Recognizing and treating myocarditis in recent-onset systemic sclerosis heart disease: Potential utility of immunosuppressive therapy in cardiac damage progression

https://doi.org/10.1016/j.semarthrit.2013.07.006Get rights and content

Abstract

Objectives

Scleroderma heart disease is a major risk of death in systemic sclerosis (SSc). Mechanisms underlying myocardial damage are still unclear. We performed an extensive study of SSc patients with recent-onset symptoms for heart disease and examined the efficacy of immunosuppressive therapy.

Methods

A cohort of 181 SSc patients was enrolled. Of these, 7 patients newly developed clinical symptoms of heart disease (heart failure, chest pain, and palpitation); all of them showed mild but persistent increase in cardiac enzymes. These patients underwent Holter ECG, 2D-echocardiography, perfusional scintigraphy, delayed-enhancement-cardiac magnetic resonance (DE-CMR), coronary angiography, and endomyocardial biopsy. Patients were treated for at least 12 months and followed-up for 5 years.

Results

Ventricular ectopic beats (VEBs) were found in 4 patients, wall motion abnormalities in 3, pericardial effusion in 6, and DE in CMR in 6 with T2-hyperintensity in 2. In all patients, histology showed upregulation of endothelium adhesion molecules and infiltration of activated T lymphocytes, with (acute/active myocarditis in 6) or without (chronic/borderline myocarditis in 1) myocyte necrosis. Parvovirus B19 genome was detected in 3. None showed occlusion of coronary arteries or microvessels. Compared with SSc controls, these patients more often had early disease, skeletal myositis, c-ANCA/anti-PR3 positivity, VEBs, pericardial effusion, and systolic and/or diastolic dysfunction. Immunosuppressive therapy improved symptoms and led to cardiac enzyme negativization; however, 2 patients died of sudden death during follow-up.

Conclusions

Myocarditis is a common finding in SSc patients with recent-onset cardiac involvement. Its early detection allowed to timely start an immunosuppressive treatment, preventing cardiac damage progression in most cases.

Introduction

Systemic sclerosis (SSc) is a connective tissue disease characterized by diffuse vascular damage, aberrant activation of immune system and fibrosis of the skin and internal organs. Cardiac involvement is common in SSc [1]. Clinical presentation may include dyspnea, chest pain, arrhythmias and conduction delays, pericardial effusion, and heart failure, although most patients are asymptomatic at early stages. Once symptomatic, SSc heart disease represents a major predictor of mortality, along with pulmonary arterial hypertension and lung fibrosis [2], [3], [4], [5], [6].

The pathogenesis of cardiac damage in SSc is still controversial and poorly understood. The vascular mechanism hypothesis is traditionally the most credited, dating back to initial necropsy studies. In 1976, Bulkley et al. [7] described focal lesions ranging from contraction band necrosis to replacement fibrosis unrelated to epicardial coronary artery disease, suggesting that myocardial fibrosis might be caused by ischemic necrosis and reperfusion damage following intermittent vascular spasms. Alexander et al. [8] first described cardiac Raynaud's phenomenon in SSc patients, and myocardial perfusion defects inducible by cold, exercise, or pharmacological stress were documented by functional imaging studies, including SPECT [9], [10], PET [11], and cardiac magnetic resonance (CMR) [12], [13]. Additional necropsy studies also identified structural abnormalities of intramural coronary vessels (i.e., concentric intimal hypertrophy and fibrinoid necrosis) [14], which may account for impaired coronary flow reserve in these patients [15], [16].

Nonetheless, our knowledge about the pathological substrate underlying SSc heart disease mostly relies on post-mortem observations. Little is known, instead, in patients with recent-onset cardiac involvement. Ischemic necrosis may account for focal areas of replacement fibrosis, but it does not explain the diffuse interstial fibrosis detectable even in patients with subclinical heart disease by endomyocardial biopsy [17]. In fact, SSc patients commonly experience progression of cardiac dysfunction despite composite treatment with vasoactive and antiaggregation drugs. Recent studies using delayed-enhancement (DE) CMR seemed to discount the vascular mechanism hypothesis as the primary cause of myocardial fibrosis in SSc. In subclinical consecutive SSc patients, fibrosis was found to have non-coronary distribution and to be midwall with predominantly linear pattern [18], [19], similar to pattern of fibrotic remodeling that follows myocardial lymphocyte infiltration in sarcoidosis [20] and other inflammatory cardiomyopathies [21] or in idiopathic dilated cardiomyopathy [22]. Additionally, the inflammatory and autoimmune nature of SSc, as well as its possible association with skeletal myositis, suggests that myocardial inflammation may play a crucial role in SSc heart disease. Myocarditis, in fact, has been occasionally reported in SSc patients with acute and severe cardiac symptoms [23], [24], [25], [26], [27], [28]. Moreover, some cardiotropic viruses causing myocarditis have been involved in SSc pathogenesis [29], [30].

