Sirolimus-eluting iron bioresorbable scaffold versus cobalt-chromium everolimus-eluting stents in patients with coronary artery disease: Rationale and design of the IRONMAN-II trial.

BACKGROUND: The previous first-in-human study established the preliminary safety and effectiveness of the novel thin-strut iron bioresorbable scaffold (IBS). The current study aims to directly compare the imaging and physiological efficacy, and clinical outcomes of IBS with contemporary metallic drug-eluting stents (DES). METHODS: A total of 518 patients were randomly allocated to treatment with IBS (257 patients) or metallic DES (261 patients) from 36 centers in China. The study is powered to test noninferiority of the IBS compared with the metallic everolimus-eluting stent in terms of the primary endpoint of in-segment late lumen loss at 2 years, and major secondary endpoints including 2-year quantitative flow ratio and cross-sectional mean flow area measured by optical coherence tomography (OCT) (limited to the OCT subgroup, 25 patients in each group). CONCLUSION: This will be the first powered randomized trial investigating the safety and efficacy of the novel thin-strut IBS compared to a contemporary metallic DES. The findings will provide valuable evidence for future research of this kind and the application of metallic bioresorbable scaffolds.

Biolimus-coated versus paclitaxel-coated balloons for coronary in-stent restenosis (BIO ASCEND ISR): a randomised, non-inferiority trial.

BACKGROUND: The treatment of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation remains challenging in current clinical practice. AIMS: The study was conducted to investigate a novel biolimus-coated balloon (BCB) for the treatment of coronary DES-ISR compared with the best-investigated paclitaxel-coated balloon (PCB). METHODS: This was a prospective, multicentre, randomised, non-inferiority trial comparing a novel BCB with a clinically proven PCB for coronary DES-ISR. The primary endpoint was in-segment late lumen loss (LLL) at 9 months assessed by an independent core laboratory. Baseline and follow-up optical coherence tomography were performed in a prespecified subgroup of patients. RESULTS: A total of 280 patients at 17 centres were randomised to treatment with a BCB (n=140) versus a PCB (n=140). At 9 months, LLL in the BCB group was 0.23±0.37 mm compared to 0.25±0.35 mm in the PCB group; the mean difference between the groups was -0.02 (95% confidence interval [CI]: -0.12 to 0.07) mm; p-value for non-inferiority<0.0001. Similar clinical outcomes were also observed for both groups at 12 months. In the optical coherence tomography substudy, the neointimal area at 9 months was 2.32±1.04 mm2 in the BCB group compared to 2.37±0.93 mm2 in the PCB group; the mean difference between the groups was -0.09 (95% CI: -0.94 to 0.76) mm2; p=non-significant. CONCLUSIONS: This head-to-head comparison of a novel BCB shows similar angiographic outcomes in the treatment of coronary DES-ISR compared with a clinically proven PCB. (ClinicalTrials.gov: NCT04733443).

Proline metabolic reprogramming modulates cardiac remodeling induced by pressure overload in the heart.

Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed after TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. In addition, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance. Our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis during cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.

Nanosponge for Iron Chelation and Efflux: A Ferroptosis-Inhibiting Approach for Myocardial Infarction Therapy.

Myocardial infarction (MI), a consequence of coronary artery occlusion, triggers the degradation of ferritin, resulting in elevated levels of free iron in the heart and thereby inducing ferroptosis. Targeting myocardial ferroptosis through the chelation of excess iron has therapeutic potential for MI treatment. However, iron chelation in post ischemic injury areas using conventional iron-specific chelators is hindered by ineffective myocardial intracellular chelation, rapid clearance, and high systemic toxicity. A chitosan-desferrioxamine nanosponge (CDNS) is designed by co-crosslinking chitosan and deferoxamine through noncovalent gelation to address these challenges. This architecture facilitates direct iron chelation regardless of deferoxamine (DFO) release due to its sponge-like porous hydrogel structure. Upon cellular internalization, CDNS can effectively chelate cellular iron and facilitate the efflux of captured iron, thereby inhibiting ferroptosis and associated oxidative stress and lipid peroxidation. In MI mouse models, myocardial injection of CDNS promotes sustainable retention and the suppression of ferroptosis in the infarcted heart. This intervention improves cardiac function and alleviates adverse cardiac remodeling post-MI, leading to decreased oxidative stress and the promotion of angiogenesis due to ferroptosis inhibition by CDNS in the infarcted heart. This study reveals a nanosponge-based nanomedicine targeting myocardial ferroptosis with efficient iron chelation and efflux, offering a promising MI treatment.

