Introduction

Carcinoid heart disease is a rare disease that occurs most commonly in patients with neuroendocrine tumors (NETs) that have metastasized to produce carcinoid syndrome. Carcinoid heart disease is the initial presentation of carcinoid syndrome in 20% of patients and occurs in up to half of patients with carcinoid syndrome [1]. Patients with carcinoid syndrome have clinical symptoms of diarrhea, hypotension, and bronchospasm, and in cases of cardiac involvement have signs and symptoms of congestive heart failure. Serotonin appears to play a central role in the development of valvular carcinoid heart disease, and medical therapy has been used to target the serotonin biochemical pathway in an attempt to control symptoms in patients with carcinoid syndrome. While carcinoid heart disease is rare, it is associated with significant morbidity and mortality. In this comprehensive review of the literature, we will present current concepts in the diagnosis and treatment of carcinoid heart disease.

Etiology and Pathophysiology

The incidence of NETs is estimated to be 6.98 per 100,000 in the general population and has increased 6.4-fold between 1973 and 2012 [2]. The highest incidence rates were found to be in gastroenteropancreatic sites (3.56 per 100,000), lung (1.49 per 100,000), and from unknown primary sites (0.84 per 100,000). Survival varies by stage, grade, age at diagnosis, primary site, and decade of diagnosis and has been improving over time, likely due to improvements in therapy [2].

Disseminated NETs can lead to carcinoid syndrome and can cause cardiac symptoms due to the release of vasoactive substances such as histamine, bradykinin, serotonin, and prostaglandins [3]. In patients with carcinoid syndrome, more than 70% of tryptophan is converted to serotonin as compared with 1% in normal situations [4]. Serotonin (5-HT) is circulated in the blood stream and is thought to play a crucial role in the development of carcinoid heart disease. Along with alterations in the metabolism of tryptophan that leads to increased production of serotonin, the activation of 5-hydroxytryptamine (5-HT) 2B receptors (located on heart valves) and interference with 5-HT transporters (which inactivates 5-HT in the lungs) are thought to lead to serotonin-mediated heart disease [5,6,7,8]. Serotonin is eventually metabolized into 5-hydroxyindoleacetic acid (5-HIAA).

Carcinoid heart disease is characterized by the plaque-like deposit of fibrous tissue which is composed of a mixture of myofibroblasts, smooth muscle cells, extracellular matrix, and an overlying endothelial layer. This primarily affects the heart valves, but can also involve other structures of the heart such as the cardiac chambers, the vena cava, pulmonary artery, and the coronary sinus [9].

Clinical Manifestations

Cardiac manifestations of carcinoid heart disease are usually associated with other common symptoms of the carcinoid syndrome like diarrhea, flushing, and bronchospasm [10,11,12,13]. Typically, patients are hypotensive, but others may have labile blood pressure or even be hypertensive [13]. In most cases, the right-sided valves of the heart are involved. In a case series of 74 patients, the majority (> 90%) had tricuspid valve disease showing moderate-to-severe tricuspid regurgitation, with > 80% also showing pulmonic valve involvement [1]. The predominant lesion is regurgitation but it may also cause stenosis [1]. Rarely, left-sided valvular involvement may precede the development of overt right-sided valvular disease [11]. Left-sided valve involvement is usually associated with the presence of a patent foramen ovale or atrial septal defect.

In the early phase of carcinoid heart disease, patients may be asymptomatic. Later, in the course of the disease, patients may develop fatigue and dyspnea on exertion. As the disease progresses, right-sided heart failure ensues with worsening dyspnea, edema, and ascites. Major findings on physical examination include edema and elevated jugular venous pressure. In cases of severe tricuspid regurgitation, the jugular venous pulse may show a prominent “V” wave. A palpable right ventricular impulse may be present, and murmurs of tricuspid and pulmonic valve regurgitation may be audible. In cases of pulmonic stenosis, a systolic murmur is present in the pulmonic area.

