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

JACC Asia. 2021 Sep 21;1(2):245-255. doi: 10.1016/j.jacasi.2021.07.004. eCollection 2021 Sep.

Authors

Affiliations

¹ Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Centre, Suita, Osaka, Japan.
² Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center, Research Institute, Suita, Osaka, Japan.
³ Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
⁴ Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.
⁵ Department of Cardiology, Osaka Medical College, Takatsuki, Osaka, Japan.

Abstract

Background: 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.

Objectives: This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH.

Methods: 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 >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/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.

Results: 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 ± 53.9 mg/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.

Conclusions: 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.

Keywords: ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia; IAS, International Atherosclerosis Society; International Atherosclerosis Society; LDL-C, low-density lipoprotein-cholesterol; PAD, peripheral artery disease; coronary artery; familial hypercholesterolemia; peripheral artery; stroke.

© 2021 The Authors.