Molecular biology of carcinoid heart disease: Seeking therapeutic targets in the era of targeted therapy.

Carcinoid tumors (CT) are among the least studied tumors. It is a relatively rare and slow-growing tumor with good survival in its primary form. However, metastatic carcinoid tumor comes up with many different complications contributing to increased morbidity and mortality. Metastatic form of the disease has a wide spectrum of clinical manifestations and multisystem involvement including cardiovascular manifestations, neurological manifestations, and psychiatric manifestations and so on. In this review, we are centered towards the cardiovascular manifestations of the disease, which, by far, is one of the commonest causes of death in these patients. Being a neuroendocrine tumor, cardiovascular manifestations are mainly because of biologically active substances, produced by the tumor cells, remodeling the heart. Development of targeted therapies against carcinoid heart diseases is currently limited by lack of understanding of pathophysiology of the disease processes. In this review, we aim to figure out the spectrum of carcinoid heart diseases, along with the molecular biology of the changes going on, which, in turn, will not only pave a way to the development of targeted therapies but will also extend opportunities for molecular screening of the tumor and diagnosis at an early stage, thereby, reducing the morbidity and mortality.

Carcinoid syndrome-Symptoms and therapeutic approaches.

The carcinoid syndrome (CS) is a constellation of symptoms attributed to hypersecretion of amines, prostaglandins and polypeptides. The cardinal symptoms of CS are flushing, diarrhea and bronchospasm; however, CS may present with various symptoms and signs, as: Skin: cutaneous flushes, cyanosis, pellagra, Gastrointestinal: diarrhea, nausea, abdominal cramps, vomiting, Heart: tricuspid and pulmonic valve thickening causing right heart failure, edema, Respiratory: wheezing, dyspnea.

Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration.

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.

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.

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.

Current Practice in Carcinoid Heart Disease and Burgeoning Opportunities.

OPINION STATEMENT: Cardiac surgery with tricuspid valve and potentially pulmonic valve replacement at an experienced center is currently the most effective strategy available for the treatment of carcinoid heart disease. Cardiac surgery for carcinoid heart disease requires a multidisciplinary team including cardiology, medical oncology, cardiothoracic anesthesia, and cardiac surgery. Without cardiac surgery, morbidity and mortality from carcinoid heart disease is high. Aggressive management of carcinoid before and after cardiac surgery is critical. Over time, though, circulating carcinoid hormones can lead to destruction of prosthetic valves as well, resulting in recurrent right heart failure. Percutaneous options for valve repair may be on the horizon for management of carcinoid heart disease.

Four decades of experience with carcinoid heart disease: An analysis of 84 patients.

Carcinoid heart disease (CHD) is a serious cardiac condition which is caused by elevated serotonin in the systemic circulation, secreted by neuroendocrine tumours (NET). It mostly affects the right-sided heart valves, where it causes fibrotic disturbances and is associated with worse survival. In this study, we describe a large cohort of patients with CHD and provide an insight into their survival over the past decades. All consecutive patients with a serotonin producing NET and CHD referred to the Netherlands Cancer Institute that presented with CHD or developed CHD during their follow up time were included from 1984 until 2021. Patients were divided into three time periods: 1984-2000, 2000-2010 and 2010-2018. Median N-terminal pro B-type natriuretic protein (NT-proBNP) and serum serotonin levels were stratified according to tricuspid regurgitation severity. Kaplan-Meier curves and log rank test were used for visualisation of survival. Cox regression was used for identification of the characteristics associated with disease specific mortality (DSM). A total of 84 patients with CHD were included of whom 49 (58.3%) were male. Median age at NET diagnosis was 62.3 (range 23.9-81.7) years, and median time to development of CHD was 1.1 (range 0-24.2) years. NT-proBNP was significantly higher when more severe tricuspid regurgitation (TR) was present (p = .027). Median survival from CHD diagnosis for 1984-2000, 2000-2010 and 2010-2018 were 1.3 (confidence interval [CI]: 0.9-1.6), 1.9 (CI: 1.2-2.6) and 3.9 (CI: 1.7-6.2) years (p = .025). Valve replacement surgery (VSR) occurred more frequent in later time periods. VSR (hazard ratio [HR] 0.33, p = .005) and NT-proBNP (HR 1.003, 1.00-1.005, p = .036) were significantly associated with DSM. The prognosis of patients with CHD has improved over the past decades, possibly caused by more VSR. NT-proBNP is a valuable biomarker in patients with CHD. Clinical practice should be aimed at timely diagnosis and intervention of CHD.

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.

What do we know about carcinoid heart disease in the present era?

Carcinoid heart disease (CHD) is a severe complication of carcinoid syndrome (CS) found primarily in patients with small intestine neuroendocrine neoplasms (SI-NENs). Patients who develop CHD have significantly worse morbidity and mortality outcomes, highlighting the importance of clinical practice recommendations for CHD screening, diagnosis, and treatment that are both consistent and practical. CHD is characterized by white plaque-like deposits on the endocardial surface of heart structures, generally affecting the right heart valves, causing tricuspid and pulmonary regurgitation and, less commonly, valve stenosis. Cardiac imaging is essential for both the diagnosis and management of CHD. Previously, imaging for CHD was mostly achieved by echocardiography, but more recently, imaging has become multimodal. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and 5-hydroxyindoleacetic acid in the urine (u5-HIAA) are currently the most effective markers used in screening CS patients and evaluating CHD severity. Managing patients with CHD is challenging since both systemic malignant disease and cardiac involvement must be treated concurrently. Early diagnosis and surgical intervention when required are critical to patient prognosis, especially in those without primary tumor resection. Valve replacement surgery is the most effective treatment for patients with advanced carcinoid heart disease for alleviating cardiac symptoms and contributing to survival outcomes. To deliver effective patient treatment, multidisciplinary team collaboration is needed. This review summarizes current research findings on CHD pathogenesis, clinical and epidemiological features, useful biomarkers and imaging modalities, and treatment strategies.

