Predictors of aortic stenosis in homozygous familial hypercholesterolemia: A study from the Canadian HoFH Registry

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Homozygous familial hypercholesterolemia (HoFH) (n=67). Intervention: Baseline LDL-C vs. Lower baseline LDL-C. Primary outcome: Aortic stenosis (HR 1.22, 95% CI 1.09-1.35, p=0.0003).

Q: What does this research mean for the field?

A protocol-based implementation strategy for early intensive lipid-lowering therapy significantly increases the proportion of patients achieving guideline-recommended LDL-C targets after acute coronary syndrome compared to standard care. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

Martine Paquette; Armen Erzingatzian; Isabelle L. Ruel; Zobaida Al‐Baldawi; Leslie Brown; Mark Sherman; Nathalie Laflamme; Jean Bergeron; Patrick Couture; Diane Brisson; Miriam Larouche; Daniel Gaudet; Lubomira Cermakova; Darryl Wan; Nathaniel Moulson; Gordon A. Francis; G.B. John Mancini; Brooke A. Kennedy; Robert A. Hegele; Gary F. Lewis; Brian W. McCrindle; Barbara Cifra; Thomas Ransom; Ruth McPherson; Jacques Genest; Liam R. Brunham; Iulia Iatan; Alexis Baass

doi:10.1016/j.jacl.2026.08.023

Key result

Baseline LDL-C (HR 1.22; 95% CI 1.09-1.35) and the presence of at least one null genetic variant (HR 3.73; 95% CI 1.41-9.86) independently predicted aortic stenosis in patients with HoFH.

Why the study?

Timely implementation of intensive lipid-lowering therapy and achievement of LDL-C targets after ACS remain suboptimal in routine clinical practice.

Does a protocol-based implementation strategy improve the achievement of guideline-recommended LDL-C targets at 6 months in patients with acute coronary syndrome?

Key Points

To identify univariable and multivariable predictors of aortic stenosis in individuals diagnosed with homozygous familial hypercholesterolemia.
Conducted a retrospective longitudinal study of individuals from the Canadian HoFH registry (N = 67) using clinical data collected via standardized questionnaires.
Evaluated predictors using Cox proportional hazards regression models and estimated lifetime risk using Kaplan-Meier analyses.
Aortic stenosis developed in 37% (25 of 67) of patients in the cohort (mean baseline age 22 ± 17 years; 57% female).
Independent multivariable predictors of aortic stenosis included baseline LDL-C (HR 1.22, 95% CI 1.09–1.35, P = .0003) and carrying at least 1 null genetic variant (HR 3.73, 95% CI 1.41–9.86, P = .008).
Patients with baseline LDL-C above 13 mmol/L exhibited an observed lifetime risk of aortic stenosis approaching 100%, compared with 27% in patients below this threshold (P = .0002).

Study Design

Type

Cohort (n=67)

Multicenter

Yes

Structured PICO

Does a protocol-based implementation strategy improve the achievement of guideline-recommended LDL-C targets at 6 months in patients with acute coronary syndrome?

P

Population

67 patients with homozygous familial hypercholesterolemia from a Canadian registry (mean age 22 years, 57% female) assessed for predictors of aortic stenosis.

E

Exposure

Protocol-based lipid management strategy where lipid-lowering therapy (high-intensity statins, ezetimibe, PCSK9 inhibitors) was initiated or intensified during index hospitalization using a prespecified algorithm, with reassessment and escalation at 4 weeks targeting an operational threshold of LDL-C ~55 mg/dL.

C

Comparator

Standard lipid management with a treatment goal of LDL-C <70 mg/dL.

O

Outcome

Achievement of LDL-C <70 mg/dL at 6 months.surrogate

Main Result

Hazard Ratio: 1.22 (95% CI 1.09–1.35)

p-value: p=0.0003

A protocol-based implementation strategy for early intensive lipid-lowering therapy significantly improves the achievement of guideline-recommended LDL-C targets after acute coronary syndrome compared to standard care.

Limitations

Requires external validation in an international cohort

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

May support earlier intensive lipid lowering in HoFH to curb aortic stenosis; extends observational data but leaves open need for prospective trials.

Abstract

BACKGROUND Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. This disease is associated with a major risk of both atherosclerotic cardiovascular disease and aortic stenosis (AS). The predictors of AS in this population are not well established. OBJECTIVE To investigate the univariable and multivariable predictors of AS in patients from the Canadian HoFH registry. METHODS Individuals from the Canadian HoFH registry were included in this retrospective longitudinal study. Clinical data were obtained from the treating physicians using a standardized questionnaire. Cox proportional hazards models were used to investigate the predictors of AS. The observed lifetime risk of AS was calculated using Kaplan-Meier estimates. RESULTS Among the 67 patients with HoFH, 25 (37%) developed AS. The mean age at baseline was 22 ± 17 years and women represented 57% of the cohort. The independent predictors of AS were the baseline LDL-C (hazard ratio [HR] 1.22 [1.09-1.35], P = .0003) as well as the presence of at least 1 null genetic variant (HR 3.73 [1.41-9.86], P = .008). Having a baseline LDL-C value above 13 mmol/L was associated with an observed lifelong risk of developing AS approaching 100% within this cohort, whereas having a value below this threshold was associated with a risk of 27% (P = .0002). CONCLUSION This is the first systematic evaluation within a national HoFH registry to report the univariable and multivariable predictors of AS in patients with HoFH. An external validation of our results in an international cohort of HoFH is warranted.

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Cite This Study

Paquette et al. (2026) conducted a cohort in Homozygous familial hypercholesterolemia (HoFH) (n=67). Baseline LDL-C vs. Lower baseline LDL-C was evaluated on Aortic stenosis (HR 1.22, 95% CI 1.09-1.35, p=0.0003). Baseline LDL-C (HR 1.22; 95% CI 1.09-1.35) and the presence of at least one null genetic variant (HR 3.73; 95% CI 1.41-9.86) independently predicted aortic stenosis in patients with HoFH.

synapsesocial.com/papers/6a9ab1715d9e33f25c631f49 https://doi.org/10.1016/j.jacl.2026.08.023

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Predictors of aortic stenosis in homozygous familial hypercholesterolemia: A study from the Canadian HoFH Registry

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Predictors of aortic stenosis in homozygous familial hypercholesterolemia: A study from the Canadian HoFH Registry

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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