similar valvular disease. 15 A recent metaanalysis showed valvulopathy in 22% of pergolide users and 34% of carbergoline users compared to only 4% of nonusers. 16 Diagnosis Clinical symptoms of carcinoid disease typically occur between the fifth and seventh decades of life. The classic presentation of diarrhea and flushing is present in 70% and 90% of patients, respectively. Bronchospasm and wheezing are far less common and are only present in 10% to 20% of patients. The vast majority of patients with CHD present with signs of right heart failure. In general, because tricuspid and pulmonic valve abnormalities are well tolerated, patients
American Heart Journal Month Year
tend to have vague symptoms of fatigue and dyspnea on exertion. 17,18 On examination, a palpable right ventricular impulse and presence of a new murmur may suggest cardiac involvement. The auscultatory findings can be subtle in early disease, as the murmurs of tricuspid and pulmonary valve disease may be difficult to detect because of the low pressure in the pulmonary circulation. Cardiac murmurs are audible in 90% of patients at the time of diagnosis. A CHD study investigating the frequency of murmurs (confirmed via echocardiography) found 77% to have a tricuspid regurgitation (TR) murmur, 32% with a pulmonic stenosis murmur, 31% with a pulmonic regurgitation murmur, and only 8% with no audible murmur. 6 Restricted heart rate variability and atrial fibrillation may also be present. 19,20 Jugular venous pressure examination is also important as an early, large v wave may be the first physical examination finding of significant TR. As valvular disease progresses, examination features become readily apparent with progressive peripheral edema, ascites, and pulsatile hepatomegaly. Left-sided valvular disease and left heart failure are rare. Symptoms of mitral or aortic valvular disease and associated heart failure are present in b10% of patients. 10 Excess serotonin plays a central role in most carcinoid tumors. It is broken down by monoamine oxidase and aldehyde dehydrogenase into 5-hydroxyindoleacetic acid (5-HIAA). As 5-HIAA is excreted in urine, its level in a 24-hour urine collection serves as a valuable laboratory test for carcinoid disease. Various studies have shown the sensitivity of 5-HIAA levels to be 75% to 100% and the specificity to be 88% to 100%. 10,21,22 Patients with CHD have been shown, on average, to have 2- to 4-fold higher values of serum serotonin, platelet serotonin, and urinary 5-HIAA excretion. 23 Interestingly, several investigators have linked elevated 5-HIAA levels to progression of CHD. This risk of progression is higher in those with the highest levels of 5-HIAA. 24,25 Additionally, higher urinary 5-HIAA levels are correlated with worse echocardiographic findings. 26 It is important to note that a diet high in tryptophanrich foods may falsely elevate 5-HIAA levels, potentially leading to false-positive results. Conversely, the anti-Parkinson drug levodopa may falsely lower urinary 5-HIAA levels. 1 Serotonin levels are also known to be elevated in the paraganglioma syndrome, which includes extraadrenal pheochromocytomas. Recent studies have focused on the prohormone Nterminal fragment of the brain natriuretic peptide (NTFBNP), which has been shown to have more diagnostic accuracy for CHD than ANP. 27 In addition, the role of NTFBNP in combination with chromogranin-A (CgA) (an established tumor marker for neuroendocrine tumors) 24,28,29 has also been studied. These authors found elevated plasma NTFBNP and CgA levels to be associated with CHD. Here, elevation in plasma levels of both CgA and NTFBNP was associated with greater mortality. 30
American Heart Journal Volume 0, Number 0
Figure 1
Patel et al 3
may also be noted. Lastly, TTE may also help identify pericardial effusions that may result as a consequence of myocardial carcinoid metastases. 6,31,32 In the event of limited TTE study because of poor acoustic windows, CHD may be further characterized using 3-dimensional echocardiography. As demonstrated by Bhattacharyya et al, 33 3-dimensional echocardiography can enhance observation of tricuspid and pulmonic valve anatomy and function, as well as the ability to detect the involvement of chordae and papillary muscles. Advanced image processing tools, such as myocardial deformation analysis (“strain analysis”) via TTE speckletracking, have also been explored. In one study, right ventricular function, detected by strain analysis, was reduced in patients with CHD independent of tricuspid valve dysfunction. 34 This finding implies that cardiac fibrosis occurs in the mural myocardium as well as in the valvular endocardium. The fact that a reduction in right ventricular function was detectable by strain analysis prior to overt valvular damage suggests its possible role in identifying those carcinoid patients that may be at a higher risk for developing overt CHD. 34
Management Most patients diagnosed with CHD have advanced carcinoid disease. The cornerstone of therapy is medical treatment with somatostatin analogues (such as octreotide and lanreotide), as well as standard heart failure therapy. 35
Transthoracic echocardiogram of the tricuspid valve in CHD. A, Right ventricular inflow view demonstrating thickened and retracted anterior and posterior leaflets of the tricuspid valve, resulting in malcoaptation at end-systole. B, Color flow Doppler image showing severe TR as a result of malcoaptation. (RA = right atrium, RV = right ventricle, AL = anterior leaflet of the tricuspid valve, PL = posterior leaflet of the tricuspid valve).
