Hypothyroidism, Atherosclerosis, and Cardiovascular Risk Prevention
Journal: Nat Rev EndocrinolPMID: 41198906
Abstract: Hypothyroidism affects approximately 5% of the population and is associated with an increased risk of cardiovascular disease (CVD). This review explores the complex relationship between hypothyroidism and cardiovascular risk factors, analyzes the molecular mechanisms that accelerate atherosclerosis, and discusses risk assessment and personalized treatment strategies.
Summary Translation:
Hypothyroidism is characterized by reduced thyroid hormone production and affects about 5% of the general population. Although primarily associated with metabolic and endocrine changes, hypothyroidism is also linked to an increased risk of cardiovascular disease (CVD), mainly due to accelerated atherosclerosis. While the association between overt hypothyroidism and CVD is well established, the relationship between subclinical or mild hypothyroidism and CVD remains uncertain. CVD is one of the most common non-communicable diseases globally and a leading cause of death. This narrative review delves into the intricate relationship between hypothyroidism and cardiovascular risk factors, exploring the biochemical and molecular mechanisms that increase susceptibility to CVD in hypothyroid states, while seeking potential avenues for improved management and preventive strategies by examining traditional and novel risk factors. Additionally, the review examines the role of thyroid hormones in regulating cardiac structure and function to elucidate their impact on the occurrence and progression of CVD. The article also discusses risk assessment and personalized treatment approaches for patients with hypothyroidism.
Cardiac Fibroblast Foxm1 Deletion Prevents Pressure Overload-Induced Cardiac Remodeling via the Usp10/MKK6-p38γ MAPK Axis
Journal: Cell Death DifferPMID: 41198967
Abstract: Activation of cardiac fibroblasts (CFs) plays a critical role in cardiac remodeling. This study found that deletion of the Foxm1 gene significantly alleviates pressure overload-induced cardiac remodeling, with mechanisms involving dual activation of the p38 MAPK signaling pathway, providing new targets for cardiac remodeling treatment.
Summary Translation:
Activation of cardiac fibroblasts (CFs) plays a crucial role in cardiac remodeling. However, the molecular mechanisms underlying the transition of fibroblasts to myofibroblasts remain unclear. This study found that Foxm1 expression is elevated in human heart failure (HF) samples and mouse cardiac remodeling models. CFs are the primary cell type responsible for the upregulation of Foxm1. Conditional knockout of the Foxm1 gene in CFs or myofibroblasts significantly alleviated TAC-induced cardiac remodeling and HF. Conversely, conditional overexpression of Foxm1 in CFs led to more severe pathological cardiac remodeling and dysfunction induced by TAC. Combined RNA sequencing and mass spectrometry analysis showed that Foxm1 promotes the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Mechanistically, Foxm1 not only upregulates USP10 to reduce the ubiquitination and degradation of p38γ but also directly drives the expression of MKK6 to increase the phosphorylation level of p38, acting as a dual amplifier of p38 activation. Knockout of the p38γ gene improved the exacerbated cardiac remodeling induced by TAC in Foxm1 overexpressing mice. Our findings suggest that targeting the Foxm1-USP10/MKK6-p38γ MAPK axis may be a new potential strategy for treating pathological cardiac remodeling and HF. Foxm1 promotes the activation of CFs during TAC-induced pathological cardiac remodeling by regulating the USP10/MKK6-p38γ MAPK signaling pathway. Fibrosis-promoting stimuli increase Foxm1 expression, which upregulates USP10 to reduce the ubiquitination and degradation of p38γ while directly driving the expression of MKK6 to increase the phosphorylation level of p38, thus acting as a dual amplifier of p38 activation and promoting the transition of fibroblasts to myofibroblasts. Additionally, knockout of the p38γ gene alleviated the exacerbated pathological cardiac remodeling induced by TAC in Foxm1 overexpressing mice.
COVID-19 Infection and Vaccination-Related Vascular and Inflammatory Diseases in Children and Adolescents in England: A Population-Based Retrospective Cohort Study
Journal: Lancet Child Adolesc HealthPMID: 41198364
Abstract: This study analyzes the risk of vascular and inflammatory diseases in children and adolescents in England following COVID-19 infection and vaccination. Results show that the risk of related diseases remains elevated for 12 months post-infection, while the risk of myocarditis/pericarditis is slightly increased within 4 weeks post-vaccination, but significantly lower than the risk associated with infection.
Summary Translation:
Background: The rarity of severe disease following COVID-19 infection and the rarity of adverse reactions related to vaccination are important considerations for vaccination policy. We aimed to assess the short- and long-term risks of vascular and inflammatory diseases following the first COVID-19 diagnosis and vaccination in children and adolescents. Methods: In this retrospective, population-based cohort study, we analyzed electronic health records of all individuals under 18 years of age registered with general practitioners in England, known age, sex, and residential area, from January 1, 2020, to December 31, 2022. Outcomes included arterial thromboembolic events, venous thromboembolic events, thrombocytopenia, myocarditis or pericarditis, and inflammatory diseases. COVID-19 diagnosis was defined as the first recorded positive SARS-CoV-2 PCR or antigen test or COVID-19 diagnosis code in primary or secondary care records; COVID-19 vaccination was defined as the first recorded administration of the BNT162b2 vaccine (the main vaccine during the study period). Adjusted hazard ratios (aHR) for all outcomes were estimated by adjusting for age, sex, ethnicity, region, deprivation, frequency of general practitioner contacts, and medication use, using time from the first COVID-19 diagnosis from January 1, 2020, to March 31, 2022, and time from the first COVID-19 vaccination from August 6, 2021, to December 31, 2022. Results: Among 13,896,125 individuals under 18 years of age (6,784,260 [48.8%] female and 7,111,865 [51.2%] male; 9,979,420 [71.7%] white), 3,903,410 (28.1%) were diagnosed with COVID-19. COVID-19 diagnosis (compared to undiagnosed or pre-diagnosis) was associated with increased risk of arterial thromboembolic events (aHR 2.33 [95% CI 1.20-4.51]), venous thromboembolic events (4.90 [3.66-6.55]), thrombocytopenia (3.64 [2.21-6.00]), myocarditis or pericarditis (3.46 [2.06-5.80]), and inflammatory diseases (14.84 [11.01-19.99]) within the first week post-diagnosis. Incidence decreased in weeks 2-4, but the risk of venous thromboembolic events (1.39 [1.14-1.69]), thrombocytopenia (1.42 [1.01-2.00]), and myocarditis or pericarditis (1.42 [1.05-1.91]) remained elevated for over 12 months. Among 9,245,395 individuals aged 5 to <18 years eligible for vaccination (4,510,490 [48.8%] female and 4,734,905 [51.2%] male; 6,684,140 [72.3%] white), 3,407,560 (36.9%) received the first dose of the vaccine. COVID-19 vaccination (compared to unvaccinated or pre-vaccination) was associated with an increased risk of myocarditis or pericarditis within the first 4 weeks post-vaccination (1.84 [1.25-2.72]). The absolute excess risk of myocarditis or pericarditis at 6 months post-diagnosis compared to pre-diagnosis or undiagnosed individuals was 2.24 (1.11-3.80)/100,000, while post-vaccination compared to pre-vaccination or unvaccinated individuals was 0.85 (0.07-1.91)/100,000. Explanation: Children and adolescents have a rare but elevated risk of vascular and inflammatory diseases within 12 months following the first COVID-19 diagnosis, and a rare risk of myocarditis or pericarditis within 4 weeks following the first BNT162b2 vaccination, although the risk post-vaccination is significantly lower than that associated with infection. These findings are significant for national policymakers and caregivers considering consent for child vaccination and support public health strategies for COVID-19 vaccination to mitigate the more frequent and persistent risks associated with SARS-CoV-2 infection.