UV-Triggered Hydrogel Coating of the Double Network Polyelectrolytes for Enhanced Endothelialization.

The left atrial appendage (LAA) occluder is an important medical device for closing the LAA and preventing stroke. The device-related thrombus (DRT) prevents the implantation of the occluder in exerting the desired therapeutic effect, which is primarily caused by the delayed endothelialization of the occluder. Functional coatings are an effective strategy for accelerating the endothelialization of occluders. However, the occluder surface area is particularly large and structurally complex, and the device is subjected to a large shear friction in the sheath during implantation, which poses a significant challenge to the coating. Herein, a hydrogel coating by the in situ UV-triggered polymerization of double-network polyelectrolytes is reported. The findings reveal that the double network and electrostatic interactions between the networks resulted in excellent mechanical properties of the hydrogel coating. The sulfonate and Arg-Gly-Asp (RGD) groups in the coating promoted hemocompatibility and endothelial growth of the occluder, respectively. The coating significantly accelerated the endothelialization of the LAA occluder in a canine model is further demonstrated. This study has potential clinical benefits in reducing both the incidence of DRT and the postoperative anticoagulant course for LAA closure.

Sex Differences in Clinical Outcomes Associated With Quantitative Flow Ratio-Guided Percutaneous Coronary Intervention.

Background: FAVOR III China (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease) reported improved clinical outcomes in quantitative flow ratio (QFR) relative to angiography-guided percutaneous coronary intervention (PCI), but the clinical impact of QFR-guided PCI according to sex remains unknown. Objectives: The authors sought to compare sex differences in the 2-year clinical benefits of a QFR-guided PCI strategy and to evaluate the differences in outcomes between men and women undergoing contemporary PCI. Methods: This study involved a prespecified subgroup analysis of the FAVOR III China trial, in which women and men were randomized to a QFR-guided strategy or a standard angiography-guided strategy. Sex differences in clinical benefit of the QFR guidance were analyzed for major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction, or ischemia-driven revascularization within 2 years. Results: A total of 1,126 women and 2,699 men were eligible and the occurrence of 2-year MACE was similar between women and men (10.3% vs 10.5%; P = 0.96). Compared with an angiography-guided strategy, a QFR-guided strategy resulted in a 7.9% and 9.7% reduction in PCI rates in men and women, respectively. A QFR-guided strategy resulted in similar relative risk reductions for 2-year MACE in women (8.0% vs 12.7%; HR: 0.62; 95% CI: 0.42-0.90) and men (8.7% vs 12.4%; HR: 0.69; 95% CI: 0.54-0.87) (Pinteraction = 0.61). Furthermore, QFR values were not significantly different between men and women with various angiographic stenosis categories. Conclusions: A QFR-guided PCI strategy resulted in improved MACE in both men and women at 2 years compared with an angiography-guided PCI strategy. The FAVOR III China Study [FAVOR III China]; (NCT03656848).

Aiming at early-stage vulnerable plaques: A nanoplatform with dual-mode imaging and lipid-inflammation integrated regulation for atherosclerotic theranostics.

