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Association of small nerve fiber dysfunction on pain characteristics in type 2 diabetes mellitus individuals with chronic low back pain

Abstract Type 2 diabetes mellitus (T2DM) is associated with small nerve fiber (SNF) dysfunction. Quantitative assessment of thermal perception thresholds is a validated method for evaluating SNF dysfunction. Pain characteristics such as numbness and pain irritability are commonly reported in T2DM individuals with chronic low back pain (CLBP). This study aimed to evaluate SNF dysfunction and its association with pain characteristics among T2DM individuals with CLBP. Fifty T2DM participants with CLBP underwent assessment of SNF function using a Sensitometer thermal perception device. Warm detection threshold, heat pain threshold, cold detection threshold, and cold pain threshold were measured over the lumbar region. Pain characteristics like pain irritability and numbness were recorded. One-sample Wilcoxon signed-rank test was used to compare thermal perception thresholds with published reference values. Kruskal–Wallis was used to examine their association with pain characteristics. Compared with reference values, participants demonstrated significantly higher heat pain thresholds (median 46.35 °C [IQR 1.82] vs. 43.5 °C, p  < 0.001), lower cold detection thresholds (28.15 °C [IQR 2.87] vs. 29.5 °C, p  < 0.001), and lower cold pain thresholds (2.25 °C [IQR 15.82] vs. 26 °C, p  < 0.001). Higher heat pain thresholds were significantly associated with greater pain irritability ( p  < 0.001). These findings indicate altered thermal perception suggestive of SNF dysfunction among T2DM individuals with CLBP, with greater thermal abnormalities associated with increased pain irritability.

Strategies for Optimizing Heart Failure Care in the Older Adult: A Scientific Statement From the American Heart Association

Heart failure prevalence is increasing and has a disproportionate burden on older adults. Older adults, however, may encounter unique challenges in accessing and navigating comprehensive disease-modifying, guideline-directed therapies, thus limiting use among those at highest risk of cardiovascular death or worsening heart failure. Care of the older adult with heart failure requires tailored treatment plans to overcome barriers to effective therapies in this population. This scientific statement reviews the literature on care optimization for older adults (≥65 years of age) living with heart failure and highlights strategies for clinicians who aim to deliver patient-centered, evidenced-based heart failure care in the context of common comorbidities seen in older adults. We discuss the consistent treatment effect and safety profiles of guideline-directed therapies for heart failure in older adults and how to manage multimorbidity, polypharmacy, frailty, and social needs using a shared decision-making framework. In consideration of the complexity of heart failure care of the older adult, we highlight a structured framework for therapeutic considerations in the context of benefit-to-risk ratio, multimorbidity, and social needs. We offer practical guidance on the care of older adults with advanced comorbidities who may not have been adequately represented in landmark trials. We also consider implementation strategies, health services interventions, and supportive tools that may foster optimal care in older adults with heart failure. This work is aimed at informing the practice of clinicians and health systems alike to improve outcomes and to reduce the morbidity of heart failure in older adults.

Bedside echocardiography for predicting early hemodynamic instability during continuous venovenous hemodiafiltration: a prospective observational study

Late Gadolinium Enhancement in Nonischemic Dilated Cardiomyopathy

Hydroxybenzoate-based hits from methanolic leaf fraction of Ficus exasperata Vahl: integrative biochemical, molecular, and computational discovery against bisphenol toxicity

Letter by Wang and Wang Regarding Article, “Cardiac Allograft Vasculopathy Inhibition With Alirocumab: The CAVIAR Trial”

Defining Cardiovascular Endpoints in Oncology Trials: Challenges and Opportunities: A Scientific Statement From the American Heart Association

The unprecedented expansion of approved oncology therapies has prolonged survival and transformed the prognosis for many patients diagnosed with cancer. However, cancer treatments may be associated with cardiovascular toxicities that manifest through vascular, myocardial, or metabolic pathways, potentially limiting the use of cancer therapeutics and adversely affecting outcomes. Oncology clinical trials provide an important opportunity to evaluate cardiovascular safety signals by generating data on the incidence, timing, and spectrum of toxicities. However, progress has been limited by inconsistent definitions and variable approaches to event characterization. This scientific statement aligns the advances in cardiovascular medicine and cardiovascular clinical trials to provide criteria for systematic selection, rigorous characterization, and adjudication of cardiovascular endpoints in contemporary oncology trials. The proposed framework links drug-specific mechanisms to endpoint selection and standardizes the approach to definitions of adverse cardiovascular events, including heart failure, arrhythmias, myocarditis, and thrombotic events. Definitions of major adverse cardiac events, clinical events, and surrogate endpoints are discussed, along with strategies for alignment with the Common Terminology Criteria for Adverse Events and patient-reported outcomes. Practical guidance is provided for prospective surveillance, decentralized and hybrid clinical trial designs, independent endpoint adjudication, and statistical approaches to competing risks and late-emerging toxicities. By harmonizing cardiovascular endpoint assessment across oncology trials, this scientific statement aims to enhance risk stratification, facilitate regulatory acceptance, and inform clinical decision-making, ultimately improving patient safety while supporting innovation in cancer therapeutics.

