Elsevier

Heart Failure Clinics

Volume 8, Issue 3, July 2012, Pages 413-425
Heart Failure Clinics

Pulmonary Arterial Hypertension in Connective Tissue Diseases

https://doi.org/10.1016/j.hfc.2012.04.001Get rights and content

Introduction

Pulmonary arterial hypertension (PAH) is a progressive disease caused by a remodeling of precapillary arterioles that leads to a progressive increase in pulmonary vascular resistance and right ventricular failure. PAH is associated with significant morbidity and mortality, despite the advent of specific therapies that target pathobiologic pathways implicated in the disease process.1, 2, 3 PAH can only be diagnosed by right heart catheterization (RHC), and is defined as a mean pulmonary artery pressure greater than 25 mm Hg in the absence of elevation of the pulmonary capillary wedge pressure. PAH includes a heterogeneous group of clinical entities sharing similar pathologic changes that have been subcategorized as idiopathic PAH (IPAH), familial PAH, and pulmonary hypertension associated with other diseases such as connective tissue diseases (CTDs), portopulmonary hypertension, and pulmonary hypertension related to human immunodeficiency virus infection, drugs, and toxins. An updated classification of all pulmonary hypertension syndromes has been recently published from the fourth World Symposium held at Dana Point, California, in 2008.4

The exact mechanisms involved in the pathogenesis of PAH remain vastly unknown but are likely to involve significant alterations in endothelial function,5 an understanding of which has led over the past 2 decades to targeted therapy for this disease.6 Several lines of evidence also support a role for autoimmunity in the development of the pulmonary vascular changes, including the presence of circulating autoantibodies,7 proinflammatory cytokines (eg, interleukin [IL]-1 and IL-6),8 and association of PAH with autoimmune diseases and CTDs such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). Despite the similarities in disease pathogenesis and hemodynamic perturbations, outcomes in patients with CTD-associated PAH differ significantly from other forms of PAH. In particular, patients with SSc-associated PAH (SSc-PAH) have a poorer response to therapy and significantly worse survival compared with IPAH patients.9, 10, 11 There are serologic and pathologic features suggestive of inflammation in both IPAH and SSc-PAH, although inflammatory pathways and autoimmunity are likely more pronounced in SSc-PAH, perhaps explaining clinical discrepancies between the 2 syndromes.9, 10 Other CTDs such as SLE, MCTD, and to a lesser extent rheumatoid arthritis (RA), dermatomyositis, and Sjögren syndrome, can also be complicated by PAH and are discussed separately in this review.

Section snippets

Scleroderma

SSc is a heterogeneous disorder characterized by dysfunction of the endothelium, dysregulation of fibroblasts resulting in excessive production of collagen, and abnormalities of the immune system.12 Progressive fibrosis of the skin and internal organs is a pathologic hallmark of the disease, resulting in major organ damage and failure and thus explaining the high morbidity and early death. Genetic and environmental factors are thought to contribute to host susceptibility13 in the context of

Scleroderma-associated PAH (SSc-PAH)

The prevalence of PAH in SSc patients, when the diagnosis is based on RHC for assessment of filling pressures, is about 8% to 14%.20, 21 Previous assessments based on echocardiographic measurements22, 23, 24, 25 have overestimated the true prevalence of SSc-PAH, and should not be relied on for establishing the diagnosis and initiating treatment. Echocardiography is limited in the diagnosis of PAH, because of the inaccuracy of the Doppler signal in assessing true right ventricular systolic

PAH associated with other CTDs

PAH can complicate any CTD, most frequently SSc as already discussed, but also SLE, MCTD, RA, or other diseases such as Sjögren syndrome and dermatomyositis.

Therapy for PAH related to CTD

Although randomized clinical trials of novel therapeutics for the treatment of PAH have included patients with PAH associated with CTD, the majority of the subjects included in trials were SSc-PAH. Given the differences in survival and potential differences in response to immunosuppressive therapy between the various forms of CTD-associated PAH, the generalizability of the results of the clinical trials may be limited to only SSc-PAH. However, the therapies discussed here are commonly used in

Summary

Pulmonary hypertension is a common complication of CTD, particularly SSc, for which it carries a very poor prognosis. Despite modern therapy for PAH, survival of patients with CTD-PAH remains unacceptably low. Possible reasons include an increased prevalence of pulmonary veno-occlusive lung disease in SSc-PAH patients,126 or more severe vascular lesions affecting not only proximal and distal pulmonary vessels but also the heart (such as inflammatory myocarditis) in CTD. Thus, a better

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  • Cited by (0)

    Supported by: NHLBI K23 HL092287 (S.C.M.) and P50 HL084946 (P.M.H.).

    The authors have nothing to disclose.

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