Circulation最新文献

Background: Ischemic heart disease remains a leading cause of mortality worldwide, with adverse remodeling after myocardial infarction driven by inflammation and cardiomyocyte loss. Although cytotoxic lymphocytes exacerbate myocardial injury and P16 marks cellular senescence in diseased hearts, the cell type-specific functions of P16⁺ populations remain unclear.

Methods: Using p16-CreER;R26-tdT reporter mice, we mapped P16⁺ cell heterogeneity after myocardial infarction. Senolytic effects were assessed with combined dasatinib and quercetin treatment. Transcriptomic profiling (bulk and single-cell RNA sequencing) of sorted P16⁺ cells identified secreted factors, validated through in silico predictions and quantitative polymerase chain reaction. Intercellular communication was analyzed using CellChat. Functional relevance was tested through CCL8 (cytokine [C-C motif] ligand 8) neutralization, Ccl8 deletion in P16⁺ cells, lymphocyte depletion, and intersectional genetic ablation of P16⁺ fibroblasts or macrophages using dual-recombinase systems (p16-DreER;Pdgfra-CreER;R26-lr-tdT-DTR and p16-DreER;Cx3cr1-CreER;R26-lr-tdT-DTR).

Results: P16 was induced in fibroblasts, macrophages, coronary endothelial cells, and cardiomyocytes after myocardial infarction. Dasatinib and quercetin treatment selectively eliminated P16⁺ macrophages and fibroblasts, improving cardiac function. Transcriptomic analysis identified P16⁺ fibroblasts and macrophages as the main sources of CCL8. CCL8 blockade reduced infiltration of cytotoxic lymphocytes (CD8⁺ T cells and natural killer cells), decreased cardiomyocyte apoptosis, and enhanced repair. Genetic deletion of Ccl8 in P16⁺ cells reproduced these benefits. It is important to note that ablation of P16⁺ fibroblasts, but not macrophages, diminished fibrosis and improved function, and depletion of CD8⁺ T cell attenuated adverse remodeling.

Conclusions: P16⁺ cells orchestrate maladaptive remodeling after myocardial infarction through CCL8-dependent recruitment of cytotoxic lymphocytes, particularly CD8⁺ T cells, which drive cardiomyocyte apoptosis. Targeting P16⁺ fibroblasts or blocking CCL8 offers a promising therapeutic approach for ischemic heart disease.

Background: Mortality from acute myocardial infarction (MI) has declined significantly in the past decade for nondiabetic patients. However, both morbidity and mobility of ischemic heart failure (IHF) persistently escalate in the diabetic population via incompletely understood mechanisms. Recent studies demonstrated that small extracellular vesicles (sEVs) released from nondiabetic and diabetic adipocytes (ADps) exert opposite effects on acute myocardial ischemia and reperfusion (MI/R) injury. However, whether and how ADp sEVs may protect against post-MI remodeling and IHF, and more important, whether and how diabetes may impair this protective effect, remain unknown.

Methods: sEVs were isolated from epididymal fat pads of nondiabetic animals and intramyocardially injected in nondiabetic or diabetic hearts subjected to MI (90 minutes of MI per 4 weeks of reperfusion).

Results: sEV treatment significantly attenuated post-MI cardiac remodeling and improved cardiac function in nondiabetic mice. However, the protection was not observed in diabetic hearts. In adult cardiomyocytes isolated from nondiabetic hearts, sEVs rapidly (15 minutes) activated cell salvage kinases (ERK [extracellular signal-regulated kinase], AMPK [AMP-activated protein kinase], and ACC [acetyl-CoA carboxylase]) and suppressed oxidative stress-induced cell death, suggesting sEV external surface molecules are responsible for the observed cytoprotection. The Exo-Flow (a technology detecting sEV external surface molecules) demonstrated that adiponectin (APN) is enriched on the sEV external surface. The sEVs from APN knockout mice or APN neutralization (NU) antibody pretreated sEVs failed to protect the heart against IHF. Moreover, the cardioprotective effects of sEVs were abolished in APN receptor-1 (AdipoR1)-deficient mice (the primary receptor for APN signaling in the heart) or in mice overexpressing GRK2 (G-protein-coupled receptor kinase 2, a kinase that phosphorylates and inactivates AdipoR1). Finally, diabetes significantly increased cardiac GRK2 expression and AdipoR1 phosphorylation, which prevented sEVs from exerting their beneficial effects. Restoring AdipoR1 function by knockin a mutated phosphorylation-resistant AdipoR1 (AdipoR1^S205A) via AAV9 (adeno-associated virus 9)-mediated gene delivery rescued ADp sEV cardioprotection in diabetic mice.

