Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Apr 24.
Published in final edited form as: Eur J Prev Cardiol. 2015 Oct 19;23(7):769–776. doi: 10.1177/2047487315612733

The utility of the apolipoprotein A1 remnant ratio in predicting incidence coronary heart disease in a primary prevention cohort: The Jackson Heart Study

Heidi T May 1, John R Nelson 2, Seth T Lirette 3, Krishnaji R Kulkarni 4, Jeffrey L Anderson 1,5, Michael E Griswold 3, Benjamin D Horne 1,5, Adolfo Correa 3, Joseph B Muhlestein 1,5
PMCID: PMC5913735  NIHMSID: NIHMS948144  PMID: 26481445

Abstract

Background

Dyslipidemia plays a significant role in the progression of cardiovascular disease. The apolipoprotein (apo) A1 remnant ratio (apo A1/VLDL3-C + IDL-C) has recently been shown to be a strong predictor of death/myocardial infarction risk among women >50 years undergoing angiography. However, whether this ratio is associated with coronary heart disease risk among other populations is unknown. We evaluated the apo A1 remnant ratio and its components for coronary heart disease incidence.

Design

Observational.

Methods

Participants (N = 4722) of the Jackson Heart Study were evaluated. Baseline clinical characteristics and lipoprotein subfractions (Vertical Auto Profile method) were collected. Cox hazard regression analysis, adjusted by standard cardiovascular risk factors, was utilized to determine associations of lipoproteins with coronary heart disease.

Results

Those with new-onset coronary heart disease were older, diabetic, smokers, had less education, used more lipid-lowering medication, and had a more atherogenic lipoprotein profile. After adjustment, the apo A1 remnant ratio (hazard ratio = 0.67 per 1-SD, p = 0.002) was strongly associated with coronary heart disease incidence. This association appears to be driven by the IDL-C denominator (hazard ratio = 1.23 per 1-SD, p = 0.007). Remnants (hazard ratio = 1.21 per 1-SD, p = 0.017), but not apo A1 (hazard ratio = 0.85 per 1-SD, p = 0.121) or VLDL3-C (hazard ratio = 1.13 per 1-SD, p = 0.120) were associated with coronary heart disease. Standard lipids were not associated with coronary heart disease incidence.

Conclusion

We found the apo A1 remnant ratio to be strongly associated with coronary heart disease. This ratio appears to better stratify risk than standard lipids, apo A1, and remnants among a primary prevention cohort of African Americans. Its utility requires further study as a lipoprotein management target for risk reduction.

Keywords: Lipids, lipoprotein subfractions, lipoprotein ratios, risk, gender, outcomes, apolipoproteins, remnant lipoproteins

Introduction

Cardiovascular disease (CVD) is the leading cause of death in the western world.1 Coronary heart disease (CHD) accounts for approximately half of all CVD and cardiovascular-related deaths.1 It is known that dyslipidemia plays a significant role in the progression of CVD. Low density lipoprotein cholesterol (LDL-C) is an established predictor of CHD and has been the primary target of lipid lowering therapy. However, even when LDL-C and other standard lipoprotein goals have been achieved, residual risk remains.2 Therefore, other lipoproteins have been receiving attention for their ability to enhance risk prediction beyond and in complement to standard lipid parameters. Additionally, lipoprotein ratios have also been popular for the evaluation of enhanced risk prediction because of their ability to incorporate both anti-atherogenic and pro-atherogenic lipoproteins in their measurement.

Recently, the novel apo A1 remnant ratio (apo A1/VLDL3-C + IDL-C) was evaluated for death or myocardial infarction (MI) risk among a cohort of women >50 years of age undergoing coronary angiography.3 This ratio was found to be more strongly associated with death/MI compared with standard lipids, lipoprotein subfractions, and other lipoprotein ratios. However, whether this ratio can predict risk among other populations is unknown. Therefore, the purpose of this study was to evaluate the apo A1 remnant ratio and its components for CHD prediction among a primary prevention cohort of African Americans enrolled in the Jackson Heart Study (JHS). Further, differences in risk prediction were evaluated separately for men and women.

Methods

Study population

Study participants were drawn from the JHS. The design and methods for the JHS have been previously described.4–6 The JHS is a large, community-based, observational study of African Americans who were recruited from the three counties (Hinds, Madison, and Rankin) that make up Jackson, Mississippi. In the original cohort, data and samples were collected from 5301 participants. Within this study, participants were included if they were free from CVD and had lipoprotein cholesterol subfraction results available on fasting samples obtained from their baseline visit occurring from 2000–2004. A total of 4722 participants met criteria and were evaluated.

