Diagnosis, Treatment, and Clinical Management of Pulmonary Arterial Hypertension in the Contemporary Era

Abstract

Importance Pulmonary arterial hypertension (PAH) is characterized by severe remodeling of distal pulmonary arteries, increased pulmonary vascular resistance and right ventricular dysfunction that promotes heart failure. Once regarded as largely untreatable, evidence-based decision-making now guides clinical management of patients and improves PAH outcome. Yet, misconceptions regarding the approach to PAH in the modern era are common and associated with substandard clinical care. Observations The clinical profile of PAH has changed substantially since its original description: the age at diagnosis is older than previously reported, disease severity appears greater in men compared to women, and PAH in association with connective tissue disease is identified as a particularly high risk patient subgroup. Risk stratification scales for PAH are now available at point of care, which inform treatment goals including: 6-minute walk distance >440 m, peak VO2 >15 ml/min/kg, right atrial area <18 cm2, cardiac index >2.5 l/min/m2, and absent/low symptom burden with routine physical activity. Currently, 14 therapies targeting six PAH-specific molecular intermediaries are in use clinically. Recent landmark trial data have demonstrated the critical importance of initial combination therapy in treatment-naïve patients. Taken together, these findings underscore a global shift in PAH coupling early disease detection with aggressive pharmacotherapy. Indeed, recent longitudinal data from combination therapy patients shows that the 3-year survival rate in PAH may be as high as 84% compared with 48% from the original National Institutes of Health registry on idiopathic PAH (1980-1985). Despite these gains, incomplete clinical evaluation and misdiagnosis by referring practitioners is common and associated with inappropriate therapy. Conclusions and Relevance Compared to the original clinical experience, PAH has evolved into a contemporary and treatable disease characterized by improved survival and a high standard for defining therapeutic success. However, under-awareness among clinicians regarding the importance of early and accurate PAH diagnosis persists and is a potentially reversible cause of adverse outcome in this disease.

NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension

“…Pulmonary arterial hypertension (PAH) is characterized, in part, by a fibrotic vasculopathy in pulmonary arterioles, which promotes early right heart failure and death (4). In PAH, endothelial dysfunction and vascular fibrosis are key pathogenic events that occur concurrently with changes in the normal cellular redox potential.…”

Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension

“…Interestingly, all currently approved treatments for PH are based on the “vasoconstrictor hypothesis” of PH and are directed at either inhibiting vasoconstriction (endothelin receptors) or stimulating vasodilatation (prostacyclin and inhibition of phosphodiesterase 5 (PDE5)). Clearly treatments such as prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, soluble guanylate cyclase stimulants or, rarely, certain calcium channel blockers can improve patients’ symptoms and extend life (Maron & Galie, ; Lau et al . ).…”

Diagnostic Assessment of the Pulmonary Hypertension Patient

“…13 These patients are diagnosed with pulmonary arterial hypertension (PAH) (ie, WHO Group 1 PH), which is due to a complex pulmonary arteriopathy characterized by concentric hypertrophic remodeling, plexogenic lesions, vascular fibrosis, and microthrombosis. 5 Most commonly, PAH is idiopathic but may also be due to heritable causes, particularly germline mutations in the gene encoding bone morphogenetic protein receptor-2 (BMPR2) protein. Patients may also have PAH in the setting of systemic sclerosis (or other connective tissue disease), human immunodeficiency virus (HIV), portopulmonary hypertension, and congenital heart disease due to uncorrected shunt.…”