On 2-dimensional transthoracic echocardiogram (TTE), an affected tricuspid valve typically appears thickened. With progression of disease, the leaflets become fixed and remain in half-open position, resulting in regurgitation with some degree of stenosis (Figure 1, A). Color flow Doppler and continuous wave Doppler interrogation may help further characterize the degree of TR (Figures 1, B and 2). Involvement of the pulmonic valve may also lead to thickened appearance with reduced movement. Doppler assessment is even more valuable because clear visualization of the pulmonic valve may be limited by a patient’s anatomy. As a consequence of valvular CHD, the right-sided cardiac chambers may become increasingly dilated and hypokinetic. Ventricular septal wall motion abnormalities
Medical therapy Octreotide is an 8–amino acid peptide that acts on somatostatin receptors to reduce the secretion of vasoactive peptides. 36 Lanreotide is a newer analogue whose pharmacokinetics offer less frequent administration. Treatment with octreotide has been associated with symptomatic improvement and reduced serum serotonin and urinary 5-HIAA levels. Stabilization of tumor growth following octreotide has been noted in approximately 50% of patients in duration ranging from 8 to 16 months, but tumor regression is extremely rare. 37 Unfortunately, a decrease in serotonin levels due to octreotide therapy has not been shown to prevent or decrease the incidence of CHD. In addition, treatment of carcinoid tumor resulting in the regression of valvular disease has not been proven. 38 Cytotoxic chemotherapy is of limited value in carcinoid patients. Multiple drugs, including dacarbazine, interferon-a, doxorubicin, and 5-fluorouracil, have failed to show a significant response. 39,40 Newer chemotherapeutic agents such as toptecan have also failed to show significant improvement. 41 Surgical intervention In the absence of metastatic disease, surgical resection of the primary site is curative. 42 When hepatic metastases are present, initial or delayed surgical debulking could be
4 Patel et al
American Heart Journal Month Year
Figure 2
Transthoracic echocardiogram assessment of the tricuspid valve by continuous wave Doppler. Assessment of the tricuspid regurgitant jet by continuous wave Doppler demonstrating elevated peak velocity, gradient, and triangular-shaped flow envelope, all consistent with severe TR.
