People living with lower extremity peripheral artery disease demonstrate vascular regenerative cell deficiencies: The PAD-VRCE CardioLink-17 study.

OBJECTIVE

Vascular regenerative cell exhaustion (VRCE), a shift in the circulating progenitor cell profile, has been linked with adverse cardiometabolic outcomes. Whether VRCE is also involved in the pathogenesis and vascular repair mechanisms of peripheral artery disease (PAD) is unknown. In this study, we sought to compare the circulating vascular regenerative cell content of adults living with PAD with those without PAD.

METHODS

PAD-VRCE CardioLink-17 (NCT06626646) was an observational cross-sectional study of 20 adults with symptomatic PAD and 20 without PAD. Circulating progenitor cell profiles were documented using a multiparametric flow cytometry assay based on the differential expression of aldehyde dehydrogenase activity in provascular progenitor cells combined with primitive and/or lineage-specific hematopoietic or endothelial cell markers.

RESULTS

Individuals with PAD had a median (range) ankle brachial index of 0.82 (0.35-0.84). The two groups were well-matched for age and gender, but individuals with PAD had higher rates of dyslipidemia, higher weight, and blood pressure. Those with PAD had fewer circulating ALDHhiSSClowCD133+ (44.0 ± 3.4% vs 49.7 ± 3.0%; P < .001) and ALDHhiSSClowCD34+CD133+ (42.5 ± 4.9% vs 49.0 ± 4.9%; P < .001) cells, representing rare multipotent myeloid progenitors with vessel repair function. Individuals with PAD also had fewer ALDHhiSSCmidCD86+CD163- monocytes (2.5 ± 2.4% vs 4.1 ± 2.1%; P = .001), indicating a reduced monocytic contribution to systemic inflammation. By contrast, participants with PAD exhibited a higher frequency of ALDHhiSSChi granulocyte precursors (0.48 ± 0.4% vs 0.22 ± 0.1%; P = .008), the primary drivers of systemic inflammation.

CONCLUSIONS

Our findings provide evidence of a novel association between PAD and the well-documented VRCE phenotype. Accordingly, reversal of VRCE may represent a potential therapeutic target in patients with PAD.

CLINICAL RELEVANCE: Vascular regenerative cell exhaustion may contribute to peripheral artery disease and may represent a novel and viable therapeutic opportunity for peripheral artery disease.