Carcinoid heart disease in patients with midgut neuroendocrine tumours

Carcinoid heart disease (CHD) is the main complication of carcinoid syndrome (CS) associated with metastatic small intestine neuroendocrine tumours (NETs). The pathophysiology of CHD is partly understood but vasoactive hormones secreted by NETs, especially serotonin, play a major role, leading to the formation of fibrous plaques. These plaque‐like deposits involve the right side of the heart in >90% of cases, particularly the tricuspid and pulmonary valves, which become thickened, retracted and immobile, resulting in regurgitation or stenosis. CHD represents a major diagnostic and therapeutic challenge for patients with NET and CS and is associated with increased risk of morbidity and mortality. CHD often occurs 2–5 years after the diagnosis of metastatic NET, but diagnosis of CHD can be delayed as patients are often asymptomatic for a long time despite severe heart valve involvement. Circulating biomarkers (5HIAA, NT‐proBNP) are relevant tools but transthoracic echocardiography is the key examination for diagnosis and follow‐up of CHD. However, there is no consensus on the optimal indications and frequency of TTE and biomarker dosing regarding screening and diagnosis. Treatment of CHD is complex and requires a multidisciplinary approach. It relies on antitumour treatment, control of CS and surgical valve replacement in cases of severe CHD. However, cardiac surgery is associated with a high risk of mortality, notably due to perioperative carcinoid crisis and right ventricular dysfunction. Timing of surgery is the most crucial point of CHD management and relies on the case‐by‐case determination of the optimal compromise between tumour progression, cardiac symptoms and CS control.


| INTRODUCTION
Neuroendocrine tumours (NETs) are rare and occur in around seven per 100,000 individuals, with an increasing incidence over the last decades. 1 They mainly arise in the small intestine, rectum, pancreas and lung. NETs can typically produce hormones, and oversecretion can result in functioning syndromes. Carcinoid syndrome (CS) occurs in 20%-30% of patients with small intestine NETs, especially when they are associated with liver metastases. [2][3][4] The main symptoms of CS are cutaneous flushing (80%), diarrhoea (75%), abdominal pain (60%) and bronchospasm (10%). 5 These symptoms are related to the hypersecretion of vasoactive hormones by the tumour or metastases into the systemic circulation, mainly serotonin but also histamine, dopamine, tachykinins, bradykinins and prostaglandins. 2,5 The main complication of CS is carcinoid heart disease (CHD) or Hedinger syndrome. It concerns 20%-35% of patients with CS and is associated with increased morbidity and mortality. 4 2022, using the following keywords "carcinoid heart disease", "carcinoid valve disease", "surgery", "valve replacement", "survival" and/or "prognosis". After excluding duplicates, only full articles published in English language reporting on >20 patients with CHD were included.

| PATHOPHYSIOLOGY
Vasoactive substances secreted by NETs play a major role in CHD development and progression, especially serotonin (or 5-hydroxytryptamine ). The effects of serotonin are mediated by its interaction with serotonin receptors, notably the 5-HT2B receptors. 9,10 These receptors are mainly located in the heart, particularly in interstitial valve cells, cardiomyocytes and pulmonary artery endothelial cells (Figure 1). The activation of these receptors by serotonin induces the production of proinflammatory cytokines, mitosis initiation and upregulation of growth factors such as TGF-ß1, leading to the proliferation of fibroblasts, smooth muscle cells and extracellular matrix proteins. These mechanisms ultimately lead to the formation and deposition of fibrous plaques on the endocardium of valve leaflets, but also on the subvalvular apparatus (chordae and papillary muscles) and on the intima of the efferent arteries. 9 These plaque-like deposits are mainly composed of fibroblasts and leiomyocytes, within an abundant extracellular matrix rich in collagen.
Such deposits can involve all the heart structures, particularly the cardiac valves which become thickened, retracted and immobile, resulting in regurgitation or stenosis. Other substances secreted by the tumour can favour the development and progression of CHD, including vasoactive substances (e.g., prostaglandins, histamine, bradykinin) and substance F I G U R E 1 Pathophysiology of carcinoid heart disease in patients with neuroendocrine tumours and carcinoid syndrome. Adapted from Delhomme et al. 11 with fibroblast proliferative properties such as tachykinins (substance P, neurokinin A, neuropeptide K) or (transforming growth factor-β). 9 CHD involves the right side of the heart in >90% of cases, typically in patients with intestinal NETs and liver metastases ( Figure 1).
In the absence of liver metastases, vasoactive substances produced by intestinal NETs and excreted through the portal circulation are metabolized by the healthy liver and do not classically induce CS nor CHD. Conversely, in the presence of liver metastases, the hepatic metabolism is outstripped and vasoactive substances, directly secreted into the inferior vena cava, reach the right side of the heart. 9,11 Hence, involvement of tricuspid and pulmonary valves is the most typical presentation of CHD. Left-sided heart involvement is rarer because of the additional pulmonary metabolism of vasoactive substances. 12 However, left-sided valvular involvement may arise in patients with patent foramen ovale (PFO) establishing a right-to-left shunt, or in the case of high circulating levels of serotonin exceeding pulmonary elimination capacity or, more rarely, in patients with bronchial NETs. 13 Evidence of the key role of serotonin in the pathophysiology of CHD is advocated by the presence of similar heart involvement induced by serotoninergic drugs used in the treatment of migraine or Parkinson's disease or by different dopamine agonists. 9 These drugs similarly activate the 5-HT2B receptors, causing valvular fibrosis. Preliminary animal studies have also demonstrated the effects of serotonin on heart valves. Elangbam et al. 14 showed that repeated serotonin injections in rats resulted in valvular alterations similar to those observed in CHD. Another study found that overexpression of 5-HT2B receptors was associated with a myocardial hypertrophy in transgenic mice. 15 Although the role of serotonin is predominant, other factors, including genetic factors, are most likely involved in the pathophysiology of CHD, requiring further investigation. Indeed, despite exposure to similar levels of intracardiac plasma and platelet serotonin, the development of valve dysfunction is heterogeneous between patients. This underlines individual heart valve susceptibility and suggests that development of valvular dysfunction does not depend on serotonin levels only. 16