considered. The delayed surgical approach is usually reserved for larger initial size tumors, in which case debulking may be attempted after hepatic artery ligation or embolization. 43,44 Hepatic cytoreductive surgery is associated with a higher mean survival rate and should be the preferred therapeutic strategy in operable patients. 45 Current recommendations suggest strong consideration for hepatic resection. Because of the high rate of recurrence after resection (84% at 5 years), surgical debulking is usually a palliative measure rather than a cure. 46
Indications for cardiac surgery The indications for cardiac surgery include progressive fatigue, significantly impaired exercise capacity, and progression of right ventricular failure. 47 Recent studies showing a decrease in mortality rates have expanded the role of surgery in the management of CHD. Although a retrospective study by Moller et al 35 showed a decrease in perioperative mortality from 25% in the 1980s to 9% between 1995 and 2000, studies conducted at other centers recently have shown higher perioperative mortality rates of 18% to 20%. 48,49 Infection, right heart failure, carcinoid crises, and coagulopathy represent the most common causes of perioperative mortality. 48 Most long-term complications are related to the tumor itself. Progression of carcinoid disease is the most common cause of mortality past 30 days after surgery. The other common causes of death include right ventricular failure and infection. 49
Limited data exist for the surgical management of patients with left-sided valvular disease. One study reported surgical treatment of 11 patients who underwent valvular replacement. Aortic valve regurgitation was present in 6 patients, 4 of these patients had aortic valve replacement, and 2 had valve repair. Mitral regurgitation was noted in 7 patients, 6 of whom underwent valve replacement and 1 repair. Among the 9 surgical survivors, 8 had functional improvement in their symptoms, leading to the conclusion that surgery (valvuloplasty or valve repair) should be considered in select patients with left-sided involvement. 50 Although recent studies have demonstrated no significant difference in survival between bioprostheses versus mechanical prostheses, an increase in the use of bioprosthetic valves has been noted. 51–53 Despite medically controlled levels of vasoactive agents, the life expectancy of patients with bioprosthetic valves is still unfortunately lower than that of the bioprosthetic valves themselves. In a study by Bhattacharyya et al, 49 9% (2 out of 22) of patients developed bioprosthesis degeneration during a 26-month median follow-up period. Notably, no patients required reoperation. The exact timetable for the expected deterioration of the bioprosthetics and need for reoperation is not well described. The choice of valve prosthesis should be individualized to patient’s preference, desires, symptoms, and prognosis. The advantages and disadvantages of both valve types should be thoroughly explained to the patient so that he or she is an integral part of the decision-making process.
American Heart Journal Volume 0, Number 0
Intraoperative management The intraoperative management of a patient undergoing surgery is complex and requires a knowledgeable anesthesiologist. Many common medications used during the induction of anesthesia are known to induce the carcinoid crisis. This may result in labile blood pressure with signs of extreme hypo- or hypertension, severe flushing, arrhythmias, and bronchoconstriction. 54 Drugs that are considered to trigger mediator release include opioids (particularly meperidine and morphine), neuromuscular blockers (atracurium, mivacurium, and d-tubocurarine), epinephrine, norepinephrine, dopamine, and isoproterenol. 55 Succinylcholine (mediator release) and thiopental (histamine release) have controversial relative contraindications. 56,57 More recently, anesthetic management of these patients has focused on preventing mediator release with the use of somatostatin analogues. Intraoperative octreotide has been shown to prevent crises during surgery. 56,58 It is therefore recommended that intravenous octreotide (50-100 μg/h) be started at least 2 hours before surgery, with continued infusion for 48 hours after surgery. Patients may also require subcutaneous octreotide, depending on previous somatostatin analog requirements and current control of carcinoid syndrome. 59 Invasive percutaneous therapy Balloon valvuloplasty has been performed to treat pulmonary or tricuspid valves, but the results of the outcomes are mixed. In selected patients, valvuloplasty has produced symptomatic improvement, although rapid recurrent symptoms have been observed as well. 60,61 Prognosis The prognosis of patient’s with carcinoid disease depends on the tumor size, site of origin, metastasis, histology, and presence of the carcinoid syndrome. Carcinoid tumors of less than 1 cm (particularly in the small bowel) have a more favorable prognosis. The rate of nodal and distant metastasis increases with size. Overall 5-year survival for carcinoid tumors of the appendix is 98%, gastric (types I/II) is 81%, rectum is 87%, small intestinal is 60%, colon is 62%, and gastric types III/IV is 33%. 4 Long-term survival is related to excessive urinary excretion of 5-HIAA of N500 μmol in 24 hours, but the main predictor of prognosis is the presence of severe structural and functional abnormalities of the tricuspid valve. 62 Plasma CgA is an independent predictor of prognosis. 63 Natriuretic peptides produced in response to increased wall tension by the atria and ventricles of the heart are also associated with CHD. Increased levels of ANP have been shown to predict a worse prognosis. 23 Involvement of the heart is associated with an increased risk of morbidity and a higher mortality. Pellikka et al 6 showed a reduction in 3-year survival rate
