Endothelium-Dependent Regulation of the Mechanical Properties of Aortic Valve Cusps

El-Hamamsy, Ismaı̈l; Balachandran, Kartik; Yacoub, Magdi H.; Stevens, L.; Sarathchandra, Padmini; Taylor, Patricia M.; Yoganathan, Ajit P.; Chester, Adrian H.

doi:10.1016/j.jacc.2008.11.056

Cited by 127 publications

(88 citation statements)

References 14 publications

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“…Additionally, the presence of α-SMA-positive stress fibers (Fig. 3A) (37,38) that respond to vasoactive mediators such as endothelin-1 (ET-1) and serotonin (4,5). We asked if we could measure the extent of EMT via a functional transformation of the normally noncontractile VEC to a contractile VIC.…”

Section: Resultsmentioning

confidence: 99%

Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve

Balachandran

Alford

Wylie-Sears

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial-mesenchymal transformation (EMT) is a critical event for the embryonic morphogenesis of cardiac valves. Inducers of EMT during valvulogenesis include VEGF, TGF-β1, and wnt/β-catenin (where wnt refers to the wingless-type mammary tumor virus integration site family of proteins), that are regulated in a spatiotemporal manner. EMT has also been observed in diseased, strain-overloaded valve leaflets, suggesting a regulatory role for mechanical strain. Although the preponderance of studies have focused on the role of soluble mitogens, we asked if the valve tissue microenvironment contributed to EMT. To recapitulate these microenvironments in a controlled, in vitro environment, we engineered 2D valve endothelium from sheep valve endothelial cells, using microcontact printing to mimic the regions of isotropy and anisotropy of the leaflet, and applied cyclic mechanical strain in an attempt to induce EMT. We measured EMT in response to both low (10%) and high strain (20%), where low-strain EMT occurred via increased TGF-β1 signaling and high strain via increased wnt/β-catenin signaling, suggesting dual strain-dependent routes to distinguish EMT in healthy versus diseased valve tissue. The effect was also directionally dependent, where cyclic strain applied orthogonal to axis of the engineered valve endothelium alignment resulted in severe disruption of cell microarchitecture and greater EMT. Once transformed, these tissues exhibited increased contractility in the presence of endothelin-1 and larger basal mechanical tone in a unique assay developed to measure the contractile tone of the engineered valve tissues. This finding is important, because it implies that the functional properties of the valve are sensitive to EMT. Our results suggest that cyclic mechanical strain regulates EMT in a strain magnitude and directionally dependent manner.tight junctions | cytokines | activated myofibroblast C ardiac valves are sophisticated structures that function in a complex mechanical environment, opening and closing more than 3 billion times during the average human lifetime (1). Initially considered passive flaps of tissue, it is now acknowledged that valves contain a highly heterogeneous population of endothelial (VEC) and interstitial (VIC) cells. The VICs exist as synthetic, myofibroblast, or smooth muscle-like phenotypes (2, 3) and alter their tone in response to vasoactive mediators (4-7). The VECs line the surface of the valve leaflet and are unique in their ability to undergo endothelial-mesenchymal transformation (EMT), a process that is crucial for valvulogenesis (8, 9). Recent clinical evidence of EMT has been observed in pathologies such as ischemic cardiomyopathy and concomitant mitral regurgitation and is correlated with increased leaflet mechanical strains (10, 11). These pathological strains can be oriented obliquely to cell and tissue orientation (12, 13), suggesting the possible interaction between mechanical forces and tissue architecture in regulating EMT.Prior work has focused on the regulation of ...

