Polypharmacy in mice disrupts left ventricular function and structure and promotes proteome reorganisation in an age- and sex-specific fashion

BACKGROUND AND PURPOSE: Most older people use polypharmacy (≥5 medications), particularly those with cardiovascular disease. The effects of polypharmacy on the cardiovascular system are not well described. We examined the effect of a chronic polypharmacy regimen on left ventricular (LV) function, structure and proteome in young and old mice of both sexes. EXPERIMENTAL APPROACH: Young (4 months) and old (23 months) C57BL/6JArc male and female mice were treated with an oral polypharmacy regimen (therapeutic doses of oxybutynin, oxycodone, citalopram, simvastatin and metoprolol) or control. Blood pressure and echocardiography were assessed after 4 and 9 weeks of treatment, respectively. After 10 weeks of treatment, LV histology and proteome was assessed. KEY RESULTS: Polypharmacy reduced heart rate in all groups, whereas its effect on LV structure varied by age and sex. Relative LV wall thickness increased, and LV diameter decreased with polypharmacy in older males, consistent with concentric hypertrophy. The LV proteome showed dysregulation in structural proteins, calcium handling proteins, metabolic enzymes and antioxidants. When comparing polypharmacy against age- and sex-matched controls, 195 unique differentially expressed proteins were identified, most in old males (141 proteins). Co-expression network analysis linked LV structural changes with expression of proteins involved in protein folding and trafficking and linked heart rate effects with desmosomal protein expression. CONCLUSIONS AND IMPLICATIONS: These findings suggest that, in mice, polypharmacy affected cardiac function and structure differently depending upon age and sex, with older males being the most affected. Further investigation may elucidate mechanisms and inform personalised medicine.