Pulmonary hypertension: diagnosis and management

Abstract

Pulmonary arterial hypertension is a progressive, symptomatic, and ultimately fatal disorder for which substantial advances in treatment have been made during the past decade. Effective management requires timely recognition and accurate diagnosis of the disorder and appropriate selection among therapeutic alternatives. Despite progress in treatment, obstacles remain that impede the achievement of optimal outcomes. The current article provides an overview of the pathobiologic mechanisms of pulmonary arterial hypertension, including genetic substrates and molecular and cellular mechanisms, and describes the clinical manifestations and classification of pulmonary arterial hypertension. The article also reviews established approaches to evaluation and treatment, with emphasis on the appropriate application of calcium channel blockers, prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors. In addition, the authors discuss unresolved issues that may complicate patient management, such as the clinical importance of mild or exercise-related pulmonary arterial hypertension, and they identify avenues by which treatment may advance in the future through the use of combination treatment, outcomes assessment, and exploration of alternative pharmacologic strategies.

FIGURE 1.

The 3 mechanistic pathways known to be disturbed in patients with pulmonary arterial hypertension (PAH). The short, thick, black arrows depict aberrations observed in these pathways in patients with PAH. The points at which drug treatment affects these mechanistic processes are shown in gray circles. AA = arachidonic acid; CCB = calcium channel blocker; ETRA = endothelin receptor antagonist (eg, bosentan [dual], ambrisentan, and sitaxsentan [receptor A selective]); PDE5i = phosphodiesterase 5 inhibitor (eg, sildenafil). Left, The nitric oxide (NO) pathway. Nitric oxide is created in endothelial cells by type III (ie, endothelial) NO synthase (eNOS), which in pulmonary arterial smooth muscle cells (PASMCs) induces guanylate cyclase (GC) to convert guanylate triphosphate (GTP) to cyclic guanylate monophosphate (cGMP). Cyclic GMP is a second messenger that constitutively maintains PASMC relaxation and inhibition of PASMC proliferation by ultimately reducing inward flux of calcium ions (Ca⁺⁺). Cyclic GMP is removed by the PDE5 enzyme to yield the inactive product 5′GMP. Patients with PAH have reduced expression and activity of eNOS. Middle, The prostacyclin pathway. The production of prostaglandin I2 (PGI₂ [ie, prostacyclin]) is catalyzed by prostacyclin synthase (PS) in endothelial cells. In PASMCs, PGI₂ stimulates adenylate cyclase (AC), thus increasing production of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Cyclic AMP is a second messenger that constitutively maintains PASMC relaxation and inhibition of PASMC proliferation. Patients with PAH have reduced expression and activity of PS. Right, The endothelin (ET) pathway. Big- (ie, pro-) ET is converted in endothelial cells to ET₁ (a 21-amino acid peptide) by endothelin-converting enzyme (ECE). ET₁ binds to PASMC ET_A and ET_B receptors, ultimately leading to PASMC contraction, proliferation, and hypertrophy. Endothelin 1 also binds to endothelial cell ET_B receptors (not illustrated). Patients with PAH have increased expression and activity of ECE.

FIGURE 2.

Schematic flowchart for evaluation of suspected pulmonary hypertension. The solid arrows indicate progression of tests for evaluation of pulmonary hypertension. The course of evaluation may vary depending on specific results of tests; eg, right heart catheterization may be performed directly after echocardiography. Echocardiographic findings need to be clarified or confirmed before proceeding to evaluation of potential underlying causes of pulmonary hypertension. The dotted arrows point to some potential substrates or characteristics of pulmonary hypertension that may be elucidated by the associated test. The diagnoses shown are not all inclusive. HIV = human immunodeficiency virus; ILD = interstitial lung disease; PE = pulmonary embolism; PFT = pulmonary function test; RAE = right atrial enlargement; RH = right heart; RVE = right ventricular enlargement; RVSP = right ventricular systolic pressure; SLE = systemic lupus erythematosus. Adapted from Circulation.

FIGURE 3.

Algorithm for the pharmacologic management of pulmonary arterial hypertension. Assessment of risk for each patient includes clinical variables as outlined in the table below the algorithm. Patients deemed to be at highest risk on the basis of clinical assessment should be considered for early intravenous (iv) therapy. Those at lower risk are candidates for oral therapy. Patients should be followed up closely, and their response to therapy should be assessed within several months. If treatment goals are not met, addition of a second agent may be warranted. CCB = calcium channel blocker; ETRA = endothelin receptor antagonist; PDE5 = phosphodiesterase 5; RV = right ventricular; WHO = World Health Organization. Adapted from Circulation.

FIGURE 4.

Graph of continuous right ventricular (RV) systolic pressure as measured during a 12-month period, showing the trend of daily median values during treatment of a patient with pulmonary arterial hypertension. From J Heart Lung Transplant, with permission from Elsevier.