The Clinical Associations and Physiological Mechanisms Linking Bone and Cardiac Health
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Abstract
Osteoporosis and cardiovascular disease represent two significant clinical burdens worldwide, which have been found to be clinically intertwined. The skeleton is highly sensitive to mechanical stimuli with osteocytes/osteoblasts sensing mechanical strain and activating bone remodeling. Bone is multifaceted exhibiting endocrine/paracrine functions and connections to the central nervous system through which it modulates a number of tissues including itself. During osteoporosis, bone cellular network integrity and the anabolic response to loading is compromised. Thus, the clinical associations of cardiovascular and skeletal health may be explained by crosstalk via bone-humoral and/or bone-neural mechanisms. To investigate the links among heart and bone health clinically, the impact of osteoporosis on cardiovascular disease patient outcomes was examined utilizing data from Cerner Health Facts. Next, cellular and animal studies were undertaken to determine the effects of bone cell-secreted molecules and in vivo bone mechanical loading on cardiac physiology. The Health Facts analysis revealed a significant association of history of osteoporosis with prolonged length of hospital stay, elevated NT-proBNP levels and greater mortality in patients admitted for cardiovascular disease. Men with a history of osteoporosis displayed worse overall outcomes for cardiovascular disease compared to women including remaining hospitalized for 1.02 days longer and having 2.13-fold higher mortality. In vitro studies showed that administration of conditioned media from bone cells exposed to fluid flow shear stress enhanced cardiomyocyte cell viability during CoCl2 treatment (p<0.05) and hypoxia/reoxygenation (p<0.05). In vivo, tibia mechanical loading in adult mice acutely and transiently lowered heart rate (p<0.01) and enhanced heart rate variability (p<0.01), which was mediated by neuronal afferents in the hindlimb and downregulated sympathetic nervous system tone. This cardiac response to loading was largely diminished by middle age. Daily tibia loading over three weeks in adult mice resulted in significantly lower resting heart rate (p<0.05) and higher heart rate variability (p<0.05) compared to non-loaded mice. These findings suggest that endocrine/neural pathways associated with bone mechanical loading may regulate cardiac physiology and link bone and cardiovascular health. Investigation of bone-heart crosstalk networks could aid in identifying novel therapeutic targets to improve standard of treatment for musculoskeletal and cardiovascular diseases.
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Introduction -- Review of literature -- Methodology -- Results -- Discussion
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Ph.D. (Doctor of Philosophy)