Study of effect modifiers of genetically predicted CETP reduction

Genetic variants in drug targets can be used to predict the effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of a genetically predicted lower CETP levels on biomarkers and cardiovascular outcomes. We found sex and BMI to be modifiers of the association between genetically predicted lower CETP and lipid biomarkers in UK Biobank participants. Female sex and lower BMI were associated with higher HDL-cholesterol and lower LDL-cholesterol for a same genetically predicted reduction in CETP concentration. We found that sex also modulated the effect of genetically lower CETP on cholesterol efflux capacity in samples from the Montreal Heart Institute Biobank. However, these modifying effects did not extend to sex-differences in cardiovascular outcomes in our data. Our results provide insight on the clinical effects of CETP inhibitors in the presence of effect modification based on observational genetic data. The approach can support precision medicine applications and help assess the external validity of clinical trials.

Study of effect modifiers of genetically predicted CETP reduction

Genetic variants in drug targets can be used to predict the effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of a genetically predicted lower CETP levels on biomarkers and cardiovascular outcomes.We found sex and BMI to be modifiers of the association between genetically predicted lower CETP and lipid biomarkers in UK Biobank participants. Female sex and lower BMI were associated with higher HDL-cholesterol and lower LDL-cholesterol for a same genetically predicted reduction in CETP concentration. We found that sex also modulated the effect of genetically lower CETP on cholesterol efflux capacity in samples from the Montreal Heart Institute Biobank. However, these modifying effects did not extend to sex-differences in cardiovascular outcomes in our data.Our results provide insight on the clinical effects of CETP inhibitors in the presence of effect modification based on observational genetic data. The approach can support precision medicine applications and help assess the external validity of clinical trials.

Mini Right Anterior Thoracotomy Approach versus Sternotomy for Resection of Intracardiac Myxoma

Objective The standard approach in treating cardiac myxoma is the median full sternotomy. After recent advances in surgical techniques, the mini right anterior thoracotomy has emerged as an alternative method. Methods We performed a retrospective study to compare the clinical outcomes of the mini right anterior thoracotomy approach with those of the sternotomy approach for resection of cardiac myxoma at the Montreal Heart Institute. There were 20 patients treated using a mini right anterior thoracotomy (4–5 cm) and 23 patients were treated using a median sternotomy. Results No early mortalities were found in either group. Although the cardiopulmonary bypass time and aorta cross-clamp time were not significantly different between the two groups (64.3 mn ± 18 and 37.2 mn ± 15 vs 54.3 mn ± 25 and 37.20 mn ± 2), preoperative blood loss (106 mn ± 95 vs 338 mn ± 270) was significantly less in the mini right anterior thoracotomy group. The intensive care unit and hospital stay (1.65 days ± 1.2 and 5.70 days ± 3) were shorter with the mini right anterior thoracotomy approach. Conclusions A minimally invasive surgery through mini right anterior thoracotomy is a good alternative technique for treating cardiac myxoma. Despite the small size of the experience, there is a clear diminution in preoperative blood loss and an interesting trend toward a shorter intensive care unit and hospital stay.

Abstract 17214: Differential Relationships Between Serum Cholesterol Efflux Capacities Measured From Three Cell Models and Coronary Artery Disease Status in the Montreal Heart Institute Biobank

Recent clinical trials and Mendelian randomization studies suggest that raising HDL-cholesterol (HDL-C) concentration by itself is insufficient to lower cardiovascular (CV) risk, despite the established inverse relationship between HDL-C and cardiovascular risk. CV protection may derive from other characteristics of HDL. Such characteristics include the cholesterol efflux capacity of serum, the process by which HDL particles accept cholesterol from macrophages and other cell types. Recently, higher cholesterol efflux capacity was inversely associated with incident CV events over a >9 year period of follow-up, with a 67% risk reduction in the highest quartile of efflux. In our study, cholesterol efflux capacity was measured for 2000 patients from the Montreal Heart Institute Biobank as the ratio of pooled control serum. When comparing unadjusted cholesterol efflux values between 1000 controls and 1000 cases with previous myocardial infarction (MI), we observed significant decreases of efflux capacity in cases with J774 macrophages in basal and cAMP-stimulated conditions, with human HepG2 hepatocytes and with BHK cells expressing human ABCA1. In regression models of MI status against efflux variables, also adjusted for age, sex, HDL-C, triglycerides and statin use, the reduction in cholesterol efflux capacity in cases vs. controls remained highly significant for J774 cells in basal (p value = 5.8x10-11) and cAMP-stimulated conditions (p = 5.3x10-8), while the difference was lost with HepG2 cells (p=0.16) and was reversed for ABCA1-dependent efflux using BHK-ABCA1 cells (p=5.9x10-4). Thus, the relationship of cholesterol efflux capacity of serum HDL and cardiovascular status is heterogeneous, which suggest that the repertoire of cholesterol transporters expressed in cells and samples characteristics, such as the HDL proteome and lipidome, interact in a unique manner for each cell type. Future work will consist in identifying sources of such differences at the molecular level.