Porcine heterograft valve replacement in carcinoid heart disease

J

THORAC CARDIOVASC SURG

81:100-105, 1981

Porcine heterograft valve replacement in carcinoid heart disease A 53-year-old man with a pancreatic carcinoid tumor and liver metastases had the carcinoid syndrome with involvement of the tricuspid valve by carcinoid plaque. The mitral valve was involved by unrelated myxomatous degeneration (floppy valve). Each valve was replaced by a Hancock glutaraldehyde-prepared porcine heterograft prosthesis. When the patient died of complications of the tumor 8 months postoperatively, both valves had clinically normal function. Nevertheless, the carcinoid plaque, which was present in all four cardiac chambers and almost completely covered the endocardial surfaces of both atria, extended onto both prostheses. This eventually might have interfered with prosthetic valve function.

Frederick J. Schoen, M.D., Ph.D., Gainesville, Fla., Richard J. Hausner, M.D., Jimmy F. Howell, M.D., H. Liston Beazley, M.D., and Jack L. Titus, M.D., Ph.D., Houston, Texas

Cardiac involvement occurs in approximately half of cases of the carcinoid syndrome! and is characterized by the deposition of fibrous tissue on the mural and valvular endocardium," 3 which may lead to hemodynamically significant tricuspid and pulmonic valvular abnormalities. Involvement of the left side of the heart occasionally occurs. Because cardiac impairment may lead to death of patients with the carcinoid syndrome," surgical repair of carcinoid-related cardiac lesions has been carried out. 5 - 11 We report here the interesting autopsy findings in a patient with carcinoid heart disease who underwent valve replacement eight months prior to death.

Case report In 1974, a 53-year-old man with abdominal pain and obstructive jaundice underwent choledochoduodenostomy for pancreatic carcinoid tumor with hepatic metastases. He had a history of a heart murmur dating back to the age of 21 years, but denied activity or exercise limitation. Three years later he From the Department of Pathology, Universityof florida College of Medicine, Gainesville, Fla. (Dr. Schoen), and the Departments of Pathology (Drs. Hausner and Titus), Surgery (Dr. Howell), and Medicine (Dr. Beazley), The Methodist Hospital and the Baylor College of Medicine, Houston, Texas. During a portion of this study Dr. Schoen was a recipient of an American Lung Association Clinical Training Fellowship. Received for publication April 25, 1980. Accepted for publication May 12, 1980. Address for reprints: Dr. Frederick J. Schoen, Departmentof Pathology, Peter Bent Brigham Hospital, 721 Huntington Ave., Boston, Mass. 02115.

100

Table I. Preoperative cardiac catheterization data * Site

Right atrium Right ventricularoutflow Pulmonary artery Pulmonary capillary wedge Left ventricle Aorta

Pressures: Systolic/diastolic (mean), in mm Hg

v = 21 32/8 32/8 V = 26 98/58 98/55

(8) (17) (12) (65) (65)

Hemodynamic data at rest

Arteriovenous oxygendifference (%) Cardiac output (L/min) Cardiac index (Lzrnin/m")

4.9 4.3 2.6

"Additional findings: Valves-Mitral regurgitation (3+) with flail anterior and posterior leaflets; tricuspid regurgitation (4+). Coronary arteries-Normal. Right ventricle-Enlarged. Left ventricle-Normal size, normal contractility, and moderately decreased ejection fraction.

returned with diarrhea, weight loss, and ankle edema which were considered to be due to the carcinoid syndrome secondary to the liver involvement. Infarction of the right hepatic lobe by metallic coil embolization to the right hepatic artery was performed, with subsequent reduction of urinary 5-hydroxyindole acetic acid (5-HIAA) excretion from 550 to 200 mg124 hr (normal 2 to 7). Congestive heart failure was managed with digitalis and diuretics. In mid-1978 he returned again with congestive heart failure. He was cachectic and in moderate respiratory distress with a blood pressure of 110170 mm Hg. Heart rate was 80 beats/min and irregular. Jugular venous pressure was elevated. There was a left ventricular thrust with the apical impulse palpated in the sixth intercostal space in the anterior axillary line and a mitral systolic thrill. Although the first and

