Background: Atherosclerotic cardiovascular disease (ASCVD) susceptibility is influenced by the flux of bone marrow-derived vascular regenerative (VR) cells. Regenerative cell exhaustion (RCE) can shift the balance toward impaired vessel repair. We hypothesized that South Asian (SA) individuals, compared to White Europeans (WE), may exhibit impaired VR flux as a mechanism of atherosclerosis.
METHODS AND RESULTS: We performed an analysis of prospectively collected data from 165 individuals of self-reported SA and WE background from the IPE-PREVENTION and ORIGINS-RCE studies with prevalent ASCVD or Type 2 Diabetes (T2D). Venous blood was processed to enumerate VR cell content using a high throughput flow cytometry assay based on high aldehyde dehydrogenase (ALDHhi) activity as a marker of cell differentiation and cell surface marker phenotyping. The primary outcome was the difference in frequency of circulating ALDHhi progenitor cells, ALDHhi monocytes, and ALDHhi granulocytes between SA and WE. RCE and VR flux was also compared across the spectrum of T2D and ASCVD risk. Analysis was also performed in high risk T2D patients defined as diagnosis of T2D and >2 cardiovascular risk factors (documented ASCVD, hypertension, dyslipidemia, smoking, or eGFR 30-60 mL/min/1.73m2). 75% of the population were males, and in comparison, to the WE cohort, the SA cohort was younger, had lower BMI, but higher prevalence of T2D. SA (vs. WE) exhibited lower ALDHhi progenitor cell content. This was observed for the ALDHhiSSClow population (pro-angiogenic secretome) and ALDHhiSSCmid (regulating pro-inflammatory vs. pro-arteriogenic polarization). Frequencies of ALDHhiSSChi (granulocyte proinflammatory propagators) were comparable between SA and WE. SA exhibited a lower count of ALDHhiSSClow progenitor cells with the pro-vascular (CD133+CD34+) phenotype, lower frequencies of monocyte precursors with vessel regenerative polarization (ALDHhiSSCmidCD14+CD163+) and higher frequencies of cells with pro-inflammatory polarization (ALDHhiSSCmidCD86+CD163–). These differences persisted in models of multiple linear regression. VR flux was similar in low-risk T2D between SA and WE. SA with high risk T2D exhibited markedly greater RCE compared to WE.
Conclusion: We demonstrate that defects in VR flux, independent of conventional risk factors, are observed in people of SA vs. WE descent. Our data specifically point towards RCE that affects angiogenic capacity and ischemia-induced collateralization pathways. Furthermore, SA (vs. WE) with high risk T2D exhibit a severe RCE phenotype. These data provide a translational framework for heightened vascular risk in SA populations.
