We investigate the impact of pulse pressure on long-term outcomes for patients treated with drug-coated balloons (DCBs) or drug-eluting stents (DESs). REC-CAGEFREE I was an investigator-initiated, non-inferiority trial conducted at 43 sites in China from Feb 5, 2021, to May 1, 2022, which randomized 2272 participants to DCB or DES treatment for de novo, non-complex lesions. In this post hoc analysis, participants were stratified into three groups based on pulse pressure tertiles (< 46, 46–60, and > 60 mmHg). The primary outcome was the 2-year device-oriented composite endpoint (DoCE), including cardiovascular death, target-vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularization. 2272 participants were included in the analysis. At 2 years, DoCE occurred in 35/723 (4.9

BACKGROUND:This study aimed to evaluate the diagnostic value of the exercise stress high-frequency QRS (HFQRS) electrocardiogram in coronary microvascular dysfunction. METHODS:We consecutively enrolled patients aged 20 years or older with chest pain between January 2022 and January 2024, all of them underwent HFQRS analysis and coronary angiography. The sensitivity, specificity, and positive predictive value of HFQRS for predicting coronary microcirculatory dysfunction were calculated using coronary angiography-based microvascular resistance (caIMR) ≥25.1 as the gold standard for determining coronary microcirculatory dysfunction. We used the area under the ROC curve (AUC) to evaluate the predictive accuracy of HFQRS and the diagnostic value of exercise HFQRS for coronary microvascular dysfunction (CMVD). RESULTS:A total of 139 patients were included. We found a moderate correlation between the caIMR values and the number of positive HFQRS leads. (R = 0.757, P < .001). Multifactorial logistic regression analysis showed that the number of positive leads on the HFQRS was an independent predictor of caIMR (9.17, CI 1.02-82.73, P = .048). The area under the ROC curve for the prediction of caIMR by the number of positive HFQRS leads was 0.81 (95% CI 0.73-0.89). The sensitivity, specificity, negative predictive value, and positive predictive value of HFQRS for the prediction of coronary microcirculatory dysfunction were 0.686, 0.971, 0.986, and 0.500, respectively. CONCLUSIONS:Our study found that exercise HFQRS is an important predictor of coronary microvascular disease, that there is a correlation between the number of positive exercise HFQRS leads and CMVD, and that exercise stress HFQRS is a noninvasive and reliable indicator for the diagnosis of CMVD.

BACKGROUND:Coronary artery calcification (CAC) serves as a significant predictor of cardiovascular events; however, its underlying molecular mechanisms remain incompletely elucidated. PTBP1, an RNA-binding protein with profound regulatory functions, plays a critical role in post-transcriptional regulation. Nevertheless, its function and mechanism in vascular calcification have yet to be fully explored. METHODS:RNA sequencing analysis revealed decreased skipping of exon 4 in CARD8 within human aortic smooth muscle cells (HASMCs) calcification model. RNA immunoprecipitation and minigene reporter assays were employed to validate the effect of PTBP1 on CARD8 splicing patterns. Functional experiments were conducted to untangle the regulatory role of CARD8 in HASMCs calcification. A HASMC calcification model and a CAC mouse model were established, and techniques including RNA interference and overexpression were utilized to systematically investigate the mechanistic role of the PTBP1/CARD8 axis in CAC. RESULTS:In vitro experiments, PTBP1 directly bound to CARD8 pre-mRNA and regulated its alternative splicing process. Functional studies demonstrated that knock down of PTBP1 significantly inhibited the calcification of HASMCs, while concurrent knock down of CARD8 reversed the protective effect. Mechanistic studies revealed that CARD8 deficiency promoted NLRP3 inflammasome assembly, enhanced Caspase-1 activation and IL-1β and IL-18 secretion, thereby driving the osteogenic-like transdifferentiation and calcification process of HASMCs. Animal experiments further verified that PTBP1 knock down significantly alleviated the degree of CAC in mice, and the effect was dependent on the expression level of CARD8. CONCLUSION:This study untangles a novel mechanism whereby PTBP1 promotes CAC by regulating CARD8 alternative splicing to activate the NLRP3 inflammasome. These findings provide new insights into the pathophysiology of CAC and suggest potential targets for developing novel therapeutic strategies.

