The current understanding of the role of specific molecular mechanisms causing pulmonary hypertension (PH) in people with pulmonary fibrosis (PF) is growing but still in its infancy, according to a review published in Respiratory Research.

PH is a common comorbidity in people with PF and is a significant predictor of PF mortality. With the many clinical trials designed to explore the development of PH among patients with PF having yielded results that were inconclusive at best, it remains imperative for the medical community to gain an enhanced understanding of the development of PH secondarily to PF (PF-PH).

In the current review, investigators sought to provide a comprehensive translational overview of PH in patients with PF — from clinical diagnosis and outcome to the latest understanding of the histology and molecular pathophysiology of PF-PH.


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The latest definition of PH includes an increased pulmonary vascular resistance of ≥3 Wood units, and with a mean pulmonary arterial pressure threshold of >20 mm Hg. Use of this revised PH definition could change the paradigm of PH in patients with PF.

The current understanding of PH pathogenesis in individuals with PF relies mainly on data from patients with idiopathic pulmonary fibrosis (IPF). The high prevalence of PH among patients with PF is particularly disconcerting since PH is a strong predictor of mortality among individuals with PF.

Until recently, it was thought that PH arose exclusively from fibrotic destruction of lung parenchyma, leading to hypoxic vasoconstriction and loss of vascular bed density. Because of this perception, the potential molecular and cellular dysregulation of vascular remodeling as a driver of PF-PH has been underinvestigated. 

Recent findings have demonstrated no association between the severity of fibrosis and the development of PH. With the knowledge that significant molecular and vascular histologic differences exist between patients with and without PH, the etiologic concept of PF-PH has shifted. The high prevalence of PH in patients with PF is of great concern, since the role of PH on survival among patients with IPF has been well described. In patients with IPF, PH is a strong comorbidity, but its symptoms are difficult to identify. PH prevalence in PF is usually investigated in patients with IPF who are awaiting lung transplantation.

In patients with IPF, pulmonary function tests — forced vital capacity and diffusing capacity of the lung for carbon monoxide — are used to assess lung function impairment. Thoracic echocardiography is the most commonly utilized diagnostic tool to screen patients for PH, serving as a noninvasive cardiovascular imaging technique that can estimate pulmonary hemodynamics.

The cardiopulmonary exercise test is another noninvasive test that can be used to detect PH among patients with PF. Cardiac magnetic resonance imaging is a more advanced noninvasive cardiovascular imaging technique that is available at more specialized centers.

Currently, no approved treatment exists for PH in patients with PF. With a growing body of evidence on the specific molecular mechanisms that drive the development of PH in patients with PF, the paradigm is shifting slowly from a “passive state,” in which PH development was due only to hypoxic vasoconstriction and loss of vascular bed density, to an “active process,” in which specific molecular and cellular players are involved.

“Our understanding of these mechanisms is still in its early days, and an extensive research to deepen our knowledge is crucial to find specific drugs for this life-threatening disease,” the researchers concluded.

Reference

Ruffenach G, Hong J, Vaillancourt M, Medzikovic L, Eghbali M. Pulmonary hypertension secondary to pulmonary fibrosis: clinical data, histopathology and molecular insights. Published online November 18, 2020. Respir Res. doi:  10.1186/s12931-020-01570-2