ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association Developed in Collaboration With the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association

Pulmonary hypertension (PH) is a complex, multidisciplinary disorder. Recent advances have led to increased recognition and new therapies. While some data exist to form treatment guidelines, other areas have been inadequately explored. Pathology and Pathogenesis: Pulmonary arterial hypertension (PAH) is a syndrome resulting from restricted flow through the pulmonary arterial circulation resulting in increased pulmonary vascular resistance and ultimately in right heart failure. Multiple pathogenic pathways have been implicated in the development of PAH, including those at the molecular and genetic levels and in the smooth muscle and endothelial cells and adventitia. The imbalance in the vasoconstrictor/vasodilator milieu has served as the basis for current medical therapies, although increasingly it is recognized that PAH also involves an imbalance of proliferation and apoptosis (favoring the former). Classification and Epidemiology: While previously considered a rare disease, the most recent evidence from a French registry suggests that the prevalence of PAH is about 15 per million (1). Idiopathic pulmonary arterial hypertension (IPAH) is more prevalent in women and was the most common type of PAH in the French registry. Familial PAH often results from a mutation in the bone morphogenic protein receptor-2 (BMPR2) and is inherited as an autosomal dominant disease with incomplete penetrance and genetic anticipation. PAH is also associated with congenital heart disease (CHD), connective tissue diseases, drugs and toxins, human immunodeficiency virus (HIV), portal hypertension, hemoglobinopathies, and myeloproliferative disorders. Primary PH formerly encompassed idiopathic, familial, and anorexigen induced PAH. These groups together comprise World Health Organization (WHO) Group I PAH. Other WHO categories include Group II, PH with left heart disease, Group III, PH associated with lung diseases and/or hypoxemia, Group IV, PH due to chronic thrombotic and/or embolic disease, and Group V, miscellaneous causes of PH (Table 1). Natural History and Survival: The prognosis of PAH is poor, with an approximately 15% mortality within 1 year on modern therapy (2). Predictors of a poor prognosis include: advanced functional class, poor exercise capacity as measured by 6-minute walk (6MW) test or cardiopulmonary exercise test, high right atrial (RA) pressure, significant right ventricular (RV) dysfunction, evidence of RV failure, low cardiac index, elevated brain natriuretic peptide (BNP), and underlying diagnosis of scleroderma spectrum of diseases. Screening and Diagnostic Assessment: Patients at sufficient risk for the development of PAH to warrant periodic screening include those with a known BMPR2 mutation, scleroderma spectrum of diseases, and portal hypertension who are undergoing evaluation for liver transplantation. The most appropriate study to obtain in patients suspected of having PH based on history, physical examination, chest x-ray (CXR), and electrocardiogram (ECG) is an echocardiogram. Evaluation for other potential etiologies, such as thromboembolic disease, is appropriate in all patients suspected of having PAH. The diagnosis of PAH requires confirmation with a complete right heart catheterization (RHC). The current hemodynamic definition of PAH is a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg; a pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mm Hg; and a pulmonary vascular resistance (PVR) greater than 3 Wood units (3). Acute vasodilator testing, which involves the administration of pharmacologic agents to test the presence of pulmonary vasoreactivity, has prognositic value and should be performed in all IPAH patients who might be considered potential candidates for long-term calcium-channel blocker therapy. Those with overt right heart failure or hemodynamic instability should not undergo acute vasodilator testing. The definition of an acute responder is a reduction in mPAP of at least 10 mm Hg to an absolute mPAP of less than 40 mm Hg without a decrease in cardiac output. Vasodilator testing should be performed by centers with experience in the administration of these agents and the interpretation of the results. Evidenced-Based Treatment Algorithm: Goals of treatment include improvement in the patient's symptoms, quality of life, and survival. Objective assessments to measure treatment response include improvement in exercise capacity (6MW test, cardiopulmonary exercise test, treadmill test), hemodynamics, and survival. General measures that should be addressed include diet, exercise, appropriate vaccinations, and avoidance of pregnancy. Warfarin anticoagulation is recommended in all patients