(Circulation. 2000;102:2781.)
© 2000 American Heart Association, Inc.
Clinical Cardiology: New Frontiers |
Primary Pulmonary Hypertension
A Vascular Biology and Translational Research "Work in Progress"
Correspondence to Stephen Archer, MD, FRCPC, Heart and Stroke Chair in Cardiovascular Research, Chair Cardiology Division, Department of Medicine, University of Alberta, WMC 2C2.36, 8440 112th Street, Edmonton, Alberta, Canada T6G 2B7. E-mail sarcher{at}cha.ab.ca
Abstract
Abstract—Primary
pulmonary hypertension (PPH) is a syndrome of dyspnea, chest pain, and
syncope defined by increased pulmonary vascular resistance and the
absence of a known cause. It also occurs in a familial form, which is
linked to unidentified genes on chromosome 2. This syndrome is
characterized by abnormalities of pulmonary vascular biology in each
compartment of the blood vessel. The lumen has a prothrombotic
diathesis, the endothelium displays an excessive production of
vasoconstrictors relative to vasodilators, and the smooth muscle cells
are depolarized and calcium-overloaded, which is due in part to reduced
expression of voltage-gated potassium channels (Kv). This causes
vasoconstriction and may promote cell proliferation. The adventitia
displays excessive remodeling, which is associated with exaggerated
metalloproteinase and elastase activity. Conceptually, PPH seems to
require a permissive genotype, a susceptible phenotype (eg, endothelial
dysfunction) and, in many cases, an exogenous trigger (eg, an
anorexigen). Although there is not a generally accepted, unifying
hypothesis regarding its cause, impaired function and the expression of
vascular and platelet Kv channels suggest PPH may be a disease of the
ion channels. Abnormal matrix metalloproteinase and elastase activity
could also explain the abnormal vascular tone, platelet activation, and
remodeling in PPH. Although calcium-channel blockers and prostacyclin,
particularly when coadministered with warfarin, improve survival, PPH
has a 5-year mortality rate of 
50%. Pharmacological and gene
therapies aimed at enhancing the activity of prostacyclin, nitric oxide
synthases, and Kv channels or at inhibiting endothelin and matrix
metalloproteinases are promising areas for future
development.
Key Words: hypertension, pulmonary • ion channels • potassium • endothelin • nitric oxide • platelets
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