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The role of nitric oxide locally in the mitral valve and systemically during physiological challenges and in early stages of myxomatous mitral valve disease

Sophia Gry Moesgaard 


Nitric oxide (NO) plays a key role in numerous physiological processes including vasodilation, platelet aggregation, leukocyte adhesion and vascular remodeling. It is a free-radical gas produced from L-arginine in a reaction catalysed by nitric oxide synthase (NOS). Endothelial derived NO is implicated in the pathogenesis of several cardiovascular diseases, and may play an important role as a marker of these diseases and their therapeutic intervention. Myxomatous mitral valve disease (MMVD) is a thickening and/or enlargement of the mitral valve often leading to mitral valve prolapse and eventually chronic heart failure, which is commonly seen in humans, dogs and pigs. Studies have shown that both valvular and vascular endothelia are affected early in the course of the disease, suggesting that endothelial derived mediators such as NO are likely to be involved in the pathogenesis of MMVD. However, little is known about the role of NO in the mitral valve and its local and systemic involvement in MMVD, which is the focus of the present thesis.
The thesis consists of in vitro studies on the local release of NO and expression of NOS in the porcine mitral valve and in vivo studies of plasma markers of NO availability in relation to physiological and genetic variations as well as clinical measures of MMVD in the dog.
The in vitro results show that NO can be measured directly from the surface of the porcine mitral valve and appears to play a physiological role in the mitral valve. The physiological NO release seems to be mainly released from the mitral valve endothelium via endothelial NOS (eNOS). In sows mild pathological changes occur in the mitral valve comparable to early changes in human and canine valves with MMVD. These early mitral valve changes are associated with an increased NO release in the chordal and central areas of the valve leaflet and an increased eNOS and inducible NOS (iNOS) mRNA expression in the central area of some of the valve leaflets. It is suggested that the increased eNOS expression plays a protective role which may include inhibition of leukocyte and platelet adhesion and regulation of valve remodeling and angiogenetic processes. The iNOS expression is mainly associated with valvular interstitial cells which are involved in tissue matrix production and remodeling processes of the valve.
The in vivo studies measured plasma markers of NO bioavailability such as the stable metabolites nitrate and nitrite (NOx) and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) in dogs. These markers have all been shown to correlate well with local measurements of endothelial function in human patients. It was shown that when measured in dogs the markers were sensitive to different physiological and genetic variations 9 Sophia Moesgaard afhandling.indd9 9 10/09/07 8:55:52 10 such as exercise, breed, gender and stress during clinical examination (white coat effect). Plasma NOx has previously been shown to be decreased in dogs during asymptomatic stages of MMVD, whereas ADMA was not affected. Short-term treatment with angiotensin converting enzyme (ACE) inhibitors did not, however, affect the plasma concentrations of NOx and ADMA in dogs with asymptomatic MMVD. These findings indicate that the concentration of these plasma markers are either not affected by ACE inhibition in the dog or that ACE inhibition only affects the concentration in symptomatic dogs. More studies including dogs of different breeds with different stages (asymptomatic as well as symptomatic) of MMVD are needed to conclude whether endothelial dysfunction is indeed present and plays a role in canine MMVD. Furthermore, a combination of local measurements of endothelial function and systemic markers would provide more convincing and detailed evidence on how well these markers correlate with endothelial function in dogs.
In conclusion, the data presented in this thesis suggest that NO plays a local role in both physiological as well as pathological processes of the porcine mitral valve. NO release including the expression of eNOS and iNOS appears to be increased at early stages of MMVD. Exact, repeatable measurements of endothelial function and systemic NO production in the dog still remain to be established and should be tested in standardized control dogs as well as symptomatic cardiovascular patients since studies indicate that systemic NO concentration is influenced by several factors. However, the clear exercise induced effect on plasma markers of endothelial function may enable assessment of endothelial function, whereby some of the background disturbances can be avoided.