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Background: Familial hypercholesterolemia (FH) is a monogenic disease characterized by a high concentration of low-density lipoprotein cholesterol. This population is considered to be at high cardiovascular risk; however, disease evolution remains heterogeneous among individuals. The coronary artery calcium (CAC) score is currently the best predictor of incidental major cardiovascular events in primary prevention in the general population. Few studies have described the CAC score in FH populations. Methods: The objective of our study was to determine the predictors of the CAC score in FH patients. We retrospectively studied FH patients followed at the Montreal Clinical Research Institute (IRCM) Lipid Clinic who had a cardiac scan for CAC score, using the Agatston method, between 2013 and 2019. Results: Final analysis included 62 FH patients. Mean age was 48 ± 14 years old, and 48% were men. Overall, 25 patients had a CAC score of 0 (40%), and 37 patients had a nonzero CAC score (60%). Sex, age, Montreal-FH-SCORE (MFHS), waist circumference, and statin exposure in years were significant predictors (P ≤ 0,05) of a nonzero CAC score in a univariate model. MFHS was the only factor that remained significant in a multivariate model (odds ratio 1.34, 95% confidence interval 1.11–1.61, P = 0.002). Conclusions: In conclusion, we found that MFHS, which includes traditional cardiovascular risk factors, was a predictor of a nonzero CAC score in FH patients. This finding suggests that MFHS may play a role in determining the cardiovascular risk and therefore the intensity of treatment in FH patients. Résumé: Contexte: L’hypercholestérolémie familiale (HF) est une maladie monogénique caractérisée par une forte concentration de cholestérol des lipoprotéines de basse densité. La population touchée est considérée comme étant exposée à un risque cardiovasculaire élevé; toutefois, l’évolution de la maladie demeure hétérogène d’une personne à l’autre. À l’heure actuelle, le score calcique coronaire (SCC) est le meilleur outil prédictif de manifestations cardiovasculaires majeures fortuites en prévention primaire dans la population générale. Peu d’études ont décrit le SCC dans des populations atteintes de HF. Méthodologie: L’objectif de notre étude était de déterminer les facteurs prédictifs du SCC chez les patients atteints de HF. Nous avons étudié de façon rétrospective des patients atteints de HF qui étaient suivis à la clinique de lipides de l’Institut de recherches cliniques de Montréal (IRCM) et chez qui le score SCC avait été mesuré pendant un examen de tomodensitométrie cardiaque, au moyen de la méthode d’Agatston, entre 2013 et 2019. Résultats: L’analyse finale a porté sur 62 patients atteints de HF. L’âge moyen était de 48 ± 14 ans et la proportion d’hommes était de 48 %. Dans l’ensemble, 25 patients avaient un SCC de 0 (40 %) et 37, un SCC différent de zéro (60 %). Le sexe, l’âge, le score MFHS (Montreal-FH-SCORE), le tour de taille et le nombre d’années d’exposition aux statines ont été des facteurs prédictifs significatifs (p ≤ 0,05) d’un SCC différent de zéro dans un modèle à une variable. Le score MFHS est le seul facteur qui est demeuré significatif dans un modèle à plusieurs variables (rapport de cotes : 1,34; intervalle de confiance à 95 % : 1,11 à 1,61; p = 0,002). Conclusions: En conclusion, nous avons observé que le score MFHS, qui englobe les facteurs classiques de risque cardiovasculaire, était un facteur prédictif d’un SCC différent de zéro chez les patients atteints de HF. Cette observation semble indiquer que le score MFHS pourrait jouer un rôle dans la détermination du risque cardiovasculaire et, par conséquent, dans l’intensité du traitement chez les patients atteints de HF.

Multifactorial chylomicronemia syndrome (MCS) is a complex disease including a genetic component and the presence of lifestyle-related risk factors. We hypothesized that, in subjects with MCS, there would be a greater decrease in plasma triglycerides (TG) with a low-fat (F) diet than with a low-carbohydrate (C) diet. In secondary analyses, we tested the effect of both diets on TG concentration according to the presence or absence of a rare variant in the LPL gene. This randomized crossover dietary intervention included 12 adult subjects with MCS. Subjects followed 2 isocaloric diets, low-C (C, 35%; F, 45%) and low-F (F, 20%; C, 60%), in random order. Each diet lasted 3 weeks, followed by a 6-hour test meal. Diets were separated by a 2-week washout period. TG concentration in fasting subjects decreased by 55% during low-F diet (P = .002) and by 48% during low-C diet (P = .005). The difference between the 2 diets was not significant. However, we observed a more pronounced decrease in TG concentration (65% ± 17%) with the low-F diet compared with the low-C diet (46% ± 31%) (P = .06) in subjects carrying a rare variant in the LPL gene. This is the first study to show that dietary intervention is effective in MCS subjects. In addition, we highlighted the importance of the genetic profile in the choice of treatment by suggesting that subjects with a rare variant of the LPL gene have a greater reduction of TG concentration with a low-F diet than with a low-C diet.

To assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and statin efficacy, we measured in vivo HMGCR mRNA and lipid levels in French Canadian individuals affected by heterozygous familial hypercholesterolemia due to the deletion of more than 15 kb of the LDLR gene.Men and women carrying the AA genotype at rs3846662, and no APOE4 allele, had higher levels of total cholesterol (5.43 vs. 4.58 mmol/l, P0.05) and LDL-cholesterol (5.20 vs. 4.39 mmol/l, P0.05) at baseline. However, with regard to statin efficacy, the penetrance of the AA genotype was sex dependent. Indeed, the percentage reduction in LDL-cholesterol upon statin treatment was significantly decreased in women with the AA genotype compared with women without it (38.4 vs. 46.2%, P0.05), whereas this was not observed in men. Although both men and women bearing the AA genotype showed a higher ratio of full-length HMGCR mRNA/total HMGCR mRNA compared with individuals without it (n=37, P0.05), overall transcription of HMGCR was decreased and increased in men and women carrying this genotype, respectively (n=37, P0.01 and P0.05). Finally, in our familial hypercholesterolemia cohort, HMGCR alternative splicing explained between 22 and 55% of the variance in statin response.rs3846662 polymorphism and the alternative splicing of HMGCR mRNA significantly impact women's response to statin therapy.

Objective. To determine whether the side effects of methotrexate can be decreased by the concurrent use of leucovorin, without affecting the efficacy of the methotrexate. Methods. We conducted a multicenter randomized, double-blind, placebo-controlled trial of leucovorin administration, 2.5–5.0 mg orally, to be given 24 hours after the single, weekly, oral dose of methotrexate. Every 3 weeks for 52 weeks, patients were evaluated for rheumatic disease activity and side effects. Dosage adjustments for both methotrexate and leucovorin were made as needed, according to a defined protocol. The primary outcome evaluated was the frequency of study withdrawals because of side effects and/or inefficacy. Secondary outcomes evaluated included the frequency of side effects and the relative efficacy of methotrexate in the leucovorin and placebo treatment groups. Results. Ninety-two evaluable patients were analyzed (44 took leucovorin and 48 placebo). Twenty-two patients withdrew early because of side effects unresponsive to our protocol, and 1 because of inefficacy; 17 had been taking placebo and 6 had been taking leucovorin (35% versus 14%,P < 0.02). The number of visits during which side effects were reported was reduced by almost 50% in the leucovorin treatment group (P < 0.001). There were significant reductions in the frequencies of all common side effects. At 52 weeks, disease activity was similar in both patient groups. Conclusion. The methotrexate–leucovorin protocol used significantly reduces common side effects of methotrexate therapy without significantly altering efficacy.