Plasminogen Activator Inhibitor-1

Hypertension is the most common reversible risk factor for stroke, myocardial infarction, and heart failure, affecting >60 million individuals in the United State alone and 1 billion globally.1 According to the World Health Organization, hypertension is now the leading cause of preventable death worldwide.2 Importantly, the prevalence and complications of hypertension increase significantly with age. However, despite the availability of many antihypertensive agents of distinct pharmacologic classes and evidence-based guideline recommendations for stepwise, multidrug regimens, control of hypertension remains suboptimal, with target blood pressure achieved in <50% of patients.1 Although patient noncompliance and submaximal dosing of antihypertensive agents contribute to lack of blood pressure control, there is an unmet need for new approaches for treatment of hypertension. In this issue of Circulation , Boe et al3 report that pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1) is protective against the development of hypertension, cardiac hypertrophy, and periaortic fibrosis (ie, arteriosclerosis) in mice treated with N ω-nitro-l-arginine methyl ester (l-NAME) to inhibit endothelial nitric oxide synthase.Article see p 2318Because the molecular basis for primary or essential hypertension is unknown, the treatment of hypertension, excluding secondary or identifiable hypertension with known causes (eg, chronic renal disease, renovascular, hyperaldosteronism, Cushing syndrome, pheochromocytoma), has been based primarily on targeting the underlying physiologic determinants of blood pressure—namely, intravascular volume (eg, diuretics), neurohormonal drive (eg, centrally acting agents, renin angiotensin system blockade), systemic vascular resistance (eg, vasodilators), and cardiac inotropy and chronotropy (eg, beta blockers; Figure). Another hallmark of hypertension is vascular remodeling of both small (inward eutrophic remodeling that decreases lumen area and increases systemic vascular resistance) and large …