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Asymptomatic Intracranial Artery Stenosis/Occlusion in Heterozygous Familial Hypercholesterolemia: Its Frequency and
Sayaka Funabashi1,2, Yu Kataoka1, Mika Hori3,4
1Department of Cardiovascular Medicine National Cerebral and Cardiovascular Center Suita Japan.
Insights
Atherosclerotic cardiovascular disease risk is elevated in heterozygous familial hypercholesterolemia (HeFH). Asymptomatic intracranial artery stenosis/occlusion (IASO) affects 13.6% of HeFH patients, increasing major adverse cardiovascular events risk.
Area of Science:
- Cardiovascular Medicine
- Neurology
- Genetics
Background:
- Heterozygous familial hypercholesterolemia (HeFH) significantly elevates the risk of premature atherosclerotic cardiovascular disease, including coronary artery disease and ischemic stroke.
- Asymptomatic intracranial artery stenosis/occlusion (IASO) is a critical, yet under-characterized, cause of ischemic stroke in HeFH patients.
Purpose of the Study:
- To investigate the prevalence of asymptomatic intracranial artery stenosis/occlusion (IASO) in patients with heterozygous familial hypercholesterolemia (HeFH).
- To compare the incidence of major adverse cerebrovascular and cardiovascular events in HeFH patients with and without asymptomatic IASO.
- To assess the impact of IASO on cardiovascular outcomes in HeFH patients despite lipid-lowering therapies.
Main Methods:
- Analysis of 147 clinically diagnosed HeFH subjects undergoing magnetic resonance imaging/magnetic resonance angiography for IASO evaluation (≥50% diameter stenosis).
- Comparison of major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, acute coronary syndrome) between HeFH patients with and without asymptomatic IASO.
- Long-term observational period of 12.4 years, with multivariate Cox proportional hazards modeling to adjust for clinical characteristics.
Main Results:
- Asymptomatic IASO was identified in 13.6% of the HeFH patient cohort.
- Patients with HeFH and IASO exhibited suboptimally controlled on-treatment low-density lipoprotein cholesterol levels and higher triglyceride levels compared to those without IASO.
- Asymptomatic IASO was associated with a 4.04-fold increased likelihood of major adverse cardiovascular events in HeFH patients, a finding robustly confirmed by multivariate analysis.
Conclusions:
- Asymptomatic intracranial artery stenosis/occlusion is a prevalent finding in Japanese subjects with HeFH, occurring in 13.6% of cases.
- HeFH patients with IASO demonstrate an elevated risk of cerebrovascular and cardiovascular events, even with lipid-lowering therapies.
- Asymptomatic IASO represents a significant phenotypic marker of atherosclerosis in HeFH, critically impacting long-term patient outcomes.
Background:
The atherogenic characteristics of heterozygous familial hypercholesterolemia (HeFH) increase the risk of premature atherosclerotic cardiovascular disease including not only coronary artery disease but ischemic stroke. Asymptomatic intracranial artery stenosis/occlusion (IASO) is a major cause of ischemic stroke, but it has not yet been fully characterized in patients with HeFH.
Methods And Results:
This study analyzed 147 clinically diagnosed subjects with HeFH who underwent magnetic resonance imaging/magnetic resonance angiography imaging for evaluation of IASO (≥50% diameter stenosis). Major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, and acute coronary syndrome) were compared in patients with HeFH with and without asymptomatic IASO. Asymptomatic IASO was observed in 13.6% of patients with HeFH. The untreated low-density lipoprotein cholesterol level (240±95 versus 244±75 mg/dL; P=0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, P=0.71; high-intensity statin, P=0.81; ezetimibe, P=0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, P=0.39; low-density lipoprotein apheresis, P=0.14), on-treatment low-density lipoprotein cholesterol level in patients with both HeFH and IASO was still suboptimally controlled (97±62 versus 105±50 mg/dL; P=0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; P=0.001). During the 12.4-year observational period (interquartile range, 6.2-24.6 years), asymptomatic IASO exhibited a 4.04-fold greater likelihood of experiencing a major adverse cardiovascular event (95% CI, 1.71-9.55; P=0.001) in patients with HeFH. This increased risk of a major adverse cardiovascular event was consistently observed in a multivariate Cox proportional hazards model adjusting clinical characteristics (hazard ratio, 4.32 [95% CI, 1.71-10.9]; P=0.002).
Conclusions:
A total of 13.6% of Japanese subjects with HeFH presented with asymptomatic IASO. Despite lipid-lowering therapies, patients with both HeFH and IASO more likely had elevated risk of cerebrovascular and cardiovascular events. Our findings highlight asymptomatic IASO as a phenotypic feature of HeFH-related atherosclerosis, which ultimately affects future outcomes.
