The possible role of myocardial biopsy in systemic sclerosis

O. Liangos, L. Neure, U. Kühl1, M. Pauschinger1, J. Sieper, A. Distler, P. L. Schwimmbeck1 and J. Braun

Department of Nephrology and Rheumatology and
1 Department of Cardiology and Pulmonology, Freie Universität Berlin, Universitätsklinikum Benjamin Franklin, 12200 Berlin, Germany

Abstract

The histopathological features of heart involvement in systemic sclerosis (SSc) are not widely known. In internal and transplantation medicine, myocardial biopsies are increasingly used to diagnose cardiomyopathies including myocarditis. In two SSc patients presenting with dyspnoea with no evidence of pulmonary involvement, the cause of the compromised heart function was sought by myocardial biopsy. Immunohistological analysis revealed an increased number of CD3+ + T cells indicating myocarditis in one, and increased amounts of fibroblasts in both SSc patients. The authors think that myocardial involvement in SSc should be differentially evaluated and they propose the use of myocardial biopsies as a tool to distinguish between inflammatory and fibrotic forms of heart involvement in SSc patients.

Heart involvement can be a serious complication of systemic sclerosis (SSc) with increased mortality. Its histopathological features are incompletely defined. The technique of myocardial biopsy is now recognized as an established and safe procedure to diagnose cardiomyopathies, especially myocarditis. We describe two SSc patients with dyspnoea and evidence of cardiac but no significant pulmonary involvement who underwent myocardial biopsy to evaluate the cause of the compromised heart function. Immunohistological analysis of the specimen revealed an increased number of CD3+ + T cells indicating myocarditis in one but not the other case. Increased amounts of fibroblasts were found in the myocardium of both SSc patients in comparison with six controls. However, fibrosis was only seen in one patient. In conclusion, myocardial involvement can be differentially evaluated in SSc patients by myocardial biopsy. More frequent use of this tool in SSc heart disease might lead to more differentiated therapies.

Case reports

Case 1
A 57-year-old female patient with known SSc (scleroderma) was referred to our clinic with gradually increasing exertional dyspnoea, orthopnoea, and a history of pre-syncopal and syncopal episodes. The disease had been initially diagnosed in 1990, with predominant dermatological and limited pulmonary manifestations in the form of sclerosis of the skin, sclerodactyly, Raynaud's phenomenon and a radiologically suspected, but functionally insignificant pulmonary fibrosis with normal arterial blood oxygen saturation and pulmonary function tests.

On physical examination, the patient complained of dyspnoea while in the supine position but had no tachypnoea (16 breaths/min). Skin examination showed increased thickness, coarse skin creases, microstomy and telangiectasia. A third heart sound with no murmurs and some bibasilar, fibrotic rales sclerophonia was heard over both lung bases. The heart rate and blood pressure were 90/min and 120/80 mmHg, respectively.

The resting electrocardiogram (ECG) showed sinus rhythm and a left bundle branch block. The 24-h Holter monitoring revealed intermittent atrial fibrillation, third grade intermittent sinuatrial block with an arrest of 5.22 s, frequent supraventricular and ventricular premature beats with ventricular couplets, one triplet and a short supraventricular tachycardia. The pulmonary function tests were again normal and chest X-rays were unchanged compared with the ones taken years earlier. On electrophysiological examination, a prolonged duration of atrio-His bundle conduction with 106 ms as well as His bundle-ventricular conduction with 71 ms was detected. Echocardiography revealed inferior and anterior wall hypokinesia. On stress radionuclide ventriculography, decreased left ventricular ejection fraction (34%) with an increase of 10% on exertion was measured. Myocardial scintigraphy showed no significant signs of myocardial ischaemia. Cardiac catheterization demonstrated a normal right atrial pressure of 5 mmHg (normal 3–6 mmHg) and a normal peak pulmonary arterial pressure of 23 mmHg (normal 17–32 mmHg), but an elevated left ventricular end diastolic pressure with 15 mmHg (normal 5–12 mmHg). Left ventriculography demonstrated regional anterior and inferior hypokinesia, whilst the coronary angiogram was unremarkable. Endomyocardial biopsies taken from the right ventricular septum demonstrated mild but significant interstitial and subendocardial fibrosis (Fig. 1Go), degenerative atrophy with consecutive hypertrophy of groups of heart muscle cells and no signs of acute or chronic myocarditis or vasculitis.