Understanding to what extent either ischemic injury or inflammation contributes to myocardial damage and fibrosis is needed to define a proper treatment for SSc heart disease. Also, identifying SSc patients at high risk of cardiac deterioration at latent or early stages is essential for preventing cardiac mortality. We performed an observational cohort study enrolling 181 SSc patients, with the aim of evaluating SSc patients with recent-onset heart involvement. Seven patients who newly developed cardiac symptoms during the observation period were recruited and underwent an extensive examination including DE-CMR and endomyocardial biopsy. In 5 of these patients (71%), we found DE patterns suggestive of myocarditis (patchy midwall DE with or without subepicardial DE); remarkably, in all the patients (100%), we obtained histological evidence of myocarditis. In addition, for the first time, we detected Parvovirus B19 genome in myocardial samples of 3 SSc myocarditis patients (43%). Steroid and immunosuppressive therapy improved clinical symptoms and normalized cardiac enzyme levels. However, 2 patients died of sudden cardiac death during a 5-year follow-up. Early disease, pericardial effusion, systolic and/or diastolic dysfunction, ventricular ectopic beats (VEBs), c-ANCA/anti-PR3 positivity, and skeletal myositis identified SSc patients at high risk of myocarditis.

Section snippets

Patient recruitment, noninvasive assessment, and follow-up

According to 1980 ACR criteria [31], 181 SSc patients were enrolled in an observational cohort study with the aim of evaluating SSc patients who showed, between January and December 2007, recent-onset cardiac involvement. In this cohort we studied 7 SSc patients with recent-onset cardiac involvement, defined as new onset of cardiologic symptoms, such as chest pain, palpitation, and dyspnea, or signs of heart failure (i.e., lower limb edema, jugular turgescence, and/or hepatojugular reflux,

Clinical features and noninvasive examination.

Among 181 SSc patients, 7 patients with clinical evidence of recent-onset cardiac involvement between January and December 2007 were recruited. Rheumatologic and cardiologic features of these 7 patients are summarized in Table 1, Table 2, respectively.

Early disease (disease duration ≤3 years from the onset) was present in 3, diffuse skin involvement in 5, skin ulcers in 4, lung involvement (mild–moderate ground-glass appearance on high-resolution computed tomography with a restrictive pattern

Discussion

In the present study, SSc patients with recent-onset heart disease underwent an extensive noninvasive and invasive evaluation, including CMR and endomyocardial biopsy. Strikingly, all SSc patients who newly developed symptoms and signs of cardiac involvement were found to have biopsy-proven myocarditis. Factors associated with myocardial inflammation included early disease, skeletal myositis, c-ANCA positivity, and pericardial effusion. Moreover, for the first time, we detected Parvovirus B19

Conclusion

Myocarditis is a mechanism of myocardial damage in SSc patients with recent-onset cardiac involvement, and immunosuppressive therapy can be useful in preventing cardiac damage progression. Since clinically evident SSc heart disease is a major predictor of mortality in SSc patients, it will be important to recognize and treat myocarditis patients at subclinical or very early stages. The role of Parvovirus B19 and c-ANCA/anti-PR3 autoantibodies in SSc myocarditis remains to be further elucidated.

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      SSc includes a wide spectrum of symptoms, varying from very mild cutaneous and internal organ involvement to diffuse fibrosis responsible for organ failure. Myocarditis with acute and definitively severe cardiac symptoms in SSc can be investigated with echocardiography or CMR and its definitive diagnosis is reached by EMB [66,132–136]. Pieroni et al studied 181 SSc patients; among 7 with newly developed clinical symptoms of heart disease, biopsy examination revealed acute/active myocarditis in six [136].

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    This work is attributed to Division of Rheumatology and Division of Cardiology of Catholic University.

    1

    These two authors contributed equally to this work.

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