Peroxisome proliferator-activated receptor a gene regulates left ventricular growth in response to exercise and hypertension

Background-Left ventricular hypertrophy (LVH) occurs as an adaptive response to a physiological (such as exercise) or pathological (valvular disease, hypertension, or obesity) increase in cardiac work. The molecular mechanisms regulating the LVH response are poorly understood. However, inherited defects in fatty acid oxidation are known to cause severe early-onset cardiac hypertrophy. Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates genes responsible for myocardial fatty acid oxidation and is downregulated during cardiac hypertrophy, concomitant with the switch from fatty acid to glucose utilization. Methods and Results-The role of PPARalpha in left ventricular growth was investigated in 144 young male British Army recruits undergoing a 10-week physical training program and in 1148 men and women participating in the echocardiographic substudy of the Third Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg study. A G/C polymorphism in intron 7 of the PPARa gene significantly influenced left ventricular (LV) growth in response to exercise (P=0.009). LV mass increased by 6.7+/-1.5 g in G allele homozygotes but was significantly greater in heterozygotes for the C allele (11.8+/-1.9 g) and in CC homozygotes (19.4+/-4.2 g). Likewise, C allele homozygotes had significantly higher LV mass, which was greater still in hypertensive subjects, and a higher prevalence of LVH in the Third MONICA Augsburg study. Conclusions-We demonstrate that variation in the PPARalpha gene influences human left ventricular growth in response to exercise and hypertension, indicating that maladaptive cardiac substrate utilization can play a causative role in the pathogenesis of LVH.