Notch1 signaling activation alleviates coronary microvascular dysfunction through histone modification of Nrg-1 via the interaction between NICD and GCN5.

The Notch signaling pathway is related to endothelial dysfunction in coronary atherosclerosis. Our objective was to explore the role of Notch signaling in coronary microvascular dysfunction (CMD). CMD models were constructed by sodium laurate injection in vivo and homocysteine (Hcy) stimulation in vitro. The binding ability of Notch Intracellular Domain (NICD)/H3K9Ac/GCN5 (General Control Non-derepressible 5) to Neuregulin-1 (Nrg-1) promoter was examined by chromatin immunoprecipitation. Immunofluorescence staining was conducted to detect CD31 positive cells, NICD localization, and co-localization of NICD and GCN5. Flow cytometry and Tunel staining were conducted to identify the apoptosis. Hematoxylin and eosin staining, quantitative real-time PCR, western blot, immunohistochemical staining, co-immunoprecipitation, and double luciferase report analysis were also conducted. Notch signaling pathway-related protein levels were decreased, levels of Nrg-1 and the phosphorylation of ErbB2 and ErbB4 were enhanced in CMD models. Interference with Nrg-1 further increased the apoptosis in Hcy-induced cardiac microvascular endothelial cells (CMECs). Meanwhile, the activation of the Notch signaling pathway increased the levels of Nrg-1 and the phosphorylation of ErbB2 and ErbB4, as well as inhibited the apoptosis induced by Hcy. Furthermore, NICD and histone acetyltransferase enzyme GCN5 could regulate Nrg-1 promoter activity by affecting the expression of acetylation-modified protein H3K9Ac. In addition, NICD also interacted with GCN5. In vivo results also confirmed that the activation of the Notch signal alleviated CMD. Notch signaling pathway regulates Nrg-1 level through synergistic interaction with GCN5, thereby mitigating CMD.

Clinical research of drug-coated balloon after rotational atherectomy for severe coronary artery calcification.

BACKGROUND: Current research results show that drug-coated balloons (DCB) have unique advantages in the treatment of in-stent restenosis, small vessel disease, bifurcation lesions, and de novo lesions, but the data regarding rotational atherectomy (RA) followed by DCB treatment in calcified lesions, especially severe coronary artery calcification (CAC), are limited. METHODS: A retrospective study was conducted on 318 individuals with severe CAC who underwent RA-assisted PCI at the First Affiliated Hospital of Zhengzhou University from May 2018 to July 2021. Among them, 57 patients (RA/DCB group) were treated with DCB, and 261 patients (RA/DES group) were treated with drug-eluting stents (DES). The two groups' clinical baseline data, lesion characteristics, intraoperative complications, in-hospital adverse events, and major adverse cardiovascular and cerebrovascular events (MACCE) were compared throughout the follow-up period. RESULTS: The baseline clinical data, intraoperative complications, and in-hospital adverse events were not significantly different between the two groups. The anatomical categories in the RA/DES group were more complex and included left main coronary disease, bifurcation disease, and multivessel disease. Although target lesion revascularization (13.79% vs. 7.02%) and MACCE (18.77% vs. 12.28%) occurred more frequently in the RA/DES group than in the RA/DCB group, there was no statistically significant difference (p > 0.05). Multivariate Cox regression analysis showed that bifurcation lesions (HR 2.284, 95% CI 1.063-4.908, p = 0.034), total length of DCB/DES (HR 1.023, 95% CI 1.005-1.047, p = 0.014) and SYNTAX score (HR 1.047, 95% CI 1.013-1.082, p = 0.006) were independent risk factors for MACCE during the follow-up period. CONCLUSION: Drug-coated balloon treatment after rotational atherectomy appears safe and effective in selected severe coronary artery calcification.

Drug-Coated Balloon-Only Angioplasty Outcomes in Diabetic and Nondiabetic Patients with De Novo Small Coronary Vessels Disease.

