Mrudang Mathur

All Publications

• Tricuspid valve leaflet remodeling in sheep with biventricular heart failure: A comparison between leaflets. Acta biomaterialia Kostelnik, C. J., Meador, W. D., Lin, C., Mathur, M., Malinowski, M., Jazwiec, T., Malinowska, Z., Piekarska, M. L., Gaweda, B., Timek, T. A., Rausch, M. K. 2025

  Abstract

  Tricuspid valve leaflets are dynamic tissues that can respond to altered biomechanical and hemodynamic loads. Each leaflet has unique structural and mechanical properties, leading to differential in vivo strains. We hypothesized that these intrinsic differences drive heterogeneous, disease-induced remodeling between the leaflets. Although we previously reported significant remodeling changes in the anterior leaflet, the responses among the other two leaflets have not been reported. Using a sheep model of biventricular heart failure, we compared the remodeling responses between all tricuspid leaflets. Our results show that the anterior leaflet underwent the most significant remodeling, while the septal and posterior leaflets exhibited similar but less pronounced changes. We found several between-leaflet differences in key structural and mechanical metrics that have been shown to contribute to valvular dysfunction. Diseased animals exhibited significantly larger septal and anterior leaflets, thicker anterior and posterior leaflets, and stiffer anterior leaflets. Additionally, the septal leaflet's anisotropy index significantly decreased. Also, the septal and anterior leaflets showed increased collagen fiber dispersion near the atrial surface. As for remodeling markers, alpha-smooth muscle actin (alpha-SMA), Ki67, matrix-metalloprotease 13 (MMP13), and transforming growth factor beta-1 (TGF-beta1) were upregulated in spatially and leaflet-dependent patterns. That is, we observed increased expression of these markers within septal leaflets' near-annulus and belly regions, increased expression in anterior leaflets' belly region, and varied expression in posterior leaflets. These findings underscore the need to consider leaflet-specific remodeling to fully understand tricuspid valve dysfunction and to develop targeted therapies for its treatment and more accurate computational models. STATEMENT OF SIGNIFICANCE: Our study is significant as it advances our understanding of tricuspid valve remodeling by providing a comprehensive analysis of all three leaflets in a sheep model of biventricular heart failure. Unlike prior works that focused primarily on the anterior leaflet or generalized leaflet changes, we integrated morphological, histological, immunohistochemistry, biaxial mechanical testing, and two-photon microscopy to quantify differences between all three tricuspid valve leaflets (anterior, posterior, and septal) across multiple functional scales. This comprehensive approach highlights the unique remodeling response of each leaflet. Our findings offer critical insights for developing targeted therapeutic strategies and improving computational models of disease progression.

  View details for DOI 10.1016/j.actbio.2025.03.052

  View details for PubMedID 40180007

• Tricuspid valve edge-to-edge repair simulations are highly sensitive to annular boundary conditions. Journal of the mechanical behavior of biomedical materials Haese, C. E., Dubey, V., Mathur, M., Pouch, A. M., Timek, T. A., Rausch, M. K. 2024; 163: 106879

  Abstract

  Transcatheter edge-to-edge repair (TEER) simulations may provide insight into this novel therapeutic technology and help optimize its use. However, because of the relatively short history and technical complexity of TEER simulations, important questions remain unanswered. For example, there is no consensus on how to handle the annular boundary conditions in these simulations. In this short communication, we tested the sensitivity of such simulations to the choice of annular boundary conditions using a high-fidelity finite element model of a human tricuspid valve. Therein, we embedded the annulus among elastic springs to simulate the compliance of the perivalvular myocardium. Next, we varied the spring stiffness parametrically and explored the impact on two key measures of valve function: coaptation area and leaflet stress. Additionally, we compared our results to simulations with a pinned annulus. We found that a compliant annular boundary condition led to a TEER-induced "annuloplasty effect," i.e., annular remodeling, as observed clinically. Moreover, softer springs led to a larger coaptation area and smaller leaflet stresses. On the other hand, pinned annular boundary conditions led to unrealistically high stresses and no "annuloplasty effect." Furthermore, we found that the impact of the boundary conditions depended on the clip position. Our findings in this case study emphasize the importance of the annular boundary condition in tricuspid TEER simulations. Thus, we recommend that care be taken when choosing annular boundary conditions and that results from simulations using pinned boundaries should be interpreted with caution.

  View details for DOI 10.1016/j.jmbbm.2024.106879

  View details for PubMedID 39742687

• Leaflet remodeling reduces tricuspid valve function in a computational model JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS Mathur, M., Malinowski, M., Jazwiec, T., Timek, T. A., Rausch, M. K. 2024; 152: 106453

  Abstract

  Tricuspid valve leaflets have historically been considered "passive flaps". However, we have recently shown that tricuspid leaflets actively remodel in sheep with functional tricuspid regurgitation. We hypothesize that these remodeling-induced changes reduce leaflet coaptation and, therefore, contribute to valvular dysfunction. To test this, we simulated the impact of remodeling-induced changes on valve mechanics in a reverse-engineered computer model of the human tricuspid valve. To this end, we combined right-heart pressures and tricuspid annular dynamics recorded in an ex vivo beating heart, with subject-matched in vitro measurements of valve geometry and material properties, to build a subject-specific finite element model. Next, we modified the annular geometry and boundary conditions to mimic changes seen in patients with pulmonary hypertension. In this model, we then increased leaflet thickness and stiffness and reduced the stretch at which leaflets stiffen, which we call "transition-λ." Subsequently, we quantified mean leaflet stresses, leaflet systolic angles, and coaptation area as measures of valve function. We found that leaflet stresses, leaflet systolic angle, and coaptation area are sensitive to independent changes in stiffness, thickness, and transition-λ. When combining thickening, stiffening, and changes in transition-λ, we found that anterior and posterior leaflet stresses decreased by 26% and 28%, respectively. Furthermore, systolic angles increased by 43%, and coaptation area decreased by 66%; thereby impeding valve function. While only a computational study, we provide the first evidence that remodeling-induced leaflet thickening and stiffening may contribute to valvular dysfunction. Targeted suppression of such changes in diseased valves could restore normal valve mechanics and promote leaflet coaptation.

  View details for DOI 10.1016/j.jmbbm.2024.106453

  View details for Web of Science ID 001180594300001

  View details for PubMedID 38335648

  View details for PubMedCentralID PMC11048730