Primary Pulmonary Hypertension

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 approximately 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.

Alterations of cellular bioenergetics in pulmonary artery endothelial cells

“…Thus, there are substantial changes in bioenergetics of IPAH endothelial cells, which may have consequences for pulmonary hypertensive responses and potentially in development of novel imaging modalities for diagnosis and evaluation of treatment. cellular respiration ͉ nitric oxide ͉ oxygen consumption ͉ pulmonary hypertension ͉ mitochondrion I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease of unknown etiology characterized by a progressive increase in pulmonary artery pressure and vascular growth (1,2). Secondary forms of pulmonary arterial hypertension (PAH) are associated with known diseases, such as collagen vascular diseases or portal hypertension but in the absence of an identifiable etiology are classified as IPAH.…”

“…Secondary forms of pulmonary arterial hypertension (PAH) are associated with known diseases, such as collagen vascular diseases or portal hypertension but in the absence of an identifiable etiology are classified as IPAH. Abnormalities in vasodilators, specifically nitric oxide (NO), have been implicated in the pathogenesis of pulmonary hypertension (1)(2)(3)(4)(5). NO is produced in the lung by NO synthases (NOS; EC 1.14.13.39) (6)(7)(8).…”

The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted

“…6). Endothelial dysfunction is one of the earliest abnormalities in PAH, resulting in an imbalance of endothelium-derived vasoactive factors; with increased vasoconstrictors (endothelin, thromboxane, 5-HT; all of which lead to an increase in PASMC [Ca 2ϩ ] i ) and decreased vasodilators (like NO or prostacyclin, which in contrast lead to a decrease in PASMC [Ca 2ϩ ] i ) (2). The promoted high [Ca 2ϩ ] i -state leads to NFAT activation in PASMC and regulation of multiple genes that might positively reinforce NFAT activation.…”

“…Endothelial dysfunction, an early abnormality in PAH, leads to an increase in vasoconstrictors (like endothelin) over vasodilators (like prostacyclin) (2). Correction of these abnormalities by blockade of the endothelin axis or enhancement of the prostacyclin axis is the basis of the current treatment for PAH; however the morbidity and mortality remains high (3).…”

“…Correction of these abnormalities by blockade of the endothelin axis or enhancement of the prostacyclin axis is the basis of the current treatment for PAH; however the morbidity and mortality remains high (3). More effective therapies for PAH will have to directly and selectively target the mechanisms leading to the proproliferative and antiapoptotic environment in the vascular wall; the recently described abnormalities in the PA smooth muscle cell (PASMC) K ϩ channels and mitochondria are such mechanisms (2,(4)(5)(6)(7).…”