HDL Efflux Capacity and Incident Cardiovascular Events in the Dallas Heart Study A Rohatgi,* A...
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Transcript of HDL Efflux Capacity and Incident Cardiovascular Events in the Dallas Heart Study A Rohatgi,* A...
HDL Efflux Capacity and Incident Cardiovascular Events
in the Dallas Heart Study
A Rohatgi,* A Khera, JD Berry, EG Givens, CR Ayers, KE Wedin, IJ Neeland, IS Yuhanna, DJ
Rader, JA de Lemos, PW Shaul*corresponding author
Donald W. Reynolds Cardiovascular Clinical Research Center
0%
5%
10%
15%
20%
25%
0 1 2 3 4Years
Niaspan
Placebo
CETPI
A H T D
AIM-HIGH
HPS2
DalcetrapibTorcetrapib
Drug Class
TrialHDL-C change
NIACIN
AIM-HIGH 25%
HPS2-THRIVE
15%
CETPI
Torcetrapib 72%
Dalcetrapib 35%
Boden WE, et al. NEJM 2011;365:2255-67Barter PJ, et al. NEJM 2007;357:2109-22
Schwartz GG, et al. NEJM 2012;367:2089-99HPS2-THRIVE. NEJM 2014;371:203-12
Rader DJ, Hovingh GK. Lancet 2014;384:618-625
HDL Function: Reverse Cholesterol Transport
apoA-I
apoA-I
apoA-I
ABCA1
ABCA1
ABCG1
SRB1
VLDL
Cholesterol efflux
Adorni MP, et al. J Lipid Res 2007;48:2453-62
Macrophage
Liver
Bile/Feces
Khera AV, et al. NEJM 2011;364:127-35
Study Objective
Objective: Perform a systematic evaluation of the epidemiology of cholesterol efflux capacity in a large unselected population free of cardiovascular disease
.
Hypothesis: Cholesterol efflux capacity varies by sex, race and adiposity and is associated with incident cardiovascular events
Baseline
Follow up
9.4 years
Metabolic phenotype
Cholesterol Efflux Capacity
ASCVD (n=132): MI/Stroke
PCI/CABG CV Death
N = 2924
Age = 30-65 (median 42)
57% Women
49% Black
Dallas Heart Study
Lipoprotein composition
Methods
ACAT inhibitor
cAMP
% effluxApoB-depleted plasma
Total
Normalized efflux
% effluxsample
% effluxreference
Cholesterol Efflux
Capacity
Sankaranarayanan S, et al. J Lipid Res 2011;52:2332-40
NHDL Cholesterol
(mg/dL)Cholesterol Efflux Capacity
(Normalized)
Women 1657 51 [43-61] 0.99 [0.83-1.18]
Men 1267 44 [37-52] 1.01 [0.84-1.20]
p-value <0.0001 0.1
Black 1443 49 [42-60] 0.98 [0.81-1.18]
Non-Black 1481 45 [38-55] 1.01 [0.85-1.19]
p-value <0.0001 0.002
Cholesterol efflux capacity is expressed as a ratio of percent cholesterol efflux of the sample normalized to the percent cholesterol efflux of a reference sample.
HDL-C and Efflux by Sex and Race
Determinants of HDL-C and Efflux
HDL Cholesterol Cholesterol Efflux Capacity
Model R2 = 0.35 Model R2 = 0.03
VariableStd beta estimate
VariableStd beta estimate
Total cholesterol 0.22 Total cholesterol 0.12
Alcohol intake 0.18 HDL-C 0.09
Age 0.13 Male sex 0.05
Exercise dose 0.08 Hypertension 0.04
Black race 0.07 Alcohol intake 0.03
Smoking -0.06 Black race -0.07
Waist to hip ratio -0.08
Body mass index -0.17
Male sex -0.23
Log Triglyceride -0.39 Model R2 reflects the total contribution of the model to the variance in the dependent variable (range 0.0-1.0).
