Treatment Pathways

PAH: Disease Mechanisms and Today’s Treatment Pathways

Part 1: The Pathophysiology of PAH

Pulmonary Arterial Hypertension, or PAH, is an unrelenting and deadly disease that severely impairs patients’ physical functions.

While the etiology of PAH is not fully understood, the pathophysiology of the disease is well-established.

Over the course of the disease, PAH manifests as remodeling of the small pulmonary arteries, resulting in vasoconstriction, smooth muscle cell proliferation, and platelet aggregation. This, along with a host of other vascular changes such as plexiform lesion formation, leads to increased resistance to blood flow within the pulmonary vessels, resulting in increased pressure across the heart and lungs.

While the heart can initially compensate, the progressive increases in pulmonary vascular resistance overloads the right ventricle, ultimately leading to decreases in cardiac output and right heart failure.

While there is currently no cure for PAH, physicians can help patients feel better and participate in daily activities by therapeutically targeting multiple known pathogenic pathways.

Part 2: Primary Disease Pathways

The pathogenesis of PAH is characterized by chronic over or under production of several naturally occurring substances present in small arterioles in the lungs.

These include Prostacyclin, Endothelin-1, and Nitric Oxide. Let’s take a closer look at the primary disease pathways associated with each of these substances.

The Prostacyclin Pathway

PAH may be characterized by abnormally low levels of prostacyclin, or PGI2, a naturally occurring metabolite of arachidonic acid that is endogenous to the body.

Prostacyclin carries out several important actions to help maintain proper heart and lung function. Prostacyclin deficiency has been linked with increased pulmonary arterial pressure, disease severity, and disease progression.

Complications in the lungs caused by inadequate levels of prostacyclin include constriction of the small pulmonary arteries, hypertrophy and proliferation of vascular smooth muscle cells, and heightened risk of blood clotting.

Additionally, data suggests insufficient prostacyclin levels may be associated with pulmonary arterial inflammation.

Therapies which aim to compensate for missing prostacyclin, known as prostacyclin-class medications, are currently formulated for multiple routes of administration including inhaled, oral, subcutaneous, and IV.

Endothelin-1 Pathway

Endothelin-1 is a peptide produced by vascular endothelial cells that may be over-expressed in PAH.

Excess endothelin-1 is associated with arteriolar vasoconstriction, smooth muscle cell proliferation, and inflammation, and can be compensated for with Endothelin-1 class medications, such as Endothelin Receptor Antagonists, or ERAs.

ERAs are currently formulated for oral administration.

The Nitric Oxide Pathway

Another substance that may be deficient in PAH is nitric oxide, a signaling molecule associated with multiple physiological functions.

Nitric Oxide deficiency leads to vasoconstriction and smooth muscle cell proliferation.

Nitric-oxide class medications aim to compensate for nitric oxide deficiency, and are currently available for oral administration.

Part III: Act Now to Impact PAH Outcomes

PAH is a progressive disease with very poor prognosis. Rate of progression can be rapid and unpredictable, underscoring the urgency to treat quickly. In the absence of targeted therapy, median survival was shown to be less than 2.8 years. Since the advent of targeted therapy, 61.2% are alive 5 years after diagnosis.

Current treatment guidelines recognize the need to treat multiple pathogenic pathways simultaneously, which is shown to provide greater clinical benefit than monotherapy focused on a single pathway.

In selecting combination therapy protocols, physicians should consider etiological, socioeconomic, lifestyle, and tolerability factors to ensure patients are able to adhere to treatment regimens.

Research shows that achieving low-risk status within 1-year of diagnosis leads to better 5-year prognosis.

When treating patients with a progressive disease, it is imperative to monitor the early or “leading” signs of disease changes. In PAH, changes in right heart function precede changes in other parameters such as exercise tests and functional class, often referred to as “lagging” indicators. Optimized treatment would be expected to benefit right heart function early, thereby improving overall patient function.

Current treatment guidelines recommend multi-parameter risk assessment at baseline,3 follow-up risk assessment as often as every 3 months, echocardiography as often as every 3 to 6 months, co-management of treatment with an expert PAH center, and prompt escalation of therapy when patients do not reach low risk status.

Delaying therapy for as little as a 6 weeks - whether initial or sequential combination - can have a detrimental impact on patients. By acting now, you can help improve your patient’s prognosis.

Visit PAHInitiaitive.com/HCP to find more PAH disease state education and resources for you, your practice and your patients.