Sanjeev Bhattacharyya

Carcinoid Heart Disease

Carcinoid tumors are relatively rare neuroendocrine malignancies most commonly originating from enterochromaffin cells in the gastrointestinal tract. The incidence is ≈1 in 100 000 of the general population.1 They usually grow slowly over years, commonly causing no symptoms at all until they become large or have metastasized. Carcinoid tumors of midgut origin may secrete large amounts of vasoactive substances, including 5-hydroxytryptamine (5-HT), tachykinins, and prostaglandins. These are largely inactivated by the liver. Carcinoid syndrome occurs when tumor cells metastasize to the liver as the vasoactive substances produced are able to reach the systemic circulation via the hepatic vein. Clinically, this is characterized by flushing, diarrhea, and bronchospasm. Over the past decade, several new therapies for carcinoid tumors have emerged to reduce symptoms and cause tumor regression. Most notably, the development of somatostatin analogs, which inhibit the release of various biogenic amines and peptides, including serotonin, has resulted in a marked improvement in symptoms.2 These may also have contributed to increased survival, although this has not been proved.2,3 Rarely, surgical resection is curative for nonmetastatic disease. Otherwise, reduction of symptoms, improvement in quality of life, and improvement in survival by inhibition of tumor hormones or reduction of tumor load are the main goals. Metastatic disease of the liver may be debulked either surgically or by hepatic artery embolization in selected patients. Interferon therapy and targeted radionuclide therapy may stabilize or reduce the tumor. Chemotherapy is rarely an option except for pancreatic, bronchial, and high-grade neuroendocrine tumors. Carcinoid heart disease (CHD) was first reported in 1954.4 Several series have reported CHD in up to 70% of cases of carcinoid syndrome.5,6 Development is thought to relate to the vasoactive substances secreted by the metastatic tumor cells in the liver, reaching the right heart. This is associated with deposition …

Drug-induced fibrotic valvular heart disease

The initial association between the development of valvular heart disease and drugs stems from observations made during the use of methysergide and ergotamine for migraine prophylaxis in the 1960s. Since then, the appetite suppressants fenfluramine and dexfenfluramine, the dopamine agonists pergolide and cabergoline, and more recently, the recreational drug ecstasy (3,4 methylenedioxymethamphetamine; MDMA) have been implicated. Results from clinical trials show that drug dose and treatment duration affect both the risk of developing the disease and its severity. The natural history of the disease remains unclear, although regression of valvular lesions after the end of treatment has been reported. Interference with serotonin metabolism and its associated receptors and transporter gene seems a likely mechanism for development of the drug-induced valvular heart disease. Physicians need to balance the benefits of continued therapy with these drugs against possible risks. Further investigation is needed to assist with treatment decisions. Continued vigilance is necessary because several commonly prescribed treatments interact with serotonergic pathways.

Features of Carcinoid Heart Disease Identified by 2- and 3-Dimensional Echocardiography and Cardiac MRI

Background—Carcinoid heart disease is a rare form of valvular heart disease. We sought describe the spectrum of carcinoid heart disease identified by echocardiography and cardiac MRI. Method and Results—Two hundred fifty-two patients with carcinoid syndrome underwent a range of investigations including 2D transthoracic echocardiography, 3D transthoracic echocardiography and transesophageal echocardiography, and cardiac MRI. Fifty-two patients had evidence of carcinoid heart disease. Involvement of the tricuspid, pulmonary, mitral, and aortic valves were found in 47 (90%), 36 (69%), 15 (29%), and 14 (27%), respectively. Myocardial metastases were found in 2 (3.8%) patients. Several patterns of disease were identified depending on the extent and severity to which each leaflet and its associated subvavlular apparatus was affected. Thirteen of 15 (87%) patients with left-sided carcinoid involvement had a patent foramen ovale. Three patients with severe degree of shunting had severe valvular regurgitation. Patients with mild/moderate degree of shunting had mild or moderate valvular regurgitation. Three-dimensional transthoracic echocardiography/transesophageal echocardiography provided detailed anatomic information particularly for the tricuspid and pulmonary valves. Cardiac MRI allowed complementary assessment of valvular heart disease and delineation of myocardial metastases. Gallium-68 octreotide positron emission tomography identified neuroendocrine metastases. Conclusions—Carcinoid heart disease is a heterogeneous disease with a wide spectrum of echocardiographic findings. A multimodality approach is needed in patients with this complex pathology.