BACKGROUND:Nicorandil, an adenosine triphosphate-sensitive potassium-channel opener with nitrate-like properties, may reduce reperfusion injury and microvascular obstruction in ST-segment elevation myocardial infarction (STEMI), but large-scale randomized evidence on long-term clinical outcomes is inconclusive. OBJECTIVES:The CLEAN trial aimed to assess whether adjunctive intravenous nicorandil improves 12-month clinical outcomes in patients with STEMI undergoing primary percutaneous coronary intervention. METHODS:In this multicenter, randomized, double-blind, placebo-controlled trial conducted at 49 hospitals in China, patients aged 18 to 80 years with STEMI within 12 hours of symptom onset were randomly assigned (1:1) to receive intravenous nicorandil (6 mg bolus before reperfusion followed by 6 mg/h infusion for 48 h) or matching placebo. Oral nicorandil was prohibited during follow-up. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, or unplanned hospitalization for heart failure within 12 months. RESULTS:Between January 2021 and December 2023, 1,503 patients were enrolled and randomly assigned to nicorandil (n = 748) or placebo (n = 755). The primary composite outcome occurred in 98 patients (13.1%) in the nicorandil group (113 events over 717.2 person-years) and 99 (13.1%) in the placebo group (136 events over 710.3 person-years), with no significant difference between groups (rate ratio: 0.869; 95% CI: 0.650-1.162; P = 0.3429). Among secondary outcomes, nominal reductions were observed in cardiovascular death (1.9% vs 3.6%; HR: 0.515; 95% CI: 0.269-0.983) and target-vessel revascularization (1.1% vs 3.0%; HR: 0.322; 95% CI: 0.143-0.727), whereas rates of nonfatal myocardial infarction and unplanned hospitalization for heart failure were similar between groups. Adverse events did not differ between groups. CONCLUSIONS:In patients with STEMI undergoing primary percutaneous coronary intervention, adjunctive intravenous nicorandil did not significantly reduce the 12-month primary composite outcome. These findings do not support routine use of intravenous nicorandil in unselected patients with STEMI. (Clinical Efficacy and sAfety of Intravenous Nicorandil; NCT04665648).

BACKGROUND:Pathological cardiac remodeling is a hallmark of numerous cardiovascular diseases and develops into heart failure. As a systemic disease, effective treatments for cardiac remodeling from a tissue crosstalk perspective are still significantly unmet. METHODS:Hepatocyte-specific ChREBP (carbohydrate response element binding protein) knockout and overexpressed mice, global ApoM (apolipoprotein M) KO and adeno-associated virus-mediated hepatic ApoM knockdown or overexpressed mice, cardiomyocyte-specific ChREBP overexpressed mice, as well as S1PR1 (sphingosine-1-phosphate receptor 1) knockdown mice were used in isoproterenol- and transverse aortic constriction-induced cardiac remodeling models. RNA sequencing and LC-MS/MS analysis were used to detect changed pathways and the interaction between ChREBP and SURF4 (surfeit 4). RESULTS:We found increased ChREBP expression in the liver, but not in the heart, especially in the cytosol of hepatocytes, but not the nucleus, in isoproterenol- or transverse aortic constriction-induced mice. Hepatocyte-specific ChREBP deficiency protected against isoproterenol- and transverse aortic constriction-induced cardiac remodeling. Mechanistically, hepatocyte ChREBP deficiency increased ApoM expression in the liver and its secretion, not by transcriptional regulation of ApoM, but by increasing its secretion through the release of SURF4. ApoM overexpression in the liver or ApoM-containing HDL (high-density lipoprotein) injection can both ameliorate cardiac remodeling through the sphingosine-1-phosphate/S1PR1 pathway in the heart. CONCLUSIONS:This work identifies the hepatic ChREBP-SURF4-ApoM axis as a critical pathway in cardiac remodeling, and induction of hepatic ApoM secretion constitutes a new promising approach for treating cardiac remodeling and heart failure.

