Intensive lipid lowering therapy reduces large, but not small, dense low-density lipoprotein particles measured by gel electrophoresis, in elderly patients with atrial fibrillation

Abstract

Low-density lipoprotein (LDL) cholesterol (LDL-C) is considered causative in atherosclerotic diseases, and LDL lowering therapy (LLT) has clearly demonstrated an effect on clinical endpoints. Despite numerous effective LLTs being readily available, attainment to recommended LDL-C targets are low and a large number of high-risk patients would benefit from more intensive treatment. LDL-C has significant limitations as a risk marker, and measuring small, dense LDL (sdLDL) particles has been proposed as a novel tool to improve cardiovascular risk stratification. Epidemiological studies have found an association between elevated levels of sdLDL and increased risk of cardiovascular disease and in-vitro studies suggest that sdLDL particles have increased atherogenic potential, but no studies have yet proven that adjusting treatment according to sdLDL measurements improves clinical outcomes. There are several methods for measuring and quantifying sdLDL; nuclear magnetic resonance, gel electrophoresis, ultracentrifugation and ion mobility are among the most commonly used. These methods are not directly comparable as they separate particles based on different physicochemical properties and the variability between methods is high. As there is no method generally accepted as a reference or a gold standard, each method must be validated separately. With regard to lowering sdLDL, the clinical trials published have been contradictory, possibly due to use of different methods in quantifying sdLDL and the poor comparability between them. The present study sought to evaluate the effects of a commonly used regime to lower LDL-C, atorvastatin 40mg plus ezetimibe 10mg, in a randomized, double blinded, placebo-controlled trial of 30 elderly patients with atrial fibrillation. Patient characteristics and study design have already been published. LDL subfractions were measured by a gel electrophoresis system (Lipoprint LDL ) that separates LDL into LDL1 and LDL2 (larger, more buoyant particles) and LDL3 into seven (smaller, denser particles) based on size and electrical charge. Blood samples were collected at baseline and after six months of follow-up. At inclusion there were no significant differences between the two groups. Atorvastatin/ezetimibe significantly reduced LDL-C (p< 0.001) and the larger, more buoyant particles LDL1 and LDL2 (p< 0.001), but had no effect on the sdLDL particles (Figure 1). Should measuring sdLDL be important in order to define risk and imply reductions in clinical outcomes, the results of this trial suggest that Lipoprint LDL, a commonly used gel electrophoresis system, would not be suitable to evaluate the treatment effect of a statin and ezetimibe. Further and larger studies are warranted, with regard to both identifying which method to use and whether measuring sdLDL yields clinically relevant information in the evaluation of patients at risk of atherosclerotic cardiovascular disease.