# Mitochondrial metabolic modulation to minimize ischemic damage in donor heart

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2020 · —

## Abstract

Patients with end stage heart failure (HF) require mechanical circulatory support, and if eligible, heart
transplantation (HT) to save their life. Up to 20% of patients die while listed for heart transplantation. The
supply of donor hearts has reached a plateau since the only current source of donor hearts consists of patients
with irreversible severe brain damage (donation after brain death, DBD). Thus, there is an urgent need to
expand the heart donor pool. A potential source of such donor hearts is from DCD (donation after circulatory
death) donors. DCD donors have increased the transplantation rates of solid organs including liver, lungs and
kidney. Unfortunately, DCD protocol induces a sustained warm ischemic time that damages myocardium
precluding its use for clinical transplantation. Thus, the ischemia (ISC) form DCD protocol, the potential
myocardial injury from storage, and reperfusion (REP) associated injury combine to represent additional risks
to exacerbate injury in the DCD heart precluding their use in clinical transplantation.
 Although the warm ischemia is inevitable in DCD hearts, REP injury can be decreased through proper
interventions applied at the onset of REP. We propose that development of new strategies to prevent REP
injury will reduce damage to the DCD heart. Mitochondria are critical targets and mediators of cardiac injury
during REP. Our previous studies found that temporary and reversible inhibition of mitochondrial respiration at
the time of REP in hearts following ISC decreases cardiac injury. Protection involved the reduction of the ROS
generation and inhibition of the opening of the mitochondrial permeability transition pores. We propose that
the use of rapid onset and reversible inhibitors of respiration immediately before and during early REP will
decrease cardiac injury in DCD hearts. The ex vivo DCD human heart represents a unique opportunity to
translate this robust cardiac protection derived from strong pre-clinical data to human disease.
 Myocytes injured during ISC-REP activate internal cell-based mechanisms of inflammation including
the NOD like receptor protein 3 (NLRP3) inflammasome. ROS derived from damaged mitochondria activates
the NLRP3 inflammasome and perpetuates tissue injury further. This project takes the unique approach to
combine complimentary interventions to blunt acute mitochondrial-driven injury and attenuate longer-term REP
damage from inhibition of inflammasome signaling. The potential mechanistic relationship of damaged
mitochondria and the activation of inflammasome signaling are studied in the DCD heart model.
 We hypothesize that the initial protection of mitochondria followed by attenuation of mitochondria-
activated inflammatory signaling will protect the DCD heart function, enabling it to be used for heart
transplantation. Our novel strategy is to use amobarbital treatment to rapidly, reversibly and transiently
modulate mitochondrial respiration to decrease acute ISC-REP injury f...

## Key facts

- **NIH application ID:** 9898257
- **Project number:** 5I01BX003859-03
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Mohammed Quader
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898257

## Citation

> US National Institutes of Health, RePORTER application 9898257, Mitochondrial metabolic modulation to minimize ischemic damage in donor heart (5I01BX003859-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898257. Licensed CC0.

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