Lipoprotéine(a) et microcalcification de la valve aortique

La sténose aortique (SA) est la maladie valvulaire la plus fréquente dans notre société. Elle est caractérisée par un remodelage fibrocalcique conduisant à une obstruction progressive du flux sanguin. La lipoprotéine(a) (Lp[a]), une lipoprotéine similaire à la lipoprotéine de faible densité, est un facteur de risque génétique fortement associé à la SA. Malheureusement, les concentrations plasmatiques de Lp(a) sont très peu influencées par des facteurs extrinsèques, tels qu’un régime alimentaire ou une médication hypolipidémiante. Des études suggèrent que la Lp(a) serait associée aux processus de calcification dans le développement de la SA. La tomographie par émission de positons couplée à la tomographie axiale permet de détecter le processus précoce lié à calcification de la valve aortique. En effet, cette technique d’imagerie nucléaire permet d’identifier et de quantifier la microcalcification au niveau de la valve aortique, un marqueur fortement lié au développement futur de calcium. L’impact de la Lp(a) sur la microcalcification de la valve aortique n’a jamais été évalué. La mesure de la microcalcification chez des individus sans SA ayant des concentrations plus ou moins élevées de Lp(a) a été effectuée. Notre hypothèse était que les individus ayant des concentrations élevées de Lp(a) ont une microcalcification plus élevée, lorsque comparée aux individus ayant des concentrations plus faibles de Lp(a). Les résultats de cette étude ont révélé que les individus sans SA mais ayant des concentrations élevées de Lp(a) présentent une microcalcification plus importante que les individus ayant de plus faibles concentrations de Lp(a). La réalisation de ce projet de recherche nous a permis d’observer cliniquement un processus actif de calcification chez des individus avec des concentrations élevées de Lp(a), et ce, malgré l’absence clinique de la maladie, illustrant l’importance de cette lipoprotéine dans le développement de la SA.Aortic stenosis (AS) is the most common valve disease in our society. It is characterized by fibrocalcific remodelling leading to progressive obstruction of blood flow. Lipoprotein(a) (Lp[a]), a lipoprotein similar to low-density lipoprotein, is a genetic risk factor strongly associated with AS. Plasma concentrations of Lp(a) are very little influenced by extrinsic factors, such as diet or lipid-lowering medication. Studies suggest that Lp(a) would be associated with calcification processes in the development of AS. Positron emission tomography coupled with computed tomography allows the early process related to calcification of the aortic valve to be detected. This nuclear imaging technique identifies and quantifies microcalcification at the aortic valve, a marker strongly linked to the future development of calcium. The impact of Lp(a) on aortic valve microcalcification has never been evaluated. Microcalcification measurements in individuals without AS with high or low concentrations of Lp(a) were performed. Our hypothesis was that individuals with high concentrations of Lp(a) have higher microcalcification when compared to individuals with lower concentrations of Lp(a). The results of this study revealed that individuals without AS but with high concentrations of Lp(a) have a higher microcalcification than individuals with lower concentrations of Lp(a). The completion of this research project allowed us to observe clinically an active calcification process in individuals with high concentrations of Lp(a) despite the clinical absence of the disease, illustrating the importance of this lipoprotein in the development of AS

Genetic Variation in LPA, Calcific Aortic Valve Stenosis in Patients Undergoing Cardiac Surgery, and Familial Risk of Aortic Valve Microcalcification.

