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Background

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 diagnosis is usually made after excluding other known causes of pulmonary hypertension. Dresdale and colleagues first reported a hemodynamic account of IPAH in 1951. For additional resources, please visit Pulmonary Arterial Hypertension.

Pathophysiology

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 with IPAH have a familial form, which has only recently been characterized. Some cases may be related to sporadic genetic defects. The most common genetic defect in these cases is related to the BMPR-II gene.

Early in the disease, 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 of the pulmonary vasculature. 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.

Associated conditions

IPAH 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 PPH. Additionally, exposure of the pulmonary circulation to substances in the splanchnic circulation that normally are 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. However, 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 the underlying disease.

Other associations with IPAH include exposure to anorexigens and other alpha-adrenergic stimulants (eg, cocaine, amphetamines) and HIV seropositivity. How these associated conditions predispose to or cause PPH remains unknown.

In most cases of APAH, such as in connective tissue disease, the incidence of pulmonary hypertension is higher (>10% in some studies) than for IPAH, which has an incidence of 1-2 cases per million per year (see below).

Frequency

United States

IPAH is responsible for approximately 125-150 deaths per year and has an incidence rate of approximately 1-3 cases per million population per year. The incidence and prevalence of IPAH are considerably higher than those for pure IPAH.

International

The worldwide incidence of IPAH approximates that observed in the United States.

Mortality/Morbidity

IPAH has no cure. Untreated, IPAH leads to right-sided heart failure and death. The overall survival rate in one study was approximately 30% at 3 years. Prior to the 1990s, therapeutic options were limited. The recent emergence of prostacyclin analogues, endothelin receptor antagonists, and other novel drug therapies has greatly improved the outlook for patients with IPAH and IPAH-like diseases. In one study, the use of long-term prostacyclin agents resulted in a 5-year mortality rate greater than 65%. With newer therapies, perhaps in combination, these figures are expected to further improve.

Race

No racial predilection is recognized.

Sex

IPAH occurs at a female-to-male ratio ranging from 2-9:1, depending on the treatment center sampled; however, the reasons for this female predilection remain unknown.

Age

Typically, younger women of childbearing age develop IPAH. However, it can also affect women in their fifth and sixth decades of life or older.

Clinical

History

The average time from symptom onset to diagnosis has been reported to be approximately 2 years. Despite recent attempts at increasing the awareness of PAH, especially APAH, this delay in diagnosis has not changed appreciably in recent years.

• Early symptoms are nonspecific. Often, neither the patient nor physician recognizes the presence of the disease, which leads to delays in diagnosis. Complicating matters, PPH requires an extensive workup in an attempt to elucidate an identifiable cause of the elevated pulmonary artery pressure.
• The most common symptoms reported in a national prospective study are as follows:
  • Dyspnea is present in 60%.
  • Weakness is present in 19%.
  • Recurrent syncope is present in 13%.
  • Women are more likely to be symptomatic than men.

Physical

Physical findings in persons with PAH can be quite variable.

• Physical examination of the cardiovascular system often reveals the following findings:
  • The pulmonic component of the second heart sound is usually increased, which may demonstrate fixed or paradoxic splitting in the presence of severe right ventricular dysfunction. Occasionally, the second heart sound may be palpable.
  • Pulmonic regurgitation (Graham Steell murmur) may also be apparent.
  • A murmur of tricuspid regurgitation can be present, and a right ventricular lift (heave) may be noted.
  • Jugular venous pulsations may be elevated in the presence of volume overload, right ventricular failure, or both. Large V waves are often present because of the commonly present severe tricuspid regurgitation.
• Other findings may include (1) hepatomegaly with palpable pulsations of the liver and (2) an abnormal abdominal-jugular reflex. Ascites is not uncommonly present in untreated patients or in patients with worsening decompensated right heart failure.
• Lung examination findings are usually normal.
• Extremity examination may reveal pitting edema of varying degrees. Patients who are bedridden may have presacral edema.

Causes

The strict definition of IPAH is pulmonary hypertension with no known cause. However, associations have been recognized (eg, liver cirrhosis, stimulant abuse, HIV infection; see Associated conditions in Pathophysiology).