Lipoprotein(a) as a Potential Causal Genetic Risk Factor of Cardiovascular Disease A Rationale for Increased Efforts to Understand its Pathophysiology and Develop Targeted Therapies
ABSTRACT 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.
SourceAvailable from: Rocco RomagnuoloJournal of Biological Chemistry 03/2015; · 4.60 Impact Factor
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ABSTRACT: Diet has a significant relationship with the risk of coronary heart disease (CHD). Traditionally the effect of diet on CHD was measured with the biomarker for low-density lipoprotein (LDL) cholesterol. However, LDL is not the only or even the most important biomarker for CHD risk. A suitably integrated view of the mechanism by which diet influences the detailed CHD pathogenetic pathways is therefore needed in order to better understand CHD risk factors and help with better holistic CHD prevention and treatment decisions. A systematic review of the existing literature was conducted. From this an integrated CHD pathogenetic pathway system was constructed. CHD biomarkers, which are found on these pathways, are the only measurable data to link diet with these CHD pathways. They were thus used to simplify the link between diet and the CHD mechanism. Data were systematically analysed from 294 cohort studies of CHD biomarkers constituting 1 187 350 patients. The resulting integrated analysis provides insight into the higher-order interactions underlying CHD and high-glycemic load (HGL) diets. A novel "connection graph" illustrates the measurable relationship between HGL diets and the relative risks attributed to the important CHD serological biomarkers. The "connection graph" vividly shows that HGL diets not only influence the lipid and metabolic biomarkers, but also the inflammation, coagulation and vascular function biomarkers in an important way. A focus primarily on the low density lipoprotein cholesterol biomarker for CHD risk has led to the traditional guidelines of CHD dietary recommendations. This has however inadvertently led to HGL diets. The influence of HGL diets on the other CHD biomarkers is not always fully appreciated. Thus, new diets or other interventions which address the full integrated CHD impact, as shown in this paper, are required.
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ABSTRACT: Mipomersen (Kynamro®), a second-generation 2′-O-methoxyethyl chimeric antisense oligonucleotide (ASO), inhibits the synthesis of apolipoprotein B (apoB) and is indicated in the US as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH) at a dose of 200 mg subcutaneously (SC) once weekly. The pharmacokinetic (PK) properties of mipomersen are generally consistent across all species studied, including mouse, rat, monkey, and humans. After SC administration, mipomersen is rapidly and extensively absorbed. It has an apparent plasma and tissue terminal elimination half-life of approximately 30 days. Mipomersen achieves steady-state tissue concentrations within approximately 4–6 months of once-weekly dosing. It does not exhibit PK-based drug–drug interactions with other concomitant medications, either involving competition for plasma protein binding or alterations in disposition of any evaluated drugs. Furthermore, mipomersen does not prolong the corrected QT (QTc) interval. There have been no ethnic- or gender-related differences in PK observed. In clinical trials, both as a single agent and in the presence of maximal lipid-lowering therapy, mipomersen has demonstrated significant dose-dependent reductions in all measured apoB-containing atherogenic lipoproteins. Overall, mipomersen has well-characterized PK and pharmacodynamic properties in both animals and humans, and is an efficacious adjunct treatment for patients with HoFH.Clinical Pharmacokinetics 01/2015; 54(2). DOI:10.1007/s40262-014-0224-4 · 5.49 Impact Factor