Discrete Subaortic Stenosis: Perspective Roadmap to a Complex Disease

Discrete subaortic stenosis (DSS) is a congenital heart disease that results in the formation of a fibro-membranous tissue, causing an increased pressure gradient in the left ventricular outflow tract (LVOT). While surgical resection of the membrane has shown some success in eliminating the obstruction, it poses significant risks associated with anesthesia, sternotomy, and heart bypass, and it remains associated with a high rate of recurrence. Although a genetic etiology had been initially proposed, the association between DSS and left ventricle (LV) geometrical abnormalities has provided more support to a hemodynamic etiology by which congenital or post-surgical LVOT geometric derangements could generate abnormal shear forces on the septal wall, triggering in turn a fibrotic response. Validating this hypothetical etiology and understanding the mechanobiological processes by which altered shear forces induce fibrosis in the LVOT are major knowledge gaps. This perspective paper describes the current state of knowledge of DSS, articulates the research needs to yield mechanistic insights into a significant pathologic process that is poorly understood, and proposes several strategies aimed at elucidating the potential mechanobiological synergies responsible for DSS pathogenesis. The proposed roadmap has the potential to improve DSS management by identifying early targets for prevention of the fibrotic lesion, and may also prove beneficial in other fibrotic cardiovascular diseases associated with altered flow

Recent advances in biological pumps as a building block for bioartificial hearts

The field of biological pumps is a subset of cardiac tissue engineering and focused on the development of tubular grafts that are designed generate intraluminal pressure. In the simplest embodiment, biological pumps are tubular grafts with contractile cardiomyocytes on the external surface. The rationale for biological pumps is a transition from planar 3D cardiac patches to functional biological pumps, on the way to complete bioartificial hearts. Biological pumps also have applications as a standalone device, for example, to support the Fontan circulation in pediatric patients. In recent years, there has been a lot of progress in the field of biological pumps, with innovative fabrication technologies. Examples include the use of cell sheet engineering, self-organized heart muscle, bioprinting and in vivo bio chambers for vascularization. Several materials have been tested for biological pumps and included resected aortic segments from rodents, type I collagen, and fibrin hydrogel, to name a few. Multiple bioreactors have been tested to condition biological pumps and replicate the complex in vivo environment during controlled in vitro culture. The purpose of this article is to provide an overview of the field of the biological pumps, outlining progress in the field over the past several years. In particular, different fabrication methods, biomaterial platforms for tubular grafts and examples of bioreactors will be presented. In addition, we present an overview of some of the challenges that need to be overcome for the field of biological pumps to move forward

Ancillary documents for NIH grant applications: The pages beyond the science.

Preparing a grant proposal is no small feat, especially for research (R-series) grants from the National Institutes of Health. The National Institutes of Health is the largest public funder of biomedical research in the world, and as such, procuring a research grant from the National Institutes of Health is one of the ultimate benchmarks of success for a surgeon-scientist. Most investigators are familiar with the page limits for most R-series grants (12 pages for an R01 and 6 pages for an R21), with the addition of a single page allotted for the specific aims. Interestingly, despite the usual focus on the aforementioned research section, the rest of the application can routinely consist of an additional 100 to 150 pages, which means that pages allotted for the specific aims and research strategy represent only 10% of the complete application package. For busy surgeons, it is this abundance of ancillary documentation that can make preparing a research grant particularly onerous. Fortunately, for some, support exists within the department to help prepare much of this documentation by drawing from previous sources, templates, and boilerplate language that has been developed. Although these resources can significantly reduce the burden on individual investigators, there is a danger of leaning on generalized templates that can dilute the message of the overall grant proposal and introduce extraneous or incorrect information that can ultimately impact the cohesiveness and ultimately the competitiveness of the grant. The focus of this article is to educate surgeon-scientists regarding the purpose and importance of the ancillary information required for National Institutes of Health research grants and how to make the most of institutional resources while tailoring these materials to create a cohesive, competitive grant application

Immunologic Roles of Hyaluronan in Dermal Wound Healing

Hyaluronic acid (HA), a glycosaminoglycan ubiquitous in the skin, has come into the limelight in recent years for its role in facilitating dermal wound healing. Specifically, HA’s length of linearly repeating disaccharides—in other words, its molecular weight (MW)—determines its effects. High molecular weight (HMW)-HA serves an immunosuppressive and anti-inflammatory role, whereas low molecular weight (LMW)-HA contributes to immunostimulation and thus inflammation. During the inflammatory stage of tissue repair, direct and indirect interactions between HA and the innate and adaptive immune systems are of particular interest for their long-lasting impact on wound repair. This review seeks to synthesize the literature on wound healing with a focus on HA’s involvement in the immune subsystems

Significance of aortoseptal angle anomalies to left ventricular hemodynamics and subaortic stenosis: A numerical study

