South Asian adults with ASCVD exhibit a reduction in circulating vascular regenerative cell content compared to White European adults: a sub-analysis of the ORIGINS-RCE CardioLink-13 study

Abstract Background Compared to people of other races and ethnicities, South Asian (SA) adults are disproportionately affected by a higher burden of type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). We previously found that compared to individuals of White European (WE) descent with T2D, SA individuals with T2D exhibited profoundly less vascular regenerative (VR) cell content. Given that VR cells critically regulate vessel homeostasis, we postulated that the "vascular regenerative cell exhaustion" phenomenon we had observed may also contribute to the prevalence of ASCVD in SA populations. Purpose The ORIGINS-RCE CardioLink-13 study compared the frequencies of VR cells and cell types in individuals of SA and WE ethnicities with either 1) T2D and cardiovascular-risk factors or 2) documented ASCVD. This sub-analysis was conducted to determine if there are differences in the frequency of circulating VR cells and cell types in SA and WE individuals with ASCVD. Methods Among the 120 self-identified SA and WE adult participants (≥40 years of age), 23 SA and 41 WE individuals had ASCVD. Peripheral blood samples were processed for pro-inflammatory vs. pro-vascular progenitor cell enumeration as well as measurement of reactive oxygen species (ROS) production using a unique high aldehyde dehydrogenase (ALDHhi) activity-based flow cytometry assay in combination with side scatter properties (SSC) and lineage specific cell surface markers to identify progenitor cell populations. Results Compared to samples from the WE participants, the SA adults had a lower frequency of ALDHhiSSClowCD133+ (59% vs. 48%, P<0.001) cells and ALDHhiSSClowCD34+CD133+ (56% vs. 45%, P<0.001) progenitor cells with previously established pro-angiogenic properties. We also observed that SA participants had a decreased frequency of ALDHhiSSClowCD34+CD133+CD45- (0.0019% vs. 0.0005%, P<0.05) cells which may represent a rare population of circulating endothelial progenitor cells with vasculogenic functions. SA participants also exhibited a shift in monocyte polarization from a reparative phenotype towards a pro-inflammatory state, as demonstrated by a decrease in ALDHhiSSCmidCD14+CD163+ (86% vs. 78%, P<0.01) monocytes and an increase in ALDHhiSSCmidCD86+CD163- (8.2% vs. 13%, P<0.01) cells. There were no significant differences in the frequency of circulating granulocytes (ALDHhiSSChi cells) suggesting comparable inflammatory granulocyte burden between SA and WE adults, with no meaningful difference in intracellular ROS production in ALDHhi progenitor cell subsets, as previously observed in participants with T2D. Conclusions South Asian adults with ASCVD demonstrate a loss of vascular regenerative cells suggesting a compromised ability to repair damaged vessels which may contribute to their elevated cardiovascular risk.