Brief communicationSustained benefit of verapamil in pulmonary hypertension with progressive systemic sclerosis
References (6)
- H Kambara et al.
Primary pulmonary hypertension: Beneficial therapy with diltiazem
Am Heart J
(1981) - B Wood et al.
Rapid attenuation of response to nifedipine in primary pulmonary hypertension
Chest
(1982) - R Salerni et al.
Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis
Ann Intern Med
(1977)
Cited by (28)
Does transformation of microvascular endothelial cells into myofibroblasts play a key role in the etiology and pathology of fibrotic disease?
2007, Medical HypothesesFibrosis is a major cause of human death and disability. It has been hypothesized widely that activation of resident tissue fibroblasts is responsible for the increase in matrix protein synthesis present in fibrotic tissue. More recent studies in vitro of the physiology of human dermal microvascular endothelial cells and their transformation into spindle-shaped cells by proinflammatory cytokines may provide a new explanation for the increase in myofibroblasts in fibrotic diseases.
In cell culture human dermal microvascular endothelial cells transform reversibly into 2 distinct cell phenotypes observed in the endothelium in vivo: an epithelioid phenotype present in a homeostatic microvasculature and a more spindle-shaped phenotype present in an inflammed and a reactive microvasculature. When epithelioid endothelial cell cultures are exposed to proinflammatory cytokines typically increased in fibrosis in vivo (e.g. TNF-α and IL-β) for sustained periods, epithelioid dermal microvascular endothelial cells transform into a spindle-shaped morphology. Many of the transformed cells are identified as myofibroblast-like cells by electron microscopy (cytoplasmic microfilaments with attachment plaques), matrix protein synthesis (type I collagen, α smooth muscle actin, calponin) and by RT-PCR analysis of matrix protein mRNA. Following injury to an endothelial cell culture a similar (but reversible) transformation into myofibroblast-like cells also is induced. Drugs known to slow the clinical progression to fibrosis in vivo (e.g. phosphodiesterase inhibitors, antibodies to inflammatory cytokines) are the the same drug types capable of inhibiting endothelial cell tranformation in vitro. The in vivo and in vitro observations made on blood vessel physiology and pathology following sustained inflammation support a hypothesis that endothelial cell transformation into myofibroblast-like cells may begin to explain the increase in matrix proteins and myofibroblasts pathognomonic of fibrotic disease. The experimental and clinical evidence leading to and supporting this hypothesis is presented and discussed in this report.
Pulmonary vascular manifestations of mixed connective tissue disease
2005, Rheumatic Disease Clinics of North AmericaPulmonary hypertension associated with connective tissue disease
2002, Progress in Cardiovascular DiseasesPulmonary arterial hypertension is a life threatening complication of several connective tissue diseases including scleroderma (both diffuse and limited scleroderma, or the CREST syndrome—calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangectasia), systemic lupus erythomatosis (SLE), mixed connective tissue disease (MCTD), and less commonly, rheumatoid arthritis (RA) and dermatomyositis/polymyositis. This report reviews the occurrence of this complication, potential etiologies, clinical presentation, and treatment options. Copyright 2002, Elsevier Science (USA). All rights reserved.
Pulmonary hypertension in connective tissue diseases
2002, Revue de Medecine InternePropos. – L’hypertension artérielle pulmonaire est une complication rare mais bien connue des connectivites. L’objet de cet article est de faire le point sur la littérature et de rapporter l’expérience du centre des maladies vasculaires pulmonaires de l’hôpital Antoine-Béclère sur la physiopathologie, le diagnostic et le traitement de cette complication des connectivites.
Actualités et points forts. – La sclérodermie et surtout sa forme limitée le CREST syndrome (calcifications sous-cutanées, syndrome de Raynaud, dysmotilité œsophagienne, sclérodactylie et télangiectasies) est la première connectivite à se compliquer d’hypertension artérielle pulmonaire. La dyspnée d’effort est le maître symptôme et est souvent d’emblée sévère. L’échocardiographie est un excellent examen de dépistage mais le cathétérisme cardiaque droit demeure l’examen de référence indispensable pour confirmer le diagnostic et évaluer la réversibilité sous vasodilatateur en aigu. Les données hémodynamiques sont sensiblement moins sévères que celles des hypertensions artérielles pulmonaires primitives, peut-être en raison d’un diagnostic plus précoce. En revanche, une moindre proportion de patients ayant une connectivite présente une réponse vasodilatatrice en aigu suggérant la constitution rapide de lésions vasculaires irréversibles. Le traitement vasodilatateur par perfusion continue de prostacycline est, dans notre expérience, décevant et n’améliore pas la survie de ces patients contrairement à ce que l’on observe dans l’hypertension artérielle pulmonaire primitive. Enfin, nous avons observé quelques cas d’amélioration de l’hypertension artérielle pulmonaire sous traitement immunosuppresseur lourd.