| CLINICAL PRESENTATION
CHD generally occurs 2-5 years after the initial diagnosis of metastatic NETs, and despite the presence of valvular involvement, cardiac symptoms are often absent for a long time. 7,[17][18][19] Indeed, approximately 60% of patients with moderate to severe tricuspid regurgitation have mild symptoms or are even asymptomatic. When symptoms such as asthenia and/or dyspnoea are present, they are mainly related to right-sided heart involvement.
Murmurs of right-sided valvular disease are rare, as tricuspid regurgitations are usually silent even at an advanced stage, due to low velocities in the right heart. On physical examination, jugular vein distension, hepatomegaly and peripheral oedema may be found. Ascites unfrequently occurs in patients with intestinal NETs even associated with peritoneal carcinomatosis; its presence should prompt the search for CHD. However, physical examination is normal in about 40% of patients with CHD, thus a clinical evaluation is recommended every 6 months. 8,18 Finally, left-sided heart failure symptoms are most generally absent, unless left-sided valvular involvement has developed or in cases of advanced stage CHD with global heart failure. Finally, in rare cases, CHD can present with non-specific symptoms of constrictive pericarditis, restrictive cardiomyopathy, and hypoxia or even cyanosis due to PFO. 20 The resting electrocardiogram is usually normal, but right axial deviation may be observed, with a right bundle branch block. Lowvoltage QRS complexes may be present in the rare cases of pericardial effusion.
Serotonin is metabolised into 5HIAA by monoamine oxidases present in the liver and lungs. 5HIAA concentration is measured in a 24-h urine sample after exclusion of certain medications and foods which could interfere with dosing. 3 Levels of 5HIAA reflect serotonin hypersecretion; hence they are greater in patients with intestinal NET and high metastatic burden and/or CS. Additionally, higher 5HIAA levels (notably, above 300 μmol/24 h) are significantly correlated with significant increases in the risks of CHD occurrence and progression. 21,22 Therefore, it is recommended to measure 24-h urinary 5HIAA in all patients with midgut NET, with or without CS (evidence level 2, grade B) ( Table 1). 8 Plasmatic 5HIAA dosing is easier to perform than urinary measurement and thus stands as an interesting alternative for screening patients for CHD. A recent prospective multicentric study showed that plasmatic 5HIAA levels were correlated with the presence of CS (AUC = 0.697; p = .007) and CHD (AUC = 0.923; p < .001) among patients with intestinal NETs, and suggested low impact of specific diet on its levels. 23 Hence, plasmatic 5HIAA measurement may replace urinary dosing for diagnosis and follow-up of patients with midgut NET in the future.