HDL CholesterolCholesterol
Efflux Capacity
HDL Cholesterol 0.07*
HDL Particle concentration 0.52* 0.15*
HDL Particle size 0.72* 0.02
Total Cholesterol 0.06* 0.15*
LDL Cholesterol -0.15* 0.10*
Triglyceride -0.45* 0.05*
Body Mass Index -0.23* -0.02
Waist to Hip Ratio -0.38* 0.02
Truncal Fat (Dexa) -0.20* 0.004
Visceral Fat (MRI) -0.41* 0.03
HOMA-IR -0.29* -0.05*Values are Spearman correlation coefficients. * p<0.05, otherwise p=NSCEC=cholesterol efflux capacity; HOMA-IR: Homeostatic model assessment
Correlations with Lipoprotein/Metabolic Variables
HDL variables
Lipids
Adiposity
Insulin Res
Cholesterol Efflux Capacity and ASCVD Events
0 1 2 3 4 5 6 7 8 90%
2%
4%
6%
8%
10%
Years
Q1
Q2
Q3Q4
Low efflux
Hi efflux
N=132
ASCVD Events:MIStrokePCI/CABGCV death
Log rank p=0.002
ASCVD: atherosclerotic cardiovascular disease
Unadjusted
TRF-adjusted
Unadjusted
TRF-adjusted
TRF + HDL-C
TRF + HDL-P
TRF + HDL-C + HDL-P
HDL cholesterol
Cholesterol Efflux Capacity
0.64 (0.40-1.03)
0.80 (0.47-1.37)
0.44 (0.27-0.73)
0.30 (0.18-0.50)
0.31 (0.18-0.52)
0.34 (0.20-0.56)
0.33 (0.19-0.55)
1.0Hazard Ratio
0.1 10
TRF + HDL-P 1.08 (0.59-1.99)
Hazard Ratio Q4 vs Q1 (95% CI)
HDL-C, Efflux Capacity and ASCVD Events
N=132/2416 for atherosclerotic cardiovascular disease events. Traditional risk factors (TRF) = age, sex, ethnicity, diabetes, hypertension, current smoking, body-
mass index, total cholesterol, log triglycerides, statin use. HDL-C = HDL cholesterol. HDL-P = HDL particle concentration
Q2
Q3
Q4
Q2
Q3
Q4
Primary ASCVD
Hard ASCVD
0.71 [0.46-1.10]
0.42 [0.26-0.68]
0.33 [0.19-0.55]
0.69 [0.39-1.21]
0.46 [0.25-0.84]
0.40 [0.21-0.74]
Hazard Ratio1.00.1 10
84/2402
132/2416 Hazard Ratio (95% CI)
Q1 Referent
Q1 Referent
Primary ASCVD: MI, stroke, coronary revascularization, and CV death Hard ASCVD: MI, stroke, death from MI or stroke. Models adjusted for age, sex, ethnicity, diabetes, hypertension, current smoking, BMI, total
cholesterol, log triglycerides, statin use, HDL-C, and HDL-P.
Efflux Capacity and Hard ASCVD Events
ModelPrimary ASCVD
(N=132/2416)Total CVD
(N=172/2416)
HR (95% CI) HR (95% CI)
Unadjusted 0.75 (0.61-0.91) 0.84 (0.71-0.98)
TRF-adjusted 0.65 (0.53-0.80) 0.75 (0.63-0.89)
TRF + HDL-C 0.66 (0.54-0.81) 0.77 (0.64-0.91)
TRF + HDL-P 0.69 (0.56-0.84) 0.79 (0.67-0.94)
TRF + HDL-C + HDL-P
0.68 (0.55-0.84) 0.79 (0.67-0.94)
Hazard ratios and 95% CIs for 1 SD increase in efflux capacity. Primary ASCVD: MI, stroke, coronary revascularization, and CV deathTotal CVD: ASCVD + peripheral revascularization, CHF and afib hospitalization
Continuous Efflux Capacity and Cardiovascular Events
Efflux Capacity Improves Risk Prediction of ASCVD Events
Model C-statistic
Integrated Discrimination Improvement
(IDI)
Net Reclassification
Index (NRI)
Traditional Risk Factors
0.827
0.02 0.37Traditional Risk
Factors + Efflux capacity
0.841
P value/95% CI
p=0.02 p=0.0008 (0.18-0.56)
Traditional Risk Factors: age, sex, ethnicity, diabetes, hypertension, smoking, BMI, total cholesterol, log triglyceride, statin use
Summary• In contrast to HDL cholesterol, cholesterol efflux capacity (CEC)
is minimally correlated with risk factors, lipoproteins, adiposity, or insulin resistance.
• CEC is inversely associated with incident atherosclerotic CV events in a population-based study free of CVD
• This association is not attenuated by traditional risk factors, HDL cholesterol, or HDL particle concentration
• CEC, as a measure of reverse cholesterol transport, may provide the ability to interrogate key mechanisms related to cardiovascular disease in humans
Implications
Other Disease Pathways
Therapeutic Response
LDL cholesterol
Non-HDL cholesterol
HDL cholesterol
HDL Function/Flux
Risk Prediction
Coronary Disease
Free Stable ACS