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.

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.

Carcinoid Heart Disease: a Review.

PURPOSE OF REVIEW: The development of carcinoid heart disease (CHD) is a fibrotic complication of neuroendocrine neoplasms (NEN) which is associated with a poor prognosis. This review aims to summarise the clinical features, investigations and management of this condition. RECENT FINDINGS: CHD can affect up to 50% of NET patients with carcinoid syndrome. However, it is often not screened for appropriately and recognised late when patients become symptomatic. A screening strategy with biomarkers and multimodality imaging is necessary for early recognition. Management by an experienced multidisciplinary team with appropriate medical therapeutic strategies and where indicated surgical intervention is needed to optimise clinical outcomes. CHD is a poor prognostic factor, but recently, outcomes have improved due to the multidisciplinary approach and centralised care of CHD-NET patients.

Update in carcinoid heart disease - the heart of the matter.

Carcinoid heart disease (CHD) is a paraneoplastic cardiac manifestation occurring in patients with carcinoid syndrome (CS) and advanced neuroendocrine malignancy. In about 20-40% of patients with CS, chronic exposure to tumor-released circulating vasoactive peptides typically results in right-sided valvular fibrosis leading to valve dysfunction and right heart failure. CHD remains a significant cause of morbidity and mortality. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Early diagnosis and timely surgical intervention in selected patients are of utmost importance and offer a survival benefit. In patients with advanced carcinoid heart disease, valve replacement surgery is the most effective option to alleviate cardiac symptoms and contribute to survival outcomes. A collaboration of a multidisciplinary team in centers with experience is required to provide optimal patient management. Here, we review the current literature regarding CHD presentation, pathophysiology, diagnostic tools, and available treatment strategies.

Carcinoid Heart Disease: Prognostic Value of 5-Hydroxyindoleacetic Acid Levels and Impact on Survival: A Systematic Literature Review.

BACKGROUND: Carcinoid heart disease (CHD) can develop in patients with carcinoid syndrome (CS), itself caused by overproduction of hormones and other products from some neuroendocrine tumours. The most common hormone is serotonin, detected as high 5-hydroxyindoleacetic acid (5-HIAA). This systematic literature review summarises current literature on the impact of CHD on survival, and the relationship between 5-HIAA levels and CHD development, progression, and mortality. METHODS: MEDLINE, Embase, Cochrane databases, and grey literature were searched using terms for CHD, 5-HIAA, disease progression, and mortality/survival. Eligible articles were non-interventional and included patients with CS and predefined CHD and 5-HIAA outcomes. RESULTS: Publications reporting on 31 studies were included. The number and disease states of patients varied between studies. Estimates of CHD prevalence and incidence among patients with a diagnosis/symptoms indicative of CS were 3-65% and 3-42%, respectively. Most studies evaluating survival found significantly higher mortality rates among patients with versus without CHD. Patients with CHD reportedly had higher 5-HIAA levels; median urinary levels in patients with versus without CHD were 266-1,381 versus 67.5-575 µmol/24 h. Higher 5-HIAA levels were also found to correlate with disease progression (median progression/worsening-associated levels: 791-2,247 µmol/24 h) and increased odds of death (7% with every 100 nmol/L increase). CONCLUSIONS: Despite the heterogeneity of studies, the data indicate that CHD reduces survival, and higher 5-HIAA levels are associated with CHD development, disease progression, and increased risk of mortality; 5-HIAA levels should be carefully managed in these patients.

Serotonin levels and 1-year mortality in patients with neuroendocrine tumors: a systematic review and meta-analysis.

Aim: Elevated serotonin in patients with neuroendocrine tumors (NETs) may impact heart failure incidence but a quantitative relationship has not been established. Materials & methods: Systematic review and meta-analysis of studies assessing 24-h urinary 5-hydroxyindoleacetic acid (u5-HIAA) and mortality in patients with NETs (2007-2017) with a primary outcome of 1-year mortality risk and 24-h u5-HIAA. Results: We identified 1715 records of which 12 studies including 755 patients (3442 person-years with 376 deaths) were eligible for meta-analysis. Mean u5-HIAA was 149.2 mg/24 h (standard deviation: 96.6) and mortality was 13.0%. The meta-regression equation showed an 11.8% (95% CI: 8.9-17.0%; I2  = 93.0%) increase in 1-year mortality for every ten-unit increase in u5-HIAA. Conclusion: Serotonin measured by its metabolite u5-HIAA is predictive of 1-year all-cause mortality in patients with NETs.