The vulnerable plaques in atherosclerosis can cause severe outcome with great danger of acute cardiovascular events. Thus, timely diagnosis and treatment of vulnerable plaques in early stage can effectively benefit the clinical management of atherosclerosis. In this work, a targeting theranostic strategy on early-stage vulnerable plaques in atherosclerosis is realized by a LAID nanoplatform with X-CT and fluorescent dual-mode imaging and lipid-inflammation integrated regulation abilities. The iodinated contrast agents (ICA), phenylboronic acid modified astaxanthin and oxidized-dextran (oxDEX) jointly construct the nanoparticles loaded with the lipid-specific probe LFP. LAID indicates an active targeting to plaques along with the dual-responsive disassembly in oxidative stress and acidic microenvironment of atherosclerosis. The X-CT signals of ICA execute the location of early-stage plaques, while the LFP combines with lipid cores and realizes the recognition of vulnerable plaques. Meanwhile, the treatment based on astaxanthin is performed for restraining the progression of plaques. Transcriptome sequencing suggests that LAID can inhibit the lipid uptake and block NF-κB pathway, which synergistically demonstrates a lipid-inflammation integrated regulation to suppression the plaques growing. The in vivo investigations suggest that LAID delivers a favorable theranostics to the early-stage vulnerable plaques, which provides an impressive prospect for reducing the adverse prognosis of atherosclerosis.

ROS-responsive & scavenging NO nanomedicine for vascular diseases treatment by inhibiting endoplasmic reticulum stress and improving NO bioavailability.

Vascular diseases seriously threaten human life and health. Exogenous delivery of nitric oxide (NO) represents an effective approach for maintaining vascular homeostasis during pathological events. However, the overproduction of reactive oxygen species (ROS) at vascular injury sites would react with NO to produce damaging peroxynitrite (ONOO-) species and limit the therapeutic effect of NO. Hence, we design a ROS-responsive NO nanomedicine (t-PBA&NO NP) with ROS scavenging ability to solve the dilemma of NO-based therapy. t-PBA&NO NP targets NO and anti-oxidant ethyl caffeate (ECA) to the injury sites via collagen IV homing peptide. The ROS-triggered ROS depletion and ECA release potently alleviate local oxidative stress via ROS scavenging, endoplasmic reticulum and mitochondrial regulation. It subsequently maximizes vascular modulation effects of NO, without production of harmful compounds, reactive nitrogen species (RNS). Therefore, it significantly increases competitiveness of human umbilical vein endothelial cells (HUVECs) over human aortic smooth muscle cells (HASMCs) both in vitro and in vivo. The strategy proved effective in inducing faster re-endothelialization, inhibiting neointimal formation and restoring vascular homeostasis. The synergy between ROS depletion and NO therapy served as a new inspiration for the treatment of cardiovascular diseases and other ROS-associated illnesses.

Immune patterns of cuproptosis in ischemic heart failure: A transcriptome analysis.

Cuproptosis is a recently discovered programmed cell death pattern that affects the tricarboxylic acid (TCA) cycle by disrupting the lipoylation of pyruvate dehydrogenase (PDH) complex components. However, the role of cuproptosis in the progression of ischemic heart failure (IHF) has not been investigated. In this study, we investigated the expression of 10 cuproptosis-related genes in samples from both healthy individuals and those with IHF. Utilizing these differential gene expressions, we developed a risk prediction model that effectively distinguished healthy and IHF samples. Furthermore, we conducted a comprehensive evaluation of the association between cuproptosis and the immune microenvironment in IHF, encompassing infiltrated immunocytes, immune reaction gene-sets and human leukocyte antigen (HLA) genes. Moreover, we identified two different cuproptosis-mediated expression patterns in IHF and explored the immune characteristics associated with each pattern. In conclusion, this study elucidates the significant influence of cuproptosis on the immune microenvironment in ischemic heart failure (IHF), providing valuable insights for future mechanistic research exploring the association between cuproptosis and IHF.

Efficacy and safety of olmesartan medoxomil­amlodipine besylate tablets (Sevikar®) in older patients with essential hypertension: Subgroup analysis from the Sevikar study.

Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.

Effects of coronary artery disease in patients with permanent left bundle branch area pacing: A retrospective study.