Effects of Fish Oil Supplementation on Cardiovascular Events in Hemodialysis Patients
Journal: N Engl J MedPMID: 41201837
Abstract: Hemodialysis patients have a high mortality rate from cardiovascular disease, and the efficacy of fish oil supplementation in reducing this risk is uncertain. This randomized controlled trial shows that daily fish oil supplementation significantly reduces the incidence of serious cardiovascular events and is well tolerated.
Summary Translation:
Background: Cardiovascular disease is a leading cause of death in hemodialysis patients, yet effective preventive therapies remain limited. Supplementation with n-3 polyunsaturated fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have cardiovascular benefits in the general population, but its efficacy in hemodialysis patients is uncertain. Methods: In a double-blind, randomized, placebo-controlled trial conducted at 26 centers in Canada and Australia, we randomly assigned adult patients undergoing maintenance hemodialysis to receive daily fish oil (4g n-3 polyunsaturated fatty acids [1.6g EPA and 0.8g DHA]) or corn oil placebo. The primary endpoint was a composite of serious cardiovascular events, including cardiovascular and non-cardiovascular death, fatal and non-fatal myocardial infarction, peripheral vascular disease leading to amputation, and fatal and non-fatal stroke. Secondary endpoints included an expanded primary endpoint to include non-cardiovascular death, individual components of the primary endpoint, and first cardiovascular events or death from any cause. Results: Between November 28, 2013, and July 22, 2019, a total of 1,228 participants were randomized; 610 were assigned to the fish oil group and 618 to the placebo group. During a follow-up of 3.5 years, the incidence of serious cardiovascular events was significantly lower in the fish oil group than in the placebo group (0.31 vs. 0.61/1000 patient-days; hazard ratio [HR] 0.57; 95% CI 0.47-0.70; P<0.001). The incidence of the expanded primary endpoint, including non-cardiovascular death, appeared lower in the fish oil group, with an HR of 0.77 (95% CI 0.65-0.90). The HR for cardiovascular death was 0.55 (95% CI 0.40-0.75); for fatal and non-fatal myocardial infarction, it was 0.56 (95% CI 0.40-0.80); for peripheral vascular disease leading to amputation, it was 0.57 (95% CI 0.38-0.86); for fatal and non-fatal stroke, it was 0.37 (95% CI 0.18-0.76); and for first cardiovascular events or death from any cause, it was 0.73 (95% CI 0.61-0.87). There were no significant differences in adherence to the trial protocol or adverse event rates between the two groups. Conclusion: Daily supplementation of n-3 fatty acids in maintenance hemodialysis patients can reduce the incidence of serious cardiovascular events.
Inconsistency of eGFR Based on Creatinine and Cystatin C with Clinical Outcomes: A Meta-Analysis
Journal: JAMAPMID: 41202182
Abstract: There may be discrepancies between estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcr) and cystatin C (eGFRcys). This study found that eGFRcys significantly lower than eGFRcr is associated with higher all-cause mortality, cardiovascular events, and risk of renal failure.
Summary Translation:
Importance: Estimated glomerular filtration rate (eGFR) may differ based on whether creatinine or cystatin C is used for calculation, but the prevalence and significance of these differences remain unclear. Objective: To assess the prevalence of inconsistency between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater inconsistency, and evaluate the association of inconsistency with adverse outcomes. Data Source: Participants from the Chronic Kidney Disease Prognosis Consortium (CKD-PC). Study Selection: Participants with simultaneous measurements of cystatin C and creatinine and recorded clinical outcomes. Data Extraction and Synthesis: Individual-level meta-analysis will be conducted from April 2024 to August 2025. Primary outcomes and measures: The primary independent measure is a large negative eGFR difference (eGFRdiff), defined as eGFRcys being at least 30% lower than eGFRcr. Secondary (dependent) outcomes include all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and need for renal replacement therapy. Results: A total of 821,327 individuals from 23 outpatient cohorts (mean [SD] age 59 [12] years; 48% female; 13.5% diabetes; 40% hypertension) and 39,639 individuals from 2 inpatient cohorts (mean [SD] age 67 [16] years; 31% female; 30% diabetes; 72% hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. In outpatient participants, during an average (SD) follow-up of 11 (4) years, a large negative eGFRdiff was associated with higher all-cause mortality (28.4 vs 16.8/1000 person-years [PY]; hazard ratio [HR] 1.69 [95% CI 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8/1000 PY; HR 1.61 [95% CI 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8/1000 PY; HR 1.35 [95% CI 1.27-1.44]), heart failure (13.2 vs 8.6/1000 PY; HR 1.54 [95% CI 1.40-1.68]), and need for renal replacement therapy (2.7 vs 2.1/1000 PY; HR 1.29 [95% CI 1.13-1.47]). Conclusion and significance: In CKD-PC, 11% of outpatient participants and 35% of inpatients had eGFRcys at least 30% lower than eGFRcr. In outpatient settings, eGFRcys being at least 30% lower than eGFRcr is associated with significantly higher rates of all-cause mortality, cardiovascular events, and renal failure.
The Frailty Scale Captures Multidimensional Frailty and Predicts Mortality in Heart Failure
Journal: J Am Coll CardiolPMID: 41196240
Abstract: Frailty is associated with poor prognosis in heart failure patients. This study confirms that the Clinical Frailty Scale (CFS) effectively reflects physical and cognitive function and independently predicts 2-year all-cause mortality, serving as a practical screening tool for heart failure management.
