Elevated Angiotensin 1–7/Angiotensin II Ratio Predicts Favorable Outcomes in Patients With Heart Failure

Background: ACE2 (angiotensin-converting enzyme 2) and Ang 1–7 (angiotensin 1–7) are endogenous negative regulators of the renin-angiotensin system exerting cardioprotective effects in models of heart failure. Recombinant human ACE2 markedly increased plasma Ang 1–7 and lowered Ang II levels in phase II clinical trials. We hypothesize that the dynamic state of this renin-angiotensin system protective arm could influence long-term outcomes in patients with heart failure. Methods: One hundred ten patients with heart failure were prospectively enrolled from our outpatient clinic and the emergency department. Comprehensive circulating and equilibrium levels of plasma angiotensin peptide profiles were assessed using novel liquid chromatography-mass spectrometry/mass spectroscopy techniques. Plasma aldosterone, B-type natriuretic peptide, active renin concentration, and clinical profiles were captured at baseline. During a median follow-up of 5.1 years (interquartile range, 4.7–5.7 years), composite clinical outcomes were assessed using all-cause in-patient hospitalizations and mortality. Results: Circulating and equilibrium angiotensin peptide levels strongly correlated in our patient cohort. Adjusting for covariates, elevated equilibrium (hazard ratio, 0.38 [95% CI, 0.18–0.81] P =0.012), and circulating (hazard ratio, 0.38 [95% CI, 0.18–0.80] P =0.011) Ang 1–7/Ang II ratios were associated with improved survival. Lower hospitalization duration was also associated with elevated equilibrium ( P <0.001) and circulating ( P =0.023) Ang 1–7/Ang II ratios. Importantly, individual Ang 1–7 and Ang II peptide levels failed to predict all-cause mortality or hospitalization duration in our patient cohort. Conclusions: We extensively profiled plasma angiotensin peptides in patients with heart failure and identified elevated Ang 1–7/Ang II ratio, as an independent and incremental predictor of beneficial outcomes, higher survival rate, and decreased hospitalization duration. These findings provide important clinical evidence supporting strategies aiming to promote the beneficial Ang 1–7/Mas axis concurrent with renin-angiotensin system blockade therapies inhibiting the detrimental Ang II/AT 1 receptor axis.