Primary care detection reveals substantial cumulative LDL-C exposure in underrecognized heterozygous FH

Background

Heterozygous familial hypercholesterolaemia (HeFH) causes lifelong low-density lipoprotein cholesterol (LDL-C) elevation and markedly increased premature atherosclerotic cardiovascular disease (ASCVD) risk. In low-middle Southeast European settings lacking national registries, detection remains limited and reliance on single LDL-C measurements may underestimate cumulative atherogenic exposure.

Purpose

To determine the diagnostic yield of systematic ESC/EAS-aligned primary care screening for previously unrecognized HeFH and quantify cumulative LDL-C burden prior to diagnosis.

Methods

In a prospective single-centre, consecutive cohort (2024–2025), 1,000 unselected adults (mean age 52.8±13 years) were screened. Individuals with untreated or highest documented pre-treatment LDL-C ≥4.9 mmol/L underwent structured phenotypic assessment after exclusion of secondary causes. HeFH suspicion was defined using Dutch Lipid Clinic Network criteria (possible 3–5; probable 6–8). Serial LDL-C values were used to calculate cumulative LDL-C burden (mmol/L-years) by trapezoidal integration. Time-weighted average (TWA) LDL-C was derived as burden divided by exposure duration.

Results

Fifty-one individuals (5.1%) had LDL-C ≥4.9 mmol/L. Sixteen (1.6%, 95% CI 0.8–2.4%) fulfilled criteria for suspected HeFH, including seven probable cases (1 in 143 screened). None had prior structured FH evaluation. Diagnostic delay averaged 13.8±5.3 years, corresponding to a cumulative pre-diagnostic LDL-C burden of 102±37 mmol/L-years and a TWA LDL-C of 6.6±0.9 mmol/L. Pre-treatment LDL-C strongly correlated with diagnostic delay (r=0.80, p<0.001).

Despite identical LDL-C thresholds, suspected HeFH individuals (n=16) had markedly greater cumulative LDL-C exposure than non-FH participants (n=35): 102±37 vs 39.5±21 mmol/L-years, (mean difference 62.5 mmol/L-years, 95% CI 42.6–82.4; p<0.0001) with a 2.6-fold higher burden. TWA LDL-C was also higher: 6.6±0.9 vs 4.4±0.5 mmol/L (mean difference 2.2 mmol/L, 95% CI 1.72–2.68; p<0.0001).

Conclusions

ESC/EAS-aligned screening revealed a higher-than-expected prevalence of previously unrecognized HeFH and prolonged diagnostic delay, resulting in >100 mmol/L-years of cumulative LDL-C exposure. Although this burden was derived from documented measurements and may potentially underestimate true lifetime exposure, structured phenotypic assessment demonstrated marked heterogeneity with suspected HeFH patients showing a 2.6-fold greater cumulative burden. These findings support cumulative LDL-C as a biomarker that more accurately reflects preventable ASCVD risk than single measurements and highlight the importance of integrating cumulative biomarker–based assessment into primary care cardiovascular risk pathways, especially in regions without national FH registries.