Research Article: Low-Density Lipoprotein Electronegativity Is a Novel Cardiometabolic Risk Factor

Date Published: September 9, 2014

Publisher: Public Library of Science

Author(s): Jing-Fang Hsu, Tzu-Chieh Chou, Jonathan Lu, Shu-Hua Chen, Fang-Yu Chen, Ching-Chu Chen, Jeffrey L. Chen, MacArthur Elayda, Christie M. Ballantyne, Steven Shayani, Chu-Huang Chen, Stefan Kiechl.


Low-density lipoprotein (LDL) plays a central role in cardiovascular disease (CVD) development. In LDL chromatographically resolved according to charge, the most electronegative subfraction–L5–is the only subfraction that induces atherogenic responses in cultured vascular cells. Furthermore, increasing evidence has shown that plasma L5 levels are elevated in individuals with high cardiovascular risk. We hypothesized that LDL electronegativity is a novel index for predicting CVD.

In 30 asymptomatic individuals with metabolic syndrome (MetS) and 27 healthy control subjects, we examined correlations between plasma L5 levels and the number of MetS criteria fulfilled, CVD risk factors, and CVD risk according to the Framingham risk score.

L5 levels were significantly higher in MetS subjects than in control subjects (21.9±18.7 mg/dL vs. 11.2±10.7 mg/dL, P:0.01). The Jonckheere trend test revealed that the percent L5 of total LDL (L5%) and L5 concentration increased with the number of MetS criteria (P<0.001). L5% correlated with classic CVD risk factors, including waist circumference, body mass index, waist-to-height ratio, smoking status, blood pressure, and levels of fasting plasma glucose, triglyceride, and high-density lipoprotein. Stepwise regression analysis revealed that fasting plasma glucose level and body mass index contributed to 28% of L5% variance. The L5 concentration was associated with CVD risk and contributed to 11% of 30-year general CVD risk variance when controlling the variance of waist circumference. Our findings show that LDL electronegativity was associated with multiple CVD risk factors and CVD risk, suggesting that the LDL electronegativity index may have the potential to be a novel index for predicting CVD. Large-scale clinical trials are warranted to test the reliability of this hypothesis and the clinical importance of the LDL electronegativity index.

Partial Text

Cardiovascular disease (CVD) is a significant public health problem and is a source of economic burden in the United States and globally [1], [2]. The identification of major CVD risk factors is important for preventing, controlling, and treating this disease. Classic CVD risk factors include hypertension, dyslipidemia, diabetes mellitus, obesity, decreased physical exercise, and smoking [3]–[5]. Among these, the most evident causal disorder for CVD is dyslipidemia, or hypercholesterolemia [6], [7].

Levels of total plasma triglycerides and cholesterol, as well as LDL and HDL, have traditionally been monitored as predictors of cardiovascular events [31], [32]. In our study, we have investigated beyond total LDL levels and have examined whether plasma levels of electronegative L5 LDL may be a novel predictor of CVD. Similar to our previous findings, we showed that plasma L5 levels are increased in asymptomatic individuals with MetS [26]. Furthermore, we found that plasma L5 levels in asymptomatic MetS subjects were not only correlated with CVD risk factors and CVD risk but were also correlated with the number of MetS criteria fulfilled and, therefore, CVD progression. These strong correlations demonstrate that circulating L5 may have potential as a predictor of CVD progression and adverse cardiac events.