Cyclosporine A-enhanced cardioplegia preserves mitochondrial basal respiration after ischemic arrest

Perfusion. 2024 Jan;39(1):36-44. doi: 10.1177/02676591211025746. Epub 2021 Jun 30.

Abstract

Background: Mitochondrial permeability transition pore (mPTP) opening plays a crucial role in cell death during ischemia-reperfusion injury (IRI). Cyclosporine A (CsA) inhibits mPTP opening. This study aimed to investigate the effects of CsA treatment during cardioplegia on the mitochondrial function and cardiac IRI.

Methods: Landrace pigs (52.9 ± 3.7 kg) were subjected to midline sternotomy, cardiopulmonary bypass at 34°C and 90 minutes of cardiac arrest. They received either a single shot of standard 4°C cold histidine-tryptophan-α-ketoglutarate (HTK)-Bretschneider solution (n = 11) or HTK-Bretschneider plus 1.2 mg/L CsA (histidine-tryptophan-α-ketoglutarate plus cyclosporine A (HTK/CsA); n = 11). During reperfusion global left-ventricular function was assessed and myocardial biopsies were harvested at baseline, during ischemia and 45 minutes following reperfusion. High-resolution respirometry and hydrogen peroxide production were measured. Immunohistochemical stainings for apoptosis-inducing factor and hypoxia-inducible factor-1α as well as a flow cytometry-based JC-1 mitochondrial membrane potential assay were performed.

Results: Hemodynamic parameters were comparable between both groups. The cytochrome C release (HTK: 930.3 ± 804.4 pg/mg, HTK/CsA: 699.7 ± 394.0 pg/mg, p = 0.457) as well as PGC1α content (HTK: 66.7%, HTK/CsA: 33.3%, p = 0.284) was lower in the HTK/CsA group. Respiratory measurements revealed that the oxygen flux under basal respiration was higher in the HTK/CsA group (8.2 ± 1.3 pmol·O2·s-1·mg-1·ww) than in the HTK group (3.8 ± 1.4 pmol·O2·s-1·mg-1·ww, p = 0.045). There were no significant differences regarding histological surrogates of apoptosis and necrosis.

Conclusions: Supplementing cardioplegic solutions with CsA enhances the basal mitochondrial respiration thereby exerting a cardioprotective effect and diminishing IRI-induced damage. CsA seems to preserve mitochondrial function via non-ROS related pathways.

Keywords: cardiac arrest; cardioplegia; cyclosporine A; ischemia-reperfusion injury; mitochondrial transition pore.

MeSH terms

  • Animals
  • Cardioplegic Solutions / pharmacology
  • Cardioplegic Solutions / therapeutic use
  • Cyclosporine* / pharmacology
  • Cyclosporine* / therapeutic use
  • Glucose / pharmacology
  • Heart Arrest, Induced
  • Histidine
  • Ischemia
  • Ketoglutaric Acids
  • Mannitol
  • Mitochondria / metabolism
  • Myocardial Reperfusion Injury* / drug therapy
  • Myocardial Reperfusion Injury* / metabolism
  • Myocardial Reperfusion Injury* / prevention & control
  • Potassium Chloride
  • Procaine / pharmacology
  • Respiration
  • Swine
  • Tryptophan

Substances

  • Cyclosporine
  • Histidine
  • Ketoglutaric Acids
  • Tryptophan
  • Cardioplegic Solutions
  • Mannitol
  • Potassium Chloride
  • Glucose
  • Procaine