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

Abstract

Background: The 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 results: We 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.

Conclusion: Genetic 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 information: clinicaltrials.gov Identifier: NCT00729430.

Conflict of interest statement

The commercial affiliation of author WH with OmegaQuant does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Quantitative assessment of cardiac remodeling and myocardial fibrosis by cardiac magnetic resonance imaging.

From left to right, a short-axis cine image, a late gadolinium enhancement (LGE) infarction image, and a myocardial extracellular volume (ECV) map in a matching short-axis location of the left ventricle are shown, respectively. LGE characterizes areas of subendocardial infarct (white arrows). An ECV map was constructed by serial T1 maps before and after gadolinium contrast injection. Non-infarct fibrosis was determined from the ECV maps with matching segments containing LGE removed.

Fig 2. Markedly different fatty acid desaturase activity was seen in patients with various rs-1535 genotypes.

Fatty acid desaturase activity was assessed by the ArA/LA ratio in red blood cell membrane assay. Note that patients with GG alleles have diminished ArA/LA ratio consistent with reduced fatty acid desaturase activity.

Fig 3. Significant improvement of post-AMI LV remodeling from omega-3 fatty acids treatment in patients with the rs1535 GG genotype.

Note the divergent response in LVESVi improvement over the first 6 months after the index AMI in patients with GG allele who were assigned O-3FA compared to placebo. This divergence of cardiac remodeling response to O-3FA treatment was not observed in the AA and AG groups.

Fig 4. O-3FA treatment effects on cardiac remodeling related biomarkers.

Patients with the GG genotype experienced substantial reduction of NT-proBNP, and Galectin-3, and serum lipoprotein A, when assigned O-3FA.

Fig 5. Effects on EPA, DHA, and O3I levels from treatment assignment, stratified by rs-1535 genotypes.

P-values were adjusted by the Bonferroni method. The p-values came from paired Wilcoxon tests that compare for each sub-group the baseline against 6-month values.