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January, 1981

Fig. 1. Gross and microscopic documentation of extensive bilateral involvement of the heart with carcinoid plaque. a, Gross photograph of the right atrium. The fibrous plaque covers virtually the entire endocardial surface and extends onto the porcine heterograft prosthetic valve. The superior vena cava is at the upper right hand comer of the photograph. b, Gross photograph of the right ventricular outflow tract. The pulmonary valve (seen at the top) has a typical carcinoid deformity with thickening and retraction of the cusps. Right ventricular endocardial plaques are also present. c, Gross photograph of the left atrium. There is almost complete endocardial coverage with carcinoid plaque, which focally extends onto the sewing ring of the prosthesis. d. Photomicrograph of carcinoid plaque on right atrial endocardial surface showing preservation of the elastic lamina (arrowheads), which separates the fibrosis (P) from the underlying atrial myocardium. (Movat pentachrome, x63.) second heart sounds were normal, there was a right-sided third heart sound. A grade 3-4/6 holosystolic murmur was audible in the mitral area and radiated to both axillae. There was also a systolic ejection murmur heard at the base of the heart, which increased in intensity toward the neck. The liver was tender and palpable to 5 cm below the right costal margin. There was moderate pitting edema of both legs to the

knee. An electrocardiogram showed atrial fibrillation and left ventricular strain or digitalis effect and a chest roentgenogram showed cardiomegaly. Echocardiography demonstrated dilatation of the left atrium to over 6.0 cm and flail mitral valve. Cardiac catheterization revealed moderate mitral regurgitation with flail anterior and posterior leaflets and an enlarged right ventricle with marked tricuspid regurgitation (Table I).

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Schoen et al.

The Journal of Thoracic and Cardiovascular Surgery

Fig. 2. Carcinoid plaque deposition on porcine heterograft tricuspid valve prosthesis. a, Low-power photomicrograph of section through right atrial wall and porcine heterograft valve prosthesis. The relationship of our patient's atrial muscle (A), carcinoid plaque (P), porcine muscle shelf transplanted with prosthesis (M) and prosthesis cusp (C) is shown. (Movat pentachrome, x9.) b, Detail of region boxed in a. There is extraordinarily close apposition of carcinoid plaque (P) to the prosthesis, here the transplanted porcine muscle (M), and the suture (8). (Movat pentachrome, x58.) The cardiac index was 2.6 L'min/m", The pulmonary capillary wedge pressure was 12 mm Hg. The coronary arteries and left ventricular contractility were normal. In July, 1978, the tricuspid and mitral valves were each replaced by a No. 29 Hancock glutaraldehyde-preserved porcine heterograft prosthesis. Intraoperative findings included endocardial fibrosis affecting the right atrium, the left atrium, and the right ventricular outflow tract. Fibrotic changes of both the tricuspid and mitral valves were found. There was prolapse of the mitral valve with disruption of the chordae

tendineae to the posterior leaflet. The patient tolerated the operation well without complications. Postoperatively, complete heart block necessitated placement of a permanent epicardial pacemaker via a subcostal approach. He was discharged on the twentieth postoperative day. Two months postoperatively, he again presented with lower extremity edema and ascites which responded to diuretics and albumin. Echocardiogram at this time showed normal function of the tricuspid and mitral prosthetic valves. His condition subsequently deteriorated, primarily as a re-

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Table II. Surgical correction of the valvular deformities in carcinoid heart disease Age, sex of patient

Functional lesion(s)

5

35, F

TR, PS

6

50, M

TR, PS

7

26, F

TS, PS

8 9

59, M 46, F

TR TS, PS

10

24, F

TR, PS

II

31, M

TR, PS

Reference

57, M This study

TR, MR:j:

Procedure

Prosthesis

T-valvuloplasty P-valvulectomy TVR Starr-Edwards P-commissurotomy TVR Kay-Shiley P-commissurotomy TVR Bjork-Shiley Bjork-Shiley (2) TVR PVR TVR Heterograft (2) PVR T-valvuloplasty P-valvulotomy Heterograft (2) TVR MVR

Duration of carcinoid syndrome at operation

5-H1AA* (mg/24 hr)

19 yr

Site of primary tumor

Liver metastases

Ileum

+

Outcomet

Died early postop. Alive, 6 mo Alive, I yr

8 yr

90

Ileum

0

9 yr

40

Ileum

+

3 yr 14 yr

220 41

Ileum Ileum

+ +

3 mo

III

Unknown

+

7 yr

789

Ileum

+

Died, 4 mo Alive, 8 mo Died, 22 mo Died, 3 wk

16 mo

550

Pancreas

+

Died, 8 mo

Legend: TR, Tricuspid regurgitation. PS,Pulmonary stenosis. MR, Mitral regurgitation. TVR, Tricuspid valve replacement. PVR, Pulmonary valve replacement.