Summary Translation:
Background: Frailty is prevalent among heart failure patients and is associated with adverse outcomes. However, the CFS’s ability to accurately capture the degree of physical and cognitive decline and its prognostic value in contemporary heart failure treatment remain uncertain. Objective: This study aims to explore the extent to which CFS reflects physical and cognitive function domains and its association with 2-year all-cause mortality in hospitalized heart failure patients using data from the Japanese Acute Decompensated Heart Failure Registry-NEXT (JROADHF-NEXT). Methods: This study included 3,905 hospitalized heart failure patients from a prospective, nationwide, multicenter registry (JROADHF-NEXT). Patients were categorized into 6 groups based on CFS (1-2, 3, 4, 5, 6, and 7-9). Physical function was assessed through gait speed, the 5-times sit-to-stand test, the Short Physical Performance Battery (SPPB), grip strength, and the 6-minute walk distance; cognitive function was measured using the Mini-Cog test. The primary outcome was all-cause mortality within 2 years post-discharge. Results: Physical function metrics and Mini-Cog scores deteriorated progressively with increasing CFS severity. During the 2-year follow-up, 725 patients (18.6%) died, with mortality rates increasing gradually with higher CFS scores. Incorporating CFS into prognostic models significantly improved discrimination compared to models based on SPPB and Mini-Cog testing. Conclusion: CFS is an independent predictor of 2-year mortality and a robust comprehensive measure of physical and cognitive frailty in heart failure patients. CFS provides a practical screening tool that complements formal frailty assessments based on performance in contemporary heart failure management.
Comparison of Liberal and Restrictive Transfusion Strategies in High Cardiac Risk Patients Postoperatively: The TOP Randomized Clinical Trial
Journal: JAMAPMID: 41205227
Abstract: The controversy surrounding postoperative transfusion thresholds is significant. This trial shows that in high cardiac risk patients, a liberal transfusion strategy (hemoglobin <10 g/dL) does not reduce the risk of 90-day mortality or major ischemic events compared to a restrictive strategy (hemoglobin <7 g/dL), but reduces non-myocardial infarction cardiac complications.
Summary Translation:
Importance: Guidelines for postoperative red blood cell transfusion recommend transfusion when hemoglobin levels are <7 g/dL. However, the safety of this strategy in high cardiac event risk patients undergoing major surgery remains unclear. Objective: To assess the risk of death or major ischemic events within 90 days in high cardiac event risk patients undergoing major vascular or general surgery, comparing liberal transfusion strategies to restrictive transfusion strategies. Design, Setting, and Participants: This parallel, single-blind, randomized clinical superiority trial included 1,428 (≥18 years) high cardiac risk veterans undergoing major vascular or general surgery. Participants were enrolled from February 2018 to March 2023 at 16 U.S. Department of Veterans Affairs medical centers. Interventions: 714 participants with postoperative hemoglobin <10 g/dL were randomly assigned to the liberal strategy group (transfusion threshold <10 g/dL), and 714 to the restrictive strategy group (transfusion threshold <7 g/dL). Primary outcomes and measures: The primary endpoint was a composite of all-cause mortality, myocardial infarction, coronary revascularization, acute kidney injury, or ischemic stroke within 90 days post-randomization. Secondary endpoints included a composite of cardiac complications (arrhythmias, heart failure, and non-fatal cardiac arrest) excluding myocardial infarction. Results: Among 1,424 analyzed veterans (mean age 69.9 [SD 7.9] years; 1,393 males [97.8%]; 268 Black [18.8%]; 48 Hispanic [4.1%]; 1,071 White [75.2%]), 1,297 (91.1%) underwent vascular surgery. On day 5 post-randomization, the mean hemoglobin difference between transfusion strategies was 2.0 g/dL. The incidence of the primary outcome was 9.1% (61/670) in the liberal group and 10.1% (71/700) in the restrictive group (relative risk 0.90; 95% CI 0.65-1.24). The incidence of non-myocardial infarction cardiac complications as one of the five secondary endpoints was 5.9% (38/647) in the liberal group and 9.9% (67/678) in the restrictive group (relative risk 0.59; 99% CI 0.36-0.98). Conclusion and significance: In high cardiac event risk patients undergoing major vascular or general surgery, a liberal transfusion strategy does not reduce the incidence of 90-day mortality or major ischemic outcomes compared to a restrictive strategy.
Contemporary Diagnosis and Treatment of Aortic Regurgitation: A Recent Review
Journal: J Am Coll CardiolPMID: 41194752
Abstract: Aortic regurgitation (AR) is progressive and often underestimated; delayed intervention can lead to left ventricular remodeling and heart failure. This review summarizes advances in multimodal imaging diagnosis, surgical innovations, and transcatheter replacement techniques, as well as the clinical application prospects of dedicated AR devices.
Summary Translation:
Aortic regurgitation (AR) is progressive and often underestimated; if not intervened in a timely manner, it can lead to adverse left ventricular remodeling and heart failure. Despite Class I recommendations for intervention, many patients (especially the elderly, frail, and those with multiple comorbidities) remain untreated. Advances in high-fidelity multimodal imaging techniques—including cardiac magnetic resonance, four-dimensional flow imaging, and speckle-tracking echocardiography—have enabled earlier detection of remodeling and more accurate quantification of regurgitant burden. These techniques are redefining treatment thresholds and may achieve biomarker-imaging composite staging of the disease. Surgical intervention remains the gold standard for primary AR treatment. Contemporary surgical treatment plans are individualized based on patient age, anatomical structure, and aortic root pathology. While surgical aortic valve replacement remains the primary treatment for most candidates, valve-sparing root surgery, Ross procedure, and aortic valve leaflet repair are increasingly being used in carefully selected low-risk patients at experienced centers. Transcatheter aortic valve replacement is rapidly evolving as a viable option, helping to fill the treatment gap for patients with surgical contraindications or high risk. However, devices optimized for calcific aortic stenosis face technical challenges in primary AR—including large and non-calcified annuli, elliptical aortic roots, and high stroke volumes—leading to poor anchoring, residual paravalvular regurgitation, and device embolization. Systems designed specifically for AR, with leaflet engagement anchoring and enhanced sealing capabilities, have shown promising results in feasibility studies and pivotal trials and have received commercial approval in Europe, with U.S. authorization expected. This recent review integrates current insights into the pathophysiology of AR, diagnostic advancements, and surgical and transcatheter technological innovations, highlighting knowledge gaps and proposing research priorities to accelerate healthcare accessibility for this historically underserved population.
