AIMS:We investigated the impact of aerobic exercise on clinical outcomes in patients with diabetes undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS:We analyzed a nationwide prospective population database from the Korean National Health Insurance System. We included 8225 patients with diabetes who had undergone PCI and documented their aerobic exercise habits before and after the procedure (mean interval: 2.0 years). The patients were categorized into four groups: persistent non-exercisers, new exercisers, exercise discontinuers, and exercise maintainers. The primary outcome was major adverse cardiovascular events (MACE), a composite of all-cause death, myocardial infarction, revascularization, and heart failure. We assessed the risk of clinical events using inverse probability-weighted Cox proportional hazards models. During a mean follow-up of 4.9 years, exercise maintainers, discontinuers, and new exercisers were associated with a significantly lower risk of MACE compared to non-exercisers. The lowest risk was observed in exercise maintainers (maintainers: aHR, 0.78; 95% CI: 0.71-0.86; discontinuers: aHR, 0.88; 95% CI: 0.79-0.98; new exercisers: aHR, 0.89; 95% CI: 0.80-1.00). A J-curve relationship between the amount of aerobic exercise and adverse clinical outcomes was observed, with the lowest risk identified at 1000-1499 MET-min/week. Benefits diminished with exercise intensity ≥1500 MET-min/week. CONCLUSION:Aerobic exercise maintenance after PCI was associated with a reduced risk of cardiovascular events in patients with diabetes, with a moderate amount of exercise providing maximal benefit. Therefore, aerobic exercise is advisable for patients with diabetes undergoing PCI, and the optimal exercise dosage warrants further research. LAY SUMMARY:This large-scale prospective population study, based on the Korean National Health Insurance System, demonstrated that maintaining aerobic exercise in patients with diabetes undergoing percutaneous coronary intervention is significantly associated with a lower risk of cardiovascular events.A J-curve relationship was observed between the amount of aerobic exercise and clinical outcomes, with the lowest risk observed at 1000-1499 MET-min/week for both new exercisers and the entire study population.However, exercising beyond 1500 MET-min/week offers diminishing returns, highlighting the need for balanced exercise intensity.

BACKGROUND:The long-term clinical outcomes of clopidogrel monotherapy versus aspirin monotherapy after percutaneous coronary intervention (PCI) remain uncertain. We conducted a 10-year follow-up of the HOST-EXAM trial to assess the very long-term effects of clopidogrel versus aspirin monotherapy in this setting. METHODS:In HOST-EXAM, patients who had completed dual antiplatelet therapy without clinical events for 6-18 months after PCI were randomly assigned to receive clopidogrel 75 mg once daily or aspirin 100 mg once daily. This study is an investigator-initiated 10-year extended follow-up of the HOST-EXAM trial. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium type ≥3 bleeding. The primary analysis was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov (NCT02044250) and is complete. FINDINGS:From March 26, 2014, to May 29, 2018, 5530 patients were enrolled and 5438 were randomly assigned to the aspirin group (n=2728) or the clopidogrel group (n=2710). Clinical follow-up status was ascertained on May 1, 2025, resulting in a median follow-up duration of 10·5 years (IQR 9·4-11·4) after PCI and a completion rate of 92·8%. Clopidogrel was associated with a lower rate of the primary composite endpoint than aspirin (Kaplan-Meier estimate 25·4% for the clopidogrel group vs 28·5% for the aspirin group; hazard ratio 0·86 [95% CI 0·77-0·96]; log-rank p=0·0050). Clopidogrel was also associated with a lower rate of the thrombotic endpoint (17·3% vs 20·0%; log-rank p=0·0024) and bleeding endpoint (9·1% vs 10·8%; log-rank p=0·020). All-cause mortality was similar between groups. INTERPRETATION:During 10 years of follow-up, clopidogrel monotherapy, compared with aspirin monotherapy, was associated with lower rates of the primary composite, ischaemic, and bleeding outcomes, but not all-cause mortality after PCI. These findings support consideration of clopidogrel as an alternative to aspirin for long-term antiplatelet monotherapy during the chronic maintenance phase after PCI. FUNDING:Ministry of Health & Welfare, South Korea.

