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Perspectives on the Future of Fundamental Sciences in Cardiovascular Medicine

Medication non-adherence, admission causes, and length of stay among patients with uncontrolled diabetes mellitus in a Malaysian tertiary hospital

COL1A1-Enhanced CD44/SLC7A11 Interaction and Cystine Uptake Result in CD34 ⁺ Foam-Like Macrophage Accumulation in Transplant Arteriosclerosis

BACKGROUND: Chronic transplant arteriosclerosis is the primary cause of long-term graft failure. Selectively targeting specific inflammatory macrophage subpopulations is essential for inhibiting the primary triggers of inflammatory and immune responses. Therefore, elucidating the origins and regulatory mechanisms of these macrophages in allograft arteriosclerosis is key for the development of targeted therapies. METHODS: We performed single-cell RNA sequencing and spatial transcriptomics or integrated transcriptomic data from human chronic allograft vasculopathy specimens and mouse vascular allograft models. Flow cytometry and immunofluorescence staining were used to characterize macrophage subpopulations within remodeled allograft arteries. To determine cellular origins, CD34 + lineage tracing and depletion strategies were used. The interactions among COL1A1 (collagen type 1 α1), CD44, and SLC7A11 (solute carrier family 7 member 11) were analyzed using proximity ligation assays and coimmunoprecipitation. Furthermore, metabolic profiles were investigated with ultraperformance liquid chromatography coupled with high-resolution mass spectrometry. To validate the role of cystine transport in macrophage differentiation, we used pharmacologic inhibitors and a genetic approach using myeloid-specific Slc7a11 knockout mice (Lysm- Slc7a11 -KO). The mechanisms identified in vivo were further corroborated through in vitro experiments. RESULTS: We identified a novel proinflammatory foam-like macrophage phenotype in allograft arterial adventitia. These macrophages primarily originated from bone marrow–derived CD34 + lineage cells and exhibit heightened de novo lipogenesis and proinflammatory activity. Their lipogenesis is driven by increased cystine uptake, facilitated by enhanced membrane expression of the CD44–SLC7A11 complex, which activates mTORC1 (mechanistic target of rapamycin complex 1)–HIF-1α (hypoxia-inducible factor 1α) signaling. We also revealed that fibroblast-secreted COL1A1 is essential for anchoring the complex to the cell membrane through its direct interaction with CD44. Blocking COL1A1, CD44, or SLC7A11 effectively attenuated mTORC1–HIF-1α signaling, inflammation, and lipogenesis in macrophages as well as accumulation of foam-like cells and intimal hyperplasia in allograft arteries. CONCLUSIONS: This study has revealed previously uncharacterized foam-like macrophages in transplant arteriosclerosis, with COL1A1-enhanced amino acid metabolism modulating lipogenesis and foamy macrophage formation. This study offers potential therapeutic targets to modulate immune response and enhance transplant outcomes.

Valorization of slag and banana leaf ash in five natural fiber-reinforced sustainable cementitious composites: early age mechanical and microstructural insights

Correction to: 2026 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association

Retraction Note: Anomaly detection with grid sentinel framework for electric vehicle charging stations in a smart grid environment

Loss of STMP1 Perturbs Mitochondrial Cristae and Drives Cellular Inflammation and Heart Failure

