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Background: Decreased physical capacity is associated with increased risk of mortality and decreased quality of life. Despite wide inter-individual variation in physical capacity, there is familial aggregation, independent of age, sex, BMI, and body composition, suggesting heritability of this trait. Master regulators of lipid/glucose homeostasis and energy metabolism, peroxisome-proliferator activated receptor (PPAR) pathway genes are involved in mitochondrial expression/turnover/bioenergetics, skeletal muscle protein catabolism, and atherosclerosis, and their expression is affected by exercise training. We therefore hypothesized that there would be novel variants in PPAR-pathway genes associated with physical capacity in post-MI patients.
Methods: We tested our hypothesis in TRIUMPH, a prospective multicenter study specifically designed to assess post-MI health status outcomes, including physical limitation, as well as hard cardiovascular end-points. Physical limitation was assessed by the Seattle Angina Questionnaire Physical Limitation (SAQ_PL) Score, a highly reproducible measure that has been validated against objective treadmill exercise performance duration. Subjects were genotyped for low frequency non-synonymous coding variants using the Human Illumina Exome BeadChip microarray. Associations between 223 previously identified PPAR-pathway genes and SAQ_PL score were tested using two burden test analyses.
Results: Lower SAQ_PL scores were associated with increased risk of mortality and cardiovascular rehospitalization at 1 year. Out of 223 PPAR-pathway genes, PPARGC1B, the gene encoding PGC1β, was the only one to reach genomic threshold significance (<2.94E-4) by burden testing. This association validated in two independent cohorts.
Conclusions: This is the first description of an association between PPARGC1B and physical capacity in humans and may identify important novel potential therapeutic targets.
Poster Hall, Hall C
Friday, March 17, 2017, 10:00 a.m.-10:45 a.m.
Session Title: Novel Mechanisms Underlying Ischemia-Reperfusion Injury in AMI
Abstract Category: 1. Acute and Stable Ischemic Heart Disease: Basic
Presentation Number: 1124-299
- 2017 American College of Cardiology Foundation