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. 2026 Jan 21:12:1625385.
doi: 10.3389/fcvm.2025.1625385. eCollection 2025.

Reducing mitochondrial dysfunction through combination therapy to limit ischemia-reperfusion injury in male DCD rats

Zachary Kiernan #  1 , Gina Labate #  1 , Qun Chen #  2   3 , Mohammed Quader #  1   3   4
Affiliations

Reducing mitochondrial dysfunction through combination therapy to limit ischemia-reperfusion injury in male DCD rats

Zachary Kiernan et al. Front Cardiovasc Med. .

Abstract

Introduction: Two predominant pathways contribute to ischemia reperfusion injury (IRI) following donation after circulatory death (DCD): mitochondrial permeability transition pore (MPTP) opening and Calpain-1 (CPN1) activation. Each pathway has established inhibitors; Cyclosporine A (CyA) and MDL-28170 (MDL), respectively, which are effective in modulating IRI in a DCD heart with 25 min of warm ischemia time (WIT). We studied the effect of co-administering CyA and MDL during reperfusion on infarct size and graft function in DCD rat hearts with extended WIT of 35 min.

Methods: Male rats were exposed to 35 min of warm ischemia followed by 90 min of reperfusion. During reperfusion, hearts were given either 0.5 mM of CyA, 10 mM of MDL, or mixed CyA and MDL. Cardiac function and coronary flow rates were monitored throughout reperfusion and infarct size at the end of reperfusion.

Results: Infarct size in hearts treated with mixed CyA + MDL (31.59 ± 7.1%) was less than that of MDL-treated hearts (33.26 ± 4.3%) but larger than CyA-treated hearts (25.49 ± 5.9%). Graft function and coronary flow rates were variable amongst groups. CyA-treated hearts had more profound infarct size reduction when compared to MDL, and no additional synergistic effect was seen with combination treatment.

Discussion: Our results indicate that MPTP opening contributes significantly to the development of IRI in DCD hearts.

Keywords: MDL-28170; MPTP; cyclosporine A; donation after circulatory death; heart failure.

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Conflict of interest statement

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author QC declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Experimental design. Experimental design comparing continuous beating-heart donation (CBD) and donation after circulatory death (DCD) procedures. The red section indicates ventilator termination, which initiates the ischemic period. The yellow sections represent in-vivo ischemia periods, while the blue sections represent ex-vivo reperfusion on the Langendorff apparatus. The reperfusion period for DCD hearts is divided into 5 categories based on the treatment paradigm used.
Figure 2
Figure 2
Infarct size measurements across experimental groups as measured using triphenyL–tetrazolium chloride (TTC) staining and digital planimetry. Effects of MDL-28170 (MDL), cyclosporine A (CyA) and combination treatment on infarct size in DCD rat hearts following 35 min of ischemia. Infarct size in DCD hearts treated with CyA (25.49 ± 5.90%), MDL (33.26 ± 4.35%) and combination CyA + MDL (31.59 ± 7.14%) were significantly lower than vehicle hearts (40.16 ± 4.06%). Infarct size in hearts treated with mixed CyA + MDL was lower than that of MDL alone, but no statistically significant difference was noted. Furthermore, combination treatment did not exceed the infarct size reduction produced by CyA treatment alone. One-way analysis of variance used for statistical analysis. All data expressed as mean ± SD. † Represents statistical significance (p < 0.05) between CBD hearts and all other groups. * Represents statistical significance (p < 0.05) between vehicle hearts and all other groups.
Figure 3
Figure 3
Comparison of aggregated left ventricular developed pressure (LVDP) (A), rate pressure product (RPP) (B), and coronary effluent (C) across experimental groups. A balloon catheter connected to a pressure transducer was placed into the left ventricle to record LVDP and RPP throughout the 90 min of reperfusion. Of the treated hearts, LVDP was highest in the CyA group (43.71 ± 4.97 mmHg) and lowest in the mixed CyA + MDL group (27.22 ± 13.45 mmHg). No differences were noted between the mixed CyA + MDL group and CyA-treated (43.71 ± 31.05 mmHg) or MDL treated (36.52 ± 18.61 mmHg) hearts. Of the treated hearts, RPP was highest in the CyA-treated hearts (10,332 ± 8,417 mmHg*BPM) and lowest in the mixed CyA + MDL group (4,747 ± 2,965 mmHg*BPM). Coronary effluent was collected for 1 min at 15, 30, 45, 60 and 90 min of reperfusion. Flow rates varied between groups, with the highest rate in the MDL-treated hearts (18.18 ± 4.35 mL/min) and lowest in the mixed CyA + MDL group (13.46 ± 3.81 mL/min). One-way analysis of variance used for statistical analysis. All data expressed as mean ± SD. † Represents statistical significance (p < 0.05) between CBD hearts and all other groups.
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