Advancing care in familial hypercholesterolemia Improving risk stratification and precision care

Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated, while patients with homozygous FH (HoFH) face a substantial burden of premature atherosclerotic cardiovascular disease (ASCVD). This thesis investigates opportunities to improve detection, risk stratification, and treatment across the continuum of care.
The first part examines genetic approaches to cardiovascular prevention. Evaluation of the Dutch cascade screening program demonstrates the continued effectiveness of family-based case finding. Validation of a high-throughput FH genotyping array supports its potential use in large-scale screening, provided that positive results are confirmed and persistent clinical suspicion after a negative result prompts comprehensive sequencing. Analyses of the international HICC registry show that LDLR variant functional severity is associated with lipid phenotype, treatment response, and cardiovascular risk in HoFH. Polygenic risk scores may further refine risk assessment in families with premature ASCVD.
The second part addresses clinical care in HoFH. It identifies variation in the management of pregnancy, substantial global disparities in access to lipid-lowering therapies, and persistently low attainment of low-density lipoprotein (LDL) cholesterol goals. It also examines the contributions of traditional risk factors and sex to cardiovascular outcomes.
The final part explores advanced lipid-lowering therapies and coronary imaging. Studies involving evinacumab assess whether intensive LDL-cholesterol lowering may slow coronary atherosclerosis progression, while a review of liver-directed RNA and gene-editing therapies considers future treatment strategies.