Author + information
- Received January 23, 2012
- Revision received April 12, 2012
- Accepted April 16, 2012
- Published online August 21, 2012.
- ↵⁎Reprint requests and correspondence:
Dr. Sotirios Tsimikas, Vascular Medicine Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92993-0682
Recent published studies have provided increasing evidence that lipoprotein(a) [Lp(a)] may be a potential causal, genetic, independent risk factor for cardiovascular disease (CVD). Lp(a) levels >25 mg/dl are present in ∼30% of Caucasians and 60% to 70% of Blacks. Lp(a) is composed of apolipoprotein B-100 and apolipoprotein (a) [(apo(a)]. Circulating Lp(a) levels are primarily influenced by the LPA gene without significant dietary or environmental effects, mediating CVD risk throughout the patient's lifetime. Recent clinical outcomes studies, meta-analyses, and Mendelian randomization studies, in which randomization of Lp(a) levels is achieved through the random assortment of LPA gene variants thereby removing confounders, have shown that genetically determined Lp(a) levels are continuously and linearly related to risk of CVD. Currently, Lp(a) pathophysiology is not fully understood, and specifically targeted therapies to lower Lp(a) are not available. We provide a rationale for increased basic and clinical investigational efforts to further understand Lp(a) pathophysiology and assess whether reducing Lp(a) levels minimizes CVD risk. First, a detailed understanding of Lp(a) synthesis and clearance has not been realized. Second, several mechanisms of atherogenicity are known to varying extent, but the relative contributions of each are not known. Lp(a) may be atherothrombotic through its low-density lipoprotein moiety, but also through apo(a), including its ability to be retained in the vessel wall and mediate pro-inflammatory and proapoptotic effects including those potentiated by its content of oxidized phospholipids, and antifibrinolytic effects. Finally, development of specific Lp(a)-lowering agents to potently lower Lp(a) will allow testing of mechanistic hypotheses in animal models and the design of randomized clinical trials to assess reduction in CVD. A convergence of academic, scientific, pharmaceutical, and National Institutes of Health priorities and efforts can make this a reality in the next decade.
Dr. Tsimikas is named as an inventor of and receives royalties from patents awarded to the University of California for the use of oxidation-specific antibodies, is a co-founder and has equity interest in Atherotope, is a consultant to ISIS Pharmaceuticals, Genzyme, and Quest Pharmaceuticals, and has received investigator-initiated grants from Merck and Pfizer. Dr. Hall consults for the University of Southern Florida. Stephen J. Nicholls, MD, PhD, served as Guest Editor of this paper.
- Received January 23, 2012.
- Revision received April 12, 2012.
- Accepted April 16, 2012.
- American College of Cardiology Foundation
- What is Lp(a)?
- What is the contribution of Lp(a) to genetic risk of CVD and specifically atherothrombosis?
- What are the biological mechanistic underpinnings of the atherogenicity of Lp(a)?
- What are the gaps in the basic understanding of Lp(a) biology?
- What are the gaps in clinical medicine and the rationale for developing targeted and specific therapies for lowering plasma Lp(a) levels?