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FIG. 1. Endomyocardial biopsy from the patient presented in case 2 (original magnification x400). Immunohistochemical staining of T cells with the marker CD3 shows numerous positively red stained cells.

 
The erythrocyte sedimentation rate (ESR) was 12 mm/l h (normal <15 mm) and the C-reactive protein (CRP) was <6 mg/l (normal <6 mg/l). No rheumatoid factor was found (<25 kU/l by nephelometry). Antinuclear antibodies (ANA) were present (immunofluorescence on HEP-2 cells) but the titre was not significant: 1:160 (positive >= 1:320). Antibodies recognizing double-stranded desoxyribonucleic acid (dsDNA), extractable nuclear antigens (ENA) and anti-cardiolipin antibodies were not found.

For therapy, a cardiac pacemaker was implanted, and an angiotensin converting enzyme (ACE) inhibitor (initially 5 mg of ramipril once daily with a target dose of 10 mg) and D-penicillamine in an initial dose of 150 mg to be increased to a dose of 300 mg twice daily over 8 weeks, were prescribed. A control echocardiography after 10 months of treatment showed diminished dimensions of the left atrium and ventricle and improved contractility, but the patient's symptoms were only slightly ameliorated.

Case 2
A 58-yr-old female patient was admitted to this hospital for cardiological evaluation after experiencing acute left heart failure with subsequent respiratory failure and mechanical ventilation during a rather mild hypertensive episode with an arterial blood pressure of 170/100 mmHg. Chest X-ray and echocardiography during that episode showed marked central and peripheral venous congestion, pulmonary oedema and anteroseptal hypokinesia but normal left ventricular contractility. Thallium scintigraphy was normal. No cardiac insufficiency or angina pectoris was known previously. A total thyroidectomy had been performed due to thyroid carcinoma 20 yr ago. Eighteen months before admission, breast cancer was detected and treated with local excision, axillary lymph node dissection and irradiation. The patient is currently in full remission and continues to be regularly controlled. In the same year, severe Raynaud's phenomenon with acral necrosis occurred. The condition was treated with high-dose steroids and calcium channel blockers. Steroids were discontinued after a few weeks of therapy due to resolution of the symptoms. In the following year, diffuse skin thickening, microstomia and dysphagial symptoms subsequently developed. The diagnosis of scleroderma was established a few weeks prior to hospitalization.

On admission, the patient was comfortable at rest, without dyspnoea or peripheral oedema, no pulmonary rales and normal heart sounds. The skin was diffusely thickened and rigid, preventing fist closure and mouth opening; several telangiectatic lesions in the facial skin were noted. Resting ECG showed slow R-wave progression from V1 to V3 with complete R-wave loss in V3 and Q-waves in II, III and AVF. Twenty-four-hour Holter ECG and thallium myocardial scanning were both completely normal. On echocardiography, no myocardial hypertrophy and no significant abnormalities in contractility were observed. Cardiac catheterization revealed a normal coronary angiogram, whereas global left ventricular function was mildly reduced with a cardiac index of 2.5 l/min/m2 (normal 2.6–4.2 l/min/m2). A marked contractile deficit was seen in the apical region. Myocardial biopsy of the right interventricular septum was performed. Histological and immunocytochemical analysis showed signs of chronic myocarditis. Although no endomyocardial fibrosis was present, immunohistochemical staining for fibroblasts showed a marked infiltration of the myocardium with fibroblasts (Fig. 2Go, see also Methods and Results sections). Molecular biological testing for the presence of viral RNA of cardiotropic viruses (e.g. coxsackie B) was negative. Only a slight intimal fibrosis of the small vessels interpreted as non-specific was observed. Laboratory evaluation revealed elevated ANA (titre 1:640), but negative results for antibodies against dsDNA, ENA and anti-cardiolipin, a negative rheumatoid factor, a normal ESR with 11/1 h, and an only slightly elevated CRP (14 mg/l).