β(IV)-Spectrin/STAT3 Complex Regulates the Direction of Hypertrophic Growth in Myocardial Cells
Journal: Circ ResPMID: 41196954
Abstract: The β(IV)-spectrin/STAT3 complex determines the direction of myocardial cell growth under chronic stress by regulating microtubule properties and sarcomere transcript distribution, providing a new mechanism for targeted therapy of myocardial hypertrophy.
Summary Translation:
Background: Myocardial hypertrophy is defined as stress-induced increases in cardiac mass/volume and is a major risk factor for adverse cardiovascular events such as heart failure and arrhythmias. Under this broad definition, the direction of growth of cells and organs varies depending on the type and duration of stress, significantly impacting cardiac function, but the mechanisms regulating the direction of hypertrophy remain unclear. This study evaluates the role of the cytoskeletal protein βIV-spectrin and the related hypertrophic factor STAT3 (signal transducer and activator of transcription 3) in guiding the direction of hypertrophic growth.
Methods: By modifying the interaction between βIV-spectrin and STAT3 or directly regulating STAT3 phosphorylation, transgenic mouse models with altered STAT3 signaling were constructed. Mice were assessed at baseline, after aortic constriction, or aortocaval fistula. Unbiased screening of gene expression in these structurally different states was conducted to identify pathways regulating myocardial cell length/width. In vitro experiments were performed in primary mouse myocardial cells, and these pathways were validated in vivo to regulate growth patterns for therapeutic intervention.
Results: Deletion of βIV-spectrin or direct activation of STAT3 promotes myocardial cell length increase over width, leading to left ventricular cavity dilation (eccentric hypertrophy) and reduced contractile function. In contrast, retention of βIV-spectrin favors an increase in myocardial cell width without left ventricular dilation (concentric hypertrophy) and maintains contractile function after aortic constriction or aortocaval fistula. Differentially expressed genes related to microtubules were identified in eccentric and concentric hypertrophy states, including the transport driver KIF20A (kinesin family member 20A). In vitro experiments indicated a correlation between βIV-spectrin/STAT3 signaling, KIF20A expression, microtubule density, and the spatial distribution of the sarcomere gene actc1 mRNA. Finally, pharmacological inhibition of STAT3 after chronic aortic constriction for 6 weeks successfully restored concentric growth and improved contractile function.
Conclusion: These data indicate that βIV-spectrin/STAT3 plays a novel and critical role in regulating the geometric shape of myocardial cells under chronic stress by modifying microtubule properties and sarcomere transcript distribution. This research further elucidates that the growth process of myocardial hypertrophy and its direction are independent pathways in cardiac remodeling.
Triple vs. Dual Lipid-Lowering Therapy in Acute Coronary Syndrome: The ES-BempeDACS Randomized Clinical Trial
Journal: CirculationPMID: 41200807
Abstract: This study compares the efficacy and safety of triple lipid-lowering therapy (high-intensity statin + ezetimibe + bempedoic acid) versus dual therapy in patients after acute coronary syndrome (ACS), showing that triple therapy is safe but does not improve LDL-C target rates.
Summary Translation:
Background: Current guidelines recommend a stepwise strategy to achieve low-density lipoprotein cholesterol (LDL-C) targets after acute coronary syndrome (ACS). Early intensive strategies using lipid-lowering agents (LLTs) in combination starting from the onset of ACS may be more effective. However, the role of bempedoic acid in ACS (especially when used in combination with high-intensity statins and ezetimibe) remains unclear. The ES-BempeDACS study (Efficacy and Safety of Bempedoic Acid in Acute Coronary Syndrome) aims to compare the efficacy and safety of triple lipid-lowering therapy (high-dose high-intensity statin + ezetimibe + bempedoic acid) versus standard treatment (high-dose high-intensity statin + ezetimibe) after ACS.
Methods: ES-BempeDACS is a multicenter, independent, pragmatic, prospective, randomized, open-label, endpoint-blinded controlled trial conducted from November 2023 to October 2024 in 12 hospitals in Spain. The primary endpoint is the proportion of patients achieving LDL-C <55 mg/dL (<1.4 mmol/L) at 8 weeks post-ACS between the triple lipid-lowering therapy and standard treatment groups.
Results: A total of 206 patients (mean age 59.5±10.9 years; 21.4% female) were randomly assigned to the triple lipid-lowering therapy group or the standard treatment group (dual lipid-lowering therapy) within 72 hours of ACS onset. The baseline LDL-C level was 133.6±28.8 mg/dL. After 8 weeks, 59.4% of patients in the triple lipid-lowering therapy group achieved LDL-C <55 mg/dL, compared to 53.1% in the control group (dual lipid-lowering therapy) (P=0.376). The percentage change in LDL-C levels was 57.5±17.8% in the triple therapy group and 56.9±18.5% in the dual therapy group (P=0.823). Similar results were observed for reductions in non-high-density lipoprotein cholesterol (triple therapy group 49.0±25.4 vs dual therapy group 49.1±31.2; P=0.970) and triglyceride levels (triple therapy group 14.9±36.9 vs dual therapy group 16.8±36.0; P=0.718), with no differences in adverse events. Conclusion: Both dual and triple lipid-lowering therapies achieve high LDL-C target rates (<55 mg/dL) at 8 weeks after ACS. Adding bempedoic acid to statin-ezetimibe therapy is safe but does not improve the proportion of patients achieving LDL-C targets at 8 weeks. Larger randomized studies are needed to confirm our findings. Trial registration: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2021-006550-31.
FGF13 Regulates Voltage-Gated Sodium Channel-Independent Cardiac Cell Electrical Signal Transmission via Cx43 Transport
Journal: Circ ResPMID: 41200819
Abstract: FGF13 regulates cardiac cell electrical signal transmission through microtubule-dependent connexin 43 (Cx43) transport, independent of voltage-gated sodium channels (VGSC), providing a new target for arrhythmia treatment.
