Although overt cardiac involvement is rare, case reports have documented constrictive pericarditis [5], endocarditis [6], and myocarditis [7]. Postmortem studies of some patients without clinical cardiac involvement have described gross deformities of the valves and pericardium [5] and macrophages that yield positive results on periodic acid-Schiff staining in the myocardium [5, 8]. Electron microscopy has been used after death to document rod-shaped bacillary bodies in the myocardium of two patients without clinical cardiac involvement who died of untreated Whipple disease. We report an atypical presentation of Whipple disease with predominant cardiac involvement and show that Whipple bacillus was evident in myocardial tissue by electron microscopy before death.

Case Report

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A 44-year-old woman was referred for evaluation of heart failure. She had been healthy until 9 months before presentation, at which time she noted dyspnea on exertion, increased abdominal girth, edema of the lower extremities, and pain in the right upper quadrant after a viral illness. Echocardiography had shown biatrial enlargement and mild global dysfunction of the left ventricle, which suggested viral myocarditis. The patient's condition improved with administration of furosemide and enalapril, but she then developed additional symptoms, including anorexia; weight loss; and several episodes of watery, light-brown stool per day. During the month before admission, she noted further increased abdominal girth, frequent dizzy spells, and dyspnea that had progressed to the point that she could no longer speak in complete sentences. Her medical history was otherwise unremarkable.

Physical examination showed a thin, ill woman in respiratory distress. Vital signs included a systolic blood pressure of 70 mm Hg, a pulse of 80 beats/min, a respiratory rate of 44 breaths/min, and normal temperature. Cardiovascular examination showed a jugular venous pressure of 12 cm H₂O with large "V" waves, a nondisplaced palpable apical impulse, a right ventricular heave, and a palpable pulmonary component of the second heart sound. On auscultation, the second heart sound was accentuated and a grade III/VI systolic murmur was detected at the left upper border of the sternum. The abdomen was distended, and bowel sounds were normal; the liver span was enlarged and pulsatile. Trace pretibial edema was noted in the extremities. Results of neurologic examination were normal.

Initial laboratory test results showed hyponatremia and microcytic anemia. Chest radiography showed basilar atelectasis. Electrocardiography showed sinus rhythm, an abnormality of the left atrium, and flattening of the T waves. Echocardiography showed biatrial enlargement, normal systolic function of the left ventricle, enlargement of the right ventricle, abnormal motion of the septum consistent with volume overload of the right ventricle, moderate tricuspid and mitral regurgitation, and a thickened pericardium.

Cardiac catheterization showed an ejection fraction of 60%, mild mitral regurgitation, and normal coronary arteries. Cardiac output was 3.5 L/min, and the cardiac index was 1.8 L/min · m^–2. Hemodynamic examination showed the following: right atrial pressure, 10 mm Hg; right ventricular pressure, 40/10 mm Hg; pulmonary arterial pressure, 40/16 mm Hg; pulmonary capillary wedge pressure, 14 mm Hg; left ventricular pressure, 84/15 mm Hg; and aortic pressure, 84/50 mm Hg. Simultaneous recordings of right and left ventricular pressures showed elevation and equalization at end diastole with a square-root pattern that suggested constrictive pericardial disease or restrictive cardiomyopathy.

Magnetic resonance imaging of the heart confirmed biatrial enlargement and dilatation of the vena cavae and hepatic veins. Focal areas of pericardial and pleural thickening and small (0.5 to 1.0 cm) lymph nodes in the mediastinum were evident. Computed tomography of the abdomen and pelvis showed extensive hypodense aortocaval lymph nodes that prompted us to do upper endoscopy and small-bowel biopsy. The bowel had a speckled, white mucosal pattern on endoscopy. Histologic examination of the small intestine showed prominent vacuoles; dilated lymphatic vessels; and macrophages with foamy, gray-blue cytoplasm. The macrophages were resistant to diastase and yielded positive results on periodic acid-Schiff staining, factors that are consistent with Whipple disease.

The patient had recurrent syncope in the hospital because of complete heart block and a slow junctional escape rhythm of 30 beats/min. Biopsy of the right ventricular endomyocardium was done during implantation of a temporary pacemaker. The biopsy specimen showed macrophages that yielded positive results on periodic acid-Schiff staining (Figure 1), and the Whipple bacillus was identified by electron microscopy (Figure 2). We believe that this is the first documentation of the presence of Whipple bacillus by electron microscopy in the myocardium of a patient before death.

