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Macrovascular Residual Risk Studies

13 June 2016
Remnant cholesterol levels are predictive of coronary heart disease in primary prevention patients
Results from the Jackson Heart and Framingham Offspring Cohort Studies provide strong support for interventions targeting remnant cholesterol to prevent coronary heart disease.
Joshi PH, Khokhar AA, Massaro JM, Lirette ST, Griswold ME, Martin SS, Blaha MJ, Kulkarni KR, Correa A, D’Agostino RB, Sr, Jones SR, Toth PP, on behalf of the Lipoprotein Investigators Collaborative (LIC) Study Group. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort Studies. Am Heart Assoc J 2016;5:e002765.
Objective: To investigate the association of levels of remnant lipoprotein cholesterol (remnant cholesterol), the triglyceride-enriched precursors to low-density lipoprotein, with incident coronary heart disease (CHD) in the primary prevention setting.
Study design: The study involved two prospective, longitudinal observational US cohorts: the Jackson Heart Study and the Framingham Offspring Cohort Study
Study population: Data from 4,114 US black subjects (mean age 53.8 years, 64% women, 11% on lipid-lowering therapy) from the Jackson Heart Study, and 818 predominantly white subjects (mean age 57.3 years, 52% women, 8% on lipid-lowering therapy) from the Framingham Offspring Cohort Study. In each cohort, the subjects were followed up for 8 years.
Efficacity measures:

·       Remnant cholesterol, defined as the sum of cholesterol in the densest very low-density lipoprotein (VLDL) subfraction (i.e.  VLDL3) and intermediate-density lipoprotein.


·       Coronary heart disease events, was defined as a composite of myocardial infarction (MI), CHD death, and revascularization including coronary artery bypass graft surgery or angioplasty.

Methods: Multivariable-adjusted hazard ratios (HRs) for remnant cholesterol were calculated to investigate associations with incident CHD events, separately for each cohort and combined.
Main results:

Over the follow-up period, there were 146 CHD events in the combined cohorts, 112 events in the Jackson Heart Study, and 34 events in the Framingham Offspring Cohort Study.

 In the combined cohorts, there was a 23% increase in CHD risk per 1-SD increase in remnant cholesterol (HR 1.23, 95% CI 1.06–1.42, p<0.01), after adjustment for cardiovascular risk factors (age, sex, body mass index, smoking, blood pressure, diabetes, and lipid-lowering therapy). This association was slightly attenuated by adjustment for high-density lipoprotein cholesterol (HDL-C) but remained statistically significant (HR 1.20, 95% CI 1.03–1.40, p=0.02). Results were similar for the individual cohorts (Table).

 There was a trend for an interaction between HDL-C and remnant cholesterol levels (p=0.07). The highest CHD risk was in subjects with the lowest HDL?C and highest remnant cholesterol levels.


 Table. Association between remnant cholesterol and CHD events


HR (95% CI)*



1.23 (1.06–1.42)


Jackson Heart Study

1.18 (1.00–1.39)


Framingham Offspring Cohort Study

1.46 (1.05–2.04)


* Hazard ratio associated with a 1 standard deviation increase in remnant cholesterol, adjusted for cardiovascular risk factors (see above)
Authors’ conclusion: Remnant cholesterol levels are predictive of incident CHD in this diverse group of primary prevention subjects. Interventions aimed at reducing remnant cholesterol to prevent CHD warrant further intensive investigation.


The results of this analysis provide further support for remnant lipoprotein cholesterol as an independent contributor to lipid-related cardiovascular risk. Indeed, in the combined analysis, each standard deviation increase in remnant cholesterol was associated with 23% increase in risk of CHD. These findings are consistent with other studies, including the Honolulu Heart Study in more than 1100 men followed for over 17 years.1 Mendelian randomization studies add to this, with the risk of ischaemic heart disease increased nearly 3-fold for each 39-mg/dL increase in nonfasting remnant cholesterol levels (based on nonfasting triglycerides measurement).2 Mechanistic studies provide a rationale, showing that remnant particles are retained in the arterial wall and therefore contribute to the development of atherosclerosis, by upregulation of pro-inflammatory cytokines, monocyte recruitment and activation, as well as increased production of prothrombotic factors.3Taken together, the accumulating body of evidence supports a causative role for remnant lipoproteins in atherosclerosis.

The question that remains, however, is how best to target remnant cholesterol, as recognized by recently published guidelines for cardiovascular disease prevention.4 In this context, there are a number of novel treatments in development with therapeutic potential. These include an antisense oligonucleotide inhibitor of apolipoprotein CIII, a key component of remnant lipoproteins which inhibits lipoprotein lipase and hepatic lipase, as well as possibly promoting very low-density lipoprotein assembly.5,6 Other possibilities may include a selective peroxisome proliferator-activated receptor modulator (SPPARM), with initial studies showing reduction in remnant cholesterol by up to 50%.7

Definitive outcomes studies are needed to demonstrate whether such interventions will reduce the high residual risk that persists despite well controlled low-density lipoprotein cholesterol levels. Moreover, there is also interest whether such interventions will not only favourably impact atherogenic lipoproteins, but also inflammation associated with atherosclerosis.8


1. Imke C, Rodriguez BL, Grove JS et al. Are remnant-like particles independent predictors of coronary heart disease incidence? The Honolulu Heart Study Arterioscler Thromb Vasc Biol 2005;25:1718–22.

2. 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;61:427–36.

3. Proctor SD, Mamo JC. Intimal retention of cholesterol derived from apolipoprotein B100- and apolipoprotein B48-containing lipoproteins in carotid arteries of Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol 2003;23:1595–600.

4. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016; DOI: ehw106 First published online: 23 May 2016.

5. Wyler von Ballmoos MC, Haring B, Sacks FM. The risk of cardiovascular events with increased apolipoprotein CIII: A systematic review and meta-analysis. J Clin Lipidol 2015;9:498-510.

6. Gaudet D, Alexander VJ, Baker BF. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373:438-47.

7. Ishibashi S, Yamashita S, Arai H et al. Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 2016;249:36-43.

8. Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. 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;128:1298–309.

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