Department of Rheumatology and Clinical Immunology,
1 Department of Cardiology, Angiology and Pulmonology,
2 Department of Dermatology and
3 Institute of Pathology, Charité, University Hospital, Humboldt University Berlin, Germany
Correspondence to:
G. Riemekasten, Department of Rheumatology and Clinical Immunology, Schumannstraße 20/21, D-10117 Berlin, Germany.
Abstract
A 42-yr-old woman with dermatomyositis had two myocardial infarctions, episodes of acute chest pain and an acute lung oedema. These events were initially misinterpreted as atherosclerotic ischaemic heart disease accompanying the autoimmune disease. The lack of improvement of cardiac symptoms with anti-ischaemic and immunosuppressive drugs indicated other mechanisms. Intracoronary drug provocation as well as myocardial biopsy revealed a coincidence of small-vessel disease and vasospastic angina as a cause for the severe cardiac symptoms. After initiating therapy with high doses of calcium channel blockers, marked improvement of cardiac symptoms occurred. In the pathogenesis of cardiac involvement in dermatomyositis, two different mechanisms should be considered: inflammatory processes due to dermatomyositis and vasoconstriction caused by an impaired regulation of vascular tone, such as abnormal vessel reactivity or disturbed neuropeptide release. Signs of this generalized vasopathy are Raynaud's phenomenon, Prinzmetal's angina and small-vessel disease, which can coincide. In patients with severe cardiac symptoms and autoimmune diseases, Prinzmetal's angina should be excluded by intracoronary drug provocation using acetylcholine.
KEY WORDS: Prinzmetal's angina, Small-vessel disease, Raynaud's phenomenon, Dermatomyositis, Case report
A 42-yr-old woman was admitted to our hospital for diagnosis and treatment of possible heart involvement in dermatomyositis. Six years ago, Raynaud's phenomenon and photosensitivity had developed and, 1 yr later, she complained of an itching maculopapular rash, especially on the legs. Subsequently, the patient suffered from hair loss, morning stiffness in the legs and arthralgia. Occasionally, left-sided chest pain and dyspnoea occurred without apparent clinical sequelae.
One year prior to admission to our clinic, the patient presented typical symptoms of an acute myocardial infarction with characteristic clinical signs and ECG changes (Fig. 1a), and was admitted to a local hospital. During the post-infarction period, a distal muscle weakness, accompanied by myalgias and an elevated creatine kinase, developed. Histology of an M. tibialis biopsy disclosed an inflammatory myopathy. Treatment with 100 mg prednisone improved all symptoms and led to a decrease of elevated muscular enzymes. On coronary arteriography, an elevated left ventricular end diastolic pressure (18 mmHg), but no significant stenosis of epicardial coronary arteries, was detectable; however, anteroseptal and posterior hypokinesia indicated myocardial infarction corresponding to the q-waves in several leads. The patient was discharged without consulting a rheumatologist.
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General physical examination revealed an asthenic patient with no signs of cardiopulmonary failure. The skin appeared dry with multiple depigmented lesions of 0.51 cm in diameter, and an itching papular exanthema on the lower legs and forearms.
Laboratory parameters are shown in Table 1. Anti-sarcolemma and anti-smooth muscle antibodies were detected by immunofluorescence using rat tissue sections. Further antibody screening including antinuclear antibodies, anticardiolipin antibodies, anti-double-stranded (ds) DNA antibodies, anti-ENA antibodies and antibodies against Borrelia burgdorferi, as well as assays for complement (C3, C4), were negative or normal.