IMPORTANCE: Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with CAD vs those without CAD is unknown. OBJECTIVE: To study the associations of LPA variants with CAVS in a cohort of patients undergoing heart surgery and LPA with CAVS in patients with CAD vs those without CAD and to determine whether first-degree relatives of patients with CAVS and high lipoprotein(a) (Lp[a]) levels showed evidence of aortic valve microcalcification. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study included patients undergoing cardiac surgery from the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec (QUEBEC-CAVS) study and patients with CAD, patients without CAD, and control participants from 6 genetic association studies: the UK Biobank, the European Prospective Investigation of Cancer (EPIC)-Norfolk, and Genetic Epidemiology Research on Aging (GERA) studies and 3 French cohorts. In addition, a family study included first-degree relatives of patients with CAVS. Data were collected from January 1993 to September 2018, and analysis was completed from September 2017 to September 2018. EXPOSURES: Case-control studies. MAIN OUTCOMES AND MEASURES: Presence of CAVS according to a weighted genetic risk score based on 3 common Lp(a)-raising variants and aortic valve microcalcification, defined as the mean tissue to background ratio of 1.25 or more, measured by fluorine 18-labeled sodium fluoride positron emission tomography/computed tomography. RESULTS: This study included 1009 individuals undergoing cardiac surgery and 1017 control participants in the QUEBEC-CAVS cohort; 3258 individuals with CAVS and CAD, 41 100 controls with CAD, 2069 individuals with CAVS without CAD, and 380 075 control participants without CAD in the UK Biobank, EPIC-Norfolk, and GERA studies and 3 French cohorts combined; and 33 first-degree relatives of 17 patients with CAVS and high Lp(a) levels (≥60 mg/dL) and 23 control participants with normal Lp(a) levels (<60 mg/dL). In the QUEBEC-CAVS study, each SD increase of the genetic risk score was associated with a higher risk of CAVS (odds ratio [OR], 1.35 [95% CI, 1.10-1.66]; P = .003). Each SD increase of the genetic risk score was associated with a higher risk of CAVS in patients with CAD (OR, 1.30 [95% CI, 1.20-1.42]; P < .001) and without CAD (OR, 1.33 [95% CI, 1.14-1.55]; P < .001). The percentage of individuals with a tissue to background ratio of 1.25 or more or CAVS was higher in first-degree relatives of patients with CAVS and high Lp(a) (16 of 33 [49%]) than control participants (3 of 23 [13%]; P = .006). CONCLUSIONS AND RELEVANCE: In this study, a genetically elevated Lp(a) level was associated with CAVS independently of the presence of CAD. These findings support further research on the potential usefulness of Lp(a) cascade screening in CAVS

Lipoprotein(a), oxidized phospholipids, and aortic valve microcalcification assessed by 18F-sodium fluoride positron emission tomography and computed tomography

Background Lipoprotein(a) (Lp[a]) is the preferential lipoprotein carrier of oxidized phospholipids (OxPLs) and a well-established genetic risk factor for calcific aortic valve stenosis (CAVS). Whether Lp(a) predicts aortic valve microcalcification in individuals without CAVS is unknown. Our objective was to estimate the prevalence of elevated Lp(a) and OxPL levels in patients with CAVS and to determine if individuals with elevated Lp(a) but without CAVS have higher aortic valve microcalcification. Methods We recruited 214 patients with CAVS from Montreal and 174 patients with CAVS and 108 controls from Québec City, Canada. In a second group of individuals with high (≥75 nmol/L, n = 27) or low (<75 nmol/L, n = 28) Lp(a) levels, 18F-sodium fluoride positron emission tomography/computed tomography was performed to determine the difference in mean tissue-to-background ratio (TBR) of the aortic valve. Results Patients with CAVS had 62.0% higher Lp(a) (median = 28.7, interquartile range [8.2-116.6] vs 10.9 [3.6-28.8] nmol/L, P < 0.0001), 50% higher OxPL-apolipoprotein-B (2.2 [1.3-6.0] vs 1.1 [0.7-2.6] nmol/L, P < 0.0001), and 69.9% higher OxPL-apolipoprotein(a) (7.3 [1.8-28.4] vs 2.2 [0.8-8.4] nmol/L, P < 0.0001) levels compared with individuals without CAVS (all P < 0.0001). Individuals without CAVS but elevated Lp(a) had 40% higher mean TBR compared with individuals with low Lp(a) levels (mean TBR = 1.25 ± 0.23 vs 1.15 ± 0.11, P = 0.02). Conclusions Elevated Lp(a) and OxPL levels are associated with prevalent CAVS in patients studied in an echocardiography laboratory setting. In individuals with elevated Lp(a), evidence of aortic valve microcalcification by 18F-sodium fluoride positron emission tomography/computed tomography is present before the development of clinically manifested CAVS.La lipoprotéine(a) (Lp[a]), la principale lipoprotéine assurant le transport des phospholipides oxydés (PLOx), est un facteur de risque génétique bien établi de la sténose aortique calcifiante (SAC). On ignore si la présence de Lp(a) est un facteur prédictif de la microcalcification de la valve aortique chez les individus non atteints de SAC. Notre objectif était d'estimer la prévalence de taux élevés de Lp(a) et de PLOx chez des patients atteints de SAC et de déterminer si la microcalcification de la valve aortique est plus marquée chez les individus affichant des taux élevés de Lp(a) en l'absence de SAC. Méthodologie Nous avons recruté 214 patients atteints de SAC à Montréal et 174 patients atteints de SAC et 108 patients témoins à Québec (Canada). Dans un second groupe de patients présentant des taux de Lp(a) élevés (≥ 75 nmol/l, n = 27) ou faibles (< 75 nmol/l, n = 28), une tomographie par émission de positons au fluorure de sodium marqué au 18F a été réalisée en vue de comparer la valeur moyenne du rapport signal/bruit (RSB) de la valve aortique. Résultats Les patients atteints de SAC présentaient des taux de Lp(a) plus élevés de 62,0 % (médiane = 28,7, intervalle interquartile [de 8,2 à 116,6] vs 10,9 [de 3,6 à 28,8] nmol/l, p < 0,0001), des taux de OxPL-apolipoprotéine-B plus élevés de 50 % (2,2 [de 1,3 à 6,0] vs 1,1 [de 0,7 à 2,6] nmol/l, p < 0,0001) et des taux de PLOx-apolipoprotéine(a) plus élevés de 69,9 % (7,3 [de 1,8 à 28,4] vs 2,2 [de 0,8 à 8,4] nmol/l, p < 0,0001) comparativement aux patients non atteints de SAC (toutes les valeurs p < 0,0001). Les patients non atteints de SAC mais présentant des taux élevés de Lp(a) avaient un RSB moyen supérieur de 40 % à celui des individus affichant un faible taux de Lp(a) (RSB moyen = 1,25 ± 0,23 vs 1,15 ± 0,11, p = 0,02). Conclusions Des taux élevés de Lp(a) et de PLOx sont associés à la prévalence de la SAC chez des patients étudiés par échocardiographie. Chez les individus présentant un taux élevé de Lp(a), les signes d'une microcalcification de la valve aortique, décelés par tomographie par émission de positons au fluorure de sodium marqué au 18F /tomodensitométrie sont présents avant l'apparition des manifestations cliniques de la SAC

