Hyperkinemia and cardiac failure in the carcinoid syndrome

Hyperkinemia and Cardiac Failure in the Carcinoid Syndrome* JULES R . SCHWABER, M .D .

f and

DANIEL S . LUKAS, M .D .

New York, New York

S

INCE the first report of carcinoid heart disease

inoperable gastric neoplasm found at laparotomy was diagnosed histologically as carcinoid tumor . There were multiple hepatic metastases . Following surgery the patient noted increasing pigmentation of the skin and experienced episodic flushes characterized by erythrocyanosis and burning discomfort of the face, neck, trunk and extremities . These episodes had become more frequent prior to the present hospitalization . Physical examination at this time revealed a well nourished white man who, however, showed evidence of recent weight loss . A persistent violaceous red complexion of the face, neck, upper part of the chest and distal extremities was punctuated by focal areas of increased pigmentation and telangiectasiae . The neck veins were distended and there were a few rales at the bases of both lungs . The blood pressure was 120/80 mm . Hg . The heart was slightly enlarged to the left . A heaving left ventricular apical impulse was present, as well as a thrill over the right carotid artery . Occasional ventricular premature contractions interrupted the basic sinus rhythm . The heart rate was 85 per minute . The heart sounds were normal except for considerable accentuation of the pulmonic component of the second sound . A grade 2/4 moderately rough systolic murmur and an early systolic click were heard in the second and third left intercostal spaces parasternally. The peripheral pulses were strong . The ankles showed 2-plus pitting edema. The liver was nodular and markedly enlarged. Cardiac fluoroscopy and roentgenogram of the chest (Fig . 1) revealed slight enlargement of the left and right ventricles and prominence of the right atrial border . The right main pulmonary artery was enlarged . The electrocardiogram was normal except for occasional ventricular premature contractions . Laboratory data included : hemoglobin, 13 .4 gm . per cent ; white blood cell count 10,400 per cu . mm., with normal differential count ; urinalysis, negative ; blood urea nitrogen, 13 .2 mg. per cent ; serum alkaline phosphatase, 21 .4 Bodansky units ; serum total cho-

by Isler and Hedinger in 1953 [1], the effects of excess circulating 5-hydroxytryptamine on the heart have aroused considerable interest . Several case reports have documented the presence of pulmonic and tricuspid valvular disease in patients with metastatic carcinoid tumors [2-4] . The comprehensive pathologic studies of MacDonald and Robbins [5] defined the gross, microscopic and histochemical characteristics of the endocardial lesions . Although considerable information is available on the circulatory effects of transitory elevations of serotonin in various laboratory animals and to a lesser degree in man, little is known about the influence on cardiovascular function of chronically increased concentrations of this compound, as occurs in the carcinoid syndrome . We have recently obtained hemodynamic data on two patients with metastatic carcinoid disease and the carcinoid "flush syndrome ." Both patients manifested hyperkinemia . In each, the high output was associated with a narrow arteriovenous oxygen difference, low peripheral vascular resistance, and cardiac failure without evidence of valvular involvement . We propose to describe these patients and to discuss the abnormalities in cardiovascular function in the light of previously demonstrated effects of serotonin on the circulation . CASE REPORTS

H. K ., a fifty-two year old white butcher, was admitted to the hospital with a two year history of abdominal cramps, diarrhea, dyspnea and palpitations . Two years previously, he had been evaluated for the presence of melena, and a gastrointestinal series showed a filling defect in the stomach . An CASE I .

