ACE-S

Objective: Angiotensin-converting-enzyme-inhibitors (ACEi) are widely used for treating hypertension and cardiovascular diseases and block Angiotensin-II (Ang-II) formation from Angiotensin-I (Ang-I). The therapeutic response to ACE inhibition critically depends on in vivo pharmacologic efficacy and affected by dosing, patient compliance and patient specific compensatory mechanisms, all being relevant topics for the clinical management of hypertension. Design and method: Samples were collected from 19 hypertensive patients and 7 confirmed primary aldosteronism (PA) patients. Hypertensive patients were investigated at baseline and after 4 weeks on therapy with a single daily dose of perindopril. Two consecutive off-therapy baseline samples separated by 4 hours and two samples on stable therapy (PRE-DOSE, 4 h POST-DOSE) were collected. PA patients were sampled before and after 14 day administration of ramipril. All samples were analysed by LC-MS/MS based RAAS Triple-A testing which involves the calculation of ACE-S, the ratio between plasma equilibrium levels of Ang-II and Ang-I as a novel marker for circulating ACE activity. ACE activity was further measured by analyzing the time dependent conversion of spiked Ang-I (LC-MS/MS) and by performing a clinical colorimetric ACE assay. Treatment adherence was confirmed by quantification of plasma drug levels. Results: ACE-S was significantly lower in all patients on perindopril or ramipril therapy compared to baseline (MEDIANS: 0.35 vs. 2.75 pM/pM, p < 0.001). While eqAng-II levels were increased up to 5-fold compared to baseline levels in a subset of patients due to renin up-regulation, ACE-S stayed significantly suppressed in all samples investigated. In contrast, ACE inhibition appeared to be less effective using classical enzymatic approaches assessing ACE activity, which typically involve a high dilution of the sample in combination with excess of substrates. Conclusions: The novel angiotensin based marker ACE-S can be used to monitor pharmacologic efficacy of ACE inhibitors independent of their chemical structure. As part of the RAAS Triple-A test that is currently validated in screening for secondary forms of hypertension, ACE-S has the potential to support the clinical management of first-line non-responders in terms of optimizing ACEi dosing and visualizing patient specific compensatory mechanisms, thereby improving the overall control rates in hypertension.