# Reduction of cardiac injury in DCD hearts with prolonged ischemic period: Role of MPTP opening and calpain activation

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2024 · —

## Abstract

Patients with end-stage heart failure (HF) require mechanical circulatory support, and if eligible, heart
transplantation (HTx). The supply of donor hearts has reached a plateau since the only current source of donor
hearts consists of patients with irreversible complete brain damage (donation after brain death, DBD). However,
the number of eligible HT recipients increased exponentially. Unfortunately, due to this demand-supply
mismatch, up to 20% of patients die while listed for HTx. Thus, there is an urgent need to expand the heart donor
pool. A potential new 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, by 50%.
Unfortunately, DCD protocol induces a sustained warm ischemic time that damages the myocardium precluding
its use for clinical transplantation. Thus, the ischemia (ISC) from 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 routine use in clinical transplantation. A limited number of HTx are performed
utilizing DCD hearts under strict protocol with very short ischemia times (<20 minutes). Extending the acceptable
ischemia time (35 minutes) will allow significant additional DCD hearts to be utilized for HTx. Although the warm
ISC is inevitable in DCD hearts, REP injury can be decreased through interventions applied at the onset of
REP. We propose that the 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. Mitochondrial permeability
transition pore (MPTP) opening is considered a final step to induce cell death during ISC-REP. Since MPTP
opening predominantly occurs during REP, there is a window of opportunity to decrease MPTP opening by
applying intervention at the onset of REP. Cyclosporine A (CyA) is a classic MPTP inhibitor that decreases
cardiac injury in hearts following ISC-REP. We propose that administration of the CyA at the onset of REP can
reduce cardiac injury in the DCD hearts. Calpain1 and 2 (CPN1/2) are calcium-dependent proteases that are
activated during ISC-REP. Activation of CPN1/2 impairs cardiac function by degrading structural proteins,
including spectrin and junctophilin-2 (JPH2). Activation of CPN1/2 also contributes to mitochondrial dysfunction
during ISC-REP. In addition, activation of CPN1/2 increases inflammation by cleaving and activating caspase-1.
Therefore, we will test if the administration of CPN1/2 inhibitor (MDL-28170, MDL) can decrease cardiac injury
in DCD hearts. We will further test if the combined treatment with CyA and MDL can provide additional protection
compared to individual CyA or MDL treatment in DCD hearts, especially with a longer ischemia period. Aim 1
will evaluate the MPTP opening and CPN1/2 ac...

## Key facts

- **NIH application ID:** 10871818
- **Project number:** 5I01BX003859-07
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Mohammed Quader
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871818

## Citation

> US National Institutes of Health, RePORTER application 10871818, Reduction of cardiac injury in DCD hearts with prolonged ischemic period: Role of MPTP opening and calpain activation (5I01BX003859-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10871818. Licensed CC0.

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