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Background Post-operative atrial fibrillation (POAF) occurs in up to 40% of patients following coronary artery bypass grafting (CABG) and is associated with a higher risk of stroke and mortality. This study investigates how POAF may be mitigated by epicardial placement of aseptically processed human placental membrane allografts (HPMAs) before pericardial closure in CABG surgery. This study was conducted as a pilot feasibility study to collect preliminary for a forthcoming multi-center randomized controlled trial. Methods This retrospective observational study of patients undergoing CABG surgery excluded patients with pre-operative heart failure, chronic kidney disease, or a history of atrial fibrillation. The “treatment” group ( n  = 24) had three HPMAs placed epicardially following cardiopulmonary bypass decannulation but before partial pericardial approximation and chest closure. The only difference in clinical protocol for the control group ( n  = 54) was that they did not receive HPMA. Results HPMA-treated patients saw a significant, greater than four-fold reduction in POAF incidence compared to controls (35.2–8.3%, p  = 0.0136). Univariate analysis demonstrated that HPMA treatment was associated with an 83% reduction in POAF (OR = 0.17, p  = 0.0248). Multivariable analysis yielded similar results (OR = 0.07, p  = 0.0156) after controlling for other covariates. Overall length of stay (LOS) between groups was similar, but ICU LOS trended lower with HPMA treatment ( p  = 0.0677). Post-operative inotrope and vasopressor requirements were similar among groups. There was no new-onset post-operative heart failure, stroke, or death reported up to thirty days in either group. Conclusions Epicardial HPMA placement can be a simple intervention at the end of CABG surgery that may provide a new approach to reduce post-operative atrial fibrillation by modulating local inflammation, possibly reducing ICU and hospital stay, and ultimately improving patient outcomes.

Following myocardial infarction (MI), myocardial inflammation plays a crucial role in the pathogenesis of MI injury and macrophages are among the key cells activated during the initial phases of the host response regulating the healing process. While macrophages have emerged as attractive effectors in tissue injury and repair, the contribution of macrophages on cardiac cell function and survival is not fully understood due to complexity of the in vivo inflammatory microenvironment. Understanding the key cells involved and how they communicate with one another is of paramount importance for the development of effective clinical treatments. Here, novel in vitro myocardial inflammation models were developed to examine how both direct and indirect interactions with polarized macrophage subsets present in the post‐MI microenvironment affect cardiomyocyte function. The indirect model using conditioned medium from polarized macrophage subsets allowed examination of the effects of macrophage‐derived factors on stem cell‐derived cardiomyocyte function for up to 3 days. The results from the indirect model demonstrated that pro‐inflammatory macrophage‐derived factors led to a significant downregulation of cardiac troponin T (cTnT) and sarcoplasmic/endoplasmic reticulum calcium ATPase (Serca2) gene expression. It also demonstrated that inhibition of macrophage‐secreted matricellular protein, osteopontin (OPN), led to a significant decrease in cardiomyocyte store‐operated calcium entry (SOCE). In the direct model, stem cell‐derived cardiomyocytes were co‐cultured with polarized macrophage subsets for up to 3 days. It was demonstrated that anti‐inflammatory macrophages significantly increased cardiomyocyte Ca2+ fractional release while macrophages independent of their subtypes led to significant downregulation of SOCE response in cardiomyocytes. This study describes simplified and controlled in vitro myocardial inflammation models, which allow examination of potential beneficial and deleterious effects of macrophages on cardiomyocytes and vise versa. This can lead to our improved understanding of the inflammatory microenvironment post‐MI, otherwise difficult to directly investigate in vivo or by using currently available in vitro models. This manuscript contains new findings to improve our understanding on both beneficial and deleterious actions of macrophages on cardiomyocyte by demonstrating significant changes in cardiomyocyte calcium‐handling function as well as its relationship with macrophage‐secreted matricellular proteins. This study provides insights into currently not well‐known cell–cell interactions in the post‐MI inflammatory microenvironment.

