Hemodynamic Characterization of a Mouse Model for Investigating the Cellular and Molecular Mechanisms of Neotissue Formation in Tissue-Engineered Heart Valves

James, Iyore; Yi, Tai; Tara, Shuhei; Best, Cameron; Stuber, Alexander J.; Shah, Kejal V.; Austin, Blair F.; Sugiura, T.; Lee, Yong Ung; Lincoln, Joy; Trask, Aaron J.; Shinoka, Toshiharu; Breuer, Christopher K.

doi:10.1089/ten.tec.2015.0011

Cited by 15 publications

(16 citation statements)

References 22 publications

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“…It was based on previous experiments performed in rats and on surgical technical reports [12,14,15], where the working HHT model showed outcomes superior to those of the nonworking one. This included achieving almost systemic orthotopic-like blood pressures in the right ventricle and the LV, no major macroscopic enlargement of the LA, appropriate diastolic relaxation, and responsiveness to β-receptor agonist drugs similar to that of the native heart.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, several research groups have investigated different approaches towards increased loading of the left ventricular side in order to create a fully loaded, ‘working' HHT model [8,11,12,13,14,15]. In spite of these important pioneering studies on the improvement of myocardial loading in HHT models, these approaches could only generate a native-analogous, fully loaded myocardial environment via integrating a combined heart-lung transplantation approach into the murine system [16].…”

Section: Introductionmentioning

confidence: 99%

“…With the presence of pulmonic tissue in the peritoneal cavity, the practicability and long-term functionality of these combined models are expected to be highly limited [11]. Other initial attempts have focused on the combined transplantation of the pulmonary valve and the heart for generating biventricularly loaded model systems [15]. However, a systematic hemodynamic and electrical assessment of biventricularly loaded HHT model systems in order to investigate their representative value for the native situation is missing.…”

Section: Introductionmentioning

confidence: 99%

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Hemodynamic Assessment of a Murine Heterotopic Biventricularly Loaded Cardiac Transplant in vivo Model

et al. 2016

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Background: Heterotopic heart transplantation (HHT) in rodent animal models represents an important technique enabling studies on organ transplantation immunology and pharmaceutical development. Recent investigations used nonworking HHT designs, with the left ventricle (LV) bypassed in the anastomosis system. In spite of their principal success, the lack of orthogonal ventricular filling leads to myocardial atrophy. However, when focusing on the cellular and molecular mechanisms involved in the in vivo remodeling of the myocardium or cell-based cardiovascular implants, a nonworking model is suboptimal as it lacks the native-analogous hemodynamic and metabolic situation. Here we present the hemodynamic and electrical assessment of a biventricularly loaded murine HHT method without the need for a combined heart-lung transplantation approach. Methods: Heterotopic transplantations (n = 13) were performed on C57BL/6J-(H-2b) inbred mice (n = 13 donors, n = 13 recipients) by creating end-to-side anastomoses between the donors' cranial vena cava (CrVC) and the recipients' abdominal caudal vena cava (CVC), between the donors' ascending aorta and the recipients' abdominal aorta (aAo), and between the grafts' pulmonary trunk and the left atrium. After transplantation, a hemodynamic assessment using echocardiography (including 2D speckle tracking analysis) and electrocardiography was performed. Results: The loaded HHT procedure in the mice was performed with an overall success rate of 61%. In 3 of the remaining 5 cases, only atrial function was restored. The median duration of the entire surgical procedure for the recipient animal was 190 (IQR 180-250) min. The mean heart rate in the loaded HHT group was 355 ± 6 bpm in comparison to the control group with an in situ heart rate of 418 ± 61 bpm. A native-like closing and opening pattern of the aortic and mitral valves (visible on both 2D and M-mode images) was observed, confirming a native-analogous loading of the LV. Pulsed-wave Doppler provided visualization of the flow across the region of anastomoses between the pulmonary trunk and the left atrium, reaching a mean maximum velocity of 382 ± 12 mm/s. Exemplary 2D speckle tracking analysis of the LV free wall and interventricular septum revealed some differences in vector directions in one animal when compared to the orthotopic native heart, indicating an asynchronous movement of the LV. Conclusions: These results demonstrate the technical (micro)surgical feasibility of a fully loaded HHT procedure in the murine model without using a combined heart-lung transplantation approach. The acute hemodynamic performance of the HHT grafts approximated the native orthotopic situation. This model may open up new options for the investigation of cellular and molecular questions in the murine cardiovascular in vivo system in the near future.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hemodynamic Assessment of a Murine Heterotopic Biventricularly Loaded Cardiac Transplant in vivo Model

et al. 2016

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“…Several preclinical studies using decellularized heart valve grafts have been documented in the literature (Iop and Gerosa 2015; James et al 2015; Sierad et al 2015; Syedain et al 2015). The decellularized porcine SIS, CorMatrix, has also been used as a pulmonary valve replacement in porcine models (Matheny et al 2000), with explanted constructs revealing resorption of the submucosal matrix, fibrous connective tissue growth, and formation of neovasculature.…”

Section: Heart Valvesmentioning

confidence: 99%

The Heart and Great Vessels

Onwuka

King

Heuer

et al. 2017

Cold Spring Harb Perspect Med

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Cardiovascular disease is the leading cause of mortality worldwide. We have made large strides over the past few decades in management, but definitive therapeutic options to address this health-care burden are still limited. Given the ever-increasing need, much effort has been spent creating engineered tissue to replaced diseased tissue. This article gives a general overview of this work as it pertains to the development of great vessels, myocardium, and heart valves. In each area, we focus on currently studied methods, limitations, and areas for future study.

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“…Despite the translational potential of these animal models given their anatomical and physiological similarities with the human heart, working with large animals has multiple ethical and technical limitations. As an alternative, a mouse model of pulmonary cardiac valve transplantation has recently been developed to study the process of recellularization in tissue-engineered cardiac valves (James, et al, 2015). The introduction of this murine model brought the possibility of using multiple genetic tools.…”

Section: Introductionmentioning

confidence: 99%

Cardiac valve regeneration in adult zebrafish: importance of TGFß signaling in new tissue formation

Bensimon-Brito

Ramkumar

Boezio

et al. 2019

Preprint

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Cardiac valve disease can lead to severe cardiac dysfunction and is thus a frequent cause of morbidity and mortality. Its main treatment is valve replacement, which is currently greatly limited by the poor recellularization and tissue formation potential of the implanted valves. As we still lack suitable animal models to identify modulators of these processes, here we used the adult zebrafish and found that, upon valve decellularization, they initiate a striking regenerative program that leads to the formation of new functional valves. After injury, endothelial and kidney marrow-derived cells undergo cell cycle re-entry and differentiate into new extracellular matrix-secreting valve cells. The Transforming Growth Factor beta (TGFβ) signaling pathway promotes this process by enhancing progenitor cell proliferation as well as valve cell differentiation. These findings reveal a key role for TGFβ signaling in valve regeneration and also establish the zebrafish as a model to identify and test factors promoting valve recellularization and growth.

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Hemodynamic Characterization of a Mouse Model for Investigating the Cellular and Molecular Mechanisms of Neotissue Formation in Tissue-Engineered Heart Valves

Cited by 15 publications

References 22 publications

Hemodynamic Assessment of a Murine Heterotopic Biventricularly Loaded Cardiac Transplant in vivo Model

Hemodynamic Assessment of a Murine Heterotopic Biventricularly Loaded Cardiac Transplant in vivo Model

The Heart and Great Vessels

Cardiac valve regeneration in adult zebrafish: importance of TGFß signaling in new tissue formation

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