Ten Years of Scientific Discovery With the UK Biobank Cardiovascular Magnetic Resonance Imaging Study

The UK Biobank Imaging Study, with its dedicated cardiovascular magnetic resonance substudy, has redefined the scale and scope of cardiovascular research, generating high-quality imaging in 100 000 participants with linkage to rich genetic, demographic, lifestyle, and clinical data. The resource has enabled transformative discoveries across genomics, epidemiology, and biomedical engineering and has served as a global blueprint for population imaging studies. Its success has been accelerated by an equitable data access model that fosters international collaboration. The UK Biobank cardiovascular magnetic resonance experience illustrates the power of large-scale imaging cohorts and sets a benchmark for future initiatives aimed at improving cardiovascular health through integrated, collaborative science. Looking ahead, efforts should focus on harmonization across cohorts, adherence to rigorous methodological standards, and multidisciplinary collaboration to drive meaningful clinical translation. This article provides an overview of the UK Biobank and its cardiovascular magnetic resonance substudy, systematically reviews publications to date, discusses limitations and methodological considerations, and highlights future directions.

SREBP1 Transactivation of NHE3 Impairs Cardiac Contraction and Aggravates Heart Failure

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion (ie, Na + /H + and Ca 2+ ) cycling underlies reduced cardiac contractility. The mechanisms linking myocardial stress to this ion dysregulation remain incompletely understood. Although the metabolic transcription factor SREBP1 (sterol regulatory element-binding protein 1) remodels cardiac metabolism, its role in HFrEF without metabolic comorbidities, particularly regarding ion handling, remains undefined. METHODS: Cardiac tissues from HFrEF patients and mice subjected to transverse aortic constriction (TAC) were analyzed for SREBP1 transactivation of sodium-hydrogen exchanger 3 (NHE3). Cardiomyocyte-specific SREBP1 transgenic ( Srebp1a -Tg) and knockdown (Cre- Srebf1 f/f ) mice were generated. AAV9 vectors carrying Slc9a3 (encoding NHE3), Srebp1a or shRNA against Slc9a3 , driven by the cardiomyocyte-specific cTnT promoter, were used to validate the role of the SREBP1-NHE3 in HFrEF. RESULTS: SREBP1 was activated in human hearts with HFrEF because of dilated cardiomyopathy, but without diabetes or hyperlipidemia, and in TAC-induced HFrEF mouse hearts. Srebp1a -Tg mice exhibited impaired cardiac contractility with dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis identified increased NHE3 expression in Srebp1a -Tg mice, confirmed by NHE3 upregulation in TAC hearts and human failing hearts. ChIP-seq, ChIP, and promoter reporter assay demonstrated direct transcriptional regulation of SLC9A3 (encoding NHE3) by SREBP1. NHE3 activity was enhanced in cardiomyocytes isolated from Srebp1a -Tg mice or those underwent TAC, whereas cardiomyocyte-specific Srebf1 knockdown in TAC mice reduced NHE3 activity. Cardiomyocyte-specific knockdown of Srebf1 or Slc9a3 restored calcium handling and improved cardiac function in TAC mice. In Srebp1a -Tg mice, NHE3 knockdown alleviated Na + and Ca 2+ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre- Srebf1 f/f mice and controls, which offset the protective effect because of SREBP1 loss in the context of Na + and Ca 2+ overload. CONCLUSIONS: SREBP1 directly transactivates cardiac NHE3 during the progression of HFrEF, leading to dysregulated calcium handling and impaired contractility, revealing a novel, noncanonical role for SREBP1 in the pathophysiology of heart failure and offering a potential new therapeutic target.