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Section: Resultsmentioning

confidence: 99%

Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve

Balachandran

Alford

Wylie-Sears

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

155

123

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“…This reduction indicates that eNOS might be involved in the fibrosa susceptibility in CAVD pathogenesis . Moreover, inhibition of eNOS expression results in increased cusp stiffness of the aortic valve (El-Hamamsy et al, 2009). Statins decreased the amount of calcification and increased VEC eNOS in rabbits, which suggests that eNOS may protect against CAVD.…”

Section: Endothelial Dysfunctionmentioning

confidence: 95%

“…Studies have demonstrated that VECs interact with VICs in a complex hemodynamic and mechanical environment to maintain aortic valve cusp tissue integrity. Additionally, VECs regulate VIC function through paracrine signals, such as controlling VIC contractility and leaflet mechanics (El-Hamamsy et al, 2009). More specifically, valvular endothelial dysfunction has been implicated as the initiator of inflammatory reactions, blood clots, and even calcification .…”

Section: Cellular Interactionmentioning

confidence: 99%

Calcific Aortic Valve Disease

2013

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“…It was reasoned that the pulmonary autograft, although subjected to systemic pressure would, as a living valve, be able to adapt. as it turns out, the aortic valve has several sophisticated features that are dependent on its viability [4][5][6] . The different parts of the aortic valve change their size and shape during the cardiac cycle.…”

Section: Rationalementioning

confidence: 99%

“…This property can affect left ventricular workload and possibly coronary flow, together with stress distribution on the valve leaflets. Furthermore, living aortic valve leaflets modify their stiffness in response to humoral and endothelial-derived signals, allowing them to adapt to changes in haemodynamic conditions 5 .…”

Section: Rationalementioning

confidence: 99%

The Ross Procedure reassessed

Pepper¹

2015

ICFJ

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RationaleThe search for an ideal biological heart valve substitute has been going on for half a century. In 1960 lower and shumway 1 described the feasibility of replacing the aortic valve in dogs with a native pulmonary valve. In london, Ross had already pioneered the homograft clinically in 1962 2 but it had become clear that a valve taken from a deceased person would have a limited durability. To use the pulmonary valve which has the same embryological origin as the aortic valve and is a living autologous valve substitute, was a ground breaking idea. In 1967 Ross performed this procedure (on humans) 3 and replaced the pulmonary valve with an aortic homograft in a patient predicting that placed in a low pressure, high compliance circuit, the durability of the homograft would be greater than in the systemic circulation. It was reasoned that the pulmonary autograft, although subjected to systemic pressure would, as a living valve, be able to adapt. as it turns out, the aortic valve has several sophisticated features that are dependent on its viability [4][5][6] . The different parts of the aortic valve change their size and shape during the cardiac cycle. This property can affect left ventricular workload and possibly coronary flow, together with stress distribution on the valve leaflets. Furthermore, living aortic valve leaflets modify their stiffness in response to humoral and endothelial-derived signals, allowing them to adapt to changes in haemodynamic conditions 5 . Early Results of the Ross ProcedureIn the year 2000, David and colleagues 7 reported that the pulmonary autograft dilated and that the dilation was often accompanied by aortic regurgitation due to outward displacement of the three commissures. David compared the results of the free standing autograft root to the aortic root inclusion technique. several other authors confirmed the findings of early dilatation in the free-standing neo-aortic root 8,9 . as this problem became widely known, fewer surgeons continued to perform the operation, but sievers 10 re-examined the problem and adapted the original sub-coronary technique with some minor changes and demonstrated excellent valve function and lack of dilation of an aortic root at medium term follow up of 7-8 years 11 .In 2009 Takkenberg 12 undertook a meticulous, systematic review and meta-analysis of all publications on the Ross procedure in the preceding 8 years. 39 studies were selected which contained information on early mortality and long term outcomes such as late deaths and re-operations. The authors controlled heterogeneity caused by age by dividing the population into three categories: consecutive series in children and adults, adult patients, and a paediatric series. Early mortality and linearised rates of post operative adverse events were calculated for each study and pooled on a logarithmic scale using the inverse variant method in a fixed effects model. some of the series included were quite small containing only 31 patients. as David has pointed out 13 series such as these will inc...

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Endothelium-Dependent Regulation of the Mechanical Properties of Aortic Valve Cusps

Abstract: These data highlight the role of the endothelium in regulating the mechanical properties of aortic valve cusps and underline the importance of valve cellular integrity for optimal valve function.

Cited by 127 publications

References 14 publications

Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve

Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve

Calcific Aortic Valve Disease

The Ross Procedure reassessed

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