Lipid and lipoprotein particle quantification and stratification

Lipoprotein levels were obtained during exam 1. At the time of exam 1, blood samples were collected, centrifuged, and stored cryogenically. From these cryogenically stored samples, cholesterol concentrations of lipoprotein classes and their subclasses were measured using single vertical spin density gradient ultra-centrifugation based on the Vertical Auto Profile (VAP; Atherotech, Birmingham, AL, USA).7 Apo A1 was estimated by the VAP method using the procedure described previously.8 Apo A1 was also measured directly using the Abbott Architect/C8000 immunoassay to confirm the results obtained using VAP estimated apo A1 (r = 0.908, p < 0.0001).

Other risk factor, demographic, and clinical assessments

Participant information collected included age, diabetes status (diabetes mellitus: fasting blood glucose >125 mg/dl, clinical diagnosis of diabetes mellitus, or anti-diabetic medication use; insulin resistance: fasting glucose 110–125 mg/dl; and normal: fasting glucose <110 mg/dl), systolic blood pressure, diastolic blood pressure, highest education level obtained (did not graduate from high school, high school graduate or equivalent (GED), or college), smoking (never, former, or current), and alcohol use in the last year. Anthropometric measurements include waist circumference (in centimeters) and weight and height to calculate body mass index ((BMI) kg/m2).

Follow-up and event assessment

Average length of follow-up was 5.54 ± 1.48 years. CHD was defined as CHD death, MI, and CHD cardiac procedure, based on interventional ICD-9 procedure codes and adjudication.9 Participants not listed as deceased were censored at their last known contact date.

Statistical analysis

The Pearson chi-square statistic and Student’s t test were used to examine baseline characteristics and lipoprotein levels comparing those experiencing and not experiencing a CHD event, stratified by gender. Pearson correlations were calculated to examine linear correlations between lipoproteins. Multivariable Cox hazard regression was performed to determine hazard ratios. Hazard ratios are reported per standard deviation (SD) increase. Models were adjusted by age, gender, diabetes, BMI, education, alcohol, smoking, systolic blood pressure, diastolic blood pressure, and lipid lowering medications. The covariables used in the modeling were all clinically agreed-upon risk factors for CVD, chosen a priori as potential confounders of associations between the lipoproteins and outcomes. Linearity on the log-hazard was checked via both Martingale and deviance residuals. The proportional hazard assumption was evaluated with Schoenfeld residuals. All assumptions were deemed appropriate. Two-tailed p-values are presented with 0.05 designated as nominally significant. All analyses were performed with Stata, v13.1 (Statacorp; College Station, TX, USA).

Results

Participant characteristics

A total of 4722 participants were evaluated for this study, with the majority being female (64%, n = 3018). Table 1 displays the baseline characteristics of the population stratified by experiencing and not experiencing the primary outcome of CHD among females and males. Those who experienced an event were older, had diabetes, less education, were former or current smokers, had a higher systolic blood pressure, and were taking lipid-altering medications. However, waist circumferences did not significantly differ. Average lipoprotein levels are also displayed in Table 1. As expected, those with new-onset CHD had a more dyslipidemic profile.

Table 1.

Baseline characteristics and lipoprotein summaries of males and females stratified by experiencing and not experiencing the primary outcome of coronary heart disease.

