ALPHA-1-Antitrypsin Preserves Cardiac Function and Reduces Damages Linked to Warm Ischemia/Reperfusion Injury in a Rodent Model of Cardiac Arrest and Resuscitation

Objectives: Pharmacological resuscitation therapies targeting warm ischemia/reperfusion injury (IRI) are absent in clinical practice. Recently α-1-antitrypsin (AAT), a protease inhibitor used for the treatment of pulmonary disease, has been identified as a potent drug with anti-inflammatory and immunomodulatory properties. Therefore, in the present study we aimed to investigate whether these beneficial properties of AAT might also reduce myocardial damage and IRI in a rat model of cardiac arrest and resuscitation.

Methods: The experiments were performed using male Lewis rats (300 ± 10 g) and a computer-controlled automated rodent resuscitation device. The rats were treated with either 0.9% NaCl vehicle (control group) or AAT (80 or 240 µg/kg groups) during cardiac arrest. After return of spontaneous circulation, the hemodynamic condition of the animals was stabilized by fluid administration. Then, after a 30-minute stabilization period, left-ventricular (LV) cardiac contractility was evaluated in vivo using a Millar microtip pressure-volume catheter. Additionally, immunohistochemical staining was performed for the nitro-oxidative stress markers nitrotyrosine and 4-hydroxy-2-nonenal. DNA-strand breaks were evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL).

Result: We found significantly increased LV contractility in both AAT groups compared with controls (P_max: 91.13 ± 2.91 vs. 96.37 ± 2.19 vs. 104.73 ± 1.48 mm Hg; dP/dt_max: 2,958 ± 205 vs. 3,372 ± 127 vs. 4,017 ± 107 mm Hg/sec; control vs. AAT 80 µg/kg vs. AAT 240 µg/kg; *p < 0.05 vs. control). Furthermore, AAT treatment significantly decreased the number of TUNEL-positive nuclei (control: 40.8 ± 13.1% vs. AAT 240 µg/kg: 22.8 ± 11.5%; *p < 0.05) in the AAT groups compared with controls.

Conclusion: Our findings show that AAT protects LV cardiac cells from warm IRI during resuscitation and hereby preserves myocardial contractile function. Therefore, AAT could be a promising candidate in pharmacologic resuscitation therapy.

Publication History

Article published online:
19 February 2021