Case Report

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A 54-year-old white man presented with fatigue and a 20-kg weight loss during the previous 6 months. He could walk only two blocks and had noted increasing abdominal girth. He denied orthopnea, paroxysmal nocturnal dyspnea, and lower-extremity swelling. He also denied abdominal pain, hematochezia, melena, diarrhea, and flushing. He was thin, mildly tremulous, and afebrile and had no evidence of sepsis. His blood pressure was 112/70 mm Hg, and his pulse was 110 beats/min. His thyroid gland was normal. The jugular venous pressure was 15 cm H_2O. A cardiac examination showed a 2 to 3+ parasternal lift and hyperdynamic left ventricular impulse. Right- and left-sided S₃ were present. A grade 2/6 systolic ejection murmur was heard over the second right intercostal space. Rales were heard over both lung bases. An abdominal examination showed a moderately distended abdomen with an enlarged liver. He had trace edema. The skin color was normal with no telangiectasia. His leukocyte count was normal, and his hemoglobin level was 119 mg/L. The electrolytes and liver function tests were normal except for a cholesterol level of 2.5 mmol/L (97 mg/dL) and an alkaline phosphatase level of 2.6 µkat/L (156 U/L) (normal range, 0.5 to 1.8 µkat/L [30 to 110 U/L]). The thyroid-stimulating hormone level was normal, and the thiamin level and erythrocyte transketolase activity were within normal limits. He was in sinus tachycardia. The chest roentgenogram showed mild cardiomegaly with prominence of pulmonary vasculature and mild interstitial edema.

An echocardiogram showed a hyperdynamic left ventricle with an ejection fraction of 0.75 and four-chamber dilatation. Left ventricular end-diastolic, left ventricular end-systolic, and left atrial dimensions were 6.4 cm, 4.0 cm, and 5.4 cm, respectively. No clinically significant tricuspid regurgitation or pulmonary stenosis was noted; these valves were not thickened. Cardiac catheterization showed the following pressures: right atrium, 16 mm Hg; right ventricle, 50/14 mm Hg; pulmonary artery, 50/25 mm Hg; pulmonary wedge, 28 mm Hg; and aorta, 100/56 mm Hg. Thermodilution cardiac output was 15.4 L/min. Systemic vascular resistance was calculated to be 389 dynes/s x cm^–5. Oxygen saturation measurements showed no left-to-right shunt. A hepatic angiogram showed no arteriovenous fistula. An abdominal computed tomographic scan showed moderate hepatomegaly with irregular focal areas of enhancement. A liver biopsy revealed a carcinoid tumor. The urine 5-HIAA level was 36.1 µmol/24 h (normal range, 9.4 to 31.4 µmol/24 h). Substance P was elevated at 283 pmol/L (382 pg/mL; mean normal value, 76 pg/mL; 1 SD, 82 pg/mL). The patient was started on oral furosemide, 40 mg once daily, which mildly improved the symptoms of heart failure. A trial of low-dose oral metoprolol was initiated, but the patient could not tolerate this medication. He is currently taking only diuretics and is categorized in New York Heart Association class II.

Discussion

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In 1963, Schwaber and Lukas [1] published the only description of high-output heart failure in the carcinoid syndrome. Hemodynamic data on two patients with metastatic carcinoid disease showed increased cardiac output, low systemic vascular resistance, and absence of valvular involvement. The investigators proposed that, in addition to causing endocardial fibrotic lesions, serotonin reduces systemic vascular resistance by causing systemic vasodilation, thereby increasing cardiac output [1]. Experimental data, however, have thus far failed to show a consistent vasodilating effect of serotonin. Rudolph and Paul [2], studying the hemodynamic effects of continuous intravenous infusion of serotonin in eight dogs, found that serotonin decreased systemic vascular resistance, resulting in a rise in cardiac output to 7.7 L/min but that it also increased pulmonary vascular resistance [2]. MacCanon and Horvath [3] showed that single intravenous injections of serotonin in dogs increased cardiac output by 29.3% as well as increased systemic vascular resistance and pulmonary vascular resistance.

One of the tachykinins, substance P, has been isolated from carcinoid tumor tissue. In addition to urine 5-HIAA, it is an important tumor marker in diagnosing the carcinoid syndrome [4]. Substance P is a potent vasodilator, releasing endothelium-derived relaxing factor from the vascular endothelium [5].

Our patient had a relatively low urine 5-HIAA level but an unusually high substance P compared with levels measured in a study by Lundin and colleagues [4]. Among 68 patients with the carcinoid syndrome, they found that the median values for urine 5-HIAA and substance P were 363 µmol/24 h and 25 pmol/L, respectively. Our patient's markedly elevated cardiac output with low systemic vascular resistance is consistent with the potent vasodilating effect produced by a high level of substance P. Thus, carcinoid heart disease may present only as high-output failure without the typical right-sided fibrotic lesions when substance P is the primary neurohormone produced.

Researchers have recently discovered novel substance P antagonists, including FK 224, FR 11360, and RP 67580 [6-8]. These agents may have future uses for the treatment of high-output heart failure in the carcinoid syndrome.