Incidence and Predictors of Extracranial Bleeding on Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation: A COMBINE-AF Analysis

BACKGROUND: Extracranial bleeding is the most common complication of oral anticoagulant (OAC) therapy for atrial fibrillation (AF), but its clinical importance for patients may be underrecognized. We sought to characterize extracranial bleeding events according to standardized severity definitions, identify baseline risk factors for bleeding, and quantify their population attributable fraction in patients with AF receiving OACs. METHODS: We analyzed patients receiving OACs from 5 pivotal randomized trials testing a direct OAC or warfarin in patients with AF (COMBINE-AF [A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation]). The primary outcome was extracranial clinically relevant bleeding, defined as a first episode of extracranial major or clinically relevant nonmajor bleeding according to International Society on Thrombosis and Haemostasis criteria. The Kaplan-Meier method was used to calculate the cumulative incidence of bleeding by category. Multivariable Cox regression models were used to estimate adjusted hazard ratios (HRs) with 95% CI. Logistic regression models were used to calculate average population attributable fraction with 95% CI. RESULTS: Of 73 737 patients treated with OACs, 10 634 experienced clinically relevant extracranial bleeding over a mean follow-up of 705 days (cumulative incidence, 26% [95% CI, 18%–35%]; 7.6 per 100 person-years). This included 3188 major bleeds (cumulative incidence, 7% [95% CI, 6%–7%]; 2.1 per 100 person-years) and 7446 clinically relevant nonmajor bleeds (cumulative incidence, 19% [95% CI, 12%–28%]; 5.2 per 100 person-years). The distribution of bleeding sites differed by severity, with gastrointestinal bleeds comprising 26% of clinically relevant bleeds, 49% of major bleeds, and 15% of clinically relevant nonmajor bleeds. Risk factors for extracranial bleeding were consistent across severity bleeding categories, and baseline covariates in our multivariable models accounted for 66% to 69% of the population attributable bleeding risk. CONCLUSIONS: Extracranial clinically relevant bleeding is common among patients with AF treated with OACs and may more accurately reflect the overall burden of bleeding than major bleeding alone. Our models explained about two-thirds of the average population attributable risk, suggesting that additional unmeasured or unknown factors contribute to bleeding risk.

Facilitation of Autophagosome-Lysosome Fusion by LAPTM4A: A Novel Strategy for Attenuating Myocardial Ischemia-Reperfusion Injury

BACKGROUND: Myocardial ischemia-reperfusion (MIR) injury compromises therapeutic effects of revascularization and leads to functional impairment and exacerbation of structural damage in the heart. Limiting the damage caused by MIR is crucial but is still an unmet clinical need because of the complexity of the underlying mechanisms. Increasing evidence suggests that lysosomal autophagy plays a significant regulatory role in MIR injury. The specific mechanisms involved remain to be fully understood. METHODS: We here systematically analyzed the murine MIR model database to screen the potentially protective lysosome-localized proteins against MIR injury. The positive hits were further functionally screened and validated for their capability on autophagy and hypoxia/reoxygenation insults of cardiomyocytes. After exploring the detailed molecular mechanism underlying the protective effects of the target protein, we generated target gene cardiac-specific knockout mice and overexpression mice to verify its function in mouse MIR injury models. RESULTS: LAPTM4A (lysosome-associated protein transmembrane 4 alpha) stood out as a significant protective lysosome-localized protein from the screening. LAPTM4A deficiency significantly heightened the inflammatory response and cell death both in primary cardiomyocytes and in a MIR-induced mouse model. Conversely, LAPTM4A overexpression exerted protective effects on cell viability and myocardial damage. Mechanistically, LAPTM4A interacts with Rubicon (Run domain Beclin1-interacting and cysteine-rich domain–containing protein), hindering its engagement within the Beclin1 complex, resulting in a robust augmentation of autophagic flux and thereby mitigating cardiac damage during reperfusion. It is important to note that Rubicon knockdown markedly reversed the aggravated injury induced by LAPTM4A knockdown, further verifying the effects of LAPTM4A depend on Rubicon. CONCLUSIONS: Our findings screened out and validated that LAPTM4A is a lysosome-localized protein exerting protective effects against MIR injury by facilitating autophagic flux. Targeting LAPTM4A represents a promising therapeutic strategy for mitigating MIR injury.

