Tricuspid and Pulmonary Valve Involvement in Carcinoid Disease

Abstract

We report the case of a 62-year-old woman in whom carcinoid disease had been diagnosed 6 years earlier. She subsequently developed tricuspid and pulmonary valve disease. Both valves were incompetent and mildly stenotic. The tricuspid valve required surgery; the pulmonary valve was explored but not treated.

Valve surgery in patients with carcinoid disease is discussed in light of the prognosis of these patients, the timing of valvular lesion presentation, and the choice of prosthesis. The justification for multiple-valve procedures in such cases is also considered.

Cardiac involvement in patients with carcinoid disease has been well documented. ¹ Early reports described right-sided heart involvement. More recently, ^2,3 both right- and left-sided heart disease have been reported. Progress in the medical and surgical treatment of patients with carcinoid disease is leading to an increase in the number of such patients presenting with valvular dysfunction. Because the prognosis ^4–6 of the basic disease has improved, valve replacement surgery is now a reasonable option in patients with severe valvular dysfunction.

Case Report

We report the case of a 62-year-old woman who had presented to the department of gastroenterology in January 1988 with diarrhea and flushing of the skin. Colonoscopy with biopsies had revealed a moderately differentiated adenocarcinoma of the sigmoid colon. Further screening had revealed diffuse liver metastasis. Laboratory results showed elevated levels of 5-hydroxyindoleacetic acid (5-HIAA). These levels, together with the flushing and the liver metastasis, led to the tentative diagnosis of carcinoid disease—a diagnosis subsequently confirmed by liver biopsies. The patient had undergone resection of a carcinoid tumor from the sigmoid colon and terminal ileum. Adjuvant therapy included chemotherapy and H₁- and H₂-receptor antagonists (antihistamines). Due to persisting high levels of 5-HIAA, somatostatin therapy was started in an attempt to control the hy-persecretory activity of the tumor. Despite this treatment, the acid levels remained at 8 to 9 times the normal value.

In December 1994, the patient developed a congestive cough and dyspnea. She was in New York Heart Association (NYHA) functional class II. Echocardiographic examination revealed leaflet thickening and fibrosis, along with thickening of the chordae tendineae and papillary muscle, resulting in massive regurgitation of the tricuspid valve (4/4) and a transvalvular gradient of 7 mmHg. The pulmonary valve leaflets also showed fibrous deposits and thickening, leading to valvular insufficiency of 1 to 2 on a scale of 4 and mild stenosis. Subsequent cardiac catheterization showed a mean right atrial pressure of 11 mmHg, a systolic right ventricular pressure of 34 mmHg, and a mean pulmonary pressure of 12 mmHg. The transvalvular pulmonary gradient was 8 mmHg, and the left ventricular ejection fraction was 73%. The patient was referred to our department for surgical treatment.

At surgery, the tricuspid leaflets were visibly fibrotic and thickened, and the chordae tendineae were adherent. With the patient under moderate hypothermia, myocardial protection was achieved with cool crystalloid cardioplegic solution (myocardial temperature, 10 °C). After a median sternotomy, tricuspid valve replacement was performed through a right atriotomy at an esophageal temperature of 25 °C. The prosthetic valve was a 27-mm mechanical Sulzer Carbomedics valve (Sulzer Carbomedics, a part of the Cardiovascular Prosthesis Division of Sulzer Medica; Austin, Tex). The pulmonary valve was examined through a pulmonary arteriotomy. The valve was only slightly incompetent, the stenosis was mild, and the right ventricular contractility was good. Accordingly, the pulmonary valve was not replaced.

The cross-clamp time was 44 minutes. The initial attempt to wean the patient from cardiopulmonary bypass was unsuccessful, due to right ventricular dysfunction. Ketanserin, a known selective serotonin (5-HT₂) receptor antagonist, was administrated intravenously, along with noradrenaline. Reperfusion was instituted for 10 minutes. The patient was then successfully weaned from bypass. Her postoperative recovery was uneventful, and she was discharged after a hospital stay of 23 days.