| N-terminal pro-B-type natriuretic peptide (NT-proBNP)
NT-proBNP is a hormone secreted by cardiomyocytes in response to both volume and pressure overload. Its level may vary according to age and gender and may increase in cases of renal failure or obesity.
Several studies have shown that, among patients with NETs, concentration of NT-proBNP was significantly higher in patients with CHD than in those without. 24,25 A cutoff of 260 pg/mL had a sensitivity and specificity of 92% and 91%, respectively, for the diagnosis of CHD. 24 NT-proBNP levels have also been found to be associated with CHD progression and mortality. 19 Hence, NT-proBNP is also recommended as a routine biomarker for diagnostic and prognostic evaluation of CHD in patients with NETs (Table 1). 4,24-26

| Chromogranin A
Chromogranin A is a glycoprotein secreted by NETs and is the most commonly used biomarker in patients with NETs. Its concentration correlates with metastatic tumour volume and is higher in functioning NETs. It has a sensitivity close to 100% for the detection of severe heart involvement, but its specificity is as low as 30%. Indeed, there are many causes of false positives (in particular, use of proton pump inhibitors, gastritis and renal failure). Chromogranin A may also be a prognostic marker in patients with CHD, but its specificity regarding cardiac involvement is questioned. 25

| CARDIAC IMAGING
Transthoracic echocardiography (TTE) is the key examination for the diagnosis of CHD (Table 1). CHD mainly involves heart valves and results in thickening of valve leaflets, chordae and papillary muscles, secondary to the formation of plaque-like deposits. 27 Chordae may fuse together and shrink, and the leaflets thickening progressively leads to a retraction and a reduction of leaflets mobility, resulting in a regurgitation or less frequently in a stenosis. Right-sided valves are most frequently involved, but all four valves may be affected, particularly at an advanced stage, or in the case of associated PFO. Careful analysis of all valves is essential. Several echocardiographic assessment scores for CHD have been proposed in the literature, but none are currently validated for routine practice. 8,28 Recently, the European Neuroendocrine Tumour Society (ENETS) CHD Task Force proposed a synoptic reporting of echocardiography in CHD to assess cardiac T A B L E 1 Proposed recommendations for diagnosis, follow-up and prognosis evaluation of carcinoid heart disease in patients with neuroendocrine tumours.
involvement in a standardised and homogeneous way at the time of diagnosis but also for follow-up. 29 The tricuspid valve is the most frequently affected valve, occurring in >90% of patients with CHD. 27 Its involvement is typical, with a thickening of the leaflets and a progressive reduction of leaflet mobility. In more severe cases, leaflets may be fixed and may not coapt, leading to severe tricuspid regurgitation ( Figure 2). Subvalvular structures may also be involved and cases of fusion of chordae with papillary muscles have been described.
The pulmonary valve is the second most frequently affected valve (50%-70% of cases). Carcinoid pulmonary valve involvement is similar to the tricuspid valve, leading to leaflet thickening and reduction of excursion of valve cusps, resulting in pulmonary regurgitation and also pulmonary stenosis ( Figure 3). However, assessment of the pulmonary valve is difficult, due to the poor acoustic window on TTE, resulting in its visualization in <60% of cases. 30 Finally, aortic and mitral valves involvement is observed in around 15%-30% of cases with similar features to right-sided valves. 27,31,32 These valvular lesions cause regurgitations and progressively lead to the dilatation of the right ventricular cavities and ultimately to right ventricular dysfunction. A PFO should be systematically searched for by agitated saline contrast-enhanced echocardiography, as left-sided valve involvement is associated with PFO in >80% of cases. 27,31,33 TTE also allows the detection of pericardial effusion in 5%-10% of cases and myocardial metastases in about 5% of patients with CHD. 29 Others echocardiographic techniques can be used to assess valve involvement, such as transoesophageal echocardiography or 3D TTE, especially when the assessment in 2D TTE is difficult, notably for the evaluation of the pulmonary valve (Table 1). 3D TTE can also be helpful for the evaluation of ventricular dysfunction, as well as the assessment of the myocardial strain which quantifies regional myocardial functions, but these new techniques need to be validated. 34 Cardiac computed tomography (CT) scan can also be used for the assessment of CHD. While TTE is the gold standard for the diagnosis of CHD, CT allows the evaluation of all four valves including the pulmonary valve which is difficult to assess by TTE, the evaluation of ventricular volumes, the detection of possible myocardial metastases and the assessment of the coronary arteries before surgery. 4 Figure 4).
However, cardiac MRI is rarely performed in practice due to its cost and limited accessibility. Nuclear medicine imaging currently plays a limited role in the assessment of CHD but proves useful for the detection of myocardial metastases.