Aims: Myocardial ischemia can affect traditional right ventricular (RV) pacing parameters, but it is unclear whether coronary artery disease (CAD) impact the pacing parameters and electrophysiological characteristics of left bundle branch area pacing (LBBaP) as a physiological pacing representative. Methods: Patients who underwent coronary angiography (CAG) after/before the LBBaP procedure and underwent percutaneous coronary intervention after LBBaP procedure were divided into CAD group and Non-CAD group according to visual CAG. Pacing parameters and electrophysiological characteristics were recorded at LBBaP implantation. Multivariate logistic regression analysis was implemented to evaluate the association between CAD and higher capture threshold. Sensitivity analyses were conducted to verify result stability. Results: A total of 176 patients met inclusion criteria (115 Non-CAD patients and 61 CAD patients) with a mean age of 71.1 ± 9.0 years. Compared with the Non-CAD patients, CAD patients had the higher capture threshold (0.67 ± 0.22 V vs. 0.82 ± 0.28 V, P < 0.001) and lower R-wave amplitude (12.5 ± 4.8 mV vs. 10.1 ± 2.7 mV, P = 0.001). Moreover, CAD was independently associated with higher capture threshold (adjusted Odds ratio (OR) 3.418, 95% confidence interval (CI): 1.621-7.206, P = 0.001), which was further validated through sensitivity analyses. Conclusion: Patients without CAD might have safer pacing parameters in the LBBaP procedure. Besides, CAD might be the risk factor of capture threshold increase during permanent LBBaP implantation.

Effectiveness and safety of ivabradine in Chinese patients with chronic heart failure: an observational study.

AIMS: A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well-known HR-lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. METHODS AND RESULTS: This multicentre, single-arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment-emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor-neprilysin inhibitor (ARNI) or beta-blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P < 0.001). At Month 6, improvements in the KCCQ CSS and OSS of ≥5 points were observed in 72.1% and 74.1% of patients, respectively (both P < 0.001). Left ventricular ejection fraction increased by 12.1 ± 11.6 (P < 0.001), and 66.7% of patients showed improvement in NYHA class (P < 0.001). At Month 6, the overall proportion of patients in NYHA Classes III and IV was reduced to 13.5% and 2.1%, respectively. Serum brain natriuretic peptide (BNP) and N-terminal pro-BNP changed by -331.9 ng/L (-1238.6, -134.0) and -1113.8 ng/L (-2202.0, -297.2), respectively (P < 0.001). HR reductions and improvements in NYHA and KCCQ scores with ivabradine were similar with and without use of ARNIs or beta-blockers. Of 498 TEAEs in 296 patients (29.5%), 73 TEAEs in 55 patients (5.5%) were considered related to ivabradine [most frequent sinus bradycardia (n = 7) and photopsia (n = 7)]. TEAEs were reported in a similar number of patients in ARNI and beta-blocker subgroups (21.9-35.6%). CONCLUSIONS: Ivabradine treatment reduced HR and improved cardiac function and health-related quality of life in Chinese patients with chronic HF. Benefits were seen irrespective of whether or not patients were also taking ARNIs or beta-blockers. Treatment was well tolerated with a similar profile to previous ivabradine studies.

Intracardiac echocardiography guided electrified J-wire trans-septal puncture: A prospective randomized controlled trial.

BACKGROUND: Application of electrocautery to a J-wire is used to perform transseptal puncture (TSP), but with limited evidence supporting safety and efficacy. We conducted a prospective randomized controlled trial to evaluate the safety and efficacy of this technique. METHODS: Two hundred consecutive patients were randomized in a 1:1 fashion to either the ICE-guided electrified J-wire TSP group or a conventional Brockenbrough (BRK) needle TSP group. The TSP was performed with a 0.032″ guidewire under 20 W, "coag" mode and was compared to TSP using the BRK needle. The primary safety endpoints were complications related to TSP. The primary efficacy endpoints included the TSP success rate, the total TSP time, and the total procedure time. RESULTS: All patients complete the procedure safely. The electrified J-wire TSP group had a significantly shorter TSP time than BRK needle TSP group. The total procedure time, number of TSP attempts required to achieve successful LA access, width of the intra-atrial shunt at the end of ablation were similar between the two groups. The incidence of new cerebral infarction detected by MRI were similar between the two groups (3/32 patients in the J-wire TSP group and 2/26 patients in conventional BRK TSP group, p = .82). And no difference in the incidence of residual intra-atrial shunt (4.3% vs. 6%, p = .654) during the 3-month's follow up. CONCLUSION: Using an electrified J-wire for TSP under the guidance of ICE appears to be as safe as and more efficient than conventional BRK needle TSP, which may be especially useful in the era of non-fluoroscopy AF ablation.

