Lipoprotein(a) and cardiovascular disease
- Robert S Rosenson, MD
Robert S Rosenson, MD
- Professor of Medicine
- Mount Sinai School of Medicine
- Director, Cardiometabolic Disorders
- Mount Sinai Heart
- James H Stein, MD
James H Stein, MD
- Robert Turell Professor in Cardiovascular Research
- Director, Preventive Cardiology
- Department of Medicine, Cardiovascular Medicine Division
- University of Wisconsin School of Medicine and Public Health
- University of Wisconsin Hospital and Clinics
- Paul Durrington, MD
Paul Durrington, MD
- Professor of Medicine
- Physician to Manchester Royal Infirmary
- University of Manchester
Most trials of lipid-lowering therapy for the prevention of cardiovascular disease (CVD) focused on lowering low density lipoprotein cholesterol levels. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention".)
Although other dyslipidemias, such as an elevated level of lipoprotein(a), also may promote atherosclerosis, interventions directed toward altering these have only infrequently been evaluated in controlled clinical trials . Elevated serum lipoprotein(a), also referred to as Lp(a), is a risk factor for CVD. There is a causal relationship between Lp(a) excess and risk for myocardial infarction. (See 'Risk factor versus cause' below.)
This topic will review the genetics, structure, and function of Lp(a), as well as its association with atherosclerotic cardiovascular disease. Possible indications for screening and therapy will also be addressed. The association between Lp(a) and aortic valve sclerosis is discussed separately. (See "Aortic valve sclerosis and pathogenesis of calcific aortic stenosis", section on 'Pathogenesis of calcific aortic valve disease'.)
STRUCTURE AND FUNCTION
Lipoprotein(a) [Lp(a)] is a modified form of low density lipoprotein in which a large glycoprotein, apolipoprotein(a) [apo(a)] is covalently bound to apolipoprotein B by a disulfide bridge . The apo(a) chain contains five cysteine rich domains known as "kringles" . The fourth kringle is homologous with the fibrin-binding domain of plasminogen, a plasma protein that dissolves blood clots when activated. Because of this structural similarity to plasminogen, Lp(a) interferes with fibrinolysis by competing with plasminogen binding to molecules and cells. This impairs plasminogen activation, plasmin generation, and fibrinolysis [4,5]. Lp(a) also binds to macrophages via a high-affinity receptor that promotes foam cell formation and the deposition of cholesterol in atherosclerotic plaques .
Serum lipoprotein(a) [Lp(a)] levels are primarily genetically determined. In families of European descent without familial hypercholesterolemia, greater than 90 percent of the variability in Lp(a) levels can be explained by polymorphisms at the apolipoprotein(a) [apo(a)] gene locus (isoforms), also referred to as the LPA gene (Online Mendelian Inheritance in Man [MIM] 152200) . One important LPA polymorphism is the kringle IV type 2 size polymorphism, which results in a large number of differently sized isoforms of apo(a) . There is a strong inverse relationship between the size of the apo(a) isoforms and the Lp(a) concentrations [7,9-11]. A significant proportion (30 to 60 percent) of the population variation in Lp(a) levels is determined by this polymorphism .
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- STRUCTURE AND FUNCTION
- Measurement of serum Lp(a) concentration
- CVD RISK
- Cerebrovascular disease
- Patients with hypertension
- Risk factor versus cause
- MECHANISMS OF CVD RISK
- Myocardial infarction due to vasospasm
- Aggressive LDL-C reduction
- Lp(a) reduction
- - Lipid-lowering drugs
- - Apheresis
- - Antisense therapy
- SUMMARY AND RECOMMENDATIONS