BACKGROUND:The performance of third-generation drug-eluting stents with ultrathin struts and advanced polymer technology in complex percutaneous coronary intervention (PCI) remains unclear. This study compared the clinical outcomes of Coroflex ISAR polymer-free sirolimus-eluting stent (SES) and Orsiro biodegradable polymer SES, 2 third-generation drug-eluting stents, based on PCI complexity. METHODS:A post hoc analysis of the HOST-IDEA (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Coronary Intervention With Next-Generation Drug-Eluting Stent Platforms and Abbreviated Dual Antiplatelet Therapy) trial, which randomized 2013 patients undergoing PCI with Coroflex ISAR or Orsiro SES based on the duration of dual antiplatelet therapy (3 versus 12 months), was conducted herein. The baseline characteristics were balanced through propensity score matching. Complex PCI satisfied ≥1 of the following criteria: ≥3 stents implanted, ≥3 lesions or vessels treated, bifurcation PCI, total stent length of ≥60 mm, left main PCI, or heavy calcification. Target lesion failure (TLF) at 1 year, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization, was the primary end point. RESULTS:Each stent group comprised 546 patients after propensity score matching. In total, 336 and 756 patients underwent complex PCI and noncomplex PCI, respectively. Complex PCI exhibited a significant association with a higher risk of TLF compared with noncomplex PCI (5.7% versus 1.3%, P<0.01). In the complex PCI group, the TLF rate in the Coroflex ISAR SES group was significantly higher than that in the Orsiro SES group (8.9% versus 2.4%; hazard ratio [HR], 3.74 [95% CI, 1.24-11.26]; P=0.02). However, the TLF rates in the 2 stent groups in the noncomplex PCI group were comparable (1.1% versus 1.6%; HR, 0.66 [95% CI, 0.19-2.35]; P=0.53; P for interaction=0.04). Multivariable analysis identified Coroflex ISAR SES and chronic kidney disease as independent predictors of TLF. CONCLUSIONS:Orsiro SES was associated with significantly better TLF outcomes than the Coroflex ISAR SES in complex PCI; however, no significant difference was observed in noncomplex PCI.

Background Cardiovascular diseases remain the leading cause of death worldwide, accounting for approximately 19.41 million deaths annually. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for disease modeling and therapy. However, variability in differentiation efficiency and maturation state remains a significant challenge. Calcium signaling plays a pivotal role in cardiac differentiation and maturation, with mitochondrial calcium dynamics closely linked to transcriptional activation. Recent evidence suggests that closure of the mitochondrial permeability transition pore promotes cardiomyocyte differentiation by stabilizing calcium homeostasis and reducing oxidative stress. Methods We investigated the effect of 7-aminoindole (7-AI), a mitochondrial calcium uniporter inhibitor, on cardiomyocyte differentiation. Mouse embryonic stem cells and hiPSCs were treated with 7-AI during the cardiac progenitor stage (day 4). Nuclear calcium levels, Ca2+/calmodulin-dependent protein kinase (CaMK) activation, CREB phosphorylation, and cardiac marker expression were assessed. Results 7-AI increased nuclear calcium levels, activated CaMK and CREB, and upregulated cardiac-specific markers, including cTnT, α-SA, and MYH6/7. The resulting cardiomyocytes exhibited improved sarcomere organization and enhanced contractility. Moreover, CREB-deficient cells failed to exhibit these effects, confirming that CREB activation is essential for 7-AI-mediated cardiac maturation. Conclusions Collectively, our findings demonstrate that inhibition of mitochondrial calcium influx redistributes calcium to the nucleus, thereby activating the CaMK-CREB signaling axis and promoting cardiomyocyte differentiation. Targeting mitochondrial calcium handling at the cardiac progenitor stage provides a mechanistic and pharmacological approach to enhance the structural and functional maturation of cardiomyocytes for therapeutic application.

BACKGROUND AND OBJECTIVES:The HOST-EXAM Extended trial demonstrated the long-term benefits of clopidogrel over aspirin monotherapy following dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). This sub-study evaluated these therapies in patients with and without previous cardiovascular disease (CVD). METHODS:A total of 5,438 patients were randomized to aspirin (100 mg daily) or clopidogrel (75 mg daily) monotherapy. Previous CVD was defined as previous myocardial infarction, cerebrovascular accident, or peripheral artery disease, present in 1,137 patients; 4,301 had no CVD. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to ACS, and major bleeding (Bleeding Academic Research Consortium [BARC] type 3 or 5). Secondary endpoints included thrombotic and any bleeding events (BARC type ≥2). Median follow-up was 5.8 years. RESULTS:The primary endpoint occurred more frequently in patients with previous CVD than in those without (18.1% vs. 13.7%, hazard ratio [HR], 1.045; 95% confidence interval [CI], 1.037-1.054; p<0.001). Regarding the treatment estimates for the primary endpoint between those with and without previous CVD, no significant interaction was observed (CVD group: HR, 0.784; 95% CI, 0.596-1.033 and non-CVD group: HR, 0.794; 95% CI, 0.675-0.934, respectively; interaction p=0.951). For thrombotic and bleeding composite endpoints, CIs were overlapping across CVD strata, indicating no clear heterogeneity. CONCLUSIONS:Clopidogrel was associated with a lower risk of the primary endpoint versus aspirin after PCI, with no evidence of effect modification by previous CVD.

