Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options

Abstract

Lipoprotein(a) (Lp(a)) was discovered more than 50 years ago, and a decade later, it was recognized as a risk factor for coronary artery disease. However, it has gained importance only in the past 10 years, with emergence of drugs that can effectively decrease its levels. Lp(a) is a low-density lipoprotein (LDL) with an added apolipoprotein(a) attached to the apolipoprotein B component via a disulphide bond. Circulating levels of Lp(a) are mainly genetically determined. Lp(a) has many functions, which include proatherosclerotic, prothrombotic and pro-inflammatory roles. Here, we review recent data on the role of Lp(a) in the atherosclerotic process, and treatment options for patients with cardiovascular diseases. Currently 'Proprotein convertase subtilisin/kexin type 9' (PCSK9) inhibitors that act through non-specific reduction of Lp(a) are the only drugs that have shown effectiveness in clinical trials, to provide reductions in cardiovascular morbidity and mortality. The effects of PCSK9 inhibitors are not purely through Lp(a) reduction, but also through LDL cholesterol reduction. Finally, we discuss new drugs on the horizon, and gene-based therapies that affect transcription and translation of apolipoprotein(a) mRNA. Clinical trials in patients with high Lp(a) and low LDL cholesterol might tell us whether Lp(a) lowering per se decreases cardiovascular morbidity and mortality.KEY MESSAGESLipoprotein(a) is an important risk factor in patients with cardiovascular diseases.Lipoprotein(a) has many functions, which include proatherosclerotic, prothrombotic and pro-inflammatory roles.Treatment options to lower lipoprotein(a) levels are currently scarce, but new drugs are on the horizon.

Keywords: Lipoprotein(a); atherosclerosis; pathophysiology; treatment.

Figure 1.

Molecular structure of apolipoprotein(a). Apolipoprotein(a) contains 10 subtypes of KIV repeats, as one copy of KIV₁, multiple copies of KIV₂ and one copy each of KIV₃ to KIV₁₀, KV and inactive protease-like (P) domain.

Figure 2.

Role of lipoprotein(a) in the atherosclerotic process. The three defined roles of lipoprotein(a) in progression of the atherosclerotic process include its proatherogenic, prothrombotic, and pro-inflammatory effects. hsCRP, high sensitivity C-reactve protein; IL-6, interleukin 6; TNFα, tumour necrosis factor α.