Project Details
Description
PROJECT SUMMARY / ABSTRACT
Left heart disease (LHD) leads to pulmonary hypertension (PH-LHD, aka Group 2 PH), right ventricular (RV)
failure, and increased mortality and morbidity. Advances in pulmonary vascular biology gleaned from study of
the pulmonary arterial (PA) circulation in Group 1 PH and relevant animal models have led to effective therapies
for Group 1 PH. Trials of Group 1 PH therapies in PH-LHD have shown highly variable (favorable, neutral or
harmful) effects. We propose that two critical knowledge gaps contribute to variability in therapeutic response
and impede progress in treating PH-LHD: (1) the lack of a mechanistically informative hemodynamic
classification system defining the nature (vasoconstriction vs remodeling) and location (PA vs pulmonary venous
(PV)) of pulmonary vascular disease in LHD, and (2) lack of understanding of vessel specific (PV vs PA)
biological pathways mediating pulmonary vascular disease in PH-LHD. The objective of this proposal is to
address these knowledge gaps and enable therapeutic innovation in PH-LHD. Based on extensive preliminary
studies in human and experimental (Exp) PH-LHD, our central hypothesis is that PH-LHD is a phenotypically
diverse entity whose ultimate therapeutic approach will be defined by unique hemodynamic phenogroups and
vessel specific (PA vs PV) pathophysiological perturbations. In human and Exp PH-LHD, we will use novel
hemodynamic assessments to phenotype PH-LHD according to pulmonary vascular resistance (PVR),
vasoreactivity, and the longitudinal distribution of PVR (Aim 1). Findings will be validated in human PH-LHD by
assessing phenogroup-specific differences in aerobic capacity, RV reserve function and exertional lung
congestion. Findings in Exp PH-LHD will be validated by defining PA and PV remodeling (quantitative
histomorphometry). Our broad hypothesis is that both the primary mechanism and location of the elevated PVR
in PH-LHD have clinical implications and anatomical underpinnings. In human and Exp PH-LHD, we will then
(Aim 2) use histochemical, proteomic, and transcriptomic based techniques and bioinformatic analyses to define
vessel specific mechanisms across PH-LHD phenogroups. These studies will couple the Aim 1 hemodynamic
phenotyping approach to vessel specific vascular biology. In Aim 3, we will determine if therapeutic agents based
on our omics studies in human and Exp PH-LHD will ameliorate PV or PA remodeling and delay the progression
of PH in Early or Late Exp PH-LHD phenogroups. The research outcome from this work will be a new
hemodynamic classification of PH-LHD linked to specific pathophysiology and therapeutic targets, thus enabling
individualized medicine approaches to PH-LHD.
Status | Active |
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Effective start/end date | 6/1/23 → 5/31/24 |
Funding
- National Heart, Lung, and Blood Institute: $803,492.00
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