ABSTRACT. 1.6 million Americans suffer from functional tricuspid valve regurgitation (FTR); that is, tricuspid valve leakage due to valve-extrinsic factors such as pulmonary hypertension-induced right ventricular remodeling. Of those patients, only approximately 8-10 thousand are surgically treated. This undertreatment of patients with FTR has been declared “a public health crisis”. While the reasons for undertreatment are multi-fold, one is unarguably that available treatment options have suboptimal outcomes while being high-risk; thus, tilting the risk-benefit scale toward conservative treatment. For example, FTR recurs in as many as 10-30% of patients treated via the gold-standard surgical technique tricuspid valve annuloplasty. Additionally, mortality rates of re- operation are exorbitantly high (>30%). Clearly, better therapeutic approaches are needed to treat FTR and to stop undertreatment of a large patient population. Our collaborative team has recently shown in two separate sheep models that the tricuspid valve leaflets grow and fibrotically remodel in FTR. The discovery of tricuspid valve (mal)adaptation now raises the possibility to both harness the valve’s native ability to grow, and thereby counteract disease, and to therapeutically target leaflet fibrosis. However, before being able to use our new knowledge toward improving treatment of FTR and toward overcoming today’s massive undertreatment, tricuspid valve maladaptation must be better understood: To date, we don’t know its stimuli, the mechanisms of its detrimental effects on valve function, or how therapy may be used to suppress fibrosis. The objective of this current proposal is to overcome these gaps in knowledge. To this end, we will test our central hypothesis that disease-induced leaflet strains stimulate leaflet maladaptation which, in turn, hinders valve coaptation and contributes to FTR, and that leaflet maladaptation may be halted by counteracting disease-induced stimuli. We will pursue our objective in three aims: 1) Identify the stimuli of tricuspid valve maladaptation, 2) Delineate the mechanisms through which maladaptation impedes valve function, 3) Test whether prophylactic intervention halts maladaptation. To accomplish these aims, we will combine innovative, chronic sheep models with in-vitro flow loop valve characterization using high-speed 3D imaging, and extensive mechanical, compositional, and biological tissue phenotyping. Our team has a long collaborative track record of studying tricuspid valve function and disease, and is supported by a senior colleague with 30 years of experience in in-vitro valve experimentation. Upon conclusion of this work, we expect to have identified the stimuli for tricuspid valve maladaptation, understand the mechanisms through which it impedes valve function, and have shown that it can be halted through surgical intervention. Thus, we will have shed light on a recently identified disease mechanism of the tricuspid valve and suggested it as a novel therapeutic target. Our work will therefore pave the way toward a better understanding and better treatment of FTR as a public health crisis. While our work is surgically-focused, it is equally important to transcatheter repair strategies which amplifies the significance of our work and its impact.

PROJECT NARRATIVE. Leakage of the tricuspid valve, which is located between the right atrium and right ventricle, is extremely common and, if not treated, can significantly impact the health of patients. The current gold-standard for treatment is a surgical approach known as tricuspid annuloplasty, which unfortunately does not have high long-term success rates and fails in approximately one third of patients. This proposal is relevant to public health as we aim to better understand a new tricuspid valve disease mechanism, tricuspid valve maladaptation, that could be used as future therapeutic target toward improving the currently poor outcomes for patients with tricuspid valve regurgitation.