* From the Department of Medicine and the Cardio-Pulmonary Laboratory, New York Hospital-Cornell Medical Center, New York, New York . This study was aided by grants from the National Heart Institute (H-3918), the American Heart Association, and the New York Heart Association . Manuscript received August 1, 1961 . f U . S . Public Health Service Research Fellow . Present address : 2nd Medical Division, Bellevue Hospital, New York, New York . 846

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Fic . 1 . Patient H . K. Posteroanterior roentgenogram of chest . Diaphragm is displaced upward by large liver . lesterol, 369 mg . per cent ; cholesterol esters, 117 mg . per cent ; serum total protein, 7 .0 gm. per cent with 4 .7 gm. per cent albumin ; bromsulfalein retention, 5 per cent in forty-five minutes ; serum uric acid 4 .3 mg . per cent . A reaction to the glucose tolerance test was normal . Urinary excretion of 5-hydroxyindole acetic acid was 12 to 18 mg . per twenty-four hours (normal 2 to 9 mg . per twenty-four hours) . Blood serotonin assay, performed by Dr. Maurice Rapport utilizing the rabbit ear vessel method [6], revealed the platelet serotonin concentration to be 0 .3 to 0 .5 µg. per 10 9 platelets (normal values, 0 .3 to 0 .7 µg . per 10 9 platelets) . Protein-bound iodine in the serum was 6 .8 µg. per 100 ml . Radioiodine uptake was 40 per cent in forty-eight hours . The venous pressure was equivalent to 178 mm . saline solution . Cardiac catheterization revealed a remarkable hemodynamic pattern consistent with high output cardiac failure. (Table i .) No evidence of stenosis or regurgitation of either the tricuspid [7,8] or pulmonic valve was present during rest or exercise . That the increased flow had overtaxed the functional capacity of the left ventricle was demonstrated by the elevated pulmonary "capillary" pressures . Right ventricular dysfunction was similarly demonstrated by the increased end diastolic pressure . Although an increased oxygen consumption accounted for some of the increase in output, the narrow arteriovenous oxygen difference indicated that the output was raised out of proportion to the hypermetabolism . The systemic vascular resistance was reduced to less than half the normal range . The increase in pulmonary arterial pressure was due to the pulmonary venous hypertension, since the pulmonary vascular resistance was normal . Cardiac output and stroke volume fell during exercise, but were appropriate for the degree

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of effort involved . Attempts to induce an acute flush during the procedure were not successful . Digitalization after the catheterization resulted in a weight loss of 2 .3 kg . and recession of the edema . During the patient's prolonged hospital course, metastases to the skeletal and nervous systems developed . He failed to respond to a course of radiation therapy and died of his disease approximately eight months after entering the hospital . Autopsy confirmed the presence of metastatic carcinoid disease, revealing three distinct gastric carcinoids and massive metastases to the liver, abdominal and mediastinal nodes, and skeleton . Foci of metastatic tissue extended into the fibrous septums of the cavernous sinus . The heart, with the exception of mild generalized hypertrophy (weight 370 gm .), was essentially free of disease . Pericardial and epicardial surfaces were glistening and smooth . The endocardial surfaces were thin, smooth, semitransparent . Valve circumferences were normal, and the leaflets were thin, delicate and free of deformity . The chordae tendineae of the mitral and tricuspid valves were discrete and delicate . The coronary arteries exhibited focal thickening, with small gray yellow plaques which caused no significant narrowing of the lumina . Microscopic examination revealed a few scattered small islands of fibrosis in the left ventricular myocardium . CASE II . C . E ., a sixty-six year old retired hardware store operator, was referred to the hospital for chemotherapy. He had experienced abdominal cramps and postprandial flushing episodes during the previous eighteen months . One year prior to admission a nodular carcinoid tumor had been excised from the jejunoileal junction . Hepatic metastases