Females (N = 3018) Males (N = 1704)
No CHD (N = 2932) CHD (N = 86) p-value No CHD (N = 1646) CHD (N = 58) p-value
Age, years 54.46 (12.65) 64.87 (9.48) <0.001 52.98 (12.91) 63.41 (10.27) <0.001
Education
  <High school 470 (16%) 23 (27%) 0.008 287 (17%) 18 (32%) 0.012
  High school/GED 1234 (42%) 39 (45%) 701 (43%) 23 (41%)
  College 1216 (42%) 24 (28%) 653 (40%) 15 (27%)
Diabetes status 517 (18%) 39 (46%) <0.001 231 (14%) 23 (40%) <0.001
Smoking status
  Never 2200 (76%) 53 (62%) 0.008 956 (59%) 27 (47%) 0.031
  Former 425 (15%) 22 (26%) 376 (23%) 22 (38%)
  Current 286 (10%) 11 (13%) 300 (18%) 9 (16%)
Alcohol use 1166 (40%) 24 (28%) 0.024 977 (60%) 29 (50%) 0.143
Body mass index, kg/m2 32.90 (7.64) 31.17 (6.56) 0.040 29.87 (6.21) 29.05 (5.28) 0.323
Waist, cm 100.33 (16.88) 101.57 (14.38) 0.505 101.00 (15.26) 102.19 (12.70) 0.558
Systolic BP 125.86 (18.48) 135.88 (21.45) <0.001 127.61 (17.63) 132.21 (17.33) 0.051
Diastolic BP 77.51 (10.04) 77.09 (12.16) 0.707 81.82 (10.45) 76.66 (9.61) <0.001
Lipid-altering medications 313 (12%) 16 (21%) 0.012 147 (10%) 14 (27%) <0.001
Apo A1/remnants, VAP, mg/dl 6.44 (3.16) 5.42 (2.40) 0.003 5.52 (2.55) 4.74 (1.85) 0.023
Apo A1/remnants, immunoassay, mg/dl 6.25 (2.97) 5.36 (2.32) 0.006 5.16 (2.36) 4.47 (1.81) 0.027
Apo A1, VAP, mg/dl 157.66 (23.47) 156.03 (26.63) 0.528 143.87 (20.99) 138.65 (17.55) 0.064
Apo A1, immunoassay, mg/dl 154.37 (27.50) 154.87 (27.76) 0.868 135.32 (21.91) 131.71 (18.54) 0.216
IDL-C, mg/dl 16.28 (8.18) 19.23 (8.87) 0.001 16.48 (7.57) 18.07 (7.40) 0.116
VLDL3-C, mg/dl) 12.90 (4.60) 13.95 (4.62) 0.036 13.97 (4.87) 15.36 (5.61) 0.033
Remnantsa, mg/dl 29.18 (12.11) 33.19 (12.86) 0.003 30.45 (11.74) 33.43 (11.91) 0.057
VLDL-C, mg/dl 21.49 (9.00) 22.94 (8.29) 0.139 23.96 (10.26) 26.47 (13.24) 0.071
Non-HDL-C, mg/dl 144.00 (38.23) 153.88 (46.85) 0.019 146.53 (38.53) 146.10 (32.54) 0.933
Triglycerides, mg/dl 102.73 (67.13) 116.23 (59.51) 0.065 121.36 (141.76) 132.33 (96.40) 0.559
LDL-C, mg/dl 122.55 (35.79) 130.91 (44.11) 0.034 122.61 (36.41) 119.60 (31.29) 0.534
HDL-C, mg/dl 56.78 (14.45) 56.09 (15.62) 0.667 47.62 (12.42) 44.81 (10.69) 0.090
Apo B, mg/dl 96.10 (22.62) 103.73 (27.48) 0.002 99.49 (23.49) 100.00 (19.46) 0.871
Apo B/Apo A1, mg/dl 0.62 (0.18) 0.68 (0.19) 0.006 0.71 (0.20) 0.73 (0.16) 0.330
Triglycerides/HDL-C, mg/dl 2.01 (1.68) 2.29 (1.38) 0.130 2.89 (3.89) 3.24 (2.81) 0.496
Total cholesterol/HDL-C, mg/dl 3.70 (0.99) 3.90 (1.10) 0.070 4.28 (1.21) 4.41 (1.01) 0.398
Open in a new tab

Continuous variables are expressed as mean (standard deviation) and discrete variables as n (%). CHD: coronary heart disease; GED: high school graduate or equivalent; BP: blood pressure; VAP: Vertical Auto Profile; Apo: apolipoprotein; IDL-C: intermediate density lipoprotein cholesterol; VLDL-C: very low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol

a

Remnants = VLDL3-C + IDL-C.

Correlations among the different lipoprotein parameters and ratios are displayed in Supplementary Table 1 in the Supplementary Material online. The apo A1 remnant ratio utilizing the calculated apo A1 (VAP) was very highly correlated to the ratio using the directly measure apo A1 (r = 0.985). Apo A1 and remnants were very weakly inversely correlated (r = −0.111, p < 0.001), with VLDL3-C (r = −0.165, p < 0.001) being more so than IDL-C (r = −0.071, p < 0.001). Such results indicate how both components of the apo A1 remnant ratio, apo A1 and remnants, contribute complementarily and are measurements of different lipoprotein abnormalities.

CHD incidence

There were a total of 144 (3%) CHD events over a median of 5.68 years (maximum 8.22 years) of follow-up. The no CHD group had 5.72 median years of follow-up and the CHD group had 3.30 median years of follow-up (p < 0.001). Table 2 displays hazard ratios for CHD risk for the different lipoproteins adjusted for age, gender, diabetes, BMI, education, smoking, alcohol, systolic blood pressure, diastolic blood pressure, and lipid-altering medication use among the entire population. Among the overall population, the apo A1 remnant ratio was strongly associated with CHD risk, with a 33% risk reduction per 1-SD decrease (Table 2). This association appears to be driven more by the IDL-C (hazard ratio = 1.23 per 1-SD, p = 0.007) than VLDL3-C (hazard ration = 1.13 per 1-SD, p = 0.120). This may indicate that among African Americans, IDL-C is the remnant parameter that needs added evaluation since it appears that VLDL3-C attenuates CHD risk prediction. Apo A1 (VAP), apo B, and the ratios of apo B/apo A1 and total cholesterol/HDL-C were also significant predictors of risk.

Table 2.

Multivariable hazard ratios for different lipoprotein parameters to coronary heart disease incidence overall and by sex.

