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Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling.

BACKGROUND: We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors. METHODS: Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrels C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer-Lemeshow goodness of fit test along calibration plots. RESULTS: Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65). CONCLUSIONS: The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures.

BackgroundCOVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post-COVID-19 are not known.MethodsData from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR+)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based International Classification of Diseases version-10 (ICD-10) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score-matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components.ResultsThe risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94-2.25]; P

This article focuses on screening the major secreted proteins by the ischemia-challenged cardiac stromal fibroblasts (CF), the assessment of their expression status and functional role in the post-ischemic left ventricle (LV) and in the ischemia-challenged CF culture and to phenotype CF at single cell resolution based on the positivity of the identified mediators. The expression level of CRSP2, HSP27, IL-8, Cofilin-1, and HSP90 in the LV tissues following coronary artery bypass graft (CABG) and myocardial infarction (MI) and CF cells followed the screening profile derived from the MS/MS findings. The histology data unveiled ECM disorganization, inflammation and fibrosis reflecting the ischemic pathology. CRSP2, HSP27, and HSP90 were significantly upregulated in the LV-CABG tissues with a concomitant reduction ion LV-MI whereas Cofilin-1, IL8, Nrf2, and Troponin I were downregulated in LV-CABG and increased in LV-MI. Similar trends were exhibited by ischemic CF. Single cell transcriptomics revealed multiple sub-phenotypes of CF based on their respective upregulation of CRSP2, HSP27, IL-8, Cofilin-1, HSP90, Troponin I and Nrf2 unveiling pathological and pro-healing phenotypes. Further investigations regarding the underlying signaling mechanisms and validation of sub-populations would offer novel translational avenues for the management of cardiac diseases.