View larger version (141K): [in this window] [in a new window]   Figure 1. Right ventricular myocardial biopsy specimen viewed by light microscopy. Disordered myofibrils and numerous bacilli can be seen (arrows) (periodic acid-Schiff; original magnification, x100).

View larger version (147K): [in this window] [in a new window]   Figure 2. Myocardial biopsy specimen taken before death, viewed by electron microscopy. Whipple bacillus is evident (arrow) (original magnification, x15 000).

Discussion

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Cardiac involvement in Whipple disease is relatively common and may manifest as pancarditis with valvular, myocardial, and pericardial inflammation; fibrosis; and deformity [5]. In one series [4], as many as 30% of patients with Whipple disease were reported to have heart murmurs (usually aortic insufficiency). In an autopsy series of 19 patients [5], McAllister and Fenoglio described clinical findings that included a pansystolic murmur and deformity of at least one valve in 10 patients. Adhesive pericarditis or constriction was present with macrophages that yielded positive results on periodic acid-Schiff staining in 16 of the 19 patients in that series. Cardiac involvement has also been documented by electron microscopy in two patients who died of untreated Whipple disease, neither of whom had clinical signs of cardiac involvement [9]. Coronary arteritis and lymphocytic myocarditis have rarely been reported in association with Whipple disease [6, 10]. Speculation that conduction abnormalities may be caused by myocarditis has resulted from reports of high-grade atrioventricular block that required placement of a pacemaker and caused sudden death [5, 6] and from a report of right bundle-branch block that resolved with antibiotic therapy [11]. Polymerase chain reaction was recently used to document the presence of a gene that encoded the 16s ribosomal RNA of T. whippelii in the aortic valve of a patient with predominantly intestinal Whipple disease who developed endocarditis [12].

In most patients, cardiac manifestation of Whipple disease is preceded or overshadowed by prominent gastrointestinal manifestation. In fact, cardiac symptoms of ascites, peripheral edema, and pleural effusion may be wrongly attributed to hypoalbuminemia. A study by de Takats and colleagues [7] reported dilated cardiomyopathy in a patient with intestinal Whipple disease, but endomyocardial biopsy did not show macrophages that yielded positive results on periodic acid-Schiff staining or electron microscopic findings characteristic of the disease.

The initial presentation of our patient and the subsequent course of disease was also atypical because of the domination by cardiac symptoms. The patient was treated with trimethoprim-sulfamethoxazole and was given a permanent pacemaker. She has now received treatment for more than 1 year, and her cardiac and gastrointestinal symptoms have been markedly alleviated. Her systolic blood pressure has increased to 110 mm Hg, and her exercise tolerance has improved to New York Heart Association functional class II. She reports no diarrhea or abdominal discomfort, and her weight has increased by 13.6 kg (30 pounds).

Whipple disease with cardiac involvement was suspected in our patient because of the manifestation in several organ systems and the findings of hypodense abdominal lymphadenopathy on computed tomography. The patient's initial presentation was dominated by congestive heart failure, and she subsequently had pericardial constriction, syncope, and complete heart block caused by myocardial involvement. The diagnosis was confirmed by macrophages that yielded positive results on periodic acid-Schiff staining of small-bowel and endomyocardial biopsy specimens and by Whipple bacillus seen on electron microscopy of myocardial tissue.

Dr. Murray: Merck and Co., West Point, PA 19486.

Dr. Furth: Department of Pathology, University of Pennsylvania, 6 Founder's Pavilion, 3400 Spruce Street, Philadelphia, PA 19104.

Dr. Kim: 95 Bay Driveway, Plandome, NY 11030.

Dr. Pollack: University of Florida, Department of Gastroenterology, PO Box 100214, Gainesville, FL 32610-0214.

Dr. Haimowitz: Hospital of the University of Pennsylvania, Department of Dermatology, Jonathan Rhoads Pavilion, 2nd Floor, 3600 Spruce Street, Philadelphia, PA 19104.

Dr. Nisenbaum: Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104-4283.

Dr. Kochman: Gastrointestinal Division, University of Pennsylvania Medical Center, 3 Dulles, 3400 Spruce Street, Philadelphia, PA 19104.

Dr. Freedman: University of Pennsylvania Medical Center, 8 Maloney, 3400 Spruce Street, Philadelphia, PA 19104.

Dr. Pine: Medical Center at Princeton, 253 Witherspoon Street, Princeton, NJ 08540.