BACKGROUND:Drug-coated balloons (DCBs) are attractive for treating de novo coronary lesions, especially when involving bifurcations; however, their efficacy compared with drug-eluting stents (DES) remains uncertain. OBJECTIVES:The aim of this study was to assess the prognosis of DCBs vs DES in patients with noncomplex bifurcation and nonbifurcation lesions. METHODS:This was a prespecified subgroup analysis of the REC-CAGEFREE I (Paclitaxel-Coated Balloon for Treatment of De-Novo Non-Complex Coronary Artery Lesions) trial, which was an investigator-initiated, noninferiority trial conducted at 43 sites in China that randomized 2,272 participants to paclitaxel-coated balloons (the DCB group) or sirolimus-eluting stents (the DES group) for the treatment of de novo lesions, regardless of vessel diameter. The primary outcome was a device-oriented composite endpoint (DoCE) at 24 months. Participants were stratified according to the presence vs absence of bifurcation, and inverse probability of treatment weighting (IPTW) was performed to adjust for between-group imbalances. RESULTS:A total of 2,257 of 2,272 participants (99.3%) with available angiographic results were included. At 24 months, the DoCE had occurred in 46 of 773 patients in the bifurcation group (6.0%) and 64 of 1,484 patients in the nonbifurcation group (4.3%) (HRIPTW: 1.39; 95% CI: 0.87-2.21; P = 0.164). Of the 798 bifurcation lesions, 719 (90.1%) had DCB or DES treatment in the main vessel. A significant interaction for the DoCE was observed between bifurcation or nonbifurcation and assigned treatment (Pinteraction = 0.031). In the nonbifurcation group, the DoCE occurred in 46 of 735 patients with DCBs (6.3%) and 18 of 749 (2.4%) with DES (HRIPTW: 2.67; 95% CI: 1.64-4.33; P < 0.001); the in bifurcation group, the DoCE occurred in 26 of 394 patients with DCBs (6.7%) and 20 of 379 (5.3%) with DES (HRIPTW: 1.03; 95% CI: 0.53-2.01; P = 0.934). CONCLUSIONS:DCBs were associated with a numerically comparable risk for DoCE compared with DES in noncomplex bifurcations at 2 years. However, these findings should be interpreted as hypothesis generating only. (Paclitaxel-Coated Balloon for Treatment of De-Novo Non-Complex Coronary Artery Lesions; NCT04561739).

Myocardial infarction (MI) initiates robust inflammatory responses. While moderate inflammation facilitates the clearance of necrotic debris, sustained inflammation promotes fibrosis and exacerbates MI progression. Fungal polysaccharides have shown significant anti-inflammatory activity, but role of Morchella polysaccharide (MCP) in modulating MI-associated inflammation remains unclear. In this study we investigated whether MCP ameliorated myocardial infarction injury and elucidated the underlying mechanisms focusing on the gut microbiota and associated metabolites. MI mice were established in mice by permanent ligation of the left anterior descending (LAD) coronary artery. MCP (200, 600 mg·kg−1·d−1. i.g.) was administered daily from D7 prior-MI induction and continued for 3 or 7 days post-MI. We showed that MCP administration significantly alleviated cardiac inflammation in post-MI mice. Metabolite screening identified 12-hydroxy-eicosapentaenoic acid (12-HEPE) as a critical mediator of MCP’s anti-inflammatory effects. Intestinal metabolomic screening revealed that MCP markedly upregulated the abundance of the beneficial genus Lactobacillus. Eliminating the intestinal flora using a broad-spectrum antibiotic cocktail for 2 weeks abolished MCP-induced 12-HEPE elevation and anti-inflammation in post-MI mice. On the other hand, direct supplementation of 12-HEPE (200 µg·kg−1·d−1, i.p.) beginning 7 days prior to MI induction attenuated the inflammation. In conclusion, this study reveals that MCP attenuates post-MI inflammation by enriching beneficial gut bacteria such as Lactobacillus and increasing their metabolite 12-HEPE.