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)

Arterial function, biomarkers, carcinoid syndrome and carcinoid heart disease in patients with small intestinal neuroendocrine tumours.

PURPOSE: Carcinoid heart disease (CHD) is a life-threatening complication of carcinoid syndrome (CS) characterised by tricuspid regurgitation (TR). However, there is an unmet need for earlier diagnosis of CHD. We cross-sectionally assessed the prevalence and potential predictive or diagnostic markers for CS and CHD in a contemporary cohort of patients with small intestinal neuroendocrine tumours (SI-NETs). METHODS: Biochemical characteristics, hepatic tumour load, measures of arterial and endothelial function, atherosclerosis, and transthoracic echocardiography were analysed in a prospective cross-sectional setting. RESULTS: Among the 65 patients studied, 29 (45%) had CS (CS+ ), and 3 (5%) CHD. CS+ was characterised by significantly higher hepatic tumour load, S-5-HIAA and fP-CgA, higher frequency of diarrhoea and flushing, and more frequent PRRT compared to CS- (for all, P < 0.05). Central systolic, central mean, and central end-systolic blood pressures were significantly higher in CS+ than in CS- (for all, P < 0.05). Subjects with grades 2-4 TR had higher hepatic tumour burden, fP-CgA, and S-5-HIAA compared to those with grades 0-1 TR, but measures of vascular function did not differ. fP-CgA (P = 0.017) and S-5-HIAA (P = 0.019) but not proBNP increased significantly according to the severity of TR. CONCLUSION: Although CS is common, the prevalence of CHD was found to be lower in a contemporary cohort of SI-NET patients than previously anticipated. Measures of arterial or endothelial function or carotid atherosclerosis do not identify subjects with mild TR. Echocardiography remains the most sensitive means to diagnose CHD in CS patients with high tumour burden and elevated CgA and 5-HIAA.

The prevalence, operations, and outcomes of carcinoid heart disease.

BACKGROUND: Carcinoid heart disease (CHD) is a sequela of carcinoid liver metastases (LM). The true prevalence of CHD is unknown due to infrequent screening by transthoracic echocardiography (TTE). Octreotide is believed to protect against new and recurrent CHD, but supporting data are scant. This study determined CHD prevalence and outcomes in patients screened by TTE and treated with octreotide. METHODS: Records of carcinoid patients from 2001 to 2021 were reviewed. Survival was estimated by Kaplan-Meyer curves and compared by log-rank. RESULTS: Among 282 patients screened by TTE, overall survival was lower in CHD (n = 40) versus non-CHD (n = 242) patients (p < 0.001). Despite octreotide therapy, 21 patients developed CHD. Among patients with inoperable LM, survival was lower in CHD patients without valve replacement (VR) (p < 0.001), but similar between CHD patients with VR and non-CHD patients. CHD patients with VR and hepatic cytoreduction had survival similar to CHD patients without VR. CONCLUSION: VR improves survival in CHD patients with inoperable LM. Hepatic cytoreduction after VR should be reserved for carefully selected cases. Our data do not support a protective effect of octreotide.

WITHDRAWN: Dealing With the Right Side: Carcinoid Heart Disease.

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Journal of Cardiothoracic and Vascular Anesthesia, 36 (2022) 2793-2802, http://dx.doi.org/10.1053/j.jvca.2021.10.030. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

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.

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.

Outcomes of surgical treatment for carcinoid heart disease: A systematic review and meta-analysis.

BACKGROUND: Carcinoid heart disease (CaHD) develops from vasoactive substances released by neuroendocrine tumors, which can cause significant patient morbidity and mortality without surgical intervention. We performed a systematic review and meta-analysis to elucidate granular perioperative details and long-term outcomes in these patients. METHODS: Electronic search of Ovid, Scopus, Cumulative Index of Nursing and Allied Health Literature, and Cochrane Controlled Trials Register was performed to examine surgical treatment of carcinoid disease. Nine articles comprising 416 patients were selected. Study-level data were extracted and pooled for meta-analysis. RESULTS: Mean patient age was 63 years (95% confidence interval, 57-70) with 53% (95% confidence interval, 46-61) of patients being male. In addition, 75% (95% confidence interval, 54-96) of neuroendocrine tumors originated from the small bowel or colon and 98% (95% confidence interval, 93-100) had liver metastases. Right heart failure was present in 48% (95% confidence interval, 14-81). Moderate or severe regurgitation was present in 97% (95% confidence interval, 95-99) of tricuspid and 72% (95% confidence interval, 58-83) of pulmonary valves. In addition, 99% (95% confidence interval, 98-100) of tricuspid and 59% (95% confidence interval, 38-79) of pulmonary valves were replaced. Bioprosthetic valves were used in 80% (95% confidence interval, 68-93) of tricuspid positions. Mean hospital duration of stay was 16 days (95% confidence interval, 7-25). Thirty-day mortality was 9% (95% confidence interval, 6-12). Mean follow-up was 25 months (95% confidence interval, 11-39). Median survival was 3 years (95% confidence interval, 2.5-3.5). CONCLUSION: For patients >18 years of age, surgical treatment of carcinoid heart disease can be performed with a reasonable safety profile. However, overall survival appears to have ongoing effects of the primary disease.