HDL‐3 is a Superior Predictor of Carotid Artery Disease in a Case‐Control Cohort of 1725 Participants

Kim, Daniel S.; Burt, Amber; Rosenthal, Elisabeth; Ranchalis, Jane; Eintracht, Jason F.; Hatsukami, Thomas S.; Furlong, Clement E.; Marcovina, Santica M.; Albers, John J.; Jarvik, Gail P.

doi:10.1161/jaha.114.000902

Cited by 38 publications

(34 citation statements)

References 52 publications

(69 reference statements)

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“…Functional aspects of the HDL-P not captured by HDL-C measures may explain the recent failures of interventions to raise HDL-C to prevent CVD mortality ( 8,15 ). Of the many functional aspects of HDL, one of the most promising is RCT, whereby lipids are removed from peripheral cells and atherosclerotic plaque by HDL-borne association between PLTPa and acute CVD ( 37,62 ) refl ect sampling of subjects already with signifi cant atherosclerotic disease, and therefore, higher PLTPa, which may be a consequence of the underlying pathophysiological processes or a compensatory change.…”

Section: Discussionmentioning

confidence: 99%

“…The study population is a subset (n = 1,115) of the previously described CLEAR study ( 8,(10)(11)(12)(40)(41)(42)(43)(44)(45)(46)(47) PLTP region SNP associations with PLTPa. SNPs with у 1% frequency identifi ed in the PLTP region between 50 kb upstream of the fi rst codon or downstream of the last (n = 124 SNPs) were included in our analyses of the genetic predictors of PLTPa.…”

Section: Samplementioning

confidence: 99%

“…To help identify the specifi c components of HDL responsible for cardioprotection, we have found that the HDL3 subfraction is the superior predictor of carotid artery disease (CAAD) when compared with HDL2, HDL-C, or apoA1 ( 8 ), and that this association is independent of the HDL3-associated ( 9 ) and cardioprotective ( 10-13 ) paraoxonase 1 (PON1) enzyme activity ( 8 ). Other work has determined that concentrations of the medium-sized (but not small or large) HDL-Ps differ signifi cantly between CAAD cases and controls, and that medium HDL-P concentration is highly correlated with HDL3 ( 14,15 ).…”

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confidence: 99%

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PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Kim

Burt

Ranchalis

et al. 2015

Journal of Lipid Research

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Cholesterol carried on HDL (HDL-C) has long been believed to be cardioprotective, based on consistent epidemiologic fi ndings of an inverse relationship between incident CVD and HDL-C levels in subjects healthy at baseline ( 1, 2 ). Estimates from the Framingham Heart Study found that risk of myocardial infarction (MI) increased by 25% for each 5 mg/dl decrease in HDL-C below median values of HDL-C for both healthy men and women ( 2 ). Similar fi ndings of the cardioprotective effects of HDL-C have also been reported in subjects with CVD at baseline ( 3 ).In confl ict with these epidemiologic fi ndings, recent attempts to establish a causal relationship between HDL-C Abstract Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a casecontrol study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A fi nal stepwise regression considering both nongenetic and genetic variables identifi ed the combination of covariates that explained maximal PLTPa variance. PLTPa was signifi cantly associated with CAAD (7.90 × 10 ؊ 9 ), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels ( P = 0.0042), diabetes ( P = 7.28 × 10 ؊ 5 ), paraoxonase 1 (PON1) activity ( P = 0.019), statin use ( P = 0.026), PLTP SNP rs4810479 ( P = 6.38 × 10 ؊ 7 ), and PCIF1 SNP rs181914932 ( P = 0.041) were all signifi cantly associated with PLTPa. PLTPa is signifi cantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of

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Section: Discussionmentioning

confidence: 99%

Section: Samplementioning

confidence: 99%

mentioning

confidence: 99%

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PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Kim

Burt

Ranchalis

et al. 2015

Journal of Lipid Research

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“…In fact, several previous studies have shown that small dense HDL subspecies (i.e., HDL3 subclass), besides their role in reverse cholesterol transport, show additional properties, such as antioxidant, anti-inflammatory, cytoprotective, anticoagulant, and anti-infectious properties, not exhibited by large light HDL (18). This increased value of HDL3 in atheroprotection has been recently supported by several epidemiological studies that have shown an inverse association of HDL3 and not HDL2 with disease progression and clinical event presentation (66,67). Interestingly, both enzymes, LCAT and PON1, have been shown to inhibit LDL oxidation in the absence of HDL and to enhance the antioxidant activity of HDL (68).…”

