Background and Aims: Heart failure with preserved ejection fraction (HFpEF) exhibits profound phenotypic heterogeneity, which likely contributes to variable therapeutic response. We developed a physiology-informed digital twin-AI framework to predict individual hemodynamic and myocardial energetic responses to accelerated atrial pacing and tested whether simulated physiologic response corresponds to responders in the myPACE randomized clinical trial. Methods: Patient-specific digital twins were constructed for 146 HFpEF patients and used to train a variational autoencoder that generated a virtual HFpEF population (n = 25,000). The model simulated pacing-induced changes in left atrial pressure (LAP), systolic blood pressure (SBP), cardiac output (CO), and cardiac efficiency (CE; derived from myocardial oxygen-demand estimates). These simulations served as labels to train classifiers based on clinical variables available in myPACE, allowing us to examine associations with clinical end points and test a hypothesized relationship between CE and treatment response. Results: Simulations revealed heterogeneous physiological responses, with 95.6% of virtual patients showing reduced LAP, 47.0% an SBP reduction greater than 8.5 mmHg, 93.8% increased CO, and 36.1% improved CE. Classifiers reproduced these patterns with high fidelity. In the myPACE trial, patients classified as having CE improvement or a larger SBP reduction experienced significantly greater 1-month improvements in quality-of-life scores and larger NT-proBNP reductions. Conclusions: A physiology-informed digital twin-AI framework can predict hemodynamic and energetic responses corresponding to clinical benefit in HFpEF patients receiving accelerated atrial pacing. CE improvement functioned as a mechanistic indicator, while SBP reduction served as an accessible clinical correlate, offering mechanistically grounded guidance for patient-specific pacing and motivating prospective validation. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04721314 ### Funding Statement This study was funded by NIH grant HL173346 and the Michigan Medicine-PKUHSC Joint Institute for Translational and Clinical Research. We also acknowledge support from the Michigan Biology of Cardiovascular Aging Postdoctoral Fellowship, which provided funding for the training and career development of Feng Gu during this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB committees of the University of Michigan, the University of Wisconsin-Madison, and the University of Vermont gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The virtual cohort generated by the GenAI model is available in the corresponding Git repository (https://github.com/beards-lab/PhysicalAI.git). Data from the myPACE randomized clinical trial is available from the original corresponding investigators upon reasonable request.

Background: Chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD) frequently occur together, with systemic inflammation linking these two conditions. Recently, the high-sensitivity C-reactive protein to albumin ratio (hsCAR) has been identified as a composite biomarker of inflammation and nutrition. Thus, this study aimed to examine the prognostic value of hsCAR in patients with COPD–CAD undergoing percutaneous coronary intervention (PCI). Methods: In this cohort study, consecutive patients with COPD–CAD who underwent PCI between 2014 and 2019 were enrolled and categorized into tertiles by hsCAR values. The primary endpoint was major adverse cardiac events (MACEs), including cardiac death, target vessel revascularization (TVR), and nonfatal myocardial infarction (MI). Patients underwent a follow-up for up to 4 years, and the incidence of MACEs was compared between the hsCAR groups using Kaplan–Meier curves and Cox regression analyses. Results: A total of 262 patients were enrolled. Over a median follow-up of approximately 4 years, higher hsCAR levels were associated with an increased incidence of MACEs. The cumulative incidence of MACEs was highest in Group C (hsCAR ≥0.079). The incidence of MACEs was significantly higher in Group C than in Group A (19.5% vs. 5.7%; hazard ratio (HR) = 3.27, 95% confidence interval (CI): 1.08–9.86; p = 0.035). Receiver operating characteristic (ROC) curve analysis confirmed the associated discriminatory ability (area under the curve (AUC) = 0.651; p = 0.004). Restricted cubic spline (RCS) analysis showed a linear increase in the risk of MACEs as the absolute value of hsCAR exceeded 0.0446. Subgroup analyses revealed consistent associations across strata, with no significant interactions. Conclusion: Elevated baseline hsCAR is an independent predictor of long-term MACEs in patients with COPD–CAD undergoing PCI. As an inexpensive and readily available biomarker, hsCAR could be used for post-PCI risk stratification to guide targeted secondary prevention in this high-risk population.

