Perhaps the most interesting aspect of the role of the renin-angiotensin system in maintaining or enhancing physical performance has come from observations that an insertion (I)/deletion (D) polymorphism of the ACE gene has a phenotypic effect on exercise performance and response to training.14 Homozygotes for the D allele (which have higher serum ACE activity) demonstrate improved strength and power performance, whereas I/I homozygotes show better endurance performance. There is evidence that this is also true in COPD populations.15,16 These observations suggest that a stratified or personalized genotype-directed approach to exercise training or other performance-enhancing therapy could be envisaged. Shrikrishna et al4 did not observe differences in the response to ACE inhibition between these genotypes, but the study may have lacked statistical power for this analysis, and it is a shame that they were not able to stratify their trial for genotype. The choice of quadriceps muscle strength (quadriceps muscle voluntary contraction) as a stratification tool is understandable given that we know that muscle weakness is related to longer-term clinical outcomes. However, using an arbitrary cutoff of a continuous, volitional variable risks introducing bias due to regression to the mean, which probably augmented the expected placebo effect observed in both arms of the trial. Moreover, the choice of stratification measure was somewhat counterintuitive in a trial of ACE inhibition given that the D/D polymorphism is related to both increased muscle strength and higher serum ACE activity, although this was mitigated somewhat by the choice of muscle endurance as the primary outcome in the trial. Furthermore, distinguishing discrete domains of endurance and strength performance may be difficult, particularly in COPD, which is known to cause a marked reduction in muscle oxidative capacity that, in turn, may affect tasks traditionally considered in the strength category.