Lipoprotein(a) and Cardiovascular Disease: A Missing Link for Premature Atherosclerotic Heart Disease and/or Residual Risk

Abstract

Lipoprotein(a) or lipoprotein "little a" [Lp(a)] is an under-recognized causal risk factor for cardiovascular (CV) disease (CVD), including coronary atherosclerosis, aortic valvular stenosis, ischemic stroke, heart failure, and peripheral arterial disease. Elevated plasma Lp(a) ($50 mg/dL or $100 nmol/L) is commonly encountered in almost 1 in 5 individuals and confers a higher CV risk compared with those with normal Lp(a) levels, although such normal levels have not been generally agreed upon. Elevated Lp(a) is considered a cause of premature and accelerated atherosclerotic CVD. Thus, in patients with a positive family or personal history of premature coronary artery disease (CAD), Lp(a) should be measured. However, elevated Lp(a) may confer increased risk for incident CAD even in the absence of a family history of CAD, and even in those who have guideline-lowered LDL cholesterol (,70 mg/dL) and continue to have a persisting CV residual risk. Thus, measurement of Lp(a) will have a significant clinical impact on the assessment of atherosclerotic CVD risk, and will assume a more important role in managing patients with CVD with the advent and clinical application of specific Lp(a)-lowering therapies. Conventional therapeutic approaches like lifestyle modification and statin therapy remain ineffective at lowering Lp(a). Newer treatment modalities, such as gene silencing via RNA interference with use of antisense oligonucleotide(s) or small interfering RNA molecules targeting Lp(a), seem very promising. These issues are herein reviewed, accumulated data are scrutinized, metaanalyses and current guidelines are tabulated, and Lp(a)related CVDs and newer therapeutic modalities are pictorially illustrated.

Developing a Hybrid Risk Assessment Tool for Familial Hypercholesterolemia: A Machine Learning Study of Chinese Arteriosclerotic Cardiovascular Disease Patients

“…Although lp(a) is 198.04 ± 228.51 mg/L in the high-risk group of HFHRAT and the modified process has a lower lp(a) value, the high lp(a) still has a good effect on FH risk assessment ( 52 ). However, its effect may be covered up as a continuous variable ( 60 ), and its normal cutoff value has not yet been generally agreed upon, which could hardly be leveled into the categorical variable.…”

Lipoprotein(a) Modulates Carotid Atherosclerosis in Metabolic Syndrome

“…Conversely, there is a lack of clinical evidence on how aggressive lipoprotein(a) lowering reduction improves the following ASCVD risk reduction. Attention should be then maintained on the other modifiable CV risk factors ( Ruscica et al, 2021 ; Melita et al, 2022 ). Furthermore, we should acknowledge a considerable amount of outlier—especially toward higher values—that should affect statistical analysis.…”

Atherogenic Dyslipidemias: Unmet Needs and the Therapeutic Potential of Emerging and Novel Approaches and Drugs

“…Epidemiology has consistently demonstrated an association between high Lp(a) levels and risk of atherosclerotic disease in different vascular districts [ 93 , 94 ], and these findings were recently corroborated in mendelian randomization studies [ 95 , 96 ]. Lp(a) in the general population is primarily genetically determined (70 to 90% of the interindividual variation) [ 97 , 98 ], though impairment of renal function may also lead to “acquired” hyperlipoprotein(a)emia [ 99 ].…”

“…What seems clear is that there is a positive linear association between Lp(a) levels and CV risk [ 100 , 101 ], and that values higher than 180–200 mg/dL may determine a risk such as the one endowed by HeFH [ 15 , 96 ]. Importantly, hyperlipoprotein(a)emia might turn out to be a target for the personalized reduction in the residual risk that remains in patients in secondary prevention notwithstanding a good control of traditional risk factors [ 94 , 102 , 103 ]. In a recent large epidemiological Danish study, the authors estimated that to achieve a 20% and 40% risk reduction of major adverse coronary events (MACEs) in secondary prevention, plasma Lp(a) levels should be lowered by 50 mg/dL and 99 mg/dL, respectively, for 5 years [ 104 ].…”