Cardiac ischemic reperfusion injury (IRI) is paradoxically instigated by reestablishing blood‐flow to ischemic myocardium typically from a myocardial infarction (MI). Although revascularization following MI remains the standard of care, effective strategies remain limited to prevent or attenuate IRI. We hypothesized that epicardial placement of human placental amnion/chorion (HPAC) grafts will protect against IRI. Using a clinically relevant model of IRI, swine were subjected to 45 min percutaneous ischemia followed with (MI + HPAC, n = 3) or without (MI only, n = 3) HPAC. Cardiac function was assessed by echocardiography, and regional punch biopsies were collected 14 days post‐operatively. A deep phenotyping approach was implemented by using histological interrogation and incorporating global proteomics and transcriptomics in nonischemic, ischemic, and border zone biopsies. Our results established HPAC limited the extent of cardiac injury by 50% (11.0 ± 2.0% vs. 22.0 ± 3.0%, p = 0.039) and preserved ejection fraction in HPAC‐treated swine (46.8 ± 2.7% vs. 35.8 ± 4.5%, p = 0.014). We present comprehensive transcriptome and proteome profiles of infarct (IZ), border (BZ), and remote (RZ) zone punch biopsies from swine myocardium during the proliferative cardiac repair phase 14 days post‐MI. Both HPAC‐treated and untreated tissues showed regional dynamic responses, whereas only HPAC‐treated IZ revealed active immune and extracellular matrix remodeling. Decreased endoplasmic reticulum (ER)‐dependent protein secretion and increased antiapoptotic and anti‐inflammatory responses were measured in HPAC‐treated biopsies. We provide quantitative evidence HPAC reduced cardiac injury from MI in a preclinical swine model, establishing a potential new therapeutic strategy for IRI. Minimizing the impact of MI remains a central clinical challenge. We present a new strategy to attenuate post‐MI cardiac injury using HPAC in a swine model of IRI. Placement of HPAC membrane on the heart following MI minimizes ischemic damage, preserves cardiac function, and promotes anti‐inflammatory signaling pathways.

Objectives Wound dehiscence is defined as the partial or complete separation of the layers of a surgical wound. Wound dehiscence and infections are of significant concern in the field of surgery as they can lead to a range of complications, including infection, delayed healing, increased healthcare costs, and patient discomfort. For patients at high risk of sternal wound dehiscence and infection, optimization of wound closure is critical. Novel technologies are increasingly being developed to optimize wound closure following median sternotomy for cardiac surgery. Aseptically processed amnion-chorion placental allografts (aACPA) are one such example. Placental allografts maintain the inherent growth factors and matrix proteins native to the tissue, all of which are known in the literature for their roles within the natural closure of wounds Methods Twenty-six patients who underwent cardiac surgery requiring a median sternotomy at a single center undertaken by a single surgeon were included in this study. All patients included were deemed high-risk for sternal complications and had at least one sternal risk factor. Before closure, 160 mg of aACPA was added to the sternotomy wound to support wound repair. Data were collected for rates of sternal complications, as well as general demographics and past medical history of patients included in this study, and appropriate analyses were carried out. Results At their 14- and 30-day follow-up visits, none of the patients had experienced sternal wound dehiscence or infection, with their sternotomy wounds showing excellent signs of normal wound closure. A comprehensive sternal pain evaluation was carried out, which elicited no significant pain in any patients, a sign that sternal closure was successful and stable. The addition of the aACPA into our clinical practice has also contributed to no longer requiring postoperative chest stabilization adjuncts, resulting in significant financial and resource savings for our group. Conclusions In this study, the amnion-chorion placental allograft showed promise as an effective solution to support sternal wound closure in high-risk patients. Its inherent growth factors and ECM (extracellular matrix) may directly address the specific challenges faced by these high-risk individuals. This innovative treatment offers a novel and advanced approach to support wound closure in patient populations that are particularly vulnerable to complications.

Background: Sternal wound complications following median sternotomy result in poor outcomes. Novel approaches such as placental allografts are being explored to optimize wound closure. Methods: This study evaluated consecutive patients undergoing median sternotomy by a single surgeon as sternal closure strategies evolved. Initially, wires with autologous platelet-rich plasma (PRP) were used (Group 1). Subsequently, suture tapes with PRP and an aseptically processed amnion–chorion placental allograft (aACPA) were added (Group 2). Finally, PRP was discontinued (Group 3). Sternal infection, dehiscence, pain outcomes, hospital length of stay, and patient risk factors were analyzed. Results: Compared to Group 1, Groups 2 and 3 demonstrated significantly lower infection (0.7%, 0% vs. 9.3%, p = 0.0001) and dehiscence rates (0%, 0% vs. 8.7%, p < 0.0001). Significant postoperative pain at two weeks decreased from Group 1 to Groups 2 and 3 (18.7%, 4.7%, 3.1%, p < 0.0001), with similar improvements at one month (12.0%, 2.0%, 1.5%, p = 0.0005). Despite higher median risk factors in Group 3 than in Groups 1 and 2 (3 vs. 2, 2, p = 0.0305), a trend toward reduced hospital stay was observed (6 vs. 8, 7 days, p = 0.2298). Conclusions: Adding aACPA to sternal closure significantly reduced infections, dehiscence, and pain in high-risk cardiac surgery patients, with sustained benefits and no increase in operative times. These findings highlight aACPA’s potential to mitigate sternal complications, warranting further study in larger cohorts.