Medical image classification encounters significant difficulties stemming from multi-source noise interference and intricate structural patterns. The extraction of global and local information is crucial for improving classification performance. However, convolutional neural networks are restricted in their ability to capture global context owing to the limitations imposed by the kernel size on their receptive fields. Although Transformers can effectively model global dependencies and feature interactions via attention mechanisms, they are computationally demanding and prone to overlooking critical features. Certain hybrid models such as convolutional neural networks integrated with Transformers achieved remarkable outcomes but often compromise efficiency. To address these issues, a lightweight convolution Transformer-KAN is proposed. It can effectively extract the global and local features while ensuring minimal computational expense. Its architecture incorporates an adaptive graph channel attention module and a channel aggregation module to effectively optimise and recalibrate inter-channel interactions, improving the classification accuracy. Experimental results demonstrated that the proposed network architecture accomplished state-of-the-art performance on the ISIC2018, COVID-19, Brain Tumor and Lung lesion datasets.

BACKGROUND:In embarking on randomized clinical trials (RCTs), researchers can hypothesize that a more intensive treatment is better than a less intensive treatment (positive hypothesis) or that a less intensive treatment is similar or noninferior to a more intensive treatment (negative hypothesis). Researchers may design noninferiority RCTs (NI-RCTs) to support negative hypotheses and standard RCTs (S-RCTs) to support negative or positive hypotheses. Regardless of hypotheses, S-RCTs and NI-RCTs should produce consistent results when assessing similar participants, interventions, control, and outcomes. OBJECTIVE:To compare effect estimates in S-RCTs with positive hypotheses versus NI-RCTs and in S-RCTs with negative hypotheses versus NI-RCTs. DESIGN:Meta-research. SETTING:98 meta-analyses. PARTICIPANTS:468 RCTs, including 153 NI-RCTs and 315 S-RCTs (149 positive and 166 negative hypotheses). INTERVENTION:S-RCTs as the exposure and NI-RCTs as the control. MEASUREMENTS:The ratio of effect estimates between S-RCTs and NI-RCTs in each meta-analysis was combined across meta-analyses. RESULTS:Standard RCTs with positive hypotheses produced effect estimates 1.47 (95% CI, 1.27 to 1.70) times larger than NI-RCTs; among RCTs rated as having low risk of bias for blinding, the ratio was 1.01 (CI, 0.70 to 1.45), whereas among those rated as having high or unclear risk of bias for blinding, the ratio was 1.81 (CI, 1.41 to 2.33). Standard RCTs with negative hypotheses did not produce statistically different effect estimates from NI-RCTs (ratio, 0.93 [CI, 0.84 to 1.03]). LIMITATION:Findings may be limited by residual differences between S-RCTs and NI-RCTs in the same meta-analysis. CONCLUSION:The researchers' hypotheses may bias the results of published RCTs, especially those with high or unclear risk of bias for blinding. The effect of researchers' hypotheses should be assessed in systematic reviews and clinical practice guidelines when RCTs addressing the same clinical question report conflicting hypotheses. PRIMARY FUNDING SOURCE:The Shenzhen Municipal Government, Guangdong Province, China, and the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences.

ABO blood group antigens represent more than surface markers on red blood cells. They are pivotal genetic determinants that affect susceptibility to various diseases and variations in drug response. Polymorphisms in the ABO gene produce glycosyltransferases with distinct structures and functions, leading to differential risk for cancers, cardiovascular diseases, and infectious diseases. The ABO gene exerts its profound influence on disease pathogenesis primarily through the regulation of ABH antigens, interfacing with critical pathophysiological pathways such as coagulation, inflammation, and cellular signaling. Epidemiological data link non-O blood groups with heightened incidence of gastric, pancreatic, ovarian, and bladder cancers. Individuals with non-O blood groups present higher concentrations of von Willebrand factor (vWF), which predisposes them to atherosclerosis, thrombosis, and ischemic heart disease. This contrasts sharply with the risk profile of group O individuals, who show a greater likelihood of contracting gastrointestinal infections—notably from Helicobacter pylori, noroviruses, and Vibrio cholerae—and tend to suffer from more severe symptoms. Furthermore, functional variations in ABO glycosyltransferases can directly modulate drug efficacy. Consequently, the development of predictive models for disease risk and treatment response based on ABO blood typing holds significant promise for advancing personalized prevention and therapeutic strategies for cancer, cardiovascular, and infectious diseases.

