Author Contributions:
Muhammad Hamza Shah – Conceptualization, Writing – original draft, Writing – review and editing
Eleni Flari - Writing – original draft, Writing – review and editing
Brandon S H Low - Writing – original draft, Writing – review and editing
Subham Roy - Writing – original draft, Writing – review and editing
Arjun Ahluwalia - Writing – original draft, Writing – review and editing
Aditya Gaur - Writing – original draft, Writing – review and editing
John Hanna - Writing – original draft, Writing – review and editing
Ashna Arif - Writing – original draft, Writing – review and editing
Amer Harky - Writing – original draft, Writing – review and editing, Supervision
Acknowledgements: Muhammad Hamza Shah affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study planned have been explained.
Data Availability Statement: Data availability is not applicable to this article as no new data were created or analysed in this study.
Abstract: Carcinoid Heart Disease (CaHD) is a severe complication arising in patients with carcinoid syndrome, primarily impacting the heart’s right side through valvular dysfunctions such as tricuspid regurgitation and pulmonary stenosis. The pathology is closely linked to serotonin-induced fibrosis, challenging both diagnosis and treatment. Advances in echocardiography and cardiac MRI have significantly improved the early detection and assessment of CaHD, while management strategies have evolved to include both medical treatments, like somatostatin analogues and novel pharmacotherapies, and surgical interventions, notably valve replacement surgeries. Despite progress, debates persist around the optimal timing for surgery and the choice between bioprosthetic and mechanical valves, given the distinct risks and benefits of each. This review synthesises the current understanding of CaHD, emphasising diagnostic advancements and the spectrum of treatment options, and advocates for ongoing research to refine therapeutic approaches..
Keywords: Carcinoid Heart Disease, Neuroendocrine Tumours, Pathophysiology, Diagnosis, Management, Serotonin, Multidisciplinary Care, Cardiac Imaging, Valve Replacement
Abbreviations: CaHD: Carcinoid Heart Disease, MRI: Magnetic Resonance Imaging, NET: Neuroendocrine Tumour, TVR: Tricuspid Valve Replacement, PVR: Pulmonary Valve Replacement, 5-HT: 5-Hydroxytryptamine (Serotonin), 5-HIAA: 5-Hydroxyindoleacetic Acid, NT-proBNP: N-terminal pro b-type Natriuretic Peptide, TTE: Transthoracic Echocardiography, TOE: Transesophageal Echocardiography, CT: Computed Tomography, ECG: Electrocardiogram, CXR: Chest X-Ray, NYHA: New York Heart Association, PRRT: Peptide Receptor Radionuclide Therapy, RHF: Right Heart Failure,
Introduction:
Carcinoid Heart Disease (CaHD) represents a challenging cardiac pathology, predominantly observed in patients with carcinoid syndrome. This syndrome primarily arises from neuroendocrine tumours that are most often located in the gastrointestinal tract or bronchopulmonary system.1 Notably, up to 50% of patients with carcinoid tumours develop symptoms of the carcinoid syndrome, leading to CaHD, which significantly influences morbidity and mortality.2 Historically, untreated CaHD has been associated with a 3-year survival rate as low as 31%, markedly lower than the 68% in patients without cardiac involvement. However, the landscape of CaHD prognosis has considerably improved due to advancements in cardiac imaging, antitumor treatments, and surgical interventions.1 A retrospective study highlighted that median survival rates have increased from 1.5 years in the 1980s to 4.4 years in the late 1990s, largely attributed to the rise in cardiac surgery rates among these patients.3
CaHD is characterised by its distinctive involvement of the right side of the heart, particularly affecting the tricuspid and pulmonary valves. The result is a spectrum of valvular dysfunctions, predominantly leading to conditions such as tricuspid regurgitation, pulmonary stenosis, and ultimately right-sided heart failure.3 The pathophysiological processes underlying CaHD implicates various molecular pathways and cellular mechanisms. Most resources cite vasoactive substances, particularly serotonin, in stimulating fibroblast growth and fibrogenesis, contributing to the characteristic cardiac valvular fibrosis observed in CaHD.1,3,4 Despite the progress in understanding the disease, many aspects of its pathophysiology remain elusive, prompting ongoing research to uncover the intricate mechanisms and potential therapeutic targets.
Similarly, the diagnostic journey of CaHD has been revolutionised over the years, transitioning from a primarily echocardiography-based approach to a more comprehensive, multimodal strategy. Advanced imaging modalities, including cardiac magnetic resonance and speckle-tracking echocardiography, have enriched the diagnostic arsenal, allowing for more nuanced visualisation and assessment of the cardiac structures involved in CaHD.5 These advancements have not only improved diagnostic precision but have also facilitated the early detection of CaHD, potentially altering the clinical course of the disease. Furthermore, the management of CaHD is inherently complex, demanding a comprehensive, multidisciplinary approach that encompasses medical and surgical strategies. Medical management focuses on controlling the systemic malignancy and managing the release of vasoactive substances, primarily through the use of somatostatin analogues. In cases where valvular disease progresses, surgical approaches, such as valve replacement surgeries, become paramount. These procedures have shown promise in alleviating cardiac symptoms and enhancing patient survival.6 However, they are accompanied by their own set of challenges, including the careful selection of suitable candidates and the meticulous management of perioperative risks.
In this comprehensive review, we aim to synthesise our current understanding of CaHD, summarising its pathophysiology, the nuances of its diagnostic modalities, and the spectrum of its management strategies, while also exploring the frontier of emerging therapies and diagnostic tools that hold the promise of improving CaHD care.
Methodology:
This review evaluates the current understanding and management strategies of Carcinoid Heart Disease. The inclusion criteria for this review were limited to full-text articles written in English, covering the period from 2000 to 2023. This timeframe was selected to provide a comprehensive overview of the evolution of treatment protocols and diagnostic advancements in the field, capturing both longstanding practices and recent innovations.
Multiple databases were utilised for a thorough literature search, including PubMed, EMBASE, Google Scholar, the Cochrane Library, and Scopus. Key terms specifically related to Carcinoid Heart Disease were employed in the searches, such as “Carcinoid Heart Disease,” “Serotonin Heart Valve Disease,” “Neuroendocrine Tumours Cardiac Complications,” “Carcinoid Tumours Heart,” and “Right Heart Valve Dysfunction Carcinoid.” To broaden the search strategy, additional sources were identified through a manual examination of references listed in recent reviews focusing on CaHD and related cardiovascular complications. Strict exclusion criteria were applied, which involved omitting standalone abstracts, case reports, posters, and any unpublished or non-peer-reviewed material. This approach was aimed at maintaining the integrity of the review by ensuring the inclusion of only high-quality and scientifically robust evidence.
The scope of the review was not restricted to a specific number of studies, intending to encompass a comprehensive array of knowledge on Carcinoid Heart Disease. It included diverse study designs such as descriptive studies, animal-model studies, cohort studies, and observational studies. This inclusive approach ensured a wide-ranging understanding of Carcinoid Heart Disease, covering research conducted in both pre-clinical and clinical settings. A summary of the methodology used is provided in Table 1, illustrating the depth and breadth of the literature search and selection process.