Pancreatic cancer cachexia promotes cardiac dysfunction through altered adrenergic signalling 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 the sympathetic nervous system. However the impact of cachexia on cardiac adrenergic signalling 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 β1-adrenergic receptor (β1-AR) in the heart, along with evidence of increased adrenergic tone. Pharmacological blockade with the β1-selective antagonist metoprolol partially restored adrenergic responsiveness in PDAC mice, suggesting that elevated adrenergic drive contributes to β1-AR desensitization. The impaired β1-AR sensitivity blunted the chronotropic response to dobutamine and reduced inotropic reserve under adrenergic stress. Together these findings uncover disruption of cardiac adrenergic signalling in PDAC cachexia. KEY POINTS: Pancreatic cancer-associated cachexia promotes β1-adrenergic receptor desensitization in the heart. Pancreatic cancer-induced β1-adrenergic receptor desensitization is partly mediated by increased adrenergic transmission to the heart. β1-adrenergic receptor desensitization in mice with pancreatic cancer reduces contractile reserve under adrenergic stress.