BACKGROUND: The revascularization of small vessels using drug-eluting stents remains challenging. The use of the drug-coated balloon is an attractive therapeutic strategy in de novo lesions in small coronary vessels, particularly in the diabetic group. This study aimed to assess the outcomes of DCB-only angioplasty in small vessel disease. METHODS: A total of 1198 patients with small vessel disease treated with DCB-only strategy were followed. Patients were divided into the diabetic and nondiabetic groups. Clinical and angiographical follow-up were organized at 12 months. The primary endpoints were target lesion failure and secondary major adverse cardiac events. RESULTS: There was a significantly higher rate of target lesion failure among diabetic patients compared to nondiabetic [17 (3.9%) vs. 11 (1.4%), P=0.006], taken separately, the rate of target lesion revascularization significantly differed between groups with a higher rate observed in the diabetic group [9 (2%) vs. 4 (0.5%), P=0.014]. Diabetes mellitus remained an independent predictor for TLF (HR: 2.712, CI: 1.254-5.864, P=0.011) and target lesion revascularization (HR: 3.698, CI: 1.112-12.298, P=0.033) after adjustment. However, no significant differences were observed between groups regarding the target vessel myocardial infarction (0.6% vs. 0.1%, P=0.110) and MACE [19 (4.4%) vs. 21 (2.7%), P=0.120]. CONCLUSION: Drug-coated balloon-only treatment achieved lower incidence rates of TLF and MACE. Diabetes is an independent predictor for target lesion failure and target lesion revascularization at one year following DCB treatment in small coronary vessels. We observed no significant differences between groups regarding MACE in one year.

Comparison of Intracoronary and Intravenous Ultrasound-targeted Microbubble Destruction-mediated Ang1 Gene Transfection on Left Ventricular Remodeling in Canines With Acute Myocardial Infarction.

Intravenous ultrasound-targeted microbubble destruction (IV-UTMD) has made distinct but limited progress in gene therapy. Intracoronary (IC) injection may lead to more gene transfection than IV injection. This study compared the therapeutic effects of IC-UTMD-mediated and conventional IV-UTMD-mediated gene transfection in acute myocardial infarction (MI). A canine MI model was successfully established through transcatheter coronary artery embolism, and the animals were divided into several treatment groups: IC injection with UTMD and the negative control plasmid (IC-UTMD); IC injection of the angiopoietin 1 (Ang1) plasmid (IC-Ang1); IC injection with UTMD and the Ang1 plasmid (IC-UTMD-Ang1); and IV injection with UTMD and the Ang1 plasmid (IV-UTMD-Ang1). At 12 hours after injection, more green fluorescence was observed from the fluorescein isothiocyanate-labeled Ang1 plasmid in the IC-UTMD-Ang1 group. After 1 month, compared with the IV-UTMD-Ang1 group, echocardiography showed that the IC-UTMD-Ang1 group exhibited increased left ventricular systolic function and myocardial infusion, with lower fibrous tissue levels and higher blood vessel density and Ang1 mRNA and protein levels. Similar cardiac troponin I and N-terminal pro-B type natriuretic peptide levels were observed in all groups. Compared with IV-UTMD, IC-UTMD can enhance Ang1 plasmid transfection efficiency after MI, promote gene expression and angiogenesis, and improve left ventricular remodeling without decreasing safety.

Molsidomine Attenuates Ventricular Electrical Remodeling and Arrhythmogenesis in Rats With Chronic ß-Adrenergic Receptor Activation Through the NO/cGMP/PKG Pathway.