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Five days after admission, the patient suddenly developed acute chest pain followed by rapidly progressing pulmonary congestion and radiological signs of lung oedema. Therefore, she was intubated and treated with nitroglycerin and diuretic drugs. There were no signs of acute myocardial infarction, and following vasodilator and diuretic therapy, cardiopulmonary function rapidly improved. Subsequent invasive cardiovascular investigation revealed an unchanged left ventricular function compared to the results of earlier examinations. Coronary arteriography demonstrated a spontaneous coronary constriction of the circumflex artery (CX), which immediately resolved with intracoronary nitroglycerin. Myocardial biopsy revealed fibrosis of the myocardium and signs of small-vessel disease, but no indications of myositis (Fig. 2). Four days after the acute left ventricular failure, the patient developed typical symptoms of dermatomyositis with diffuse and symmetrical weakness, muscle pain and tenderness, elevated muscle-associated enzymes as well as characteristic electromyographic findings. This diagnosis was confirmed by skeletal muscle histology and immunofluorescence showing perifascicular myofibril atrophy, endothelial hyperplasia of blood vessels and deposition of immune complexes. High-dose methylprednisone therapy at 250 mg/day initially improved all clinical symptoms and could be tapered to 10 mg within 3 weeks. For long-term immunosuppression, oral cyclosporin A therapy was initiated at 200 mg/day. However, episodes of acute chest pain and dyspnoea recurred spontaneously and the patient was repeatedly admitted to the emergency rooms of different hospitals. ECG revealed inconsistent ST segment elevation, however, without any significant increase in cardiac enzymes. The failure to improve cardiac symptoms with immunosuppressive drugs indicated mechanisms different from inflammation of the myocardium, such as vasospastic angina. Therefore, elective coronary arteriography was performed, including a provocation test with intracoronary acetylcholine. The induction of vasospastic coronary constriction, ST elevation and severe chest pain as described before uncovered concomitant vasospastic angina (Prinzmetal's angina) in addition to the known small-vessel disease (Fig. 3
). Therefore, therapy with aspirin, methylprednisone and cyclosporin A was supplemented by the calcium channel blocker diltiazem. A dose titration of diltiazem up to 360 mg/day was not sufficient to control coronary vasospasm. Only additional calcium antagonism with amlodipine 5 mg/day markedly improved anginal symptoms to less than one or two weak episodes per month requiring no further hospital admissions for angina.
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Discussion
Cardiac involvement in dermatomyositis was considered to be uncommon for a long time. This was supported by studies of 32 patients with dermato/polymyositis showing that only two patients developed clinical, but often non-specific, signs of cardiac involvement such as palpitation and dyspnoea [1]. In contrast, studies performed recently using non-invasive diagnostic techniques revealed cardiac involvement in >70% of all patients [2]. Upon autopsy, about one-third of patients with dermato/polymyositis had morphological changes in the myocardium [3]. Besides malignancies and pulmonary disorders, cardiac involvement is one of the most important causes of death in dermato/polymyositis, as shown in a long-term follow-up, with a frequency increasing with age [2, 4]. Thus, in a study of 76 patients without any malignant diseases, 5 yr survival was 70%. Seven out of 76 patients died from complications of cardiac involvement with left ventricular failure due to cardiomyopathy, arrhythmia or cor pulmonale [5, 6]. Further risk factors for poor prognosis were acute onset of the autoimmune disease, fever, arthritis, hypergammaglobulinaemia and lung fibrosis [5]. Therefore, the prognosis of patients with dermato/polymyositis is markedly determined by cardiac involvement.
In most studies, dermato- and polymyositis were combined because of similar symptoms and the low incidence of both diseases (<1:100000). Nevertheless, different pathogenic mechanisms have been demonstrated. In polymyositis, T-cell-mediated cytotoxic reactivity against muscle fibres is detectable, whereas in dermatomyositis vascular damage is caused by humoral mechanisms directed against small vessels and capillaries [7]. Complement-mediated lysis of cellular membranes and vascular hyperplasia are detectable, followed by coagulation, infarction and finally reduction of capillaries [8]. Cardiac abnormalities include pericarditis and myocarditis with secondary fibrosis of the myocardium or the conduction system [9]. Besides these myocardial inflammatory diseases, a proliferation of smooth muscle cells of the small vessels can occur, which causes a decrease in capillary blood flow. This so-called small-vessel disease is inconsistently found in dermatomyositis and causes clinical symptoms like arrhythmia and angina pectoris [10]. Autopsies from 20 patients with dermato/polymyositis revealed myocarditis in six patients, whereas four of them also had small-vessel disease [3]. In our case, the high end diastolic pressure indicated impaired left ventricular function compatible with restrictive cardiomyopathy and abnormally increased resistance of ventricular filling secondary to small-vessel disease and fibrosis.
