Specific Aims Tricuspid regurgitation is a very common etiology of valvular cardiomyopathy. In the United States alone, there are an estimated 1.3 million patients with severe tricuspid regurgitation. Severe tricuspid regurgitation carries an ominous prognosis as observational data demonstrate 1-year mortality rates are as high as 46%. At present, there are no effective therapeutics that counteract the cardiac effects of tricuspid regurgitation, and treatment consists of diuretics for volume overload or surgical correction. Surgical treatment is both high risk and quite costly. The in-hospital mortality for surgical repair of tricuspid regurgitation remains at 8-10%, and the average cost of hospitalization is >$80,000. Both medical and surgical treatment of tricuspid regurgitation is difficult because tricuspid regurgitation compromises both right atrial and right ventricular function due to continual volume overload, but the mechanisms underlying the pathological changes in each chamber are undefined. These key unanswered questions will be addressed in this proposal. One barrier to understanding the detrimental molecular effects of tricuspid regurgitation on the right atrium and right ventricle is the lack of robust animal models of severe tricuspid regurgitation. Rodent models of valvular cardiomyopathy are limited because it is technically challenging to induce valve disease due to the small size of the animals. In addition, evaluation of right atrial and ventricular structure and function in rodents can be quite challenging even with the most experienced echocardiographer. Finally, mice and rats do not provide sufficient tissue to perform multi-omics studies, which has further hampered our ability to gain mechanistic insights. Large animal models may circumvent some of these challenges, and offer additional advantages, as they are widely believed to better recapitulate human physiology. However, a large animal model of severe tricuspid regurgitation is lacking, but our supplement will close this important knowledge gap. In our preliminary studies, we show endovascular-mediated damage of the tricuspid valve results in significant tricuspid regurgitation and right heart remodeling. When comparing right atrial and ventricular volumes of two pigs to our historic controls, we observed significant right heart remodeling with increased right atrial and right ventricular end-diastolic volumes. Thus, we provide proof of principle data that we have generated a large animal model of severe tricuspid regurgitation, and this lays the groundwork for further mechanistic and multi- omic exploration of this highly translational model. In this supplemental proposal, we will further refine our porcine model of severe tricuspid regurgitation and then perform a deep molecular phenotypic evaluation of both the right atrium and right ventricle to delineate the molecular underpinnings of right heart remodeling. Then, we will compare and contrast the effects of right...