Features of Carcinoid Heart Disease Identified By Two- and Three- Dimensional Echocardiography and Cardiac Magnetic Resonance Imaging

Background—Carcinoid heart disease is a rare form of valvular heart disease. We sought describe the spectrum of carcinoid heart disease identified by echocardiography and cardiac MRI. Method and Results—Two hundred fifty-two patients with carcinoid syndrome underwent a range of investigations including 2D transthoracic echocardiography, 3D transthoracic echocardiography and transesophageal echocardiography, and cardiac MRI. Fifty-two patients had evidence of carcinoid heart disease. Involvement of the tricuspid, pulmonary, mitral, and aortic valves were found in 47 (90%), 36 (69%), 15 (29%), and 14 (27%), respectively. Myocardial metastases were found in 2 (3.8%) patients. Several patterns of disease were identified depending on the extent and severity to which each leaflet and its associated subvavlular apparatus was affected. Thirteen of 15 (87%) patients with left-sided carcinoid involvement had a patent foramen ovale. Three patients with severe degree of shunting had severe valvular regurgitation. Patients with mild/moderate degree of shunting had mild or moderate valvular regurgitation. Three-dimensional transthoracic echocardiography/transesophageal echocardiography provided detailed anatomic information particularly for the tricuspid and pulmonary valves. Cardiac MRI allowed complementary assessment of valvular heart disease and delineation of myocardial metastases. Gallium-68 octreotide positron emission tomography identified neuroendocrine metastases. Conclusions—Carcinoid heart disease is a heterogeneous disease with a wide spectrum of echocardiographic findings. A multimodality approach is needed in patients with this complex pathology.

Analysis of 150 Patients With Carcinoid Syndrome Seen in a Single Year at One Institution in the First Decade of the Twenty-First Century

Carcinoid heart disease (CHD), reported in 50% to 70% of patients with carcinoid syndrome, is thought to be related to the production of 5-hydroxytryptamine by the tumor. The development of new therapeutic modalities designed to reduce tumor hormone production may have altered the development of CHD. Currently, echocardiography is performed when clinical suspicion of CHD exists. The aim of this study was to establish the prevalence of CHD in the setting of modern treatment regimens and delineate whether a screening program for CHD is needed. One hundred fifty patients with carcinoid syndrome were screened for CHD by transthoracic echocardiography. The functional status of patients was classified according to New York Heart Association class. Thirty patients (20%) were found to have CHD. Of those with CHD, 14 (47%) had left- and right-sided valvular lesions. Patent foramen ovale was present in all patients with left-sided CHD. Forty-three percent of patients were in New York Heart Association class I, 40% in class II, 13% in class III and 3% in class IV. Eight patients (27%) with moderate or severe valvular lesions were in class I. Thirty-seven percent of patients with CHD had no physical signs. In conclusion, the presence of symptoms or abnormalities on clinical examination has a low sensitivity for the presence of CHD. Therefore, screening with echocardiography, even in patients who are asymptomatic, should be advocated.

Usefulness of N-terminal Pro–Brain Natriuretic Peptide as a Biomarker of the Presence of Carcinoid Heart Disease

We sought to investigate whether N-terminal pro-brain natriuretic peptide (NT-pro-BNP) can be used as a biomarker for the detection of carcinoid heart disease (CHD); 200 patients with carcinoid syndrome were screened for CHD using transthoracic echocardiography. A carcinoid score was formulated to quantify severity of CHD. NT-pro-BNP was measured in all patients before echocardiography. Patients were categorised into New York Heart Association class. CHD was present in 39 patients (19.5%). NT-pro-BNP was significantly higher in those with CHD (median 1,149 pg/ml) than in those without CHD (median 101 pg/ml, p <0.001). The sensitivity and specificity of NT-pro-BNP at a cut-off level of 260 pg/ml for detection of CHD were 0.92 and 0.91, respectively. NT-pro-BNP positively correlated both with carcinoid score (r = 0.81, p <0.001) and New York Heart Association class (p <0.001). The number of patients screened to diagnose 1 case of CHD decreased from 5.1 to 1.4. In conclusion, NT-pro-BNP seems to be an excellent biomarker of CHD. A high negative predictive value may allow it to provide a screening test for CHD.

