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Introduction: Peripheral artery disease (PAD) is a well-described risk factor for mortality, but few studies have examined secular trends in mortality over time for patients with PAD. We characterized trends in mortality in patients with PAD in recent years among Medicare patients. Methods: We used Medicare claims to identify patients with a new diagnosis code for PAD between January 1, 2006 and December 31, 2018 using International Classification of Diseases (ICD) diagnosis codes. The primary outcome of interest was the 1-year all-cause age-adjusted mortality rate. Our secondary outcome was the 5-year all-cause mortality rate. Multivariable regression was used to identify factors which predict mortality at 1 year. Results: We identified 4,373,644 patients with a new diagnosis code for PAD during the study period. Between 2006 and 2018, 1-year all-cause age-adjusted mortality declined from 12.6% to 9.9% (p < 0.001). One-year crude all-cause mortality also declined from 14.6% to 9.5% (p < 0.001). Similar results were observed for 5-year age-adjusted mortality rates (40.9% to 35.2%, p < 0.001). Factors associated with increased risk of death at 1 year included age ⩾ 85 years (hazard ratio [HR] 3.030; 95% CI 3.008–3.053) and congestive heart failure (HR 1.86; 95% CI 1.85–1.88). Patients who were regularly dispensed statins, ace-inhibitors, beta-blockers, antithrombotic agents, and anticoagulants all had lower mortality (range OR 0.36; CI 0.35–0.37 for statins to OR 0.60; CI 0.59–0.61 for anticoagulants; all p < 0.001). Conclusion: Among US Medicare patients diagnosed with PAD between 2006 and 2019, 1-year age-adjusted mortality declined by 2.7%. This decline in mortality among patients with PAD occurred in the context of a younger mean age of diagnosis of PAD and improved cardiovascular prevention therapy. [ABSTRACT FROM AUTHOR]

Aims: To develop a clinical risk model to identify individuals at higher risk of developing new‐onset diabetes and who might benefit more from weight loss pharmacotherapy. Materials and Methods: A total of 21 143 patients without type 2 diabetes at baseline from two TIMI clinical trials of stable cardiovascular patients were divided into a derivation (~2/3) and validation (~1/3) cohort. The primary outcome was new‐onset diabetes. Twenty‐seven candidate risk variables were considered, and variable selection was performed using multivariable Cox regression. The final model was evaluated for discrimination and calibration, and for its ability to identify patients who experienced a larger benefit from the weight loss medication lorcaserin in terms of risk of new‐onset diabetes. Results: During a median (interquartile range) follow‐up of 2.3 (1.8–2.7) years, new‐onset diabetes occurred in 1013 patients (7.7%). The final model included five independent predictors (glycated haemoglobin, fasting glucose, age, body mass index, and triglycerides/high‐density lipoprotein). The clinical risk model showed good discrimination (Harrell's C‐indices 0.802, 95% confidence interval [CI] 0.788–0.817 and 0.807, 95% CI 0.788–0.826) in the derivation and validation cohorts. The calibration plot demonstrated adequate calibration (2.5‐year area under the curve was 81.2 [79.1–83.5]). While hazard ratios for new‐onset diabetes with a weight‐loss therapy were comparable across risk groups (annual risks of <1%, 1%–5%, and >5%), there was a sixfold gradient in absolute risk reduction from lowest to highest risk group (p = 0.027). Conclusions: The developed clinical risk model effectively predicts new‐onset diabetes, with potential implications for personalized patient care and therapeutic decision making. [ABSTRACT FROM AUTHOR]

The article discusses the role of senescent cells, also known as "zombie cells," in the aging process and their impact on the cardiovascular system. These cells accumulate in the body as we age and secrete harmful substances that can damage neighboring cells, leading to a decline in tissue function and age-related diseases. The article explores the potential of senolytics, which eliminate senescent cells, and senomorphics, which suppress the inflammatory secretome associated with senescence, as therapeutic approaches to rejuvenate the cardiovascular system. The challenges in developing these treatments include identifying senescence biomarkers, minimizing off-target effects, and determining optimal timing and treatment duration. The article concludes that the removal of senescent cells shows promise in mitigating cardiovascular risk in the elderly and calls for further research and clinical trials to advance the field. [Extracted from the article]

