ACE phenotyping as a first step toward personalized medicine for ACE inhibitors. Why does ACE genotyping not predict the therapeutic efficacy of ACE inhibition?

Angiotensin (Ang)-converting enzyme (ACE) inhibitors are widely used for the treatment of cardiovascular diseases. Not all patients respond to ACE inhibitors, and it has been suggested that genetic variation might be a useful marker to predict the therapeutic efficacy of these drugs. In particular, the ACE insertion (I)/deletion (D) polymorphism has been investigated in this regard. Despite a decade of intensive research involving the genotyping of thousands of patients, we still do not know whether ACE genotyping helps in predicting the success of ACE inhibition. This review critically addresses the concept that predictive information on therapeutic efficacy of ACE inhibitors might be obtained based on ACE genotyping. It answers the following questions: Do higher ACE levels really result in higher Ang II levels? Is ACE the only converting enzyme in humans? Does ACE inhibition affect ACE expression? Why does ACE have 2 catalytically active domains? What is the relevance of ACE inhibitor-induced signaling through membrane-bound ACE? The review ends with the proposal that ACE phenotyping may prove to be a better first step toward personalized medicine for ACE inhibitors than ACE genotyping.