A Case of Carcinoid Syndrome Due to Malignant Metastatic Carcinoid Tumor with Carcinoid Heart Disease Involving Four Cardiac Valves.

BACKGROUND Carcinoid tumor, benign, low-grade malignant, and high-grade malignant, can be associated with the release of vasoactive substances that cause symptoms including cutaneous flushing, diarrhea, and bronchospasm. In 50-60% of patients with carcinoid syndrome, the vasoactive substances cause fibrosis of the pulmonary and tricuspid heart valves which lead to regurgitation and right-sided heart failure. The right side of the heart is usually affected because monoamine oxidases in the lungs usually inactivate the vasoactive substances. CASE REPORT A 62-year-old woman presented with a four-month history of diarrhea and abdominal discomfort. The patient had bilateral pelvic masses and elevated serum CA125 and an elevated urinary 5-hydroxyindoleacetic acid (5-HIAA). Total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) identified a primary appendiceal carcinoid tumor with bilateral ovarian metastases. Post-operatively, a computed tomography (CT) scan showed cardiomegaly. Transthoracic echocardiography showed morphologic changes that affected all four heart valves, consistent with carcinoid heart disease but without a patent foramen ovale (PFO). The patient was evaluated for valve replacement surgery, but surgery was not performed due to the degree of heart failure. CONCLUSIONS This report describes a rare case of carcinoid heart disease with involvement of all four cardiac valves, but without the presence of a PFO, possibly due to a large amount of vasoactive substances in the patient's circulation, as supported by the patient's elevated urinary 5-HIAA. This rare presentation highlights the importance of early diagnosis and treatment with tumor resection and, if possible, Cardiac valve replacement to prevent irreversible heart failure.

Echocardiography in functional midgut neuroendocrine tumors: When and how often.

The management of patients with midgut neuroendocrine tumors (MNET) is rapidly evolving. Current preoperative detection rates of primary tumor sites are higher than ever and progression-free survival in patients with already advanced disease is expanding due to the implementation of novel efficacious treatment strategies. This survival benefit may potentially translate into a need for a multidisciplinary approach to an even more heterogenous variety of clinical conditions, among these, carcinoid syndrome (CS) and carcinoid heart disease (CHD). The latter often triggers substantial morbidity and mortality, hence a systematic screening, an accurate diagnosis, as well as effective interventions are critically important. The rarity of the disease has result in a relative lack of statistically powerful evidence, which in turn may have rendered significant variability between practices. In this regard, despite recent guidelines, the optimal follow-up of patients with CHD remain debatable to some authors, perhaps due to the preponderance of certain schools throughout the manuscript. Herein, we present a concise and practical guidance document on clinical screening and echocardiographic surveillance of patients with CHD based on a comprehensive review of the literature, and complemented by our experience at the Center for Carcinoid and Neuroendocrine Tumors at The Mount Sinai Hospital.

Carcinoid Syndrome and Carcinoid Heart Disease as Manifestations of Non-Metastatic Ovarian Neuroendocrine Tumour.

The carcinoid syndrome is rare but it is associated with carcinoid heart disease in more than a half of the cases. Carcinoid heart disease is typically characterised by morphological and functional modifications of right-sided valves. Its aetiology is probable multifactorial but serotonin appears to play a key role in the development of this valvular disease. Unlike gastrointestinal neuroendocrine tumours, ovarian neuroendocrine tumours can present with carcinoid syndrome and carcinoid heart disease in the absence of liver metastases; such ovarian neuroendocrine tumours are a unique clinical entity. The additional burden of cardiac impairment in these patients represents a significant reduction in survival. Early recognition and surgical valve replacement before advanced heart failure is established may improve the clinical outcome. We report the case of a woman with an ovarian neuroendocrine tumour and highly symptomatic carcinoid heart disease who was submitted to tumour resection followed by valvuloplasty. She demonstrated an outstanding clinical improvement and has remained free of tumour and symptomatology.