The auscultatory findings may be subtle, as the murmurs of tricuspid and pulmonary valve regurgitation are sometimes difficult to detect due to the low pressure in the right heart chambers. These right-sided murmurs are accentuated by inspiration. In the rare instance of left sided disease, murmurs of mitral and aortic disease may be present. In the presence of a significant right to left shunt, patients may have central cyanosis, in addition to other signs of heart failure [14]. In one of the earliest reports on this condition, Biorck K. et al. [15] reported a case of a patient with cyanosis in association with pulmonary stenosis and tricuspid insufficiency, in whom the postmortem analysis showed that in addition to the cardiac valvular lesion, there was a malignant carcinoid tumor of the jejunum with metastases to the liver.

Although valvular involvement appears to be the dominant clinical presentation of carcinoid heart disease, other atypical presentations include coronary artery vasospasm with ST segment elevation [16, 17], atrial fibrillation [18], ventricular tachycardia, ventricular fibrillation, and cardiac arrest [19,20,21]. Carcinoid heart disease has also been reported to provoke coronary artery vasospasm, angina, and in-stent thrombosis in patients with established ischemic heart disease [22]. Infrequently, carcinoid heart disease may present as an isolated intra-cardiac mass, without any valvular involvement [23, 24]. Rarely, patients may present with heart failure due to pericardial disease and constrictive pericarditis, in the absence of significant valvular disease [10, 25].

Diagnosis

Biomarkers

The measurement of serum biomarkers may be useful to identify carcinoid heart disease. Both elevated 5-hydroxyindoleacetic acid (5-HIAA) levels and elevated N-terminal pro b-type natriuretic peptide (NT-proBNP) levels are sensitive and specific predictors of carcinoid heart disease [26]. The European Neuroendocrine Tumor Society (ENETS) recommends screening patients with elevated 5-HIAA levels for carcinoid heart disease using transthoracic echocardiography [27]. Furthermore, one study suggested elevated NT-proBNP levels may be useful to select patients who should undergo diagnostic echocardiogram, allowing for more judicious use of this imaging modality [28]. NT-proBNP levels also correlate well with many of the echocardiographic scoring systems for severity of carcinoid heart disease [26].

Imaging

Two-dimensional transthoracic echocardiography (2D TTE) is often the diagnostic imaging test of choice for patients suspected of having carcinoid heart disease. Echocardiography is recommended in all patients with carcinoid syndrome and a high suspicion of carcinoid heart disease, based on a recent expert statement by the American College of Cardiology (ACC) [29••]. The ACC expert consensus statement recommends that for those with established mild valvular disease, a repeat echocardiogram and clinical assessment should occur every 6 months [30]. While for those with established moderate-to-severe valvular disease, a repeat echocardiogram and clinical assessment should occur every 3 months [29••], whereas the ENETS guideline recommends repeating the TTE annually among this group [27]. The TTE often demonstrates fibrous deposition along the pulmonic and tricuspid valves, which are noted to move in a “board-like” pattern [30]. This leads to significant tricuspid regurgitation with a characteristic Doppler pattern (Fig. 1).

Fig. 1
figure 1

Transthoracic echocardiogram in a modified RV inflow view showing thickened, fixed, and non-coapting tricuspid valve leaflets (arrowheads) (a), color flow Doppler imaging of severe tricuspid valve regurgitation (arrow) (b), and the characteristic “dagger-”shaped Doppler pattern (arrow) with an early peak pressure and rapid decline (c)

Full size image

Three-dimensional transthoracic echocardiography (3D TTE) allows for visualization of all valve leaflets at the same time, which makes it a more sensitive test for diagnosing carcinoid heart disease, as not all valve leaflets are always involved [30, 31]. Transesophageal echocardiography (TEE) may be particularly useful in visualizing the pulmonic valve, which is often poorly visualized on TTE [32].

