Severe Carcinoid Heart Disease with Left-Sided Involvement

Ahmadreza Karimianpour, DO
Gary P. Miller, MD
Brian W. Zagol, MD
Volume 55 - Issue 11 - November 2015

A 73-year-old woman with no known history of coronary artery disease presented to the emergency department with complaints of sudden-onset left-sided substernal chest pain characteristic of myocardial infarction, but no other symptoms such as flushing, hypotension, or bronchospasm.

Physical examination. Her blood pressure was 168/76 mm Hg, her heart rate was 77 beats per min, her respiratory rate was 17 breaths per min, her temperature was 37.3°C, and her oxygen saturation was 100% via nasal cannula with a flow rate of 2 L per min. Auscultation of the heart revealed a regular rate and rhythm, with a grade 2/6 systolic murmur on the right second intercostal spaces radiating to the carotids, and a grade 3/6 holosystolic murmur on the left lower sternal border. Jugular venous distension was noted at the angle of the jaw. The rest of the physical examination results were unremarkable.

Diagnostic tests. Serial cardiac marker test results returned negative. An electrocardiogram showed normal sinus rhythm with no abnormalities. Subsequent left-heart catheterization revealed minor nonobstructive coronary artery disease.

Echocardiography then was performed, the results of which showed congestive cardiomyopathy with an ejection fraction of 45% to 50% and biatrial enlargement. Moderate to severe mitral regurgitation and severe tricuspid regurgitation secondary to immobile leaflets also were noted (Figure 1).
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Transesophageal echocardiography revealed a patent foramen ovale, tricuspid valve thickening with immobile leaflets, a dilated right atrium, and thickened mitral and aortic valve leaflets (Figure 2). Color Doppler flow examination revealed
severe tricuspid regurgitation exceeding the Nyquist limit, and moderate to severe mitral regurgitation (Figure 3).

Right-heart catheterization revealed normal pulmonary artery pressure and no significant intracardiac shunts, with a ratio of total pulmonary blood flow to total systemic blood flow (Qp/Qs ratio) of 0.97, findings consistent with a patent foramen ovale rather than an atrial septal defect.

Review of imaging results revealed findings suggestive of cardiac carcinoid syndrome with left-sided valve involvement due to the presence of a patent
foramen ovale.

CT of the abdomen, a 24-hour 5-hydroxyindoleacetic acid (5-HIAA) urine test, and a serum chromogranin A test were ordered. The 5-HIAA test results returned at 47.1 mg/24 h (reference range, 0-14.9 mg/24 h), and serum chromogranin A results returned at 177 nmol/L (reference range, 0-5 nmol/L). Abdominal CT scans revealed multiple hypodense lesions measuring 2 to 3 cm in diameter that were believed to be metastatic in origin.

Discussion. When a carcinoid tumor is located strictly within the small intestine, excess serotonin produced by the tumor is released into afferent hepatic circulation and faces hepatic metabolism to 5-HIAA, which then is excreted by the renal system and has little effect on the body. However, when carcinoid tumors metastasize to the liver, serotonin production at the site of metabolism saturates nearly all enzymes; excess serotonin then escapes first-pass metabolism and enters systemic circulation, causing a set of distinct symptoms known as carcinoid syndrome.1

Characteristic signs and symptoms of carcinoid syndrome include long-standing cutaneous vasomotor flushing, telangiectasia, GI hypermotility, secretory diarrhea, bronchospasm, hypotension, labile blood pressure, extremity swelling, hepatomegaly, abdominal pain, bloating, anorexia, and early satiety.2

The prevalence of carcinoid tumors is 1 to 2 per 100,000, of which 10% lead to carcinoid syndrome. Approximately 50% of patients with carcinoid syndrome develop carcinoid heart disease within 2 years.2