Perspectives et projets. – De nouvelles stratégies thérapeutiques faisant appel soit à des analogues stables de la prostacycline utilisables par voie orale, inhalée ou sous-cutanée, soit à de nouvelles molécules (antagonistes des récepteurs de l’endothéline) sont en cours d’évaluation. La place des immunosuppresseurs reste à définir.
Purpose. – Pulmonary hypertension is a rare but well-known life-threatening complication of connective tissue diseases. The aim of this article is to analyse the available literature and to report the experience of a pulmonary vascular diseases centre about this complication.
Current knowledge and key points. – Scleroderma and its limited variant, the CREST syndrome (calcification, Raynaud phenomenon, esophageal dysmotility, sclerodactily, telangiectasia), is the most common connective tissue disease affected by pulmonary hypertension. Dyspnea is the main symptom and is frequently severe. Echocardiography is an excellent exam to detect pulmonary hypertension. However, right heart catheterization is necessary to confirm the diagnosis of pulmonary hypertension and to test vasoreactivity with a potent vasodilator such as nitric oxide. Pulmonary hypertension is less severe in patients with connective tissue diseases perhaps because of an earlier diagnosis. A significantly lower proportion of patients presents an acute vasodilator response, suggesting an early constitution of irreversible pulmonary vascular lesions. Continuous intravenous epoprostenol therapy seems to be less effective as compared with patients with primitive pulmonary hypertension and does not improve survival. So, we observed dramatic improvement in rare cases after immunosuppressive therapy.
Future prospects and projects. – New treatments with oral, subcutaneous or inhaled stable prostacyclin analogs or with an endothelin receptor antagonist are currently being evaluated. The role of immunosuppressive therapy has to be defined.
Manifestations of Scleroderma pulmonary disease
1998, Clinics in Chest MedicineScleroderma (also known as systemic sclerosis) is a disease of unknown cause characterized by the synthesis and deposition of excessive extracellular matrix and vascular obliteration in various organs.7 Although the most common clinical manifestation of scleroderma is hidebound skin, internal organ compromise occurs frequently and is the major determinant of survival.79 Scleroderma (Ssc) has an incidence of approximately 10 cases per million population per year,7 with a range of 1 to 20 new cases per million per year130 and is approximately one-fourth as prevalent as systemic lupus erythematosus (SLE). It is three times more common in women than in men and is slightly more common in blacks than in whites.79, 84, 88 Pulmonary involvement is a significant cause of morbidity and mortality (Table 1) and ranks behind only the skin, peripheral vasculature, and esophagus in frequency of organ involvement.7 Respiratory symptoms were initially attributed to cutaneous changes affecting the chest wall, but in 1898 Von Notthaft154 was the first to conclude that Ssc could directly involve the lungs. Early detection of pulmonary involvement is an important predictor of survival, even in the absence of cardiac and renal involvement.6 Pulmonary complications are the most frequent cause of death in patients with scleroderma7 although only rarely are respiratory symptoms the presenting manifestation, and in these cases occupational exposure (for example to silica) may play a role.81 The most common pulmonary manifestations of scleroderma are pulmonary fibrosis, which occurs in approximately 80% of affected cases, and pulmonary arterial hypertension (PAH), which occurs in approximately 50%.7 Scleroderma is divided into two broad categories on the basis of its clinical features7, 16(Table 2): the limited form, which comprises 60% of cases, usually manifests as the CREST syndrome consisting of calcinosis, Raynaud's phenomenon, esophageal dilatation and dysmotility (Fig. 1), sclerodactyly and telangiectasias; and the diffuse form, which comprises 40% of cases.79 Various circulating antibodies are also found in association with scleroderma although their clinical implications are unknown16, 85, 140, 141(Table 3). (See also the article by Evans in this issue.)
In this article we review the classification of Ssc and the clinical features, pathogenesis, diagnostic modalities, histopathologic characteristics, and management strategies of pulmonary manifestations of this disease.
To assess the pulmonary and systemic hemodynamic effects of oral captopril in patients with connective tissue disease and pulmonary hypertension, we performed right heart catheterization in eight patients with diffuse systemic sclerosis, the CREST syndrome, or mixed connective tissue diseases prior to and immediately following administration of captopril (dose range 12.5 to 50.0 mg, short-term study). Four of these patients underwent repeat right heart catheterization after three to six months of oral captopril therapy (long-term study). In the short-term study, oral captopril produced a significant decrease in mean pulmonary vascular resistance from 6.2 ± 3.6 to 4.6 ± 3.8 units (p<0.01). This was accompanied by a significant decrease in mean pulmonary artery pressure, mean blood pressure, mean systemic vascular resistance and a significant increase in cardiac output. Similar changes in pulmonary hemodynamics were noted in the long-term study. Thus, oral captopril is capable of producing an acute and sustained reduction in pulmonary vascular resistance in patients with pulmonary hypertension associated with the aforementioned connective tissue diseases. (Chest 1992; 192:1407-12)