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FIG. 2. Endomyocardial biopsy from the patient presented in case 1. Note the darkly red stained septae of fibrous tissue among the myocardial cells (arrows) (original magnification x400, kindly provided by the Department of Pathology, Universitätsklinikum Benjamin Franklin).

 
For therapy, ACE inhibitors (enalapril, 20 mg daily) to reduce blood pressure and heart failure and nifedipine (5 mg three times daily) for Raynaud's phenomenon were given. The myocarditis interpreted as a manifestation of the underlying connective tissue disease was treated with azathioprine 50 mg/twice daily and prednisolone 30 mg/daily initially with subsequent tapering of the dose.

Methods

In addition to the clinical routine histology and immunohistochemistry, myocardial biopsy material from the two patients was used for further immunohistochemical examinations. Two tissue specimens from explanted human hearts (one with chronic myocarditis, the other with ischaemic cardiomyopathy), obtained from the heart transplant centre of the Deutsches Herzzentrum Berlin frozen in liquid nitrogen and stored at -80°C, and biopsy material from four patients with underlying diseases other than scleroderma (two with dilative cardiomyopathy of unknown origin, two with coronary heart disease) were examined as controls. Immunohistochemical examination was carried out with frozen sections of the tissue (6 µm thickness) that were thaw-mounted on coated glass slides and stored at -80°C. After acetone fixation, sections were incubated with the primary antibodies [anti-CD3 1:75 (Dako, Hamburg, Germany); anti-fibroblast (AS02) 1:100 (Dianova, Hamburg, Germany); anti-CD68 1:150 (Dako); anti-CD8 1:50 (Dako)]. After washing, immunohistochemical staining using the alkaline phosphatase anti-alkaline phosphatase method and counterstaining with haematoxylin was performed. The sections were examined by light microscopy and immunohistochemically positive cells were counted at a magnification of 400x (see Table 1Go). Isotype-matched antibodies were used as a negative control. Per patient a representative high power field was selected and counted using a graticule. The measured value of the high power field was converted to a value per square millimetre using a conversion factor of 0.0625. The mean values are given plus standard deviation (S.D.). The Kruskall–Wallis test was used for statistical analysis.


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TABLE 1. Quantification of myocardial infiltration (cell counts/mm2) in the two cases with and in six controls without scleroderma heart disease

 

Results

Immunohistological analysis of the biopsy specimens revealed an increased amount of CD3+ + T cells (Table 1Go) and HLA-DR expression (not shown) as signs of chronic myocarditis in the second (Fig. 1Go) but not the first SSc case. This was similar in the patient with viral myocarditis (Table 1Go). In contrast, all examined patients had similar amounts of CD68 + macrophages (Table 1Go). Significant fibrosis was only seen in the first patient (Fig. 2Go). However, an increased amount of AS02-positive fibroblasts (Fig. 3Go) was found in the myocardium of both SSc patients (876 ± 17/mm2) in comparison with the controls (425 ± 113/mm2); this difference was statistically significant (P = 0.04).



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FIG. 3. Endomyocardial biopsy from the patient presented in case 2 (original magnification x400). Immunohistochemical staining of fibroblasts with the marker AS02 shows numerous positively red stained cells.

 