Patel et al 5
associated with the presence of cardiac involvement (31% vs 68%). Development and progression of CHD complicate the carcinoid syndrome and contribute to a worse prognosis. In patients with severe cardiac involvement and well-controlled systemic disease, valve replacement surgery is an effective treatment modality that can relieve intractable symptoms and contribute to improved outcomes. 7
Future directions As noted above, the elevated serum levels of NTFBNP and CgA have been associated with CHD. Further advancements in such neurohormone-based diagnostic techniques may be helpful in early detection. In addition, further developments in ultrasound-imaging based detection, such as strain analysis, could be helpful towards developing a routine screening scheme for CHD in patients with known carcinoid tumors. In addition, the better understanding of the molecular mechanisms underlying the progression of fibrosis in CHD would lead to the development of appropriate targets for targeted molecular therapy. In carcinoid tumors, overexpression of factors associated with promotion of tumor growth and angiogenesis, such as vascular endothelial growth factor and vascular endothelial growth factor receptor subtypes, has been observed. 64 Protein kinase inhibitors with activity targeted to tyrosine kinase receptors may play a role in the future. Another potential target for therapeutic agents may be the rapamycin (mTOR) pathway, as it represents a major regulatory component of energy utilization and proliferation. 65,66 One of the key limitations in developing targeted agents has been the inability to accurately identify targets in a particular tumor. The need to define cross talk between the pathways involved in growth-promoting signals and the integration of tumor microenvironment signaling is therefore a key requirement in developing more effective therapies.
Conclusion Research has implicated the role of various vasoactive agents, particularly serotonin, in the deleterious effects of the carcinoid disease on the heart. Right heart failure associated with the valvular and endomyocardial fibrosis is associated with severe symptomatic functional limitations and survival decline. Early recognition and curative surgeries decrease the likelihood of CHD and confer an excellent prognosis. The innovative and multidisciplinary approach to the therapy of the disease has significantly improved outcomes, although cardiac surgery remains the only modality to benefit mortality. Advances in the fields of pathological research and biochemical engineering leading to targeted antifibrosis therapy combined with the liberal use of cardiac surgery are certain to improve patient outcomes.
6 Patel et al
Acknowledgements We would like to thank Dr Susan Wiegers, Dr Martin Keane, and Dr Pravin Patil for their help with the echocardiographic images presented in this article.
Disclosures Funding: No extramural funding was used to support this work. Conflict of interest: The authors report no conflict of interest.
References 1. Fox DJ, Khattar RS. Carcinoid heart disease: presentation, diagnosis, and management. Heart 2004;90(10):1224-8. 2. Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer 2001;92 (8):2204-10. 3. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97(4):934-59. 4. Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005;128(6):1717-51. 5. Pandya UH, Pellikka PA, Enriquez-Sarano M, et al. Metastatic carcinoid tumor to the heart: echocardiographic-pathologic study of 11 patients. J Am Coll Cardiol 2002;40(7):1328-32. 6. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993;87(4):1188-96. 7. Bernheim AM, Connolly HM, Hobday TJ, et al. Carcinoid heart disease. Prog Cardiovasc Dis 2007;49(6):439-51. 8. Mansencal N, Mitry E, Pilliere R, et al. Prevalence of patent foramen ovale and usefulness of percutaneous closure device in carcinoid heart disease. Am J Cardiol 2008;101(7):1035-8. 9. Mansencal N, Mitry E, Forissier JF, et al. Assessment of patent foramen ovale in carcinoid heart disease. Am Heart J 2006;15(5): 1129.e1-6. 10. Gustafsson BI, Hauso O, Drozdov I, et al. Carcinoid heart disease. Int J Cardiol 2008;129(3):318-24. 11. Oates JA, Melmon K, Sjoerdsma A, et al. Release of a kinin peptide in the carcinoid syndrome. Lancet 1964;1(7332):514-7. 12. Dahl CF, Allen MR, Urie PM, Hopkins PN. Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals. BMC Med 2008;6:34. [34-7015-6-34]. 13. 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. 14. 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. 15. Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease. Lancet Neurol 2007;6(9):826-9. 16. Simonis G, Fuhrmann JT, Strasser RH. Meta-analysis of heart valve abnormalities in Parkinson's disease patients treated with dopamine agonists. Mov Disord 2007;22(13):1936-42. 17. Caplin ME, Buscombe JR, Hilson AJ, et al. Carcinoid tumour. Lancet 1998;352(9130):799-805.
