We have previously reported premature, extensive aortic calcifications in patients with homozygous familial hypercholesterolemia (hmzFH) due to mutations in the low-density lipoprotein receptor gene (LDL-R). The objective of this study was to measure the degree of aortic calcification in heterozygous FH (htzFH) compared to both hmzFH and controls. We hypothesized that the LDL-R gene may contribute to aortic calcifications in a gene-dosage effect.

Patients with htzFH due to the French Canadian mutation (Δ15 kb del. null allele) were selected. All patients underwent computed tomographic scan to measure vascular calcification. We used 22 hmzFH patients from our previous study and patients undergoing computed tomographic virtual colonoscopy as controls.

Mean age for htzFH was 50 ± 15 years; initial cholesterol level before treatment was 10.45 ± 1.73 mmol/L. Major cardiovascular events occurred in 9 of 17 patients. A strong correlation between age and calcium score was found (r = 0.72, P = .0016). There was a strong correlation between the cholesterol-year score (an index of lifelong cholesterol burden) and the aortic calcium score (r = 0.62, P = .0105). Aortic calcifications in htzFH subjects occurred later than in hmzFH patients, but much earlier than in controls, suggesting a gene-dosage effect of LDL-R mutations and aortic calcium deposition.

Aortic calcification was observed in patients with htzFH but presented at a later time and were less extensive than in hmzFH (34 vs 14 years, respectively). Because aortic calcifications may be partly independent of serum cholesterol levels in patients with familial hypercholesterolemia, implications for screening and the timing of treatment initiation may need reassessment.