Nonidiopathic Pulmonary Hypertension

Updated: Dec 20, 2017
  • Author: Nader Kamangar, MD, FACP, FCCP, FCCM; Chief Editor: Ryland P Byrd, Jr, MD  more...
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Pulmonary hypertension (PH), defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise, is often characterized by a progressive and sustained increase in pulmonary vascular resistance that eventually may lead to right ventricular (RV) failure. It can be a life-threatening condition if untreated. Treatment success rates vary according to the specific cause.

Cardiac disorders, pulmonary diseases, or both in combination are the most common causes of nonidiopathic pulmonary hypertension (see the images below). Cardiac diseases produce PH via volume or pressure overload, though subsequent intimal proliferation of pulmonary resistance vessels adds an obstructive element. Perivascular parenchymal changes, along with pulmonary vasoconstriction, are the mechanisms of PH in respiratory diseases.

Gross pathology on patient who died of severe pulm Gross pathology on patient who died of severe pulmonary arterial hypertension secondary to persistent patent ductus arteriosus.
Close-up view of gross pathology on patient who di Close-up view of gross pathology on patient who died of severe arterial pulmonary hypertension secondary to persistent patent ductus arteriosus.

Therapy for PH is targeted at the underlying cause and its effects on the cardiovascular system. Novel therapeutic agents, such as prostacyclin and others undergoing clinical trials, have led to the possibility of specific therapies for these once untreatable disorders.

For patient education resources, see the Lung and Airway Center.



Pulmonary hypertension was previously divided into two categories, primary and secondary, depending on whether a specific cause could be identified. Between 1973 and 2013, five world symposia have been held on hypertension to incorporate new information about the pathology of the disease, as well as to evaluate advances in diagnostics and histology that have refined classifications and enabled customization of treatment. [1]

In 1998, the World Health Organization (WHO) proposed a clinical classification of pulmonary hypertension into five main groups on the basis of similarities in pathophysiology, clinical presentation, and therapeutic options. This classification was later revised in Venice in 2003 and in Dana Point in 2008 to further clarify classifications. [2] Recognition of fetal causes and developmental abnormalities resulted in a new pediatric-specific classification. [3]

Group 1, pulmonary arterial hypertension (PAH), is further divided into the following four subgroups:

  • Subgroup 1 - Idiopathic PAH (IPAH)
  • Subgroup 2 - Heritable PAH, including those with BMPR2 and ALK2 gene mutations
  • Subgroup 3 - Drug- and toxin-induced PAH (Aminorex, fenfluramine derivatives, and toxic rapeseed oil have been identified as definite risk factors for PAH. [2] )
  • Subgroup 4 - Conditions with known localization of lesions in the small pulmonary arterioles, including collagen-vascular disease (scleroderma/ CREST syndrome), congenital left-to-right shunts, portopulmonary hypertension, HIV-associated pulmonary hypertension, schistosomiasis, and chronic hemolytic anemia
  • Subgroup 5 – Persistent pulmonary hypertension of the newborn

Group 2, pulmonary hypertension owing to left-sided heart disease, consists of left-sided myocardial and valvular diseases and extrinsic compression of the pulmonary veins (eg, tumors) and pulmonary veno-occlusive disease.

Group 3, pulmonary hypertension owing to lung diseases and/or hypoxia, consists of diseases that cause inadequate arterial oxygenation. Such conditions include lung disease (eg, chronic obstructive pulmonary disease [COPD] and interstitial lung disease), impaired respiration (eg, obstructive sleep apnea [OSA] [4] and alveolar hypoventilation disorders), and long-term exposure to high altitude.

Group 4, chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH occurs in a minority of patients after acute embolism. Approximately 0.1% of survivors develop progressive pulmonary hypertension. Less than 1% of these patients have deficiencies of antithrombin 3, protein C, or protein S. No consistent defect in fibrinolytic activity has been identified.

Pathologically, these patients have a full range of pulmonary hypertensive lesions, including plexogenic lesions in the small pulmonary arteries. These patients present with progressive dyspnea and exercise intolerance. Physical examination findings demonstrate RV failure and PAH.

Group 5, pulmonary hypertension with unclear or multifactorial etiologies, is further divided into the following four subgroups:

  • Subgroup 1 - Hematologic disorders, including myeloproliferative disorders
  • Subgroup 2 - Systemic disorders, including sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, and vasculitis
  • Subgroup 3 - Metabolic disorders, including glycogen storage disease, Gaucher disease, and thyroid disorders
  • Subgroup 4 - Miscellaneous conditions, including tumor obstruction, mediastinal fibrosis, and chronic renal failure on dialysis

On the basis of information adapted from the executive summary of the world symposium on Primary Pulmonary Hypertension in Evian, France, in 1998, pulmonary hypertension may be divided into the following functional classes:

  • Class I – These are patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope in patients.
  • Class II – These are patients with pulmonary hypertension resulting in slight limitation of physical activity. The patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near-syncope.
  • Class III – These are patients with pulmonary hypertension resulting in marked limitation of physical activity. Patients are comfortable at rest, but even less-than-ordinary activity causes undue dyspnea or fatigue, chest pain, or near-syncope.
  • Class IV – These are patients with pulmonary hypertension who are unable to perform any physical activity without symptoms. These patients manifest signs of right-sided heart failure, dyspnea or fatigue may even be present at rest, and discomfort is increased by any physical activity.

In 2015, the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines reported two hemodynamic subsets of pulmonary hypertension due to left-sided heart disease: isolated postcapillary pulmonary hypertension and combined postcapillary and precapillary pulmonary hypertension. Patients in the first group had a better prognosis. [5]

One study used the New York Heart Association classification system to evaluate the functional capacity of 36 patients with pressure-volume loop measurements. The findings suggest that such analysis may be promising in assessing patients with progressive but less symptomatic disease. [6]



The overall prevalence of pulmonary hypertension in the general population is unknown, owing to the heterogeneity of the disease. In specific subgroups of pulmonary hypertension patients, studies have estimated the prevalence as follows:

  • In an observational study of 277 patients with HIV infection, 0.46% of patients had pulmonary hypertension. [7] In comparison with prior studies, [8] no change in prevalence rate was seen with modern highly active antiretroviral treatment (HAART).
  • A systematic review of several studies of patients with OSA estimated the prevalence of pulmonary hypertension to be 15-20%. [9]
  • A systematic review of several studies among patients with COPD estimated the prevalence of pulmonary hypertension to be 10-30%. [10]
  • In scleroderma patients, the incidence has been estimated to be 6-60% of all patients, with the variance based on the extent of disease. [11]


Increasing pulmonary arterial pressure is associated with a progressive decline in survival for patients with COPD or interstitial lung diseases. The prognosis of patients with nonidiopathic pulmonary hypertension is variable and depends on the severity of hemodynamic derangement and the underlying primary disorder.

Patients with severe pulmonary hypertension or right-sided heart failure survive approximately one year. Patients with moderate elevations in pulmonary arterial pressure (mean pressure below 55 mm Hg) and preserved right-sided heart function have a median survival of three years from diagnosis.

On the basis of Centers for Disease Control and Prevention (CDC) Pulmonary Hypertension Surveillance from 1980 to 2002, the following mortality data were reported [12] :

  • The age-standardized death rates for the total US population increased from 5.2 to 5.4 deaths per 100,000 population.
  • The main increase in death rates was seen among women, with an increase from 3.3 to 5.5 deaths per 100,000 population, and blacks, with an increase from 4.6 to 7.3 deaths per 100,000 population.
  • The death rate in males decreased over this time, from 8.2 to 5.4 deaths per 100,000 population.