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(Circulation. 2001;103:226.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Left Ventricular Hypertrophy With Exercise and ACE Gene Insertion/Deletion Polymorphism

A Randomized Controlled Trial With Losartan

Saul G. Myerson, MRCP; Hugh E. Montgomery, BSc, MD, MRCP; Martin Whittingham, RAMC; Mick Jubb, RAMC; Michael J. World, BSc, MD, FRCP; Steve E. Humphries, PhD, MRCPath; Dudley J. Pennell, MD, FRCP, FESC

From the Centre for Cardiovascular Genetics (S.G.M., H.E.M., S.E.H.), University College London, London, UK; Royal Defence Medical College (M.W., M.J., M.J.W.), Gosport, Hampshire, UK; and the Cardiovascular Magnetic Resonance Unit (D.J.P.), Royal Brompton Hospital, London, UK.

Correspondence to Dr Hugh Montgomery, UCL Cardiovascular Genetics, Rayne Institute, 5 University St, London WC1E, UK. E-mail h.montgomery{at}ucl.ac.uk

Background—Local cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophic responses. The absence (deletion [D]) of a 287-bp marker in the ACE gene is associated with greater myocardial ACE levels and exercise-related LV growth than is its presence (insertion [I]), an effect potentially mediated through either increased activity of the cellular growth factor angiotensin II on the angiotensin type 1 (AT₁) receptor or increased degradation of growth-inhibiting kinins. We sought to confirm ACE genotype–associated exertional LV growth and to clarify the role of the AT₁ receptor in this association.

Methods and Results—One hundred forty-one British Army recruits homozygous for the ACE gene (79 DD and 62 II) were randomized to receive losartan (25 mg/d, a subhypotensive dose inhibiting tissue AT₁ receptors) or placebo throughout a 10-week physical training program. LV mass, determined by cardiac magnetic resonance, increased with training (8.4 g, P<0.0001 overall; 12.1 versus 4.8 g for DD versus II genotype in the placebo limb, P=0.022). LV growth was similar in the losartan arm: 11.0 versus 3.7 g for DD versus II genotypes (P=0.034). When indexed to lean body mass, LV growth in the II subjects was abolished, whereas it remained in the DD subjects (-0.022 versus 0.131 g/kg, respectively; P=0.0009).

Conclusions—ACE genotype dependence of exercise-induced LV hypertrophy is confirmed. Additionally, LV growth in DD (unlike II) subjects is in excess of the increase in lean body mass. These effects are not influenced by AT₁ receptor antagonism with the use of losartan (25 mg/d). The 2.4-fold greater LV growth in DD men may be due to the effects of angiotensin II on other receptors (eg, angiotensin type 4) or lower degradation of growth-inhibitory kinins.

Key Words: hypertrophy • myocardium • genetics • angiotensin • exercise

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