In a non-diabetic postinfarction population using a novel graphical exploratory data analysis tool, a subgroup of patients at high risk for recurrent coronary events was identified at high HDL-C and CRP levels. Subgroup patients had low levels of Lp-PLA2
and large HDL particles. These results parallel findings from a primary coronary events study (PREVEND) that also identified a high-risk subgroup at high HDL-C and CRP levels with presumptive evidence of large HDL particles [8
]. Thus in both primary and secondary coronary event studies, high-risk subgroups with large HDL particles have been identified at high levels of HDL-C and CRP. Unlike PREVEND [8
], the current study did not show a prominent high-risk subgroup at low HDL-C. This may relate to different pathophysiologic mechanisms underlying primary and secondary coronary risk development.
Further studies in the high-risk subgroup were performed with TaqIB, a functional CETP
polymorphism, to probe early stages of HDL metabolism. Genotype distributions in the study population were similar to values in healthy populations indicating absence of genotype-related survival effects for postinfarction patients [11
]. For blood markers, B2 allele carriers (less CETP activity) had higher levels of triglycerides and SAA. Multivariable modeling indicated only TaqIB (B2 allele carriers at higher risk) and high apoB levels as significant risk predictors. Support for TaqIB functional effects was suggested by genotypic differences in HDL subfraction distributions as a function of nonHDL-C (rough measure of cholesterol-acceptor particles). Further support resulted from correlation studies of Lp-PLA2
with HDL subfractions showing for B1 homozygotes cholesterol shift with higher Lp-PLA2
from large to small particle subfractions, especially to H3c,. This was consistent with the reported preferential association of Lp-PLA2
in HDL particles with the H3c subfraction [21
]. Such a shift was not seen in B2 allele-carriers.
The B2 allele (decreased CETP activity, increased HDL-C) associated with risk in the high-risk subgroup. Recent meta-analyses of TaqIB suggest lower B2-associated CVD risk [11
]; while other studies suggest higher risk [12
]. Such differences have been attributed to study type with population-based studies demonstrating high B2 allele-associated risk and high-risk population studies demonstrating low B2 allele-associated risk [12
It is of interest to note recent efforts to reduce CVD risk by raising HDL-C levels. There are striking similarities with current study findings and clinical trials with the drug, torcetrapib, [22
]. In both cases, CVD events were associated with raised HDL-C levels. While off-target effects of torcetrapib, especially increased blood pressure, could not be excluded as a factor [22
], this is irrelevant in the current study as reduced CETP activity was not by pharmacologic means. Indeed, a recent study comparing torcetrapib and the B2 allele revealed concordant effects on blood lipids and lipoproteins but increased blood pressure only for torcetrapib [15
]. The current approach allows identification of high-risk individuals embedded in larger patient populations. Excluding such patients may allow validation of the use of such drugs in selected populations.
We believe that B2 allele-associated risk derives in some part from pro-atherogenic transformation of HDL [9
]. Although our finding of differential effects on HDL subfraction distributions in B2 allele carriers versus B1 homozygotes as a function of nonHDL-C demonstrated interaction of TaqIB genotypes with a measure of cholesterol-acceptor particle levels, definitive conclusions regarding a potential role for impaired HDL particle remodeling in the establishment of B2-associated risk were not possible from such results as neither CETP mass nor activity were actually measured. The inflammatory environment and CETP activity could have direct effects on HDL as well as indirect effects involving prolonged residence time of altered HDL in the inflammatory milieu of the high-risk subgroup [9
]. Alterations of HDL constituents could potentially result especially for apoA1, paraoxonase, Lp-PLA2
, lecithin:cholesterol acyl-transferase (LCAT), and SAA [9
]. Consistent with this notion are our findings in the high-risk subgroup of lower levels of Lp-PLA2
; and in B2 allele carriers higher levels of SAA, an apolipoprotein closely associated with HDL [31
]. High SAA levels displace apoA1 in HDL resulting in loss of apoA1 functionality and impaired activity of LCAT, paraoxonase, and also Lp-PLA2
] (especially notable in view of our finding of lower Lp-PLA2
in the high-risk subgroup). That lower Lp-PLA2
levels were associated with the high-risk subgroup contrary to the generally held belief that high Lp-PLA2
levels are pro-atherogenic may be reflective of the notion that Lp-PLA2
in LDL is pro-atherogenic; whereas Lp-PLA2
in HDL is anti-atherogenic [21
]. Other pro-atherogenic effects of SAA on HDL include increased cholesterol delivery to vascular walls as SAA-enriched HDL binds strongly to vascular proteoglycans facilitating cholesterol retention and further HDL alteration [31
Study limitations included lack of direct evidence of impaired HDL particle remodeling in association with the B2 allele. Also, no direct evidence was provided on the role of inflammation in dysfunctional HDL although high SAA in B2 carriers was highly suggestive. Additional risk factor data (exercise, diet, ethanol, mental status, and social support) were lacking. Specifically focused future studies could be oriented at addressing all these issues as well as replicating current study findings. Strengths of the study included use of an exploratory data analysis tool that can identify risk-based subgroups anywhere in a bivariate risk domain.
Study results demonstrate that high levels of HDL-C and CRP define a subgroup of postinfarction patients at high risk for recurrent coronary events. Additionally, the B2 allele of the TaqIB polymorphism of CETP was demonstrated to be associated with recurrent events in the high-risk subgroup. Future studies should aim to examine specific mechanisms leading to HDL dysfunction and to characterize resultant particles. Such patients should be considered in future drug trials involving raising HDL-C levels as this could aid in validating valuable approaches by excluding such patients.
A subgroup of postinfarction patients at high risk for recurrent coronary events was identified at high HDL cholesterol and high C-reactive protein levels. Within the subgroup, the TaqIB polymorphism of CETP, well-known to demonstrate differences in transfer protein activity, was found to be associated with recurrent risk.