BACKGROUND AND PURPOSE:Myocardial infarction (MI) is accompanied by acute release of numerous inflammatory factors, leading to fibrosis and ultimately cardiac dysfunction. Daucosterol (DAU), a natural sterol compound, has been demonstrated to have anti-inflammatory properties and the ability to mitigate liver fibrosis. This study aims to investigate the therapeutic potential of DAU in MI and explores the underlying mechanisms. EXPERIMENTAL APPROACH:Various doses of DAU were administered to mice before MI. The cardioprotective effects of DAU were evaluated at both in vivo and in vitro levels. KEY RESULTS:In surgically-induced MI mouse models, DAU treatment reduced cardiac inflammation, attenuated myocardial fibrosis and improved cardiac function. Mechanistically, ZBTB16 expression was significantly suppressed in MI and reversed by DAU treatment by RNA-seq analysis and validation. Specifically, by restoring ZBTB16 protein levels, DAU inhibited S100A8 expression through transcriptional regulation of S100A8 by ZBTB16, thereby alleviating cardiac inflammation and fibrosis. Depletion of ZBTB16 exacerbated cardiac dysfunction in mice. CONCLUSION AND IMPLICATIONS:DAU alleviates post-infarction cardiac inflammation and fibrosis through modulation of ZBTB16/S100A8, thereby improving post-infarction cardiac remodelling and protecting heart function.

IntroductionThe pathogenesis of human heart failure is diverse, and a large number of animal models have emerged to better understand the development of heart failure in humans. Among them, there are several methods of induction in mouse heart failure models, each with its advantages and disadvantages. The use of drug induced heart failure models has greatly facilitated basic research and reduced the disadvantages of time-consuming and labor-intensive surgical modeling.MethodsIn our experiments, we used a combination of isoprenaline (ISO) and phenylephrine (PE) for modeling; we aimed to evaluate whether it is superior to conventional drug-induced models, especially those induced by isoprenaline alone. The ISO and PE were administered for 2 weeks by subcutaneous implantation with a micro-osmolar pump, and the mice were monitored dynamically for cardiac ultrasound and blood pressure.ResultsRNA sequencing of myocardial tissues after execution of mice further clarified that hypertrophy, fibrosis genes, Sympathetic nervous system (SNS), and Renin-angiotensin-aldosterone system (RAAS) pathways were upregulated.DiscussionTherefore, we conclude that the ISO/PE-induced mouse heart failure model can activate both the SNS and RAAS, through the activation of both α-adrenergic receptor (α-AR) and β-adrenergic receptor (β-AR), which is more consistent with the development of human heart failure than the ISO-induced model and is expected to be a unique and representative heart failure modeling method.