Section: Discussionmentioning

confidence: 89%

ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia

Cubedo¹,

Padró²,

Alonso

et al. 2016

Journal of Lipid Research

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Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders associated with premature coronary artery disease (CAD) (1). This disorder appears by mutations in the gene that encodes the LDL receptor (LDLR) and it is characterized by a lifelong exposure to high plasma LDL-cholesterol levels (LDL-C). FH patients show an important decrease in their life expectancy because of an increase in CAD frequency, the principal causes of mortality being sudden death and myocardial infarction (2). Clinical expression of CAD in FH patients varies considerably across cohorts and individual patients treated to guidelines (3, 4), suggesting the contribution of additional factors to the atherosclerotic burden in these patients. Indeed, a recent study has reported lipoprotein (a) [Lp(a)] levels as one of those additional factors that influence CVD in FH patients (5).HDLs have proved to be atheroprotective in several epidemiological, clinical, and experimental studies (6-13). Indeed, HDLs are considered key players in the progression of CAD because of their multiple antiatherogenic effects (14) in addition to their role in reverse cholesterol transport. Increasing evidence suggests that HDL atheroprotective effects lie in HDL composition, highlighting the importance of HDL quality rather that HDL quantity in CVD (14-17). Moreover, the existence of several HDL subpopulations with differential contribution to these HDL-related antiatherogenic properties has underscored the relevance of HDL composition in HDL functionality (15,18).A recent study has demonstrated that FH is associated with quantitative and qualitative modifications of HDL Abstract HDL composition rather than HDL-cholesterol (HDL-C) levels seems to be a key determinant of HDL-induced atheroprotection. Heterozygous familial hypercholesterolemia (FH) patients, with lifelong exposure to high LDL levels, show a high prevalence of premature coronary artery disease. We hypothesized that HDL of FH patients might have a modified protein composition and investigated the proteomic signature of HDL obtained from FH patients and their unaffected relatives. HDLs were characterized by 2D electrophoresis/MS in 10 families from the SAFE-HEART cohort (3 individuals/family: 2 with genetic FH diagnosis and 1 non-FH relative) clinically characterized and treated as per guidelines. FH patients had lower apoA-I levels and a differential HDL distribution profile of apoL1 and apoA-IV. ELISA validation revealed decreased apoL1 serum levels in FH patients. ApoL1 levels were able to predict presentation of an ischemic cardiac event, and apoL1/HDL-C ratio was associated with the survival rate after the event. FH patients who died because of a fatal cardiac event had lower apoL1 and LCAT content in HDL3 an average of 3.5 years before the event than those who survived. Changes in HDL protein composition could affect patients' prognosis. The proteomic profile of apoL1 is modified in HDLs of high cardiovascular risk patients, and apoL1 plasma levels are significantly lower in serum...

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“…33 Evidence from the National Heaert, Lung and Blood Institute Exome Sequencing Project reported a PON1 V109I variant that decreases PON1 arylesterase and increases ischemic stroke risk. 34 In contrast to the PON1 organophosphate activity assays, numerous studies used PON1 single nucleotide polymorphisms that predict organophosphate activity assays as proxies for PON1 function and failed to show mendelian randomization evidence of PON1 with CVD.…”

Section: Genetic Epidemiology: Hdl Particlesmentioning

confidence: 99%

The High-Density Lipoprotein Puzzle

Rosenson

2016

ATVB

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High-density lipoprotein (HDL) cholesterol is a robust biomarker of atherosclerotic cardiovascular disease (CVD) events. In observational studies and many clinical trials of statin therapy, HDL cholesterol levels are inversely associated with CVD events. In the Emerging Risk Factors Collaboration that included 302,430 participants enrolled in 68 long-term prospective studies, for every 15 mg/dL increase in HDL cholesterol, the hazard ratio for coronary heart disease (CHD) events was 0.71 (95% confidence interval: 0.68-0.75) in models that were stratified by sex and trial group and further adjusted for age, systolic blood pressure, smoking status, history of diabetes mellitus, and body mass index.1 These associations remained significant in models that included triglycerides and non-HDL cholesterol.Low levels of HDL cholesterol are inversely associated with apolipoprotein B-containing lipoproteins; thus, HDL cholesterol has been considered no more than a biomarker for atherogenic lipoproteins. Several studies have investigated the association between HDL cholesterol, atherogenic lipoproteins, and CVD. [2][3][4] In multivariate models that include apolipoprotein B or low-density lipoprotein (LDL) particle concentration, HDL cholesterol was not associated with increased cardiovascular risk. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) that included study participants with low levels of HDL cholesterol (men <45 mg/dL and women <47 mg/dL) and nonelevated triglycerides (<400 mg/dL), the risk of future CHD events was linearly associated with baseline and 6-month levels of apolipoprotein B but not with HDL cholesterol. 4 These analyses indicate that low levels of HDL cholesterol are not associated with CVD events after adjustment for atherogenic lipoprotein concentrations.

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HDL‐3 is a Superior Predictor of Carotid Artery Disease in a Case‐Control Cohort of 1725 Participants

Cited by 38 publications

References 52 publications

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia

The High-Density Lipoprotein Puzzle

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