Efficacy and safety of olmesartan medoxomil-amlodipine besylate tablet in Chinese patients with essential hypertension: A prospective, single-arm, multi-center, real-world study.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.

Left bundle branch pacing better preserves ventricular mechanical synchrony than right ventricular pacing: a two-centre study.

AIMS: Left bundle branch pacing (LBBP) has been shown to better maintain electrical synchrony compared with right ventricular pacing (RVP), but little is known about its impact on mechanical synchrony. This study investigates whether LBBP better preserves left ventricular (LV) mechanical synchronicity and function compared with RVP. METHODS AND RESULTS: Sixty patients with pacing indication for bradycardia were included: LBBP (n = 31) and RVP (n = 29). Echocardiography was performed before and shortly after pacemaker implantation and at 1-year follow-up. The lateral wall-septal wall (LW-SW) work difference was used as a measure of mechanical dyssynchrony. Septal flash, apical rocking, and septal strain patterns were also assessed. At baseline, LW-SW work difference was small and similar in two groups. SW was markedly decreased, while LW work remained mostly unchanged in RVP, resulting in a larger LW-SW work difference compared with LBBP (1253 ± 687 mmHg·% vs. 439 ± 408 mmHg·%, P < 0.01) at last follow-up. In addition, RVP more often induced septal flash or apical rocking and resulted in more advanced strain patterns compared with LBBP. At 1 year follow-up, LV ejection fraction (EF) and global longitudinal strain (GLS) were more decreased in RVP compared with LBBP (ΔLVEF: -7.4 ± 7.0% vs. 0.3 ± 4.1%; ΔLVGLS: -4.8 ± 4.0% vs. -1.4 ± 2.5%, both P < 0.01). In addition, ΔLW-SW work difference was independently correlated with LV adverse remodelling (r = 0.42, P < 0.01) and LV dysfunction (ΔLVEF: r = -0.61, P < 0.01 and ΔLVGLS: r = -0.38, P = 0.02). CONCLUSION: LBBP causes less LV mechanical dyssynchrony than RVP as it preserves a more physiologic electrical conduction. As a consequence, LBBP appears to preserve LV function better than RVP.

Adventitial delivery of miR-145 to treat intimal hyperplasia post vascular injuries through injectable and in-situ self-assembling peptide hydrogels.

