Disparate results of ACE inhibitor dosage on exercise capacity in heart failure: a reappraisal of vasodilator therapy and study design

Despite manifest benefits of angiotensin converting enzyme (ACE) inhibitors on the prognosis of patients with heart failure, there is a lack of consis tency in the results of trials investigating the effects; of ACE inhibitors on exercise capacity. The inconsistencies cannot be: readily explained by variations in effects: on known neurohumoral or conventional haemodynamic f actors. Drawing on insights from physiology of pump-load interactions, in a normal circulation there is an optimal extent of systemic vasodilation at which the delivery of hydraulic energy from the cardiac pump is maximal (th e 'impedance matchpoint'). In heart failure, the vasoconstrictive effects s hift the operating point towards mismatch at higher resistances, and optima l vasodilatory therapy would reshift the operating point to the matchpoint. Excessive dosage, however, would cause overvasodilatation leading to a red uction in cardiac power output and consequently compromising exercise abili ty. High levels of ACE inhibitors may not therefore improve exercise abilit y. Another potential reason for the observed inconsistencies is that the of ten used parallel-group study design (ideal for mortality studies) may not be suitable for investigating drug effects on exercise capacity because dro pouts from such studies would introduce occult selection biases, thereby co nfounding treatment effects. In conclusion, this reappraisal of the conflic ting observations reported on ACE inhibitor effects on exercise capacity ha s highlighted a proposition that there is an optimal dosage of ACE: inhibit ors which will most enhance exercise capacity, and this will require furthe r well designed cross-over studies to elucidate. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.