Aortic valve phenotype in HoFH shifted from to calcified aortic stenosis since statins

Aortic stenosis in homozygous familial hypercholesterolaemia: a paradigm shift over a century

Literature - Bélanger AM, Akioyamen LE, Ruel I, et al. - Eur Heart J. 2022 Sep 7;43(34):3227-3239. doi: 10.1093/eurheartj/ehac339.

Introduction and methods


Severe calcified aortic stenosis (AS) is an important long-term complication of homozygous familial hypercholesterolemia (HoFH) [1]. The first cases of AS in FH patients were published in the 1940s and 1950s [2-5]. In the pre-statin era, supravalvular AS (SVAS) was described as a feature in HoFH. However, it is unclear whether the introduction of statins in 1987 affected the AS phenotype in patients with HoFH.

Aim of the study

The aim of this study was to summarize the aortic valve phenotype and to determine whether the introduction of statins affected the AS phenotype in patients with HoFH.


The researchers conducted a systematic review according to the MOOSE and PRISMA guidelines. Several databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PubMed, AfricaWide, and Scopus) were searched for English-language case-control, cohort, cross-sectional studies, and case reports published up to 10 November 2021 that examined the association between HoFH and AS. Studies in which the diagnosis of HoFH was not based on clinical grounds and genotyping were excluded, as were studies without objective confirmation of AS. A total of 19 cross-sectional or retrospective cohort studies (n=424) were selected with a moderate or strong global rating. The selected studies were stratified by publication date, using 1990 as a cut-point between the pre-statin era and the period when statins were introduced. The year 2000 was arbitrarily selected as the starting point for long-term statin use.


The researchers were interested in the frequency of valvular AS (VAS) and SVAS in patients with HoFH in the pre-statin era (< 1990), during the period when statins were introduced (1990-2000), and during the period of long-term statin use (> 2000). Because of the small sample sizes and the high degree of clinical heterogeneity in the included studies, a meta-analysis was not performed.

Main results

  • In the pre-statin era, VAS was diagnosed in 20 (57%) and SVAS in 18 (51%) of 35 patients with HoFH, resulting in a VAS:SVAS ratio of 53%:47%.
  • During the period when statins were introduced, VAS was diagnosed in 12 (41%) and SVAS in 11 (38%) of 29 patients with HoFH with a VAS:SVAS ratio of 52%:48%.
  • During the period of long-term statin use VAS was diagnosed in 113 (35%) and SVAS in 13 (4%) of 325 patients with HoFH, representing a VAS:SVAS ratio of 90%:10%/.
  • Patients with HoFH and long-term statin use had lower odds of developing VAS (OR: 0.53; 95%CI: 0.32-0.92) and SVAS (OR: 0.05; 95%BC: 0.02-0.11), compared with patients with HoFH from the pre-statin era or the period when statins were introduced.


The results of this systematic review show that VAS and SVAS are frequent in patients with HoFH. The prevalence of early AS has decreased and the phenotype of AS has shifted to calcified AS, which may be due to long-term statin use.


1. Awan Z, Alrasadi K, Francis GA, et al. Vascular calcifications in homozygote familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2008;28:777-785.

2. Cook CD, Smith HL, Conrad WG, et al. Xanthoma tuberosum, aortic stenosis, coronary sclerosis and angina pectoris: report of a case in a boy thirteen years of age. Am J Dis Child (1911). 1947;73:326-333.

3. Rigdon RH, Willeford G. Sudden death during childhood with xanthoma tuberosum: review of literature and report of a case. J Insur Med (1946). 1950;5:29-32.

4. Barr DP, Rothbard S, Eder HA. Atherosclerosis and aortic stenosis in hypercholesteremic xanthomatosis. J Am Med Assoc, 1954;156:943-947.

5. Boas EP, Elster SK, Adlersberg D. Calcific aortic stenosis; study of serum cholesterol, with observations on calcific aortic stenosis in familial xanthomatosis and hypercholesteremia. Am Heart J. 1954;48:485-496.

Find this article online at Eur Heart J.

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