Summary Translation:
Background: Fibroblast growth factor homologous factors (FHFs) mutations are associated with arrhythmias. Although FHFs are most commonly characterized as regulators of voltage-gated sodium channels (VGSCs), recent studies suggest they have broader, non-VGSC-related functions, including regulating connexin 43 (Cx43) gap junctions and hemichannels, which have often been underexplored or overlooked. Methods: In constitutive cFgf13KO mice, cardiac conduction and myocardial cell action potentials were assessed by pharmacologically targeting Cx43 gap junctions and hemichannels. The regulatory effect of fibroblast growth factor (FGF) 13 on Cx43 abundance and subcellular distribution was characterized. Potential novel mechanisms by which FGF13 regulates Cx43 were explored through proximity labeling proteomics. Results: FGF13 deficiency prolonged QRS and QT intervals. The Cx43 gap junction decoupling agent Gap19 significantly prolonged QRS duration in cFgf13KO mice, leading to conduction system block, while this was not observed in wild-type mice. Optical mapping showed significantly reduced conduction velocity during ventricular pacing. Microscopy revealed abnormal Cx43 transport in cFgf13KO myocardial cells, with reduced localization at intercalated discs, suggesting decreased membrane Cx43 but increased Cx43 hemichannels. The resting membrane potential of cFgf13KO myocardial cells was depolarized, and the action potential duration at 50% repolarization was prolonged. Using the Cx43 hemichannel inhibitor Gap19, expressing FGF13, or expressing a mutant FGF13 that cannot bind VGSCs restored these parameters to near wild-type levels, emphasizing the non-VGSC-dependent regulatory role of FGF13. To assess the functional impact of resting membrane potential depolarization, hearts were subjected to low potassium treatment, showing no significant response in wild-type hearts, but complete restoration of conduction velocity in cFgf13KO hearts. Proteomics analysis indicated that FGF13 may be involved in vesicle-mediated transport regulation. FGF13 deficiency disrupts microtubule stability and reduces the expression of microtubule proteins and the major cardiac microtubule regulator MAP4. Conclusion: FGF13 regulates microtubule-dependent Cx43 transport and targeted localization through a non-VGSC-dependent mechanism, affecting cardiac electrical signal transmission.
Transcatheter Mitral Valve Replacement for Severe Mitral Annular Calcification: Main Results of the SUMMIT-MAC Study
Journal: J Am Coll CardiolPMID: 41194751
Abstract: The SUMMIT-MAC study confirms that the Tendyne transcatheter mitral valve replacement system is safe and effective for treating severe mitral annular calcification (MAC)-related mitral valve disease, significantly improving patients’ heart failure symptoms and quality of life.
Summary Translation:
Background: Severe mitral annular calcification (MAC) poses significant risks. Patients with this condition require safe and effective transcatheter treatment options. Objective: To evaluate the safety and efficacy of the Tendyne transcatheter mitral valve system in symptomatic patients with severe MAC-related mitral valve disease. Methods: The SUMMIT-MAC study is the first prospective clinical trial aimed at assessing the treatment effects of the Tendyne system for severe MAC. All patients had severe MAC with significant mitral valve dysfunction and high surgical risk. An independent core laboratory assessed mitral valve disease. Adverse events were adjudicated by an independent clinical events committee. The primary endpoint was the proportion of patients without all-cause mortality and heart failure hospitalization (HFH) within 12 months post-procedure. Results: A total of 103 patients (mean age 78.0±6.5 years; 55% female) with severe MAC and mitral regurgitation (MR) or stenosis underwent treatment with the Tendyne system. Almost all patients had mitral regurgitation at baseline (97% had regurgitation grade >2+). The technical success rate was 94.2%, and the 30-day mortality rate was 6.8%. The primary endpoint was achieved—60.4% of patients were free from all-cause mortality and heart failure hospitalization at 12 months (performance goal: 43%; p=0.0002). Heart failure symptoms significantly improved (NYHA functional class I/II: 30.6% at baseline vs 87.5% at 12 months; p<0.0001), and quality of life significantly increased (Kansas City Cardiomyopathy Questionnaire overall summary score mean paired increase of 18.7±24.4 points; p<0.0001). Conclusion: In the first report of the main results from the SUMMIT-MAC clinical trial, transcatheter mitral valve replacement using the Tendyne system successfully treated MAC-related mitral valve disease and significantly improved heart failure symptoms and quality of life.
Genetic Programming-Based Deep Learning Ensemble Model for Explainable Arrhythmia Detection in Electrocardiograms
Journal: NPJ Digit MedPMID: 41198945
Abstract: A genetic programming-based deep learning ensemble model was developed for arrhythmia detection and atrial fibrillation recurrence prediction from electrocardiograms (ECGs), demonstrating strong interpretability and excellent performance.
Summary Translation:
Cardiovascular disease remains the leading cause of death in developed countries. This study proposes a deep learning ensemble model for detecting arrhythmias from electrocardiograms and predicting atrial fibrillation (AF) recurrence, combined with explainable artificial intelligence (XAI) methods. Validation was performed using two datasets: Guangdong Provincial People’s Hospital (Dataset G, 1,172 patients, mean age 71.4±6.3 years, 66% female, 20.5% with arrhythmias) and Liverpool Heart and Chest Hospital (Dataset L, 909 patients, mean age 60.5±10.71 years, 33% female, 29.7% with arrhythmias). Our ensemble model outperformed individual models and voting models, with areas under the receiver operating characteristic curve (ROC-AUC): Dataset G 0.980 (95% confidence interval: 0.956-0.998, p=0.03), Dataset L 0.799 (95% confidence interval: 0.737-0.856, p=0.07). The model trained on the combined training set achieved ROC-AUCs of 0.980 (95% confidence interval: 0.952-1.0) and 0.800 (95% confidence interval: 0.739-0.861) on the test sets of Datasets G and L, respectively. The ensemble model’s precision-recall curve area for predicting AF recurrence was 0.765 (95% confidence interval: 0.669-0.849), while individual models achieved 0.737 (95% confidence interval: 0.648-0.821). Explainable artificial intelligence (XAI) enhanced the model’s interpretability in clinical applications.
High-Sensitivity Cardiac Troponin I and Dementia Risk: A 25-Year Longitudinal Study of Whitehall II
Journal: Eur Heart JPMID: 41206213
Abstract: Subclinical myocardial injury in midlife (indicated by elevated high-sensitivity cardiac troponin I) is associated with accelerated cognitive decline, brain structural changes, and increased risk of dementia in later life.
