Insulin Resistance Compromises the Pentose Phosphate Pathway and Impairs Left Ventricular Assist Device-Mediated Myocardial Recovery in Obese Patients With Heart Failure.

Abstract

BACKGROUND: End-stage heart failure (HF) remains a major global health challenge, and left ventricular assist devices (LVADs) represent an important therapeutic option. LVAD-mediated mechanical unloading improves cardiac function and promotes myocardial recovery in many patients with HF; however, this recovery response is suboptimal in obese patients. The mechanisms by which LVAD-mediated unloading induces myocardial recovery, and how obesity alters these processes to blunt myocardial recovery, remain poorly understood. METHODS: Patients with HF receiving LVAD support were recruited to investigate the correlation between patients' body mass index and the myocardial recovery response following LVAD implantation. In parallel, a mouse model of heterotopic cervical heart transplantation was used to simulate LVAD-mediated cardiac unloading. Single-nucleus RNA sequencing and stable-isotope tracing metabolomics were performed to explore the changes of signaling pathways and metabolic processes in unloaded hearts. In vitro cyclic stretch assays were used to evaluate how reduced mechanical load regulates cardiomyocyte metabolic pathways. Unloaded hearts from HF mice were used to determine whether the identified metabolic processes contribute to unloading-induced myocardial recovery. Furthermore, the unloaded hearts from obese HF mice were used to evaluate whether these metabolic adaptations are attenuated by obesity. RESULTS: HF patients with a higher body mass index (≥28.0) and greater insulin resistance tended to have poorer LVAD-mediated myocardial recovery. Single-nucleus RNA sequencing showed that mechanical unloading activated myocardial insulin signaling and increased glucose uptake. Stable-isotope tracing metabolomics further revealed that glucose taken up by unloaded hearts was preferentially shunted into the pentose phosphate pathway. Mechanistically, reduced mechanical stress attenuated Hippo pathway activation in cardiomyocytes, facilitating insulin signaling and enhancing pentose phosphate pathway flux. In unloaded hearts from HF mice, increased pentose phosphate pathway flux could reduce oxidative stress and exert cardioprotective effects. However, these benefits were blunted by insulin resistance in obese mice, whereas treatment with insulin sensitizers alleviated insulin resistance and restored unloading-mediated cardioprotection. CONCLUSIONS: In failing hearts, mechanical unloading leads to activation of insulin signaling, resulting in increased glucose uptake and enhanced pentose phosphate pathway flux to protect cardiomyocytes against oxidative stress. However, this cardioprotective effect is attenuated by obesity-induced insulin resistance. Administration of insulin sensitizers has the potential to improve LVAD-mediated myocardial recovery in obese patients with HF.