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Vascular regenerative deficiencies in people with elevated lipoprotein(a): the Lp(a)-VRCE CardioLink-16 translational
Michael Moroney1,2, Jack H Casey1,2, Hwee Teoh1,3,4
1Division of Cardiac Surgery, St Michael's Hospital of Unity Health Toronto, 30 Bond Street, Toronto, ON, Canada M5B 1W5.
Insights
Elevated Lipoprotein(a) [Lp(a)] levels are linked to fewer vascular regenerative (VR) cells and more pro-inflammatory cells. This suggests compromised vessel repair in individuals with high Lp(a), a risk factor for atherosclerotic cardiovascular disease (ASCVD).
Area of Science:
- Cardiovascular Science
- Regenerative Medicine
- Immunology
Background:
- Lipoprotein(a) [Lp(a)] is a known causal risk factor for atherosclerotic cardiovascular disease (ASCVD).
- Depletion of vascular regenerative (VR) progenitor cells indicates compromised vascular repair in cardiometabolic disorders.
- The impact of elevated Lp(a) on VR cell properties is not well understood.
Purpose of the Study:
- To investigate if elevated Lipoprotein(a) [Lp(a)] levels affect vascular regenerative (VR) cell content and properties.
- To determine the relationship between Lp(a) levels and the cellular mechanisms of vascular repair.
Main Methods:
- Cross-sectional study (CardioLink-16) of 40 individuals, comparing 20 with Lp(a) ≥100 nmol/L and 20 with Lp(a) <100 nmol/L.
- Analysis of peripheral blood mononuclear cells using multi-parameter flow cytometry to identify VR progenitor cells (high ALDH activity).
- Assessment of cell surface markers to differentiate primitive vs. mature cells and inflammatory monocyte polarization.
Main Results:
- Individuals with Lp(a) ≥100 nmol/L had significantly lower frequencies of pro-angiogenic VR progenitor cells (ALDHhiSSClowCD133+ and ALDHhiSSClowCD34+CD133+).
- The high Lp(a) group showed a higher frequency of M1-polarized pro-inflammatory monocytes (ALDHhiSSCmidCD86+CD163-).
- A lower frequency of granulocyte precursor cells (ALDHhiSSChiCD49d+) involved in vessel repair was observed in the high Lp(a) group.
Conclusions:
- Elevated Lp(a) levels (≥100 nmol/L) are associated with a reduced number of vascular regenerative (VR) cells.
- Individuals with high Lp(a) exhibit an increased proportion of pro-inflammatory monocyte precursor cells.
- These cellular changes suggest that vascular repair capacity may be impaired in individuals with elevated Lp(a).
Aims:
Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD); however, the relationship between Lp(a) and the capacity for vascular repair remains unclear. Depletion of vascular regenerative (VR) progenitor cells has been shown to be a novel indicator of compromised vascular repair in people living with cardiometabolic disorders. The purpose of this study was to determine if elevated levels of Lp(a) modify VR cell content properties.
Methods And Results:
The cross-sectional, multi-site Lipoprotein(a) and Vascular Regenerative Cell Content CardioLink-16 [Lp(a)-VRCE] study enrolled 40 individuals-20 with Lp(a) ≥100 nmol/L and 20 with Lp(a) <100 nmol/L. Isolated peripheral blood mononuclear cells were analysed by multi-parameter flow cytometry. VR progenitor cells were identified based on high aldehyde dehydrogenase (ALDH) activity, in combination with primitive vs. mature lineage-specific cell surface markers. The Lp(a) ≥100 nmol/L group exhibited baseline characteristic differences compared with the Lp(a) <100 nmol/L group such as lower estimated glomerular filtration rate (86.9 vs. 100.1 mL/min/1.73 m2), lower total cholesterol (4.0 vs. 4.8 mmol/L), greater statin use (90 vs. 60%), and a higher prevalence of ASCVD (60 vs. 25%). The Lp(a) ≥100 nmol/L group had lower frequencies of pro-angiogenic ALDHhiSSClowCD133+ (P = 0.0008) and ALDHhiSSClowCD34+CD133+ (P = 0.005) progenitor cells with pro-angiogenic secretory function. Compared with those in the Lp(a) <100 nmol/L group, individuals in the Lp(a) ≥100 nmol/L group demonstrated a higher frequency of M1-polarized pro-inflammatory monocytes (ALDHhiSSCmidCD86+CD163-; P = 0.007) and a lower frequency of ALDHhiSSChiCD49d+ granulocyte precursor cells (P = 0.04) that are involved in vessel repair.
Conclusion:
In this translational study, people with an Lp(a) ≥100 nmol/L had fewer VR cells and more pro-inflammatory polarized monocyte precursor cells than those with Lp(a) levels <100 nmol/L. These findings suggest that vessel repair activities may be compromised in individuals with elevated Lp(a) levels.
Registration:
Lp(a)-VRCE ClinicalTrials.gov: NCT06626659.
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