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Relapsing Congestive Cardiomyopathy in Wegener's Granulomatosis

1997; Elsevier BV; Volume: 72; Issue: 9 Linguagem: Inglês

10.4065/72.9.848

1942-5546

I. Delèvaux, Bruno Hoen, Christine Selton‐Suty, P Canton,

Amyloidosis: Diagnosis, Treatment, Outcomes

Congestive cardiomyopathy is a highly unusual complication of Wegener's granulomatosis. In this report, we describe a 37-year-old man with histologically proven Wegener's granulomatosis who had two episodes of severe hypokinetic cardiomyopathy that responded well to cyclophosphamide. The theory that cardiomyopathy might be related to cardiac involvement in Wegener's granulomatosis and the beneficial effect of cyclophosphamide in this condition are discussed. Congestive cardiomyopathy is a highly unusual complication of Wegener's granulomatosis. In this report, we describe a 37-year-old man with histologically proven Wegener's granulomatosis who had two episodes of severe hypokinetic cardiomyopathy that responded well to cyclophosphamide. The theory that cardiomyopathy might be related to cardiac involvement in Wegener's granulomatosis and the beneficial effect of cyclophosphamide in this condition are discussed. Cardiac manifestations of Wegener's granulomatosis are infrequent,1Grant SC Levy RD Venning MC Ward C Brooks NH Wegener's granulomatosis and the heart.Br Heart J. 1994; 71: 82-86Crossref PubMed Scopus (77) Google Scholar, 2DeRemee RA McDonald TJ Weiland LH Wegener's granulomatosis: observations on treatment with antimicrobial agents.Mayo Clin Proc. 1985; 60: 27-32Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 3Hoffman GS Kerr GS Leavitt RY Hallahan CW Lebovics RS Travis WD et al.Wegener granulomatosis: an analysis of 158 patients.Ann Intern Med. 1992; 116: 488-498Crossref PubMed Scopus (2570) Google Scholar and cardiomyopathy is highly unusual.1Grant SC Levy RD Venning MC Ward C Brooks NH Wegener's granulomatosis and the heart.Br Heart J. 1994; 71: 82-86Crossref PubMed Scopus (77) Google Scholar Herein we describe a patient who had two episodes of severe cardiomyopathy that responded well to treatment with cyclophosphamide. A 37-year-old man was admitted to the hospital for the first time in October 1988 with a 3-week history of fever, arthralgia, and ulcers of the nasal septum. At age 22 years, he had been treated for 9 months with isoniazid and ethambutol hydrochloride for a putative pulmonary tuberculosis. At that time, a chest roentgenogram showed nodular infiltrates of the right apex while the patient was symptomless. Sputum examinations failed to reveal acid-fast bacilli, and sputum cultures remained negative. On admission, the patient's general condition was slightly impaired, and physical examination disclosed only encrusted nasal tissue and rhinitis. The erythrocyte sedimentation rate (ESR) was 84 mm in 1 hour, and serum C-reactive protein was 152 mg/L. Renal function was normal. Urinalysis showed moderate proteinuria (0.7 g/day) and microhematuria (83,000 erythrocytes/mL). Cytoplasmic-staining antineutrophil cytoplasmic autoantibodies (cANCAs) were positive with use of an immunofluorescence technique. A chest roentgenogram showed excavated nodular opacities in both apexes and in right Fowler's lobe. Electrocardiographic findings were normal. Nasal biopsy showed multinucleated giant-cell infiltrates and necrotizing vasculitis. The patient was diagnosed as having Wegener's granulomatosis and was given prednisone (1 mg/kg daily) and trimethoprim-sulfamethoxazole (T-S) (two doublestrength tablets daily). All symptoms disappeared, and results of laboratory studies returned to normal within a few days. The patient was dismissed 2 weeks after initiation of treatment. In January 1989, the patient was readmitted to the emergency department because of acute pulmonary edema. At that time, the ESR was 4 mm in 1 hour, C-reactive protein was less than 5 mg/L, and cANCAs were negative. The electrocardiographic findings remained normal. Echocardiography showed hypokinetic cardiomyopathy, with a left ventricular ejection fraction (LVEF) calculated as 40%. Coronary angiography revealed normal coronary vasculature. Endomyocardial biopsy was performed at the conclusion of coronary angiography, and histologic analysis of one myocardial fragment showed normal findings. Cardiac failure was treated with diuretics and nitrocompounds. The dosage of prednisone was tapered to 0.5 mg/kg daily, oral administration of cyclophosphamide (100 mg daily) was begun, and T-S therapy was maintained unchanged. The patient's cardiac condition rapidly improved. He was dismissed