Beta-Blockers Prevent The Terminal Engraftment Of Malignant Plasma Cells In Chronic Intermittent Hypoxia-Exposed Mice

Sleep apnea is a disorder that is characterized by long pauses between breaths due to airway obstruction or a lack of neural drive, resulting in chronic intermittent hypoxia (CIH). We previously showed that CIH promotes the terminal engraftment of a malignant plasma cell line in the bone marrow of the typically resistant C57BL6/J mouse strain. CIH increases sympathetic tone and we hypothesized that blocking adrenergic receptors would protect CIH-exposed mice from the lethal engraftment of malignant plasma cells. To test this hypothesis C57BL6/J mice were divided into two groups (n=10 each). One group received propranolol in their food and water to block beta-adrenergic receptors and the other group served as a control. The propranolol dosage was established to significantly reduce beta-adrenergic activity, as measured by heart rate and response to dobutamine. Mice were exposed to CIH for 10 hours a day (nadir 10% O2), 12 cycles per hour, for seven days, followed by tail vein injection with 1x106 5TGM1 plasma cells. After an additional 28-day exposure, mice were returned to normal housing and monitored daily for signs of terminal disease, including paralysis of the hind limbs. Mice that received propranolol in their diet had a significantly higher rate of survival (p= 0.03), suggesting that the sympathetic nervous system plays a critical role in supporting terminal engraftment of malignant cells in the bone marrow in the setting of intermittent hypoxia. Human retrospective studies suggest better outcomes in myeloma patients taking propranolol. Our results in a mouse myeloma model support the hypothesis that sympathetic activity activated by intermittent hypoxia contributes to myeloma pathogenesis.