BackgroundIschemic heart disease (IHD) and type 2 diabetes mellitus (T2DM) are leading causes of disability-adjusted life years globally among adults aged 55 years and older. Although both diseases share common risk factors and pathophysiological pathways, previous research has predominantly addressed these conditions in isolation. The co-occurrence patterns and regional variations of IHD and T2DM burden remain poorly understood. We aimed to characterize the global co-occurrence patterns of IHD and T2DM from a spatial perspective and to identify the corresponding risk factors distinguishing different burden regions.MethodsUsing data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 database, we extracted age-standardized disability-adjusted life year (DALY) rates for IHD and T2DM among individuals aged 55 years and older from 204 countries and territories. Based on quartile distributions of global DALY rates for both diseases, we classified countries into four distinct burden regions: Low-Burden Regions (56 countries), T2DM-Dominant Regions (46 countries), IHD-Dominant Regions (46 countries), and Dual-Burden Regions (56 countries). We examined temporal trends from 1990-2021, computed population attributable fractions for major risk factors, and used machine learning-based SHAP (Shapley Additive Explanations) analysis to screen and quantify the effects of corresponding risk factors distinguishing regional classifications.ResultsDual-Burden Regions were distributed across multiple geographic areas including the Caribbean and Central America, Persian Gulf states, Balkan Peninsula, Southeast Asia, West Africa, Eastern Mediterranean, and Northern Europe. The spatial distribution revealed distinct geographic clustering, with higher IHD rates in Eastern Europe and Central Asia, and elevated T2DM rates in Pacific Island nations and parts of the Middle East. Countries and territories with the highest burden for both diseases included North African countries (eg, Morocco: IHD 25,193.1/100,000 and T2DM 32,197.24/100,000) and Pacific Island nations such as Fiji exhibiting IHD burden of 24,758.17 per 100,000 and T2DM burden of 32,197.24 per 100,000. Marshall Islands showed IHD burden of 25,107.72/100,000 and T2DM burden of 22,122.46/100,000, while Nauru demonstrated the highest IHD burden (39,483.92/100,000). High systolic blood pressure contributed most to IHD burden globally (49.79%), while high body-mass index dominated T2DM burden (51.89%). Environmental factors demonstrated clear regional gradients, with household air pollution ranging from 4·58% in Low-Burden to 14.43% in Dual-Burden Regions for IHD. High body-mass index contributed 51.89% to T2DM burden globally, with regional variation from 40.61% in IHD-Dominant to 51.36% in Low-Burden Regions. SHAP analysis identified sociodemographic index (SDI2021) as the primary factor distinguishing Low-Burden from Dual-Burden Regions for both IHD (mean |SHAP| = 1.245) and T2DM (mean |SHAP| = 1.317). Diet high in processed meat consistently showed strong discriminatory power across multiple regional comparisons for T2DM (SHAP values 0.923-1.721), while secondhand smoke emerged as a critical differentiator with SHAP values exceeding 1.0 across various regional distinctions. Diet low in vegetables served as a primary differentiator between Low-Burden and T2DM-Dominant Regions (mean |SHAP| = 1.188).ConclusionThe co-occurrence of IHD and T2DM exhibits pronounced global heterogeneity, with Pacific Island nations and multiple geographic regions including Gulf states, North Africa, and other areas bearing disproportionate dual-burden. Socioeconomic development level fundamentally characterizes dual-burden status, while dietary and environmental factors serve as key regional differentiators. Intervening in modifiable risk factors, particularly processed meat consumption, vegetable intake, and environmental exposures, can fundamentally reduce the global burden of these co-occurring diseases.

The increasing incidence of coronary heart disease, driven by socio-economic development and population aging, poses significant challenges. Coronary calcification, a major factor complicating percutaneous coronary interventions (PCI), often necessitates rotational atherectomy (RA) for lesion preparation. However, the impact of different RA rotational speeds on procedural and clinical outcomes remains unclear. While low-speed RA (LSRA) has been suggested to reduce intraoperative slow flow, evidence is inconsistent, and the benefits of combining LSRA with high-speed RA (HSRA) are not well established. This study aims to evaluate the effectiveness of different rotational speed protocols to guide clinical practice. This single-center, randomized controlled trial will target patients with severe coronary artery calcification scheduled for RA. An estimated 210 patients will be enrolled based on sample size calculation, randomly assigned in a 1:1:1 ratio to different rotational speed protocols using a random number table. These will include a continuous low-speed rotation (LSRA) group (140,000 rpm), a continuous high-speed rotation (HSRA) group (180,000 rpm), and a high-speed to low-speed rotation (HSRA + LSRA) group (initially 180,000 rpm, followed by 100,000 rpm). The primary endpoint is the incidence of complications during RA, including coronary artery spasm, slow/no reflow, dissection, burr entrapment, guidewire fracture, and perforation. Secondary outcomes encompass intravascular imaging (IVUS or OCT) assessments (detecting calcific ring disruption and measuring the target lesion’s minimum lumen area (MLA) and minimum lumen diameter (MLD)); in-hospital cardiac death, acute stent thrombosis, and heart failure occurrences; and the 1-year incidence of major adverse cardiovascular and cerebrovascular events (MACCE). The RACE study evaluates the impact of different rotational speeds in coronary rotational atherectomy, aiming to provide guidance for clinical practice. The findings may help standardize RA procedures and inform future clinical guidelines, improving procedural consistency and patient outcomes. ChiCTR2300076194. Registered on September 27, 2023.