848

Carcinoid Syndrome-Schwaber, Lukas TABLE I

DATA OBTAINED BY CARDIAC CATHETERIZATION IN FOUR PATIENTS WITH METASTATIC CARCINOID TUMORS With Flush Syndrome

Without Flush Syndrome Normal Subjects*

H. K.

C. E.

J. W .

C. R .

Determination

Rest

Ventilation (L./min ./M .2) (BTPS) Arterial oxyhemoglobin saturation (%,) Oxygen consumption (ml./min ./M .s) Arteriovenous oxygen difference (vol . %) Cardiac output (L./min./M .1) Heart rate (beats/min,) Stroke index (ml ./min ./M .s) Pressures (mm . Hg) Pulmonary "capillary" mean Pulmonary artery Systolic/Diastolic Mean Right ventricle Systolic/Diastolic Right atrium (mean) Brachial artery Systolic/Diastolic Mean Pulmonary vascular resistance (dynes sec. em. - 5) Systemic vascular resistance (dynes sec. cm . -s)

Exercise

Rest

During Flush

Rest

Exervise

Rest

Exercase

7 .02 16,50 4 .94 5 .32 3 .09 4 .38 3 .34 8 .85 91 .4 98 .6 92 .5 90 .5 94 .1 98 .4 98 .8 97 9 222 317 158 181 104 142 121 309 2 .74 5 .91 3 .46 3 .53 3 .91 4 .92 4 .22 7 .65 8 .08 5 .36 4 .57 5 .13 2 .65 2 .89 2 .86 4 .04 92 100 100 96 100 104 96 116 88 54 46 53 26 28 30 35 2

2

37/23 66/37 30/12 32/11 19/8 24/9 31 51 19 19 10 16 36/12 66/22 33/10 35/11 22/1 23/2 12 20 7 6 2 2

25

40

8

8

-1

11/2 7 14/1 1

121/71 150/82 155/72 161/75 88/57 90 110 98 112 72 34 94 103 92 255 438 771 856 887 1,622

. . . . . . 298 . ..

121/72 100 83 1,739

Rest

4 .33 ± 97 134 ± 4 .07 ± 3 .33 ± 84 ± 40 ±

Exercise

1 .30 11 .30 ± 97 26 310 ± 0 .66 6 .45 ± 0 .63 4 .89 ± 14 117 ± 8 42 ±

5 ± 2 17/7 10 15/3 3

12

19/6 ± 4/2 11 ± 2 19/3 ± 4/1 2 ± 1 119/73 91 83 1,304

± + ± ±

16/10 10 30 266

2 .59 57 0 .81 0 .88 15 6

7 ± 2 22/8 13 22/2 1

± ± ± ±

4/2 3 4/2 2

71 ± 36

* Mean ± S .D. of data obtained in this laboratory.

were observed at the time of surgery . The patient was treated with a serotonin antagonist (methylsergide, Sandoz) without significant amelioration of his symptoms . In the months preceding admission the frequency and intensity of his flushing episodes increased . A typical flush was elicited by food intake, emotional excitement, abdominal palpation, or it would arise spontaneously . It was characterized by cutaneous erythema and burning sensation, resembling that of a sunburn, spreading from the face and neck to the anterior portion of the chest, upper extremities and feet . Associated with the flushing were tachycardia, palpitations, numbness and tingling of the extremities, and abdominal cramping . A typical attack would subside within fifteen to thirty minutes . Physical examination revealed a well nourished white man with cutaneous erythema of the face and trunk, which fluctuated in intensity and became marked during the flush episodes . The liver edge was 10 cm . below the costal margin . The heart was not enlarged ; its rate was 100 per minute . The neck veins were moderately distended but showed no abnormal pulsations . The second heart sound was normally split . The blood pressure was 128/70 mm . Hg . Brawny edema of the legs and feet was present . Laboratory data included : hemoglobin, 12 gm. per cent ; white blood cell count, 7,600 per cu . mm ., with normal differential count ; platelet count, 350,000 per cu . mm. ; urinalysis, negative . Sternal marrow showed normal cellular elements. Bromsulfalein retention