MVR, Mitral valve replacement. • Highest measured 5-HIAA (5-hydroxyindole acetic acid). t As stated in case report. t Mitral lesion was myxomatous degeneration, not carcinoid deformity.

suit of nutritional problems and secondary debilitation. Because of increasing ascites, a LeVeen peritoneovenous shunt was placed and provided some clinical improvement. Urinary 5-HIAA was determined to be 310 mg/24 hr shortly before he died in April, 1979. Pathologic findings. Examination of the specimens taken at the time of the cardiac operation showed typical endocardial plaques of carcinoid heart disease in the right atrium and focally on the ventricular surface of the tricuspid valve. These plaques consisted of spindle cells in a matrix of mucopolysaccharide-rich fibrous tissue lacking elastic fibers. The tricuspid valve was otherwise normal and set apart from the carcinoid plaques by a normal elastic lamina. The mitral valve showed myxomatous degeneration with superimposed fibrosis (not of the carcinoid type) secondary to valvular insufficiency of long duration. Autopsy revealed extensive replacement of the pancreas by a neoplasm composed of uniform small cells with regular round or ovoid nuclei, primarily in a trabecular pattern of interanastomosing ribbons. Some areas contained solid nests of similar cells. Perineural invasion and lymphatic accumulations of tumor cells were prominent. A 2.5 em diameter, partially endobronchial tumor deposit with identical structure was present in the upper lobe of the right lung and caused 75% obstruction of the right upper lobe bronchus. Additional metastatic deposits of carcinoid tumor were present in the liver, spleen, adrenal glands, and kidneys, as well as mesenteric lymph nodes and submucosal gastric lymphatics. The hepatic metastases were extensive and a 5 em diameter necrotic focus of apparent tumor was present in the right hepatic lobe. A metallic coil occluded the right hepatic artery. No other lesions were found in the respiratory, gastrointestinal, or endocrine systems. There was no tumor in mediastinal lymph nodes. The heart weighed 450 gm. Pericardial adhesions secondary to the operation were present. There were typical plaques

of carcinoid heart disease in all four chambers of the heart with considerably greater involvement of the atria than the ventricles (Fig. I). Although the valve prostheses were well seated and intact grossly, there were fibrous plaques of the carcinoid type on both prostheses, which extended over the valve sewing rings onto the bases of the heterograft cusps. These plaques were most prominent on the tricuspid prosthesis (Fig. 2). There was moderate, diffuse thickening of the pulmonic valve cusps, producing probable pulmonary stenosis and insufficiency. The superior vena cava was involved with carcinoid plaque extending for a distance of 2 em from the right atrium. There was no evidence of a patent foramen ovale or other intracardiac communication. The myocardium was free of necrosis and fibrosis, and no carcinoid metastases were present. The coronary arteries had no significant lesions.

Comment Cardiovascular lesions occurring in the carcinoid syndrome are unique and pathognomonic. Involvement consists of the deposition of a peculiar type of fibrous tissue, the carcinoid plaque, superimposed on the endocardium of the cardiac chambers, the valve cusps, and occasionally the major blood vessels." The plaquelike thickenings are composed predominantly of smooth muscle cells and collagen fibers embedded in an acid mucopolysaccharide-rich matrix material. 3 Elastic fibers are not present in the plaque. The underlying structures are otherwise unremarkable, including the endocardial elastic tissue layer. Carcinoid heart lesions are found most frequently on the right side of the heart, where they may result in tricuspid and pulmonic valvular dysfunction, charac-

The Journal of Thoracic and Cardiovascular Surgery

104 Schoen et al.

teristically tricuspid regurgitation and pulmonary stenosis, which may cause death. 2. 4 Left-sided cardiac lesions are uncommon, however, and generally are not functionally significant. The exact pathogenesis of the carcinoid plaque is uncertain, but it may be related to the healing of repeated episodes of endothelial cell damage. Serotonin'" and bradykinin.P both produced by carcinoid tumors, have been implicated as the agents producing the injury. The fact that these compounds are inactivated by the liver and by the lungs explains why the carcinoid syndrome is most common in cases in which the tumor empties into the systemic (rather than the portal) circulation and those in which there are massive liver metastases. I It also explains why leftsided involvement in carcinoid heart disease is infrequent. 2 Left-sided cardiac involvement may occur, however, in the syndrome associated with primary bronchial carcinoid. 14. 15 In the present case, the primary site of the carcinoid tumor most probably was the pancreas. The abdominal orientation of the metastatic lesions and lack of lymph node involvement in the chest suggest that the lung was not the primary site of the tumor. The pulmonary lesion was either metastatic or, perhaps, a second primary carcinoid. In any event, the presence of carcinoid tumor in the lung may explain the extensive deposition of left-sided carcinoid plaques in our patient. Since cardiovascular lesions in the carcinoid syndrome tend to develop in those patients whose neoplastic disease is slowly progressive, consideration has been given to surgical repair of symptomatic valvular lesions (Table II). Wright and Mulder" attempted surgical repair of carcinoid heart disease, but their patient died in the early postoperative period. Subsequently, Aroesty and associates" reported successful replacement of the tricuspid valve with a Starr-Edwards prosthesis and, more recently, successful prosthetic valve replacement for right-sided carcinoid lesions has been described by several other groups.J"!" Tricuspid annuloplasty with pulmonary valvotomy was done in one patient with carcinoid heart disease by Garcia and coworkers. 11 Their patient died of gastrointestinal hemorrhage 3 weeks postoperatively. The report of McGuire, Pugh, and Dunn 10 described restrictive cardiomyopathy as a late complication after porcine heterograft valve replacement for carcinoid heart disease. Catheterization 13 months postoperatively in their case revealed apparently normal function of the prostheses. Although an autopsy was not obtained when the patient died of progressive cardiac failure, the authors suggested that endocardial splinting resulting from extensive carcinoid fibrosis may be the

