NET-Induced Carcinoid Heart Disease Affecting Both Tricuspid and Aortic Valves Due to Patent Foramen Ovale and Right/Left Shunt: A Multi-imaging Challenge to Nuclear Medicine.

ABSTRACT: Carcinoid heart disease (Hedinger syndrome) is a long-term consequence in hormone-active neuroendocrine tumors with hepatic metastases and carcinoid syndrome. Because of serotonin, excess multiple cardiac and pulmonary symptoms evolve, which are further complicated by a patent foramen ovale due to right-left shunting. We present a 53-year-old man with an ileum-neuroendocrine tumor including gross liver metastases and long-term stable disease who subsequently developed Hedinger syndrome. Initially experiencing progressive dyspnea, he eventually experienced severe hypoxemia due to patent foramen ovale. 99mTc-MAA lung perfusion scintigraphy quantitatively identified the right-left shunting, whereas 68Ga-FAPI-46 PET/CT characterized the typical fibrous heart valve thickening due to serotonin-induced fibroblast proliferative properties.

Carcinoid heart disease: a potentially fatal complication of carcinoid syndrome.

Carcinoid heart disease is a unique and serious cardiac complication of the neuroendocrine tumour that affects the right side of the heart, especially the tricuspid and pulmonic valves, eventually causing right heart failure. We present a middle-aged man with a history of well-differentiated neuroendocrine tumours of the small intestine with extensive metastases to the liver, mesentery and spine who is receiving monthly octreotide therapy. He presented with generalised fatigue, severe ascites and worsening dyspnoea. Both the transthoracic echocardiography and transoesophageal echocardiography revealed severe tricuspid and pulmonic regurgitations. He was considered a poor surgical candidate, underwent transcatheter pulmonic valve replacement with two bioprosthetic valve-in-valve implantations and was discharged in a stable condition.

Patent foramen ovale in carcinoid heart disease: The potential role for and risks of percutaneous closure prior to cardiothoracic surgery.

Neuroendocrine tumours (NETs) are rare but once metastasised, can lead to the release of vasoactive substances into the systemic circulation, and the classical features of carcinoid syndrome (CS) such as flushing and diarrhoea. A consequence of CS is carcinoid heart disease (CHD) which primarily affects the right-sided heart valves and can eventually lead to right heart failure. In this cohort, tricuspid and/or pulmonary valve replacement provides symptomatic relief. A patent foramen ovale (PFO) in patients with CHD can lead to the shunting of oxygen deficient blood to the systemic circulation causing hypoxaemia and reduced exercise tolerance. Additionally, the haemodynamic changes caused by regurgitant right-sided heart valves can increase the patency of a PFO allowing the passage of vasoactive substances to the systemic circulation thereby affecting the left-sided heart valves. We present data on the incidence of PFO in patients referred for surgery at our centre, in which the standard approach is to close the defect at time of cardiothoracic surgery. In addition, we present a series of four cases that highlight how the option of percutaneous PFO closure prior to open valve surgery may reduce haemodynamic instability and open a window of opportunity to enhance preoperative status. Percutaneous PFO closure then acts as a bridge to definitive cardiothoracic surgery, although there are risks in such an approach.

Management and outcomes of carcinoid heart disease with liver metastases of midgut neuroendocrine tumours.

OBJECTIVE: Despite recent advances in surgical and interventional techniques, knowledge on the management of carcinoid heart disease (CHD) remains limited. In a cohort of patients with liver metastases of midgut neuroendocrine tumours (NETs), we aimed to describe the perioperative management and short-term outcomes of CHD. METHODS: From January 2003 to June 2022, consecutive patients with liver metastases of midgut NETs and severe CHD (severe valve disease with symptoms and/or right ventricular enlargement) were included at Beaujon and Bichat hospitals. All patients underwent clinical evaluation and echocardiography. RESULTS: Out of 43 (16%) consecutive patients with severe CHD and liver metastases of midgut NETs, 79% presented with right-sided heart failure. Tricuspid valve replacement was performed in 26 (53%) patients including 19 (73%) cases of combined pulmonary valve replacement. The 30-day postoperative mortality rate was high (19%), and preoperative heart failure was associated with worse survival (p=0.02). Epicardial pacemakers were systematically implanted in operated patients and 25% were permanently paced. A postoperative positive right ventricular remodelling was observed (p<0.001). A greater myofibroblastic infiltration was observed in pulmonary versus tricuspid valves (p<0.001), suggesting that they may have been explanted at an earlier stage of the disease than the tricuspid valve, with therefore potential for evolution. CONCLUSIONS: We observed a high postoperative mortality rate and baseline right-sided heart failure was associated with worse outcome. In surviving patients, a positive right ventricular remodelling was observed. Prospective, multicentre studies are warranted to better define the management strategy and to identify biomarkers associated with outcome in CHD.

