Cardiac valve structure and function are primarily determined during early development. Consequently, abnormally-formed heart valves are the most common type of congenital heart defects. Several adult valve diseases can be backtracked to abnormal valve development, making it imperative to completely understand the process and regulation of heart valve development. Epithelial-to-mesenchymal transition (EMT) plays an important role in the development of heart valves. Though hemodynamics is vital to valve development, its role in regulating EMT is still unknown. In this study, intracardiac hemodynamics were altered by constricting the outflow tract (OFT)/ventricle junction (OVJ) of HH16–17 (Hamilton and Hamburger (HH) Stage 16–17) chicken embryos, ex ovo for 24 h. The constriction created an increase in peak and time-averaged centerline velocity along the OFT without changes to volumetric flow or heart rate. Computational fluid dynamics was used to estimate the level of increased spatially-averaged wall shear stresses on the OFT cushion from AMIRA reconstructions. OFT constriction led to a significant decrease in OFT cushion volume and the number of invaded mesenchyme in the OFT cushion. qPCR analysis revealed altered mRNA expression of a representative panel of genes, vital to valve development, in the OFT cushions from banded hearts. This study indicates the importance of hemodynamics in valve development.

Background: Stroke is known to affect both men and women; however, incidence and outcomes differ between them. Therefore, the discovery of novel, sex-specific, blood-based biomarkers for acute ischemic stroke (AIS) patients has the potential to enhance the understanding of the etiology of this deadly disease in the content of sex. The objective of this study was to identify serum metabolites associated with male and female AIS patients. Methods: Metabolites were measured with the use of untargeted, reverse-phase ultra-performance liquid chromatography-tandem mass spectrometry quantification from blood specimens collected from AIS patients. Samples were collected from 36 patients comprising each of 18 men and women with matched controls. Metabolic pathway analysis and principal component analysis (PCA) was used to differentiate metabolite profiles for male and female AIS patients from the control, while logistic regression was used to determine differences in metabolites between male and female AIS patients. Results: In female AIS patients, 14 distinct altered metabolic pathways and 49 corresponding metabolites were identified, while 39 metabolites and 5 metabolic pathways were identified in male patients. Metabolites that are predictive of ischemic stroke in female patients were 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC (P-16:0/20:4) (AUC = 0.914, 0.765–1.000), 1-(1-enyl-palmitoyl)-2-palmitoyl-GPC (P-16:0/16:0) (AUC = 0.840, 0.656–1.000), and 5,6-dihydrouracil (P-16:0/20:2) (AUC = 0.815, 0.601–1.000). Significant metabolites that were predictive of stroke in male patients were 5alpha-androstan-3alpha,17beta-diol disulfate (AUC = 0.951, 0.857–1.000), alpha-hydroxyisocaproate (AUC = 0.938, 0.832–1.000), threonate (AUC = 0.877, 0.716–1.000), and bilirubin (AUC = 0.817, 0.746–1.000). Conclusions: In the current study, the untargeted serum metabolomics platform identified multiple pathways and metabolites associated with male and female AIS patients. Further research is necessary to characterize how these metabolites are associated with the pathophysiology in male and female AIS patients.

Background: Whether gender differences exist in late-onset of Alzheimer’s disease (LOAD) treated with cholinesterase inhibitors (ChEIs) is not fully understood. This study investigated demographic and pharmacological characteristics in LOAD patients to determine gender differences in LOAD patients treated with ChEIs alone and ChEIs with other medications. Methods: This 5-year retrospective data analysis included 9290 LOAD AD patients with 2949 men patients and 6341 women. Potential predictors of demographic and pharmacological characteristics associated gender differences in patients treated with and without ChEIs therapy were determined using univariate analysis, while multivariable models adjusted for demographic and pharmacological variables. Results: In the adjusted analysis, men patients with LOAD that presented with a history of alcohol use (ETOH) (OR = 1.339, 95% CI, 1.072–1.672, p = 0.010), treated with second generation antipsychotics (SGAs) (OR = 1.271, 95% CI, 1.003–1.610, p = 0.047), citalopram (OR = 5.103, 95% CI, 3.423–7.607, p < 0.001), memantine (OR = 4.409, 95% CI, 3.704–5.249, p < 0.001), and buspirone (OR = 2.166, 95% CI, 1.437–3.264, p < 0.001) were more likely to receive ChEIs therapy, whereas older men were less likely to be treated with ChEIs therapy. Women who were African Americans (OR = 1.387, 95% CI, 1.168–1.647, p < 0.001), that received memantine (OR = 3.412, 95% CI, 3.034–3.837, p < 0.001), selective serotonin reuptake inhibitor (SSRIs) (OR = 1.143, 95% CI, 1.016–1.287, p = 0.026), and a history of ETOH (OR = 2.109, 95% CI, 1.724–2.580, p < 0.001) were more likely to receive ChEIs therapy, whereas older women were less likely to receive ChEIs therapy. Conclusion: In both men and women patients, those with increasing age were less likely to be treated with ChEI therapy, while patients treated with memantine were also likely to receive ChEI therapy. Our findings highlight the importance for clinicians to optimize ChEI in LOAD to improve treatment effectiveness and eliminate gender differences in ChEI therapy.

Collagen fibers are essential structural components of mitral valve leaflets, their tension apparatus (chordae tendineae), and the associated papillary muscles. Excess or lack of collagen fibers in the extracellular matrix (ECM) in any of these structures can adversely affect mitral valve function. The organization of collagen fibers provides a sophisticated framework that allows for unidirectional blood flow during the precise opening and closing of this vital heart valve. Although numerous ECM molecules are essential for the differentiation, growth, and homeostasis of the mitral valve (e.g., elastic fibers, glycoproteins, and glycans), collagen fibers are key to mitral valve integrity. Besides the inert structural components of the tissues, collagen fibers are dynamic structures that drive outside-to-inside cell signaling, which informs valvular interstitial cells (VICs) present within the tissue environment. Diversity of collagen family members and the closely related collagen-like triple helix-containing proteins found in the mitral valve, will be discussed in addition to how defects in these proteins may lead to valve disease.

The COVID-19 pandemic has led to significant loss of life and severe disability, justifying the expedited testing and approval of messenger RNA (mRNA) vaccines. While found to be safe and effective, there have been increasing reports of myocarditis after COVID-19 mRNA vaccine administration. The acute events have been severe enough to require admission to the intensive care unit in some, but most patients fully recover with only rare deaths reported. The pathways involved in the development of vaccine-associated myocarditis are highly dependent on the specific vaccine. COVID-19 vaccine-associated myocarditis is believed to be primarily caused by uncontrolled cytokine-mediated inflammation with possible genetic components in the interleukin-6 signaling pathway. There is also a potential autoimmune component via molecular mimicry. Many of these pathways are similar to those seen in viral myocarditis, indicating a common pathophysiology. There is concern for residual cardiac fibrosis and increased risk for the development of cardiomyopathies later in life. This is of particular interest for patients with congenital heart defects who are already at increased risk for fibrotic cardiomyopathies. Though the risk for vaccine-associated myocarditis is important to consider, the risk of viral myocarditis and other injury is far greater with COVID-19 infection. Considering these relative risks, it is still recommended that the general public receive vaccination against COVID-19, and it is particularly important for congenital heart defect patients to receive vaccination for COVID-19.