Association of Pulmonary Vascular Remodeling With Cardiac Structure and Function, Pulmonary Pressure, and Heart Failure in Late Life: The Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND: Aging is associated with increases in pulmonary pressure related to concomitant age-associated left ventricular remodeling, diastolic dysfunction, and declines in pulmonary function. Little is known regarding morphological changes in the pulmonary arterial vasculature underlying these associations. Our aim was to determine the associations between pulmonary vascular arterial remodeling, reflected in distal pruning and proximal dilation, and cardiac structure and function, pulmonary pressure, and functional outcomes. METHODS: Among 2275 participants in the community-based Atherosclerosis Risk in Communities study (ARIC) who underwent echocardiography and noncontrast cardiac computed tomography at study visit 7 (2018–2019), we quantified the fraction of total pulmonary vascular area comprised of arterial vessels with cross-sectional area <5 mm 2 (aBV5/aTBV) and arterial vessels with cross-sectional area >10 mm 2 (aBVg10/aTBV) using a validated image processing approach. We assessed the associations of aBV5/aTBV and aBVg10/aTBV with echocardiographic measures of cardiac structure and function and pulmonary artery systolic pressure using multivariable linear regression models adjusted for demographics and cardiovascular risk factors. We also evaluated associations of pulmonary vascular arterial remodeling metrics with circulating NT-proBNP (N-terminal pro–B-type natriuretic peptide), self-reported dyspnea, and incident heart failure. RESULTS: Mean age was 80±4 years, 61% were women, 22% reported Black race, and mean left ventricular ejection fraction was 64±7%. Mean aBV5/aTBV was 0.30±0.08, and aBVg10/aTBV was 0.45±0.09. Lower aBV5/aTBV, reflecting greater distal pruning, and higher aBVg10/aTBV, reflecting greater proximal dilation, were both associated with greater left ventricular remodeling, worse diastolic function, and worse systolic function. Lower aBV5/aTBV and higher aBVg10/aTBV demonstrated nonlinear associations with greater pulmonary artery systolic pressure. Both lower aBV5/aTBV and higher aBVg10/aTBV were associated with higher circulating NT-proBNP and greater odds of moderate to severe dyspnea. Higher aBVg10/aTBV, in particular, was associated with greater risk of incident heart failure over a 4-year follow-up with a hazard ratio of 1.25 (95% CI, 1.03–1.51) per one SD in aBVg10/TBV. CONCLUSIONS: Among older adults, pulmonary vascular arterial remodeling is associated with greater left ventricular remodeling, worse diastolic and systolic dysfunction, greater pulmonary artery systolic pressure, greater odds of significant dyspnea, and greater risk of heart failure development. Our findings clarify the morphologic changes in the pulmonary vasculature that link cardiac dysfunction to higher pulmonary pressure in late life and may appear before symptomatology.

Correction to: Forecasting the Burden of Cardiovascular Disease and Stroke in Women in the United States through 2050: A Scientific Statement from the American Heart Association

Loss of the Coronary Artery Disease Risk Gene <i>LMOD1</i> in Vascular Smooth Muscle Cells Triggers Rapid-Onset Coronary Atherosclerosis

BACKGROUND: Atherosclerosis is the primary underlying cause of coronary artery disease. LMOD1 is a coronary artery disease risk gene whose role in coronary artery pathophysiology is unknown. Whole-body loss of Lmod1 causes a lethal neonatal visceral myopathy in mice, necessitating unique approaches for the study of vascular smooth muscle cell (VSMC) phenotypes. METHODS: Control mice ( Lmod1 WT carrying a Cre recombinase allele) and VSMC-restricted Lmod1 knockout mice ( Lmod1 SMKO ) were subjected to various atherogenic regimens. Atherosclerosis and LMOD1 (leiomodin 1) expression in mouse and human coronary arteries were assessed by histopathology and confocal immunofluorescence microscopy. Coronary arteries from Lmod1 WT and Lmod1 SMKO mice were analyzed with assorted stains and antibodies, immunogold lineage tracing, and spatial metabolomics. Aortic smooth muscle cells from Lmod1 WT and Lmod1 SMKO mice were subjected to lipid loading with or without lentivirus carrying wild-type or actin nucleation–deficient Lmod1 ( Lmod1 ND . Mice harboring an intronic deletion of Lmod1 or Lmod1 ND were engineered using clustered regularly interspaced short palindromic repeats. RESULTS: A lethal neonatal visceral myopathy occurred in Lmod1 SMKO mice using Myh11-CreER T2 , prohibiting further investigation. In contrast, Lmod1 SMKO mice generated with Itga8-CreER T2 survived and were therefore used in all subsequent studies. Under atherogenic conditions, Lmod1 SMKO mice displayed little vascular disease in several organs but developed diffuse, occlusive coronary atherosclerosis with fibrous caps. No such disease was observed in Lmod1 WT mice. Time-course studies documented lipid insudation and VSMC migration into the intima of coronary arteries of Lmod1 SMKO mice as early as 8 days after the regimen. Immunogold lineage tracing revealed that 46% of coronary plaque cells were of VSMC origin. Spatial metabolomics uncovered multiple lipid species within coronary atheromata of Lmod1 SMKO mice. In vitro studies demonstrated elevated lipid accumulation in Lmod1 SMKO VSMCs, which was rescued by viral-mediated Lmod1 WT or Lmod1 ND expression. An intronic deletion of Lmod1 , comprising a conserved orthologous sequence where the single nucleotide variant associated with coronary artery disease exists, showed attenuated LMOD1 expression. Heterozygous Lmod1 SMKO mice, with a comparable reduction in LMOD1, displayed no coronary artery disease. Similarly, VSMC-restricted expression of Lmod1 ND resulted in negligible coronary atherosclerosis. CONCLUSIONS: Under atherogenic conditions, Lmod1 SMKO mice present with rapid-onset coronary atherosclerosis. LMOD1 safeguards coronary homeostasis, apparently in an actin nucleation–independent manner.

