Tricuspid Valve Maladaptation: Its Stimuli, its Effect on Valve Function, and itsResponse to Therapy

摘要。三尖瓣返流严重影响了160多万美国人。在大多数病人中，

ABSTRACT. Tricuspid valve regurgitation severely impacts more than 1.6 million Americans. In most patients, tricuspid regurgitation is considered “functional” or due to valve-extrinsic factors. The valve itself is considered intact and thus viewed as an innocent bystander. Therefore, most treatment strategies focus on these valve- extrinsic factors and ignore the valve itself. Recently, we have shown that tricuspid regurgitation may not be so functional after all. In two separate sheep models of functional tricuspid regurgitation, we showed that the tricuspid valve leaflets fibrotically remodel, i.e., maladapt. Those leaflets grow in area and become both thicker and stiffer. Through computational studies, we further showed that maladaptation reduces leaflet compliance and their ability to successfully coapt, thus impeding valve function. These findings are of critical importance as tricuspid maladaptation may be a predictor for disease progression and patient outcomes. They may also explain the limited success of current treatment strategies. That is, they may explain why tricuspid valve repairs fail long- term in as many as 30% of patients. Finally, tricuspid maladaptation may also serve as a pharmacological target for future therapies. While others have shown that human tricuspid valve leaflets may remodel in disease by increasing their area, it has yet to be shown that they also thicken and stiffen. Thus, tricuspid maladaptation has not been fully confirmed in patients, a knowledge gap that stands between our novel discovery and improved diagnostic and therapeutic strategies for tricuspid regurgitation. The primary objective of this Administrative Supplement is to fill this knowledge gap. Specifically, we aim to demonstrate that human tricuspid valves also maladapt by thickening and stiffening. To this end, we will take an in-vitro approach using donated cadaver hearts. We will also explore a secondary objective and determine whether those valve properties are age and/or sex dependent. Thus, our specific aims are: 1) Demonstrate that human tricuspid valves maladapt in disease via thickening and stiffening; and 2) Test whether human tricuspid valve thickness and stiffness are age- and sex-dependent. The expected outcome of this work will be two-fold. First, at the conclusion of our work, we will know whether human tricuspid valves also maladapt. This is critically important to translating our research on sheep (as funded through the parent R01) to patients. Thereby, the combined work of this supplement and the parent grant will provide insight into the fundamental pathophysiology of heart valve disease. Additionally, we may thereby establish tricuspid maladaptation as a novel therapeutic target in patients. Second, we will have tested whether tricuspid valve thickness and stiffness are sex- and age-dependent. This is highly important to our understanding of basic valvular physiology/pathophysiology and will also likely inform differential treatment strategies dependent on patient sex and age. Overall, our effort will shed new light on a deadly disease and clearly leverages our parent grant with the help of the CAROL Act.