Neuronal Regulation of Aortic Valve Cusps

Abstract

Heart valves have long been considered exclusively passive structures that open and close in response to changes in transvalvular pressure during the cardiac cycle. Although this is partly true, recent evidence suggests that valves are far more sophisticated structures. Microscopic examination of heart valves reveals a complex network of endothelial cells, interstitial cells, an extracellular matrix and a rich network of intrinsic nerves. The distribution of these nerve networks varies between the four valves, but is remarkably conserved between species. The present review will focus mainly on aortic valve innervation for several reasons: it is most commonly involved in disease processes, it lies in a unique hemodynamic environment and is exposed to extreme mechanical forces. These nerves are likely to play a significant role in the modulation of aortic valve structure and function and its adaptation to different hemodynamic and humoral conditions. The objectives of this review are first to describe the anatomy of aortic valve innervation, then detail the functional significance of innervation to the valve and finally make the case for the clinical relevance of understanding the neural control of aortic valves and its potential pharmacologic implications.

Cellular and Neuronal Aspects in Aortic Stenosis

“…Both sides of the aortic valve cusps, the fibrosa and ventricularis, are lined by endothelial cells 1,2,3 . These valvular endothelial cells are able to respond to stress placed on the cusps, particularly shear stress and can produce several vasoactive mediators, such as nitric oxide, endothelins and prostaglandins 1,7,8 , thus translating mechanical stimuli into biological responses, referred to as mechanotransduction 3 .…”

“…Below the layer of endothelial cells lining the outer and inner layer of the aortic cusps (the fibrosa and ventricularis), the extracellular matrix is found, composed of elastin, collagen and proteoglycans 10 . In addition to the elastin, collagen and proteoglycans in this extracellular matrix, a population of valve interstitial cells can be found 2,3 . These consist of fibroblasts, smooth muscle cells and myofibroblasts 2,3,11 .…”

“…In addition to the elastin, collagen and proteoglycans in this extracellular matrix, a population of valve interstitial cells can be found 2,3 . These consist of fibroblasts, smooth muscle cells and myofibroblasts 2,3,11 . The proportion of these different cells comprising the interstitial cell component will depend on the condition and state of health of the valve 2 .…”

“…The proportion of these different cells comprising the interstitial cell component will depend on the condition and state of health of the valve 2 . These cells possess important secretory and proliferative properties to repair and maintain the extracellular matrix 2,3 . They also have contractile properties and express the same structural genes as cardiac muscle, such as cardiac troponin T, I and C, cardiac myosin light chain and beta myosin heavy chain 2,12 .…”

“…For quite some time the physiological approach to cardiac valve function held the belief that these are purely passive structures merely moving in response to changes in transvalvular pressure generated by atrial and ventricular contractions 1,2,3 . Today, this "passive hypothesis" is being challenged as numerous studies have shown that mammalian cardiac valves are capable of independent contraction during various stages of the cardiac cycle 1,4,5 .…”