Overall Males Females
Apo A1/remnants, VAP 0.67 (0.52, 0.86), p = 0.002 0.57 (0.36, 0.88), p = 0.012 0.73 (0.55, 0.98), p = 0.037
Apo A1/remnants, immunoassay 0.69 (0.54, 0.87), p = 0.002 0.55 (0.36, 0.85), p = 0.007 0.76 (0.58, 1.01), p = 0.055
Apo A1, VAP 0.81 (0.66, 0.99), p = 0.036 0.68 (0.48, 0.95), p = 0.024 0.89 (0.70, 1.14), p = 0.358
Apo A1, immunoassay 0.85 (0.70, 1.04), p = 0.121 0.65 (0.45, 0.95), p = 0.026 0.96 (0.75, 1.21), p = 0.713
IDL-C 1.23 (1.06, 1.44), p = 0.007 1.24 (0.99, 1.55), p = 0.057 1.23 (1.00, 1.51), p = 0.051
VLDL3-C 1.13 (0.97, 1.32), p = 0.120 1.21 (0.99, 1.49), 0.064 1.05 (0.84, 1.31), p = 0.668
Remnantsa 1.21 (1.03, 1.41), p = 0.017 1.25 (1.00, 1.56), p = 0.047 1.17 (0.95, 1.45), p = 0.143
VLDL-C 1.08 (0.94, 1.23), p = 0.289 1.19 (0.99, 1.43), p = 0.070 0.98 (0.78, 1.23), p = 0.844
Non-HDL-C 1.18 (0.99, 1.40), p = 0.060 1.16 (0.88, 1.52), p = 0.289 1.19 (0.96, 1.48), p = 0.115
Triglycerides 1.04 (0.92, 1.18), p = 0.498 1.05 (0.93, 1.19), p = 0.425 1.01 (0.75, 1.34), p = 0.968
LDL-C 1.16 (0.98, 1.38), p = 0.091 1.08 (0.82, 1.44), p = 0.576 1.21 (0.97, 1.51), p = 0.083
HDL-C 0.83 (0.68, 1.01), p = 0.068 0.64 (0.44, 0.93), p = 0.019 0.93 (0.74, 1.19), p = 0.578
Apo B 1.23 (1.04, 1.46), p = 0.016 1.20 (0.92, 1.58), p = 0.186 1.25 (1.01, 1.56), p = 0.042
Apo B/Apo A1 1.31 (1.10, 1.57), p = 0.003 1.36 (1.04, 1.78), p = 0.022 1.28 (1.01, 1.61), p = 0.039
Triglycerides/HDL-C 1.05 (0.93, 1.18), p = 0.415 1.06 (0.95, 1.19), p = 0.309 0.98 (0.71, 1.37), p = 0.922
Total cholesterol/HDL-C 1.23 (1.04, 1.46), p = 0.019 1.31 (1.04, 1.65), p = 0.024 1.16 (0.91, 1.48), p = 0.231
Open in a new tab

Hazard ratios are presented as per standard deviation. Models were adjusted by age, sex, BMI, education, smoking, alcohol use, systolic blood pressure, diastolic blood pressure, diabetes, and lipid-altering medications. Apo: apolipoprotein; VAP: Vertical Auto Profile; IDL-C: intermediate density lipoprotein cholesterol; VLDL-C: very low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol

a

Remnants: VLDL3-C + IDL-C.

Sex specific outcomes

A total of 63.9% (n = 3018) of the population studied was female. Women were older than men (54.8 ± 12.7 vs. 53.3 ± 13.0, p < 0.001). More women than men had diabetes, women had a greater BMI, but less smoking and alcohol consumption, and lower blood pressure. Men had a more atherogenic lipoprotein profile. There were a total of 86 (2.8%) and 58 (3.4%) CHD events for women and men, respectively. Table 2 displays lipoprotein associations with CHD by sex. In general, associations among the lipoproteins with CHD were stronger among men than women. The apo A1 remnant ratio and the ratio of apo B/apo A1 were the only parameters that remained significantly associated with CHD incidence among both sexes. Supplementary Table 2 shows associations of lesser studied ratios to CHD incidence. The ratio of apo A1/IDL-C was highly predictive.

Sensitivity analysis

Since the distribution of diabetics (no CHD: 17% vs. CHD: 43%) and those taking lipid-altering medications (no CHD: 11% vs. CHD: 23%) is very different among those with and without a follow-up CHD diagnosis, we performed a stratified analysis which is excluded these patients to determine whether associations remain despite their exclusion and potential confounding. A total of 3286 (70%) patients were evaluated, with 2070 (63%) being female and 1216 (37%) being male. Even though the sample size decreases, many associations become stronger, particular among men (Table 3).

Table 3.

Multivariable hazard ratios for different lipoprotein parameters to coronary heart disease incidence among patients with no history of diabetes or use of lipid lowering medications.

