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Lipoprotein(a) as a risk factor for calcific aortic valvulopathy in heterozygous familial hypercholesterolemia

      Highlights

      • Lp(a) levels above 30–50 mg/dL associate with calcific aortic valve stenosis.
      • he-FH patients have marked lifelong elevation of serum LDL-cholesterol level.
      • AVC among he-FH patients is more frequent than in the general population.
      • Lp(a) life years is a useful metric of cumulative burden of Lp(a).
      • Apo(a) antisense oligonucleotides effectively lower Lp(a) concentration.

      Abstract

      A large number of epidemiological studies in ethnically diverse populations show that lipoprotein(a) [Lp(a)] levels above 30–50 mg/dL are significantly associated with calcific aortic valve stenosis, although less so in African Americans. Patients with heterozygous familial hypercholesterolemia (he-FH) have a marked lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) level, and the prevalence of aortic valve calcification (AVC) is at least two-fold higher among adult he-FH patients compared with healthy controls. Additionally, Lp(a) levels above 50 mg/dL were recently found to be an independent risk factor for AVC among asymptomatic statin-treated he-FH patients. Given that worldwide an estimated 1.4 billion people have an Lp(a) level over 50 mg/dL, and that one out of 250 individuals has he-FH, then globally about 5 million he-FH patients should have an Lp(a) level higher than 50 mg/dL. However, because Lp(a) levels are, on average, significantly higher in he-FH patients than the general population, the actual number of he-FH patients with such high Lp(a) levels must be even higher.
      We proposed recently that Lp(a) life-years is a useful metric of cumulative burden of risk for atherosclerotic cardiovascular disease (ASCVD), and now posit that this metric may be extended to the development of AVC. The Lp(a) life-years illustrates the age-dependent exposure to a given Lp(a) level (years x mg/dL). Effective novel pharmacotherapies using apo(a) antisense oligonucleotides (ASOs) or small interfering RNA (siRNA)-based therapies targeting the hepatic expression of apo(a) offer unprecedented potential for significant reduction in the cumulative exposure of the aortic valves to Lp(a), and need to be tested in controlled clinical trials on the progression of AVC.

      Keywords

      Abbreviations:

      apoB (apolipoprotein B), AMI (acute myocardial infarction), AS (aortic stenosis), ASCVD (atherosclerotic cardiovascular disease), ASO (antisense oligonucleotide), AVC (aortic valve calcification), CETP (cholesteryl ester transfer protein), he-FH (heterozygous familial hypercholesterolemia), LDL-C (low-density lipoprotein cholesterol), LDLR (low-density lipoprotein receptor), Lp(a) (lipoprotein(a)), LPA (lysophosphatidic acid), MACE (major adverse cardiac event), mAb (monoclonal antibody), OxPLs (oxidized phospholipids), PCSK9 (proprotein convertase subtilisin/kexin type 9), siRNA (small interfering RNA), TAVI (transcatheter aortic valve implantation)
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