Response by DeRubertis et al to Letter Regarding Article, “Drug-Eluting Resorbable Scaffold Versus Balloon Angioplasty for Below-the-Knee Peripheral Artery Disease: 2-Year Results From the LIFE-BTK Trial”

Response by Fearon et al to Letter Regarding Article, “Cardiac Allograft Vasculopathy Inhibition With Alirocumab: The CAVIAR Trial”

Letter by Chen et al Regarding Article, “Drug-Eluting Resorbable Scaffold Versus Balloon Angioplasty for Below-the-Knee Peripheral Artery Disease: 2-Year Results From the LIFE-BTK Trial”

Correction for Newman et al., The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity

A generative model for bipartite gene-sharing networks

Gene-sharing networks provide a powerful framework to study the evolution of viruses and mobile genetic elements. These bipartite networks, which link genes to the genomes that contain them, exhibit characteristic degree distributions: a scale-free distribution for genes and an exponential-like decay for genomes. Here, we propose a mechanistic model that explains these patterns through fundamental evolutionary processes including horizontal gene transfer, capture of new genes, emergence of new genomes, and gene loss. Using a mean-field approximation, we derive analytical expressions for the asymptotic gene and genome degree distributions, recapitulating a power-law distribution for genes and an exponential distribution for genomes. Numerical simulations validate these predictions and yield parameter values that closely fit empirical data from dsDNA viruses, RNA viruses, and prokaryotic pangenomes. This simple model with only two parameters provides a generative framework for bipartite gene-sharing networks, offering qualitative and quantitative insights into the main evolutionary forces driving genome plasticity. Setting the gene loss rate to zero, the gene and genome degree distributions of the model closely fit the empirically observed distributions. Thus, evolution of viruses appears to be dominated by gene gain, in agreement with the results of independent reconstructions of viral evolution.

Spatiotemporal control of Atg2 association with the ER during autophagosome formation

Autophagy degrades various intracellular components by sequestering them within membrane vesicles called autophagosomes and delivering them to lysosomes or vacuoles. Previous studies have revealed that the conserved, bridge-like lipid transfer protein Atg2 tethers autophagosome precursors to the endoplasmic reticulum (ER) and mediates lipid supply from the ER to drive their expansion into autophagosomes. However, how Atg2 docks onto the ER has remained unclear. Here, we show in Saccharomyces cerevisiae that Atg2 interacts with the ER-resident VAP family protein Scs2. This interaction is mediated by a phospho-FFAT motif in Atg2 and the major sperm protein domain of Scs2 and enhanced by phosphorylation of the motif by the autophagy-initiating kinase Atg1, which is activated at the autophagosome formation site upon autophagy induction. This interaction cooperates with the N-terminal region of Atg2, which contains a weakly amphipathic helix, to mediate Atg2 association with the ER. Thus, the Atg2–Scs2 interaction functions as a spatiotemporal switch that controls Atg2–ER association. We also show that mammalian ATG2 interacts with the VAP-like proteins MOSPD1 and MOSPD3 to promote autophagosome formation. Collectively, this study reveals a conserved mechanism that initiates lipid transfer during autophagosome formation.