Overall Males Females
Apo A1/remnants, VAP 0.58 (0.41, 0.82), p = 0.002 0.39 (0.20, 0.76), p = 0.006 0.70 (0.47, 1.03), p = 0.071
Apo A1/remnants. immunoassay 0.59 (0.42, 0.83), p = 0.002 0.40 (0.21, 0.77), p = 0.006 0.70 (0.48, 1.03), p = 0.068
Apo A1, VAP 0.79 (0.61, 1.03), p = 0.081 0.69 (0.45, 1.07), p = 0.097 0.86 (0.62, 1.18), p = 0.351
Apo A1, immunoassay 0.83 (0.63, 1.08), p = 0.163 0.69 (0.43, 1.12), p = 0.134 0.90 (0.65, 1.23), p = 0.508
IDL-C 1.26 (1.01, 1.58), p = 0.042 1.56 (1.08, 2.25), p = 0.018 1.13 (0.85, 1.50), p = 0.409
VLDL3-C 1.23 (0.98, 1.54), p = 0.074 1.36 (0.98, 1.90), 0.066 1.13 (0.84, 1.54), p = 0.418
Remnantsa 1.27 (1.01, 1.59), p = 0.040 1.52 (1.06, 2.18), p = 0.022 1.14 (0.85, 1.53), p = 0.387
VLDL-C 1.16(0.92, 1.48), p = 0.208 1.24 (0.91, 1.68), p = 0.179 1.09 (0.77, 1.55), p = 0.634
Non-HDL-C 1.23 (0.97, 1.55), p = 0.081 1.27 (0.88, 1.82), p = 0.204 1.20 (0.89, 1.63), p = 0.283
Triglycerides 1.10 (0.95, 1.26), p = 0.192 1.08 (0.91, 1.29), p = 0.384 1.29 (0.81, 2.04), p = 0.283
LDL-C 1.20 (0.95, 1.51), p = 0.125 1.20 (0.84, 1.73), p = 0.317 1.20 (0.89, 1.61), p = 0.244
HDL-C 0.81 (0.62, 1.05), p = 0.114 0.68 (0.43, 1.08), p = 0.100 0.88 (0.64, 1.21), p = 0.440
Apo B 1.32 (1.05, 1.65), p = 0.017 1.36 (0.96, 1.93), p = 0.083 1.28 (0.95, 1.73), p = 0.100
Apo B/Apo A1 1.38 (1.10, 1.73), p = 0.006 1.49 (1.08, 2.07), p = 0.017 1.30 (0.96, 1.75, p = 0.093
Triglycerides/HDL-C 1.12 (0.96, 1.31), p = 0.138 1.10 (0.92, 1.33), p = 0.298 1.33 (0.81, 2.18), p = 0.261
Total cholesterol/HDL-C 1.28 (1.02, 1.61), p = 0.033 1.36 (1.01, 1.83), p = 0.041 1.20 (0.88, 1.65), p = 0.252
Open in a new tab

Hazard ratios are presented as per standard deviation among the overall study population (N = 3286) and by males (n = 1216) and females (n = 2070). Models were adjusted by age, sex, BMI, education, smoking, alcohol use, systolic blood pressure, and diastolic blood pressure. Apo: apolipoprotein; VAP: Vertical Auto Profile; IDL-C: intermediate density lipoprotein cholesterol; VLDL-C: very low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol

a

Remnants: VLDL3-C + IDL-C.

Discussion

Study summary

This is the first study in African American men and women that demonstrates that the apo A1 remnant ratio is associated with CHD incidence. This association appears to be primarily driven by the IDL-C denominator. IDL-C was associated with CHD among both sexes, and the ratio of apo A1/IDL-C was found to be as or more predictive of CHD than any of the other parameters or ratios evaluated. Advanced lipoprotein testing was shown to have a stronger association for CHD prediction over standard lipid panel parameters. Of the standard lipid parameters, only high density lipoprotein cholesterol (HDL-C) among men was associated with CHD incidence. These results also further support the importance of apo B and the apo B/apo A1 ratio in CHD risk assessment over and beyond that of standard lipid parameters, including non-HDL-C.10–12

Differences in CHD risk by ethnicity and sex

The prevalence of CHD disease among those ≥20 years is 6.4%, affecting males (7.9%) more often than females (5.1%).1 However, among African Americans the prevalence of CHD is higher among females (7.1%) than males (6.8%).1 Additionally, African Americans have the highest CHD mortality of any ethnic group; however, this increased risk is not reflected in the standard lipid panel. Compared with Caucasians, African Americans have lower triglycerides and higher HDL-C.13,14 Despite these apparent lipid advantages in the standard lipid panel, African American men and women have much higher rates of CVD compared with Caucasians: 44.4% and 48.9% vs. 36.6% and 32.4%, respectively.1 These differences in CVD rates between African Americans and Caucasians overall and by sex include effects from other disease states, socio-economics, and educational differences. Thus, the apo A1 remnant ratio and IDL-C may be important additions to standard risk predictors.

