Basic Pathology of Pulmonary Arterial Hypertension (PAH)

Vinicio de Jesus Perez, MD, Assistant Professor of Pulmonary Medicine, Stanford School of Medicine

Lung biopsy of PAH patient showing obstructive vascular lesions that range in appearance from vessels coated by thick layers of smooth muscle cells to complex plexogenic lesions (top photo).  Normal lung biopsy (bottom).

Summer 2016

Why are PAH patients limited in their capacity to carry out regular activities?

PAH is a disorder of small pulmonary arteries that is characterized by obstructive lesions that impair blood flow and access to the oxygen exchange portions of the lungs. As a result, oxygen content in blood is reduced and body tissues are receiving less oxygen that is required for generation of the energy required to sustain normal tissue activity.

What does PAH look like under the microscope?

The lungs of PAH patients are burdened with obstructive vascular lesions that range in appearance from vessels coated by thick layers of smooth muscle cells to complex plexogenic lesions characterized by tortuous labyrinthine vascular channels that trap blood flow. The distribution and abundance of these lesions is variable and impossible to estimate based on the diagnostic imaging studies obtained during the diagnostic work-up and can only be appreciated when lung biopsy samples are available. An example of these lesions can be found in figure 1.

What is the impact of vascular pathology in the response to medical therapy?

This has been the subject of great interest as most of the studies dealing with vascular pathology in PAH have been done prior to the advent of modern PAH therapy. Since most of the modern therapies have been shown to influence the severity of vascular remodeling in preclinical models of PAH, it was speculated that introduction of these therapies could serve to reduce the number or even normalize the appearance of lesions. However, two recent reports have challenged this posture by revealing advanced obstructive vascular lesions in lung samples of patients on long-term PAH therapies suggesting that clinical improvement may be independent of the capacity of these drugs to prevent progression and/or reverse pulmonary vascular pathology.

How do the presence of these vascular lesions affect my cardiac function?

Patients with PAH mostly present with signs of right heart failure such as fluid buildup, worsening shortness of breath and inability to carry day to day activities independently. The right side of the heart is primarily responsible for pumping venous blood into the lungs to facilitate oxygen uptake and delivery to the rest of the body. In PAH patients, a large proportion of the blood vessels are obstructed by pathological lesions, which force the right ventricle to increase the effort to pump blood across the lesions until it can no longer do so, at which point the signs and symptoms of right heart failure becomes evident. 

What can be done to treat these vascular lesions? Is there any chance that medications can make then shrink or disappear?

Unfortunately, there is no evidence that currently available PAH therapies can reverse established obstructive vascular lesions. However, there are ongoing efforts to achieve greater understanding of the genetic and molecular triggers that drive cells to damage the pulmonary arteries. Promising agents shown to prevent and reverse pulmonary obstruction in pre-clinical models of PAH are currently being investigated in the context of phase 2 and 3 clinical trials. Therefore, there is great hope that these treatments could show the capacity to reduce the burden of obstructive vascular lesions and improve clinical outcomes.

What is the take home message?

PAH is characterized by obstructive vascular lesions that overwhelm the capacity of the right side of the heart to deliver blood to the lung. At present, none of the approved therapies have been shown to reverse these vascular changes but novel agents are currently under investigation in ongoing trials that hold the promise to target the source of vascular obstruction in PAH. Reduced burden of obstructive vascular lesions is expected to relieve the right heart and improve delivery of blood to the lungs and increase the systemic oxygen supply resulting in more energy and improved tolerance to physical activity.

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