Genetic Variation in LPA, Calcific Aortic Valve Stenosis in Patients Undergoing Cardiac Surgery, and Familial Risk of Aortic Valve Microcalcification

Importance: Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with CAD vs those without CAD is unknown. Objective: To study the associations of LPA variants with CAVS in a cohort of patients undergoing heart surgery and LPA with CAVS in patients with CAD vs those without CAD and to determine whether first-degree relatives of patients with CAVS and high lipoprotein(a) (Lp[a]) levels showed evidence of aortic valve microcalcification. Design, Setting, and Participants: This genetic association study included patients undergoing cardiac surgery from the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec (QUEBEC-CAVS) study and patients with CAD, patients without CAD, and control participants from 6 genetic association studies: the UK Biobank, the European Prospective Investigation of Cancer (EPIC)-Norfolk, and Genetic Epidemiology Research on Aging (GERA) studies and 3 French cohorts. In addition, a family study included first-degree relatives of patients with CAVS. Data were collected from January 1993 to September 2018, and analysis was completed from September 2017 to September 2018. Exposures: Case-control studies. Main Outcomes and Measures: Presence of CAVS according to a weighted genetic risk score based on 3 common Lp(a)-raising variants and aortic valve microcalcification, defined as the mean tissue to background ratio of 1.25 or more, measured by fluorine 18-labeled sodium fluoride positron emission tomography/computed tomography. Results: This study included 1009 individuals undergoing cardiac surgery and 1017 control participants in the QUEBEC-CAVS cohort; 3258 individuals with CAVS and CAD, 41100 controls with CAD, 2069 individuals with CAVS without CAD, and 380075 control participants without CAD in the UK Biobank, EPIC-Norfolk, and GERA studies and 3 French cohorts combined; and 33 first-degree relatives of 17 patients with CAVS and high Lp(a) levels (≥60 mg/dL) and 23 control participants with normal Lp(a) levels (<60 mg/dL). In the QUEBEC-CAVS study, each SD increase of the genetic risk score was associated with a higher risk of CAVS (odds ratio [OR], 1.35 [95% CI, 1.10-1.66]; P =.003). Each SD increase of the genetic risk score was associated with a higher risk of CAVS in patients with CAD (OR, 1.30 [95% CI, 1.20-1.42]; P <.001) and without CAD (OR, 1.33 [95% CI, 1.14-1.55]; P <.001). The percentage of individuals with a tissue to background ratio of 1.25 or more or CAVS was higher in first-degree relatives of patients with CAVS and high Lp(a) (16 of 33 [49%]) than control participants (3 of 23 [13%]; P =.006). Conclusions and Relevance: In this study, a genetically elevated Lp(a) level was associated with CAVS independently of the presence of CAD. These findings support further research on the potential usefulness of Lp(a) cascade screening in CAVS.