1. 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

2. HDL-C ≠ CHD 25% Drug Class Trial HDL-C change NIACIN AIM-HIGH 25%
Placebo
Drug Class
Trial
HDL-C change
NIACIN
AIM-HIGH
25%
HPS2-THRIVE
15%
CETPI
Torcetrapib
72%
Dalcetrapib
35%
Niaspan
20%
CETPI
AIM-HIGH
15%
HPS2
10%
Dalcetrapib
Torcetrapib 5% A H T D 0%
HPS2-THRIVE. NEJM 2014;371:203-12 1 2 3 4
Schwartz GG, et al. NEJM 2012;367:
Years
Boden WE, et al. NEJM 2011;365:
Barter PJ, et al. NEJM 2007;357:

3. HDL Function: Reverse Cholesterol Transport
apoA-I
Liver
apoA-I
ABCA1
Cholesterol efflux
ABCA1
SRB1
apoA-I
ABCG1
Macrophage
VLDL
Bile/Feces
Adorni MP, et al. J Lipid Res 2007;48:
Khera AV, et al. NEJM 2011;364:127-35
Rader DJ, Hovingh GK. Lancet 2014;384:

4. Study Objective Objective: Hypothesis:
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

5. Methods Dallas Heart Study Baseline N = 2924 Age = 30-65 (median 42)
Cholesterol Efflux Capacity
Baseline
Dallas Heart Study
ACAT inhibitor
cAMP
Metabolic phenotype
Cholesterol Efflux Capacity
Lipoprotein composition
9.4 years
N = 2924
Age = (median 42)
57% Women
49% Black
Follow up
ApoB-depleted plasma
ASCVD (n=132): MI/Stroke PCI/CABG CV Death
% efflux
Total
Normalized efflux
% effluxsample
% effluxreference
Sankaranarayanan S, et al. J Lipid Res 2011;52:

6. Cholesterol Efflux Capacity
HDL-C and Efflux by Sex and Race N
HDL Cholesterol
(mg/dL)
Cholesterol Efflux Capacity
(Normalized)
Women
1657
51 [43-61]
0.99 [ ]
Men
1267
44 [37-52]
1.01 [ ]
p-value
<0.0001
0.1
Black
1443
49 [42-60]
0.98 [ ]
Non-Black
1481
45 [38-55]
1.01 [ ]
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.

7. Determinants of HDL-C and Efflux
HDL Cholesterol
Cholesterol Efflux Capacity
Model R2 = 0.35
Model R2 = 0.03
Variable
Std beta estimate
Total cholesterol
0.22
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
0.03
Smoking
-0.06
-0.07
Waist to hip ratio
-0.08
Body mass index
-0.17
-0.23
Log Triglyceride
-0.39
Model R2 reflects the total contribution of the model to the variance in the dependent variable (range ).

8. Correlations with Lipoprotein/Metabolic Variables
HDL Cholesterol
Cholesterol Efflux Capacity
0.07*
HDL Particle concentration
0.52*
0.15*
HDL Particle size
0.72*
0.02
Total Cholesterol
0.06*
LDL Cholesterol
-0.15*
0.10*
Triglyceride
-0.45*
0.05*
Body Mass Index
-0.23*
-0.02
Waist to Hip Ratio
-0.38*
Truncal Fat (Dexa)
-0.20*
0.004
Visceral Fat (MRI)
-0.41*
0.03
HOMA-IR
-0.29*
-0.05*
HDL variables
Lipids
Adiposity
Insulin Res
Values are Spearman correlation coefficients.
* p<0.05, otherwise p=NS
CEC=cholesterol efflux capacity; HOMA-IR: Homeostatic model assessment

9. Cholesterol Efflux Capacity and ASCVD Events
Low efflux
Hi efflux
10% Q1 Q2 Q3 Q4 8%
ASCVD Events: MI 6%
Stroke
PCI/CABG
CV death 4%
N=132
Log rank p=0.002 2% 0% 1 2 3 4 5 6 7 8 9
Years
ASCVD: atherosclerotic cardiovascular disease

10. HDL-C, Efflux Capacity and ASCVD Events
HDL cholesterol
Hazard Ratio Q4 vs Q1 (95% CI)
Unadjusted
0.64 ( )
TRF-adjusted
0.80 ( )
TRF + HDL-P
1.08 ( )
Cholesterol Efflux Capacity
Unadjusted
0.44 ( )
TRF-adjusted
0.30 ( )
TRF + HDL-C
0.31 ( )
TRF + HDL-P
0.34 ( )
TRF + HDL-C + HDL-P
0.33 ( )
0.1
1.0 10
Hazard Ratio
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

11. Efflux Capacity and Hard ASCVD Events
Primary ASCVD
132/2416
Hazard Ratio (95% CI) Q1
Referent Q2
0.71 [ ] Q3
0.42 [ ] Q4
0.33 [ ]
Hard ASCVD
84/2402 Q1
Referent Q2
0.69 [ ] Q3
0.46 [ ] Q4
0.40 [ ]
0.1
1.0 10
Hazard Ratio
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.

12. Continuous Efflux Capacity and Cardiovascular Events
Model
Primary ASCVD
(N=132/2416)
Total CVD
(N=172/2416)
HR (95% CI)
Unadjusted
0.75 ( )
0.84 ( )
TRF-adjusted
0.65 ( )
0.75 ( )
TRF + HDL-C
0.66 ( )
0.77 ( )
TRF + HDL-P
0.69 ( )
0.79 ( )
TRF + HDL-C + HDL-P
0.68 ( )
Hazard ratios and 95% CIs for 1 SD increase in efflux capacity.
Primary ASCVD: MI, stroke, coronary revascularization, and CV death
Total CVD: ASCVD + peripheral revascularization, CHF and afib hospitalization

13. 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
0.37
Traditional Risk Factors +
Efflux capacity
0.841
P value/
95% CI
p=0.02
p=0.0008
( )
Traditional Risk Factors: age, sex, ethnicity, diabetes, hypertension, smoking, BMI, total cholesterol, log triglyceride, statin use

14. 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

15. Other Disease Pathways
Implications
HDL Cholesterol
HDL function
Risk Prediction
Coronary Disease
Free
Stable
ACS
Therapeutic Response
LDL cholesterol
Non-HDL cholesterol
HDL cholesterol
HDL Function/Flux
Other Disease Pathways