Remnants

Remnant lipoprotein cholesterol (RLP-C) has been shown to predict future coronary events in patients with CHD with and without type 2 diabetes mellitus, independent of elevated triglycerides, low HDL-C, and elevated LDL-C.10–12,15,16 Since African Americans have lower triglycerides and higher HDL-C levels, other lipoprotein parameters may be important markers of cardiovascular risk in the African American population.

The independence of RLP-C and IDL-C as predictors of risk for CHD in this study is not unexpected. IDL-C has been shown to be associated with CHD for many years.17 Furthermore, multiple serial coronary angiographic studies have shown that coronary artery disease (CAD) progression has a greater association with IDL mass than LDL mass as measured by analytical ultracentrifugation.18,19 Mendelian randomization has shown that RLP-C is a causal risk for ischemic heart disease. In a large study of 73,513 subjects, a 39 mg/dl increase in nonfasting RLP-C was found to be associated with 2.8-fold causal risk for ischemic heart disease.20 Further, RLP-C was shown, along with LDL-C and systolic blood pressure, to partly mediate the increased risk of ischemic heart disease because of obesity.21

Elevated RLPs are proinflammatory and prothrombotic, and increase oxidative stress. RLPs have been shown to increase adhesion molecules, VCAM-1, ICAM-1 and the chemokine monocyte, chemoattractant protein-1 (MCP-1), and E-selectin.22 Elevated RLP-C has been shown to be associated with increased fibrinogen and plasminogenic activator inhibitor-1 (PAI-1), which is the main regulator of blood fibrinolytic activity.23 Fibrinogen promotes smooth muscle cell proliferation and migration and has been shown to be associated with CVD and mortality.24,25 African Americans have been shown to have higher fibrinogen levels than Caucasians.26

Elevated RLP-C may be particularly important in African Americans, as it was recently shown in a Mendelian randomization study that elevated RLP-C was associated with both low-grade inflammation and ischemic heart disease, whereas LDL-C was only associated with ischemic heart disease, and not inflammation.27 Such studies provide possible physiological mechanisms that may contribute to the increased CHD risk among African Americans.

Ratios

The treatment of LDL-C goals has proved to be clinically effective and has led to a reduction in CHD mortality.28 However, the ability of LDL-C to predict CHD risk has been affected by the obesity epidemic,29 which has resulted in more mixed dyslipidemia. This dyslipidemic profile shift has resulted in a disproportionate relationship between LDL-C and other lipoprotein parameters. Therefore, efforts to optimize risk prediction using lipoproteins have resulted in the utilization of subfractions, apolipoproteins, and lipoprotein ratios. The increased utility of ratios over single parameters lies in their ability to measure both pro- and anti-atherogenic lipoproteins simultaneously. In addition, they can provide information on risk factors difficult to determine from individual lipoprotein parameters since they account for interactions among the lipoproteins.

The total cholesterol/HDL-C, apo B/apo A1, and the triglyceride/HDL-C ratios are some of the more popular and well-studied ratios. Many previous studies have shown these ratios to be associated with adverse CV outcomes.30–34 This study evaluated both novel and traditional ratios in an African American population. In general, the ratios outperformed standard lipids, apo A1, apo B, and VLDL3-C for CHD risk prediction. Of the ratios studied, the more novel ratios (apo A1 remnant ratio, apo A1/IDL-C, and HDL-C/remnants) predicted CHD risk similar to that of the apo B/A1 and better than the total cholesterol/HDL-C. This is now the second population based study to demonstrate that the apo A1 remnant ratio is more predictive of CHD than standard lipids, non HDL-C, and the total cholesterol/HDL-C ratio. Most importantly, these results support the enthusiasm for the use of these novel ratios in an African American population in which cardiovascular risk is frequently underestimated from their standard lipid panels. However, the predictive power of these novel ratios, including the apo A1 remnant ratio, in these epidemiologic studies requires further validation as a target in randomized clinical trials.

Study limitations

This study shares the limitations of all nonrandomized, observational studies, including the possibility of selection bias and unadjusted confounding. The population studied was African Americans without CHD, thus these results may not apply to other ethnic or higher risk groups. Additionally, serial lipoprotein measurements were not obtained so how changes in levels through modifications in lifestyle, risk factors, and treatment might have affected outcomes cannot be taken into account. The event rate was low, thus making it difficult to detect significant difference among the different subgroups. Also, it is unknown how results would compare with other advanced lipoprotein tests (nuclear magnetic resonance). However, strengths include the large sample size, the ability to adjust for multiple confounders, and standardization of data collection and follow-up.

Conclusion

Among a primary prevention African American cohort, the apo A1 remnant ratio was found to be strongly associated with CHD risk. This study supports the findings of a previous study which also reported the apo A1 remnant ratio to better stratify cardiovascular risk than standard lipids, apo A1, and remnants.3 Among this cohort, IDL-C appeared to primarily drive the ratio’s strong association to CHD incidence. Further study is required in the utility of the apo A1 remnant ratio as a lipoprotein target for the management of cardiovascular risk reduction.