natural history of the disease in patients who otherwise survive their valvular deformities. The patient whose case is reported herein had the carcinoid syndrome for at least 3 years prior to severe cardiac symptomatology. Although the tricuspid valve lesion was carcinoid, the mitral valvular dysfunction was secondary to myxomatous degeneration. He died 8 months after tricuspid and mitral valve replacements. The time required to produce carcinoid endocardial lesions is unknown. However, the presence of plaques on the valve prosthesis makes it apparent that they may develop in less than 8 months. Our patient had markedly elevated 5-HIAA during this entire time. The carcinoid plaques on the prostheses did not appear to be hemodynamically significant. However, with longer survival, as occurs in many patients with carcinoid disease, continued plaque deposition on the valve cusps may eventually lead to prosthetic valvular dysfunction. Our findings suggest that although prosthetic valve replacement for carcinoid heart disease may be appropriate in some situations, implantation of a mechanical rather than a tissue valve prosthesis might be preferable. Addendum Since this report was completed, an additional paper describing surgical repair of a carcinoid-related valvular lesion has been published (Sworn MJ, Edlin GP, McGill OAF, Mousley JS, Monro JL: Tricuspid valve replacement in carcinoid syndrome due to ovarian primary. Br Med J 1:85, 1980.)The patient was a 60-year-old womanwith an ovarian carcinoid and 5-HIAA excretion as high as 572 mg/24 hr. Liver biopsy at the time of laparotomy did not reveal metastatic lesions. Seven months later she had tricuspid regurgitation and underwent valve replacement with a CarpentierEdwards porcine bioprosthesis. No follow-up was included.

2 3 4 5 6

REFERENCES Kaplan EL: The carcinoid syndromes, Surgical Endocrinology, SR Freisen, ed., Philadelphia, 1978, J. B. lippincott Company, p 120 Roberts WC, Sjoerdsma A: The cardiac disease associated with the carcinoid.syndrome (carcinoid heart disease). Am J Med 36:5, 1964 Ferrans VJ, Roberts WC: The carcinoid endocardial plaque. An ultrastructural study. Hum Pathol 7:387, 1976 Trell E, Rausing A, Ripa J, Torp A, Waldenstrom J: Carcinoid heart disease. Clinicopathologic findings and follow-up in 11 cases. Am J Med 54:433, 1973 Wright PW, Mulder DG: Carcinoid heart disease. Report of a case treated by open heart surgery. Am J Cardiol 12:864, 1963 Aroesty JM, DeWeese JA, Hoffman MJ, Yu PN: Carcinoid heart disease. Successful repair of the valvular le-

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sions under cardiopulmonary bypass. Circulation 34: 105, 1966 Carpena C, Kay JH, Mendez AM, Redington JV, Zubiate P, Zucker R: Carcinoid heart disease. Surgery for tricuspid and pulmonary valve lesions. Am J Cardiol 32:229, 1973 Lund HG, Cleveland RJ, Greenberg LH, Lippmann M, Dollinger MR: Tricuspid valve replacement in carcinoid heart disease. West Med J 120:412, 1974 Honey M, Paneth M: Carcinoid heart disease. Successful tricuspid valve replacement. Thorax 30:464, 1975 McGuire MR, Pugh DM, Dunn MI: Carcinoid heart disease. Restrictive cardiomyopathy as a late complication. J Kans Med Soc 79:661, 1978 Garcia E, Taboada CF, Hall RJ, Cooley DA: Carcinoid

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heart disease. Cardiac surgery for intractable heart failure. Cardiovasc Dis (Bull Texas Heart Inst) 1:408,1974 McDonald RA, Robbins SL: Pathology of the heart in the carcinoid syndrome. A comparative study. Arch Pathol 63:103, 1957 Oates JA, Melmon K, Sjoerdsma A, Gillespie L, Mason DT: Release of a kinin peptide in the carcinoid syndrome. Lancet 1:514, 1964 Melmon KL, Sjoerdsma A, Mason DT: Distinctive clinical and therapeutic aspects of the syndrome associated with bronchial carcinoid tumors. Am J Med 39:568, 1965 Ricci C, Patrassi N, Massa R, Mineo C, BenedettiValentini F: Carcinoid syndrome in bronchial adenoma. Am J Surg 126:671, 1973