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Macrovascular Residual Risk THROUGH LANDMARK STUDY

4 December 2017
New analysis from Copenhagen General Population Study reaffirms the importance of elevated remnant cholesterol as a risk factor for MI

High levels of remnant cholesterol, the cholesterol content of triglyceride-rich lipoproteins, is a risk factor for myocardial infarction (MI) independent of body mass index (BMI).

Varbo A, Freiberg JJ, Nordestgaard BG. Remnant cholesterol and myocardial infarction in normal weight, overweight, and obese individuals from the Copenhagen General Population Study.
Clin Chem 2017; doi:10.1373/clinchem.2017.279463 3
Summary
Comments & References
STUDY SUMMARY
Objective: To investigate whether high remnant cholesterol is associated with high myocardial infarction risk, independent of whether an individual is normal weight, overweight, or obese.
Study design: The Copenhagen General Population Study is a prospective study of the Danish general population; the current data relate to 2003 to 2016.  Follow-up data were obtained in individuals re-invited approximately 10 years after the initial visit, starting in 2016.
Study population: Data from 106,216 adults, mean age 58 years, 55% women were included: median BMI was 26 kg/m2 (interquartile range [IQR] 23–28 kg/m2) and median calculated remnant cholesterol concentration was 0.6 mmol/L (IQR, 0.4–0.9 mmol/L) [23 mg/dL (15–35 mg/dL)]. Overall, 902 individuals had a BMI <18.5 kg/m2 (underweight), 45,926 had a BMI between 18.5 and 24.9 kg/m2 (normal weight), 42,319 had a BMI between 25 and 29.9 kg/m2 (overweight), and 17,069 had a BMI ≥30 kg/m2 (obese).
Efficacy variables: The primary outcome was MI, determined by reviewing all hospital admissions and diagnoses entered in the national Danish Patient Registry and all causes of death entered in the national Danish Causes of Death Registry.

Remnant cholesterol was a calculated variable (defined as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol) in the main analysis; directly measured remnant cholesterol (i.e. triglyceride-rich lipoprotein cholesterol) was also measured by a newly developed homogenous automated assay.
Methods: The continuous association between calculated remnant cholesterol concentrations and BMI was evaluated by polynomial regression and P values were estimated by a linear regression of calculated remnant cholesterol and BMI, including only individuals with BMI of 18.5 to 35 kg/m2 (where the association was graphically linear). The association between calculated remnant cholesterol and BMI was also estimated by median concentrations with IQRs of remnant cholesterol across BMI deciles.

Hazard ratios for MI were estimated using Cox proportional hazards regression models adjusted for age. Individuals with an MI before study entry were excluded. Interactions between calculated remnant cholesterol and BMI on risk of MI were tested using a 2-factor interaction term, remnant cholesterol*BMI on continuous scales and in groups, in the multivariable adjusted model. Results were compared with a multivariable adjusted model without the interaction term using a likelihood ratio test.
Results:

Median (IQR) remnant cholesterol for each weight category is summarized in Table 1.

 

Table 1. Median remnant cholesterol for each weight category

 

Underweight

Normal weight

Overweight

Obese

mmol/L

0.40

(0.30–0.55)

0.50

(0.37– 0.71)

0.70

(0.49 –1.00)

0.85

(0.61–1.20)

mg/dL

15 (12–21)

19 (14–27)

27 (19–39)

33 (24–46)

Remnant cholesterol was positively associated with BMI until reaching a plateau of approximately 1 mmol/L (39 mg/dL) at BMI >35 kg/m2.

Over a follow-up of up to 11 years, 1,565 individuals experienced a MI. High remnant cholesterol was consistently associated with about 2-fold increase in MI risk in individuals who were normal weight, overweight or obese (Table 2).

Table 2. Comparison of MI risk in individuals with elevated remnant cholesterol (≥1.5 mmol/L or 58 mg/dL) versus those with values <0.5 mmol/L, by weight category

 

Normal weight

Overweight

Obese

Hazard ratio              (95% CI)

2.0 (1.3–3.2)

1.9 (1.4 –2.6)

2.3 (1.4 –3.5


Remnant cholesterol and BMI were positively correlated; however, high remnant cholesterol was associated with higher MI risk across the examined BMI subcategories, indicating that remnant cholesterol is a risk factor for MI independent of overweight and obesity.

Authors’ conclusion: Remnant cholesterol and BMI were positively correlated; however, high remnant cholesterol was associated with higher MI risk across the examined BMI subcategories, indicating that remnant cholesterol is a risk factor for MI independent of overweight and obesity.

COMMENT

Evidence from both observational and genetic studuies have demonstrated that remnant cholesterol (for which triglycerides are a marker) is a causal risk factor for ischaemic heart disease.(1-3) The atherogenicity of remnant cholesterol is explained by retention of the remnants of chylomicrons and large very low-density lipoproteins (VLDL) in the arterial wall where they eventually accumulate and instigate the process of atherosclerosis.(4) Furthermore, there is also experimental evidence to suggest that remnant cholesterol may be associated with mechanisms of endothelial dysfunction, as well as inflammation.(5)

Prior to this report it was known that remnant cholesterol was also a mediator linking obesity with ischaemic heart disease.(6) It was not known, however, whether the association between high concentrations of remnant cholesterol and high risk of ischaemic heart disease was evident across the spectrum of BMI, i.e. from normal weight to obesity. The current study provides important insights. While 12% of the variation in remnant cholesterol was explained by variation in BMI, the association between elevated remnant cholesterol and risk for MI was consistent in normal weight, overweight and obese individuals, increasing risk by about 2-fold, and therefore not solely driven by adiposity. The study findings are strengthened by the large cohort size, access to data registries to confirm MI, as well as consistency between calculated and direct measurements of remnant cholesterol. While the homogeneity of the study population (white Danish individuals) may be a limitation to wider generalization of the study findings, it is relevant that the Jackson Heart Study reported similar findings in a black population.(7)

Taken together, these results reaffirm the causal association of remnant cholesterol with ischaemic heart disease, including MI. While remnant cholesterol is strongly associated with BMI, adiposity is not a driver of the higher risk of MI with higher remnant cholesterol.  

References

1. 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.

2. Jorgensen AB, Frikke-Schmidt R, West AS et al. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826 –33.

3. Varbo A, Freiberg JJ, Nordestgaard BG. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population. Clin Chem 2015;61:533–43.

4. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima inner media. Arterioscler Thromb Vasc Biol 1995;15:534 – 42.

5. 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.

6. Varbo A, Benn M, Davey Smith G et al. Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease. Circ Res 2015;116:665–7.

7. Joshi PH, Khokhar AA, Massaro JM et al. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort studies. J Am Heart Assoc 2016;5:e002765.

Key words remnant cholesterol; body mass index; ischaemic heart disease; Copenhagen General Population Study