Carcinoid heart disease is the end-stage effect of increased serum serotonin secondary to carcinoid syndrome. The exact mechanism of cardiac plaque formation is unknown, but it is believed to be secondary to the action of serotonin.3 Carcinoid heart disease is characterized by right-sided heart failure secondary to tricuspid insufficiency. The insufficiency is related largely to fibrosis, shortening, and retraction of leaflets into the right ventricle.4,5 Pulmonic valve involvement commonly is present and is manifested by immobile valvular cusps, cusp retraction, and pulmonary annular constriction that lead to pulmonary outflow obstruction and pulmonic insufficiency. Left-sided heart valve involvement occurs only in the presence of right-to-left intracardiac shunts, intrapulmonary shunts, or with bronchial carcinoid or pulmonary metastasis.2,6 Patients with significantly increased serotonin levels are at greater risk for developing carcinoid valvular heart disease.2,7

In the diagnosis of carcinoid heart disease, 24-hour urine 5-HIAA is 75% sensitive and 100% specific, whereas serum chromogranin A testing is only 68% sensitive and 86% specific for the condition.8,9 Also consider that certain medications and substances such as levodopa, ethanol, imipramine, aspirin, and phenothiazines may falsely lower 5-HIAA values, while acetaminophen, nicotine, caffeine, phenobarbital, tryptophan supplements, and certain fruits and vegetables may falsely elevate 5-HIAA values.2,10

Cardiomegaly is seen on chest radiographs in approximately 50% of patients, while pleural effusions and metastatic pleural plaques are late findings. Echocardiographic findings are paramount to the diagnosis of carcinoid heart disease. Tricuspid valve involvement is seen in 97% of patients and is manifested by leaflets that are thickened, shortened, retracted, and hypomobile. In most patients, the leaflets are rigid and fixed in a semi-open position. Severe tricuspid regurgitation is characterized by a dagger-shaped spectral profile on continuous-wave Doppler examination, with an early peak pressure and rapid decline consistent with severe tricuspid regurgitation with rapid equalization of right atrial and right ventricular pressures.

Pulmonic valve involvement is common, and changes in valve morphology are similar to those of the tricuspid valve, with leaflet thickening and retraction, and with narrowing of the pulmonary annulus resulting in significant pulmonary insufficiency and/or pulmonary stenosis.

Left-sided valve involvement is much less common and almost always seen with a patent foramen ovale. The degree of left-sided involvement seems to be proportional to the severity of the shunt. Left-sided valves have similar morphologic changes to the right-sided valvular changes, with leaflet thickening, retraction, and hypomobility.11-13

Treatment of carcinoid heart disease is directed primarily at symptomatic relief and is similar to that of other causes of heart failure. Medical treatment with diuretics and angiotensin-converting enzyme inhibitors is indicated, in addition to fluid restriction and lower-extremity compression stockings for treatment of volume overload.2 Somatostatin analogues such as octreotide and lanreotide may provide symptomatic relief but do not reverse the cardiac damage.14

Valve replacement is indicated in patients with poor exercise tolerance, accelerating fatigue, and a failing ventricle. When considering valve replacement, mechanical valves withstand the effect of vasoactive peptides. However, the need for chronic anticoagulation makes mechanical valve replacement risky in patients with significant liver metastasis. Therefore, bioprosthetic valves can be considered, even though they can be affected by vasoactive peptides.2

Balloon valvuloplasty may be considered for stenosed valves unless valvular insufficiency coexists, in which cases balloon valvuloplasty can worsen the insufficiency.15

A 2-decade analysis by Møller and colleagues16 exhibited an overall median survival of 5.9 years (95% confidence interval [CI], 5.0-6.8 years) from first diagnosis of carcinoid syndrome and 2.6 years (95% CI, 1.6-3.2 years) for those first diagnosed with carcinoid heart disease.Ultimately, patients with carcinoid heart disease die of tricuspid regurgitation and right-heart failure rather than from the primary tumor.2,17 However, a multifaceted approach including surgery, pharmacotherapy, and strict cardiac surveillance can decrease the risk of death from right-sided heart failure.16,17

Outcome of the case. The initial workup was inconclusive; however, reevaluation led to the diagnosis of severe carcinoid heart disease with both right- and left-sided valvular involvement secondary to a patent foramen ovale—just hours before considering valve replacement surgery in the patient. Given the unusual clinical presentation in this case, the correct diagnosis ultimately was made with the recognition of classic echocardiographic features of the disease.

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