BACKGROUND: Heart failure is a leading cause of morbidity and mortality worldwide, particularly among the growing elderly population. In degenerative aging and autoimmune diseases, the cytoplasmic leak of mitochondrial DNA, resulting from mitochondrial cristae compromise, triggers persistent low-grade cellular inflammation through activation of the cGAS (cyclic GMP [guanosine monophosphate]–AMP [adenosine monophosphate] synthase)–STING (stimulator of interferon genes) pathway and the IFN-I (type I interferon) response. However, how and whether mitochondrial architectural components and cardiomyocyte inflammation drive cardiac aging and failure are not yet well understood. METHODS: We investigated the function of STMP1 (short transmembrane mitochondrial protein 1), a 47–amino acid nuclear-encoded mitochondrial-localized peptide featuring a distinctive GxxxGxxxG glycine zipper domain. A mouse with cardiomyocyte-specific knockout of Stmp1 ( Stmp1 -KO) was generated to investigate its role in cardiac function. We profiled the transcriptome, proteome, and metabolome of Stmp1 -KO hearts to determine its functional mechanism of action. Electron microscopy was used to assess the impact of STMP1 depletion and functional rescue after adeno-associated virus 9–mediated gene restoration in the Stmp1 -KO mouse. RESULTS: STMP1 is downregulated specifically in cardiomyocytes, and not other cardiac cell types, in aged mice and humans. Genetic loss of Stmp1 in cardiomyocytes resulted in heart failure in vivo. STMP1 interacts with components of the cristae organizing complexes MICOS (mitochondrial contact site and cristae organizing complex) and SAM (sorting and assembly machinery). Consequent to Stmp1 loss, mitochondrial cristae were destabilized, mitochondrial DNA was mislocalized to the cytosol, and the cGAS–STING pathway was activated, with ensuing cellular inflammation and cardiomyocyte cell death. Restoration of wild-type Stmp1 or STING inhibition significantly rescued cardiac function in vivo. CONCLUSIONS: Our work reveals a mechanism connecting the micropeptide STMP1 to mitochondrial cristae architecture and cardiomyocyte cellular inflammation, both of which are present as potential drivers of heart failure and cardiac aging.

VLCEA: LLM-guided evolutionary scheduling for RCPSP via validated, hallucination-safe constraints

Left Ventricular Hypertrabeculation and Prognosis in Dilated Cardiomyopathy

BACKGROUND: Left ventricular (LV) hypertrabeculation, formerly termed LV noncompaction, is a heterogeneous myocardial entity linked to adverse cardiovascular outcomes. This study evaluated embolic risk in patients with dilated cardiomyopathy (DCM) according to the presence of hypertrabeculation and examined its prevalence and prognostic relevance across DCM genotypes. METHODS: Clinical data from 1160 patients with DCM evaluated by cardiac magnetic resonance imaging and genetic testing (n=997 [86%]) were collected from 22 international centers. End points included embolic events, advanced heart failure events, and major ventricular arrhythmias. RESULTS: LV hypertrabeculation was identified in 354 patients (30.5%) by fractal analysis and in 343 (29.7%) according to Petersen criteria, with good concordance. After a median follow-up of 5.1 years (interquartile range, 2.8–7.4), embolic events occurred in 37 patients (3.2%), advanced heart failure in 62 (5.3%), and major ventricular arrhythmias in 136 (11.7%). Hypertrabeculation was not associated with increased embolic risk (hazard ratio, 1.5 [95% CI, 0.75–3.00]), even among patients in sinus rhythm with LV ejection fraction ≤40% (hazard ratio, 1.89 [95% CI, 0.7–5.5]). In contrast, atrial fibrillation and reduced LV ejection fraction were associated with embolic events (both P <0.01). LV hypertrabeculation was not associated with an increased risk of major ventricular arrhythmias or advanced heart failure; genotype, LV ejection fraction, and late gadolinium enhancement emerged as the main predictors of adverse outcomes. The prevalence of LV hypertrabeculation varied across genotypes, with the highest prevalence observed in patients with sequence variants in motor sarcomeric genes (58%), TTN (38%), and genotype-negative status (33%), and the lowest prevalence observed among those with variants in cytoskeletal/Z-disk (7%) and nuclear envelope (5%) genes. Hypertrabeculation was not associated with adverse outcomes within any genotype. CONCLUSIONS: Although LV hypertrabeculation is common in DCM, it is not associated with worse outcomes and should not prompt differential clinical management. The embolic risk in patients with DCM and hypertrabeculation is low, including in those with reduced LV ejection fraction without atrial fibrillation, and does not support prophylactic anticoagulation in these patients.

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.