Decreased Plasma Concentration of Nitric Oxide Metabolites in Dogs with Untreated Mitral Regurgitation

Abstract

Endothelium-dependent (nitric oxide [NO]-mediated) vasodilation is impaired in humans with heart failure. This dysfunction is an important therapeutic target. The plasma concentration of the NO metabolites nitrate and nitrite (collectively referred to as NOx) is a measure of whole-body NO production, provided that the dietary intake of the ions is low. Fifty clinically healthy dogs older than I year (median 5.0 years; interquartile interval 2.6-8.2 years) were studied, including 9 controls of various breeds, 23 Cavalier King Charles Spaniels (CKCSs) with no or minimal mitral regurgitation (MR), 9 CKCSs with mild MR (regurgitant jet occupying 15-50% of the left atrial area), and 9 CKCS with moderate to severe MR (jet >50%) due to myxomatous valve disease. None of the dogs received medication. The dogs were given NOx-free water and a diet with a low concentration of NOx for 96 hours before blood sampling. Multiple linear regression analysis revealed that dog group, but not gender, age, serum creatinine concentration, and platelet count, was associated with NOx concentrations. Control dogs had the same NOx concentration (median 20.0 microM; interquartile interval 15.1-25.5 microM) as CKCSs without MR (median 18.7 microM; interquartile interval 15.5-25.9 microM). Compared to CKCSs without MR, the NOx concentration was lower in CKCSs with mild (median 12.9 microM; interquartile interval 11.0-13.5 microM; P = .04) and moderate to severe (median 11.2 microM; interquartile interval 6.9-17.1 microM; P = .02) MR. In conclusion, CKCSs with mild to severe, clinically silent MR have decreased plasma NOx concentrations, suggesting that endothelial dysfunction develops early in the course of developing MR in dogs.

Alpha-smooth muscle actin and serotonin receptors 2A and 2B in dogs with myxomatous mitral valve disease

“…If verified, this could indicate that valvular endothelial cells are phenotypically different from myocardial endothelial cells and hold a potential for differentiation and activation. Indeed, it has previously been speculated that endothelial dysfunction might be involved in the pathogenesis of MMVD (Jones et al, 2012;Moesgaard et al, 2007;Mow and Pedersen, 1999;Olsen et al, 2003;Pedersen et al, 2003). This hypothesis seems in agreement with the fact that α-SMA positive endothelial cells were found predominantly in healthy areas of the valves, perhaps representing a premature stage in the disease process.…”

Ultrasonographic measurement of flow-mediated vasodilation in dogs with chronic valvular disease

“…13 Nitric oxide metabolites have been measured in dogs with CVD in an attempt to evaluate endothelial function, although both an increase and decrease in their concentration have been reported relative to healthy controls. 14,15 FMD did not differ significantly between healthy dogs and dogs with CVD in this study. However, most dogs included in this study were in the pre-clinical stage of CVD where therapy was not required.…”

“…13 Non-invasive assessment of endothelial function by measurement of nitric oxide metabolites has been reported in dogs with naturally occurring heart disease. 14,15 Alternative techniques have recently been reported for measuring endothelial function that are suitable for use in dogs, including the measurement of brachial artery flow-mediated dilation (FMD). 16e19,a,b Flow-mediated dilation is the phenomenon whereby conduit arteries dilate in response to an increase in flow.…”

Increased NT-proANP predicts risk of congestive heart failure in Cavalier King Charles spaniels with mitral regurgitation caused by myxomatous valve disease

“…29 However, the designs of these two studies are different. Our study was not designed to explore changes in NOx by degree of MMVD.…”

“…21,22 In healthy dogs plasma NOx levels correlate with NT-proANP concentrations and increases with age. 15 Indices of increased tissue activity have been reported in the mitral valves in dogs with MMVD, 23 and signs of endothelial dysfunction have been observed in dogs with MMVD through necropsy material, 24,25 by peripheral blood flow measurements, 26,27 and through analysis of plasma cGMP or precursors 28 and end-products 29 to NO. However, to our knowledge, there are no data on changes and trends in endothelial function with regard to the progression of MMVD.…”