Atherosclerotic plaque rupture mainly contributes to acute coronary syndrome (ACS). Insufficient repair of these plaques leads to thrombosis and subsequent ACS. Central to this process is the modulation of vascular smooth muscle cells (VSMCs) phenotypes, emphasizing their pivotal role in atherosclerotic plaque stability and healing post-disruption. Here, an expansion of FSP1 + cells in a tandem stenosis (TS) model of atherosclerotic mice is unveiled, predominantly originating from VSMCs through single-cell RNA sequencing (scRNA-seq) analyses and VSMC lineage tracing studies. Further investigation identified TEA domain transcription factor 1 (TEAD1) as the key transcription factor driving the trans-differentiation of VSMCs into fibroblast-like cells. In vivo experiments using a TS model of plaque rupture demonstrated that TEAD1 played a crucial role in promoting plaque stability and healing post-rupture through pharmacological or TEAD1-AAV treatments. Mechanistically, it is found that TEAD1 promoted the expression of fibroblast markers through the Wnt4/β-Catenin pathway, facilitating the trans-differentiation. Thus, this study illustrated that TEAD1 played a critical role in promoting the trans-differentiation of VSMCs into fibroblast-like cells and subsequent extracellular matrix production through the Wnt4/β-Catenin pathway. Consequently, this process enhanced the healing mechanisms following plaque rupture, elucidating potential therapeutic avenues for managing atherosclerotic instability., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Aims: Inflammation has been implicated in the pathogenesis of desmoplakin (DSP) cardiomyopathy, and retrospective studies have described abnormal myocardial fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) findings in symptomatic patients eventually diagnosed with DSP cardiomyopathy. We aimed to prospectively investigate if ambulatory patients with DSP cardiomyopathy had myocardial FDG uptake PET/CT imaging indicative of myocardial inflammation and if they had circulating biomarker evidence of inflammation., Methods: We prospectively recruited participants with DSP cardiomyopathy and participants with titin cardiomyopathy as a comparator group. Blood samples for clinical labs and proteomic profiling, myocardial perfusion single-photon emission computed tomography (SPECT) and myocardial FDG PET/CT were obtained for all participants., Results: Ten participants with DSP cardiomyopathy (median age 36.5 years (28, 60); 80% female; 100% White and non-Hispanic) and four participants with titin cardiomyopathy (median age 55.5 years [38.5, 64]; 50% female; 100% White and non-Hispanic) were recruited. There were no significant differences between the groups in white blood cell count, ESR, hsCRP or hsTn. Three participants with DSP cardiomyopathy and two participants with titin cardiomyopathy had non-specific myocardial FDG uptake on PET/CT. All other participants had no myocardial FDG uptake. Integration of miRNA differential expression and their predicted targets from the differential expression proteomics data identified a total of 11 inverse miRNA-mRNA pairs potentially involved in the regulation of top 20 significantly enriched pathways, including pathways involved in metabolism, inflammasome/inflammatory signalling and cell death/pyroptosis., Conclusions: In a group of ambulatory patients with DSP and titin cardiomyopathy, we found no differences in FDG PET/CT findings or clinical circulating biomarkers of inflammation. However, miRNA-seq/proteomics analyses identified several enriched pathways and unique miRNA-protein pairs between DSP and titin cardiomyopathy, including pathways involved in inflammasome/inflammatory signalling. Future work will centre on evaluation during myocarditis-like episodes., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs orchestrate multiple signalling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear., Methods and Results: miRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose-containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxidized low density lipoprotein (oxLDL)-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation [Interleukin (lL)-1β, TNF-α, and IL-6]. Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signalling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-Seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p-treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes., Conclusion: These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Microporous hydrogels have been widely used for delivering therapeutic cells. However, several critical issues, such as the lack of control over the harsh environment they are subjected to under pathological conditions and rapid egression of cells from the hydrogels, have produced limited therapeutic outcomes. To address these critical challenges, cell-tethering and hypoxic conditioning colloidal hydrogels containing mesenchymal stem cells (MSCs) are introduced to increase the productivity of paracrine factors locally and in a long-term manner. Cell-tethering colloidal hydrogels that are composed of tyramine-conjugated gelatin prevent cells from egressing through on-cell oxidative phenolic crosslinks while providing mechanical stimulation and interconnected microporous networks to allow for host-implant interactions. Oxygenating microparticles encapsulated in tyramine-conjugated colloidal microgels continuously generated oxygen for 2 weeks with rapid diffusion, resulting in maintaining a mild hypoxic condition while MSCs consumed oxygen under severe hypoxia. Synergistically, local retention of MSCs within the mild hypoxic-conditioned and mechanically robust colloidal hydrogels significantly increased the secretion of various angiogenic cytokines and chemokines. The oxygenating colloidal hydrogels induced anti-inflammatory responses, reduced cellular apoptosis, and promoted numerous large blood vessels in vivo. Finally, mice injected with the MSC-tethered oxygenating colloidal hydrogels significantly improved blood flow restoration and muscle regeneration in a hindlimb ischemia (HLI) model., (© 2024 Wiley‐VCH GmbH.)