A síndrome carcinoide é rara mas encontra-se associada, em cerca de metade dos casos, a doença carcinoide cardíaca. Esta patologia cardíaca caracteriza-se tipicamente por alterações morfo-funcionais das válvulas direitas. A sua etiologia é provavelmente multifatorial mas, aparentemente, a serotonina parece exercer um papel preponderante no desenvolvimento desta doença valvular. Ao contrário dos tumores neuroendócrinos gastrointestinais, os tumores neuroendócrinos do ovário podem apresentar síndrome carcinoide e doença carcinoide cardíaca na ausência de metastização hepática, tornando os tumores neuroendócrinos do ovário uma entidade clínica única. Estas alterações cardíacas acarretam uma diminuição adicional da sobrevivência destes doentes. Portanto, o reconhecimento precoce desta entidade e a substituição valvular prévia ao estabelecimento da insuficiência cardíaca avançada podem melhorar a evolução clínica destes doentes. Os autores apresentam o caso de uma mulher com tumor neuroendócrino do ovário e doença carcinoide cardíaca muito sintomática que foi submetida a resseção tumoral seguida de valvuloplastia. A doente demonstrou uma marcada melhoria clínica e tem permanecido livre de doença e assintomática.

[Cardiovascular complications of cancers and anti-cancer therapy]. / Kardiovaskulární komplikace nádoru a jejich lécby.

In our aging population the incidence of cancer is increasing in the elderly. We are thus facing a new challenge especially considering incidence of cardiovascular diseases (CVD) in this patients population. Overall survival of cancer patients has significantly improved therefore cancer has become in many cases a chronic disease. We are about to be treating patients who either may develop a new CVD or their current CVD may deteriorate. Cancer can cause various cardiovascular conditions locally (pressure in mediastinum, effusions) or systemically (increased risk of pulmonary embolism, arrhythmias, carcinoid heart disease). Medical cancer therapy can lead to congestive heart failure (CHF) per se, by anthracycline or antiHER2 therapy direct cardiac toxicity or by number of other cardiac conditions medical treatment can cause, such as accelerated arterial hypertension due to anti-angiogenic therapy (tyrosine-kinase inhibitors, bevacizumab) or even standard chemotherapy (alkylating agents, cisplatin) or overusing steroids in cancer patients. Atrial fibrillation (AFib) also contributes to CHF development. AFib in cancer patients may develop secondary to ischaemia in anaemic patients, metabolic disorders caused by cancer or treatment, pulmonary embolism, sepsis or even as a result of direct impact of cytotoxic treatment (cisplatin, ifosfamide, gemcitabine, 5-fluorouracil, etoposide). One of major risk factors for CHF is coronary artery disease (CAD), which is a very serious late sequel of cancer therapy mainly in long time cancer survivors (testicular cancer, childhood cancer, hematologic malignancies, breast cancer). CAD may develop secondary to thoracic irradiation, dyslipidemia caused by hormonal treatment or simply as results of endothelial dysfunction caused by alkylating agents. In summary, long time cancer survivors represent a subgroup of patients at great risk of developing CVD in any form. It is crucial to mention that these patients can develop typical CVD much earlier compared to standard population and therefore require special follow-up with active surveillance.Key words: anthracycline - atrial fibrillation - cardiac toxicity - heart failure - pulmonary embolism.

Percutaneous balloon valvuloplasty in carcinoid pulmonary valve stenosis.

More than half of patients with carcinoid syndrome develop carcinoid valve disease. Both the tricuspid and pulmonary valve are often involved. Symptoms of carcinoid syndrome with flushing, diarrhea, and bronchospasm often precedes cardiac symptoms. We report a case of carcinoid initially presenting with rapid development of right heart failure due to severe pulmonary valve stenosis. In untreated carcinoid, there is a risk of carcinoid crisis with anesthesia and surgery. In local anesthesia, we performed a sub-acute balloon pulmonary valvuloplasty. The procedure was successful without any residual pulmonary valve stenosis and with immediately relief of dyspnea. The final diagnostic workup for the underlying malignancy continued the day after valvuloplasty. © 2015 Wiley Periodicals, Inc.

Metastatic small bowel neuroendocrine tumour with bilateral carcinoid heart disease.

