Genetic profiling of fatty acid desaturase polymorphisms identifies patients who may benefit from high-dose omega-3 fatty acids in cardiac remodeling after acute myocardial infarction-Post-hoc analysis from the OMEGA-REMODEL randomized controlled trial.

Raymond Y Kwong,Yin Ge,Kana Fujikura,Jonathan G Seidman,Bobak Heydari,William S Harris,Shuaib Abdullah,Elliott M Antman,Marc A Pfeffer,Michael Jerosch-Herold,Kyoichi Kaneko,Giuseppe Andò

doi:10.1371/journal.pone.0222061

Abstract

BackgroundThe double-blind OMEGA-REMODEL placebo-controlled randomized trial of high-dose omega-3 fatty acids (O-3FA) post-acute myocardial infarction (AMI) reported improved cardiac remodeling and attenuation of non-infarct myocardial fibrosis. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes.Methods and resultsWe tested the hypothesis that the genotypic status of FADS2 (rs1535) modifies therapeutic response of O-3FA in post-AMI cardiac remodeling in 312 patients. Consistent with known genetic polymorphism of FADS2, patients in our cohort with the guanine-guanine (GG) genotype had the lowest FADS2 activity assessed by arachidonic acid/linoleic acid (ArA/LA) ratio, compared with patients with the adenine-adenine (AA) and adenine-guanine (AG) genotypes (GG:1.62±0.35 vs. AA: 2.01±0.36, p<0.0001; vs. AG: 1.76±0.35, p = 0.03). When randomized to 6-months of O-3FA treatment, GG patients demonstrated significant lowering of LV end-systolic volume index (LVESVi), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and galectin-3 levels compared to placebo (-4.4 vs. 1.2 ml/m2, -733 vs. -181 pg/mL, and -2.0 vs. 0.5 ng/mL; p = 0.006, 0.006, and 0.03, respectively). In contrast, patients with either AA or AG genotype did not demonstrate significant lowering of LVESVi, NT-proBNP, or galectin-3 levels from O-3FA treatment, compared to placebo. The odds ratios for improving LVESVi by 10% with O-3FA treatment was 7.2, 1.6, and 1.2 in patients with GG, AG, and AA genotypes, respectively.ConclusionGenetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI.Clinical trial registration informationclinicaltrials.gov Identifier: NCT00729430.

Highlights

Despite significant advances in the treatment of acute myocardial infarction (AMI), adverse left ventricular (LV) remodeling remains prevalent and is a key risk factor for cardiovascular (CV) death, ventricular arrhythmias, and progression to heart failure [1]
Maladaptive inflammation following AMI plays an important role in preventing adequate tissue healing with consequent increased myocardial fibrosis and biomechanical strain, which promotes adverse left ventricular remodeling and contributes to a state of persistent inflammation that can result in a negative feedback loop [6, 7]
In this post-hoc analysis of the OMEGA-REMODEL trial, we hypothesized that personalized profiling of Fatty acid desaturase 2 (FADS2) genetic polymorphisms would result in an improved selection of patients who would respond favorably to omega-3 fatty acids (O-3FA) therapy by attenuating adverse left ventricular functional deterioration and non-infarct myocardial fibrosis during the convalescent healing phase following AMI

Summary

Introduction

Despite significant advances in the treatment of acute myocardial infarction (AMI), adverse left ventricular (LV) remodeling remains prevalent and is a key risk factor for cardiovascular (CV) death, ventricular arrhythmias, and progression to heart failure [1]. O-3FAs are a rich source of SPMs [9, 10] but are poorly consumed in western diets [11] In this post-hoc analysis of the OMEGA-REMODEL trial, we hypothesized that personalized profiling of FADS2 genetic polymorphisms would result in an improved selection of patients who would respond favorably to O-3FA therapy by attenuating adverse left ventricular functional deterioration and non-infarct myocardial fibrosis during the convalescent healing phase following AMI. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes

Methods

Results

Discussion

Conclusion