Page 147 - Small Animal Internal Medicine, 6th Edition

CHAPTER 6
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Acquired Valvular and

Endocardial Disease

DEGENERATIVE ATRIOVENTRICULAR downregulated genes relate to formation of force-resistant
VALVE DISEASE collagen bundles, basement membrane structure, matrix
metalloproteinases involved in collagen maturation and
Chronic degenerative atrioventricular (AV) valve disease is elastic fiber formation, and sarcoplasmic reticular calcium
the most common cause of heart failure in the dog; it is reuptake.
estimated to cause more than 70% of the cardiovascular Chronic mechanical stress on valve leaflet edges from
disease recognized in this species. Almost all small-breed repeated impact is thought to play a role in initiating the
dogs develop some degree of valve degeneration as they age; myxomatous degeneration process. Subsequent alterations
many dogs of larger breeds do as well. Degenerative valve in valve interstitial and endothelial cell phenotype and func-
disease also has been called endocardiosis, mucoid or myxo- tion are important to this process. These changes cause
matous valvular degeneration, chronic valvular fibrosis, and disruptions in normal extracellular matrix homeostatic
other names. Because clinically relevant degenerative valve mechanisms, leading to characteristic changes in the organi-
disease is rare in cats, this chapter focuses on canine chronic zation, quantity, and distribution of extracellular matrix
valvular disease. The mitral valve is affected most often and components. The major mediator of myxomatous degenera-
to a greater degree, therefore degenerative valve disease tion appears to be activated valve interstitial cells, which
usually is referred to as chronic (or degenerative or myxo- become transformed from their normal fibroblastic pheno-
matous) mitral valve disease (CMVD). Degenerative lesions type into a myofibroblastic, α-smooth muscle actin-positive
also affect the tricuspid valve in many dogs; however, iso- staining form (αSMA). The increase in these transformed
lated tricuspid involvement is uncommon. Thickening of the cells promotes valve matrix remodelling. Altered activity of
aortic and pulmonic valves sometimes is observed in older the various catabolic extracellular matrix enzymes (such as
animals but rarely causes more than mild insufficiency. matrix metalloproteinases, collagenases, and elastases)
The preclinical phase of CMVD is prolonged. Early valve occurs during the process of valve degeneration, which leads
lesions are evident only on post-mortem exam. As the to increased collagen, decreased elastin, and increasing valve
degenerative process continues, valve insufficiency (regurgi- stiffness. Transforming growth factor-β (TGF-β) and sero-
tation) with progressively worsening mitral regurgitation tonin (5-HT) signaling also appear to be involved in CMVD
(MR) and volume overloading of the adjacent atrium and pathogenesis. Localized production of TGF-β occurs in
ventricle eventually develop over a period of years. Although affected valves, and expression of TGF-β subtypes and their
many affected dogs do develop congestive heart failure receptors is increased. Through a mechanism involving
(CHF) and other complications, many others do not. TGF-β, 5-HT induces the transformation of valve interstitial
cells into their activated form. Valve endothelial cell signal-
ETIOLOGY AND PATHOPHYSIOLOGY ing, basement membrane damage, phenotypic changes in
Multiple factors are involved in the development of CMVD. valve endothelial cells, and increased release of vasoactive
Although the structural and cellular changes have been fairly substances are involved in the pathogenesis of CMVD.
well delineated, the molecular mechanisms and biochemical Several mediators are known to increase activity of matrix
changes involved are less clear. Studies have shown differen- metalloproteinases, including angiotensin II, endothelin,
tial expression of multiple genes, with some being upregu- norepinephrine and other catecholamines, tumor necrosis
lated and others downregulated. Affected genes appear factor (TNF)α, interleukin-1β, and possibly oxidative and
related to cell signaling, metabolism, extracellular matrix, mechanical stresses.
inflammation, cardiovascular development, basement mem- Progressive thickening of the valve spongiosa layer occurs
brane structure, and other functions. Some functions of as deposition of glycosaminoglycans (GAGs), proteoglycans,

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