Human Atherogenesis with Underlying Dysfunctional HDL-Free Cholesterol - Atherosclerotic cardiovascular disease (ASCVD) and plasma high-density lipoprotein cholesterol (HDL-C) are negatively correlated. One model assigns this correlation to the role of HDL as an acceptor of free cholesterol (FC) transfer from arterial-wall macrophages (FC efflux), and in some studies, FC efflux better predicted ASCVD than HDL-C concentration. However, interventions that increase plasma HDL failed to reduce ASCVD, and, paradoxically, several studies revealed higher ASCVD mortality among patients with very high HDL. The source of this paradox is unknown, appropriate therapies have not been formulated, and in this context, the role of the reverse process, HDL-FC influx, which may be supported by excess HDL-FC, is unknown. Mice deficient in the HDL-receptor, Scarb1-/- mice, are a robust model of the human high-HDL phenotype. Compared to wild-type mice, Scarb1-/- mice are more athero-susceptible and have higher plasma levels of HDL that is more FC-rich. This produces a state of high HDL-FC bioavailability, which we express as an index: HDL- FCBI = HDL particle number (HDL-P) x mol% HDL-FC. This conceptually new metric was first reported by this study team, which reported that HDL-FCBI increases as wild-type mice < human << Scarb1-/- mice and that more FC transfers from HDL from Scarb1-/- vs. wild-type mice to macrophages. Thus, we hypothesize that similar mechanisms underlie ASCVD among humans with very high plasma HDL-C. Our goal is to compare patients with positive (CACS>0) and negative (CACS=0) coronary artery calcium scores respectively assigned as ASCVD and non-ASCVD in three subgroups—those with high (HH), intermediate (IH), or optimal (OH) plasma HDL-C concentrations—and test whether ASCVD is associated with a high HDL-FCBI. According to our hypothesis, a) HDL-FCBI will be higher among HH vs. OH patients and among ASCVD vs. non-ASCVD patients, especially those with high plasma HDL-C, and b) the magnitude of FC transfer from HDL from ASCVD patients to macrophages will be greater than that from HDL from non-ASCVD patients, again especially among ASCVD patients with high plasma HDL-C. This hypothesis is supported by studies of Scarb1-/- mice in which a component of HDL-FCBI is reduced and with it, ASCVD—reducing HDL-P with probucol or mol% HDL-FC by increased FC esterification suppressed ASCVD. Comparison of CACS vs. HDL- FCBI of all three groups will reveal a non-linear functional relationship. Traditionally, physicians have measured HDL and LDL in terms of their total cholesterol content. These measures have had good but imperfect predictive value, mainly because the two components of TC, FC and cholesteryl esters, have distinct metabolic itineraries that may differentially contribute to ASCVD. Validation of the study-hypotheses in humans would provide a compelling rationale for measuring plasma lipoprotein FC as an ASCVD diagnostic and for the formulation of therapies that reduce plasma- and especially HDL-FC.