from the hospital after 2 weeks and underwent outpatient follow-up. Cyclophosphamide therapy was discontinued by the end of 1989, as was prednisone therapy in May 1990. At that time, cardiac function was subnormal (LVEF = 50%) without supportive treatment. In December 1991, T-S therapy was discontinued. In November 1992, after 3 years of complete remission and 11 months with no treatment, the patient complained of arthralgia. The ESR was 44 mm in 1 hour, C-reactive protein was 55 mg/L, and cANCAs were positive. Therapy with prednisone and T-S was resumed and continued throughout 1993. In December 1993, excavated opacities developed in the right upper lobe, without concomitant clinical symptoms. Orally administered methotrexate (15 mg weekly) was added to the treatment in January 1994. In October 1994, while the patient continued to do well, excavations developed in the left upper lobe. The prednisone dosage was then increased to 1 mg/kg daily but tapered again in December because of vertebral fractures. In May 1995, a chest roentgenogram disclosed a new subpleural nodule. Open-lung biopsy of this nodule showed multiple foci of necrotizing vasculitis of small and medium-sized vessels, surrounded by active fibrosis without granuloma. Methotrexate therapy was then discontinued, and cyclophosphamide treatment (100 mg/day orally) was reinitiated. Three days later, the patient was seen in the emergency department because of acute pulmonary edema. The ESR was 68 mm in 1 hour, C-reactive protein was 103 mg/L, and the cANCA titer was 32. An echocardiogram showed severe dilated hypokinetic cardiomyopathy (LVEF was calculated as 20%). Diuretic and angiotensin-converting enzyme inhibitor therapy was initiated, and cyclophosphamide treatment was continued at the same dosage. The patient's condition progressively improved, and repeated echocardiograms showed a gradual recovery of cardiac function. By December 1995, the patient was doing well. The ESR and C-reactive protein values had returned to normal, and cANCAs were negative. Pulmonary infiltrates had diminished. The left ventricle was no longer dilated or hypokinetic, and the LVEF had returned to normal (57%). Treatment with diuretics and angiotensin-converting enzyme was discontinued. No relapse of either Wegener's granulomatosis or cardiomyopathy had occurred by July 1996. In this case, the diagnosis of Wegener's granulomatosis was definite, based on the initial clinical symptoms, the positivity of cANCA, and the histopathologic findings. At the time of diagnosis, the absence of renal involvement and life-threatening manifestations prompted us to begin therapy without using cyclophosphamide. In addition to corticosteroids, we decided to use T-S, which has been proposed as an effective alternative therapy for limited variants of Wegener's granulomatosis.2DeRemee RA McDonald TJ Weiland LH Wegener's granulomatosis: observations on treatment with antimicrobial agents.Mayo Clin Proc. 1985; 60: 27-32Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Subsequently, the patient had two episodes of severe hypokinetic dilated cardiomyopathy that were responsible for acute heart failure. Although we cannot provide the histopathologic documentation that the cardiomyopathy was related to cardiac involvement of Wegener's granulomatosis, two facts support this hypothesis. First, the onset of both cardiac episodes occurred within a few weeks after an attack of the disease. Second, each episode responded favorably to prednisone plus cyclophosphamide therapy. The frequency of cardiac involvement in Wegener's granulomatosis is highly variable, ranging from 6 to 44% of cases.3Hoffman GS Kerr GS Leavitt RY Hallahan CW Lebovics RS Travis WD et al.Wegener granulomatosis: an analysis of 158 patients.Ann Intern Med. 1992; 116: 488-498Crossref PubMed Scopus (2570) Google Scholar, 4Pinching AJ Lockwood CM Pussell BA Rees AJ Sweny P Evans DJ et al.Wegener's granulomatosis: observations on 18 patients with severe renal disease.Q J Med. 1983; 52: 435-460PubMed Google Scholar Because the highest percentages were reported in autopsy studies, most cardiac manifestations may be asymptomatic. The most frequent clinical manifestations are pericarditis—often complicated by tamponade or constriction1Grant SC Levy RD Venning MC Ward C Brooks NH Wegener's granulomatosis and the heart.Br Heart J. 1994; 71: 82-86Crossref PubMed Scopus (77) Google Scholar, 3Hoffman GS Kerr GS Leavitt RY Hallahan CW Lebovics RS Travis WD et al.Wegener granulomatosis: an analysis of 158 patients.Ann Intern Med. 1992; 116: 488-498Crossref PubMed Scopus (2570) Google Scholar, 5Schiavone WA Ahmad M Ockner SA Unusual cardiac complications of Wegener's granulomatosis.Chest. 