Low-dose esmolol attenuates sepsis-induced myocardial injury: association with improved autophagic homeostasis and PI3K/Akt signaling.

Abstract

Background: Sepsis-induced myocardial injury (SIMI) contributes substantially to sepsis mortality. We investigated whether low-dose esmolol is associated with improved autophagy-related homeostasis and restored PI3K/Akt phosphorylation in SIMI.

Methods: Human peripheral blood transcriptomic datasets (GSE28750, GSE232753, GSE134347, and GSE185263) and a rat septic myocardial dataset (GSE125042) were analyzed. Sprague-Dawley rats underwent cecal ligation and puncture (CLP) and received low-dose (5 mg·kg⁻1·h⁻1) or high-dose (15 mg·kg⁻1·h⁻1) esmolol infusion starting at 4h post-CLP. Autophagy was modulated with rapamycin, 3-methyladenine (3-MA), or chloroquine (CQ). Conscious hemodynamic monitoring, serial echocardiography, survival analysis, sepsis severity scoring, cardiac troponin I (cTnI) measurement, chamber-specific transmission electron microscopy, LC3/p62 co-localization, and TFEB subcellular localization were assessed. The unified endpoint was 18 h post-CLP.

Results: Bioinformatics analyses identified Akt1 and mTOR as hub genes and highlighted PI3K/Akt signaling as a candidate pathway associated with SIMI and esmolol response. Low AKT1 expression was associated with poorer survival in septic patients and showed moderate prognostic performance (AUC = 0.750). Rat myocardial transcriptomic data showed no transcriptional suppression of PI3K/mTOR components during sepsis. Sepsis suppressed PI3K/Akt phosphorylation, with p62 and LC3-II accumulation and TFEB cytoplasmic retention. Low-dose esmolol reduced tachycardia by 15-20% without hypotension, preserved left ventricular ejection fraction, lowered cTnI (1.36 to 0.14 ng/mL) and sepsis scores (18.50 to 8.50), and improved 144 h survival (P = 0.005). High-dose esmolol caused persistent hypotension and lacked survival benefit. Low-dose esmolol partially restored PI3K/Akt phosphorylation and enhanced TFEB nuclear translocation, reduced LC3/p62 co-localization, and ameliorated chamber-specific ultrastructural damage-mitochondrial swelling in the atrium and myofibrillar disarray in the ventricle-with findings suggestive of improved autophagosome-lysosome processing. CQ aggravated myocardial injury and autophagy-marker accumulation; low-dose esmolol partially attenuated CQ-induced deterioration. Direct quantitative measurement of autophagic flux and isoform-specific functional assays targeting PI3K were not conducted in the present study.

Conclusions: Low-dose esmolol was associated with restored PI3K/Akt phosphorylation, enhanced TFEB nuclear translocation, and improved autophagy-related homeostasis in a rat SIMI model. We propose a working model in which low-dose esmolol may coordinate PI3K/Akt signaling and TFEB-mediated lysosomal adaptation to alleviate septic myocardial injury. The causal relationship cannot be definitively validated in the absence of direct flux monitoring, pathway-specific loss-of-function experiments, and isoform-specific evidence. These findings provide preclinical support for further evaluating low-dose esmolol as a candidate adjunct therapy for septic cardiomyopathy.