An experimental study to determine the optimal pretreatment in cardiac surgery

M. Fujii¹, H. Yamashita¹, Y. Kaswase¹, R. Bessho¹, Y. Ishii^2
1Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba ²Nippon Medical School, Bunkyo, Tokyo

Purpose: Patients with HFrEF are currently treated with four drug combinations: angiotensin receptor/neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors, resulting in a reduction in mortality. In this study, we examined whether myocardial protection by esaxerenone or sacubitril/valsartan may be additive effect to that provided by cardioplegic arrest.

Methods: Male Wistar rats fed a normal diet were orally administered esaxerenone (3 mg/kg; Esax, n=6) or sacubitril/valsartan (68 mg/kg; SaV, n=6) dissolving in 0.5% methyl cellulose once a day for 2 weeks from 6 weeks of age. Age-matched, untreated male Wistar rats served as controls (Control; n=6). And then, isolated rat hearts were aerobically Langendorff-perfused with bicarbonate buffer and baseline function (e.g. heart rate; HR, left ventricular developed pressure; LVDP, coronary flow; CF) was measured. Hearts were subjected to 2 minutes of STH2 infusion and 28 minutes of normothermic global ischemia followed by 60 minutes of reperfusion. The recovery of function was measured during 60 minutes of reperfusion. In addition, troponin T was measured after reperfusion as myocardial injury.

Results: Before this protocol, systolic blood pressure (mmHg) in the Esax group, the SaV group, and the Control group were 117.0±6.1*, 104.7±5.9*, and 133.3±14.1, respectively (*: p< 0.05 v Control). Hearts from both the Esax group and the SaV group recovered rapidly to a significantly higher plateau level after 5 minutes, with no differences between these groups during reperfusion. The final recovery of LVDP (expressed as percentage of preischemic value) in the Esax group, the SaV group, and the Control group, were 68.5±7.4%*, 69.3±14.3%* and 50.7±6.2%, respectively (*: p< 0.05 v Control). At the onset of reperfusion, LVEDP was significantly elevated from baseline value in all groups, indicating of contracture development during ischemia. LVEDP declined in both the Esax group and the SaV group significantly lower level than that in the Control group. Troponin T (ng per gram wet weight) in the Esax group, the SaV group, and the Control group were 77.0±14.6*, 74.2±36.6*, and 166.8±78.1, respectively (*: p< 0.05 v Control).

Conclusion: Oral administration of esaxerenone or sacubitril/valsartan to rats beforehand for 2 weeks enhances the myocardial protection afforded by STH2, and it attenuates the myocardial injury evoked by cardioplegic arrest.

Identify the source of the funding for this research project: Grants-in-Aid for Scientific Research