was 5 per cent in forty-five minutes . Serum alkaline phosphatase was 6 .6 Bodansky units ; bilirubin, 0.47 mg . per cent ; blood urea nitrogen, 14 mg . per cent ; fasting blood sugar, 70 mg. per cent ; total protein, 7 .5 gm . per cent with 5 .6 gm . per cent albumin ; uric acid, 8 .8 mg . per cent . The reaction to a serologic test for syphilis was negative . The urinary excretion of 5-hydroxyindole acetic acid was 500 to 700 mg . per twenty-four hours . Blood serotonin assays performed by Dr . Roger Des Prez utilizing the rat uterus bioassay technic [9] revealed 6 .7 to 17 µg. of serotonin bound to 10 9 platelets as compared with the normal value of 2 .07 to 2 .62 jig . per 10 9 platelets . Roentgenogram of the chest (Fig . 2) and electrocardiogram were within normal limits. Liver biopsy revealed metastatic carcinoid tumor . Cardiac catheterization (Table I) revealed a resting cardiac output of 4 .57 L . per minute per sq . M., which increased further during a flush state induced by massage of the liver and ingestion of sugar water . There was no evidence of stenosis or regurgitation of either the pulmonic or tricuspid [7,8] valve . Right ventricular insufficiency was reflected by a threefold increase in end diastolic pressure . Right atrial pressure was increased, and tall contraction waves were present . Both right atrial and right ventricular end diastolic pressures increased 3 mm . Hg during pressure on the liver, further demonstrating right ventricular dysfunction. Pulmonary vascular resistance was normal . During attempted hepatic arterial catheterization AMERICAN JOURNAL OF MEDICINE

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for regional administration of an antitumor drug, brachial arterial spasm developed . Surgical removal of a brachial arterial thrombus was followed by the administration of fibrinolysin . Persistent hemorrhage from the operative site required re-exploration to achieve hemostasis . On the evening following the second operative procedure the patient was found to be moribund ; he died despite emergency resuscitative efforts . Permission for autopsy could not be obtained . COMMENTS

The hyperkinetic cardiac state occurs in such varied conditions as anemia, thyrotoxicosis, beriberi, systemic arteriovenous fistula, Paget's disease and acute glomerulonephritis . Chronic elevation of the cardiac output, low systemic arteriovenous oxygen difference, large stroke volume and diminished peripheral vascular resistance are the cardinal hemodynamic features. Oxygen consumption is only slightly increased, except for the marked elevation in hyperthyroidism . Recently Gorlin and his coworkers [10] have described an "idiopathic high cardiac output state" which they suggested could be due to altered central and autonomic control of the circulation . Extensive laboratory studies ruled out the usual causes of hyperkinemia in the two patients described herein . Moreover, neither of them manifested anxiety at time of cardiac catheterization ; nor did they have evidence of an intracardiac shunt, which could produce a narrow systemic-pulmonary arterial blood oxygen difference . These considerations suggested that the hemodynamic disturbances were related to the metastatic carcinoid tumors . Although the literature reports evidence of acute augmentation of cardiac output during attacks of flushing in patients with the carcinoid syndrome, the possibility of sustained or chronic increase in output has received scant attention. During episodes of cutaneous flushing in four patients with metastatic carcinoid tumors, Thorson [11] observed an increase in the size and contractions of the heart, accentuation of heart sounds, appearance of atrial gallop and increased cardiac output by a ballistocardiographic method . In one patient with clinical signs of cardiac failure, cardiac catheterization demonstrated mild pulmonic stenosis with a right ventricular systolic pressure of 39 mm . Hg and a "normal" cardiac output by the Fick method despite the failure . In the later stage of a flush, hemodynamic signs of tricuspid regurgivoL . 32, JUNE 1962

FIG . 2 . chest .

Patient

C . E.