This study investigated the effects and associated underlying mechanisms of molsidomine, a nitric oxide (NO) donor, on cardiac electrical remodeling and ventricular tachycardias (VTs) induced by chronic isoprenaline (ISO) stimulation in rats. The rats were randomly divided into groups that were treated with saline (control group), ISO (ISO group), ISO + molsidomine (ISO + M group), and ISO + molsidomine + the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, ISO + M + O group) for 14 days. An electrophysiological study was performed to assess cardiac repolarization, action potential duration restitution, and the induction of action potential duration alternans and VTs in vitro. The properties of the Ca transients, Ca handling-related proteins, and NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) pathway were examined. Compared with the control group, chronic ISO stimulation prolonged the cardiac repolarization, decreased the Ca transient alternans and action potential duration alternans thresholds, and increased the maximum slope (Smax) of the action potential duration restitution curve and incidence of VTs in vitro. All these effects were attenuated by molsidomine treatment (P < 0.05). Moreover, molsidomine activated cGMP/PKG signaling and stabilized the expression of calcium handling-related proteins compared with the ISO group. However, the protective effects of molsidomine were partially inhibited by ODQ. Our results suggest that molsidomine stabilizes calcium handling and attenuates cardiac electrical remodeling and arrhythmogenesis in rats with chronic ß-adrenergic receptor activation. These effects are at least partially mediated by the activation of NO/cGMP/PKG pathway.

Vasostatin-1 Stops Structural Remodeling and Improves Calcium Handling via the eNOS-NO-PKG Pathway in Rat Hearts Subjected to Chronic ß-Adrenergic Receptor Activation.

PURPOSE: Chronically elevated catecholamine levels activate cardiac ß-adrenergic receptors, which play a vital role in the pathogenesis of heart failure. Evidence suggests that vasostatin-1 (VS-1) exerts anti-adrenergic effects on isolated and perfused hearts in vitro. Whether VS-1 ameliorates hypertrophy/remodeling by inducing the chronic activation of ß-adrenergic receptors is unknown. The present study aims to test the efficacy of using VS-1 to treat the advanced hypertrophy/remodeling that result from chronic ß-adrenergic receptor activation and to determine the cellular and molecular mechanisms that underlie this response. METHODS AND RESULT: Rats were subjected to infusion with either isoprenaline (ISO, 5 mg/kg/d), ISO plus VS-1 (30 mg/kg/d) or placebo for 2 weeks. VS-1 suppressed chamber dilation, myocyte hypertrophy and fibrosis and improved in vivo heart function in the rats subjected to ISO infusion. VS-1 increased phosphorylated nitric oxide synthase levels and induced the activation of protein kinase G. VS-1 also deactivated multiple hypertrophy signaling pathways that were triggered by the chronic activation of ß-adrenergic receptors, such as the phosphoinositide-3 kinase (PI3K)/Akt and Ca2+/calmodulin-dependent kinase (CaMK-II) pathways. Myocytes isolated from ISO + VS-1 hearts displayed higher Ca2+ transients, shorter Ca2+ decays, higher sarcoplasmic reticulum Ca2+ levels and higher L-type Ca2+ current densities than the ISO rat hearts. VS-1 treatment restored the protein expression of sarcoplasmic reticulum Ca2+ uptake ATPase, phospholamban and Cav1.2, indicating improved calcium handling. CONCLUSIONS: Chronic VS-1 treatment inhibited the progression of hypertrophy, fibrosis, and chamber remodeling, and improved cardiac function in a rat model of ISO infusion. In addition, Ca2+ handling and its molecular modulation were also improved by VS-1. The beneficial effects of VS-1 on cardiac remodeling may be mediated by the enhanced activation of the eNOS-cGMP-PKG pathway.

Short-term outcomes of drug-coated balloon versus drug-eluting stent for de novo saphenous vein graft lesions in coronary heart disease.