A 63-year-old woman was admitted with a year's history of exertional breathlessness, anxiety attacks, syncopal episodes, diarrhoea, fatigue, reduced appetite, 2 stones weight loss, and flushing affecting her face and trunk. Investigations revealed raised urine 5-hydroxy indole acetic acid (5-HIAA) and chromogranin A. CT scan demonstrated extensive soft tissue encasing the major vessels intra-abdominally, and a retroperitoneal mass. (111)In-octreotide single-photon emission CT (SPECT CT) showed increased focal activity in the mediastinum, retroperitoneum and mesenteric lymph nodes. Para aortic lymph node biopsy confirmed the diagnosis of metastatic well-differentiated grade 1 gastrointestinal neuroendocrine tumour (NET). Extensive cardiac investigations confirmed severe mitral regurgitation, moderate aortic and tricuspid regurgitation, and mild pulmonary regurgitation. The patient's symptoms of flushing and diarrhoea were controlled with octreotide LAR, and she underwent mechanical aortic and mitral valve replacement. Following discharge from surgery, she went on to develop hydronephrosis and urosepsis, followed by infective endocarditis, resulting in recurrent admissions, and eventually passed away in her sleep nearly 14 months after her initial diagnosis.

Variation in Cardiac Screening and Management of Carcinoid Heart Disease in the UK and Republic of Ireland.

AIMS: Screening for carcinoid heart disease is an important, yet frequently neglected aspect of the management of patients with neuroendocrine tumours (NETs). Screening is advocated in international guidelines, although recommendations on the modality and frequency are poorly defined. We mapped current practice for the screening and management of carcinoid heart disease in specialist NET centres throughout the UK and Republic of Ireland. MATERIALS AND METHODS: Thirty-five NET centres were invited to complete an online questionnaire outlining the size of NET service, patient selection criteria for carcinoid heart disease screening and the modality and frequency of screening. RESULTS: Twenty-eight centres responded (80%), representing over 5500 patients. Eleven per cent of centres screen all patients with any NET, 14% screen only patients with midgut NETs, 32% screen all patients with liver metastases and/or carcinoid syndrome and 43% screen all patients with evidence of syndrome or raised urinary/serum/plasma 5-hydroxyindoleacetic acid (5HIAA). The mode of screening included clinical examination, echocardiography and biomarker measurement: 89% of centres carry out echocardiography, ranging from at initial presentation only (24%), periodically without clearly defined intervals (28%), annually (36%) or less than annually (12%); three centres use a scoring system to report their echocardiograms. Fifty per cent of centres utilise biomarkers for screening (chromogranins, plasma/urinary 5HIAA or most commonly N-terminal pro-brain natriuretic peptide) at varying time intervals. CONCLUSION: There is considerable heterogeneity across the UK and Ireland in multiple aspects of screening and management of carcinoid heart disease.

Resolution of right-sided heart failure symptoms after resection of a primary ovarian carcinoid tumor.

Carcinoid tumors are rare neuroendocrine malignancies that typically originate from the gastrointestinal tract. Patients who are diagnosed with carcinoid heart disease generally have poor prognoses because of advanced metastases during staging and few therapeutic options. We present the case of a 61-year-old woman with right-sided heart failure, secondary to carcinoid heart disease caused by a primary ovarian carcinoid tumor. After undergoing surgical resection of the left ovary and fallopian tube, the patient experienced complete resolution of her heart failure symptoms. In addition to the patient's case, we discuss the diagnosis, nature, and treatment of this rare condition.

Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality.

BACKGROUND: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. METHODS: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. RESULTS: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l(-1) increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l(-1) increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. CONCLUSIONS: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.

Carcinoid heart disease: current understanding and future directions.

Carcinoid tumors are rare and aggressive malignancies. A multitude of vasoactive agents are central to the systemic effects of these tumors. The additional burden of cardiac dysfunction heralds a steep decline in quality of life and survival. Unfortunately, by the time carcinoid syndrome surfaces clinically, the likelihood of cardiac involvement is 50%. Although medical therapies such as somatostatin analogues may provide some symptom relief, they offer no mortality benefit. On the other hand, referral to surgery following early detection has shown increased survival. The prompt recognition of this disease is therefore of the utmost importance.