Epidemiology and Classification of Pulmonary Hypertension

Group 1: Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) has been the focus of the categorization of pulmonary hypertension (PH) since the first classification in 1973. A number of modifications of the subgroups of PAH were made in the Dana Point classification.

When PAH occurs in a familial context, germline mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor beta signalling family, can be detected in about 70% of cases. BMPR2 mutations have also been detected in 11% to 40% of apparently idiopathic cases without any family history. Thus, the distinction between idiopathic and familial BMPR2 mutations is artificial as all patients with a BMPR2 mutation have heritable disease whether the patient is the first identified case, possibly with a de novo mutation, or whether other family members were previously diagnosed with PAH. In addition, no BMPR2 mutation has been identified in up to 20% of families with PAH. Thus, it was decided to abandon the term “familial PAH” in the new classification and replacing it with the term “heritable.”

Additional changes in group 1 were also implemented in the Dana Point classification. The classification of PAH associated with congenital heart disease was modified to better define each condition. Hemolytic anemias, either inherited or acquired, have been reclassified as their own subcategory of PAH, based in large part upon growing awareness of PH in patients with sickle cell disease. Finally, schistosomiasis has been moved from the thromboembolic group to a subgroup of PAH.

Risk Factors for the Development of Pulmonary Arterial Hypertension

Two important changes regarding risk factors for PAH were discussed. First, based primarily on a large single-center case-control study, methamphetamine use appears to be a likely risk factor for the development of PAH. Second, although no increased risk of developing PAH with the use of selective serotonin reuptake inhibitors (SSRIs) was found in a multicenter epidemiological study, use of SSRIs in pregnant women was reported to increase the risk (OR 6.1) in the offspring of developing persistent pulmonary hypertension of the newborn (PPHN). Therefore, SSRI use in pregnancy is a potential risk factor for PPHN.

Group 2: Pulmonary Hypertension Owing to Left Heart Disease

This group has been modified to reflect the growing importance of left ventricular diastolic dysfunction as a cause of pulmonary venous hypertension. Subcategories in the new classification are: left heart systolic dysfunction, left heart diastolic dysfunction, and left heart valvular disease. No formal recommendations were made concerning patients with left heart disease and “out-of-proportion” PH, and there are currently no clinical trials that have shown benefit with PAH-approved medications in this group of patients.

Group 3: Pulmonary Hypertension Owing to Lung Diseases and/or Hypoxia

The primary modification within this group was to add another category of lung disease characterized by a mixed obstructive and restrictive pattern. This is a newly reported syndrome, characterized by the combination of pulmonary fibrosis (mainly of the lower zones of the lung) and emphysema (mainly of the upper zones of the lung) and has a reported prevalence of PH of almost 50%.

Group 4: Chronic Thromboembolic Pulmonary Hypertension

This group has been simplified to include only chronic thromboembolic PH (CTEPH). Other rare forms of obstruction of the pulmonary vasculature, such as pulmonary artery sarcoma, have been reclassified into Group 5. In addition, the distinction between proximal and distal disease has been removed as this may be quite difficult to determine and is often dependent upon the experience of each individual center. Presently there is no consensus among experts regarding the distinction between proximal and distal CTEPH. It is strongly recommended that patients with suspected or confirmed CTEPH should be referred to a center with expertise in the management of CTEPH to consider feasibility of pulmonary thromboendarterectomy.

Group 5: Pulmonary Hypertension With Unclear or Multifactorial Etiologies

This group has been reorganized from the Venice classification and includes several subgroups that were previously classified elsewhere. This includes hematological disorders such as myeloproliferative disorders, systemic disorders such as sarcoidosis, metabolic disorders such as Gaucher's disease, and lastly, a miscellaneous group of conditions including such disorders as mediastinal fibrosis and end-stage renal disease with chronic hemodialysis.