# Mechanistic insights into HIV-mediated heart failure with preserved ejection fraction

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $646,794

## Abstract

Persons living with HIV (PLWH) now live longer and suffer from many chronic conditions, which occur in PLWH
at a higher rate and at an earlier age, and continue to develop despite suppressive antiretroviral therapy (ART).
One of the abnormalities commonly found in PLWH is heart failure with preserved ejection fraction (HFpEF),
defined as diastolic dysfunction with left ventricular ejection fraction of 50% or more. The development of HFpEF
in the general population is associated with an increase in all-cause mortality, highlighting the clinical significance
of this disorder. The cellular mechanism of HFpEF in PLWH is not totally understood, but chronic inflammation,
genetic predisposition, and side effects of ART have been proposed. In this proposal, we will address the
fundamental gap in knowledge of the mechanism of HIV-associated HFpEF using two systems: 1) already
established model of isolated cardiomyocytes from rhesus monkey that mimic HFpEF pathology following CCR5
ligand exposure, and 2) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We will then
simulate chronic inflammation in vitro by treating the cells with cytokines or exposing them to an inflammatory
milieu. Our central hypothesis is that mitochondrial pathogenetic mechanisms in cardiomyocytes are
triggered by HIV-associated systemic inflammation to cause HFpEF, and that novel therapies can
counter the cellular derangements. We also hypothesize that the heterogeneity of susceptibility to
HFpEF is due to differences in genetic predilection to these pathologic mechanisms. To study our
hypothesis, we propose two aims. In Aim 1, we will determine the pathogenetic mechanisms of HFpEF in
cardiomyocytes. Isolated rhesus monkey cardiomyocytes and control hiPSC-CMs from five non-infected, non-
HFpEF donors will be exposed to an in vitro model of chronic inflammation using three systems: 1) addition of
CCR5 ligands, 2) microbial translocation, and 3) addition of non-CCR5 ligand cytokines, all of which have been
demonstrated to be altered in PLWH independent of viral replication. We will then assess the effects of these
manipulations on cardiomyocyte relaxation and function by measuring calcium transients, in addition to
mitochondrial function and ROS (as markers of cellular injury). We will also treat hiPSC-CMs and isolated
cardiomyocytes with ART to rule out a contribution of ART to diastolic dysfunction. Finally, we will generate
hiPSC-CMs from 10 HIV patients, 5 with, and 5 without HFpEF and perform RNA-sequencing to identify
candidate genes for characterization of the genetic basis of susceptibility to HFpEF. In Aim 2, we will determine
whether novel drugs protect cardiomyocytes against the cellular pathogenesis causing HFpEF. We will expose
cardiomyocytes from macaque and hiPSC-CMs to an inflammatory environment as described in Aim 1, and will
assess whether treatment with drugs downstream of inflammation and ROS (i.e., phosphodiesterase 5/9
inhibitors, soluble gu...

## Key facts

- **NIH application ID:** 9843563
- **Project number:** 5R01HL140973-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Hossein Ardehali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $646,794
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843563

## Citation

> US National Institutes of Health, RePORTER application 9843563, Mechanistic insights into HIV-mediated heart failure with preserved ejection fraction (5R01HL140973-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9843563. Licensed CC0.

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