Summary Translation:
Background and Objective: This study hypothesizes that subclinical myocardial injury in midlife (indicated by elevated cardiac troponin I levels) is associated with accelerated cognitive decline, reduced brain structural volume, and increased risk of dementia. Methods: Participants from the Whitehall II study included 5,985 individuals aged 45-69 years, whose cardiac troponin I levels were measured at baseline (1997-1999) using high-sensitivity assays and followed up until March 2023. Outcome measures included new-onset dementia; cognitive testing at six time points; and neuroimaging metrics obtained through MRI scans from 2012-2016. Cox models and linear mixed models were used to explore the association between cardiac troponin and new-onset dementia and cognitive trajectories. A nested case-control sample of 3,475 participants (695 dementia cases and 2,780 matched controls) was used to conduct reverse trajectory analyses of cardiac troponin measured at three time points (1997-1999, 2007-2009, 2012-2013). Results: During a median follow-up of 24.8 years, 606 cases (10.1%) of dementia were recorded. Doubling cardiac troponin levels was associated with a 10% increase in dementia risk (95% confidence interval 3%-17%). Participants with elevated cardiac troponin at baseline experienced faster cognitive decline. Cardiac troponin concentrations were higher in dementia patients 7 to 25 years prior to diagnosis compared to non-dementia individuals. Compared to participants with baseline cardiac troponin levels <2.5 ng/L, those with levels >5.2 ng/L had lower gray matter volumes and more pronounced hippocampal atrophy 15 years later, equivalent to aging effects of 2.7 years and 3 years, respectively. Conclusion: Subclinical myocardial injury in midlife is associated with an increased risk of dementia in later life.
Metformin Improves Walking Ability in Patients with Peripheral Artery Disease: A Randomized Clinical Trial (PERMET Trial)
Journal: JAMAPMID: 41205146
This study investigates whether metformin can improve walking ability in non-diabetic patients with peripheral artery disease (PAD), showing no significant difference in 6-minute walking distance between the metformin and placebo groups at 6 months of follow-up, not supporting the use of metformin to improve walking performance in PAD patients.
Summary Translation:
Importance: Peripheral artery disease (PAD) is a debilitating cardiovascular condition that impairs walking ability. Currently, there are few effective therapies to improve walking performance in PAD patients. Metformin is a commonly used inexpensive medication for type 2 diabetes, with multiple effects including activation of AMP-activated protein kinase, reduction of oxidative stress, and stimulation of endothelial nitric oxide synthase (eNOS). Objective: To assess whether metformin treatment improves the 6-minute walking distance compared to placebo in non-diabetic PAD patients after 6 months. Design, Setting, and Participants: A randomized double-blind clinical trial conducted at four centers in the U.S. Recruitment began on May 23, 2017, and ended on February 17, 2025, with a target enrollment of 212 patients, ultimately including 202 (95%). Participants were PAD patients aged 50 years and older, with final follow-up time until August 19, 2025. Interventions: PAD patients were randomly assigned to the metformin group (n=97) or placebo group (n=105) for 6 months. Primary outcomes and measures: The primary outcome was the change in 6-minute walking distance at 6 months (clinical minimum important difference of 8-20 meters). Secondary outcomes included maximum treadmill walking time, pain-free treadmill walking time, walking impairment questionnaire distance and speed scores, 36-item short form health survey physical functioning scores, and brachial artery flow-mediated dilation. Results were adjusted for study center and baseline values of each outcome measure. Results: Among 202 randomized patients (mean [SD] age 69.6 [8.4] years, 56 females [28%], 79 Black [39%]), 179 (89%) completed the 6-month follow-up. Compared to placebo, metformin did not significantly improve the 6-minute walking distance (metformin group: 358.6 meters to 353.2 meters, within-group change: -5.4 meters; placebo group: 359.8 meters to 354.5 meters, within-group change: -5.3 meters, adjusted between-group difference: 1.1 meters [95% confidence interval, -16.3 to 18.6 meters]; P=0.90). Metformin also did not significantly improve any secondary outcomes compared to placebo. The most common serious adverse events were cardiovascular events (3.1% in the metformin group, 1.9% in the placebo group). The most common non-serious adverse events were gastrointestinal discomfort/stomach upset (64.9% in the metformin group, 40.6% in the placebo group) and headache (37.2% in the metformin group, 49.5% in the placebo group). Conclusion and significance: In non-diabetic PAD patients, metformin treatment for 6 months did not improve the 6-minute walking distance compared to placebo. These results do not support the use of metformin to improve walking performance in PAD patients.
Endothelial Cell SRSF1 Promotes Ischemia-Induced Angiogenesis via the ATF3-KLF2-S1PR1 Pathway
Journal: Circ ResPMID: 41195527
This study found that SRSF1 expression is elevated in endothelial cells after ischemia, promoting ischemia-induced angiogenesis by regulating ATF3 alternative splicing and downstream KLF2-S1PR1 signaling pathways, providing new therapeutic targets for ischemic vascular diseases.
Summary Translation:
Background: Peripheral artery disease is a severe ischemic vascular condition lacking effective pharmacological treatments, while improving angiogenesis to restore blood perfusion is a promising therapeutic strategy. Endothelial cells are the primary cell type involved in angiogenesis in response to ischemia. However, the molecular mechanisms regulating ischemia-induced angiogenesis remain unclear. Methods: A discovery-driven approach was used to identify elevated expression of serine/arginine-rich splicing factor 1 (SRSF1) in endothelial cells after ischemia. Functional loss and gain experiments were conducted in vitro and in vivo to explore the role of SRSF1 in angiogenesis. The role of SRSF1 in ischemia-induced angiogenesis was assessed using a hindlimb ischemia mouse model. Mechanisms were explored through transcriptomics, enhanced cross-linking immunoprecipitation sequencing, RNA pull-down assays, and chromatin immunoprecipitation-quantitative polymerase chain reaction analysis. Results: Proteomics analysis showed that endogenous SRSF1 accumulates in endothelial cells of ischemic muscle and responds to hypoxia. Endothelial cell SRSF1-deficient mice exhibited impaired blood flow recovery and angiogenesis after hindlimb ischemia. Importantly, SRSF1 overexpression enhanced blood flow recovery and angiogenesis after hindlimb ischemia. SRSF1 overexpression enhanced angiogenic functions in human endothelial cells, promoting lumen formation, sprouting ability, and cell migration, while SRSF1 knockdown inhibited these functions. Mechanistically, SRSF1 directly binds to the precursor mRNA of ATF3 (activating transcription factor 3) to regulate its alternative splicing, with SRSF1 overexpression reducing the truncated ATF3Δzip2 transcript at the expense of increasing the full-length ATF3 transcript. Subsequently, ATF3 directly binds to the KLF2 (Kruppel-like factor 2) promoter, inhibiting KLF2 expression and downstream S1PR1 (sphingosine-1-phosphate receptor 1) signaling pathways. By upregulating full-length ATF3 and downregulating the KLF2-S1PR1 signaling pathway, SRSF1 promotes endothelial cell lumen formation and angiogenesis. Furthermore, prostaglandin E1 analogs can activate the SRSF1 signaling pathway, improving endothelial cell angiogenesis in vitro and in vivo. Conclusion: This study identifies SRSF1 as a novel regulatory factor in ischemia-induced angiogenesis, enhancing endothelial cell angiogenic functions through the ATF3-KLF2-S1PR1 pathway. These results suggest that targeting endothelial cell SRSF1 may be a promising therapeutic approach for ischemic vascular diseases.