Posteroanterior roentgenogram

of

tation and acute right ventricular failure appeared .; right atrial and ventricular end diastolic pressures rose by 6 mm . Hg, and right ventricular pulse pressure decreased from 34 to 10 mm . Hg [12] . Thorson has contended that episodic hyperkinemia, especially if associated with pulmonary vasoconstriction, constitutes a hemodynamic stress on the right ventricle that may contribute to the development of tricuspid and pulmonic valvular lesions [12,13] . He has also stated that the concomitant rises in venous pressure are partially responsible for edema in the carcinoid syndrome [13] . That the cardiac output increases during a carcinoid flush was confirmed by Goble et al . [14] . During cardiac catheterization of a patient with metastatic argentaffin carcinoma and secondary stenosis of the tricuspid and pulmonic valves, they observed the output to increase during an induced flush by 1 .3 L . per minute from a low value of 3 .5 L . per minute . In a paper on serotonin antagonists, Schneckloth and his co-workers [15] included data from a patient with metastatic gastric carcinoid who manifested persistent cyanosis of the face and typical severe flushing episodes . A systolic murmur of low intensity was audible at the apex, but roentgenograms of the heart and the electrocardiogram were within normal limits . The twenty-four hour urinary excretion of 5-hydroxyindole acetic acid averaged 239 mg . At catheterization, resting output by the Fick method was 8 .9 L . per minute with an arterio-

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Syndrome-Schwaber, Lukas

FIG . 3 . Record of tension developed by isolated cat papillary muscle stimulated electrically to contract once per second . At arrow in upper record, serotonin creatinin sulfate was added to muscle bath to produce concentration of 4 µg. per ml . of serotonin . Note ensuing 50 per cent increase in strength of contraction, requiring reduction in sensitivity of record at X to one half original level . In lower strip, serotonin concentration of 13 µg . per ml. (agent added at arrow) caused 72 per cent increase in contractile force .

venous oxygen difference of 3 .0 volumes per cent, oxygen consumption of 266 ml . per minute and systemic vascular resistance of 727 dynes sec . c m . -5 Although not discussed within their article, this represented the first case of carcinoid disease in which hyperkinemia presumably not related to an attack of flushing was observed . Since hyperserotoninemia is the most outstanding feature of the carcinoid syndrome, the question of whether serotonin could be responsible for the hyperkinemia arises . There is ample evidence that this agent is capable of increasing cardiac output in animals and in man . Rudolph and Paul [16] observed increases in output as great as 60 per cent associated with a 55 to 80 per cent decrease in systemic vascular resistance during intravenous infusion of 5-hydroxytryptamine at a constant rate in anesthetized dogs . MacCanon and Horvath [17] also noted a 29 per cent increase in output after injection of serotonin into the pulmonary artery of anesthetized dogs . Serotonin increases output in adrenalectomized cats [18], and in unanesthetized dogs with transection of the spinal cord at Cs [19] . In seven patients with normal pulmonary arterial pressures, infusion of 10 mg . of serotonin into the pulmonary artery during a period of seven to ten minutes was noted by Grover et al . [20] to produce an increase in output, a decrease in systemic vascular resistance and only minor variations in systemic arterial pressure . Injection of serotonin into the pulmonary artery of a patient with malignant