Discussion

Carcinoid heart disease results from neoplasms of enterochromaffin cells. Patients who have carcinoid disease can survive up to 10 years after diagnosis, because the tumors, although malignant, are slow growing. These tumors are associated with the production of biologically active substances, depending on the tumor's site of origin. ^7,8 Serotonin is a common product of carcinoid tumors. Most such tumors contain tryptophan hydroxylase, which enables them to produce serotonin after hydroxylation and subsequent decarboxylation of the tryptophan. In turn, 5-hydroxyindole acetaldehyde, the oxidation product of serotonin, produces 5-HIAA, which is excreted in urine. Elevated levels of circulating serotonin have been associated with cardiac failure, due to fibrous deposits on the endocardium. These deposits are thought to be responsible for the fibrous degeneration of the valve apparatus.

In our patient, the echocardiographic image resembled that seen in rheumatic disease, but rheumatic disease most often affects the mitral valve and is not associated with high levels of 5-HIAA. Cardiac involvement in carcinoid disease generally results in right-sided valvular lesions, accompanied by tricuspid insufficiency and pulmonary stenosis. However, in the early 1990s, Materazzo and colleagues ² and Le Metayer and co-authors ³ reported left-sided cardiac involvement in carcinoid disease.

In our opinion, patients who have symptomatic valvular lesions should be evaluated for surgical treatment. Patients who have no contraindication for valve surgery and whose cardiac symptoms develop at an early stage of the disease should undergo the surgery. When cardiac symptoms develop late in the disease process, however, the overall condition of the patient may prevent valve surgery from improving the patient's prognosis or quality of life. In these cases, we would not operate.

One hazard of valve replacement in patients with carcinoid disease is progression onto the biological valve prosthesis. Progression onto a pulmonary valve homograft and onto a tricuspid bioprosthetic valve has been reported. ^9,10 Because of the fibrous degeneration seen in cardiac valves and the similar potential in bioprosthetic valves, ¹¹ we recommend the use of mechanical prostheses in the presence of carcinoid disease. When the pulmonary and tricuspid valves are both involved, open pulmonary valvulotomy is a reasonable option. If more cardiac valves are affected, multiple valve replacement should be considered. In these cases, we recommend applying the same criteria as those used in single-valve carcinoid disease. In our patient, we did not replace the pulmonary valve be-cause the insufficiency was slight, the stenosis was mild, and the right ventricular function was good. Such conditions did not warrant the risks of mechanical valve replacement in the pulmonary position, including the increased probability of thrombosis and of overall valve-related events. ¹²

The difficulty in weaning this patient from cardiopulmonary bypass can be attributed to the complex spectrum of serotonin activity. During the operation, the tumor's release of serotonin stimulated the 5-HT₂ receptors. These receptors are located in the periphery in postsynaptic locations and cause bronchospasm and increased pulmonary resistance by vascular constriction. The immediate effect of serotonin on the serotonin ³ receptors is a negative chronotropic effect. Later, the effect on these receptors is a positive inotropic and chronotropic effect by stimulation of the release of norepinephrine. During the 1st weaning, the reperfusion period in our patient was too short; however, the 2nd reperfusion period allowed the completion of the early negative chronotropic effect. Moreover, the stimulating effect of the 5-HT₂ receptors was neutralized by ketanserin, a strong 5-HT₂ receptor antagonist without a strong affinity for serotonin ₃ receptors. The ketanserin improved the peripheral blood flow by involving the α₁ receptors. This could explain the success of the 2nd weaning.

We conclude that valve replacement is a reasonable option in patients who have cardiac carcinoid disease that includes severe valvular incompetence. Mechanical valves are preferable to bioprostheses, because the latter are more vulnerable to the progression of carcinoid disease. After surgery, weaning such a patient from cardiopulmonary bypass requires caution; adequate time must be allowed for the negative effects of serotonin to be succeeded by the positive inotropic and chronotropic effects.