Conclusions: Our study reveals that APN is enriched on the ADp-derived external surface of sEVs and is biologically active, playing a critical role in ADp-cardiomyocyte communication. Diabetes disrupts this communication by enhancing GRK2-mediated AdipoR1 phosphorylation, impairing sEV signaling, and exacerbating IHF. These findings provide new insights into the pathophysiology and therapy of IHF in diabetes.

Background: Forecasts for the future prevalence of cardiovascular disease and stroke are crucial to guide efforts to improve health outcomes across the life course for women.

Methods: Using historical trends from the 2015 to 2020 National Health and Nutrition Examination Survey, 2015 to 2019 Medical Expenditure Panel Survey, and census estimates for population growth, we estimated trends in prevalence through 2050 for cardiovascular risk factors based on suboptimal levels of Life's Essential 8 and clinical cardiovascular disease and stroke, overall and by age and race and ethnicity.

Results: Among adult women overall, the prevalence of hypertension is estimated to increase from 48.6% in 2020 to 59.1% in 2050. Diabetes (14.9% to 25.3%) and obesity (43.9% to 61.2%) will increase, whereas hypercholesterolemia will decline (42.1% to 22.3%). Prevalences of suboptimal diet, inadequate physical activity, and smoking will decline over time, and inadequate sleep will increase. Prevalences of coronary disease (6.85% to 8.21%), heart failure (2.45% to 3.60%), stroke (4.14% to 6.74%), atrial fibrillation (1.58% to 2.31%), and total cardiovascular disease and stroke (10.7% to 14.4%) will rise. Similar trends are projected in girls 2 to 19 years of age, with an increase from 19.6% to 32.0% projected in obesity. Most adverse trends are projected to be more pronounced among women and girls identifying as American Indian/Alaska Native or multiracial, Black, or Hispanic.

Conclusions: The prevalence of cardiovascular risk factors and disease in women and girls will increase over the next 30 years. Focused clinical and public health interventions are needed across the life course to address these adverse trends.

Background: Novel treatments are needed for the primary and secondary prevention of heart failure in patients with type 2 diabetes, including individuals with and those without a history of heart failure. Conflicting trial evidence exists on whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of hospitalization for heart failure (HHF) in this broad population and whether this is a class effect or varies by specific agent. Furthermore, their comparative effectiveness against sodium-glucose cotransporter-2 inhibitors (SGLT-2is) is unknown.

Methods: We emulated 2 target trials using population-based health care data from Stockholm, Sweden (2010-2021). Target trial 1 included adult patients with type 2 diabetes who newly initiated GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP-4is), and target trial 2 compared GLP-1RA with SGLT-2i. The primary outcome was HHF. Cox regression was used to estimate intention-to-treat hazard ratios, with inverse probability of treatment weighting used to balance 72 confounders. Major adverse cardiovascular events were used as the positive control outcome. Analyses were conducted for the GLP-1RA class overall and for individual agents, including liraglutide and semaglutide.

Results: Target trial 1 included 32 979 patients (42% GLP-1RA and 58% DPP-4i) with a mean age of 64 years and 40% female; and target trial 2 included 30 104 patients (49% GLP-1RA and 51% SGLT-2i) with a mean age of 63 years and 38% female. Starting a GLP-1RA was associated with a lower 3-year absolute risk of HHF than starting a DPP-4i (3.4% versus 4.3%), corresponding to a weighted hazard ratio of 0.77 (95% CI, 0.66-0.91). Absolute 3-year risks for GLP-1RA compared with SGLT-2i on HHF were 3.6% and 3.3% with a weighted hazard ratio of 1.02 (95% CI, 0.85-1.18). The absolute risk difference was largest for patients with higher predicted risk of heart failure at baseline. Results were consistent for single agents, in per-protocol analyses, and in the majority of subgroups. In positive control outcome analyses, GLP-1RA use was associated with a lower rate of major adverse cardiovascular events than DPP-4i use (weighted hazard ratio, 0.85 [95% CI, 0.74-0.99]), consistent with trial findings.

Conclusions: GLP-1RA use is associated with a lower risk of HHF compared with DPP-4i and similar risks compared with SGLT-2i in routine clinical care for patients with type 2 diabetes.