Background: As a device for percutaneous coronary intervention, drug-coated balloon (DCB) is widely used to treat in-stent restenosis. However, data regarding the use of DCB in treating de novo saphenous vein graft (SVG) lesions are limited. This study aimed to explore the outcomes of using the DCB in the treatment of de novo SVG lesions of coronary heart disease (CHD). Methods: This retrospective and observational study analyzed CHD patients with de novo SVG lesions treated with DCB or the new-generation drug-eluting stent (DES) between January 2018 and December 2020. Restenosis was the primary endpoint, whereas target lesion revascularization (TLR), major adverse cardiac events, restenosis, cardiac death, target vessel revascularization, and myocardial infarction were the secondary outcomes. Results: We enrolled 31 and 23 patients treated with DCB and DES, respectively. The baseline clinical data, lesion characteristics, and procedural characteristics were similar between the two groups. Twenty-eight (90.3%) patients in the DCB group and 21 (91.3%) in the DES group completed follow-up angiography after 1 year. The quantitative coronary angiography measurements at angiographic follow-up showing late lumen loss were -0.07 ± 0.95 mm for the DCB group and 0.86 ± 0.71 mm for the DES group (P = 0.039), and the rates of restenosis were 13.3% and 21.7% for the DCB and DES groups, respectively (P = 0.470). No significant differences were observed in the rates of MACE (16.7% vs. 26.1%, P = 0.402) and TLR (13.3% vs. 4.3%, P = 0.374) during clinical follow-up. Conclusion: Our findings suggest that when pre-dilatation was successful, DCB might be safe and effective in treating de novo SVG lesions.

Drug-coated balloons for the treatment of ostial left anterior descending or ostial left circumflex artery lesions: a patient-level propensity score-matched analysis.

BACKGROUND: Controversy exists as to the optimal treatment approach for ostial left anterior descending (LAD) or ostial left circumflex artery (LCx) lesions. Drug-coated balloons (DCB) may overcome some of the limitations of drug-eluting stents (DES). Therefore, we investigated the security and feasibility of the DCB policy in patients with ostial LAD or ostial LCx lesions, and compared it with the conventional DES-only strategy. METHODS: We retrospectively enrolled patients with de novo ostial lesions in the LAD or LCx who underwent interventional treatment. They were categorized into two groups based on their treatment approach: the DCB group and the DES group. The treatment strategies in the DCB group involved the use of either DCB-only or hybrid strategies, whereas the DES group utilized crossover or precise stenting techniques. Two-year target lesion revascularization was the primary endpoint, while the rates of major adverse cardiovascular events, cardiac death, target vessel myocardial infarction, and vessel thrombosis were the secondary endpoints. Using propensity score matching, we assembled a cohort with comparable baseline characteristics. To ensure result analysis reliability, we conducted sensitivity analyses, including interaction, and stratified analyses. RESULTS: Among the 397 eligible patients, 6.25% of patients who were planned to undergo DCB underwent DES. A total of 108 patients in each group had comparable propensity scores and were included in the analysis. Two-year target lesion revascularization occurred in 5 patients (4.90%) and 16 patients (16.33%) in the DCB group and the DES group, respectively (odds ratio = 0.264, 95% CI: 0.093-0.752, P = 0.008). Compared with the DES group, the DCB group demonstrated a lower major adverse cardiovascular events rate (7.84% vs. 19.39%, P = 0.017). However, differences with regard to cardiac death, non-periprocedural target vessel myocardial infarction, and definite or probable vessel thrombosis between the groups were non-significant. CONCLUSIONS: The utilization of the DCB approach signifies an innovative and discretionary strategy for managing isolated ostial lesions in the LAD or LCx. Nevertheless, a future randomized trial investigating the feasibility and safety of DCB compared to the DES-only strategy specifically for de novo ostial lesions in the LAD or LCx is highly warranted.

Long-term outcomes of less drug-eluting stents by the use of drug-coated balloons in de novo coronary chronic total occlusion intervention: A multicenter observational study.