The Past, Present, and The Future of Carcinoid Heart Disease.

Carcinoid heart disease is a frequent manifestation of carcinoid syndrome. It results from the release of a large amount of serotonin and subsequently fibrosis of right sided heart valves, that is, tricuspid and pulmonic valve. This article reviews the pathogenesis, clinical symptoms, diagnosis, treatment and prognosis of carcinoid heart disease. Recent developments in treating carcinoid heart disease have improved the poor prognosis associated with the disease.

A Case of Primary Insular Ovarian Carcinoid Tumor with Hyperandrogenism and Carcinoid Heart Disease.

BACKGROUND Carcinoid heart disease typically occurs in the presence of metastatic carcinoid tumor deposits in the liver, as vasoactive substances access the systemic circulation through the hepatic vein. Primary ovarian carcinoid tumors are rare neuroendocrine tumors, and can be associated with carcinoid syndrome and carcinoid heart disease. CASE REPORT We describe the case of a 40-year-old woman who presented with secondary amenorrhea, acne, hirsutism, and diarrhea. She was found to have a heart murmur on exam in the absence of severe symptoms of heart failure. Her investigations demonstrated elevated urinary 5-hydroxyindoleacetic acid (5-HIAA), chromogranin A, and free testosterone. Abdominal computed tomography enterography showed a large and hypervascular pelvic mass. Octreotide scintigraphy confirmed the diagnosis of primary ovarian carcinoid tumor in the setting of an intensely octreotide-avid mass with no evidence of distant metastases. Transesophageal echocardiography showed severe tricuspid regurgitation with severe dilation of the right heart chambers. She underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The pathology demonstrated a 14-cm carcinoid tumor of 'insular' type confined to the ovary, pT1apNX, grade 1, positive for chromogranin and synaptophysin (neuroendocrine markers) and positive mib-1 (Ki-67). Postoperatively, clinical and biochemical parameters improved significantly but her cardiac function regressed over time, resulting in a tricuspid valve replacement 6 years later. CONCLUSIONS Primary ovarian carcinoid tumors can result in carcinoid heart disease, even in the absence of liver metastases. Early diagnosis and treatment contribute to favorable outcomes.

Chromogranin A (CgA) as a biomarker in carcinoid heart disease and NETG1/G2 neuroendocrine neoplasms of the small intestine (SI-NENs) related carcinoid syndrome

IntroductionProgression of carcinoid syndrome (CS) to carcinoid heart disease (CHD) is difficult to predict. This retrospective analysis evaluates the use of chromogranin A (CgA), a biomarker widely used in the diagnosis of neuroendocrine tumours (NET), in monitoring CS and disease progression.Patients and methods108 patients with confirmed CS, selected from a group of 351 patients with neuroendocrine neoplasms of the small intestine (SI-NENs), including NETG1 well 40% and NETG2 60% moderately differentiated NET. CgA concentration was measured during initial diagnosis and clinical follow up in 84 patients, 27 of them subsequently developed CHD. The patient's overall survival (OS) was evaluated using the Kaplan-Meier method.ResultsPatients with CHD, were found to have significantly shorter OS than patients with CS but without CHD (67.22 vs. 73.03 months). Univariate and multivariate analyses revealed that initial high concentration of CgA and/or increased concentration of CgA is significantly associated with decreased median OS in patients with CS (p<0.05).ConclusionCgA has potential as a clinically useful biomarker in reporting disease status and predicting outcome in patients with CS and with CHD. (AU)