Purpose: Discrete subaortic stenosis (DSS) is an obstructive cardiac disease caused by a membranous lesion in the left ventricular (LV) outflow tract (LVOT). Although its etiology is unknown, the higher prevalence of DSS in LVOT anatomies featuring a steep aortoseptal angle (AoSA) suggests a potential role for hemodynamics. Therefore, the objective of this study was to quantify the impact of AoSA steepening on the LV three-dimensional (3D) hemodynamic stress environment. Methods: A 3D LV model reconstructed from cardiac cine-magnetic resonance imaging was connected to four LVOT geometrical variations spanning the clinical AoSA range (115°–160°). LV hemodynamic stresses were characterized in terms of cycle-averaged pressure, temporal shear magnitude (TSM), and oscillatory shear index. The wall shear stress (WSS) topological skeleton was further analyzed by computing the scaled divergence of the WSS vector field. Results: AoSA steepening caused an increasingly perturbed subaortic flow marked by LVOT flow skewness and complex 3D secondary flow patterns. These disturbances generated WSS overloads (\u3e45% increase in TSM vs. 160° model) on the inferior LVOT wall, and increased WSS contraction (\u3e66% decrease in WSS divergence vs. 160° model) in regions prone to DSS membrane formation. Conclusions: AoSA steepening generated substantial hemodynamic stress abnormalities in LVOT regions prone to DSS formation. Further studies are needed to assess the possible impact of such mechanical abnormalities on the tissue and cellular responses

Computational Assessment of Valvular Dysfunction in Discrete Subaortic Stenosis: A Parametric Study

PURPOSE: Discrete subaortic stenosis (DSS) is a left-ventricular outflow tract (LVOT) obstruction caused by a membranous lesion. DSS is associated with steep aortoseptal angles (AoSAs) and is a risk factor for aortic regurgitation (AR). However, the etiology of AR secondary to DSS remains unknown. This study aimed at quantifying computationally the impact of AoSA steepening and DSS on aortic valve (AV) hemodynamics and AR. METHODS: An LV geometry reconstructed from cine-MRI data was connected to an AV geometry to generate a unified 2D LV-AV model. Six geometrical variants were considered: unobstructed (CTRL) and DSS-obstructed LVOT (DSS), each reflecting three AoSA variations (110°, 120°, 130°). Fluid-structure interaction simulations were run to compute LVOT flow, AV leaflet dynamics, and regurgitant fraction (RF). RESULTS: AoSA steepening and DSS generated vortex dynamics alterations and stenotic flow conditions. While the CTRL-110° model generated the highest degree of leaflet opening asymmetry, DSS preferentially altered superior leaflet kinematics, and caused leaflet-dependent alterations in systolic fluttering. LVOT steepening and DSS subjected the leaflets to increasing WSS overloads (up to 94% increase in temporal shear magnitude), while DSS also increased WSS bidirectionality on the inferior leaflet belly (+ 0.30-point in oscillatory shear index). Although AoSA steepening and DSS increased diastolic transvalvular backflow, regurgitant fractions (RF \u3c 7%) remained below the threshold defining clinical mild AR. CONCLUSIONS: The mechanical interactions between AV leaflets and LVOT steepening/DSS hemodynamic derangements do not cause AR. However, the leaflet WSS abnormalities predicted in those anatomies provide new support to a mechanobiological etiology of AR secondary to DSS

The Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis.

Significance: Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease. Recent Advances: Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cell-based therapies, such as ex vivo activated macrophages, to directly or indirectly modulate IL-10 signaling. Critical Issues: Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field. Future Directions: IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis

The Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis.

Significance: Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease. Recent Advances: Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cell-based therapies, such as ex vivo activated macrophages, to directly or indirectly modulate IL-10 signaling. Critical Issues: Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field. Future Directions: IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis

Systemic enhancement of antitumour immunity by peritumourally implanted immunomodulatory macroporous scaffolds

A tumour microenvironment abundant in regulatory T (Treg) cells aids solid tumours to evade clearance by effector T cells. Systemic strategies to suppress Treg cells or to augment immunity can elicit autoimmune side effects, cytokine storms and other toxicities. Here we report the design, fabrication and therapeutic performance of a biodegradable macroporous scaffold, implanted peritumourally, that releases a small-molecule inhibitor of transforming growth factor β to suppress Treg cells, chemokines to attract effector T cells and antibodies to stimulate them. In two mouse models of aggressive tumours, the implant boosted the recruitment and activation of effector T cells into the tumour and depleted it of Treg cells, which resulted in an 'immunological abscopal effect' on distant metastases and in the establishment of long-term memory that impeded tumour recurrence. We also show that the scaffold can be used to deliver tumour-antigen-specific T cells into the tumour. Peritumourally implanted immunomodulatory scaffolds may represent a general strategy to enhance T-cell immunity and avoid the toxicities of systemic therapies

Impact of the coronavirus disease 2019 pandemic on surgical research and lessons for the future

The current coronavirus disease 2019 pandemic has had an unprecedented impact on all physicians and has resulted in dramatic changes to clinical and research operations. No study has yet looked at the impact of coronavirus disease 2019 on the surgical research community. In this study, we sought to understand the impact of the pandemic and its associated restrictions on academic surgeons. We surveyed members of the Association for Academic Surgery and the Society of University Surgeons. Survey questions included demographics, current challenges to basic and clinical research activities, attitudes toward remote work and productivity maintenance, and the solutions implemented to maintain productivity. Of 301 respondents, 70% cited a negative impact on research productivity due to mandatory building shutdowns, minimized personnel as a result of social distancing, and suspensions of animal work and clinical trials, with senior faculty and division chiefs and chairs more likely to report a negative impact (P = .001). Only 11% of respondents are documenting their financial losses, and only 19% indicated they received appropriate guidance regarding why and how to monitor the financial impact of the pandemic. Researchers have attempted to maintain research productivity through a focus on remote work, including manuscript writing, grant writing, and data analysis. Some participants have found silver linings, including more time to dedicate to research and family as a result of fewer clinical duties. Productivity strategies developed during the pandemic, including writing, remote work and meetings, and structured scheduling, are lessons that will allow the surgical research community to be resilient in the face of future disruptions