FULL TEXT: http://www.onlinejac...ontent/69/6/692
Abstract
Evidence that elevated lipoprotein(a) (Lp[a]) levels contribute to cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS) is substantial. Development of isoform-independent assays, in concert with genetic, epidemiological, translational, and pathophysiological insights, have established Lp(a) as an independent, genetic, and likely causal risk factor for CVD and CAVS. These observations are consistent across a broad spectrum of patients, risk factors, and concomitant therapies, including patients with low-density lipoprotein cholesterol <70 mg/dl. Statins tend to increase Lp(a) levels, possibly contributing to the “residual risk” noted in outcomes trials and at the bedside. Recently approved proprotein convertase subtilisin/kexin-type 9 inhibitors and mipomersen lower Lp(a) 20% to 30%, and emerging RNA-targeted therapies lower Lp(a) >80%. These approaches will allow testing of the “Lp(a) hypothesis” in clinical trials. This review summarizes the current landscape of Lp(a), discusses controversies, and reviews emerging therapies to reduce plasma Lp(a) levels to decrease risk of CVD and CAVS.
Despite significant advances in the diagnosis and therapy of cardiovascular disease (CVD), patients continue to experience myocardial infarction, stroke, peripheral arterial disease, and need for revascularization. The advances in identifying modifiable risk factors for CVD, including smoking, hypertension, dyslipidemias, diabetes mellitus, and obesity, have allowed the development of practice patterns and evidence-based guidelines in medical therapy and revascularization that have contributed to the reduction of CVD mortality. However, despite these advances, ∼40% of all deaths can be attributed to CVD (1). Furthermore, in the short time window in which clinical trials evaluate therapies, only 20% to 30% of patients benefit, and more events develop in patients on active therapy than are prevented. These observations suggest that the presence of additional modifiable risk factors contributes to CVD risk.
Lipid disorders can be broadly divided into 4 “clinical” categories: elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, and elevated lipoprotein(a) (Lp[a]). In the current genetic era, it has become apparent that only elevated levels of apolipoprotein B-100 (apoB)−containing lipoproteins (very low-density lipoprotein, intermediate-density lipoprotein, LDL, Lp[a]) are causally associated with increased cardiovascular risk. In contrast, variations in genes associated with higher HDL-C or drugs that raise HDL-C are not associated with improvement in cardiovascular risk (2,3).
At the clinical level, elevated Lp(a) has been the least studied of these 4 lipid disorders. However, this is rapidly changing with the awareness of its role in CVD and calcific aortic valve stenosis (CAVS), and the potential of novel therapies to substantially lower Lp(a). This review summarizes the Lp(a) field from a translational and clinical perspective with its relationship with CVD and CAVS.