BACKGROUND:The constant resistance ratio (cRR) is a novel nonhyperemic pressure ratio based on piezoresistive pressure microcatheter (PMC) measurements. With repeated measurements in randomized order of PMC and pressure wire techniques, this study aimed primarily to validate the diagnostic performance of cRR compared with fractional flow reserve (FFR) in coronary lesions of 30% to 90% diameter stenosis. METHODS:SUPREME II (Sensor-Equipped Ultrathin Pressure Microcatheter Versus Pressure Wire for Physiological Measurements) was a multicenter, prospective study that included 466 patients (483 vessels) from 11 centers. All target vessels were assessed using both pressure wire and PMC separately in randomized order under resting and hyperemic conditions. The primary end point was the diagnostic accuracy of the cRR using a PMC-based FFR of ≤0.80 as the reference standard. Secondary end points included the cRR "gray zone" of the cRR-FFR hybrid strategy and the proportion of patients in whom diagnosed was achieved without vasodilator use. RESULTS:The optimal cRR cutoff was 0.89, which correctly classified 82.8% of the patients, with a sensitivity and specificity of 87.0% and 80.1%, respectively, and achieved an area under the curve of 0.92 with FFRPMC as reference (area under the curve 0.90 with FFRpressure wire as reference). If FFR was added for decision-making in cases of cRR values between 0.85 and 0.91, a cRR--FFR hybrid strategy achieved a 95.3% agreement with the FFR-only strategy and allowed 68.5% of the patients to not require using vasodilator. CONCLUSIONS:In coronary stenosis of 30% to 90% diameter stenosis, cRR measurements were highly feasible. The diagnostic accuracy of cRR with FFRPMC as reference was excellent. Further, a cRR-FFR hybrid strategy may reduce vasodilator use without compromising diagnostic accuracy. REGISTRATION:URL: https://clinicaltrials.gov/study/NCT05417763; Unique Identifier: NCT05417763.

Background:Transcatheter edge-to-edge repair (TEER) has become an effective alternative for treating degenerative mitral regurgitation (DMR) in patients at high surgical risk. The SQ-Kyrin-M TEER system (SQ-Kyrin-M system) is a novel TEER device developed in China. This study aimed to evaluate the feasibility, safety, and 12-month clinical efficacy of the SQ-Kyrin-M system in patients with high-risk degenerative mitral regurgitation. Methods:In this prospective, multicenter, single-arm study (ClinicalTrials.gov: NCT06467110), 120 patients with symptomatic DMR (grade ≥3+) had the device implanted. The primary endpoint was the clinical success rate at 12 months. Secondary endpoints included technical, device, and procedural success rate; New York Heart Association (NYHA) class improvement; Kansas City Cardiomyopathy Questionnaire (KCCQ) score change; and mitral regurgitation (MR) reduction. Safety endpoints encompassed all-cause mortality, cardiovascular mortality, and major adverse event rate. Results:A total of 120 patients received the TEER procedure across 25 participating sites in China; the mean age was 71.9 years, and the mean Society of Thoracic Surgeons (STS) risk score was 9.3. At 12 months, the Kaplan-Meier estimates were 82.5% for clinical success, 7.6% for all-cause mortality, and 10.8% for major adverse events; MR ≤2+ and MR ≤1+ were achieved in 91.7 and 70.4% of the patients, respectively; 88.9% of patients were in NYHA class I or II; and KCCQ score had improved by 18.9 points. Favorable left ventricular remodeling was observed with sustained reductions in left ventricular end-diastolic and end-systolic volumes. Conclusions:This study demonstrates that the SQ-Kyrin-M system is a safe and effective therapeutic option for DMR patients.

