# Tricuspid Valve Maladaptation: Its Stimuli, its Effect on Valve Function, and its Response to Therapy > **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $191,980 ## Abstract 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 coapt successfully, 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. The ultimate goal of the parent grant is to understand tricuspid valve maladaptation as a potential therapeutic target. In fact, Aim 3 of the parent grant explores prophylactic surgery as one potential path toward preventing maladaptation and thus improving clinical outcomes. Instead, the objective of this supplement is to take a first step toward testing tricuspid maladaptation as a pharmacological target for future therapies. Therein, we are guided by our and others’ findings that remodeling of cardiac valve leaflets occurs through disease-induced endothelial-to-mesenchymal transition (endoMT) of valvular endothelial cells (VEC) and valvular interstitial cell (VIC) activation. Both phenotype changes have been suggested to be mediated through the renin-angiotensin system (RAS). Toward identifying a pharmacological target for tricuspid valve maladaptation, we thus test the hypothesis that targeted RAS inhibition suppresses the direct and indirect activation of tricuspid valve cell phenotypes that drive tricuspid valve maladaptation. Specifically, in Aim 1, we will test RAS-mediated VEC endoMT and VIC activation as a potential pharmacological target in-vitro. Thereby, our work is a critical step toward a translatable treatment and directly informs future in-vivo studies. For example, in the mitral valve, Losartan, an angiotensin II receptor inhibitor, has shown some promise to treat mitral maladaptation. Based on our work, we may be able to similarly identify safe drugs that can be used to suppress tricuspid valve maladaptation. Our effort will shed new light on a deadly cardiovascular disease and its treatment and is thus well-suited for support through the CAROL Act. ## Key facts - **NIH application ID:** 11096442 - **Project number:** 3R01HL165251-03S1 - **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN - **Principal Investigator:** MANUEL Karl RAUSCH - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $191,980 - **Award type:** 3 - **Project period:** 2022-06-20 → 2027-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/11096442 ## Citation > US National Institutes of Health, RePORTER application 11096442, Tricuspid Valve Maladaptation: Its Stimuli, its Effect on Valve Function, and its Response to Therapy (3R01HL165251-03S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11096442. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*