Adenylyl cyclase-associated protein1 (CAP1) is a human resistin receptor that plays a key role in mediating monocyte actions and connecting chronic inflammation to cardio-metabolic diseases. However, its role in endothelial-monocyte interactions and adenylyl cyclase (AC) regulation remains unclear. We demonstrate that CAP1 forms a complex with adenylyl cyclase 3 (AC3) and caveoline-1 (CAV1) in lipid rafts membrane of endothelial cells (ECs), a triple complex of CAP1-AC3-CAV1 that maintains AC3 in a suppressed state. Knockdown of CAP1 in ECs disturbs the formation of AC3-inhibitory triple complex, leading to AC3 activation, cAMP-PKA-CREB signaling, and NF-κB-mediated upregulation of ICAM-1 and VCAM-1 on ECs facilitating monocyte adhesion, as well as disruption of mitochondria and barrier functions of ECs. Resistin treatment to ECs recapitulates CAP1 knockdown by disassembling the AC3-inhibitory triple complex of CAP1-AC3-CAV1, leading to AC3 activation. In the in vivo experiment using CAP1+/- mice with normal monocytes introduced from WT bone marrow transplantation, CAP1 knockdown in ECs significantly increased monocyte extravasation and infiltration toward chemoattractant Carrageenan, leading to aggravation of inflammation. These findings identify CAP1 on ECs as a gate keeper of their homeostasis regulating endothelial-leukocyte interactions as well as barrier functions via mitochondria, implying new mechanism how endothelial dysfunction induce inflammatory diseases.

BACKGROUND AND OBJECTIVE:Patients with type 2 diabetes mellitus (T2DM) have an elevated risk of adverse cardiovascular events due to accelerated atherosclerosis and a higher burden of multivessel coronary artery disease (CAD). However, the optimal initial noninvasive test for CAD in T2DM remains unclear. This study compared coronary computed tomographic angiography (CCTA) vs. functional testing for the initial evaluation of suspected CAD in newly diagnosed T2DM. METHODS:Using data from the Korean National Health Insurance Service, we identified patients with newly diagnosed T2DM from 2007 to 2019. Among 93,152 patients, 34,694 underwent noninvasive testing for suspected CAD. After propensity score matching, 14,895 patients were included in each group. The primary outcome was a composite of acute myocardial infarction or death from CAD. Secondary outcomes included rates of invasive coronary angiography (ICA) and coronary revascularization. RESULTS:The primary outcome was lower in the CCTA group compared with the functional testing group (1.0% vs. 1.4%; adjusted hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.58-0.89; p=0.002). The ICA rate was also lower in the CCTA group (10.6% vs. 16.0%; adjusted HR, 0.67; 95% CI, 0.63-0.71; p<0.001). Coronary revascularization rates were similar (5.4% vs. 6.2%; adjusted HR, 0.92; 95% CI, 0.83-1.01; p=0.069). CONCLUSIONS:In patients with newly diagnosed T2DM and suspected CAD, CCTA as an initial test was associated with better cardiovascular outcomes compared with functional testing. Although these findings cannot establish causality due to residual confounding and selection bias, they remain clinically relevant.

Alzheimer's disease (AD) impacts more than half a million people worldwide, with no cure available. The regulatory approval of three anti-amyloid monoclonal antibodies (mAbs), including aducanumab, lecanemab, and donanemab, has established immunotherapy as a therapeutic approach to modify disease progression. Its multifactorial pathology, which involves amyloid-β (Aβ) plaques, tau neurofibrillary tangles, neuroinflammation, and cerebrovascular dysfunction, limits the efficacy of single-target therapies. The restricted blood-brain barrier (BBB) penetration and amyloid-related imaging abnormalities (ARIA), together with small treatment effects, demonstrate the necessity for advanced biologic therapies. Protein engineering advancements have created bispecific antibodies that bind to pathological proteins (e.g., Aβ, tau) and BBB shuttle receptors to boost brain delivery and dual therapeutic effects. This review combines existing information about antibody-based therapy in AD by focusing on bispecific antibody formats and their preclinical and clinical development, as well as biomarker-based patient selection and upcoming combination strategies. The combination of rationally designed bispecific antibodies with fluid and imaging biomarkers could show potential for overcoming existing therapeutic challenges and delivering significant clinical advantages.