IntroducciónLa progresión hacia la afectación cardiaca en el síndrome carcinoide (SC) es difícil de predecir. En el presente análisis retrospectivo se evaluó el uso de la cromogranina A (CgA), un biomarcador ampliamente utilizado en el diagnóstico de los tumores neuroendocrinos (TNE), en el seguimiento del SC y en la progresión de la enfermedad.Pacientes y métodosSe incluyeron 108 pacientes con SC confirmado, seleccionados de un grupo de 351 pacientes con tumores neuroendocrinos del intestino delgado (TNE-ID). El 40% de pacientes tenían un TNE G1 bien diferenciado y un 60% un TNE G2 moderadamente diferenciado. Los niveles de CgA se determinaron en el momento del diagnóstico y durante el seguimiento en 84 pacientes, 27 de los cuales desarrollaron afectación cardiaca. La supervivencia global de los pacientes se evaluó mediante el método de Kaplan-Meier.ResultadosLos pacientes con afectación cardiaca tuvieron una supervivencia global significativamente más corta que aquellos sin ella (67,22 frente a 73,03 meses). El análisis univariado y multivariado mostró que los niveles inicialmente altos de CgA y/o los niveles elevados de CgA durante la evolución se asocian de forma significativa con una menor supervivencia global en los pacientes con SC (p<0,05).ConclusiónLa CgA constituye un biomarcador clínicamente útil para evaluar la progresión de la enfermedad y la afectación cardiaca en pacientes con SC. (AU)

Ablation of typical atrial flutter as therapeutic component in carcinoid heart disease: a case report.

BACKGROUND: Carcinoid heart disease is the cardiac manifestation of carcinoid syndrome. There is limited research on rhythm management in patients with carcinoid heart disease. The association of typical atrial flutter and carcinoid heart disease in particular is poorly described. CASE PRESENTATION: Here we present a case of a 77-year-old German woman with carcinoid heart disease and recurrent typical atrial flutter complicating the postoperative course after tricuspid valve replacement and its successful long-term rhythm control by ablation therapy. CONCLUSION: There is limited evidence on rhythm management in patients with the rare diagnosis of carcinoid heart disease. Typical atrial flutter repeatedly complicated the postoperative course of our patient with carcinoid heart disease and could finally be treated curatively by ablation. Radiofrequency ablation should be considered as a valuable therapeutic component in the challenging therapy of this disease.

Transcatheter Pulmonary Valve Implantation in Carcinoid Heart Disease.

Carcinoid heart disease is a rare condition affecting mostly tricuspid and pulmonary valves causing right-sided heart failure. Surgical valve replacement is the mainstay of treatment when patients become symptomatic and/or in the presence of right heart remodeling. We present a case of severe pulmonary valve regurgitation secondary to carcinoid heart disease occurring 4 years after a surgical tricuspid replacement, successfully treated with direct transcatheter pulmonary valve implantation without pre-stenting.

Chromogranin A (CgA) as a biomarker in carcinoid heart disease and NETG1/G2 neuroendocrine neoplasms of the small intestine (SI-NENs) related carcinoid syndrome.

INTRODUCTION: Progression of carcinoid syndrome (CS) to carcinoid heart disease (CHD) is difficult to predict. This retrospective analysis evaluates the use of chromogranin A (CgA), a biomarker widely used in the diagnosis of neuroendocrine tumours (NET), in monitoring CS and disease progression. PATIENTS AND METHODS: 108 patients with confirmed CS, selected from a group of 351 patients with neuroendocrine neoplasms of the small intestine (SI-NENs), including NETG1 well 40% and NETG2 60% moderately differentiated NET. CgA concentration was measured during initial diagnosis and clinical follow up in 84 patients, 27 of them subsequently developed CHD. The patient's overall survival (OS) was evaluated using the Kaplan-Meier method. RESULTS: Patients with CHD, were found to have significantly shorter OS than patients with CS but without CHD (67.22 vs. 73.03 months). Univariate and multivariate analyses revealed that initial high concentration of CgA and/or increased concentration of CgA is significantly associated with decreased median OS in patients with CS (p<0.05). CONCLUSION: CgA has potential as a clinically useful biomarker in reporting disease status and predicting outcome in patients with CS and with CHD.

