Original contributionFibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases
Introduction
Connective tissue diseases (CTD) such as systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) can be complicated by severe pulmonary arterial hypertension (PAH), a condition that worsens these patients' prognosis dramatically [1]. Indeed, SSc represents one of the leading pathologic conditions associated with PAH. The prevalence of PAH has been estimated to be as high as 50% of cases in certain forms of CTD [2]. In a recent cross-sectional national screening, we observed that at least 8% of scleroderma patients displayed moderate to severe PAH [3]. Similarly, pulmonary vascular centers have reported that a significant proportion of patients with PAH have CTD. For instance, 15% of the patients included in the French Registry in 2002-2003 displayed CTD, thus corresponding to the second leading form of PAH in France after idiopathic PAH [4]. In patients with CTD, PAH is the leading cause of mortality and necessitates intensive medical treatment [5]. Treatment with continuous intravenous epoprostenol has been associated with improved exercise capacity, cardiopulmonary hemodynamics, New York Heart Association functional class, and dyspnea indices in patients with SSc who have PAH [6]. However, survival remains poor in this subset of patients; and response to intravenous epoprostenol is less effective than that in idiopathic PAH [7]. A new orally administered treatment based on antagonization of the endothelin 1 protein, a potent vasoconstrictive and mitogenic agent with effects on smooth muscle cells produced by pulmonary endothelial cells, has shown some efficacy in CTD patients and has been approved for treatment of PAH patients classified as New York Heart Association III (patients with marked limitation of physical activity; they are comfortable at rest, but less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope) [8]. However, endothelin receptor antagonists seem to show less impressive effects in patients with SSc than those in other forms of PAH [9]. Noteworthy, in small collectives of patients having SLE with PAH, beneficial effects of immunosuppressive therapy have been reported [10], [11], highlighting a possible link between a systemic inflammatory condition and pulmonary vascular disease.
Until now, lesions of the pulmonary arterial system, more or less similar to those occurring in idiopathic PAH, have been thought to be responsible for pulmonary hypertension in these patients [12]. Primary alterations of the pulmonary venous and capillary system may rarely lead to severe pulmonary hypertension mimicking idiopathic PAH [1]. Since the Third World Symposium on Pulmonary Hypertension in 2003, the entity of PAH includes idiopathic and familial forms, forms associated with other pathologic conditions, pulmonary venoocclusive disease (PVOD), as well as pulmonary capillary hemangiomatosis (PCH) [1]. PVOD is considered to be a rare subtype of PAH, showing an estimated prevalence of 0.1 to 0.2 per million persons and per year [13]. Historical reports and large case studies have extrapolated a proportion of PVOD in PAH ranging from 5% to 25% [14], [15]. In fact, although rare, differentiation between PAH and PVOD/PCH is of clinical importance because vasodilator therapy may elicit acute pulmonary edema in the latter disease and it is recommended that PAH therapies be used only with great caution in cases of PVOD/PCH [16].
In our clinical experience, PAH associated with CTD is frequently resistant to PAH therapy and may even lead to severe pulmonary edema [17]. We hypothesized that PAH in patients with CTD could be associated with fibrous remodeling of pulmonary veins and venules, thus explaining the difficulties in the management of PAH in that setting.
Section snippets
Materials and methods
Lung samples from 8 patients with CTD-associated PAH were studied, corresponding to 4 limited SSc, 2 SLE, 1 mixed CTD, and 1 rheumatoid arthritis (Table 1). All patients had severe PAH; and subjects with associated CTD had no interstitial lung disease or, when present, interstitial disease corresponded only to modest alterations in lung function, which could not explain the appearance of pulmonary hypertension (Table 2). All patients had been followed since the primary diagnosis of PAH at the
Pulmonary arteries/arterioles in CTD-associated PAH
Lung samples had been collected from the lung periphery to examine systematically the lobular vascular bed. In 6 cases, samples taken from the subsegmentary and even segmentary pulmonary arteries were examined. These arteries showed unspecific changes, such as atherosclerotic alterations. We followed the recent consensus on the assessment of vasculopathies in pulmonary hypertension, established at the Third World Symposium on Pulmonary Hypertension, to classify the vascular lesions [18]. In all
Discussion
Our findings suggest a frequent venoocclusive disease–like involvement of the postcapillary vascular bed in lungs of patients who have PAH associated with CTD. Increased presence of inflammatory elements seems to be related to this observation. In addition, we found morphological peculiarities involving the pulmonary arterial tree and the capillary level in this subset of PAH.
References (30)
- et al.
Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis
Am J Med
(1983) - et al.
Immunosuppressive therapy in connective tissue diseases–associated pulmonary arterial hypertension
Chest
(2006) - et al.
Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection
Hum Pathol
(1997) - et al.
Clinical classification of pulmonary hypertension
J Am Coll Cardiol
(2004) - et al.
Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study
Arthritis Rheum
(2005) - et al.
Pulmonary arterial hypertension in France: results from a national registry
Am J Respir Crit Care Med
(2006) - et al.
Treatment of pulmonary hypertension secondary to connective tissue diseases
Thorax
(1999) - et al.
Pulmonary arterial hypertension in systemic sclerosis: clinical manifestations, pathophysiology, evaluation, and management
Treat Respir Med
(2004) - et al.
Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease
Ann Intern Med
(2000) - et al.
Bosentan therapy for pulmonary arterial hypertension
N Engl J Med
(2002)