Supplementary Material

suppl-tab

Acknowledgments

This study was presented in the poster session of the 2014 American College of Cardiology Scientific Sessions.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by an in-kind grant from Atherotech; The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN2682 01300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities, with additional support from the National Institute on Biomedical Imaging and Bioengineering.

Footnotes

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JRN is a consultant for Atherotech and KRK is an employee of Atherotech. No other conflicts exist.

References

  • 1.Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics – 2013 update: A report from the American Heart Association. Circulation. 2012;127:e6–e245. doi: 10.1161/CIR.0b013e31828124ad. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Cholesterol Treatment Trialists’ (CTT) Collaboration. Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681. doi: 10.1016/S0140-6736(10)61350-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.May HT, Nelson JR, Kulkarni KR, et al. A new ratio for better predicting future death/myocardial infarction than standard lipid measurements in women >50 years undergoing coronary angiography: The apolipoprotein A1 remnant ratio (Apo A1/[VLDL3 + IDL]) Lipids Health Dis. 2013;12:55. doi: 10.1186/1476-511X-12-55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Taylor HA, Jr, Wilson JG, Jones DW, et al. Toward resolution of cardiovascular health disparities in African Americans: Design and methods of the Jackson Heart Study. Ethn Dis. 2005;15:S6–4–17. [PubMed] [Google Scholar]
  • 5.Sempos CT, Bild DE, Manolio TA. Overview of the Jackson Heart Study: A study of cardiovascular diseases in African American men and women. Am J Med Sci. 1999;317:142–146. doi: 10.1097/00000441-199903000-00002. [DOI] [PubMed] [Google Scholar]
  • 6.Wyatt SB, Diekelmann N, Henderson F, et al. A community-driven model of research participation: The Jackson Heart Study Participant Recruitment and Retention Study. Ethn Dis. 2003;13:438–455. [PubMed] [Google Scholar]
  • 7.Kulkarni KR, Garber DW, Marcovina SM, et al. Quantification of cholesterol in all lipoprotein classes by the VAP-II method. J Lipid Res. 1994;35:159–168. [PubMed] [Google Scholar]
  • 8.Kulkarni KR, Tiwari H, Jones SR. A novel approach to measure apolipoprotein A/apolipoprotein A1 ratio using the Vertical Auto Profile method. Diab Vasc Dis Res. 2007;4:266. [Google Scholar]
  • 9.Keku E, Rosamond W, Taylor HA, Jr, et al. Cardiovascular disease event classification in the Jackson Heart Study: Methods and procedures. Ethn Dis. 2005;15:S6–62–70. [PubMed] [Google Scholar]
  • 10.Pencina MJ, D’Agostino RB, Zdrojewski T, et al. Apolipoprotein B improves risk assessment of future coronary heart disease in the Framingham Heart Study beyond LDL-C and non-HDL-C. Eur J Prev Cardiol. 22:1321–1327. doi: 10.1177/2047487315569411. Epub ahead of print 29 January 2015. [DOI] [PubMed] [Google Scholar]
  • 11.Thanassoulis G, Williams K, Ye K, et al. Relations of change in plasma levels of LDL-C, Non-HDL-C, and apo B with risk reduction from statin therapy: A meta-analysis of randomized trials. J Am Heart Assoc. 2014;3:e000759. doi: 10.1161/JAHA.113.000759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Sierra-Johnson J, Fisher RM, Romero-Corral A, et al. Concentration on apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-1 ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: Findings from a multi-ethnic US population. Eur Heart J. 2009;30:710–717. doi: 10.1093/eurheartj/ehn347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Freedman DS, Strogatz DS, Eaker E, et al. Differences between black and white men in correlates of high density lipoprotein cholesterol. Am J Epidemiol. 1990;132:656–669. doi: 10.1093/oxfordjournals.aje.a115707. [DOI] [PubMed] [Google Scholar]
  • 14.Haffner SM, D’Agostino R, Jr, Goff D, et al. LDL size in African Americans, Hispanics, and non-Hispanic whites: The insulin resistance atherosclerosis study. Arterioscler Thromb Vasc Biol. 1999;19:2234–2240. doi: 10.1161/01.atv.19.9.2234. [DOI] [PubMed] [Google Scholar]
  • 15.Manolio TA, Pearson TA, Wenger NK, et al. Cholesterol and heart disease in older persons and women. Review of an NHLBI workshop. Ann Epidemiol. 1992;2:161–176. doi: 10.1016/1047-2797(92)90051-q. [DOI] [PubMed] [Google Scholar]
