# DO HEART FAILURE AND AGING POTENTIATE DIAPHRAGM VASCULAR DYSFUNCTION?

> **NIH NIH R15** · KANSAS STATE UNIVERSITY · 2021 · $456,000

## Abstract

PROJECT SUMMARY: Heart failure (HF) disproportionally afflicts the aged impairing muscle O2
transport, crippling the quality of life and predisposing the diaphragm to failure. This scenario has
become all-too-common with the COVID-19 pandemic revealing HF as a major comorbidity and elderly
patients disproportionally represented in the death toll. Established HF animal models overwhelmingly
utilize young rather than old animals. Pathophysiologically, HF in aged individuals (HF+Aged) is a
profoundly different disease from that in younger animals. Therefore, the mechanistic bases for
dysfunction and therapeutic countermeasures must be addressed specifically in this population. HF
compromises multiple O2 transport systems (especially respiratory, cardiovascular and muscular) with
these effects coalescing in decreased skeletal muscle microcirculatory blood-myocyte O2 flux. This
proposal address the mechanistic bases for HF+old-age-induced diaphragm dysfunction from a novel
vertically-integrated perspective and assesses whether nitrate therapy and/or the sGC activator (BAY
60-2770) can protect, preserve or recover diaphragm vasomotor control in HF+Aged animals
specifically during mechanical ventilation (MV). Preliminary data support that both HF+Aged muscle
O2 delivery dysregulation can be ameliorated by strategies that increase nitric oxide (NO) bioavailability
i.e., nitrate supplementation and target sGC. We will address the global hypothesis that, in HF+Aged
rats, diaphragm vascular dysfunction reduces diaphragm O2 delivery and is exacerbated by MV via
decreased NO bioavailability. Multi-targeted therapeutic interventions directed towards central and
peripheral O2 transport system control will restore deficits in diaphragm capillary function and restore
the O2 delivery/utilization balance.
Strengths of our approach include: 1. Resolving and partitioning the perfusive and diffusive
mechanisms impairing diaphragm O2 delivery in HF+Aged and with MV. 2. Our unique intravital
diaphragm microscopy model facilitates direct observation of the microcirculation with high temporal
fidelity determination of blood-myocyte O2 flux using phosphorescence quenching during contractions.
3. Circumventing the technical impossibility of making precise micron-level spatial [NO] measurements
in contracting muscle by determining directly the endogenous NO contribution to capillary
hemodynamics. 4. Providing novel empirical evidence supporting optimal treatment strategies for older
HF patients with and without MV. 5. Testing, for the first time, the latest model of capillary function and
blood-myocyte O2 flux during contractions. The proposed studies will provide novel and important data
addressing diaphragm dysfunction in HF+Aged defining their mechanistic bases and assess the
efficacy of feasible treatment strategies for older HF patients and especially those undergoing MV.

## Key facts

- **NIH application ID:** 10203242
- **Project number:** 1R15AG078060-01
- **Recipient organization:** KANSAS STATE UNIVERSITY
- **Principal Investigator:** Brad J Behnke
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $456,000
- **Award type:** 1
- **Project period:** 2021-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10203242

## Citation

> US National Institutes of Health, RePORTER application 10203242, DO HEART FAILURE AND AGING POTENTIATE DIAPHRAGM VASCULAR DYSFUNCTION? (1R15AG078060-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10203242. Licensed CC0.

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