ABSTRACT Intravascular lithotripsy (IVL) is a promising therapy for calcified coronary lesions. This study evaluated the safety and effectiveness of a novel IVL system. The COronary CAlcified Lesion Lithotripsy Procedure (COCALP) study (No. ChiCTR2300073280) was a prospective, multicenter, single‐arm trial involving 266 patients with severely calcified coronary lesions. The primary endpoint was procedural success, defined as successful stent implantation with ≤30% residual stenosis and no in‐hospital major adverse cardiovascular events (MACE). In a subgroup, calcium morphology was evaluated by optical coherence tomography (OCT) assessment. A total of 266 patients were included. The procedural success rate was 97.4% (95% confidence interval [CI]: 0.947–0.989), with the lower limit of the CI exceeding the prespecified performance goal (p < 0.001). No MACE occurred intraoperatively. During hospitalization, MACE occurred in five patients (1.9%), all of which were myocardial infarctions. MACE rates at 1 and 6 months were 2.3 and 3.4%, respectively. In the OCT subgroup (n = 76), IVL induced a 76.8% rate of calcification fracture. The minimal lumen area increased from 1.77 ± 0.72 to 2.59 ± 1.11 mm2 following IVL (p < 0.001), and further expanded to 5.22 ± 1.69 mm2 poststenting (p < 0.001). The novel IVL system demonstrated high effectiveness and safety, supporting its use for treating severely calcified coronary lesions and enhancing stent implantation success.

Hypercholesterolemia is a significant risk factor for the development of atherosclerosis. 2',3',5'-Tri-O-acetyl-N 6-(3-hydroxyphenyl) adenosine (IMM-H007), a novel AMPK agonist, has shown protective effects in metabolic diseases. However, its impact on cholesterol and triglyceride metabolism in hypercholesterolemia remains unclear. In this study, we aimed to elucidate the effects and specific mechanisms by which IMM-H007 regulates cholesterol and triglyceride metabolism. To achieve this goal, we used Apoe -/- and Ldlr -/- mice to establish a hypercholesterolemia/atherosclerosis model. Additionally, hepatocyte-specific Ampka1/2 knockout mice were subjected to a 5-week high-cholesterol diet to establish hypercholesterolemia, while atherosclerosis was induced via AAV-PCSK9 injection combined with a 16-week high-cholesterol diet. Our results demonstrated that IMM-H007 improved cholesterol and triglyceride metabolism in mice with hypercholesterolemia. Mechanistically, IMM-H007 modulated the AMPKα1/2-LDLR signaling pathway, increasing cholesterol uptake in the liver. Furthermore, IMM-H007 activated the AMPKα1-FXR pathway, promoting the conversion of hepatic cholesterol to bile acids. Additionally, IMM-H007 prevented hepatic steatosis by activating the AMPKα1/2-ATGL pathway. In conclusion, our study suggests that IMM-H007 is a promising therapeutic agent for improving hypercholesterolemia and atherosclerosis through the activation of AMPKα.