Intimal hyperplasia is a common lesion that can be observed in diverse vascular diseases. Drug-eluting stents and drug-coated balloons, which can release anti-proliferative agents to inhibit smooth muscle cell (SMC) proliferation, are developed to prevent intimal hyperplasia. However, these intervention devices still cannot achieve satisfactory clinical outcomes. In contrast to endovascular drug delivery, vascular adventitial drug delivery is a new strategy. To develop a vascular adventitial drug delivery system to treat intimal hyperplasia post vascular injuries, we loaded miR-145-5p-agomir (miR-145) into an injectable and in-situ self-assembling RAD peptide hydrogel. In vitro data showed that the miR-145 could be well incorporated into the RAD peptide hydrogels and released in a slow and controlled manner. The released miR-145 could transfect SMCs successfully, and the transfected SMCs exhibited a reduced migration capacity and higher expressions of SMC contractile biomarkers as compared to the non-transfected SMCs. In vivo data showed that the retention of the miR-145 was greatly elongated by the RAD peptide hydrogels. In addition, the application of the miR-145-loaded RAD peptide hydrogels surrounding injured arteries decreased the proliferative SMCs, promoted the regeneration of endothelium, reduced the macrophage infiltration, inhibited the neointimal formation and prevented adverse ECM remodeling via downregulation of KLF4 expression. The RAD peptide hydrogels loaded with miR-145 can successfully inhibit intimal hyperplasia after vascular injuries and thus hold great potential as an innovative extravascular drug delivery approach to treat vascular diseases. STATEMENT OF SIGNIFICANCE: Intimal hyperplasia is a common lesion that can be observed in diverse vascular diseases. Drug-eluting stents and drug-coated balloons, which can release anti-proliferative agents to inhibit smooth muscle cell (SMC) proliferation, are developed to prevent intimal hyperplasia. However, these intervention devices still cannot achieve satisfactory clinical outcomes. In contrast to endovascular drug delivery, vascular adventitial drug delivery is a new strategy. Our work here demonstrates that the RAD peptide hydrogels loaded with miR-145-5p-agomir (miR-145) can successfully reverse intimal hyperplasia after vascular injuries and thus hold great potential as an innovative vascular adventitial drug delivery approach to treat vascular diseases. Our work proposes a possible paradigm shift from endovascular drug delivery to extravascular drug delivery for vascular disorder treatment.

Targeting Nanoplatform for Atherosclerosis Inhibition and Degradation via a Dual-Track Reverse Cholesterol Transport Strategy.

As a main cause of serious cardiovascular diseases, atherosclerosis is characterized by deposited lipid and cholesterol crystals (CCs), which is considered as a great challenge to the current treatments. In this study, a dual-track reverse cholesterol transport strategy is used to overcome the cumulative CCs in the atherosclerotic lesions via a targeting nanoplatform named as LPLCH. Endowed with the active targeting ability to the plaques, the nanoparticles can be efficiently internalized and achieve a pH-triggered charge conversion for the escape from lysosomes. During this procedure, the liver X receptor (LXR) agonists loaded in nanoparticles are replaced by the deposited lysosomal CCs, leading to a LXR mediated up-regulation of ATP-binding cassette transporte ABCA1/G1 with the local CCs carrying at the same time. Thus, the cumulative CCs are removed in a dual-track way of ABCA1/G1 mediated efflux and nanoparticle-based carrying. The in vivo investigations indicate that LPLCH exhibits a favorable inhibition on the plaque progression and a further reversal of formed lesions when under a healthy diet. And the RNA-sequencing suggests that the cholesterol transport also synergistically activates the anti-inflammation effect. The dual-track reverse cholesterol transport strategy performed by LPLCH delivers an exciting candidate for the effective inhibition and degradation of atherosclerosis.

Comparison of Drug-Coated Balloon and Drug-Eluting Stent for the Treatment of Small Vessel Disease (from the Dissolve SVD Randomized Trial).

The Dissolve drug-coated balloons (DCBs) is a new-generation DCB coated with paclitaxel of balloon surface, with midchain triglyceride excipient. Although the use of DCBs is a promising technique, little is known about the the clinical efficacy of the novel Dissolve DCB in coronary small vessel disease. This study was a prospective, randomized, multicenter, noninferiority trial comparing the Dissolve DCB with the Resolute drug-eluting stent (DES) in patients with a reference vessel diameter ≥2.25 and ≤2.75 mm. Patients with a reference vessel diameter ≥2.00 and <2.25 mm were enrolled in the very small vessel registry. The angiographic and clinical follow-up were planned at 9 months and 1 year in all patients, respectively. The primary end point was 9-month in-segment percentage diameter stenosis. A total of 247 patients with small vessel disease from 10 Chinese sites were included (Dissolve DCB, n = 118; Resolute DES, n = 129); 30 patients were treated with the DCB in the very small vessel cohort. The 9-month in-segment percentage diameter stenosis was 31.2 ± 2.0% with Dissolve DCB versus 26.1 ± 2.1% with Resolute DES; the 1-sided 97.5% upper confidence limit of the difference was 10.3% (p for noninferiority = 0.0002). At 12 months, the DCB and DES groups were associated with similar rates of target lesion failure (8.5% vs 6.1%, p = 0.28) and major adverse cardiac and cerebrovascular events (20.9% vs 13.6%, p = 0.12). In conclusion, the Dissolve DCB was noninferior to the Resolute DES for the primary end point of 9-month in-segment percentage diameter stenosis in this multicenter, head-to-head, randomized trial (a safety and efficacy study of Dissolve In Treatment Of Coronary Small Vessel Disease; NCT03376646).