Discussion

Cardiac involvement in SSc occurs in up to 80% of the patients with this disease [1, 2]. Cardiac disease associated with SSc itself is among the three major causes of death in this disorder [3]. Clinically apparent heart disease in SSc is observed less frequently, in about 20–25% of the cases [2]. There is a multitude of possible symptoms ranging from overt cardiac failure to severe conduction disturbances [1, 2]. Furthermore, cardiovascular abnormalities have been described in a significant number of asymptomatic patients [4, 5]. The aetiology of myocardial involvement in SSc seems to be multifactorial, since inflammation, fibrosis and blood vessel abnormalities in different degrees have all been observed in SSc. Another possibly contributing factor is secondary to systemic and/or pulmonary hypertension, but scleroderma renal crisis is considered a distinct pathogenetic entity in SSc [6]. Accordingly, in early histopathological studies on SSc myocardial involvement, interstitial fibrosis and contraction band necrosis have been described [7, 8]. Some authors have speculated that these changes result from vascular spasms similar to the Raynaud's phenomenon of hands and feet which occurs in nearly all SSc patients [8]. Similarly, changes of global and regional systolic and/or diastolic function in both the right and left ventricle without coronary artery disease of the epicardial vessels have been interpreted as being due to interstitial myocardial fibrosis or myocardial ischaemia because of coronary vasospasm [911]. Systolic cardiac function at rest and echocardiographically assessed cardiac contractility may frequently be normal in SSc, but frequently an impaired diastolic function is found and a reduced coronary flow has been reported [12]. The possible discrepancy between clinical symptoms and the frequently normal results of standard diagnostic tests such as chest X-ray and resting echocardiography may lead to underestimation of cardiac involvement in SSc.

The information available on morphological characteristics of myocardial pathology in SSc has been almost completely confined to autopsy studies. This report outlines two clinical cases, in which symptoms of heart involvement in scleroderma led to the diagnostic procedure of endomyocardial biopsy. We show that the degree of fibrosis and inflammation clearly differed in these patients. In addition, the possible value of the recently described monoclonal antibody AS02 raised against specific antigens of human fibroblasts [13, 14] in evaluating cardiac pathology in SSc patients is demonstrated.

Dyspnoea was the major presenting symptom in both SSc patients. For a differential diagnostic approach to this common problem in SSc, it is necessary to consider lung and heart involvement as well as an elevated pulmonary and/or systemic blood pressure (see also Table 2Go). In the cases presented here there was no evidence of significant lung involvement as demonstrated by morphological (chest X-ray and in one case high resolution computed tomography) and functional techniques (stress pulmonary function testing in case 1 and arterial blood gases and resting pulmonary function testing in case 2). With regard to systemic blood pressure, the two cases differed, since the first patient had normal values, but the second had elevated measurements, at least initially. Still, severe left heart failure with pulmonary oedema and the requirement of respirator therapy could not be explained solely from the blood pressure surge of the reported extent. Thus, myocardial causes had to be looked for.


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TABLE 2. Overview of primary and secondary causes of scleroderma heart disease

 
The first diagnostic hint came from echocardiography which demonstrated localized contraction abnormalities and diastolic dysfunction but no signs of myocardial hypertrophy, valvular pathology or pericardial effusion [1, 2, 15]. A decrease in the resting ejection fraction (case 1) can be quantified by radionuclide ventriculography and Doppler echocardiography. These techniques are also suitable to demonstrate diastolic dysfunction with an elevated end diastolic pressure and impairment of the cardiac functional reserve [11, 12]—a myocardial dysfunction which has been linked to microcirculatory impairment [10]. However, this type of cardiac involvement in SSc, which can often be demonstrated by thallium scintigraphy visualizing stress-induced perfusion defects in small vessels, was not present in our two patients. Thus, small vessel disease and vasculitis, both possible features of SSc, were improbable. However, in cases presenting with undefined contractile impairment, visualization of the gross coronary vessels by coronary angiography is mandatory to exclude coronary heart disease, which was not present in our patients. The possibility of detecting coronary artery spasm by ergonovin provocation testing has not been tested in SSc patients to date. By left heart catheter, direct measurement of the left ventricular pressure detected myocardial dysfunction in both patients. Pulmonary hypertension, another possible feature of SSc, was excluded by right heart catheter. In combination with this procedure biopsies of the right ventricular septum were performed to obtain specimens for histological and immunohistological analyses as discussed below.

Tachy- and bradyarrhythmias are a possibly serious complication in SSc heart disease [1, 2, 16]. In the clinical assessment of cardiac abnormalities in SSc ECG and stress ECG are of limited value for the detection of ischaemia and conduction disturbances. In case 1 a significant asystolic interval was demonstrated by Holter ECG, the most important clinical tool to screen for conduction disturbances, premature beats or paroxysmal tachycardia. Since the patient had a history of syncope a cardiac pacemaker was implanted.

