(C25) The Angiotensin-converting Enzyme Polymorphism in the North American Irish Wolfhound: Variant-positive Prevalence and Clinical Implications

Background

An angiotensin-converting enzyme (ACE) gene polymorphism has been identified in dogs. Its functional importance appears to be variable and possibly breed-dependent.

Hypothesis

1. 
   

   The majority of Irish Wolfhounds (IWs) would be homozygous or heterozygous for the ACE-polymorphism. 
   



2. 
   

   IWs with this polymorphism would demonstrate decreased classical renin-angiotensin-aldosterone system (RAAS) pathway activation and increased alternative RAAS pathway utilization both at baseline and after angiotensin converting enzyme inhibitor (ACEi) administration. 
   



3. 
   

   IWs without the mutation would exhibit more typical RAAS pathway parameters at baseline and after ACEi administration. 
   

Animals

144 client-owned, purebred IWs were genotyped and phenotypically described via cardiovascular evaluation (auscultation, echocardiogram, and ECG) over a three year period. Eighteen IWs that were deemed phenotypically normal were then selected for RAAS fingerprinting before and after an ACEi challenge: two wild types (WT), four heterozygotes (Aa), and twelve homozygotes (aa).

Methods

All IWs were phenotypically described under the direct supervision of a boarded cardiologist.For the purposes of this study, phenotypically “normal” was categorized by a normal echocardiogram (based on values previously established for IWs), normal auscultation, and a normal sinus rhythm/sinus arrhythmia on ECG. Blood draws were performed on the pre-selected phenotypically normal IWs at baseline and post two-week ACEi challenge. Equilibrium analysis was performed to evaluate serum RAAS metabolites and enzyme activities.

Results

In our population, 46 IWs (31.9%) had atrial fibrillation and varying degrees of heart muscle dysfunction/enlargement consistent with Irish Wolfhound Cardiomyopathy. 96 IWs (66.6%) were phenotypically normal. With genotyping, 120 (83.3%) of IWs were homozygous, 19 (13.2%) were heterozygous, and 5 (3.5%) were homozygous WT for the polymorphism. 

In the selected phenotypically normal IWs, whole group analysis showed all IWs exhibited normal baseline RAAS activity. After a two-week ACEi challenge (benazepril 0.5 mg/kg every 12 hours), all IWs also displayed an appropriate inhibition of the classical RAAS pathway and a significant up-regulation of the alternative pathway. 

Conclusion:

The ACE-polymorphism appears to be non-functional in the IW. When discovering new mutations, further investigation is warranted to determine the penetrance and expressivity (as it may be breed-dependent).