Myocardial B cells have specific gene expression and predicted interactions in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy.

Introduction: Growing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells in the context of cardiomyopathy. Methods: We integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with arrhythmogenic right ventricular cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis. Results: We identified 1,100 B cells, including naive B cells and plasma cells. Cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This niche relied on ECM-receptor, contact, and paracrine interactions; and changed significantly in the context of cardiomyopathy, displaying disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation, and, in naive B cells, antigen presentation. Discussion: The human myocardium contains naive B cells and plasma cells, integrated into a diverse and dynamic niche that has distinctive features in healthy, DCM, and ARVC. Naive myocardial-associated B cells likely contribute to the pathogenesis of human DCM.

Myocardial B cells have specific gene expression and predicted interactions in Dilated Cardiomyopathy and Arrhythmogenic Right Ventricular Cardiomyopathy.

Introduction: Growing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells in the context of cardiomyopathy. Methods: We integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis. Results: We identified 1,100 B cells, including naive B cells and plasma cells. B cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This niche relied on ECM-receptor, contact, and paracrine interaction; and changed significantly in the context of cardiomyopathy, displaying disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation, and, in naive B cells, antigen presentation. Discussion: The human myocardium contains naive B cells and plasma cells, integrated into a diverse and dynamic niche that has distinctive features in healthy myocardium, DCM, and ARVC. Naive myocardial-associated B cells likely contribute to the pathogenesis of human DCM.

A murine model of Trypanosoma brucei-induced myocarditis and cardiac dysfunction.

Trypanosoma brucei is a protozoan parasite that causes human and animal African trypanosomiases (HAT and AAT). Cardiac symptoms are commonly reported in HAT patients, and intracardiac parasites with accompanying myocarditis have been observed in both natural hosts and animal models of T. brucei infection. However, despite the importance of T. brucei as a cause of cardiac dysfunction and the dramatic socioeconomic impact of African trypanosomiases in sub-Saharan Africa, there are currently no reproducible murine models of T. brucei-associated cardiomyopathy. We present the first clinically relevant, reproducible murine model of cardiac dysfunction in chronic T. brucei infection. Similar to humans, mice showed histological evidence of myocarditis and elevation of serum NT-proBNP. Serum NT-proBNP levels were elevated prior to the development of severe ventricular dysfunction. On flow cytometry, myocarditis was associated with an increase of most myocardial immune cell populations, including multiple T cell and macrophage subsets, corroborating the notion that T. brucei-associated cardiac damage is an immune-mediated event. This novel mouse model represents a powerful and practical tool to investigate the pathogenesis of T. brucei-mediated heart damage and support the development of therapeutic options for T. brucei-associated cardiac disease.

Serum Proteomic Analysis of Peripartum Cardiomyopathy Reveals Distinctive Dysregulation of Inflammatory and Cholesterol Metabolism Pathways.

BACKGROUND: The pathophysiology of peripartum cardiomyopathy (PPCM) and its distinctive biological features remain incompletely understood. High-throughput serum proteomic profiling, a powerful tool to gain insights into the pathophysiology of diseases at a systems biology level, has never been used to investigate PPCM relative to nonischemic cardiomyopathy. OBJECTIVES: The aim of this study was to characterize the pathophysiology of PPCM through serum proteomic analysis. METHODS: Aptamer-based proteomic analysis (SomaScan 7K) was performed on serum samples from women with PPCM (n = 67), women with nonischemic nonperipartum cardiomyopathy (NPCM) (n = 31), and age-matched healthy peripartum and nonperipartum women (n = 10 each). Serum samples were obtained from the IPAC (Investigation of Pregnancy-Associated Cardiomyopathy) and IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) studies. RESULTS: Principal component analysis revealed unique clustering of each patient group (P for difference <0.001). Biological pathway analyses of differentially measured proteins in PPCM relative to NPCM, before and after normalization to pertinent healthy controls, highlighted specific dysregulation of inflammatory pathways in PPCM, including the upregulation of the cholesterol metabolism-related anti-inflammatory pathway liver-X receptor/retinoid-X receptor (LXR/RXR) (P < 0.01, Z-score 1.9-2.1). Cardiac recovery by 12 months in PPCM was associated with the downregulation of pro-inflammatory pathways and the upregulation of LXR/RXR, and an additional RXR-dependent pathway involved in the regulation of inflammation and metabolism, peroxisome proliferator-activated receptor α/RXRα signaling. CONCLUSIONS: Serum proteomic profiling of PPCM relative to NPCM and healthy controls indicated that PPCM is a distinct disease entity characterized by the unique dysregulation of inflammation-related pathways and cholesterol metabolism-related anti-inflammatory pathways. These findings provide insight into the pathophysiology of PPCM and point to novel potential therapeutic targets.