The possibility of obtaining myocardial biopsies for the direct assessment of heart involvement in scleroderma has only infrequently been addressed to date [17]. Since both our patients had positive biopsies revealing different pathological diagnoses with predominant myocardial fibrosis in the first and myocarditis in the second case, we feel encouraged to suggest that the somewhat nihilistic attitude of rheumatologists should change, because it seems that the differentiation of myocardial disease in SSc might have therapeutic impact. An increased prevalence of myocardial fibrosis in SSc patients has been reported from autopsy studies [15, 18]. The affected SSc patients identified in this study also had clinical evidence of left ventricular dysfunction.

There are some problems with the interpretation of myocardial histology. First, focal distribution of myocardial changes may result in significant variation of histological findings in specimens from different areas of the heart. Therefore, more than one or two specimens should be obtained. Furthermore, subendocardial fibrosis and or lipomatosis can prevent myocardial tissue being obtained during biopsy. This should not be misinterpreted as a negative result. Finally, immunohistochemical analysis of the myocardial biopsy specimen is clearly superior to conventional histology in detecting chronic myocardial inflammation [19].

There is a very small risk of complications for cardiac catheterization and endomyocardial biopsy, mainly due to catheter insertion, but no long-term sequelae occurred in a study with 2454 biopsies performed in heart transplant recipients [20]. Indeed, cardiac catheterization has become a routine diagnostic procedure in the evaluation of coronary artery disease as well as myocarditis and, with experienced operators, the overall risk of severe complications is negligible. Thus, it can be argued that there is no reason why it should not be performed in SSc patients with undefined heart involvement, since this condition is associated with significantly increased mortality rates reported to be 60% within 2 and 75% within 5 yr, [21].

The results of the immunohistochemical stainings including the quantitative assessment of fibroblasts in the myocardial interstitium of our two patients suggest that fibroblasts are over-represented in the myocardial tissue of SSc patients in comparison with other myocardial diseases. Of interest, in case 2, fibroblast dominance was present even without interstitial fibrosis. The significance of fibroblast involvement in scleroderma has been recently reviewed [22]. Our findings, which have not been presented previously, suggest that the systemic disease process going on in SSc leads to a general increase in the number of fibroblasts in involved organs such as the myocardium. Such changes also seem to occur without the classical involvement of blood vessels characterized by an obliterative process of intima fibrosis. Our findings should encourage larger studies to be performed with follow-ups to define more precisely the possible clinical value of this observation.

Since the treatment of scleroderma heart involvement is still characterized as empirical [23, 24], treatment of the primary problem is emphasized. Options range from the pharmacological treatment of hypertension, heart failure and coronary artery spasm to cardiac pacemaking devices and cardioverters in rhythm disturbance. The role of ACE inhibitors for the control of hypertension and the prevention of renal crisis is established [6]. This medication has advantages over diuretic therapy which might lead to hypovolaemia and compromised renal function, since heart dimensions are usually normal but diastolic function is impaired. Since clinical studies showed improvement of cardiac Raynaud's phenomenon after administration of calcium antagonists, these can be considered in symptomatic patients with positive thallium scans [25, 26].

D-Penicillamine has frequently been suggested in the treatment of SSc [27] and one early patient with heart involvement was successfully treated [28], with this compound mainly acting on collagen synthesis which can be possibly useful in reducing the progression of myocardial fibrosis, but this has not been proven to date. Anti-fibrotic effects have also been described for ACE antagonists [29]. However, it is not clear whether this also applies for SSc. The cardiac effects of iloprost in SSc have not been investigated to date. Oral iloprost was recently shown to ameliorate Raynaud's attacks in SSc [30]; it is increasingly used to treat pulmonary hypertension.

In conclusion, there are clinical and scientific arguments in favour of myocardial biopsies being performed in patients with SSc heart disease. Increased numbers of fibroblasts seem to contribute to cardiac pathology in SSc.

Notes

Correspondence to: J. Braun. Back

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Submitted 6 August 1998; revised version accepted 14 December 1999.



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