The coincidence of Raynaud's phenomenon, small-vessel disease and variant angina has been described before [11], and suggests similar pathogenic mechanisms with an impaired regulation of vascular tone.
Raynaud's phenomenon, first described as cold-induced digital vasospasm, is a systemic disease with a multifactorial aetiology, and vasospasms do not just affect the digits and skin, but also internal organs including the heart, lung and kidney [12]. Its pathogenesis remains an enigma, but the main factors can be categorized as being haemorrheological, inflammatory/immunological and neurogenic in origin [12]. Repeated attacks of vasospasm may cause ischaemic reperfusion injury to the endothelium which in turn releases damaging endothelial products, thus resulting in a vicious self-propagating cycle of cause and effect [13]. The results are rarefications of capillaries, ischaemia and perivascular fibrosis. The hypothesis of dysregulated neural control of vascular tone is exemplified by studies showing a deficiency of vasodilatory neuropeptides, possibly due to sensory system damage [14]. Recently, an impaired endothelial response to acetylcholinean endothelium-dependent vasodilatorwas detectable in Raynaud's phenomenon by iontophoresis [15]. In a broad epidemiological study of European cities [16], Raynaud's syndrome was also associated with cardiovascular disorders (odds ratio 3.51). Raynaud's phenomenon is detectable in approximately one-third of all patients with dermatomyositis.
Angina pectoris symptoms in patients with angiographically normal coronary arteries may be provoked by diffuse or focal vasoconstriction of large epicardial vessels and is defined as vasospastic, variant or Prinzmetal's angina [17]. In recent studies, vasospastic angina caused up to 10% of myocardial infarctions in Asian people, but the frequency varies in different populations [18]. It was reported that vasoconstriction is caused by enhanced neurohumoral discharge as well as abnormal vessel reactivity [17]. The latter is exemplified by a constrictor response to acetylcholine instead of the normally endothelium-dependent dilatative response. Thus, for our patient, an impaired generalized response to acetylcholine can be assumed.
In contrast to the large infarctions in our patient, the cardiac damage in vasospastic angina is in general small due to an early reperfusion [18]. Thus, the prognosis of spastic or Prinzmetal's angina is usually good. However, in our patient, the coronary rest flow, shown by others [19], was decreased due to an additional small-vessel disease. Implicating reduced potential for recovery from spastic occlusion, the coincidence of these two pathomechanisms may have exaggerated hypoxia and necrosis of the myocardium. Therefore, in this patient, epicardial vasospasm of large coronary arteries resulted in transmural infarctions and in the first admission with typical ECG changes (Fig. 1a) suggesting atherosclerotic ischaemic heart disease. This misinterpretation also occurred in the second admission, showing angina pectoris symptoms and ST elevation without an increase of cardiac enzymes. In retrospect, thrombolysis was not indicated. Finally, Prinzmetal's angina in combination with decreased myocardial tolerance of ischaemia due to impaired left ventricular function following progressive small-vessel disease and necroses caused the acute left ventricular failure as the third event.
Being unaware of the vasospastic mechanism, the initially detected vasoconstriction in coronary arteriography was misinterpreted as catheter associated. Diagnostic stimulation of Prinzmetal's angina was not performed immediately and therefore treatment was not sufficient in the beginning. Furthermore, the detection of small-vessel disease explained the angina pectoris, but infarctions and lung oedema are unusual for this disease. Therefore, another coronarography was performed with an intracoronary drug provocation and Prinzmetal's angina was detected. The coincidence of Prinzmetal's angina and small-vessel disease also explained the rapid development of symptoms, their reversibility and finally the improvement of cardiac symptoms with calcium channel blockers.
Interestingly, there was relapsing activity of dermatomyositis some days after the vasotonic events, suggesting a possible role of impaired tonus regulation as a trigger mechanism, possibly due to a secondary humoral mechanism. This should be noticed for therapeutic interventions using vasodilator and immunosuppressive therapy.
In conclusion, the pathogenesis of cardiac involvement in dermatomyositis is not uniform. In patients with secondary Raynaud's phenomenon, Prinzmetal's angina and small-vessel disease may coincide, and should both be adequately diagnosed and treated with effective vasodilator therapy.
References