Dynamic component in secondary mitral regurgitation

The aim of this project initiated by researchers of the Medical University of Vienna is to investigate patients with secondary valvular regurgitation, a disease that dramatically reduces quality of life and life expectancy. In detail, the project examines the mitral valve, which prevents backwards blood flow from the left ventricle into the left atrium. If the ventricle dilates, which is the case in heart diseases such as chronic heart failure, tension forces are exerted on the valvular apparatus and the leaflets, which impedes efficient closure of the valve and promotes backward flow a so-called regurgitation. Valvular regurgitations leads to increased pressure and volume overload for the already compromised heart and drives the disease towards late stages. Previous results of this research group could established a clear link between even low-grade regurgitations and a significantly increased risk of mortality. Therapeutic approaches that exceed medical therapy remain a matter of debate, which is why a detailed understanding of the exact pathophysiologic mechanisms involved in the progression of the disease are essential for personalized and timely treatment of these patients. A few basic research studies have shown that the closing mechanism of the mitral valve display a strong dynamic component, which depends on pressure and volume loading conditions of the vascular system as well as contractility and size of the left ventricle. The contribution of these components to the severity of the regurgitation include key mechanisms for the understanding of the disease, however data on these dynamics remain scarce. Thus, the aim of this newly initiated project is to investigate patients with secondary mitral regurgitation via echocardiography using a newly developed stress protocol that simulates different loading conditions. Specifically, we hypothesize that increased pressure and volume load will lead to a rise in backward flow and that an increased contractility and size of the ventricle will lead to a decrease in regurgitation. By conducting this pilot project, we aim to unveil as yet unknown key mechanisms of mitral regurgitation and risk factors that are able to precisely predict a progression of said disease. This leads to personalized therapy and use of the best available treatment options at the right moment, especially in the advent of new transcatheter interventions. Finally, the conclusions and insights drawn from this study are hopefully able to prompt new therapy concepts for this menacing entity.

Mitral regurgitation resulting from heart failure impairs quality of life, increases the frequency of hospitalizations, and is associated with a poor prognosis. These effects on individual patients pose significant challenges for hospitals and payers. In previous studies, we demonstrated in which patients, depending on the quantified severity of mitral regurgitation, an increased mortality risk can be expected. These findings were subsequently confirmed through the therapeutic success observed in randomized studies. However, the actual severity of mitral regurgitation remains unclear in some patients, suggesting a significant dynamic component. Ultimately, the stress factors can be reduced to three main components: 1. Ischemia under increased oxygen demand, 2. Afterload, and 3. Excessive preload. In the study, a novel stress echocardiography protocol was developed, which examines these stressors under controlled and defined conditions using 1. Dobutamine stress, 2. Norepinephrine stress, and 3. Volume stress. This protocol measures the increase or decrease in mitral regurgitation using highly sensitive methods. Additionally, morphological components and their relationship to mitral regurgitation were analyzed. Detailed anatomical profiling in heart failure with reduced ejection fraction was performed, highlighting the importance of underlying morphology beyond the mitral valve itself. In a subgroup analysis, the research team demonstrated the effectiveness of guideline-directed, optimized medical therapy in reducing mitral regurgitation. Furthermore, the project utilized the new definitions of heart failure to examine secondary mitral regurgitation across the entire spectrum of heart failure. This provided an epidemiological foundation for understanding the extent of the disease, its impact, and current therapeutic strategies. A second part of the study focused on the frequently co-occurring secondary tricuspid regurgitation in these patients. The natural course, epidemiology, treatment standards, and outcomes of tricuspid regurgitation were analyzed across the full spectrum of heart failure.