Prevalence of an angiotensin-converting enzyme gene variant in dogs

Background Genetic heterogeneity of the canine angiotensin converting enzyme (ACE) gene is functionally important because the degree of aldosterone breakthrough with ACE-inhibitor therapy is greater in variant positive dogs compared to variant negative dogs, but the prevalence of the variant is not known. The purpose of this study was to determine ACE gene variant-positive prevalence in a population of 497 dogs of different breeds. Results Overall variant-positive prevalence was 31%, with 20% of dogs heterozygous and 11% of dogs homozygous. The variant was overrepresented in Irish Wolfhounds (prevalence 95%; P < .001), Dachshunds (prevalence 90%; P < .001), Cavalier King Charles Spaniels (prevalence 85%; P < .001), Great Danes (prevalence 84%; P < .001), and Bull Mastiffs (prevalence 58%; P = .02). Irish Wolfhounds were more likely to be homozygous than heterozygous (P < .001). Conclusions Nearly one-third of dogs in this study were positive for a functionally important ACE gene variant, with wide prevalence variability between breeds. The clinical importance of high ACE gene variant-positive prevalence in some breeds requires further study because the highest prevalences were found in breeds that are predisposed to heart disease and therefore may be treated with ACE-inhibitors.

Inhibition of Renal Fibrosis and Glomerular Injury by Sacubitril/Valsartan, a Combination Angiotensin Receptor Blocker and Neprilysin Inhibitor, in a Salt-Sensitive Hypertensive Model Using Angiotensin 1 Receptor Knockout Mice: The Contribution of Non-Angiotensin Blocking Effects to Renal Protection

Introduction: “Aldosterone breakthrough,” which is observed in patients receiving long term treatment with angiotensin blockade, is strongly associated with the increased risk of a declining glomerular filtration rate through the profibrotic actions of aldosterone. Sacubitril/valsartan is a newly created combination medicine (the angiotensin receptor blocker valsartan and the neprilysin-inhibitor sacubitril). Therefore, sacubitril/valsartan should have additional organ-protective actions besides the angiotensin blockade. Methods: In this study, we examined the renal protective effect of sacubitril/valsartan in a salt-sensitive hypertension model using angiotensin II type 1a receptor (AT1aR) knockout mice. An oral administration of 1% NaCl solution with sacubitril/valsartan (30 or 60 mg/kg/day) or valsartan (15 or 30 mg/kg/day) alone beginning 7 days before administration of aldosterone was examined in an aldosterone infusion AT1R knockout mouse model as an aldosterone breakthrough model. Results / Conclusion: A significant decrease in Blood Pressure (BP) was observed in the sacubitril/valsartan group compared to the valsartan group under low and high doses. In addition, the pathological analysis of the kidney for glomerular fibrosis by Sirius red staining and for injury by PAS staining demonstrated significant reductions accompanied by a significant reduction in TGF-β in the sacubitril/valsartan group compared to the valsartan group. Overall, sacubitril/valsartan, which has the dual actions of the AT1R blockade and neprilysin inhibition, may have additional clinical values for the treatment of hypertensive patients with aldosterone breakthrough.

Aldosterone breakthrough does not alter central hemodynamics

Introduction: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are widely used in congestive heart failure and chronic kidney disease, but up to 40% of patients will experience aldosterone breakthrough, with aldosterone levels rising above pre-treatment levels after 6–12 months of renin-angiotensin-aldosterone system blockade. Aldosterone breakthrough has been associated with worsening congestive heart failure and chronic kidney disease, yet the pathophysiology remains unclear. Breakthrough has not been associated with elevated peripheral blood pressure, but no studies have assessed its effect on central blood pressure. Methods: Nineteen subjects with well-controlled peripheral blood pressure on stable doses of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker had aldosterone levels checked and central blood pressure parameters measured using the SphygmoCor system. The central blood pressure parameters of subjects with or without breakthrough, defined as serum aldosterone >15 ng/dl, were compared. Results: Of the 19 subjects, six had breakthrough with a mean aldosterone level of 33.8 ng/dl, and 13 were without breakthrough with a mean level of 7.1 ng/dl. There was no significant difference between the two groups in any central blood pressure parameter. Conclusions: We found no correlation between aldosterone breakthrough and central blood pressure. The clinical impact of aldosterone breakthrough likely depends on its non-genomic, pro-fibrotic, pro-inflammatory effects rather than its regulation of extracellular volume.