American Heart Journal Month Year
18. Kaplan L. Endocrine tumors of the gastrointestinal tract and pancreas. In: Isselbacher K, Martin J, Braunwald E, eds. Harrison's principles and practices of internal medicine. 13th ed. New York: McGraw-Hill Inc; 1994. p. 1535-42. 19. Hoffmann J, Grimm W, Menz V, et al. Heart rate variability in carcinoid heart disease. Am J Cardiol 1999;83(1):128-31. [A9]. 20. Langer C, Piper C, Vogt J, et al. Atrial fibrillation in carcinoid heart disease: the role of serotonin. A review of the literature. Clin Res Cardiol 2007;96(2):114-8. 21. Kvols LK, Reubi JC. Metastatic carcinoid tumors and the malignant carcinoid syndrome. Acta Oncol 1993;32(2):197-201. 22. Feldman JM. Urinary serotonin in the diagnosis of carcinoid tumors. Clin Chem 1986;32(5):840-4. 23. 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. 24. 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. 25. Bhattacharyya S, Toumpanakis C, Chilkunda D, et al. Risk factors for the development and progression of carcinoid heart disease. Am J Cardiol 2011;107(8):1221-6. 26. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol 2005;89(3):151-60. 27. 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(7): 938-42. 28. Jensen EH, Kvols L, McLoughlin JM, et al. Biomarkers predict outcomes following cytoreductive surgery for hepatic metastases from functional carcinoid tumors. Ann Surg Oncol 2007;14(2):780-5. 29. Sondenaa K, Sen J, Heinle F, et al. Chromogranin A, a marker of the therapeutic success of resection of neuroendocrine liver metastases: preliminary report. World J Surg 2004;28(9):890-5. 30. 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(26):4293-9. 31. Moyssakis IE, Rallidis LS, Guida GF, Nihoyannopoulos PI. Incidence and evolution of carcinoid syndrome in the heart. J Heart Valve Dis 1997;6(6):625-30. 32. Howard RJ, Drobac M, Rider WD, et al. Carcinoid heart disease: diagnosis by two-dimensional echocardiography. Circulation 1982; 66(5):1059-65. 33. Bhattacharyya S, Toumpanakis C, Burke M, et al. Features of carcinoid heart disease identified by 2- and 3-dimensional echocardiography and cardiac MRI. Circ Cardiovasc Imaging 2010;3(1): 103-11. 34. Haugaa KH, Bergestuen DS, Sahakyan LG, et al. Evaluation of right ventricular dysfunction by myocardial strain echocardiography in patients with intestinal carcinoid disease. J Am Soc Echocardiogr 2011; 24(6):644-50. 35. Moller JE, Pellikka PA, Bernheim AM, et al. Prognosis of carcinoid heart disease: analysis of 200 cases over two decades. Circulation 2005;112(21):3320-7. 36. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999;17(2):600-6.
American Heart Journal Volume 0, Number 0
37. Eriksson B, Oberg K. Summing up 15 years of somatostatin analog therapy in neuroendocrine tumors: future outlook. Ann Oncol 1999;10(Suppl 2):S31-8. 38. Leong WL, Pasieka JL. Regression of metastatic carcinoid tumors with octreotide therapy: two case reports and a review of the literature. J Surg Oncol 2002;79(3):180-7. 39. Oberg K, Norheim I, Lundqvist G, Wide L. Cytotoxic treatment in patients with malignant carcinoid tumors. response to streptozocin– alone or in combination with 5-FU. Acta Oncol 1987;26(6):429-32. 40. Ritzel U, Leonhardt U, Stockmann F, Ramadori G. Treatment of metastasized midgut carcinoids with dacarbazine. Am J Gastroenterol 1995;90(4):627-31. 41. Ansell SM, Mahoney MR, Green EM, Rubin J. Topotecan in patients with advanced neuroendocrine tumors: a phase II study with significant hematologic toxicity. Am J Clin Oncol 2004;27(3):232-5. 42. Connolly HM, Nishimura RA, Smith HC, et al. Outcome of cardiac surgery for carcinoid heart disease. J Am Coll Cardiol 1995;25(2):410-6. 