# Contributions of pulmonary arterial and venous remodeling to HFpEF in the elderly

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $815,189

## Abstract

Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left
ventricular (LV) ejection fraction (HFpEF), for which no efficacious therapies exist. Pulmonary hypertension
(PH) – the most clinically recognized expression of pulmonary vascular dysfunction (PVD) – is a risk factor for
incident HF and is present in upto 83% of patients with prevalent HFpEF, among whom it portends worse
outcomes. PVD is therefore an attractive therapeutic target in HFpEF, but its pathophysiology is complex with
variable contributions from elevated left atrial pressure, pulmonary parenchymal injury, and intrinsic
pulmonary vascular dysfunction. A critical barrier to understanding PVD in HFpEF is a lack of knowledge
regarding the anatomic alterations in the pulmonary vasculature underlying abnormal hemodynamics. The
investigative team has pioneered development and validation of advanced image processing pipelines to
quantify pulmonary venous and arterial remodeling on non-contrast chest computerized tomography (CT)
scans. Their published and preliminary data from smokers in the NHLBI-funded COPDGene study show that
pulmonary vascular remodeling associates with RV dysfunction and worse functional capacity, and is more
frequently observed in HF. They now propose to extend these findings to a community-based cohort of older
adults to define the role of pulmonary vascular remodeling in the development of HFpEF. This proposal’s
central hypothesis is that activation of pro-inflammatory and pro-fibrotic pathways promotes pulmonary
vascular remodeling, partially via concomitant LV dysfunction and pulmonary parenchymal injury, leading to
PH, RV dysfunction, and ultimately HF. This project will leverage recently completed chest CT (for CAC) and
echocardiography in 1,579 Atherosclerosis Risk in Communities (ARIC) study participants at the 7th study visit
(2/2018-11/2019; age ~81±4 yrs). Novel CT-based measures of pulmonary vascular remodeling and
parenchymal injury (fibrotic, emphysematous), and advanced 3D and strain-based echo measures of RV
function will be performed. These data will be integrated with clinical assessments, outcomes surveillance,
aptamer-based proteomics, and genomics to help define the most relevant targets to prevent progressive PVD
in the very elderly. Specific aims include: (1) Define the extent to which LV dysfunction and pulmonary
parenchymal injury promote pulmonary venous and arterial remodeling in the very elderly; (2) Determine the
extent to which pulmonary vascular remodeling predicts RV dysfunction, reduced functional capacity, and
incident HFpEF; and (3) Identify proteins and protein networks that predict pulmonary vascular remodeling.
Replication will occur in COPDGene and the Framingham Heart Study, and Mendelian randomization analyses
will identify the subset of potentially causal associations. Quantifying pulmonary vascular remodeling will
identify pathophysiologically distinct morphologic PVD sub-ph...

## Key facts

- **NIH application ID:** 10446349
- **Project number:** 1R01HL160025-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Raul San Jose Estepar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $815,189
- **Award type:** 1
- **Project period:** 2022-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446349

## Citation

> US National Institutes of Health, RePORTER application 10446349, Contributions of pulmonary arterial and venous remodeling to HFpEF in the elderly (1R01HL160025-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10446349. Licensed CC0.

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