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Narrative Review: The Enigma of Pulmonary Arterial Hypertension: New Insights from Genetic Studies

John H. Newman, MD; John A. Phillips III, MD; and James E. Loyd, MD
[+] Article and Author Information

From Vanderbilt University School of Medicine, Nashville, Tennessee.


Grant Support: By an institutional research grant (M01-RR-00095) from General Clinical Research Center. Dr. Loyd is also supported by grant PO1 072058 from the National Institutes of Health, National Heart, Lung, and Blood Institute.

Potential Financial Conflicts of Interest:Grants received: J.A. Phillips III (National Institutes of Health). Grants pending: J.A. Phillips III (National Institutes of Health).

Request for Single Reprints: John H. Newman, MD, Division of Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T 1219 Vanderbilt Medical Center North, Nashville, TN 37232-2650; e-mail, john.newman@vanderbilt.edu.

Current Author Addresses: Dr. Newman: Division of Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T 1219 Vanderbilt Medical Center North, Nashville, TN 37232-2650.

Dr. Phillips: Division of Medical Genetics, Vanderbilt University School of Medicine, DD 2205 Vanderbilt Medical Center North, Nashville, TN 37232-2650.

Dr. Loyd: Division of Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, T 1218 Vanderbilt Medical Center North, Nashville, TN 37232-2650.


Ann Intern Med. 2008;148(4):278-283. doi:10.7326/0003-4819-148-4-200802190-00006
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Pulmonary arterial hypertension (PAH) occurs as an idiopathic disease (formerly called primary pulmonary hypertension) and as a consequence of other illnesses. These illnesses include connective tissue diseases, portal hypertension, diet and stimulant drug use, HIV infection, and congenital heart disease. Inherited susceptibility to PAH occurs in families and is almost always due to mutations in genes of the TGF-β family of receptors. The most common mutation leading to PAH is in bone morphogenetic protein receptor type 2 (BMPR2), originally discovered to be involved in bone healing. Mutations in BMPR2 have also been found in patients with idiopathic PAH, although the true prevalence of this susceptibility has not been determined. About 20% of individuals with a BMPR2 mutation develop symptomatic pulmonary hypertension. Evidence is growing that imbalanced activation of other TGF-β receptors coupled with reduced activity of mutated BMPR2 increases the likelihood of development of PAH. Many signaling systems have been found to participate in PAH, including K channels, serotonin, angiopoietin, and cyclooxygenases. An interaction of these signaling systems with BMPR2 is a focus of research in PAH. Approaches to altering the imbalance of activation of BMPR2 and other TGF-β receptors may yield future therapies for PAH.

Figures

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Figure 1.
Typical micrograph of lung from a patient with pulmonary arterial hypertension.

The patient has normal alveolar structures but a small pulmonary artery in which the lumen is occluded by concentric fibrosis. The artery also has increased medial smooth muscle and a reactive adventitia. Dilated small vessels border the airway above the artery.

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Figure 2.
Loss of homeostasis with bone morphogenetic protein (BMP) receptor type 2 (BMPR2) mutation.

Imbalance of increased transforming growth factor-β (TGF-β) levels and decreased BMPR2 levels leads to pulmonary arterial hypertension (PAH).

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Grahic Jump Location
Figure 3.
Signaling pathways that indicate therapeutic strategies for pulmonary arterial hypertension.

BMP = bone morphogenetic protein; BMPR2 = bone morphogenetic protein receptor type 2; COX = cyclooxygenase; iD = inhibitor of differentiation; PDGF = platelet-derived growth factor; siRNA = short inhibitory RNA; TGF-β = transforming growth factor-β; TGF-βR = transforming growth factor-β receptor.

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