Primary Pulmonary Hypertension 

Primary pulmonary hypertension (PPH) is a rare disease characterized by elevated pulmonary artery pressure with no apparent cause. PPH is also termed precapillary pulmonary hypertension or, more recently, idiopathic pulmonary arterial hypertension (IPAH). The term IPAH is now the preferred term for pulmonary arterial hypertension of unknown etiology; thus, IPAH represents pulmonary vascular disease with a spectrum of clinical presentations.

Dresdale and colleagues first reported a hemodynamic account of IPAH in 1951.^[1] However, the pathophysiology of IPAH remains poorly understood. At least 15-20% of patients previously thought to have IPAH actually have a familial form of PAH involving at least one genetic defect, which has only recently been characterized (see Pathophysiology).

Cardiac catheterization is the criterion standard test to definitively confirm any form of PAH, including IPAH. However, a thorough workup includes a range of tests to exclude all reasonable causes of secondary pulmonary hypertension (see Workup).

Until recently, calcium channel blockers (CCBs) had been the most widely used class of drugs for IPAH. Patients with IPAH in whom CCBs are contraindicated, ineffective, or poorly tolerated may respond to long-term vasodilator therapy (see Treatment and Management).

Treating IPAH requires significant knowledge of and exposure to the available therapies for IPAH and their potential complications. Because IPAH is relatively rare, management is best left to expert personnel at centers with regular exposure to these patients (see Treatment and Management).

Patient education

Patient education about this rare fatal disease is paramount. If applicable, instruct patients on how to administer their daily parenteral medication. For patient education information, see the Lung and Airway Center and Heart and Blood Vessels Center.

For more information, see the Medscape Reference article Pediatric Primary Pulmonary Hypertension.

The pathophysiology of IPAH is poorly understood. An insult (eg, hormonal, mechanical, other) to the endothelium may occur, possibly in the setting of increased susceptibility to pulmonary vascular injury (ie, multiple hit theory), resulting in a cascade of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle) proliferation.

At least 15-20% of patients previously thought to have IPAH actually have a familial form of PAH involving at least one genetic defect, which has only recently been characterized. The most common genetic defect in these cases involves the BMPR-II gene. However, only about a third of affected patients with a family history of PAH have an identifiable BMPR-II mutation. This suggests that additional genetic abnormalities and/or additional external factors may exist that predispose individuals to developing PAH.

Early in PAH, as the pulmonary artery pressure increases because of increasing right ventricle work, thrombotic pulmonary arteriopathy occurs. Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis of small muscular arteries. In later stages, as the pulmonary pressure continues to rise, plexogenic pulmonary arteriopathy develops. This is characterized by a remodeling of the pulmonary vasculature with intimal fibrosis and replacement of normal endothelial structure.

For more information, see the Medscape Reference article Persistent Newborn Pulmonary Hypertension.

Associated conditions

Pulmonary vascular disease can be associated with portal hypertension (sometimes called portopulmonary hypertension), suggesting that patients with shunting of splanchnic blood, with or without liver disease, have a higher risk of developing PAH.

Additionally, exposure of the pulmonary circulation to substances from the splanchnic circulation that are normally detoxified via the liver may contribute to the development of pulmonary hypertension. More research is necessary to better understand this relationship.

Patients with connective-tissue diseases, namely the CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) variant of scleroderma, systemic lupus erythematosus, and mixed connective-tissue disease, are also predisposed to developing IPAH-like disease. This is now termed associated PAH, or APAH.

The pathophysiologic nature of this predisposition is unclear. In the past, most experts used the term "secondary" pulmonary arterial hypertension for these diseases, indicating that, similar to IPAH, the process involves the precapillary circulation but is somehow caused by or at least associated with the underlying (predisposing) disease.

A study by Soon et al determined that unexplained iron deficiency is more prevalent in patients with idiopathic pulmonary artery hypertension than in those with chronic thromboembolic pulmonary hypertension (CTEPH).^[2] Interleukin-6 (IL-6) may play a role in this difference in prevalence.

The strict definition of IPAH is pulmonary hypertension with no known cause. However, associations have been recognized (eg, connective-tissue diseases, liver cirrhosis, exposure to anorexigens and likely other alpha-adrenergic stimulants [eg, cocaine, amphetamines],^[3] HIV infection). How these associated conditions predispose to or cause PAH remains unknown.

IPAH is responsible for approximately 125-150 deaths per year in the United States and has an incidence rate of approximately 2-6 cases per million population per year. The incidence and prevalence of APAH are considerably higher than those of IPAH. The worldwide incidence of IPAH approximates that observed in the United States, but variations in prevalence exist worldwide. A registry of patients with IPAH in France found a prevalence of IPAH of about 6 cases per million population.^[4] IPAH occurs at a female-to-male ratio ranging from 2-9:1, depending on the treatment center sampled. In the United States, the average female-to-male ratio reported in clinical trials and registries is close to 4:1. The reasons for this female predilection remain unknown.Typically, younger women of childbearing age develop IPAH. However, IPAH can also affect individuals in their fifth and sixth decades of life or older.^[5]

IPAH has no cure. Untreated IPAH leads to right-sided heart failure and death. Prior to the 1990s, therapeutic options were limited. The emergence of prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and other novel drug therapies has greatly improved the outlook for patients with IPAH and IPAH-like diseases.

For untreated IPAH, the estimated 3-year survival rate is approximately 41%. In one study of long-term continuous intravenous prostacyclin therapy, 3-year survival increased to approximately 63%.^[6] With newer therapies, perhaps in combination, these figures are expected to improve further.

Data on long-term survival in patients treated with other pulmonary vascular therapies are emerging. Patients whose disease progresses and is unresponsive to medical treatments either undergo transplantation or die of progressive right-sided heart failure.

Using the largest registry of patients with PAH to date, the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry), Benza et al analyzed factors determining survival in 2716 patients.^[7] Using this data, they derived a multivariable, weighted risk formula incorporating 19 independent factors identified as having an impact on PAH patient survival, thus allowing clinicians to incorporate factors encountered in real-world management of PAH in their overall risk/severity assessment.