Outcomes, risks and complications of cardiac surgery for carcinoid heart disease

OBJECTIVE The development of carcinoid heart disease causes significant valvular dysfunction, eventually leading to symptomatic right heart failure and impaired survival. Data regarding cardiovascular surgery are limited. We sought to identify outcomes, risks and complications of valve surgery for carcinoid heart disease. METHODS Twenty-two patients with carcinoid heart disease underwent cardiac valve surgery between 2006 and 2010. Patients were considered for surgery if (1) they had stable carcinoid tumour, (2) they had severe valvular dysfunction and (3) were symptomatic and (4) they had no other significant co-morbidities. Three patients underwent tricuspid valve replacement alone, 15 patients underwent tricuspid and pulmonary valve replacement, two patients underwent tricuspid, pulmonary and mitral valve replacement and two patients underwent quadruple valve replacement. RESULTS Overall 30-day mortality was 18%. Causes of death were right ventricular dysfunction (two patients), carcinoid crises (one patient) and pneumonia (one patient). Four patients required permanent pacemaker for complete heart block. Of those that survived initial surgery, median follow-up was 26 months (interquartile range 8-42); 1- and 2-year survival rates were 56% and 44%, respectively. There was no significant difference in survival between those patients in the New York Heart Association (NYHA) class I/II, mild/moderate right ventricular dilatation or N-terminal brain natriuretic peptide (NT-proBNP) <1245 pg ml(-1) compared with those in NYHA class III/IV, severe right ventricular enlargement or NT-proBNP > 1245 pg ml(-1), respectively. Long-term causes of death were related to advanced metastatic carcinoid tumour. No patient required re-operation for bioprosthetic degeneration. CONCLUSION Valve surgery for carcinoid heart disease is of higher risk compared with most other forms of valvular surgery. However, in those that survive the operation significant improvement in functional class occurs. Most long-term complications were related to the tumour itself rather than cardiac complications.

Risk Factors for the Development and Progression of Carcinoid Heart Disease

The development of valvular heart disease in patients with carcinoid syndrome is thought to be related to the secretion of vasoactive substances by a tumor. We sought to identify modifiable risk factors for the development of carcinoid heart disease because this may help define strategies to attenuate the disease process. Two hundred fifty-two patients with carcinoid syndrome were prospectively followed with serial echocardiograms at 6-month intervals. Clinical characteristics, biochemical markers, and radiologic markers were measured at set intervals. An echocardiographic scoring system was applied. Patients were defined as having progression of carcinoid heart disease if the echocardiographic score increased by ≥25%. After a median follow-up of 29 months, 44 patients developed carcinoid heart disease or had progression of existing valvular dysfunction. At time of progression of carcinoid heart disease compared to the previous 6 months, there was a significant increase in median levels of 5-hydroxyindoleacetic acid (5-HIAA; 791 vs 460.5 μmol/24 hours) and flushing episodes (4.5 vs 2 episodes per day). Independent predictors of the development or progression of carcinoid heart disease were a 5-HIAA level ≥ 300 μmol/24 hours and ≥ 3 episodes of flushing per day. 5-HIAA levels of ≥ 300 to 599, 600 to 899, and > 900 μmol/24 hours conferred 2.74, 3.16, and 3.40 times the risk of progression of carcinoid heart disease, respectively. In conclusion, a 5-HIAA level ≥ 300 μmol/24 hours and ≥ 3 flushing episodes per day are predictors of the development or progression of carcinoid heart disease.

Risk stratification in asymptomatic severe aortic stenosis: a critical appraisal

Aortic stenosis is one of the most common forms of acquired valvular heart disease. The development of symptoms, namely syncope, angina, or heart failure, in patients with severe aortic stenosis predicts a high likelihood of mortality. Aortic valve replacement is the current standard of care. In truly asymptomatic patients, the risk of sudden death is perceived to be low; therefore many advocate conservative management of these patients until symptoms develop. Emerging data suggest that certain markers may identify subsets of asymptomatic patients who are at a high risk of cardiac events. This review critically appraises the growing plethora of adverse prognostic markers that have been identified and evaluates how these parameters may influence clinical practice and potentially identify patients in whom early surgical intervention is warranted.

Diagnosing and Managing Carcinoid Heart Disease in Patients With Neuroendocrine Tumors: An Expert Statement

Carcinoid heart disease is a frequent occurrence in patients with carcinoid syndrome and is responsible for substantial morbidity and mortality. The pathophysiology of carcinoid heart disease is poorly understood; however, chronic exposure to excessive circulating serotonin is considered one of the most important contributing factors. Despite recognition, international consensus guidelines specifically addressing the diagnosis and management of carcinoid heart disease are lacking. Furthermore, there is considerable variation in multiple aspects of screening and management of the disease. The aim of these guidelines was to provide succinct, practical advice on the diagnosis and management of carcinoid heart disease as well as its surveillance. Recommendations and proposed algorithms for the investigation, screening, and management have been developed based on an evidence-based review of the published data and on the expert opinion of a multidisciplinary consensus panel consisting of neuroendocrine tumor experts, including oncologists, gastroenterologists, and endocrinologists, in conjunction with cardiologists and cardiothoracic surgeons.