BACKGROUND AND AIMS:Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none have been verified in Chinese patients. This study aimed to evaluate the efficacy and safety of ongericimab, a novel PCSK9 monoclonal antibody, in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. METHODS:This was a randomized, multicenter, double-blind, placebo-controlled phase 3 study designed to enroll 120 statin-intolerant adult patients. Eligible patients were randomly assigned in a 2:1 ratio to receive ongericimab 150 mg or placebo subcutaneously every 2 weeks for 12 weeks in the double-blind treatment period, followed by 40 weeks of ongericimab treatment during the open-label period. The primary endpoint was a percentage change in LDL-C from baseline to week 12. The key secondary endpoints included percentage change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), and lipoprotein(a) [Lp(a)]. RESULTS:From February 6, 2023, to September 23, 2024, a total of 139 patients were enrolled. The least-squares (LS) mean difference between ongericimab and placebo groups in LDL-C from baseline to week 12 was -66.2 % (95 % CI: 74.2 %, -58.2 %; p < 0.0001), with reductions sustained up to week 52. Ongericimab also significantly reduced levels of non-HDL-C, ApoB, TC, and Lp(a). The overall incidence of treatment-emergent adverse events was comparable between the ongericimab and placebo groups. CONCLUSION:Ongericimab significantly reduced LDL-C as well as other atherogenic lipid levels and was well tolerated in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. CLINICAL TRIAL REGISTRATION:http://www. CLINICALTRIALS:gov; Unique Identifier: NCT05621070.

Background:Heart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure cases, yet effective treatments remain limited due to its clinical heterogeneity. This study aimed to identify distinct HFpEF phenotypes using machine-learning based algorithm and to compare treatment responses across different phenogroups. Methods:Our training cohort included 2147 hospitalized patients with HF with left ventricular ejection fraction (LVEF) ≥50% at Peking University Third Hospital (2014-2023). A two-stage DeepCluster model with a fully connected neural network was used to identify HFpEF phenogroups based on 107 demographic and clinical variables from electronic medical record (EMR). Cox proportional hazard models were used to assess patients' prognosis and treatment responses. The phenotyping model was validated internally using leave-one-out cross-validation method and externally with data from the TOPCAT clinical trial (n = 1696) and a well-characterized HFpEF patient cohort from the University of Michigan Health System (UMHS, n = 128). Findings:Three distinct HFpEF phenogroups were identified. Phenogroup 1 (n = 815) had the highest burden of metabolic comorbidities, along with left ventricular hypertrophy, and both systolic and diastolic dysfunction. Phenogroup 2 (n = 608) comprised predominantly females with atrial fibrillation and structural abnormalities in the atria and right ventricle, with mainly diastolic dysfunction. Phenogroup 3 (n = 724) included younger men with unhealthy lifestyles, higher burdens of hyperlipidemia, liver dysfunction, and relatively normal cardiac morphology and function. Overall, phenogroup 1 had the highest risk of all-cause mortality. We didn't observe significant survival benefits from major HF therapies overall. However, in phenogroup 1, post-diagnostic use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) was associated with a 55% reduced risk of HF rehospitalization (HR = 0.45, 95% CI 0.20-0.99), while angiotensin receptor-neprilysin inhibitors (ARNIs) were associated with a 66% lower risk of all-cause mortality (HR = 0.34, 95% CI 0.14-0.79). The effect of ARNI on all-cause mortality differed significantly across the three phenogroups (p for interaction = 0.048). In phenogroup 2, calcium channel blockers were associated with a lower risk of all-cause mortality (HR = 0.62, 95% CI 0.38-0.99) and HF rehospitalization (HR = 0.58, 95% CI 0.38-0.88). Furthermore, our DeepCluster model was internally validated with 96.0% consistency. In external validation in the TOPCAT and UMHS cohort, we observed consistent clinical and pathophysiologic characteristics across the three identified phenogroups. Interpretation:Machine learning-based algorithm identifies HFpEF phenogroups with distinct clinical features and treatment responses. This study suggests that SGLT2i and ARNI have a role in improving the outcomes in patients with metabolic comorbidities and both systolic and diastolic impairment, while calcium channel blockers were most likely to benefit HFpEF patients with atrial fibrillation. Future prospective studies are required to further validate these findings. Funding:This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0539000), National Natural Science Foundation of China (82300291), Beijing Nova Program (20230484275), University of Michigan Medical School (UMMS) and Peking University Health Science Center (PKUHSC) Joint Institute for Translational and Clinical Research (BMU2023JI004), Clinical Cohort Construction Program of Peking University Third Hospital (BYSYDL2023009), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-003), Peking University Shi-Ji Jin-Yuan Medical Foundation (48014Y0243), and Beijing Excellent Clinical Research Program (BRWEP2024W014090203).

