Plasma and tissue angiotensin-converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a homologue of angiotensin-converting enzyme (ACE) and produces angiotensin peptides (APs), such as angiotensin 1-9 and 1-7 that are vasodilatory and natriuretic, and act to counterbalance angiotensin II. HYPOTHESIS: Evidence of ACE2 can be found in tissues and plasma of dogs. Equilibrium concentrations of renin angiotensin aldosterone system (RAAS) APs differ in dogs with heart disease compared to healthy dogs and recombinant human ACE2 (rhACE2) alters relative concentrations of APs. ANIMALS: Forty-nine dogs with and 34 dogs without heart disease. METHODS: Immunohistochemistry and assays for tissue and plasma ACE2 activity and equilibrium concentrations of plasma RAAS APs were performed. RESULTS: Immunolabeling for ACE2 was present in kidney and myocardial tissue. Median plasma ACE2 activity was significantly increased in dogs with congestive heart failure (CHF; 6.9 mU/mg; interquartile range [IQR], 5.1-12.1) as compared to control (2.2 mU/mg; IQR, 1.8-3.0; P = .0003). Plasma equilibrium analysis of RAAS APs identified significant increases in the median concentrations of beneficial APs, such as angiotensin 1-7, in dogs with CHF (486.7 pg/mL; IQR, 214.2-1168) as compared to those with preclinical disease (41.0 pg/mL; IQR, 27.4-45.1; P < .0001) or control (11.4 pg/mL; IQR, 7.1-25.3; P = .01). Incubation of plasma samples from dogs with CHF with rhACE2 increased beneficial APs, such as angiotensin 1-9 (preincubation, 10.3 pg/mL; IQR, 4.4-37.2; postincubation, 2431 pg/mL; IQR, 1355-3037; P = .02), while simultaneously decreasing maladaptive APs, such as angiotensin II (preincubation, 53.4 pg/mL; IQR, 28.6-226.4; postincubation, 2.4 pg/mL; IQR, 0.50-5.8; P = .02). CONCLUSIONS AND CLINICAL IMPORTANCE: Recognition of the ACE2 system expands the conventional view of the RAAS in the dog and represents an important potential therapeutic target.

Effect of prespecified therapy escalation on plasma NT-proBNP concentrations in dogs with stable congestive heart failure due to myxomatous mitral valve disease.

BACKGROUND: Treatment targeted to achieve reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) improves outcomes in human congestive heart failure (CHF) patients. HYPOTHESIS: A pre-specified therapeutic algorithm that increased diuretic or pimobendan usage will reduce plasma NT-proBNP concentrations in dogs with CHF secondary to myxomatous mitral valve disease (MMVD). ANIMALS: Twenty-six dogs with clinically stable CHF secondary to MMVD. METHODS: Prospective, controlled before-and-after study. Dogs were examined up to 3 times over 21 days. Treatment was prescribed based on NT-proBNP as follows: <1500 pmol/L at baseline, no treatment adjustment at any point during the study (group 1); ≥1500 pmol/L and creatinine ≤3.0 mg/dL at baseline or SC visits, treatment escalated according to the algorithm (group 2); ≥1500 pmol/L at baseline, no treatment adjustment (group 3). RESULTS: N-terminal pro-B-type natriuretic peptide decreased significantly in group 2 (mean change = -1736 pmol/L (95% CI, -804 to -2668), P < .001) but not in groups 1 or 3 (623 pmol/L [-631 to 1877 pmol/L], P = .14 and 685 pmol/L [-304 to 1068 pmol/L], P = .46, respectively). Serum BUN and creatinine did not change significantly between visit 0 and visit 2 in group 1 (median = 23 mg/dL [range 13-32] versus 19 mg/dL [12-38], P = .72 and 1.15 mg/dL [0.70-1.40] versus 0.95 mg/dL [0.70-1.10], P = .10, respectively) or group 2 (28 mg/dL [18-87] versus 43.5 mg/dL [21-160], P = .092 and 1.10 mg/dL [0.90-2.50] versus 1.55 mg/dL [0.90-3.30], P = .062, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Use of this treatment escalation algorithm allows effective targeting of treatment for CHF in dogs against an objective criterion.