High HDL-Cholesterol Paradox: SCARB1-LAG3-HDL Axis

Abstract

Purpose of the Review To evaluate recent studies related to the paradox of high HDL-C with mortality and atherosclerotic cardiovascular disease (ASCVD) risk. Recent Findings Two observational studies (Cardiovascular Health in Ambulatory Care Research Team [CANHEART] and Copenhagen City Heart Study and the Copenhagen General Population Study [Copenhagen Heart Studies]) of adults without pre-existing ASCVD have shown a significant U-shaped association of HDL-C with all-cause and cause-specific mortality. Both studies showed that low HDL-C levels consistently increased hazard risk (HR) for all-cause and cause-specific mortality. In the CANHEART study, high HDL-C levels, HDL-C > 90 mg/dL, were associated with increased HR for non-CVD/non-cancer mortality. In the Copenhagen Heart Studies, women with HDL-C ≥ 135 mg/dL showed increased HR for all-cause and CVD mortality, while men with HDL-C > 97 mg/dL showed increased HR for all-cause and CVD mortality. Genetic association studies failed to show that genetic etiologies of high HDL-C significantly reduced risk for myocardial infarction (MI), while hepatocyte nuclear factor-4 (HNF4A) was significantly associated with high HDL-C and increased MI risk. Candidate gene studies have identified scavenger receptor B class I (SCARB1) and lymphocyte activation gene-3 (LAG3) as genes significantly associated with high HDL-C and increased MI risk. Summary Low HDL-C remains as a significant factor for increased disease risk while high HDL-C levels are not associated with cardioprotection. Clinical CVD risk calculators need revision.

Particles and corrected particles of LDL and non-HDL are stronger predicters of coronary lesion in postmenopausal women

“…In the ROCs, we found HDL-C was the traditional blood lipid item with the weakest predictive ability for CHD, with the AUC under 0.50. It was consistent with the current view of the relationship between HDL and CHD [ 27 ]. In the comparison of predictive abilities between traditional and advanced lipid items, the predictive abilities of LDL-p, LDL-p-corr, non-HDL-p and non-HDL-p-corr were significantly stronger than the traditional lipid items, LDL-C and non-HDL-C. That indicated the particles of LDL and non-HDL may be better lipid indexes in CHD prevention.…”

Understanding LAG-3 Signaling

“…LAG-3 protein expression levels have been significantly associated via transcriptomic studies with high HDL cholesterol (HDL-C) and HALP (HDL-C ≥ 60 mg/dL). Indeed, LAG-3 deficiency altered lipid raft formations and cell phosphosignaling, processes leading to an enhanced proinflammatory state, and increased production of inflammatory cytokines such as TNFα [97,98].…”

SR-B1, a Key Receptor Involved in the Progression of Cardiovascular Disease: A Perspective from Mice and Human Genetic Studies

“…The available data propose that plasma HDLc levels are not an optimal therapeutic target and that the quality of the HDL particles circulating in plasma could be more critical for therapeutic interventions than HDLc concentration [14], since high HDLc levels may not always be protective against CVD [95,106]. In fact, European Society of Cardiology and European Atherosclerosis Society Guidelines for the Management of Dyslipidaemias [107] do not recommend HDLc as a target for treatment.…”