Mitochondrial dysfunction is increasingly recognized as a central contributor to the pathogenesis of cardiovascular diseases (CVDs), including heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Mitochondria, known as the powerhouses of the cell, play a vital role in maintaining cardiac energy homeostasis, regulating reactive oxygen species (ROS) production and controlling cell death pathways. Dysregulated mitochondrial function results in impaired adenosine triphosphate (ATP) production, excessive ROS generation, and activation of apoptotic and necrotic pathways, collectively driving the progression of CVDs. This review provides a detailed examination of the molecular mechanisms underlying mitochondrial dysfunction in CVDs, including mutations in mitochondrial DNA (mtDNA), defects in oxidative phosphorylation (OXPHOS), and alterations in mitochondrial dynamics (fusion, fission, and mitophagy). Additionally, the role of mitochondrial dysfunction in specific cardiovascular conditions is explored, highlighting its impact on endothelial dysfunction, myocardial remodeling, and arrhythmias. Emerging therapeutic strategies targeting mitochondrial dysfunction, such as mitochondrial antioxidants, metabolic modulators, and gene therapy, are also discussed. By synthesizing recent advances in mitochondrial biology and cardiovascular research, this review aims to enhance understanding of the role of mitochondria in CVDs and identify potential therapeutic targets to improve cardiovascular outcomes.

BACKGROUND:The optimal duration of dual antiplatelet therapy (DAPT) after coronary stenting according to bleeding risk is not well established. We aimed to evaluate the optimal duration of DAPT after coronary stenting according to bleeding risk. METHODS:In this open-label, multicentre, randomised clinical trial, patients aged 19 years and older who received percutaneous coronary intervention with a drug-eluting stent at 50 high-volume cardiology centres in South Korea were stratified into high bleeding risk (HBR) or non-HBR strata, according to Academic Research Consortium for High Bleeding Risk criteria. Patients in the HBR stratum were randomly assigned (1:1) to 1-month or 3-month DAPT, and those in the non-HBR stratum were randomly assigned (1:1) to 3-month or 12-month DAPT. The three coprimary endpoints were net adverse clinical events (all-cause death, myocardial infarction, stent thrombosis, stroke, or major bleeding), major adverse cardiac or cerebral events (cardiovascular death, myocardial infarction, definite or probable stent thrombosis, or ischaemic stroke), and any actionable non-surgical bleeding at 1 year after randomisation. Primary endpoints were assessed in hierarchical order in the intention-to-treat population. This study is registered with cris.nih.go.kr, KCT0005356, and ClinicalTrials.gov, NCT05631769, and is complete. FINDINGS:From July 24, 2020, to Sept 25, 2023, 4897 patients were enrolled (1598 in the HBR stratum and 3299 in the non-HBR stratum). In the HBR stratum, 1-month compared with 3-month DAPT did not reach non-inferiority for net adverse clinical events (144 [18·4%] of 798 vs 110 [14·0%] of 800 patients; hazard ratio [HR] 1·337 [95% CI 1·043-1·713]; p=0·82 for non-inferiority). Major adverse cardiac or cerebral events occurred in 74 (9·8%) patients in the 1-month DAPT group and 44 (5·8%) in the 3-month group; bleeding occurred in 105 (13·8%) patients in the 1-month group and 122 (15·8%) in the 3-month group. In the non-HBR stratum, 3-month was non-inferior to 12-month DAPT regarding net adverse clinical events (47 [2·9%] of 1649 vs 72 [4·4%] of 1650 patients; HR 0·657 [0·455-0·949]; p<0·0001 for non-inferiority) and major adverse cardiac or cerebral events (36 [2·2%] vs 37 [2·3%]; HR 0·984 [0·622-1·558]; p=0·0082 for non-inferiority), and superior for bleeding (120 [7·4%] vs 190 [11·7%]; HR 0·631 [0·502-0·793]; p<0·0001). INTERPRETATION:In east Asian patients with HBR, 1-month DAPT did not reach non-inferiority to 3-month DAPT for net adverse clinical events. In patients without HBR, 3-month DAPT was non-inferior to 12-month DAPT regarding net adverse clinical events and major adverse cardiac or cerebral events, and superior for bleeding. FUNDING:Medtronic and Abbott.

