Epicardial placement of human placental membrane protects from heart injury in a swine model of myocardial infarction.

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.

Human Placental Allograft Membranes: Promising Role in Cardiac Surgery and Repair.

Despite the immense investment in research devoted to cardiovascular diseases, mechanisms of progression and potential treatments, it remains one of the leading causes of death in the world. Cellular based strategies have been explored for decades, having mixed results, while more recently inflammation and its role in healing, regeneration and disease progression has taken center stage. Placental membranes are immune privileged tissues whose native function is acting as a protective barrier during fetal development, a state which fosters regeneration and healing. Their unique properties stem from a complex composition of extracellular matrix, growth factors and cytokines involved in cellular growth, survival, and inflammation modulation. Placental allograft membranes have been used successfully in complex wound applications but their potential in cardiac wounds has only begun to be explored. Although limited, pre-clinical studies demonstrated benefits when using placental membranes compared to other standard of care options for pericardial repair or infarct wound covering, facilitating cardiomyogenesis of stem cell populations in vitro and supporting functional performance in vivo. Early clinical evidence also suggested use of placental allograft membranes as a cardiac wound covering with the potential to mitigate the predominantly inflammatory environment such as pericarditis and prevention of new onset post-operative atrial fibrillation. Together, these studies demonstrate the promising translational potential of placental allograft membranes as post-surgical cardiac wound coverings. However, the small number of publications on this topic highlights the need for further studies to better understand how to support the safe and efficient use of placenta allograft membranes in cardiac surgery.

The effects of macrophages on cardiomyocyte calcium-handling function using in vitro culture models.

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.