  • 16.Lamarche B, Moorjani S, Lupien PJ, et al. Apolipoprotein A-1 and B levels and risk of ischemic heart disease during a five-year follow-up of men in the Quebec Cardiovascular Study. Circulation. 1996;94:273–278. doi: 10.1161/01.cir.94.3.273. [DOI] [PubMed] [Google Scholar]
  • 17.Gofman JW, Lindgren F. The role of lipids and lipoproteins in atherosclerosis. Science. 1950;111:166–171. doi: 10.1126/science.111.2877.166. [DOI] [PubMed] [Google Scholar]
  • 18.Mack WJ, Krauss RM, Hodis HN. Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment effects and relation to coronary angiographic progression. Arterioscler Thromb Vasc Biol. 1996;16:697–704. doi: 10.1161/01.atv.16.5.697. [DOI] [PubMed] [Google Scholar]
  • 19.Krauss RM, Lindgren FT, Williams PT, et al. Intermediate-density lipoproteins and progression of coronary artery disease in hypercholesterolaemic men. Lancet. 1987;2:62–66. doi: 10.1016/s0140-6736(87)92734-6. [DOI] [PubMed] [Google Scholar]
  • 20.Varbo A, Benn M, Tybjaerg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–436. doi: 10.1016/j.jacc.2012.08.1026. [DOI] [PubMed] [Google Scholar]
  • 21.Varbo A, Benn M, Smith GD, et al. Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease. Circ Res. 2015;116:665–673. doi: 10.1161/CIRCRESAHA.116.304846. [DOI] [PubMed] [Google Scholar]
  • 22.Park SY, Lee JH, Kim YK, et al. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation. J Pharmacol Exp Ther. 2005;312:1241–1248. doi: 10.1124/jpet.104.077826. [DOI] [PubMed] [Google Scholar]
  • 23.Koga H, Sugiyama S, Kugiyama K, et al. Elevated levels of remnant lipoproteins are associated with plasma platelet microparticles in patients with type-2 diabetes mellitus without obstructive coronary artery disease. Eur Heart J. 2006;27:817–823. doi: 10.1093/eurheartj/ehi746. [DOI] [PubMed] [Google Scholar]
  • 24.Fibrinogen Studies Collaboration. Danesh J, Lewington S, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: An individual participant meta-analysis. JAMA. 2005;294:1799–1809. doi: 10.1001/jama.294.14.1799. [DOI] [PubMed] [Google Scholar]
  • 25.Allison MA, Criqui MH, McClelland RL, et al. The effect of novel cardiovascular risk factors on the ethnic-specific odds for peripheral arterial disease in the Multi-Ethnic Study of Atherosclerosis (MESA) J Am Coll Cardiol. 2006;48:1190–1197. doi: 10.1016/j.jacc.2006.05.049. [DOI] [PubMed] [Google Scholar]
  • 26.Tracy RP, Bovill EG, Fried LP, et al. The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study. Ann Epidemiol. 1992;2:509–519. doi: 10.1016/1047-2797(92)90100-5. [DOI] [PubMed] [Google Scholar]
  • 27.Varbo A, Benn M, Tybjaerg-Hansen A, et al. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation. 2013;128:1298–1309. doi: 10.1161/CIRCULATIONAHA.113.003008. [DOI] [PubMed] [Google Scholar]
  • 28.Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N Engl J Med. 2007;356:2388–2398. doi: 10.1056/NEJMsa053935. [DOI] [PubMed] [Google Scholar]
  • 29.Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356–359. doi: 10.1001/jama.287.3.356. [DOI] [PubMed] [Google Scholar]
  • 30.Bitner V, Johnson BD, Zineh I, et al. The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: A Report From the Women’s Ischemia Syndrome Evaluation (WISE) Am Heart J. 2009;157:548–555. doi: 10.1016/j.ahj.2008.11.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Frohlich J, Dobiasova M. Fractional esterification rate of cholesterol and ratio of triglycerides to HDL-cholesterol are powerful predictors of positive findings on coronary angiography. Clin Chem. 2003;49:1873–1880. doi: 10.1373/clinchem.2003.022558. [DOI] [PubMed] [Google Scholar]
  • 32.Walldius G, Jungner I, Holme I, et al. High apolipoprotein B, low apolipoprotein A-1, and improvement in the prediction of fatal myocardial (AMORIS study): A prospective study. Lancet. 2001;358:2026–2033. doi: 10.1016/S0140-6736(01)07098-2. [DOI] [PubMed] [Google Scholar]
  • 33.Benn M, Nordestgaard BG, Jensen GB, et al. Improving prediction of ischemic cardiovascular disease in the general population using apolipoprotein B: The Copenhagen City Heart Study. Arterioscler Thromb Vasc Biol. 2007;27:661–670. doi: 10.1161/01.ATV.0000255580.73689.8e. [DOI] [PubMed] [Google Scholar]
  • 34.Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case–control study. Lancet. 2004;364:937–951. doi: 10.1016/S0140-6736(04)17018-9. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

suppl-tab
NIHMS948144-supplement-suppl-tab.pdf (155.9KB, pdf)

RESOURCES