Pulmonary Hypertension
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In their review of pulmonary hypertension, Farber and Loscalzo (Oct. 14 issue)1 suggest that chronic hypoxia causes pulmonary hypertension by producing structural changes in the vasculature. This widely accepted view postulates two major changes: thickening of the arteriolar wall with encroachment into the vessel lumen and a loss of blood vessels; more recent evidence calls this view into question. By applying quantitative stereologic techniques to this problem, we showed that hypoxia-induced vascular-wall remodeling did not reduce the maximal luminal diameter.2 Furthermore, we found that chronic hypoxia stimulated angiogenesis in the pulmonary circulation, not loss of vessels.2 More recently, Nagaoka et al. reported that in rats with chronic hypoxia and pulmonary hypertension, the administration of Rho kinase inhibitors, which are potent vasodilators, immediately returned pulmonary vascular resistance to nearly normal values.3 Clearly, rapid normalization could not occur if vascular resistance was increased as a result of fixed structural changes. Thus, two independent lines of evidence suggest that chronic hypoxic pulmonary hypertension may not be structurally based.
Paul McLoughlin, M.B., Ph.D.
Jean-Marc Hyvelin, Ph.D.
Katherine Howell, Ph.D.
University College Dublin
Dublin, Ireland
paul.mcloughlin@ucd.ie
References
Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655-1665.
Howell K, Preston RJ, McLoughlin P. Chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulation. J Physiol 2004;547:133-145.
Nagaoka T, Morio Y, Casanova N, et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 2004;287:L665-L672.
To the Editor: Farber and Loscalzo state that "pulmonary arterial hypertension comprises . . . pulmonary arterial hypertension in the setting of collagen vascular disease (e.g., in localized cutaneous systemic sclerosis, also known as the CREST syndrome)." The statement "localized cutaneous systemic sclerosis, also known as the CREST syndrome" is rather confusing. Systemic sclerosis is classified as diffuse or limited cutaneous systemic sclerosis according to the degree of clinically involved skin.1 The CREST syndrome falls within the subgroup of limited systemic sclerosis. On the other hand, localized scleroderma includes several conditions that are clinically and histopathologically similar to the skin involvement of systemic sclerosis but that do not have systemic features (e.g., linear scleroderma and morphea).
The authors also note that "a pulmonary arteriopathy occurs in limited systemic sclerosis (i.e., tight skin limited to the fingers, with digital ulcers and often pulmonary fibrosis)." However, pulmonary fibrosis is not a common manifestation of limited systemic sclerosis, and pulmonary hypertension characteristically occurs in the absence of pulmonary fibrosis in this subgroup of systemic sclerosis. In contrast, pulmonary fibrosis with secondary hypertension is common among persons with diffuse systemic sclerosis.2
Maria Tektonidou, M.D.
National University of Athens
115 27 Athens, Greece
References
LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202-205.
Silver RM. Scleroderma -- clinical problems: the lungs. Rheum Dis Clin North Am 1996;22:825-840.
The authors reply: Dr. Tektonidou suggests that the use of the term "localized cutaneous systemic sclerosis" is confusing and that it could encompass other, similar conditions without systemic symptoms. We agree that our choice of words might engender some confusion and that "limited cutaneous systemic sclerosis" would have been a better choice. She also suggests that pulmonary fibrosis is not a common manifestation of limited systemic sclerosis and that pulmonary hypertension characteristically occurs in the absence of pulmonary fibrosis. Although it is true that clinically relevant pulmonary fibrosis is more common in diffuse systemic sclerosis and that pulmonary hypertension occurs more frequently in the absence of extensive fibrosis, the distinction between these forms of systemic sclerosis is not always clear. In addition, there is a certain degree of overlap, and basilar fibrosis is very common in limited systemic sclerosis.1
Dr. McLoughlin and colleagues suggest that pulmonary hypertension associated with chronic hypoxia may not be due to structural alterations.2 We stated that chronic hypoxia causes vascular changes because there is ample and long-standing evidence to support this comment.3 In the study that Dr. McLoughlin and colleagues performed,2 the vessels showed histologic changes similar to those previously reported; alterations in angiogenesis, apoptosis, and other pathways may be additional contributors to the development of pulmonary hypertension under these conditions.
Harrison W. Farber, M.D.
Joseph Loscalzo, M.D., Ph.D.
