A New Look at Pulmonary Hypertension


Vol. 20 •Issue 10 • Page 19
A New Look at Pulmonary Hypertension

Prior to 1997, most of us in the respiratory world thought of pulmonary hypertension (PH) as either a neonatal condition or a congenital cardiac problem. Most did not make a distinction between pulmonary arterial hypretension (PAH) and PH. But the combination of the diet drugs phentermine (phen) and fenfluramine (fen), more commonly known as fen-phen, changed all that. When young, middle-aged women started dying of this rare disease, we all noticed. And make no mistake, PAH has a heavy impact on women.

PAH is, in fact, just one type of PH. The Third World Symposium for PAH, held in Venice, Italy, in 2003, defined five groups of PH.

It is important to understand the differences among these groups because treatment can vary depending on the group. Specifically, PAH is defined as an elevated pulmonary artery pressure with a mean pressure above 25 mm Hg at rest, or 30 mm Hg with exercise, in the absence of pulmonary venous hypertension or respiratory or embolic disorders.

The condition is characterized by a progressive increase in pulmonary vascular resistance, pulmonary arterial vasoconstriction and vascular remodeling, leading to right ventricular failure and death. If untreated, the average life expectancy for a patient is only 2.8 years from the time of diagnosis.

A complete patient history and an echocardiography may be suggestive of a diagnosis of PH. However, a definitive diagnosis can be made only by a right heart catheterization.

Five PH Groups

As we look at the five groups of PH, we find that Group 1 is generally called PAH and includes: idiopathic PAH; familial PAH; PAH caused by collagen vascular disease; PAH caused by portal hypertension; PAH related to HIV infection; PAH caused by drugs and toxins; and “other” forms of PAH.

Group 2 is known as pulmonary venous hypertension and is caused by left-sided heart disease or valvular dysfunction.

Group 3 is known as pulmonary hypertension associated with hypoxemia. Although we don’t fully understand the mechanism of actions, its etiology is related to COPD, interstitial lung disease, sleep-disordered breathing and chronic exposure to high altitudes.

Group 4 is better known as pulmonary hypertension due to chronic thrombotic and/or embolic disease. Thromboembolic obstruction in the proximal or distal pulmonary arteries and pulmonary embolism are the primary causes.

Group 5 is a catch-all category for miscellaneous types of pulmonary hypertension disease related to sarcoidosis, histiocytosis X, lymphangiomatosis, compressions of pulmonary vessels and other conditions.

Function Status of Patients

Once we sort out the group or type of pulmonary hypertension we are dealing with, we then need to sort out the individual’s functional class. The World Health Organization classifies the functional status of patients with PH in four categories.

  • Pulmonary hypertension patients who have not yet impacted or limited their usual activity are considered Class I.
  • Pulmonary hypertension patients who have a slight limitation of their usual physical activities are considered Class II.
  • Pulmonary hypertension patients with marked limitation of their physical activity are designated as Class III.
  • Class IV patients are unable to perform any physical activity without symptoms and may have signs of right ventricular failure.

    Why is all this important? Because the type of pulmonary hypertension and the functional class determine which medications can be used to treat them. But we are not done yet. Clinicians also have to understand the pathway of action for the medication they are considering.

    Treatment Pathways

    Three key pathways have been identified in PAH. These are the endothelin pathway, the prostacyclin pathway and the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway. The available medications impact one of these three routes.

    What we know about the endothelin pathway is basically how to manipulate endothelin-1 (ET-1), the most potent vasoconstrictive agent discovered to date. We know there are two endothelin-receptor isoforms: ETA, whose receptors are located on smooth muscle cells, and ETB, whose receptors are found for the most part on vascular endothelial cells. Currently Bosentan is the only ETA/ETB receptor antagonist approved by the U.S. Food and Drug Administration (FDA). An oral agent, it was approved in 2001.

    Selective ETA antagonists, Sitaxsentan and Ambrisentan, are currently under investigation and may be approved later this year. Preliminary data suggest they may have a longer duration and fewer side effects.

    The prostacyclin pathway, not surprisingly, involves impacting prostacyclin, an arachidonic acid metabolite that has been shown to induce vasodilation, regulate the growth of smooth muscle cells and inhibit platelet aggregation. Data show patients with PAH have low levels of prostacyclin and thromboxane, a potent vasoconstrictor and platelet agonist. There are currently three approved prostacyclin analogues: epoprostenol, treprostinil and iloprost.

    The third and final pathway is the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway. Nitric oxide is a potent selective pulmonary vasodilator. By using this pathway, clinicians seek to boost nitric oxide’s vasodilator effects. It does this by boosting the levels of cyclic guanosine monophosphate (cGMP), which is degraded by phosphodiesterase (PDE). A phosphodiesterase-5 inhibitor will stimulate the accumulation of intracellular cGMP.

    Currently, Sildenafil is the only phosphodiesterase-5 inhibitor approved by the FDA for the treatment of PAH. Though we all know this medication as Viagra, it is marketed in the PAH community under the brand name of Revatio.

    Each of the medications represented in these three pathways has its own pros and cons. Some have serious side effects. Others have delivery limitations and associated complications. Each has its own unique approval status with relation to group classification and functional class. The selection of a particular therapy is dependent on the patient’s group, clinical presentation, functional class and lifestyle.

    Who Gets PH?

    So who gets pulmonary hypertension anyway? That is a complicated question and one that brings us back to the group classification system from above. Prior to 1997, we thought of pulmonary hypertension as a neonatal or cardiac related condition. But we cannot just say that women who used phentermine or fenfluramine are the only ones at risk. There is a growing body of evidence that suggests the occurrence of pulmonary hypertension in COPD, HIV, sickle cell disease and other conditions may be more pervasive in our society than we thought. The real truth about pulmonary hypertension is we may just be seeing the tip of the iceberg. But we don’t know. Yet.

    Margaret Clark is a Georgia practitioner.

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