hypertension by Sones et al . [21] resulted in a twofold increase in cardiac output and a 45 per cent decrease in systemic vascular resistance . Whether the increased output is the result of a direct action of serotonin on the heart, or primarily on the systemic vascular bed with a secondary adjustment in output, or both, is not clear from these studies . With regard to direct cardiac action, serotonin has been found to exert an inotropic effect on the isolated cat papillary muscle [22], isolated dog, cat and rabbit hearts [23,24], in an open chest dog preparation [25], and on isolated and in situ hearts of mollusks and crustaceans [26] . We also have noted a 50 per cent increase in contractile force of a cat papillary muscle on the addition of serotonin in amounts to bring the concentration to 4 pg . per ml . in the muscle bath . (Fig . 3 .) This represents the concentration present as platelet bound serotonin in the blood of patient C. E . Although the effects of serotonin on blood vessels are complex and variable, it is capable of inducing over-all systemic vasodilatation . Sjoerdsma and coworkers [27] state that infusion of 5-hydroxytryptamine into normal human subjects invariably produces a vasodepressor response . In cats, dogs and rabbits, Page and McCubbin [28] found that the nature and magnitude of vascular response to serotonin depended on the level of pre-existing neurogenic vascular tone . When neurogenic tone was abolished by ganglionic blockade, serotonin produced a pressor response . With activation of neurogenic vasoconstriction by section of the buffer nerves, response to serotonin became depressor . The depressor effect was elicited by lower doses of serotonin and persisted longer than the pressor effect . Further explanation for the variable action of serotonin on the systemic vessels is provided by the work of Haddy and his associates [29,30] who showed that when serotonin was infused into the brachial artery of the dog, resistance of the small arteries and veins decreased and resistance of the large vessels of the limb increased . Since vasoconstrictor nerves predominantly affect the caliber of the small vessels, serotonin, by dilating the small vessels, decreased net vascular resistance in limbs initially manifesting a high degree of neurogenically induced vasoconstriction . In limbs with low small vessel resistance occurring spontaneously or induced by denervation, serotonin caused little additional dilatation of the AMERICAN JOURNAL OF MEDICINE



Carcinoid Syndrome-Schwaber, Lukas small vessels but, by constricting the large vessels, produced a net increase in total resistance . Other investigations indicate that serotonin has vasodilating properties . Roddie et al . [31] showed that the capillaries of the skin in the human hand and forearm are dilated by this agent . Feldberg and Smith [32] attributed the vasodilation produced by serotonin in isolated human skin flaps to the histamine releasing properties of this compound . In the dog's lung, bronchial collateral flow is increased by serotonin [33] . Serotonin is a potent coronary vasodilator in dogs ; however, this effect is accompanied by a small decline in the manifest mechanical efficiency of the left ventricle [34] . A clear-cut vasoconstrictive response to serotonin has been demonstrated in the lung and kidney . Although this effect of serotonin on the pulmonary vasculature is impressive in certain animals, including the dog [16,35], it is absent or slight in man [20] . Renal vasoconstriction, on the other hand, occurs both in animals and man . Schneckloth et al . [36] measured decreases in renal blood flow, glomerular filtration rate and urine flow during infusion of serotonin into normal subjects . They also observed marked reduction of renal blood flow and glomerular filtration rate but no other abnormalities of renal function in two patients with carcinoid disease . In considering other mechanisms for the production of a high cardiac output in carcinoid disease, the frequent occurrence of hypovitaminoses in patients with advanced gastrointestinal neoplastic disease raises the possibility of coexistent beriberi heart disease . Sjoerdsma et al . [27] reported that up to 60 per cent of dietary tryptophan is excreted in the urine as 5-hydroxyindole acetic acid in patients with metastatic carcinoid as opposed to 1 per cent excretion in the normal subject . This large diversion of tryptophan into production of serotonin occurs at the expense of protein synthesis and formation of nicotinic acid, and may lead to the development of pellagra . Indeed, pellagra was observed by McNeely and Jones [37] and others [13,38] in patients with metastatic argentaffin carcinomas . Hemodynamic abnormalities, however, have not been ascribed to pellagra per se . Although levels of pyruvate in blood were not measured, neither of our patients was malnourished at the time of catheterization . Both had been eating adequate quantities of a balanced hospital diet, and neither manifested voL . 32, JUNE 1962

