Pancreatic cancer cachexia promotes cardiac dysfunction through altered adrenergic signaling in the heart

Cancer cachexia is a metabolic syndrome commonly observed in patients with pancreatic ductal adenocarcinoma (PDAC), characterized by wasting of skeletal and cardiac muscle. This condition is associated with the neurohormonal stress response and activation of sympathetic nervous system. However, the impact of cachexia on cardiac adrenergic signaling remains poorly understood. Here, we used a preclinical model of PDAC cachexia to investigate how sympathetic input to the heart is altered. We found desensitization of b1-adrenergic receptor in the heart along with some evidence of increased adrenergic tone. This led to impaired chronotropic reserve and increased vulnerability to adrenergic stress. Pharmacological blockade with the b1-selective antagonist metoprolol only partially restored adrenergic responsiveness in PDAC mice, suggesting an alternative mechanism drives b1-AR desensitization. These findings uncover a previously unrecognized disruption of cardiac adrenergic signaling in PDAC cachexia and identify beta blockers as a potential strategy to improve cardiovascular outcomes in patients with PDAC.