Clinical Features and Prognosis of Patients with Carcinoid Syndrome and Carcinoid Heart Disease: A Retrospective Multicentric Study of 276 Patients.

INTRODUCTION: Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. METHODS: We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. RESULTS: Carcinoid syndrome patients had a mean age of 57 years (range 21-84) and a normal BMI of 24.9 (SD 4.5; range 13.8-39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. DISCUSSION/CONCLUSION: Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.

Outcomes and periprocedural management of cardiac implantable electronic devices in patients with carcinoid heart disease.

BACKGROUND: Carcinoid heart disease (CHD) is a rare complication of hormonally active neuroendocrine tumors that often requires surgical intervention. Data on cardiac implantable electronic device (CIED) implantation in patients with CHD are limited. OBJECTIVE: The purpose of this study was to evaluate the experience of CIED implantation in patients with CHD. METHODS: Patients with a diagnosis of CHD and a CIED procedure from January 1, 1995, through June 1, 2020, were identified using a Mayo Clinic proprietary data retrieval tool. Retrospective review was performed to extract relevant data, which included indications for implant, procedural details, complications, and mortality. RESULTS: A total of 27 patients (55.6% male; mean age at device implant 65.6 ± 8.8 years) with cumulative follow-up of 75 patient-years (median 1.1 years; interquartile range 0.4-4.6 years) were included for analysis. The majority of implanted devices were dual-chamber permanent pacemakers (63%). Among all CHD patients who underwent any cardiac surgery, the incidence of CIED implantation was 12%. The most common indication for implantation was high-grade heart block (66.7%). Device implant complication rates were modest (14.8%). No patient suffered carcinoid crisis during implantation, and there was no periimplant mortality. Median time from implant to death was 2.5 years, with 1-year mortality of 15%. CONCLUSION: CHD is a morbid condition, and surgical valve intervention carries associated risks, particularly a high requirement for postoperative pacing needs. Our data suggest that CIED implantation can be performed relatively safely. Clinicians must be aware of the relevant carcinoid physiology and take appropriate precautions to mitigate risks.

Carcinoid syndroma - diagnosis and management.

Neuroendocrine tumors (NETs, originally termed “carcinoids”) create a relatively rare group of neoplasms with an approximate incidence rate of 5 to 8 cases per 10 000 persons. NETs predominantly demonstrate indolent disease biology for many years. They become symptomatic when they are large enough or when they metastasize to the liver or the lungs, bones, or other sites. Roughly 30% to 40% of subjects with NETs develop carcinoid syndrome. Signs and symptoms of carcinoid syndrome are bronchospasm, flushing, diarrhea and cramping, cyanosis and pellagra. White plaque-like deposits on the endocardial surface of heart structures are characteristic for carcinoid heart disease. The treatment of patients with carcinoid syndrome is multi-faceted due to the necessity to manage simultaneously the systemic cancer disease as well as the signs of carcinoid syndrome and includes resection or debulking of tumor mass, biological treatment with somatostatin analogues and peptide receptor radionuclide treatment.

Managing carcinoid heart disease in patients with neuroendocrine tumors.

Carcinoid heart disease is a complex clinical entity frequently complicating the course of neuroendocrine tumors and carcinoid syndrome and is associated with significant morbidity and mortality. Although the pathogenesis of carcinoid heart disease remains poorly understood, it appears that the exposure to excessive circulating levels of serotonin contribute a key role, triggering a cascade of events that ultimately results in the development of plaque-like material on the endocardial surfaces of the valve leaflets. The occurrence of carcinoid heart disease may initially run an asymptomatic period, followed by the development of symptoms of congestive cardiac failure. The diagnosis of carcinoid heart disease is suspected by raised biomarkers, such as serum NT-pro-BNP and confirmed by imaging modalities, with echocardiogram being the gold standard to date. Carcinoid heart disease treatment remains challenging as in addition to cardiac dysfunction, tumor burden needs to be tackled with, hence requiring a multidisciplinary approach. Therapy comprises watchful waiting during the first initial stages of the disease; medications for heart failure; optimal control of serotonin secretion from the NET with pharmacotherapy, interventional means or even surgical techniques; and, in selected patients, cardiac valve replacement. The current review summarizes the literature on the diagnosis and management of carcinoid heart disease.