Fecal calprotectin: A novel predictor of ulcerated esophageal injury after atrial fibrillation catheter ablation.

BACKGROUND: Atrial esophageal fistula (AEF) is a lethal complication that can occur post atrial fibrillation (AF) ablation. Esophageal injury (EI) is likely to be the initial lesion leading to AEF. Endoscopic examination is the gold standard for a diagnosis of EI but extensive endoscopic screening is invasive and costly. This study was conducted to determine whether fecal calprotectin (Fcal), a marker of inflammation throughout the intestinal tract, may be associated with the existence of esophageal injury. METHODS: This diagnostic study was conducted in a cohort of 166 patients with symptomatic AF undergoing radiofrequency catheter ablation from May 2020 to June 2021. Fcal tests were performed 1-7 days after ablation. All patients underwent endoscopic ultrasonography 1 or 2 days after ablation. RESULTS: The levels of Fcal were significantly different between the EI and non-EI groups (404.9 µg/g (IQR 129.6-723.6) vs. 40.4 µg/g (IQR 15.0-246.2), p < .001). Analysis of ROC curves revealed that a Fcal level of 125 µg/g might be the optimal cut-off value for a diagnosis of EI, giving a 78.8% sensitivity and a 65.4% specificity. The negative predictive value of Fcal was 100% for ulcerated EI. CONCLUSIONS: The level of Fcal is associated with EI post AF catheter ablation. 125 µg/g might be the optimal cut-off value for a diagnosis of EI. Negative Fcal could predict the absence of ulcerated EI, which could be considered a precursor to AEF.

Use of intracardiac echocardiography in vein of Marshall ethanol infusion for ablation of persistent atrial fibrillation.

BACKGROUND: Few methods have been reported to demonstrate real-time effects during vein of Marshall (VOM) ethanol infusion in persistent atrial fibrillation (PeAF). OBJECTIVE: This study was to evaluate the impact of left atrial (LA) monitoring using intracardiac echocardiography (ICE) during VOM ethanol infusion. METHODS: Seventy-four consecutive patients with PeAF who underwent VOM ethanol infusion followed by radiofrequency (RF) ablation were included. Patients with findings on ICE consistent with echogenic streaming in the LA and with increased myocardial local echogenicity along the VOM area were placed into one group (group A) and those without into the other group (group B). Outcomes between the 2 groups were compared. RESULTS: Forty-six patients (62%) were placed into group A. A new ethanol-induced low-voltage area in group A was larger than that in group B (8.5 cm2 [5.5-10.2 cm2] and 4.0 cm2 (2.4-6.3 cm2]; P < .001). The RF ablation time required to achieve MI block was reduced in group A patients (263.0 seconds [196.0-351.0 seconds] vs 417.0 seconds [315.0-709.5 seconds] in group B patients; P < .001). MI block was achieved in 46 patients (100%) via an endocardial approach in group A and 27 patients (96.4%) in group B (extra coronary sinus ablation in 4 patients). One patient developed clinically significant pericardial effusions and required pericardiocentesis in group B. CONCLUSION: Presence of increased myocardial local echogenicity at the ridge and consistent echogenic streaming in the LA detected by ICE-based imaging during VOM ethanol infusion suggests increased ablated tissue in that region and lower RF ablation time during ablation for PeAF.