BACKGROUND AND OBJECTIVES:An individualized approach is recommended for prescribing dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). Asian-DAPT (ADAPT) scores were developed to assess both ischemic and bleeding risks in Asian populations. This study aimed to validate the ADAPT scores for predicting ischemic and bleeding events in patients receiving DAPT. METHODS:Patients from the Multicenter Registry of KOrean PCI foR Endpoint Analysis registry were analyzed. The ADAPT scores, comprising the ischemic-ADAPT (I-ADAPT), bleeding-ADAPT (B-ADAPT), and Net-ADAPT scores, were calculated using clinical and angiographic parameters. Co-primary endpoints included ischemic outcomes (cardiovascular death, myocardial infarction, and stent thrombosis) and bleeding outcomes (major and minor bleeding). RESULTS:A total of 4,657 patients were included in analysis. The mean age was 63.8±11.1 years, and 72.3% were male. During a median follow-up of 368 days, ischemic outcomes occurred in 0.9% (43 patients), and bleeding outcomes in 0.9% (44 patients). The I-ADAPT and B-ADAPT scores had significant predictive values for ischemic outcomes (C-statistic=0.672; 95% confidence interval [CI], 0.585-0.758; p<0.001) and bleeding outcomes (C-statistic=0.715; 95% CI, 0.642-0.789; p<0.001), respectively. Regarding the Net-ADAPT score, patients with a score >0 were at a 1.7-fold higher risk of ischemic events, while those with a score of <0 had a 1.3-fold higher risk of bleeding events. CONCLUSIONS:The ADAPT scores were validated for predicting ischemic and bleeding risks in patients receiving DAPT. This scoring system can aid in evaluating both ischemic and bleeding risks for East Asians, who exhibit unique risk profiles.

BACKGROUND:Platelet reactivity (PR) and clinical risk factors are known to have impact on outcomes in patients receiving percutaneous coronary intervention (PCI). We aimed to assess the interaction of PR and clinical risk assessment using the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS2P) on adverse clinical outcomes following PCI. METHODS:From the PTRG-DES (Platelet function and Genotype-Related Long-Term Prognosis in Drug-Eluting Stent-Treated Patients With Coronary Artery Disease) registry, 11 714 patients who underwent PCI and had a mean platelet reactivity unit (PRU) value were studied. Clinical risk was stratified using the TRS2P as low clinical risk (score 0-1) or high clinical risk (≥2), and PR was stratified as high PR (HPR, PRU ≥252) and non-HPR (PRU <252). The primary outcome was a composite of cardiac death, myocardial infarction, and stent thrombosis. Landmark analysis was performed at 1- and 12 months after PCI. RESULTS:Among total population, mean PRU was 217.8±78.7, and mean TRS2P was 1.56±1.12. Over the long-term follow-up period, the primary outcome occurred in 335 (5.3%) patients. Patients with both high clinical risk and HPR had the highest incidence of the primary outcome (9.4%), followed by high clinical risk/non-HPR (5.9%), low clinical risk/HPR (4.8%), and low clinical risk/non-HPR (3.9%) (P<0.001). Compared with low clinical risk/non-HPR patients, those with both high clinical risk and HPR had a 3.25-fold higher risk of the primary outcome (hazard ratio, 3.25 [95% CI, 2.38-4.42]; P<0.001). Both PRU and TRS2P were independent predictors of the primary outcome. In landmark analyses, the risk of primary outcome within 1 month after PCI were mainly determined by PRU, while outcome beyond 1 month after PCI was mainly determined by TRS2P. CONCLUSIONS:In the secondary prevention after percutaneous coronary intervention, platelet reactivity and clinical risk had additive value in predicting outcomes. Platelet reactivity had greater relative impact within 1 month while clinical risk had greater relative impact beyond 1 month. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04734028.

Vascular dementia (VaD) represents the second-most common dementia type after Alzheimer’s disease since it results from complications of cerebrovascular disease. Mixed pathologies combining vascular and neurodegenerative processes are the rule rather than exception in elderly dementia patients. The condition known as VaD includes various types of vascular damage that affect both large and small blood vessels in the brain which results in cerebral hypoperfusion, blood–brain barrier disruption, glymphatic dysfunction, and molecular cascades causing neuronal damage. The mechanisms of VaD include endothelial dysfunction, oxidative stress, chronic neuroinflammation, impaired glymphatic clearance, white matter demyelination, and synaptic failure. The disease susceptibility of individuals depends on genetic factors which include NOTCH3 mutations and vascular risk polymorphisms. The diagnostic field uses neuroimaging tools and fluid biomarkers such as neurofilament light chain, inflammatory markers, and Aβ/tau ratios for mixed pathology. The current practice of vascular risk management combines with new therapeutic approaches that use phosphodiesterase inhibitors for cerebral perfusion and NLRP3 inflammasome inhibitors for neuroinflammation, senolytics for cellular senescence, and remyelination agents for white matter repair. However, the majority of new treatment methods remain investigational with limited Phase III data. Future medical treatment development will depend on precision medicine approaches which use biomarker-guided treatment selection and combination strategies targeting multiple pathological mechanisms.