Published Online
on January 22, 2002

A more recent version of this article appeared on February 26, 2002

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Submitted on November 29, 2001
Revised on December 18, 2001
Accepted on December 21, 2001

Peroxisome Proliferator--Activated Receptor Gene Regulates Left Ventricular Growth in Response to Exercise and Hypertension

Yalda Jamshidi PhD, Hugh E. Montgomery BSc, MD, MRCP, Hans-Werner Hense MD, Saul G. Myerson MRCP, Ines Pineda Torra PhD, Bart Staels PhD, Michael J. World BSc, MD, FRCP, Angela Doering MD, Jeanette Erdmann PhD, Christian Hengstenberg MD, Steve E. Humphries PhD, FRCPath, MRCP, Heribert Schunkert MD, and David M. Flavell PhD^*

From the Centre for Cardiovascular Genetics, Department of Medicine (Y.J., H.E.M., S.G.M., S.E.H.), University College London Medical School, London, UK; Institut fur Epidemiologie und Sozialmedizin (H.-W. H.), University of Munster, Germany; U.325 INSERM, Département d'Athérosclérose, Institut Pasteur and Faculté de Pharmacie (I.P.T., B.S.), Université de Lille II, Lille, France; Royal Defence Medical College (M.W.), Gosport, Hampshire, UK; GSF-Forschungszentrum (A.D.), Institut fuer Epidemiologie, Neuherberg, Germany; and Klinik und Poliklinik fur Innere Medizin II (J.E., C.H., H.S.), University of Regensburg, Germany.

^* To whom correspondence should be addressed. E-mail: rmhadfl{at}ucl.ac.uk.

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 (PPAR) 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 PPAR 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 PPAR 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 PPAR 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.

Key words: genetics • hypertrophy • exercise • hypertension • fatty acids

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