CardioNETPOL National Registry of Carcinoid Heart Disease

Overview

Carcinoid tumors are neuroendocrine tumors (NETs), most commonly originating from the gastrointestinal tract, that may secrete bioactive substances such as serotonin. Persistent exposure to these mediators can lead to carcinoid syndrome and, in up to 50% of patients, carcinoid heart disease (CHD). CHD is characterized by fibrotic degeneration of cardiac valves, predominantly right-sided, resulting in progressive valvular dysfunction and a significant increase in mortality. The mechanisms underlying selective cardiac involvement and predictors of disease progression remain incompletely understood. In addition, optimal timing and selection of surgical versus transcatheter valve interventions, particularly in high-risk patients, require further clarification. This multicenter, retrospective observational registry aims to identify and characterize patients with carcinoid heart disease and at least moderate valvular involvement. CHD is defined by confirmed neuroendocrine tumor, echocardiographic evidence of ≥ moderate valvular disease with features of fibrosis, elevated NT-proBNP (\>260 ng/L), and histopathological confirmation when available. Approximately 100-120 consecutive patients will be enrolled over 12 months. Standardized data collection will include detailed echocardiographic assessment, demographic and clinical characteristics, cardiovascular risk factors, comorbidities, tumor features, oncological treatment history, and cardiac management strategies. The primary objective is to describe the clinical profile and management of patients with CHD in a real-world multicenter setting. Secondary objectives include identifying factors associated with advanced valvular dysfunction and evaluating eligibility and outcomes of transcatheter valve therapies. The registry is expected to improve risk stratification and support clinical decision-making in carcinoid heart disease.

Carcinoid tumors are well-differentiated neuroendocrine neoplasms (NETs) capable of secreting vasoactive and fibrogenic substances, including serotonin, tachykinins, histamine, and prostaglandins. Persistent exposure to these mediators, particularly in the presence of hepatic metastases bypassing first-pass metabolism, may lead to the development of carcinoid syndrome and, in a substantial proportion of patients, carcinoid heart disease (CHD). Cardiac involvement is characterized by plaque-like fibrotic thickening of the endocardium, predominantly affecting right-sided heart valves, leading to leaflet retraction, reduced mobility, and progressive valvular regurgitation and/or stenosis. Over time, this process results in right ventricular volume overload, chamber dilation, heart failure symptoms, and reduced survival. Although CHD represents a major determinant of prognosis in patients with carcinoid syndrome, important gaps remain in understanding its natural history, predictors of progression, and optimal management strategies. The incidence and severity of cardiac involvement vary considerably between individuals with similar oncologic profiles. Biomarkers such as NT-proBNP are widely used for screening and monitoring, but their integration with imaging findings and clinical variables in risk stratification requires further refinement. In addition, advances in oncological therapy have improved overall survival in NET patients, thereby increasing the clinical relevance of long-term cardiovascular complications. Surgical valve replacement has traditionally been the standard treatment for advanced valvular dysfunction in CHD. However, many patients are at elevated operative risk due to metastatic disease burden, hepatic dysfunction, malnutrition, or other comorbidities. Emerging transcatheter valve therapies, including bicaval valve implantation and transcatheter tricuspid valve replacement or repair, offer potential alternatives for selected high-risk patients. Data regarding patient selection, anatomical suitability, procedural feasibility, and outcomes in the specific context of CHD remain limited. This multicenter, retrospective, observational registry is designed to provide a comprehensive characterization of patients with carcinoid heart disease and at least moderate valvular involvement. Participating centers will identify consecutive eligible patients treated within predefined study periods to minimize selection bias. The registry reflects real-world clinical practice and does not mandate any additional diagnostic or therapeutic interventions beyond standard of care. The study population consists of adult patients with a confirmed diagnosis of neuroendocrine tumor consistent with carcinoid tumor and evidence of carcinoid-related cardiac involvement. Cardiac involvement is established by echocardiographic documentation of at least moderate valvular dysfunction in conjunction with morphological features typical of fibrotic degeneration. Elevated NT-proBNP levels are required to support the presence of hemodynamic significance. In patients undergoing cardiac surgery, histopathological confirmation of carcinoid-related fibrosis will be recorded when available. A standardized data collection framework will be applied across centers. Baseline demographic data include age, sex, body mass index, and relevant cardiovascular risk factors. Comorbid conditions such as hypertension, diabetes mellitus, chronic kidney disease, chronic liver disease, and prior cardiovascular events will be documented. Functional status will be assessed using available clinical classifications, including New York Heart Association (NYHA) class where recorded. Comprehensive echocardiographic data will form a core component of the registry. Parameters to be collected include qualitative and quantitative assessment of tricuspid and pulmonary valve morphology and function, evaluation of left-sided valves when involved, right and left ventricular dimensions and systolic function, atrial size, inferior vena cava dimensions, and estimation of pulmonary artery pressures. When available, advanced imaging modalities (e.g., three-dimensional echocardiography or cardiac magnetic resonance imaging) will be documented, but their use is not mandated by the protocol. Oncological variables will include primary tumor location, histopathological grade (if available), presence and distribution of metastases (hepatic, lymph node, bone, cardiac, or other), biochemical activity, and prior or ongoing systemic therapies. These may include somatostatin analogs, targeted therapies, peptide receptor radionuclide therapy, chemotherapy, and surgical resection of the primary tumor or metastases. Temporal relationships between oncological diagnosis, onset of carcinoid syndrome, and detection of cardiac involvement will be analyzed when data permit. Cardiac management strategies will be recorded in detail. This includes medical therapy for heart failure, timing and type of surgical valve interventions, and the use of transcatheter approaches. For patients evaluated for transcatheter procedures, anatomical considerations, procedural planning parameters, and heart team decisions will be documented where available. Procedural outcomes, in-hospital course, and short-term follow-up data will be collected in accordance with local documentation standards. The primary objective of the registry is descriptive: to define the clinical, echocardiographic, and oncological profile of patients with moderate to severe carcinoid heart disease in a contemporary, multicenter cohort. Secondary objectives include identification of clinical and imaging features associated with advanced right ventricular dysfunction, exploration of factors associated with referral for surgical versus transcatheter intervention, and assessment of early clinical outcomes following different management strategies. Where longitudinal data are available, follow-up analyses will evaluate survival, heart failure progression, need for repeat interventions, and changes in functional status. A predefined subgroup analysis will focus on patients undergoing transcatheter valve therapies to assess feasibility, safety, and short- to mid-term effectiveness in this specific population. Data will be anonymized at the site level before central aggregation. Each participating center will obtain appropriate approval from its institutional ethics or bioethics committee in accordance with national regulations. Given the retrospective and observational nature of the registry, no study-specific interventions are performed, and patient management remains entirely at the discretion of the treating physicians. By systematically collecting and analyzing real-world data from multiple centers, this registry aims to enhance understanding of carcinoid heart disease, improve risk stratification, and support evidence-based decision-making regarding timing and type of valvular intervention. The results are expected to inform future prospective studies and contribute to the development of interdisciplinary care pathways integrating cardiology and oncology expertise in the management of this complex condition.