Original ArticleCardiovascular disease in familial hypercholesterolemia: Validation and refinement of the Montreal-FH-SCORE
Introduction
Familial hypercholesterolemia (FH) is the most prevalent autosomal co-dominant genetic disease worldwide with an estimated frequency of 1:250 to 1:500.1, 2, 3 This disease is mainly caused by mutations in low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (ApoB), or proprotein convertase subtilisin/kexin-type 9 genes. Typically, FH leads to extremely high plasma LDL cholesterol (LDL-C) concentrations and high lifetime risk of cardiovascular disease (CVD). Indeed, coronary symptoms will be present in 45% of men and 20% of women with heterozygous FH (referred as FH in this article) before the age of 50 years.4 Annually, it has been estimated that 5% of myocardial infarctions before age of 60 years and 20% before age of 45 years occur in FH patients.5 However, CVD risk in FH is variable and circulating LDL-C level is not the sole indicator for risk prediction.3, 6, 7, 8, 9, 10, 11 CVD risk assessment and intensive risk factors management in FH should therefore be the cornerstone of cardiovascular prevention. The current established cardiovascular risk estimators such as the Framingham Risk Score, the Pooled Cohort Equation, and the European SCORE were created to assess CVD risk in the general population and cannot be applied to FH subjects.12 The recently developed Montreal-FH-SCORE (MFHS)13 represents the first scoring tool used to stratify CVD prevalence in FH subjects. This point scoring system uses 5 variables, namely age, high-density lipoprotein cholesterol (HDL-C), gender, hypertension, and smoking. The MFHS showed an excellent association with prevalent CVD with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 in the development cohort of 670 French Canadian adult FH. However, the MFHS has never been validated in an external cohort of FH patients.
The objectives of this study were to conduct an independent validation of the MFHS to test its association with CVD and to use the combined data from both cohorts to determine if other variables can significantly improve the prediction of prevalent CVD.
Section snippets
Validation cohort
All data of the validation cohort came from patients screened for FH at the Chicoutimi Hospital Lipid Clinic or at ECOGENE-21 Clinical Research Center (Saguenay, Québec, Canada) between 1993 and 2014. A total of 718 FH adult (aged ≥18 years) patients were included in the cohort. All these confirmed FH patients carried a classical French Canadian mutation in the LDLR gene, including deletion (del) > 15kb of the promoter and exon 1, del > 5 kb of exons 2 and 3, W66G (exon 3), E207K (exon 4),
Description of the validation cohort
In this cohort of 718 FH subjects (Table 2), 37% presented a history of CVD events. Subjects with CVD events were significantly older (aged 49 vs 38 years, P < .0001), had a higher prevalence of hypertension (34% vs 13%, P < .0001), diabetes (9% vs 3%, P = .001), and smoking (74% vs 52%, P < .0001), as well as a higher average body mass index (26.6 ± 4.6 vs 25.4 ± 4.7 kg/m2, P = .001) compared with subjects without CVD events. Triglycerides were significantly higher (1.60 [1.10–2.40] vs 1.40
Discussion
It is well established that all FH patients benefit from the early initiation of statin therapy to lower LDL-C and lifelong CVD risk, but the usefulness of add on therapies to statins still remains debated.23, 24 The clinical outcome of FH patients is variable and the identification of FH patients at higher CVD risk still remains a challenge. Indeed, precise stratification of CVD risk in FH patients could be useful to further guide treatment decisions.
Clinical variables such as age, sex,
Conclusions
This study provides external validation of the recently developed MFHS. The MFHS that combines common variables: age, HDL-C, gender, hypertension, and smoking, performed well in the validation cohort and then represents a valid and easy-to-use tool for the prediction of prevalent CVD events in French Canadian adult FH. Furthermore, we have shown that the addition of other risk factors such as Lp(a) does not significantly improve the prediction of the score. The MFHS does not alter the need for
Acknowledgment
The authors would like to thank participants their families.
Authors' contributions: E.K., D.B., and D.G. participated in data acquisition and revised the article. M.P., R.D., and A.B. designed the study, generated the hypothesis, performed statistical analysis, and wrote the article. All authors were involved in data interpretation and article development and critically revised the article for important intellectual content. All authors have approved the final version of the article. A.B. had
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2023, Nutrition, Metabolism and Cardiovascular DiseasesRecent advances in the management and implementation of care for familial hypercholesterolaemia
2023, Pharmacological ResearchANKS1A genotype predicts cardiovascular events in patients with familial hypercholesterolemia: ANKS1A and MACE risk in FH
2021, Journal of Clinical LipidologyCitation Excerpt :In addition, the coronary artery disease risk in the genetically-confirmed FH population can reach a 22-fold increase when compared to the general population with a normal LDL-C (<130 mg/dL).22 Although all FH patients are at an increased risk of major adverse cardiovascular event (MACE), this risk is heterogeneous and depend on the presence of genetics variants and clinical variables such as age, HDL-C, sex, hypertension and smoking.23,24 Understanding the additional risk factors could help to stratify the cardiovascular risk and can help to make therapeutic decisions for patients with FH.
Coronary artery disease and the risk-associated LPA variants, rs3798220 and rs10455872, in patients with suspected familial hypercholesterolaemia
2020, Clinica Chimica ActaCitation Excerpt :Elevated Lp(a) is an independent risk factor for ASCVD in the general population, as well as in patients with FH. The inclusion of Lp(a) in risk models enhances the prediction of cardiovascular risk in the FH population [4–6]. However, not all studies demonstrate a relationship between Lp(a) levels and ASCVD.
This work was supported by The Fondation Leducq Transatlantic Networks of Excellence (grant number 13CVD03) and by ECOGENE-21, a non-for-profit organization dedicated to genetic disease prevention and global health. The study funders had no role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.