Myocardial Immune Cells: The Basis of Cardiac Immunology.

The mammalian heart is characterized by the presence of striated myocytes, which allow continuous rhythmic contraction from early embryonic development until the last moments of life. However, the myocardium contains a significant contingent of leukocytes from every major class. This leukocyte pool includes both resident and nonresident immune cells. Over recent decades, it has become increasingly apparent that the heart is intimately sensitive to immune signaling and that myocardial leukocytes exhibit an array of critical functions, both in homeostasis and in the context of cardiac adaptation to injury. Here, we systematically review current knowledge of all major leukocyte classes in the heart, discussing their functions in health and disease. We also highlight the connection between the myocardium, immune cells, lymphoid organs, and both local and systemic immune responses.

In Utero Exposure to Norbuprenorphine, a Major Metabolite of Buprenorphine, Induces Fetal Opioid Dependence and Leads to Neonatal Opioid Withdrawal Syndrome.

Buprenorphine is the preferred treatment of opioid use disorder during pregnancy but can cause fetal opioid dependence and neonatal opioid withdrawal syndrome (NOWS). Notably, withdrawal severity is independent of maternal buprenorphine dose, suggesting that interindividual variance in pharmacokinetics may influence risk and severity of NOWS. Using a rat model of NOWS, we tested the hypothesis that clinically relevant doses of the active metabolite norbuprenorphine (NorBUP) can induce in utero opioid dependence, manifested as naltrexone-precipitated withdrawal signs in the neonate. Pregnant Long-Evans rats were implanted with 14-day osmotic minipumps containing vehicle, morphine (positive control), or NorBUP (0.3-10 mg/kg per day) on gestation day 9. By 12 hours post-delivery, an intraperitoneal injection of the opioid antagonist naltrexone (1 or 10 mg/kg) or saline was administered to pups. Precipitated withdrawal signs were graded by raters blinded to treatment conditions. In a separate group, NorBUP concentrations in maternal and fetal blood and brain on gestation day 20 were determined by liquid chromatography-tandem mass spectrometry. Steady-state maternal blood concentrations of NorBUP in dams infused with 1 or 3 mg/kg per day were comparable to values reported in pregnant humans treated with buprenorphine (1.0 and 9.6 ng/ml, respectively), suggesting a clinically relevant dosing regimen. At these doses, NorBUP increased withdrawal severity in the neonate as shown by an evaluation of 10 withdrawal indicators. These findings support the possibility that NorBUP contributes to fetal opioid dependence and NOWS following maternal buprenorphine treatment during pregnancy.

Reovirus: Friend and Foe.

PURPOSE OF REVIEW: Mammalian orthoreovirus (reovirus) is a powerful tool for studying viral replication and pathogenesis. Most reovirus infections are subclinical, however recent work has catapulted reovirus into the clinical spotlight. RECENT FINDINGS: Owing to its capacity to kill cancer cells more efficiently than normal cells, reovirus is under development as a therapeutic for a variety of cancers. New efforts have focused on genetically engineering reovirus to increase its oncolytic capacity, and determining how reovirus potentiates immunotherapy. Other recent studies highlight a potential role for reovirus in celiac disease (CeD). Using mouse models of CeD, reovirus caused loss of oral tolerance to dietary antigens, opening the possibility that reovirus could trigger CeD in humans. SUMMARY: We will focus on new developments in reovirus oncolysis and studies suggesting a role for reovirus as a trigger for celiac disease (CeD) that make reovirus a potential friend and foe to human health.