Cardiovascular disease remains the leading cause of mortality in the United States. Current tissue engineering approaches have fallen short of promoting fully functional cardiovascular cells and the post-myocardial infarction microenvironment is still not well understood. These gaps in knowledge are addressed in this dissertation through the development of in vitro engineered cardiac tissues using electroactive materials to enhance the differentiation of pluripotent stem cell derived cardiomyocytes and through the development of in vitro myocardial inflammation models dedicated to understanding cardiomyocytes and macrophages interactions.Specifically, piezoelectric poly (vinylidene fluoride-trifluoroethylene) (PVDF-TrFE) supports the attachment and survival of mouse embryonic stem cell derived cardiomyocytes (mES-CM) and endothelial cells (mES-EC). Characterization of mES-CM confirms expression of classical cardiac specific marker such as cTnT and Cx43, as well as efficient calcium handling properties when cultured on PVDF-TrFE including response to ryanodine receptor and β-adrenergic stimulation. MES-EC also retain their ability to uptake low density lipoprotein when cultured on PVDF-TrFE scaffolds and express classical endothelial cell specific markers such as eNOS and PECAM-1.Additionally, a novel graphene composite scaffold (PCL+G) exhibiting even distribution of graphene particles within the matrix allowing miniscule amounts of graphene to increase conductivity is developed and characterized. MES-CM seeded on conductive PCL+G scaffolds attach well and begin migrating into the scaffold matrix. They exhibit well-registered sarcomeres, express cardiac specific markers such as cTnT, MHC and Cx43 and spontaneous beat for up to two weeks. MES-CM on PCL+G scaffolds can be electrically paced and respond to ryanodine receptor and β-adrenergic stimulation. The combination of highly aligned fiber orientation and the presence of graphene promoted significantly improve calcium cycling efficiency by a fractional release of over 40%.Finally, in vitro myocardial inflammation models are developed to examine both direct and indirect co-culture of mES-CM with polarized macrophage subpopulations present in the post-MI microenvironment. Direct co-culture with macrophage subsets cause significant changes in mES-CM calcium handling function, especially in store operated calcium entry (SOCE), which is accompanied by significant increases in matricellular protein secretion, osteopontin (OPN). A pathway connecting OPN to SOCE response through ERK1/2 activation is analyzed through indirect co-culture with macrophage conditioned media and found to be affected by OPN inhibition, suggesting this pathway is involved with calcium homeostasis in the post-MI microenvironment, specifically in the pro-healing, anti-inflammatory phase.Taken together, the presented results expand the current state of research in cardiac regenerative medicine by demonstrating the potential of two electroactive biomaterials for the formation of functional cardiac tissues and by illuminating a novel target involved in changes in cardiomyocytes calcium homeostasis during post-MI healing through an in vitro engineered diseased model.

The development of functional cardiac tissue in vitro for replacing damaged heart tissues and eventually improving heart function is considered as a promising approach. This chapter discusses ongoing research efforts toward ultimately developing functional cardiac replacement tissue. Current challenges include selection of a suitable and abundant cell source for constructing physiologic tissues, mimicking native anisotropic structure and function, providing appropriate biophysical stimulations, and developing vascularized tissues for better survival and integration in vivo. In addition, various in vitro models, which can be used for investigating cardiac development and pathologies as well as for high‐throughput drug screening applications, are discussed. Various cell types considered for cardiac regeneration, including mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Various strategies have been employed in developing 3D cardiac tissue constructs using numerous types of biomaterials including hydrogels, fibrous scaffolds, and cell‐mediated or scaffold‐free biomaterials.