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Therapy of Pulmonary Hypertension

The Evolution from Vasodilators to Antiproliferative Agents

University of California, San Diego La Jolla, California

Nearly 50 years ago, Paul Wood observed that intravenous acetylcholine produced an acute reduction in pulmonary artery pressure in a patient with pulmonary artery hypertension (PAH) and postulated that a "vasoconstrictive factor" was involved in pathogenesis (1). Early approaches to therapy for pulmonary arterial hypertension were based on this concept and consisted of the administration of a variety of systemic vasodilators that also reduced pulmonary vascular resistance in some patients. The pathologic changes of pulmonary hypertension, however, whether idiopathic or associated with connective tissue diseases, congenital heart disease, human immunodeficiency virus infection, or other conditions typically consist of more extensive changes than simple hyperplasia of the smooth muscle layer and include intimal fibrosis and myointimal proliferation. Accordingly, it is not surprising that although some patients experience clinical and hemodynamic improvement with "pure" vasodilator agents, the vast majority of patients with PAH manifest little or no benefit from these drugs. Indeed, vasodilators can produce hypotension, worsening intrapulmonary gas exchange, depressed cardiac function, and even death when more advanced vasculopathy predominates over vasoconstriction (2).

Our understanding of the factors involved in the pathogenesis of PAH has evolved dramatically over the past decade and has led to the development of newer therapeutic strategies that target these processes. For example, the demonstration that the hypertensive pulmonary endothelium is deficient in its production of prostacyclin (3, 4) led to the development of continuous intravenous prostacyclin therapy (5)—the first treatment for PAH approved by the Food and Drug Administration. Nonparenteral alternative delivery modes of prostanoid therapy have now been used successfully (6, 7) and may ultimately replace the complex but highly effective intravenous route of administration. The finding that the hypertensive pulmonary endothelium overexpresses endothelin, a potent vasoconstrictor and mitogen (8), served as the rationale for investigating the endothelin receptor antagonist bosentan in PAH (9), the second drug approved by the Food and Drug Administration for this condition. Although prostacyclin is a vasodilator, its long-term therapeutic effects in PAH, as with bosentan, are exerted primarily through its antiproliferative properties (10). Accordingly, the absence of an acute vasodilator response to prostacyclin or other vasodilator, such as inhaled nitric oxide, implies that chronic vasodilator therapy is contraindicated and that chronic antiproliferative therapy with bosentan or a prostanoid is the treatment approach of choice.

In this issue of AJRCCM, Nishimura and coworkers (pp. 1403–1408) report that simvistatin, an 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA)-reductase inhibitor (statin), attenuates the vascular injury and remodeling in an animal model of PAH produced by monocrotaline and pneumonectomy (11). Animals treated with simvistatin at the induction of vascular injury manifested the most substantial effect, with near-preservation of hemodynamics, vascular morphology, and endothelial function assessed by endothelial nitric oxide gene expression. The responses to simvistatin were attenuated but were still present when it was administered 2 weeks after the induction of vascular injury. The authors conclude that statins may be of benefit in the treatment of PAH as a pulmonary vascular antiproliferative agent. The pleiotropic or cholesterol-independent effects of statins have been investigated extensively in systemic arteries and may be related to the ability of statins to inhibit the synthesis of isoprenoid intermediates that are involved in intracellular signaling processes, thereby restoring endothelial function, inhibiting smooth muscle cell proliferation, and stimulating angiogenesis (12).

Although clinicians who care for patients with PAH may be tempted to simply add a statin to the treatment of patients with PAH based on the study by Nishimura and colleagues, I believe that it is premature to do so for several reasons. First, although the animal model employed in these studies develops a pulmonary arteriopathy that is pathologically similar to that seen in human PAH, it is unclear whether these pathogenic pathways are similar or disparate; unlike the monocrotaline/pneumonectomy model, in which the injury is induced acutely, the pathogenic process in PAH is dynamic. Accordingly, the arteriopathy in PAH may be less responsive to interventions, particularly when the disease process is longstanding and advanced. Second, the incorporation of new treatments into the armamentarium should be based on results from well-designed and carefully performed clinical trials that demonstrate convincing evidence of both safety and efficacy. Finally, information regarding optimal dosing and potential interactions with other agents that are used to treat PAH are currently limited, and these data are critical before embarking on a course of treatment with any drug.

As efforts continue to develop more effective therapies for PAH, it is clear that there will be no "magic bullet" that completely reverses the vasculopathy in all cases. Clinical trials designed to target several parallel pathogenic pathways, such as combinations of prostanoids with endothelin receptor blockers or phosphodiesterase inhibitors, are currently in development in the belief that the beneficial effects of these drugs will be additive (13), as has been the case with this strategy in other disorders such as congestive heart failure. The report by Nishimura and coworkers provides encouraging support, but not proof, for a novel approach to antiproliferative therapy for PAH using statins, agents that are already in the marketplace and readily available. Although it is unlikely that statin therapy alone will be of substantial benefit in advanced PAH, the effects of the addition of a statin to other established therapies are worthy of further investigation.

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