| GUIDELINES CONCERNING SCREENING AND FOLLOW-UP FOR CHD
Recommendations about screening and follow-up of CHD vary according to the different international societies (

| Treatment of CHD
No treatment has been reported to induce regression of the fibrousplaque deposits, and CHD-related valve disease is currently considered irreversible. Medical treatment should be initiated in cases of symptoms of heart failure. Most importantly, surgical valve replacement needs to be considered whenever valve involvement is severe ( Figure 5).

| Medical treatment
In patients with symptomatic heart failure, a treatment by loop diuretic agents in combination with salt restriction is proposed. 4,8 Other treatments including angiotensin-converting enzyme inhibitors and/or aldosterone antagonists can be proposed in cases of right ventricular dysfunction. Nevertheless, these treatments, as well as betablockers, are usually used in left-sided heart failure and have not shown their effectiveness in the specific setting of CHD. 47

| Surgical treatment
The only curative treatment of CHD remains surgical and cardiac valve replacement is the gold standard treatment. However, cardiac surgery is associated with a high risk of mortality, between 5% and 10%, notably due to the risk of perioperative carcinoid crisis and refractory right ventricular dysfunction. 17 (Table 3). 48,[51][52][53][54][55] As the pulmonary valve is often poorly visualized on TTE, evaluation of pulmonary valve involvement during surgery is advised (Figure 6). In a series of 11 patients operated on for CHD with systematic intraoperative inspection of pulmonary valve, detection of severe pulmonary valve involvement resulted in unplanned replacement in 27% of patients. 56 Overall, the pulmonary valve is replaced in 70%-90% of cases (Table 3). 48,[51][52][53][54][55] Should PFO be detected, its closure is usually performed during the same procedure, accounting for 10%-40% of patients.
The type of valve prosthesis should be discussed before surgery on a case-by-case basis. 4 Bioprostheses are used in about 90% of tricuspid valve replacements and in all cases of pulmonary valve replacement (Table 3). Notably, patients with CHD often have a life expectancy lower than the presumed durability of bioprostheses.
Moreover, mechanical prostheses are associated with a high risk of thrombosis, especially when tricuspid valve is concerned, and need long-term anticoagulants which can be difficult to manage in patients with metastatic disease who are at risk of further invasive procedures.
After surgery, all patients require lifelong follow-up including clinical assessment, TTE, and 5HIAA and NT-proBNP measurements, 3-6 months after surgery and then every 6-12 months, or whenever new cardiac symptoms occur. 4,8 Recurrent carcinoid involvement of a valve bioprosthesis is possible, requiring continued optimal control of CS after surgery. 48,57 The European Society of Cardiology recommends oral anticoagulation therapy using a vitamin K antagonist for the 3 first months after surgical implantation of a bioprosthesis in the tricuspid position. 58

| Perioperative management
Preoperative management is challenging in patients with CS and key determinants of postoperative outcomes are optimal control of CS symptoms and nutritional support. 4,47 Administration of antihistaminic agents and benzodiazepines is recommended before surgery to decrease anxiety and certain medications such as angiotensinconverting enzyme inhibitors should be discontinued. 45 During the perioperative period, the anaesthesiologist plays a major role to avoid complications associated with cardiac surgery in patients with CS. Perioperative management is complex due to the high risk of haemodynamic instability, and two situations must be taken into account.
The first is the risk of carcinoid crisis causing hypotension, severe bronchospasm and characteristic facial flushing. 49 Its prevention relies on the administration of intravenous octreotide, started 12 h before anaesthesia at a dose of 50-100 μg/h until 3 days after surgery, with F I G U R E 5 Management of patients with carcinoid heart disease with severe valvular involvement.
an additional bolus of 50-100 μg during induction to prevent carcinoid crisis. 4,45,46,49 In addition, sympathomimetics or drugs that stimulate histamine release such as morphine should be avoided or used with extreme caution during surgery. Second, haemodynamic instability can be related to right ventricular dysfunction. In this case, optimal volume management is required, as well as the use of catecholamines to improve myocardial contractility. 45    to apply in a real-life setting and the latest ENETS guidance paper underlines that the indication for cardiac surgery should rely on the presence of CHD-related symptoms. 4 Surgery is recommended when any cardiac symptoms occur in patients with severe valvular heart disease. 58 However, patients can be asymptomatic for a long time and when the first symptoms occur, heart involvement is often too severe to consider surgery. Indeed, more severe preoperative dyspnoea has been found to be associated with significantly higher risk of postoperative death. 48 Therefore, it has been suggested that cardiac surgery may be performed in asymptomatic or mildly symptomatic patients, although this proposal is controversial. 18,48,54 Cardiac surgery is contraindicated in cases of severe right ventricular dysfunction because it is associated with a higher risk of postop-