Novel Methods in Pulmonary Hypertension Phenotyping in the Age of Precision Medicine (2015 Grover Conference Series)

Abstract

Among pulmonary vascular diseases, pulmonary hypertension (PH) is the best studied and has been the focus of our work. The current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics. This leads to inherent limitations, including the inability to customize treatment and the lack of clarity from a more granular identification based on individual patient phenotypes. Accurate phenotyping of PH can be used in the clinic to select therapies and determine prognosis and in research to increase the homogeneity of study cohorts. Rapid advances in the mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define novel PH phenotypes. We have recently shown that altered metabolism may affect nitric oxide levels and protein glycosylation, the peripheral circulation (which may provide insights into the response to therapy), and exhaled-breath analysis (which may be useful in disease evaluation). This review is based on a talk presented during the 2015 Grover Conference and highlights the relevant literature describing novel methods to phenotype pulmonary arterial hypertension patients by using approaches that involve the pulmonary and systemic (peripheral) vasculature. In particular, abnormalities in metabolism, the pulmonary and peripheral circulation, and exhaled breath in PH may help identify phenotypes that can be the basis for a precision-medicine approach to PH management. These approaches may also have a broader scope and may contribute to a better understanding of other diseases, such as asthma, diabetes, and cancer.

Cutaneous Iontophoresis of Vasoactive Medications in Patients with Scleroderma- Associated Pulmonary Arterial Hypertension

“…Currently, there are no established ways to test certain mechanisms of disease in a patient with PAH. We have previously shown that the cutaneous microvascular response to treprostinil iontophoresis is reduced in patients with idiopathic PAH compared to controls (9) supporting that abnormalities in the pulmonary vasomotor biology may be associated with alterations in the cutaneous microvascular vasodilatory response (10). Several other studies have shown evidence of extrapulmonary vascular involvement in PAH (11)(12)(13)(14).…”

Pulmonary Hypertension and Precision Medicine through the “Omics” Looking Glass

“…The current approach to treatment does not take into account recent and ongoing advances in genomics, metabolomics, imaging, etc. (4)(5)(6)(7)(8)(9)(10)(11).…”

“…Several nationally ranked teams of basic, translational, and clinical investigators with expertise in PVDs were awarded funds to (1): reclassify subsets of patients with PH regardless of the existing conventional World Health Organization classification system (2); define novel, clinically relevant therapeutic indices that may be useful for intermediate or primary outcomes in clinical trials (3); identify biomarkers of PH for detection and prevention research; and (4) define novel vascular disease phenotypes through endophenotyping approaches, including genomics, proteomics, metabolomics, etc. (5,14). Recently, these teams of experts convened a workshop with other NHLBI initiatives, patient advocacy organizations, regulatory agencies, and pharmaceutical industry experts to discuss current and prospective research priorities and their alignment with the NHLBI Strategic Vision on precision medicine for PVDs (Figure 1).…”

Things We “kNOw” and Do Not “kNOw” about Pulmonary Hypertension

“…The World Health Organization classifies patients with PH into five groups on the basis of etiology (3). Multiple phenotypes such as vasoconstriction, dysregulated pulmonary vascular cell proliferation and remodeling, and inflammation contribute to the PH disease process (4-6) making therapeutic design complicated (7,8).…”