43. Eriksson BK, Larsson EG, Skogseid BM, et al. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer 1998;83(11):2293-301. 44. Brown KT, Koh BY, Brody LA, et al. Particle embolization of hepatic neuroendocrine metastases for control of pain and hormonal symptoms. J Vasc Interv Radiol 1999;10(4):397-403. 45. McEntee GP, Nagorney DM, Kvols LK, et al. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990;108(6):1091-6. 46. Sarmiento JM, Heywood G, Rubin J, et al. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003;197(1):29-37. 47. Connolly HM, Schaff HV, Mullany CJ, et al. Carcinoid heart disease: impact of pulmonary valve replacement in right ventricular function and remodeling. Circulation 2002;106(12 Suppl 1):I51-6. 48. Castillo JG, Filsoufi F, Rahmanian PB, et al. Early and late results of valvular surgery for carcinoid heart disease. J Am Coll Cardiol 2008; 51(15):1507-9. 49. Bhattacharyya S, Raja SG, Toumpanakis C, et al. Outcomes, risks and complications of cardiac surgery for carcinoid heart disease. Eur J Cardiothorac Surg 2011;40(1):168-72. 50. Connolly HM, Schaff HV, Mullany CJ, et al. Surgical management of left-sided carcinoid heart disease. Circulation 2001; 104(12 Suppl 1):I36-40. 51. Ridker PM, Chertow GM, Karlson EW, et al. Bioprosthetic tricuspid valve stenosis associated with extensive plaque deposition in carcinoid heart disease. Am Heart J 1991;121(6 Pt 1):1835-8.
Patel et al 7
52. Thorburn CW, Morgan JJ, Shanahan MX, Chang VP. Long-term results of tricuspid valve replacement and the problem of prosthetic valve thrombosis. Am J Cardiol 1983;51(7):1128-32. 53. Schoen FJ, Hausner RJ, Howell JF, et al. Porcine heterograft valve replacement in carcinoid heart disease. J Thorac Cardiovasc Surg 1981;81(1):100-5. 54. Vaughan DJ, Brunner MD. Anesthesia for patients with carcinoid syndrome. Int Anesthesiol Clin 1997;35(4):129-42. 55. Ockert DB, White RD. Anesthetic management of patients with carcinoid heart disease undergoing cardiac surgery: two case reports and a review of previous experience. J Cardiothorac Anesth 1988; 2(5):658-65. 56. Claure RE, Drover DD, Haddow GR, et al. Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management. Can J Anaesth 2000;47(4):334-7. 57. Stoelting R, ed. Pharmacology and physiology in anesthetic practice. 3rd ed. Philadelphia: J.B. Lippincott-Raven Co.; 1999. 58. Marsh HM, Martin Jr JK, Kvols LK, et al. Carcinoid crisis during anesthesia: successful treatment with a somatostatin analogue. Anesthesiology 1987;66(1):89-91. 59. Bhattacharyya S, Davar J, Dreyfus G, Caplin ME. Carcinoid heart disease. Circulation 2007;116(24):2860-5. 60. Onate A, Alcibar J, Inguanzo R, et al. Balloon dilation of tricuspid and pulmonary valves in carcinoid heart disease. Tex Heart Inst J 1993;20(2):115-9. 61. Grant SC, Scarffe JH, Levy RD, Brooks NH. Failure of balloon dilatation of the pulmonary valve in carcinoid pulmonary stenosis. Br Heart J 1992;67(6):450-3. 62. 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. 63. Moran CA, Suster S, Coppola D, Wick MR. Neuroendocrine carcinomas of the lung: a critical analysis. Am J Clin Pathol 2009;131(2):206-21. 64. Silva SR, Bowen KA, Rychahou PG, et al. VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis. Int J Cancer 2011;128(5):1045-56. 65. Bago-Horvath Z, Sieghart W, Grusch M, et al. Synergistic effects of erlotinib and everolimus on bronchial carcinoids and large-cell neuroendocrine carcinomas with activated EGFR/AKT/mTOR pathway. Neuroendocrinology 2012;96(3):228-37. 66. Leung R, Lang B, Wong H, et al. Advances in the systemic treatment of neuroendocrine tumors in the era of molecular therapy. Anticancer Agents Med Chem 2013;13(3):382-8.
