Editors' ChoiceHeart Disease

Watch Your Leftovers: Remnant Cholesterol Brings Oversized Risk to Cardiovascular Health

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Science Translational Medicine  03 Dec 2014:
Vol. 6, Issue 265, pp. 265ec205
DOI: 10.1126/scitranslmed.aaa3506

The connection between obesity and cardiovascular risk is well established. Exactly how obesity translates into adverse cardiovascular outcomes, however, is a more complex question. Varbo et al. report progress toward this understanding with a pooled analysis of approximately 90,000 Danish subjects using a technique known as Mendelian randomization. This approach combines the power of large, population-based studies with the randomizing effect of chromosomal recombination. Because this randomization occurs independently of environmental factors, the genetic causation of a trait can be studied.

In this large analysis, subjects with genetically determined obesity were confirmed to have an increased risk of ischemic heart disease. One of the most striking findings was the marked contribution of “remnant cholesterol”—non-fasting total cholesterol minus low- and high-density lipoproteins (LDL and HDL) —to cardiovascular risk. These remnant particles are known to correlate with heart disease and include small cholesterol-dense particles that can easily cross endothelial barriers. The authors showed that LDL was responsible for an 8% contribution to cardiovascular risk, systolic blood pressure contributed 7%, and remnant cholesterol contributed an additional 7% of the risk for subjects with genetically determined obesity. For observationally determined obesity, the same factors had cardiovascular risk contributions of 21%, 11%, and 20%. Thus, in both conditions, the study implied that treating these three factors could improve cardiovascular outcome.

Although the study relies on an impressively sized data set, Mendelian randomization studies also have caveats, such as genetic pleiotropy and linkage disequilibrium, that can effect the estimations of causation. However, the remarkable contribution of remnant cholesterol, in addition to the traditional risk factors of blood pressure and LDL cholesterol, suggests an exciting new independent mediator that could be a target for cardiovascular risk reduction in obese patients.

A. Varbo et al., Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease. Circ. Res. CIRCRESAHA.114.304846 (2014). [Abstract]

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