SGLT2 Inhibitors and Renal Outcomes in Patients with Varying eGFR and Albuminuria: A Meta-Analysis
Journal: JAMAPMID: 41203232
This meta-analysis confirms that SGLT2 inhibitors reduce the risk of chronic kidney disease (CKD) progression in patients with type 2 diabetes, chronic kidney disease, or heart failure, and this benefit is not influenced by baseline eGFR or albuminuria levels, including patients with stage 4 CKD or microalbuminuria.
Summary Translation:
Importance: Sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce the risk of CKD progression in patients with type 2 diabetes, chronic kidney disease (CKD), or heart failure. However, their effects in patients with stage 4 CKD or minimal/no albuminuria remain unclear. Objective: To assess whether the degree of albuminuria measured by estimated glomerular filtration rate (eGFR) or urine albumin/creatinine ratio (UACR) alters the impact of SGLT2 inhibitors on renal outcomes. Data Source: Participants from SGLT2 inhibitor meta-analysis heart-kidney trialists’ alliance (SMART-C) SGLT2 inhibitor trials. Study Selection: Randomized, double-blind, placebo-controlled trials conducted in SMART-C evaluating SGLT2 inhibitors with indications for reducing CKD progression, with at least 500 participants per group and a follow-up of at least 6 months. Data Extraction and Synthesis: Inverse variance-weighted meta-analysis was used to summarize treatment effects across trials. Primary outcomes and measures: CKD progression was defined as renal failure, at least a 50% reduction in eGFR, or death due to renal failure. Other outcomes included annual eGFR decline rate and renal failure. Results: A total of 10 randomized trials included 70,361 participants (mean [SD] age 64.8 [8.7] years; 35.0% female), of whom 2,314 (3.3%) experienced CKD progression, and 988 (1.4%) progressed to renal failure. SGLT2 inhibitors reduced the risk of CKD progression (events per 1000 patient-years: 25.4 vs 40.3; hazard ratio [HR] 0.62 [95% confidence interval, 0.57-0.68]), and this was independent of baseline eGFR (eGFR ≥60 mL/min/1.73 m² HR 0.61 [95% confidence interval, 0.52-0.71]; eGFR 45-<60 mL/min/1.73 m² HR 0.57 [95% confidence interval, 0.47-0.70]; eGFR 30-<45 mL/min/1.73 m² HR 0.64 [95% confidence interval, 0.54-0.75]; eGFR <30 mL/min/1.73 m² HR 0.71 [95% confidence interval, 0.60-0.83]; trend P=0.16), and was also independent of baseline albuminuria (albuminuria ≤30 mg/g HR 0.58 [95% confidence interval, 0.44-0.76]; 30-300 mg/g HR 0.74 [95% confidence interval, 0.57-0.96]; >300 mg/g HR 0.57 [95% confidence interval, 0.52-0.64]; trend P=0.49). Although the strength of protection varied, SGLT2 inhibitors reduced the annual eGFR decline rate across all eGFR and UACR subgroups, including analyses of diabetic and non-diabetic participants separately. SGLT2 inhibitors also reduced the risk of pure renal failure (HR 0.66 [95% confidence interval, 0.58-0.75]). Conclusion and significance: This meta-analysis shows that SGLT2 inhibitors reduce the risk of CKD progression regardless of baseline eGFR or albuminuria levels, including patients with stage 4 CKD or microalbuminuria. This supports the routine use of SGLT2 inhibitors in patients with type 2 diabetes, CKD, or heart failure to improve renal outcomes across the full spectrum of kidney function.
Low-Dose Recombinant Tissue Plasminogen Activator in Coronary Artery Disease Patients with High Thrombus Burden Undergoing Direct PCI: A Randomized Trial
Journal: J Am Coll CardiolPMID: 41194755
This study evaluates the effects of administering low-dose alteplase during direct PCI in patients with ST-segment elevation myocardial infarction (STEMI) and high thrombus burden, showing that alteplase is not superior to placebo, not supporting the routine use of this therapy.
Summary Translation:
Background: In patients with ST-segment elevation myocardial infarction (STEMI) undergoing direct percutaneous coronary intervention (PCI), approximately half experience distal embolization, leading to microvascular obstruction and reduced myocardial tissue perfusion. Targeting the coronary artery with low-dose recombinant tissue plasminogen activator (alteplase) may be an effective strategy to improve microvascular obstruction without increasing the risk of systemic bleeding. Objective: To determine whether adjunctive coronary administration of low-dose alteplase can reduce microvascular obstruction or major adverse cardiovascular events (MACE) in STEMI patients with high thrombus burden undergoing direct PCI. Methods: A multicenter, randomized, double-blind trial was conducted, enrolling patients with extensive STEMI and high thrombus burden undergoing direct PCI. After establishing antegrade reperfusion, 10 mg alteplase, 20 mg alteplase, or placebo (saline) was directly injected into the infarct-related artery via a delivery catheter, with patients randomly assigned to one of the three groups. The primary endpoint was a composite of 30-day major adverse cardiovascular events (MACE), myocardial blush grade (MBG) 0/1, distal embolization, or ST-segment resolution of <50% 30 minutes post-PCI. MACE was defined as cardiovascular death, myocardial reinfarction, cardiogenic shock, or new-onset heart failure within 30 days. Results: Among 210 randomized patients, 207 received the study drug (alteplase 10 mg group 68 patients, alteplase 20 mg group 69 patients, placebo group 70 patients). The mean age was 62.6 years, with 25% being female. The median time from symptom onset to randomization was 2.9 hours. The incidence of the primary outcome was 53.3% (73 patients) in the alteplase group and 52.9% (37 patients) in the placebo group (relative risk 1.00, 95% confidence interval 0.76-1.31, P>0.99). The results were consistent across all components of the primary outcome, and the results were also consistent across all dose groups compared to the placebo group. One patient in the trial experienced serious or clinically significant bleeding (alteplase 20 mg group). The number of ventricular fibrillation episodes was trending higher in the alteplase group compared to the placebo group (10.2% vs 1.4%, relative risk 6.86, 95% confidence interval 0.91-51.4, P=0.06). Conclusion: In STEMI patients with high thrombus burden undergoing direct PCI, administration of alteplase does not outperform placebo and does not reduce the composite primary outcome of 30-day MACE, MBG 0/1, distal embolization, or ST-segment resolution of <50%. These data do not support the routine use of this therapy in STEMI patients undergoing direct PCI. (ClinicalTrials.gov NCT03335839).