BACKGROUND:Transcatheter aortic valve implantation (TAVI) in pure aortic regurgitation (AR) remains challenging because of inadequate anchoring forces. Traditional approaches, which rely solely on virtual annulus oversizing, have demonstrated limited success. We propose a novel anatomical classification system and dual-anchoring theory to optimise the TAVI strategy in patients with pure AR. AIMS:We aimed to evaluate the efficacy and safety of TAVI in pure AR using a novel anatomical classification system and dual-anchoring theory. METHODS:The AURORA trial is a prospective, multicentre, single-arm study conducted across 16 centres in China. Patients with severe pure AR underwent comprehensive anatomical assessment using multidetector computed tomography (CT). Based on the ability to provide adequate anchoring forces (≥10% of oversizing) in three zones (left ventricular outflow tract, anatomical annulus, and ascending aorta), patients were classified into 4 types. Those with anatomical types 1-3 were enrolled and underwent TAVI using the VitaFlow valve system. The primary efficacy endpoint was device success, and the primary safety endpoints included 30-day mortality and major complications. RESULTS:Among 187 screened patients, 100 patients with suitable anatomy (types 1-3) were enrolled. The mean age was 72.7±7.2 years, and the mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 9.10±5.81%. Device success was achieved in 91% of cases, with no procedural mortality. The new permanent pacemaker implantation rate was 9%. Postprocedural CT analysis in 43 patients revealed that the maximum contact forces were primarily localised between the virtual annulus and the sinotubular junction (83.7% of cases). No device failure occurred in later cases. CONCLUSIONS:The AURORA classification system shows that comprehensive anatomical assessment can lead to favourable outcomes in pure AR using conventional TAVI devices. The low pacemaker implantation rate and the absence of device failure in later cases suggest that optimal anatomical matching may be superior to aggressive oversizing strategies.

Large language models (LLMs) are rapidly advancing medical artificial intelligence, offering revolutionary changes in health care. These models excel in natural language processing (NLP), enhancing clinical support, diagnosis, treatment, and medical research. Breakthroughs, like GPT-4 and BERT (Bidirectional Encoder Representations from Transformer), demonstrate LLMs’ evolution through improved computing power and data. However, their high hardware requirements are being addressed through technological advancements. LLMs are unique in processing multimodal data, thereby improving emergency, elder care, and digital medical procedures. Challenges include ensuring their empirical reliability, addressing ethical and societal implications, especially data privacy, and mitigating biases while maintaining privacy and accountability. The paper emphasizes the need for human-centric, bias-free LLMs for personalized medicine and advocates for equitable development and access. LLMs hold promise for transformative impacts in health care.

Introduction While transcatheter aortic valve replacement (TAVR) has become a well-established standard of care for patients with symptomatic severe aortic stenosis, the optimal antithrombotic strategy post-TAVR remains a subject of debate, particularly in patients without clear indications for anticoagulation or dual antiplatelet therapy. This study aims to investigate the safety and efficacy of rivaroxaban compared with antiplatelet monotherapy in this specific patient population.Methods and analysis This study is designed as a prospective, multicentre, open-label, randomised controlled trial. A total of 454 patients, who have successfully undergone TAVR and do not have indications for long-term anticoagulation or dual antiplatelet therapy, will be consecutively enrolled from seven centres across China. Participants will be randomly assigned to receive either anticoagulation with rivaroxaban (20/15 mg) or conventional antiplatelet therapy (aspirin or clopidogrel) for 1 month. Follow-up evaluations are scheduled at 1, 3, 6 and 12 months post-procedure. After the initial 1-month antithrombotic therapy, the regimen may be adjusted by the investigator based on the patient’s clinical and imaging follow-up results. The primary endpoint is a hierarchical composite of cardiovascular death, first occurrence of myocardial infarction or stroke, first occurrence of life-threatening, disabling or major bleeding, and grade 3 or higher hypo-attenuated leaflet thickening and reduced leaflet motion at 12 months post-TAVR. The win ratio method will be employed to analyse the primary endpoint.Ethics and dissemination This trial was approved by the Ethics Committee of the Beijing AnZhen Hospital. All relevant results will be disseminated through publications in peer-reviewed journals and presentations at conferences.Trial registration number ChiCTR2400087453.

