Association between a non‐invasive assessment of frailty and vascular dysfunction in old mice

Abstract

Advancing age is characterized by not only an increased risk for cardiovascular diseases (CVDs), but also a decline in functional reserve and impaired adaptive capacity across multiple physiologic systems, also known as frailty. Impaired vascular function is a known contributor to CVDs and potentially has a role in increased frailty. In patients with overt disease, measures of frailty are related to vascular endothelial cell dysfunction. However, the relation between vascular endothelial function and frailty in a non‐disease population is unknown. It is also unknown if dysfunction of a particular vascular bed is more closely related to frailty.To examine the relation between vascular function and frailty in the context of similar genetics and environment, we studied wildtype C57BL/6 mice. In young (9 mo, n=7) and old (23–30 mo, n=27) male and female mice, we assessed endothelial‐dependent dilation (EDD) ex vivo in isolated, pressurized mesentery arteries and middle cerebral arteries (MCAs) by measuring the dilation to increasing doses of acetylcholine (ACh, 10−9 to 10−4 M) after pre‐constriction (by phenylephrine, 2 μM). Endothelium‐independent dilation (EID) was assessed by the dose response to sodium nitroprusside (SNP, 10−10 to 10−4 M) after pre‐constriction.Mouse frailty was assessed using a previously established non‐invasive 31‐item frailty index based on clinical signs of deterioration. Clinical assessments included evaluation of the integumentary, musculoskeletal, vestibulocochlear/auditory, ocular, nasal, digestive, urogenital, and respiratory systems as well as body weight, body surface temperature, and signs of discomfort. The severity of each deficit was assessed by two independent observers and assigned a value between 0–1, with a higher score indicating more severe frailty.Frailty index was ~6 fold greater in old compared with young mice (p<0.001). Maximal EDD was 16.1% lower in mesentery arteries (p=0.04) and 11.3% lower in MCAs (p=0.12) for old compared with young mice. Among the old mice, frailty index was correlated with mesentery artery maximal EDD (r=−0.53 p=0.002), and remained significant after controlling for age (partial correlation: r=−0.38, p=0.03). In contrast, there was no correlation between frailty index and MCA maximal EDD among old mice (r=0.16, p=0.21). Among old mice, there was no correlation between frailty index and maximal EID in mesentery arteries or MCAs (p>0.05).This study demonstrates that frailty, independent of age, is associated with mesentery artery endothelial dysfunction in wildtype, non‐diseased mice. However, it remains unknown whether the mesentery artery dysfunction is a cause or consequence of the greater frailty. Interestingly, we found a lack of association between frailty and cerebral artery endothelial function. Future research is needed to determine the mechanisms linking frailty and mesentery artery dysfunction.Support or Funding InformationFunded by NIH R56AG064016