Reply to Voelkel and Newman: The Light at the End of the Long Pulmonary Hypertension Tunnel Brightens

From the Authors:

We thank Dr. Voelkel and Dr. Newman for their interest in our recent manuscript (1) and their insightful commentary.

Our report focused on the challenges associated with treating pulmonary hypertension (PH) due to heart failure with preserved ejection fraction (HFpEF), interstitial lung disease (ILD), and pulmonary venoocclusive disease (PVOD)/pulmonary capillary hemangiomatosis with pulmonary arterial hypertension (PAH)-specific therapies. We likened elevated pulmonary artery pressure and right ventricular dysfunction in these PH subtypes to “the tip of the iceberg.” The intent of the analogy was to emphasize the molecular and pathological mechanisms below the surface when considering appropriate therapy and future clinical trials but does not preclude unifying mechanisms across the different PH classifications. Although discovery of distinct endophenotypes is one potential outcome of comprehensive PH phenotyping, we may also uncover similarities that are otherwise obscured by our current focus on disease-based classification (2). Thus, we concur that unifying pathobiological mechanisms do exist across World Health Organization classifications (e.g., inflammation and endothelial dysfunction) and may suggest shared therapeutic targets (3). For example, spironolactone increases survival in patients with left heart failure by improving endothelial dysfunction and reducing inflammation, providing a biological rationale for studying the treatment in PAH (4).

Dr. Voelkel and Dr. Newman underscore the extent of heterogeneity even among patients with PAH. We agree that just as there are important pathobiological differences between HFpEF-PH, ILD-PH, PVOD, and PAH that impact treatment responses, PAH clinical subtype also influences therapeutic responses (5). In addition to recognizing differential therapeutic responses in patients with PAH, based on clinically defined subtypes (e.g., idiopathic PAH, systemic sclerosis-associated PAH, and congenital heart disease–associated PAH), studies have also suggested that genetic polymorphisms (6) and gene expression patterns (7) are associated with therapeutic responses and represent encouraging progress toward personalized medicine. NHLBI-funded projects such as the PAH Biobank and Pulmonary Vascular Disease Phenomics program (PVDOMICS) as well as ongoing efforts internationally (8) are further evidence that the field is moving ahead and diving deeper below the surface. Furthermore, advances in clinical trial design including the use of master protocols and innovative methodologies (e.g., umbrella, basket, and platform trials) are particularly appealing for studying mechanistic-based therapies and/or rare diseases (9).

The field of oncology has made a tremendous amount of progress in the development of precision therapies owing in large part to the accessibility of the target tissue and the ability to stage tumor progression. In contrast, determining whether candidate or even current therapies have a direct impact on the pulmonary vasculature and/or the right ventricle is both a major challenge and an opportunity for advancing precision therapy in pulmonary vascular disease (10). Pilot studies using [¹⁸F]deoxyglucose positron emission tomography of the heart (11) and lung (12), gadolinium-enhanced magnetic resonance imaging of lung perfusion (12), and cardiac magnetic resonance imaging (13) are notable examples of the type of innovative measures of treatment responses that will be necessary to realize the potential of precision therapy in pulmonary vascular disease. Thus, we are in agreement with Voelkel, Newman, and Will Rogers that “even if you’re on the right track, you’ll get run over if you just sit there.”