Departments of Rheumatology,
1 Pathology and
2 Cardiology, St Vincent's University Hospital, Dublin, Ireland
Correspondence to:
B. Bresnihan, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
SIR, Cardiac involvement in Wegener's granulomatosis (WG) is not uncommon, with between 6 and 44% of cases having some degree of heart disease. However, cardiomyopathy resulting in clinical cardiac failure has rarely been reported. We report a case of a woman with WG presenting with acute left ventricular failure while on low-dose oral cyclophosphamide treatment. Whilst it is possible that the cyclophosphamide contributed to the cardiomyopathy, it is felt to be more likely that the disease itself was the major aetiological factor in this presentation.
A 44-yr-old woman presented with a 1 week history of increasing dyspnoea on exertion, paroxysmal nocturnal dyspnoea, orthopnoea, sweats and a cough productive of small volumes of white sputum streaked with blood. Her past medical history was of WG. This had been diagnosed 4 months previously on the basis of moderate renal impairment (secondary to focal and segmental glomerulonephritis on biopsy), a saddle nose deformity (secondary to septal collapse), a vasculitic rash, arthritis and a positive cANCA (titre 1:1280). She had been treated with a combination of oral prednisolone (initially 60 mg/day) and oral cyclophosphamide (100 mg/day) with good effect, and had been well since treatment commenced. She smoked 1015 cigarettes/ day, but had no other cardiac risk factors. She rarely drank alcohol. Her medications on presentation were cyclophosphamide 100 mg/day, prednisolone 15 mg/day and ranitidine 150 mg nocte. She had no known allergies.
On examination, she was tachypnoeic with a respiratory rate of 30, had a regular tachycardia of 120 beats/min and a normal blood pressure. Her jugular venous pressure was normal. Auscultation of her heart revealed a gallop rhythm, while examination of her lungs revealed crackles throughout both lung fields. The remainder of her examination was normal. In particular, there were no stigmata of active WG. Serum electrolytes, liver function tests and complete blood picture were normal, other than a creatinine of 285 µmol/l (normal 70150 µmol/l) and a Hb of 9.5 g/dl. Blood gas analysis showed pH 7.42, PCO2 3.71, PO2 8.3, HCO3 18.3 (on 24% O2 via nasal cannulae), she was cANCA positive (titre 1:40), and her ECG showed sinus rhythm and non-specific lateral T-wave changes. Chest X-ray revealed extensive bilateral interstitial pulmonary infiltrates, small bilateral pleural effusions and cardiomegaly. A differential diagnosis of lower respiratory tract infection (including the possibility of Pneumocystis carinii pneumonia) or pulmonary oedema secondary to left ventricular failure was considered. She was treated with i.v. cefotaxime, clarythromycin and trimethoprim/sulphamethoxazole, as well as frusemide 80 mg/day. Cyclophosphamide was discontinued. On this treatment she improved, with a significant diuresis over the next 48 h. Two-dimensional echocardiography revealed moderate impairment of left ventricular systolic function with an estimated ejection fraction of 40%. Aortic regurgitation was noted with trivial mitral regurgitation. There was no pleural effusion. Repeat chest X-ray showed resolving pulmonary oedema. Sputum and blood cultures failed to reveal any evidence of infection. On this basis, her antibiotic treatment was discontinued and low-dose captopril introduced. Clinically, she continued to improve and as her condition stabilized, further investigation was undertaken in an attempt to explain the sudden onset of her cardiac failure.
Cardiac catheterization revealed normal epicardial coronary vessels and confirmed reduced left ventricular systolic function. Right heart catheterization demonstrated a slightly elevated pulmonary capillary wedge pressure of ~20 mmHg and a cardiac output of 4.7 l/min. An endomyocardial biopsy was performed. Light microscopy revealed changes of mild myocyte hypertrophy with prominence and binucleation of myocyte nuclei, and no evidence of increased interstitial fibrosis (Fig. 1). Staining for amyloid and immunofluorescence for vasculitis were negative. Electron microscopy was abnormal, showing some disarray of myofilaments consistent with myocyte degeneration. In addition, there were tortuous intercalated discs and abnormal stacking of mitochondrial cristae (Fig. 2
). No capillary endothelial damage was visible under electron microscopic (EM) analysis.
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WG involving the heart is well described [1, 2]. However, significant cardiac complications occurring during the course of the disease are rare [3]. The commonest pathological manifestations are pericarditis and coronary arteritis with myocarditis occurring in ~25% of all cases with cardiac involvement [1]. The commonest clinical presentations are of pericarditis, superventricular arrhythmias and heart block [4]. Aortic valve involvement has occasionally been described, but cardiac muscle or vessel involvement unequivocally due to WG was noted to occur in <2% of one series of 158 patients [1]. To our knowledge, intrinsic heart muscle involvement leading to cardiac failure is very rare with only one case previously described [5]. Cyclophosphamide is a well-known cause of cardiotoxicity and myocardial necrosis [6, 7]. This appears to be a dose-related effect, and has not been reported in total doses under 200 mg/kg [8]. There is at least one case report of cardiomyopathy following i.v. cyclophosphamide therapy in a patient with WG [9], but no reports of cases using low-dose oral cyclophosphamide. It remains unclear as to whether the disease process itself or the cyclophosphamide treatment was primarily responsible for the cardiomyopathy. It seems unlikely that the cyclophosphamide treatment caused the cardiomyopathy as the dose was low (1.5 mg/kg/day, total dose <200 mg/kg). This is at the lowest end of the dose range for cardiac toxicity. There was no suggestion of a dosing error causing an iatrogenic problem. In addition, the EM findings were not consistent with cyclophosphamide toxicity, which is reported to show endothelial injury and a haemorrhagic myopericarditis [7]. The biopsy results did not show active vasculitis or inflammatory infiltration suggesting active disease. A possible explanation is that the WG caused the myocardial injury several months before, and that she subsequently developed her cardiac failure while the disease process was controlled. Precisely what precipitated the failure is unclear. The cardiomyopathy has not progressed after discontinuing the cyclophosphamide. The possibility of a third pathology accounting for the clinical picture seems unlikely as in particular the patient had demonstrated normal coronary arteries, there was no history of hypertension and no prodrome suggesting a viral myocarditis.
The pragmatic decision to cease the cyclophosphamide therapy and substitute it with azathioprine was taken in the full knowledge that 50% of people with cyclophosphamide-induced remission of WG will relapse within 12 months of ceasing the medication [1]. The clinical challenge will be in managing any subsequent relapse. Even if cyclophosphamide was not implicated in the cardiomyopathy, given that this woman now has a reduced ejection fraction, there is an increased risk of cyclophosphamide cardiotoxicity if the medication is reintroduced.
References