With recent progress in low-density lipoprotein cholesterol(LDL-C)management,the cornerstone of cardiovascular disease(CVD)prevention,residual cardiovascular risk remains[1].Lipoprotein(a)[Lp(a)]and inflammation are both listed as leading residual risk factors for CVD.Circulating levels of Lp(a)are primar-ily determined by genetics[2].

Background Data regarding the safety and efficacy of balloon expandable valves (BEVs) for transcatheter aortic valve replacement (TAVR) in patients with Sievers type 0 bicuspid aortic valve (BAV) stenosis remain limited. Aims This study aims to evaluate the clinical outcomes of BEVs implantation in patients with Sievers type 0 BAV. Methods We conducted a multicenter, retrospective study across 28 centers in China between October 2020 and March 2023. Consecutive patients with Sievers type 0 BAV anatomy undergoing TAVR with the Edwards Sapien 3 BEV were enrolled. Results The study included 131 patients with Sievers type 0 BAV (mean age 69.8 ± 7.5 years; 52.7 % male). The lateral-lateral type predominated (86.3 %). Calcification distribution analysis identified the superior leaflet margin as the most primary site (62.6 %). All procedures utilized femoral artery access. High implantation depth (The ratio of the aortic side of the prosthetic valve to the outflow tract side is > 8:2) was achieved in 80.2 % of cases. Prosthetic valves smaller than 26 mm were implanted in nearly half of the patients (49.6 %). The 30-day all-cause mortality rate was 0.8 %, with no incidence of disabling stroke. The overall technical success rate was 98.5 %. Conclusion The findings of this study demonstrate that BEVs implantation in patients with Sievers type 0 BAV is associated with favorable safety and efficacy outcomes. These results provide valuable insights for current TAVR practice in this specific patient population.

Regeneration therapeutic strategy by microRNAs for boosting cardiomyocyte proliferation in treating myocardial infarction (MI) has the challenges of efficient delivery, and toxicity and risk of sudden death. Herein, oxidative stress-relief microgels were developed for miR-19a/b delivery, modulation of inflammatory tissue microenvironment, promotion of cardiomyocyte proliferation, and maintenance of heart function post MI. The cholesterol-modified miR-19a/b was encapsulated into the cavity of β-cyclodextrin in selenoketal-containing microgels. The microgels could effectively scavenge typical reactive oxygen species (ROS), and down-regulate the intracellular ROS level and the levels of typical inflammatory factors. The microgels could improve the acute inflammatory microenvironment for better cardiomyocyte survival and cellular uptake of miR-19a/b, leading to significant promotion of cardiomyocyte proliferation in vivo. In the rat and minipig models of MI, the microgels most effectively inhibited the acute inflammatory response and reduced the cardiomyocytes apoptosis, resulting in a significant improvement of cardiac function and restriction of pathological remodeling post MI, and thereby best heart function revealed by echocardiography and histological analysis.

Macrophages play a crucial role in cardiac remodeling and prognosis after myocardial infarction (MI). Our previous studies have built a scalable method for preparing scaled stem cell nanovesicles (NVs) and demonstrated their remarkable reparative effects on ischemic heart disease. To further enhance the targeted reparative capabilities of the NVs toward injured myocardium, we employed a dual modification strategy involving platelet membrane coating and miR-181a-5p loading, creating a nanovesicle termed P-181-NV. This study aimed to investigate the efficacy of P-181-NV in targeted reparative interventions for damaged myocardium and to reveal the underlying mechanisms involved. After successful construction and characteristic analysis of P-181-NV, the in vivo tracking techniques demonstrated a significant enhancement in the targeting capacity of P-181-NV toward the injured myocardium. Moreover, P-181-NV showed marked improvements in cardiac function and remodeling as observed through ultrasound echocardiography and Masson's trichrome staining. Furthermore, P-181-NV significantly augmented myocardial cell viability, angiogenic potential, and the polarization ratio of the anti-inflammatory macrophages. The findings of this study underscore the pivotal role of platelet-membrane-coated and miR-181a-5p modified stem cell nanovesicles in facilitating postmyocardial infarction cardiac repair. By modulating macrophage polarization, P-181-NV offers a promising approach for enhancing the efficacy of targeted reparative interventions for damaged myocardium. These results contribute to our understanding of the potential of nanovesicles as therapeutic agents for cardiac repair and regeneration, presenting avenues for future research and clinical applications.