Boston University School of Medicine
Boston, MA 02118
jloscalz@bu.edu
References
Furst DE, Clements PJ, Tashkin D, Elashoff R, Goldin J, Sterz M. Among a group of patients with dyspnea and alveolitis entering the Scleroderma Lung Study (SLS), a surprising proportion have limited SSC (lSSC). Arthritis Rheum 2004;50:5426-5426. abstract.
Howell K, Preston PJ, McLoughlin P. Chronic hypoxia causes angiogenesis in addition to remodeling in the adult rat pulmonary circulation. J Physiol 2003;547:133-145.
Rabinovitch M, Gamble W, Nadas AS, Miettinen OS, Reid L. Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features. Am J Physiol 1979;236:H818-H827.
Paul McLoughlin, M.B., Ph.D.
Jean-Marc Hyvelin, Ph.D.
Katherine Howell, Ph.D.
University College Dublin
Dublin, Ireland
paul.mcloughlin@ucd.ie
References
Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655-1665.
Howell K, Preston RJ, McLoughlin P. Chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulation. J Physiol 2004;547:133-145.
Nagaoka T, Morio Y, Casanova N, et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 2004;287:L665-L672.
To the Editor: Farber and Loscalzo state that "pulmonary arterial hypertension comprises . . . pulmonary arterial hypertension in the setting of collagen vascular disease (e.g., in localized cutaneous systemic sclerosis, also known as the CREST syndrome)." The statement "localized cutaneous systemic sclerosis, also known as the CREST syndrome" is rather confusing. Systemic sclerosis is classified as diffuse or limited cutaneous systemic sclerosis according to the degree of clinically involved skin.1 The CREST syndrome falls within the subgroup of limited systemic sclerosis. On the other hand, localized scleroderma includes several conditions that are clinically and histopathologically similar to the skin involvement of systemic sclerosis but that do not have systemic features (e.g., linear scleroderma and morphea).
The authors also note that "a pulmonary arteriopathy occurs in limited systemic sclerosis (i.e., tight skin limited to the fingers, with digital ulcers and often pulmonary fibrosis)." However, pulmonary fibrosis is not a common manifestation of limited systemic sclerosis, and pulmonary hypertension characteristically occurs in the absence of pulmonary fibrosis in this subgroup of systemic sclerosis. In contrast, pulmonary fibrosis with secondary hypertension is common among persons with diffuse systemic sclerosis.2
Maria Tektonidou, M.D.
National University of Athens
115 27 Athens, Greece
References
LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202-205.
Silver RM. Scleroderma -- clinical problems: the lungs. Rheum Dis Clin North Am 1996;22:825-840.
The authors reply: Dr. Tektonidou suggests that the use of the term "localized cutaneous systemic sclerosis" is confusing and that it could encompass other, similar conditions without systemic symptoms. We agree that our choice of words might engender some confusion and that "limited cutaneous systemic sclerosis" would have been a better choice. She also suggests that pulmonary fibrosis is not a common manifestation of limited systemic sclerosis and that pulmonary hypertension characteristically occurs in the absence of pulmonary fibrosis. Although it is true that clinically relevant pulmonary fibrosis is more common in diffuse systemic sclerosis and that pulmonary hypertension occurs more frequently in the absence of extensive fibrosis, the distinction between these forms of systemic sclerosis is not always clear. In addition, there is a certain degree of overlap, and basilar fibrosis is very common in limited systemic sclerosis.1
Dr. McLoughlin and colleagues suggest that pulmonary hypertension associated with chronic hypoxia may not be due to structural alterations.2 We stated that chronic hypoxia causes vascular changes because there is ample and long-standing evidence to support this comment.3 In the study that Dr. McLoughlin and colleagues performed,2 the vessels showed histologic changes similar to those previously reported; alterations in angiogenesis, apoptosis, and other pathways may be additional contributors to the development of pulmonary hypertension under these conditions.
Harrison W. Farber, M.D.
Joseph Loscalzo, M.D., Ph.D.
Boston University School of Medicine
Boston, MA 02118
jloscalz@bu.edu
References
Furst DE, Clements PJ, Tashkin D, Elashoff R, Goldin J, Sterz M. Among a group of patients with dyspnea and alveolitis entering the Scleroderma Lung Study (SLS), a surprising proportion have limited SSC (lSSC). Arthritis Rheum 2004;50:5426-5426. abstract.
Howell K, Preston PJ, McLoughlin P. Chronic hypoxia causes angiogenesis in addition to remodeling in the adult rat pulmonary circulation. J Physiol 2003;547:133-145.
Rabinovitch M, Gamble W, Nadas AS, Miettinen OS, Reid L. Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features. Am J Physiol 1979;236:H818-H827.