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.

Keywords: exhaled breath; metabolism; peripheral circulation; phenotyping; precision medicine.

Figure 1

Phenotyping model. The model illustrates the specific tools used to collect human samples/data from patients to help better understand pulmonary vascular disease.

Figure 2

Peripheral vascular response to the iontophoresis of treprostinil in IPAH patients and controls. A, Box-and-whisker plot contrasting IPAH patients not receiving PGI₂ analogs against controls. The horizontal line marks the 300% change in PUs obtained with the Youden index. B, The arrow marks the 300% change in PUs as the best cutoff to differentiate IPAH patients from controls. The area under the receiver operating characteristic curve is 0.87 (95% confidence interval: 0.72–0.96, P < 0.0001). IPAH: idiopathic pulmonary arterial hypertension; PGI₂: prostacyclin; PUs: perfusion units.

Figure 3

Treprostinil response (measured as percent change in perfusion units) based on right ventricular (RV) function (A) and cardiac index (B). IPAH: idiopathic pulmonary arterial hypertension patients.

Figure 4

Mechanisms potentially involved in the lower response to treprostinil iontophoresis in idiopathic pulmonary arterial hypertension patients. ADMA: asymmetric dimethylarginine; MMA: N-monomethylarginine; NO: nitric oxide; PGI₂: prostacyclin; ROS: reactive oxygen species.

Figure 5

Representative areas of the average selected ion flow tube–mass spectrometry for the pulmonary arterial hypertension (PAH) and control groups. All peaks are from the NO+ precursor ion spectrum. The concentrations of specific compounds (PAH in red and controls in blue) are calculated on the basis of counts relative to the precursor counts (details in Cikach et al.).