851

glossitis, dermatitis or peripheral neuritis . Serum protein levels were normal in both . It seems unlikely that beriberi or other nutritional deficiency was responsible for the high output failure . The importance of peripheral vasodilatation in the genesis of hyperkinemia in our patients is emphasized by the chronic erythema and cutaneous vascular alterations, which were especially marked in one patient (H . K .) . We have studied two other patients with metastatic carcinoid who did not manifest chronic cutaneous erythema or repeated episodes of flushing . Cardiac output was low normal in both, and no hemodynamic abnormalities were detected despite an increase in the level of serotonin in the blood and in the urinary excretion of 5-hydroxyindole acetic acid . (Table i .) * Previous reports [27,38] have noted the lack of relationship between indices of serotonin production and the presence, frequency or severity of the flushes . This observation suggests the participation of vasoactive agents other than serotonin . In seven of nine patients with carcinoid, Waldenstrom and co-workers [38,39] found the daily urinary excretion of histamine to be higher than in normal subjects, but the magnitude of histaminuria also correlated poorly with severity of flushing . It is evident that more biochemical and physiologic studies are needed to clarify the pathogenesis of hyperkinemia and the flush syndrome in carcinoid disease . Of especial interest would be delineation of the role of the disturbances in renal blood flow and glomerular filtration in the production of the abnormalities in cardiac function . In a recent review of cases he has studied personally and of those reported in the literature, Thorson [13] concluded that cardiac failure is the leading cause of death in metastatic carcinoid disease . Among reported cases, cardiac decompensation was manifested clinically in several patients whose hearts at autopsy were surprisingly free of valvular, coronary arterial and myocardial disease [2,40,41] . As Thorson [13] has indicated, even in some patients with valvular disease, the lesions did not appear advanced enough to account for the cardiac * Both patients were women . One (J. W., age fifty-two years) had a blood serotonin level of 3 .9 µg. per 10 9 platelets and a twenty-four hour urinary excretion of 5-hydroxyindole acetic acid of 300 mg . The other (C . R ., 65 years of age) had a serum serotonin of 80 µg . per ml . and a twenty-four hour urinary excretion of 580 mg . of 5-hydroxyindole acetic acid .

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Carcinoid Syndrome-Schwaber, Lukas

failure. From our observations it appears likely that the chronic burden of hyperkinemia aggravated episodically by additional increments of cardiac output during flushing contributes to the high incidence of cardiac failure in the carcinoid syndrome . SUMMARY

Cardiac catheterization in two patients with metastatic carcinoid tumors and the typical flush syndrome revealed increased cardiac output, low systemic vascular resistance and hemodynamic evidences of cardiac failure . In one, an additional increment in cardiac output occurred during an induced attack of flushing . In neither patient could disturbances in valvular function be demonstrated . At autopsy in one case, the heart was normal with the exception of mild generalized hypertrophy . Although the hyperkinemia can be attributed to the cardiovascular effects of serotonin that have been demonstrated previously in animals and man, it was not observed in two additional patients with carcinoid tumors and hepatic metastases who did not manifest chronic cutaneous erythema or acute attacks of flushing despite elevated serotonin levels in the blood and increased urinary excretion of 5-hydroxyindole acetic acid . Hyperkinemia of itself, or in association with deformity of the tricuspid and pulmonic valves, may contribute to the high incidence of cardiac failure in the carcinoid syndrome . Acknowledgment: We are grateful to Drs . David Karnofsky and Bayard Clarkson for referring patients H . K., C. E. and J. W . to our laboratory ; to Dr . Jay Roberts and Mr . Vincent J . Cairoli for their advice and assistance in studying the effect of serotonin on the cat papillary muscle ; and to Dr . Marjorie B . Zucker for her interest and cooperation . REFERENCES 1 . ISLER, P. and HEDINOER, C. Metastasierendes Dunndarmcarcinoid mit schweren, vorwiegend das rechte Herz betreffenden Klappenfehlern and Pulmonalstenose-e in eigenartiger Symptomenkomplex? Schweiz . med. Wchnschr., 83 : 5, 1953 . 2 . THORSON, A ., BIORCK, G ., BJORKMAN, G . and WALDENSTROM, J . Malignant carcinoid of the small intestine with metastases to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid regurgitation without septal defects), peripheral vasomotor symptoms, bron-