1985; 88: 745-748Crossref PubMed Scopus (40) Google Scholar—angina pectoris,6Forstot JZ Overlie PA Neufeld GK Harmon CE Forstet SL Cardiac complications of Wegener granulomatosis: a case report of complete heart block and review of the literature.Semin Arthritis Rheum. 1980; 10: 148-154Abstract Full Text PDF PubMed Scopus (111) Google Scholar arrhythmia and heart block resulting either from pericarditis or from coronary ischemia,5Schiavone WA Ahmad M Ockner SA Unusual cardiac complications of Wegener's granulomatosis.Chest. 1985; 88: 745-748Crossref PubMed Scopus (40) Google Scholar, 6Forstot JZ Overlie PA Neufeld GK Harmon CE Forstet SL Cardiac complications of Wegener granulomatosis: a case report of complete heart block and review of the literature.Semin Arthritis Rheum. 1980; 10: 148-154Abstract Full Text PDF PubMed Scopus (111) Google Scholar and aortic valvulitis.1Grant SC Levy RD Venning MC Ward C Brooks NH Wegener's granulomatosis and the heart.Br Heart J. 1994; 71: 82-86Crossref PubMed Scopus (77) Google Scholar In contrast, congestive cardiomyopathy complicating the course of Wegener's granulomatosis is extremely infrequent. In the largest series of Wegener's granulomatosis, "cardiac muscle or vessel involvement unequivocally due to Wegener's granulomatosis" accounted for only 2 of 158 cases.3Hoffman GS Kerr GS Leavitt RY Hallahan CW Lebovics RS Travis WD et al.Wegener granulomatosis: an analysis of 158 patients.Ann Intern Med. 1992; 116: 488-498Crossref PubMed Scopus (2570) Google Scholar To the best of our knowledge, only four cases of congestive hypokinetic cardiomyopathy have been reported throughout the literature. The first two cases were reported by Fauci and associates.7Fauci AS Haynes BF Katz P Wolff SM Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years.Ann Intern Med. 1983; 98: 76-85Crossref PubMed Scopus (1681) Google Scholar They consisted of dilated congestive cardiomyopathy complicated by severe arrhythmia and cardiac arrest in two women who had previously been treated with cyclophosphamide. In the third case, a 28-year-old man had acute cardiac failure due to congestive cardiomyopathy 1 month after Wegener's granulomatosis was diagnosed and treated with prednisone and cyclophosphamide. Cardiac failure was intractable, and the patient died rapidly without having arrhythmia. Autopsy showed a dilated cardiomyopathy with typical necrotizing and granulomatous vasculitis.8Weidhase A Grone HJ Unterberg C Schuff-Werner P Wiegand V Severe granulomatous giant cell myocarditis in Wegener's granulomatosis.Klin Wochenschr. 1990; 68: 880-885Crossref PubMed Scopus (17) Google Scholar In the last case, a 39-year-old woman had a fatal nondilated congestive cardiomyopathy 2 weeks after Wegener's granulomatosis was diagnosed and cyclophosphamide therapy was instituted. No autopsy was performed.9Korzets Z Chen B Levi A Pomeranz A Bernheim J Bruderman I et al.Non-dilated congestive cardiomyopathy: a fatal sequela of Wegener's granulomatosis.J Nephrol. 1991; 4: 61-64Google Scholar The last two cases have in common with ours that cardiomyopathy occurred early after diagnosis and initiation of immunosuppressive therapy. This temporal relationship supports the hypothesis that cardiomyopathy is part of the cardiac involvement associated with Wegener's granulomatosis, which could be histopathologically demonstrated in one case. One concern has been that the cardiomyopathy might be related to the cyclophosphamide therapy. In the two cases reported by Fauci and colleagues7Fauci AS Haynes BF Katz P Wolff SM Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years.Ann Intern Med. 1983; 98: 76-85Crossref PubMed Scopus (1681) Google Scholar as well as in the last two cases, cardiomyopathy did develop in patients who had cyclophosphamide therapy. Nevertheless, cyclophosphamide-related cardiomyopathy has not been reported. Additionally, our case provides evidence against this theory. When the first episode of cardiomyopathy occurred, our patient had not received cyclophosphamide. The second episode of cardiomyopathy was revealed by an episode of acute pulmonary edema that occurred only 3 days after treatment with cyclophosphamide had been reintroduced. Therefore, implication of cyclophosphamide in the occurrence of cardiomyopathy seems unlikely, inasmuch as cyclophosphamide therapy was continued and resulted in the patient's recovery. The main point of interest in our case report is that cyclophosphamide not only did not cause cardiomyopathy but also was essential for its cure.