Toward understanding tricuspid valve leaflet (mal-)adaptation in heart disease

Date

2022-06-24

Authors

Meador, William Diederich

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Abstract

The tricuspid valve regulates blood flow between the right atrium and right ventricle of the heart. Clinically severe tricuspid regurgitation, or backflow of blood during systole, presents in 1.6 million Americans and has been linked to increased morbidity and independent prediction of mortality. In most patient cases, tricuspid regurgitation is considered functional, or caused by valve-extrinsic factors. For example, right ventricular remodeling from pulmonary hypertension can immobilize the tricuspid valve leaflets via chordal tethering or dilate the tricuspid annulus beyond leaflet surface area limits. These hindering mechanisms result in tricuspid valve incompetence and regurgitation. In other words, in functional tricuspid regurgitation, tricuspid leaflets are believed to be passive in their own dysfunction. However, tricuspid valve leaflets contain mechanobiologically sensitive valvular interstitial cells which could activate and adapt the leaflet’s fibrous network due to pathological mechanical stimulation, resulting in altered tissue properties and function. Beneficial adaptation, such as leaflet growth, or detrimental maladaptation, such as leaflet stiffening, could thus organically alleviate or contribute to tricuspid regurgitation, respectively, challenging the passive leaflet paradigm in functional tricuspid regurgitation. Prior to our work, it was unknown whether (mal-)adaptation occurs in the tricuspid leaflets in heart disease. To address this, we employed a multiscale biomechanical approach to improve our understanding of tricuspid (mal-)adaptation. In this dissertation, we first characterize the mechanical and microstructural properties of all three tricuspid leaflets in healthy sheep, reporting leaflet-specific distinctions in their collagenous networks and thus, mechanical behaviors. Second, we evaluate the tricuspid valve anterior leaflet’s propensity toward (mal-)adaptation in a biventricular heart failure model. To this end, we report strong evidence of mechanical, structural, compositional, and biological changes to these leaflets on tissue-, matrix-, and cellular-scales. Lastly, we developed a micro-bulge test device capable of simultaneous multi-scale characterizations of minuscule soft tissues. We demonstrate our device in characterizing rat tricuspid valve anterior leaflet mechanical and microstructural properties, in anticipation that small animal models could support investigations to unlock the mechanistic origins of leaflet (mal-)adaptation. With a better understanding of tricuspid valve (mal-)adaptation, our work could inform more efficacious interventional strategies to treat tricuspid regurgitation, improving patient outcomes.

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