with IPAH based on 1 prospective and 2 retrospective observational, uncontrolled trials. Diuretics are used for symptomatic management of RV volume overload. Oxygen is recommended to maintain oxygen saturation greater than 90%. Calcium channel blockers are indicated only for patients who have a positive acute vasodilator response as described in the preceding text. Patients treated with calcium channel blockers should be followed closely for both the safety and the efficacy of this therapy. Continuous intravenous epoprostenol improves exercise capacity, hemodynamics, and survival in IPAH and is the preferred treatment option for the most critically ill patients. Although expensive and cumbersome to administer, epoprostenol is the only therapy for PAH that has been shown to prolong survival. Treprostinil, a prostanoid, may be delivered via either continuous intravenous or subcutaneous infusion. Iloprost is a prostanoid delivered by an adaptive aerosolized device 6 times daily. The delivery system and side effects of the prostanoids should be carefully considered when assessing patients for prostanoid therapy. The endothelin receptor antagonists are oral therapies that improve exercise capacity in PAH. Liver function tests must be monitored indefinitely on a monthly basis. Phosphodiesterase (PDE)-5 inhibitors also improve exercise capacity and hemodynamics in PAH. In general, patients with poor prognostic indexes should be initiated on parenteral therapy, while patients with class II or early III symptoms commonly commence therapy with either endothelin receptor antagonists or PDE-5 inhibitors. Given the multiple mechanisms of action, there is scientific rationale for the use of combination therapy for PAH, which is an area of active investigation. Initial results are encouraging and more combination therapy trials are underway. Lung transplantation is an option for selected patients who progress despite optimal medical management. Reassessing Patients Over Time: How to Follow Patients on Treatment: Due to the complex nature of the disease and its treatments, PAH patients must be closely followed. In general, office visits should be more frequent for patients with advanced symptoms, right heart failure, and advanced hemodynamics and those on parenteral or combination therapy. Such patients generally should be seen every 3 months (or more frequently). Less ill patients on oral therapy generally should be seen every 3 to 6 months. Most experts obtain an assessment of functional class and exercise capacity, such as a 6MW or graded treadmill test, with each office visit. Nurse clinicians experienced in the care of PAH patients should be an integral part of chronic outpatient management. Non-Pulmonary Arterial Hypertension Pulmonary Hypertension Populations: Most cardiologists and pulmonologists will see PH associated with elevated left heart filling pressures much more frequently than PAH. Any disorder that elevates left heart filling pressures, including systolic dysfunction, diastolic dysfunction, and valvular heart disease, can result in elevated pulmonary artery pressures. Treatment should be directed at the underlying left heart disease. In rare instances, PAH-specific therapy may be considered if the underlying cause has been optimally treated, the PCWP is normal or minimally elevated, the transpulmonary gradient and pulmonary vascular resistance are significantly elevated, and the patient's symptoms suggest that PAH-specific therapy may yield clinical benefit. This subset of patients may be described as those with "disproportionate" PH (greater than expected on the basis of their elevated left heart pressure or lung disease). Experts caution against widespread treatment for non-PAH PH until clinical trial data indicate whether such patients benefit from them. The potential adverse effects of PAH-specific therapies in such patients include worsening fluid retention, pulmonary edema, and ventilation perfusion mismatch. Pulmonary Arterial Hypertension in Congenital Heart Disease: The incidence of CHD is approximately 8 per 1,000 live births (4), and approximately 30% of children who do not undergo surgical repair will develop pulmonary vascular disease. Patients with PAH related to CHD who are not candidates for surgical correction are treated similar to IPAH patients. The natural history of such patients tends to be better than those with other types of PAH. Pediatric Pulmonary Arterial Hypertension: Persistent PH of the newborn is a syndrome characterized by increased pulmonary vascular resistance, right to left shunting, and severe hypoxemia. Treatment options include inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation. Pediatric IPAH is treated similar to that in adults. A higher percentage of children are acute responders and candidates for calcium channel blockers.