Optimizing Outcomes After Transcatheter Edge-to-Edge Repair Using Transmitral Pressure Gradient and Residual Mitral Regurgitation
Journal: J Am Coll CardiolPMID: 41193089
This study shows that in patients with functional mitral regurgitation (FMR) undergoing transcatheter edge-to-edge repair (M-TEER), an increase in the mean transmitral pressure gradient (TMPG) is associated with adverse outcomes, while mild or moderate residual regurgitation with low TMPG is associated with better prognosis, suggesting a need to balance regurgitation reduction with pressure gradient.
Summary Translation:
Background: Although reducing mitral regurgitation (MR) after transcatheter mitral edge-to-edge repair (M-TEER) can improve outcomes, the impact of increased mean transmitral pressure gradient (TMPG) remains controversial. Objective: This study aims to assess the clinical significance of MR reduction and TMPG elevation after M-TEER in patients with functional mitral regurgitation (FMR). Methods: A total of 2,360 FMR patients were included, all of whom underwent echocardiographic assessment at discharge after M-TEER. Spline analysis and group-based comparisons were used to evaluate the relationship between TMPG and outcomes. Patients were divided into five groups based on the severity of residual MR and TMPG to assess the prognostic impact of postoperative hemodynamics: MR ≤ mild and TMPG <5 mmHg (n=1,702), MR ≤ mild and TMPG ≥5-<10 mmHg (n=164), moderate MR and TMPG <5 mmHg (n=361), moderate MR and TMPG ≥5-<10 mmHg (n=71), MR > moderate or TMPG ≥10 mmHg (n=62). The primary endpoint was all-cause mortality or heart failure hospitalization. Results: The incidence of primary endpoint events increased gradually with rising TMPG over 2 years, from 25.0% at 1 mmHg to 47.0% at 6 mmHg. In multivariable analysis, each 1 mmHg increase in TMPG was independently associated with the primary endpoint (HR: 1.10; 95% confidence interval: 1.02-1.17; P=0.008). Compared to MR ≤ mild, moderate MR was not associated with higher risk, while MR > moderate remained a significant predictor of the primary endpoint. Among the five groups, patients with MR ≤ mild and TMPG <5 mmHg had the lowest incidence of the primary endpoint (28.4%, 39.0%, 33.0%, 43.7%, 48.4%; P<0.001). However, patients with moderate MR and TMPG <5 mmHg showed no significant difference in event risk compared to those with MR ≤ mild and TMPG <5 mmHg (HR: 1.13; 95% confidence interval: 0.92-1.41; P=0.24). Failure to achieve MR ≤ mild and TMPG <5 mmHg was associated with larger left atrial volume index, larger effective regurgitant orifice area, elevated baseline TMPG, and use of older generation G2 devices. Conclusion: In FMR patients, increased TMPG is consistently associated with a higher risk of primary endpoints. Mild or moderate residual MR with low TMPG is associated with a more favorable prognosis, suggesting that balancing MR reduction with TMPG may aid in refining risk stratification after M-TEER. (Japan Valve Heart Disease Treatment and Prognosis Registry; UMIN000023653).
Clusterin+ Myocardial Cells Induced by Injury Suppress Inflammation and Promote Neonatal and Adult Heart Regeneration via Reprogramming Macrophages
Journal: Cell Stem CellPMID: 41205597
Abstract: This study finds that Clusterin+ myocardial cells (Clu+ CM) appear in the border zone of regenerating hearts after injury, secreting CLU that binds to macrophage TLR4, promoting macrophage repair phenotype polarization through Cpt1a-dependent fatty acid oxidation, and subsequently secreting BMP2 to activate myocardial cell BMPR1A signaling to promote proliferation, providing new mechanisms and therapeutic strategies for heart regeneration.
Summary Translation:
Adult heart injury leads to scar formation, while the neonatal heart has regenerative capacity. The mechanisms behind this difference remain unclear. By comparing spatiotemporal single-cell analyses and dual recombinase-mediated lineage tracing, we identified a population of injury-induced Clusterin+ myocardial cells (Clu+ CM) that coordinate reparative anti-inflammatory macrophage activity. Following injury, Clu+ CM appear in the border zone of regenerating hearts but are rare in non-regenerative environments. These myocardial cells secrete CLU, which binds to Toll-like receptor 4 (TLR4) on macrophages, promoting anti-inflammatory polarization through Cpt1a-dependent fatty acid oxidation. These macrophages secrete bone morphogenetic protein 2 (BMP2), activating bone morphogenetic protein receptor 1A (BMPR1A) signaling in myocardial cells, driving proliferation. Notably, reduced CLU levels in myocardial infarction patients are associated with impaired cardiac function, while CLU overexpression or transplantation of engineered CLU+ human cardiac organoids can reproduce this regenerative regulatory effect, enhancing myocardial repair in adult mice. Our findings reveal a critical cardiac-immune mechanism whereby Clu+ CM suppress inflammation and stimulate myocardial cell proliferation through reprogramming macrophages, providing potential strategies for heart regeneration.
A Mitochondria-Targeted Fluorinated Polymer Nanoparticle Inducing Mitochondrial Autophagy and Exhibiting Red Fluorescence for Atherosclerosis Treatment
Journal: Nat CommunPMID: 41203599
Abstract: This study develops mitochondria-targeted fluorinated polymer nanoparticles with mitochondrial autophagy-inducing activity and red fluorescence tracking capabilities, which can restore mitochondrial function and reduce inflammation in foam cells by activating mitochondrial autophagy, demonstrating good therapeutic effects in reducing oxidative stress and cellular senescence in atherosclerotic plaques in vivo.
Summary Translation:
Mitochondrial autophagy is crucial for the selective autophagic degradation of damaged mitochondria, helping to maintain mitochondrial and cellular homeostasis. Here, we report a fluorinated poly-pyridine that specifically targets mitochondria and exhibits high mitochondrial autophagy-inducing activity. This polymer effectively restores mitochondrial function in foam cells and reduces inflammatory responses by activating mitochondrial autophagy, and it exhibits inherent red fluorescence under physiological conditions, allowing direct tracking of its biological distribution in cells and in vivo. Furthermore, due to the anti-fouling properties of the fluorinated label, this polymer nanoparticle demonstrates high serum stability. After intravenous administration, this nanoparticle reduces oxidative stress in atherosclerotic plaques, promotes mitochondrial autophagy, and decreases cellular senescence, achieving high therapeutic efficacy. This study provides an innovative and effective strategy for the treatment of atherosclerosis and other inflammatory diseases associated with mitochondrial dysfunction.