OBJECTIVES:To investigate whether a less intense antiplatelet regimen could be used for people receiving drug coated balloons. DESIGN:Multicentre, randomised, open label, assessor blind, non-inferiority trial (REC-CAGEFREE II). SETTING:41 hospitals in China between 27 November 2021 and 21 January 2023. PARTICIPANTS:1948 adults (18-80 years) with acute coronary syndrome who received treatment exclusively with paclitaxel-coated balloons according to the international drug coated balloon consensus. INTERVENTIONS:Participants were randomly assigned (1:1) to either the stepwise dual antiplatelet therapy (DAPT) de-escalation group (n=975) consisting of aspirin plus ticagrelor for one month, followed by five months of ticagrelor monotherapy, and then six months of aspirin monotherapy, or to the standard DAPT group (n=973) consisting of aspirin plus ticagrelor for 12 months. MAIN OUTCOME MEASURES:The primary endpoint was net adverse clinical events (all cause death, stroke, myocardial infarction, revascularisation, and Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding) at 12 months in the intention-to-treat population. Non-inferiority was established if the upper limit of the one sided 95% confidence interval (CI) for the absolute risk difference was smaller than 3.2%. RESULTS:The mean age of participants was 59.2 years, 74.9% were men, 30.5% had diabetes, and 20.6% were at high bleeding risk. 60.9% of treated lesions were in small vessels, and 17.8% were in-stent restenosis. The mean drug coated balloon diameter was 2.72 mm (standard deviation 0.49). At 12 months, the primary endpoint occurred in 87 (8.9%) participants in the stepwise de-escalation group and 84 (8.6%) in the standard group (difference 0.36%; upper boundary of the one sided 95% CI 2.47%; Pnon-inferiority=0.013). In the stepwise de-escalation versus standard groups, BARC type 3 or 5 bleeding occurred in four versus 16 participants (0.4% v 1.6%, difference -1.19% (95% CI -2.07% to -0.31%), P=0.008), and all cause death, stroke, myocardial infarction, and revascularisation occurred in 84 versus 74 participants (8.6% v 7.6%, difference 1.05% (95% CI -1.37% to 3.47%), P=0.396). Treated as having hierarchical clinical importance by the win ratio method, more wins were noted with the stepwise de-escalation group (14.4% wins) compared with the standard group (10.1% wins) for the predefined hierarchical composite endpoint of all cause death, stroke, myocardial infarction, BARC type 3 bleeding, revascularisation, and BARC type 2 bleeding (win ratio 1.43 (95% CI 1.12 to 1.83), P=0.004). Results from the per-protocol and the intention-to-treat analysis were similar. CONCLUSIONS:Among participants with acute coronary syndrome who could be treated by drug coated balloons exclusively, a stepwise DAPT de-escalation was non-inferior to 12 month DAPT for net adverse clinical events. TRIAL REGISTRATION:Clinicaltrials.gov NCT04971356.

BACKGROUND:Circular RNAs derived from both nuclear and mitochondrial genomes are identified in animal cells. Mitochondria-encoded circular RNAs (mecciRNAs) are attracting more attention, and several members of mecciRNAs have already been recognized in regulating mitochondrial functions. Mitochondria dysfunctions are well-known to participate in heart failure (HF). This study was designed to investigate the RNA metabolism of mecciRNAs and the relevant roles and potential application of mecciRNAs in HF. METHODS:Compared with highly stable nuclear genome-encoded circular RNAs, the fast degradation feature of mecciRNAs is identified by RNA sequencing and a series of molecular, biochemical, and cellular experiments. The substantial protective effects of in vitro synthesized mecciRNAs were tested in both doxorubicin- and pressure overload-induced mouse models of HF. RESULTS:We discover that mecciRNAs are promptly degraded by an animal-conserved complex of helicase SUPV3L1 (suppressor of var1, 3-like protein 1) and endoribonuclease ELAC2 (elaC ribonuclease Z 2). MecciRNA degradation complex and mecciRNAs interact with mitochondrial permeability transition pore and its regulators including TRAP1 (TNF receptor-associated protein 1) and CypD (cyclophilin D). MecciRNAs regulate mitochondrial levels of TRAP1 and CypD to modulate the opening of mitochondrial permeability transition pore and the release of mitochondrial reactive oxygen species. Exogenously applied mecciRNAs interact with cytosolic TRAP1 and increase mitochondrial levels of TRAP1, and lead to a more closed state of mitochondrial permeability transition pore to constrain deleterious reactive oxygen species release. HF conditions lead to stimulated mecciRNA degradation, and administration of in vitro synthesized mecciRNAs exhibits substantial protective effects in both doxorubicin- and pressure overload-induced mouse models of HF. CONCLUSIONS:This study demonstrates the fast degradation of mecciRNAs and the associated regulations of mitochondrial reactive oxygen species release of mitochondrial permeability transition pore by mecciRNAs. HF conditions lead to dysregulated mecciRNA degradation, and exogenous mecciRNAs demonstrate treatment potential in mouse models of HF.