Cardiac magnetic resonance imaging (CMR) may be useful in identifying carcinoid heart disease, especially when echocardiographic findings are equivocal or there are technical difficulties in assessing the tricuspid valve by 2D echocardiography. Late gadolinium enhancement may allow for the identification of fibrotic changes in the myocardium that may not be apparent on echocardiogram [33]. Assessing the pulmonic valve with TTE might be difficult in adults, for which CMR provides great anatomical visualization and ability to provide an accurate and reproducible quantification of pulmonic regurgitation, regurgitant volume, and regurgitant fraction [34]. Cardiac computerized tomography (CCT) may also be used when echocardiogram is equivocal. Both the CMR and CCT share many advantages over echocardiogram, including improved visualization of valves, ability to identify rare cardiac metastasis, and quantification of chamber sizes [30, 35]. The CCT is a robust modality for structural intervention planning in the tricuspid valve and for appropriate prosthetic valve sizing [36]. These findings make the CMR and CCT particularly useful for surgical selection and planning.

Scoring Systems

Various scoring systems incorporate echocardiographic findings to either diagnose or track the progression of carcinoid heart disease (Table 1). The first echocardiographic scoring system takes into consideration tricuspid valve anatomy, tricuspid regurgitation severity, pulmonic stenosis severity, and pulmonic regurgitation severity [39]. One study recently determined that these tests are quite similar in sensitivity and specificity, but the more complex echocardiographic scoring systems may be particularly useful in tracking disease progression [37].

Table 1 Echocardiographic scoring systems in carcinoid heart disease
Full size table

Invasive Hemodynamic Testing

Cardiac catheterization offers a direct means of analyzing the degree of valve dysfunction via invasive hemodynamic pressurement. A recent report included 13 patients with a known diagnosis of carcinoid heart disease who underwent cardiac catheterization revealed that tricuspid valve regurgitation was the most prevalent pathology (92%), followed by tricuspid stenosis (38%) and mitral regurgitation (38%). Left-sided lesions were less common and less severe than their right-sided counterparts. In one study, right-sided filling pressures tended to be mild to moderately elevated with normal left-sided pressure (no patient had mean pulmonary capillary wedge pressure > 20 mmHg) [38]. These findings were consistent with the greater severity of right-sided valvular pathology (tricuspid and pulmonary) compared with left-sided disease (mitral and aortic). Overall, there was a 91% concordance between cardiac catheterization and echocardiography for the assessment of valvular lesions [38]. These findings are consistent with a prior case series of 7 carcinoid heart disease patients by Himelman et al. which demonstrated hemodynamic findings of an elevated mean right atrial pressure of 15 mmHg, with a V wave of 22 mmHg and a right ventricular pressure of 39/10 mmHg [42].

Treatment

The treatment of carcinoid valvular heart disease is focused on managing symptoms, delaying progression of valve disease, and optimal timing of surgical intervention for improved quality of life and reducing mortality. This requires early and close collaboration between the medical oncologist, cardiologist, and cardiac surgeon. This collaboration and close monitoring is essential, as there may be rapid progression of carcinoid heart disease, and surgical intervention should be considered early before a disease progresses to a point at which surgery would be too high risk [29••].

The management of right-sided heart failure from carcinoid valvular disease primarily consists of careful volume management. Patients should be aware of the symptoms and signs of heart failure such as lower extremity edema and dyspnea so that they may seek medical attention immediately at the onset of symptoms. Most commonly, loop diuretics are used with the addition of aldosterone antagonists or thiazide diuretics, if additional diuresis is needed. In patients having valvular carcinoid disease with or without right ventricular dilation and failure, caution should be taken to avoid intravascular depletion [43]. This will result in decreased cardiac output and symptoms of lightheadedness, syncope, fatigue, and dyspnea with possible hypotension. In selected cases, traditional heart failure medications like angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers can be considered, but have not been studied or shown to have proven benefit in this specific patient population. All of these cardiovascular medications are for palliation of symptoms and do not address the underlying carcinoid syndrome or carcinoid heart disease with valvular degeneration.

