Age at diagnosis determines coronary artery risk in familial hypercholesterolemia: a population-based study

Abstract Background Younger patients with phenotypic familial hypercholesterolemia (FH) have a high risk of cardiovascular disease. However, the lifetime risk of atherosclerotic cardiovascular disease (ASCVD) in gene-positive FH compared to the general population remains unknown. Purpose This study investigated the impact of age at FH diagnosis on ASCVD risk in gene-positive FH patients compared to those with negative genetic testing, and the general population. Methods We included all patients tested for FH at a tertiary lipid clinic in the Central Denmark Region from 1992 to 2023. Patients were matched 1:10 with the general population on age and sex using data from Statistics Denmark. The cohort was divided into quartiles based on age at diagnosis and further stratified by genetic test results (FH-positive or FH-negative). The primary outcome was a composite of hospital admission due to acute or chronic coronary syndrome. Outcomes were assessed using data from the Danish National Patient Registry (1977–2024), with follow-up until death or emigration. Prevalence and incidence rates were compared descriptively, while logistic regression was used for prevalent ASCVD and Cox proportional hazards models for incident ASCVD. FH-positive patients diagnosed before age 29 served as the reference group. Results A total of 2,672 patients were tested for FH, of whom 1,162 were gene-positive and 1,511 gene-negative. The control group comprised 26,741 individuals. Median age at diagnosis was 44 years 29;55, and 54.3% were female. Mean follow-up time was 14.3 ± 9.7 years. Mean LDL cholesterol levels were 6.7 ± 2.0 mmol/L in FH-positive patients and 5.3 ± 1.7 mmol/L in FH-negative patients. Among FH-positive patients, 302 (25.9%) experienced a primary outcome event, compared to 408 (27.0%) in the FH-negative group and 2,007 (7.5%) in the general population. Before genetic testing, ASCVD prevalence was low in the youngest age group (29 years) but increased significantly with age (Figure 1A). A similar pattern was observed for incident ASCVD after diagnosis, with increasing incidence rates and lifetime risk (Figure 1B + 1C). Logistic regression showed a rising risk of ASCVD with increasing age (Figure 2A). After adjusting for sex and age, age at FH diagnosis remained the strongest determinant of lifetime ASCVD risk, with patients diagnosed at a younger age having a lower risk than those diagnosed later in life (Figure 2B). Conclusion The risk of ASCVD before FH diagnosis was very low in young gene-positive patients. However, lifetime ASCVD risk was significantly elevated in all FH-tested patients —both gene-positive and gene-negative — compared to the general population. Importantly, FH-positive patients diagnosed at a younger age had a lower lifetime ASCVD risk than those diagnosed later in life.Figure 1 Figure 2