BACKGROUND:The use of drug-coated balloons is a well-established strategy for the management of coronary vessels. However, head-to-head comparisons of sirolimus-coated balloons (SCBs) and paclitaxel-coated balloons (PCBs) for treating in-stent restenosis (ISR) are currently limited. OBJECTIVES:The aim of this randomized, controlled trial (SIBLINT-ISR [Sirolimus-Coated Balloon Versus Paclitaxel-Coated Balloon for the Treatment of Coronary In-Stent Restenosis]) was to compare a novel SCB with a PCB for the treatment of ISR. METHODS:In this prospective, assessor-blinded, controlled trial, patients with eligible ISR lesions were randomized 1:1 to treatment with either an SCB (SeQuent SCB, B. Braun Melsungen; 4 μg/mm2) or a PCB (SeQuent Please NEO, B. Braun Melsungen; 3 μg/mm2). The primary endpoint was noninferiority for 9-month angiographic in-segment late lumen loss (LLL). The main secondary endpoints were procedural success, target lesion restenosis rate, and target lesion failure (cardiac death, target vessel myocardial infarction, or revascularization) at 12 months. RESULTS:A total of 258 patients with 285 lesions at 16 sites were randomly assigned to the SCB (n = 130) and PCB (n = 128) groups. At 9 months, the difference in the primary endpoint of in-segment LLL between the SCB group (0.37 ± 0.48 mm) and the PCB group (0.30 ± 0.38 mm) was 0.07 mm (95% CI: -0.05 to 0.19 mm), demonstrating noninferiority of the SCB to the PCB in terms of in-segment LLL, with a noninferiority margin of 0.20 mm (P for noninferiority < 0.0001). There were no significant differences in 12-month clinical outcomes between the SCB and PCB groups. CONCLUSIONS:In this study, a novel SCB was found to be noninferior to a PCB in terms of in-segment LLL at 9 months in treating patients with ISR. (Sirolimus-Coated Balloon Versus Paclitaxel-Coated Balloon for the Treatment of Coronary In-Stent Restenosis [SIBLINT ISR]; NCT04240444).

AIMS:Atherosclerotic cardiovascular disease (ASCVD) remains the primary global cause of mortality and disability. Older adults (≥60 years) represent a vulnerable population with elevated cardiovascular risk, establishing ASCVD quality of care (QoC) as a critical global health priority. This study aimed to investigate temporal trends in the global ASCVD QoC for adults aged ≥60 years. METHODS AND RESULTS:This analysis utilized Global Burden of Disease 2021 data across 204 countries and territories. The age-standardized quality of care index (QCI) assessed ASCVD management, with concentration indices and estimated annual percentage change (EAPC) quantifying inequalities and trends. From 1990 to 2021, global QCI for ischemic heart disease (IHD), ischemic stroke (IS), and peripheral artery disease (PAD) increased from 68.65, 63.73, 85.26 to 79.83, 75.34, 88.06. Gender disparity ratios (GDR) of QCI revealed divergent trends: IHD GDR decreased (1.10-1.08), IS GDR increased (1.11-1.12), and PAD GDR remained stable (1.00). Pronounced socio-demographic index (SDI) gradients emerged. High/high-middle SDI regions demonstrated substantially faster QCI growth for IHD/IS, while lower SDI regions showed markedly slower improvement. For PAD, high-middle SDI regions achieved the most rapid QCI gains, whereas low-middle/low SDI regions experienced declines. CONCLUSIONS:Global ASCVD QCI improvements occurred among older adults over the past three decades. However, significant disparities persist across geographic regions, SDI strata, and gender groups. These findings necessitate targeted interventions and inform policy strategies to accelerate progress toward sustainable development goals.