Pulmonary hypertension (PH) refers to the presence of abnormally high pulmonary vascular pressure. The World Health Organization (WHO) classifies patients with PH into five groups based on etiology. These groups differ in their clinical presentation, diagnostic findings, and response to treatment. It is important to note the changes in defining and classifying pulmonary hypertension in the following revised WHO Classification of PH developed by the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2009 Expert Consensus Task Force on Pulmonary Hypertension. Patients in Group 1 are considered to have pulmonary arterial hypertension (PAH), and the remaining four groups are considered to have PH.
Revised WHO Classification of Pulmonary Hypertension (PH) Groups 1-5
1. Pulmonary arterial hypertension (PAH)
1.1. Idiopathic (IPAH)
1.2. Familial (FPAH)
1.3. Associated with (APAH):
1.3.1. Connective tissue disorder
1.3.2. Congenital systemic-to-pulmonary shunts
1.3.3. Portal hypertension
1.3.4. HIV infection
1.3.5. Drugs and toxins
1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, chronic myeloproliferative disorders, splenectomy)
1.4. Associated with significant venous or capillary involvement
1.4.1. Pulmonary veno-occlusive disease (PVOD)
1.4.2. Pulmonary capillary hemangiomatosis (PCH)
1.5. Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension with left heart disease
2.1. Left-sided atrial or ventricular heart disease
2.2. Left-sided valvular heart disease
3. Pulmonary hypertension associated with lung diseases and/or hypoxemia
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Sleep disordered breathing
3.4. Alveolar hypoventilation disorders
3.5. Chronic exposure to high altitude
3.6. Developmental abnormalities
4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease (CTEPH)
4.1. Thromboembolic obstruction of proximal pulmonary arteries
4.2. Thromboembolic obstruction of distal pulmonary arteries
4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)
5. Miscellaneous: Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)
Pulmonary Arterial Hypertension (WHO Group 1)
Pulmonary arterial hypertension (PAH) is a rare and debilitating disease characterized by abnormal proliferation and contraction of pulmonary artery smooth muscle cells. This condition causes a decrease in the size of the pulmonary artery lumen, a decreased reactivity of the vascular bed, increased pulmonary vascular resistance (PVR) and elevated pressure in the pulmonary circulation (initially with normal left-sided pressures) and leads to overload-induced progressive right ventricular dilation and low cardiac output.
IPAH is more prevalent in women, and is the most common type of PAH. Familial PAH often results from a mutation in bone morphogenetic protein receptor-2 (BMPR2) and is inherited as an autosomal dominant disease. PAH is also associated with congenital heart disease, connective tissue diseases, drugs and toxins, human immunodeficiency virus (HIV), portal hypertension, hemoglobinopathies, and myeloproliferative disorders. The diagnosis of PAH requires confirmation with a complete right heart catheterization. The current hemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mmHg; a pulmonary capillary wedge pressure, or left ventricular end-diastolic pressure less than or equal to 15 mm Hg; and a pulmonary vascular resistance > 3 Wood units.
Non-PAH Pulmonary Hypertension (PH) (WHO Groups 2-5)
PH associated with elevated left heart filling pressures are more prevalent than PAH. Treatment should be directed at the underlying left heart disease. Use of PAH-specific treatments for non-PAH PH has been suggested but there are no clinical trial data to support these hypotheses. There are potential adverse side effects of PAH-specific therapies in such patients including increased fluid retention, pulmonary edema, and ventilation perfusion mismatch.
In 2009, recommendations of an international group of experts who attended the 4th World Symposium on pulmonary hypertension were published; the symposium was held in 2008. The group recommended some modifications to the nomenclature of pulmonary hypertension. A key difference from the ACCF/AHA classification is the introduction of a new category of pulmonary hypertension, called “Group 1 prime” and defined as pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH). The ACCF/AHA nomenclature lists these conditions as sub-categories of pulmonary arterial hypertension (Group 1).
Baseline Assessment of PAH
A baseline assessment to determine severity of PAH is often performed before initiation of therapy. This assessment includes the following measures as key determinants of disease severity.
Functional impairment The functional significance of PAH is determined by measuring exercising capacity and determining New York Heart Association (NYHA) or WHO functional class. The WHO functional classification recognizes the importance of near syncope and syncope. Syncope is thought to worsen the prognosis in patients with PAH. Although not explicitly stated, PAH patients who have experienced a syncopal episode are generally assigned to WHO functional class IV.
The New York Heart Association (NYHA) Classification- functional classification
Class I—patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II—patients with slight, mild limitation of activity; they are comfortable with rest or mild exertion.
Class III—patients with marked limitation of activity; they are comfortable only at rest.
Class IV—patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest.
World Health Organization (WHO) - functional classification for pulmonary arterial hypertension
Class I—no limitation of clinical activity; ordinary physical activity does not cause dyspnea or fatigue.
Class II—slight limitation in physical activity; ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest.
Class III—marked limitation of physical activity; less than ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest.
Class IV—unable to perform any physical activity without symptoms; dyspnea and/or fatigue present at rest; discomfort increased by any physical activity.
Hemodynamic derangement Pulmonary artery systolic pressure and right ventricular function can be estimated by echocardiography. Right heart catheterization is performed to accurately measure the hemodynamic parameters and confirm PAH. Right heart catheterization is often deferred until advanced therapy is indicated because it is an invasive procedure. Patients with PAH typically undergo an invasive hemodynamic assessment and an acute vasoreactivity test prior to the initiation of advanced therapy.
The acute vasoreactivity test involves administration of a short-acting vasodilator, then measuring the hemodynamic response with a right heart catheter. Agents commonly used include epoprostenol, adenosine, and inhaled nitric oxide. An acute vasoreactivity test is considered positive if mean pulmonary artery pressure decreases at least 10 mm Hg and to a value less than 40 mm Hg, with an increased or unchanged cardiac output and a minimally reduced or unchanged systemic blood pressure. Patients with a positive vasoreactivity test are candidates for a trial of calcium channel blocker therapy. In contrast, patients with a negative vasoreactivity test should be treated with alternative agents; calcium channel blockers (CCBs) have not shown to be beneficial in these patients and may be harmful.
Conventional therapies are considered in all patients with PAH regardless of the etiology; these include diuretics, oxygen therapy, anticoagulants, digoxin, and exercise. Digoxin has been shown to have beneficial effects when used with caution (i.e., patients may be at higher risk for digitalis toxicity and require close monitoring). Patients with a positive vasoreactivity test can be given a trial of CCBs. Patients with a negative vasoreactivity test require advanced therapy with prostacyclin analogues, endothelin receptor antagonists, or phosphodiesterase type 5 (PDE5) inhibitors. Various combinations of treatments have also been suggested. Lung transplantation and combined heart-lung transplantation have been performed in patients refractory to medical management. Objective assessments to measure treatment response include improvement in exercise capacity (6-minute walk distance [6MWD], cardiopulmonary exercise test, treadmill test), hemodynamics, and survival.
It is important to emphasize that the approved treatments for pulmonary arterial disease (PAH; WHO Group 1) have serious side effects and have not shown to be effective in patients with other forms of pulmonary hypertension.
Inhaled Nitric Oxide
Inhaled nitric oxide (NO) is a potent pulmonary vasodilator that is inhaled and delivered in the same manner as supplemental oxygen. Researchers note that it can reduce pulmonary artery pressure in some patients with primary PAH. Its use is being studied alone and in conjunction with other medications.