The pharmacological management of valvular disease is largely dependent on control of 5-HIAA levels through the use of somatostatin analogues [44, 45]. For patients refractory to somatostatin analogues, other options include everolimus [46], interferon alpha [47], peptide receptor radionuclide therapy [48], and telotristat etiprate [49]. Unfortunately, control of carcinoid syndrome has not shown to reverse the already established carcinoid valvular disease, but may play a role in slowing its progression [1, 37].

Surgical intervention is the only established effective treatment for carcinoid valvular heart disease. The optimal timing for surgical intervention is not clear, but evidence favors intervening prior to the development of right ventricular dilation and depressed right ventricular systolic function [50]. The current ACC consensus statement recommendations include consideration of valve surgery when symptoms are present and severe valvular disease is established [29••]. Typically, the tricuspid valve is involved, but careful attention should be placed on assessment of the pulmonic valve as often it has significant involvement and requires replacement [51]. When both the tricuspid valve and pulmonic valve are replaced, there appears to be a beneficial effect on right ventricular size and possibly right ventricular remodeling [52]. Consideration must be taken prior to surgery to control the systemic carcinoid syndrome, as uncontrolled carcinoid syndrome can result in bioprosthetic valve dysfunction [53].

The decision to pursue bioprosthetic versus mechanical valve replacement usually favors bioprosthetic valve replacement for right-sided valve pathology. Current literature supports the use of bioprosthetic valves as opposed to mechanical for several reasons [29••, 54]. One of the main considerations is long-term anticoagulation which can be problematic in carcinoid syndrome patients who often have concomitant liver and kidney disease and often need further procedures or non-cardiac surgeries. Also, mechanical valves in the tricuspid position are more prone to thrombosis and newer bioprosthetic valves have improved long-term durability. If patients have a favorable survival from carcinoid disease and bioprosthetic surgical valve deterioration occurs, transcatheter valve-in-valve replacement can be performed. In addition to valve replacement, the ACC expert consensus statement recommends the closure of patent foramen ovale at the time of initial surgery to reduce future left-sided valve involvement [29••].

To prevent perioperative carcinoid crisis, it is important to involve the medical oncologist and anesthesiologist in the preoperative surgical planning and in the perioperative management. Carcinoid crisis develops from the release of biologically active substances resulting in wide fluctuations in hemodynamics at times requiring vasopressor support. Generally, octreotide is started preoperatively and continued until the patient is stable postoperatively [59]. A multidisciplinary team including anesthesiologists, oncologists, surgeons, and cardiologists familiar with carcinoid syndrome is recommended for perioperative management.

Prognosis

The prognosis of valvular carcinoid heart disease without treatment is dismal with a median survival of only 11 months in patients with advanced heart failure [50]. The presence of valvular disease on echocardiography has been shown to be associated with worse survival when compared with those without valvular disease [1]. Once the development of valvular disease is established, the progression of valve disease also portends a worse prognosis [55, 56]. Patients with normal natriuretic peptide levels have a better prognosis even in the presence of established valve disease [58]. Moller et al. reported improved survival over the past two decades and largely attributed this to increased rates of cardiac surgery for these patients [56]. As stated above, the only established effective treatment is valve replacement. Early studies of valve surgery resulted in 30-day perioperative mortality as high as 63% [60], but with improved experience and better surgical techniques, the 30-day perioperative mortality has recently been reported as low as 3.7% [57•].

Conclusion

Carcinoid heart disease is a major cause of morbidity and mortality in patients with NETs. Serotonin appears to play a central role in the development of carcinoid valvular heart disease. Patients with carcinoid heart disease present with heart failure and both biomarkers and multimodality imaging are used for screening and diagnosis. The mainstay of treatment is valve surgery, but still carries substantial risks, and the timing of surgery remains unclear. A multidisciplinary team involving oncologists, cardiologists, cardiac surgeons, and anesthesiologist is essential for the optimal management of patients with carcinoid heart disease.