Substantially Elevated Atherosclerotic Risks in Japanese Severe Familial Hypercholesterolemia Defined by the International Atherosclerosis Society.

Abstract

The International Atherosclerosis Society (IAS) has proposed "severe familial hypercholesterolemia" (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown. This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH. This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400mg/dL, >310mg/dL plus 1 high-risk feature, or >190mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n=135) and non-severe (n=227) FH. Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol (P< 0.001) and lipoprotein(a) (P = 0.03) levels. Moreover, they more frequently received high-intensity statin (P< 0.001), PCSK9 inhibitor (P< 0.001), and lipoprotein apheresis (P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite (P< 0.001), cardiac (P< 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first (P< 0.001) and of subsequent (P< 0.001) composite outcomes in subjects with severe FH. Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management.