choconstriction and an unusual type of cyanosis : A clinical and pathological syndrome . Am . Heart J., 47 : 795, 1954 . 3 . JENKINS, J. S. and BUTCHER, P. J . A. Malignant argentaffinoma with cyanosis and pulmonic stenosis . Lancet, 268 : 331, 1955 . 4 . BRANWOOD, A. W. and BAIN, A . D . Carcinoid tumor of the small intestine with hepatic metastases, pulmonary stenosis and atypical cyanosis . Lancet, 2 : 1259, 1954 . 5 . MACDONALD, R . A . and ROBBINS, S . A . Pathology of the heart in the carcinoid syndrome . Arch. Path., 63 : 103, 1957 . 6. ZUCKER, M. B . and BORRELLI, J . Quantity, assay and release of serotonin in human platelets . J. Appl . Physiol ., 7 : 425, 1955 . 7 . SEPULVEDA, G . and LUKAS, D . S . The diagnosis of tricuspid insufficiency. Clinical features in 60 cases with associated mitral valve disease . Circulation, 11 : 552, 1955 . 8 . KILLIP, T., iii and LUKAS, D . S. Tricuspid stenosis. Physiologic criteria for diagnosis and hemodynamic abnormalities . Circulation, 16 : 3, 1957 . 9 . ERSPARMER, V . Pharmacological studies on enteramine (5-hydroxytryptanine) . ix . Influence of sympathomimetic and sympatholytic drugs on physiological and pharmacological actions of enteramine . Arch. internat . pharmacodyn ., 93 : 293, 1953 . 10 . GORLIN, R ., BRACHFELD, N ., TURNER, J . D ., MESSER, J . V. and SALAZAR, E. The idiopathic high cardiac output state . J. Clin. Invest ., 38 : 2144, 1959. 11 . TIIORSON, A . H. Hemodynamic changes during "flush" in carcinoidosis . (The carcinoid syndrome) . Am. Heart J., 52 : 444, 1956 . 12 . THORSON, A . and NORDENFELT, O . Development of valvular lesions in metastatic carcinoid disease . Brit. Heart J., 21 : 243, 1959 . 13 . THORSON, A. H. Studies on carcinoid disease. Acta med. scandinav., suppl . 334, 1958 . 14. GOBLE, A. J., HAY, D. R., HUDSON, R . and SANDLER, M. Acquired heart disease with argentaffin carcinoma . Brit. Heart J., 18 : 544, 1956. 15 . SCHNECKLOTH, R., PAGE, I . H ., DEL GRECO, F. and CORCORAN, A . C. Effects of serotonin antagonists in normal subjects and patients with carcinoid tumors. Circulation, 16 : 523, 1957 . 16 . RUDOLPH, A . M . and PAUL, M. H . Pulmonary and systemic vascular response to continuous infusion of 5-hydroxytryptamine (serotonin) in the dog . Am . J. Physiol., 189 : 263, 1957 . 17 . MACCANON, D. M. and HORVATH, S . M. Some effects of serotonin in pentobarbital anaesthetized dogs. Am . J. Physiol., 179 : 131, 1954. 18 . REID, G. Circulatory effects of 5-hydroxytryptamine . J. Phvsiol., 118 : 435, 1952. 19 . PAGE, I . H. The vascular action of natural serotonin, 5- and 7-hydroxytryptamine and tryptamine . J. Pharmacol. & Exper . Therap ., 105 : 58, 1952. 20 . GROVER, R. J., OLSON, S . K . and BLOUNT, G. S ., JR. Pulmonary vascular response to serotonin in man . Clin . Res., 6 : 62, 1958. 21 . SONES, M ., MIGNON, J . and PAGE, I . H . Cited by I . H. Page in : 5-Hydroxytryptamine . Edited by Lewis, G . P. Pergamon Press . 22 . GREEN, J. P. and NAHUM, L. H. Effects of liver AMERICAN JOURNAL OF MEDICINE



Carcinoid Syndrome-Schwaber, Lukas 23 .

24 .

25 .

26 .

27 .

28 .

29 .

30 .

31 .

32 .

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