Background: Data on drug-coated balloons (DCB) for de novo coronary chronic total occlusion (CTO) are limited. We aimed to investigate the long-term outcomes of substitution of drug-eluting stents (DES) by DCB. Methods: We compared the outcomes of less DES strategy (DCB alone or combined with DES) and DES-only strategy in treating de novo coronary CTO in this prospective, observational, multicenter study. The primary endpoints were major adverse cardiovascular events (MACE), target vessel revascularization, myocardial infarction, and death during 3-year follow-up. The secondary endpoints were late lumen loss (LLL) and restenosis until 1-year after operation. Results: Of the 591 eligible patients consecutively enrolled between January 2015 and December 2019, 281 (290 lesions) were treated with DCB (DCB-only or combined with DES) and 310 (319 lesions) with DES only. In the DCB group, 147 (50.7%) lesions were treated using DCB-only, and the bailout stenting rate was relatively low (3.1%). The average stent length per lesion in the DCB group was significantly shorter compared with the DES-only group (21.5 ± 25.5 mm vs. 54.5 ± 26.0 mm, p < 0.001). A total of 112 patients in the DCB group and 71 patients in the DES-only group (38.6% vs. 22.3%, p < 0.001) completed angiographic follow-up until 1-year, and LLL was much less in the DCB group (-0.08 ± 0.65 mm vs. 0.35 ± 0.62 mm, p < 0.001). There were no significant differences in restenosis occurrence between the two groups (20.5% vs. 19.7%, p > 0.999). The Kaplan-Meier estimates of MACE at 3-year (11.8% vs. 12.0%, log-rank p = 0.688) was similar between the groups. Conclusion: Percutaneous coronary intervention with DCB is a potential "stent-less" therapy for de novo CTO lesions with satisfactory long-term clinical results compared to the DES-only approach.

Long-term outcomes of drug-coated balloon treatment of calcified coronary artery lesions: a multicenter, retrospective, propensity matching study.

Background: Coronary artery calcification (CAC) is associated with high rates of restenosis and adverse clinical events after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Objectives: The aim of this study was to evaluate the long-term clinical outcomes of drug-coated balloon (DCB)-only treatment for de novo lesions with and without CAC. Methods: Patients with de novo coronary disease treated with the DCB-only strategy were retrospectively enrolled from three centers and categorized into a CAC group and a non-CAC group. The primary endpoint was the target lesion failure (TLF) rate during the 3-year follow-up. Secondary endpoints included the occurrence of major adverse cardiac events (MACEs), target lesion revascularization (TLR), cardiac death, myocardial infarction (MI) and any revascularization. Propensity score matching (PSM) was conducted to assemble a cohort of patients with similar baseline characteristics. Results: A total of 1,263 patients with 1,392 lesions were included, and 243 patients were included in each group after PSM. Compared with the non-CAC group, the incidence rates of TLF (9.52% vs. 4.94%, odds ratio [OR]: 2.080; 95% confidence interval [CI]: 1.083-3.998, P = 0.034) and TLR (7.41% vs. 2.88%, OR: 2.642; 95% CI: 1.206-5.787, P = 0.020) in the CAC group were higher. The incidence rates of MACE (12.35% vs. 7.82%, OR: 1.665; 95% CI: 0.951-2.916, P = 0.079), cardiac death (2.06% vs. 2.06%, OR: 0.995; 95% CI: 0.288-3.436, P = 0.993), MI (1.23% vs. 0.82%, OR: 2.505; 95% CI: 0.261-8.689, P = 0.652) and any revascularization (12.76% vs. 9.67%, OR: 1.256; 95% CI: 0.747-2.111, P = 0.738) were similar between groups. Conclusions: CAC increased the incidence of TLF and TLR without a substantial increase in the risk of MACE, cardiac death, MI, or any revascularization in patients treated with DCB-only angioplasty during the 3-year follow-up.

E3 ubiquitin ligase mind bomb 1 overexpression reduces apoptosis and inflammation of cardiac microvascular endothelial cells in coronary microvascular dysfunction.

BACKGROUND: The apoptosis and inflammation in cardiac microvascular endothelial cells (CMECs) promote the development of coronary microvascular dysfunction (CMD). The present study aimed to explore the role of E3 ubiquitin ligase mind bomb 1 (MIB1) in the apoptosis and inflammation in CMECs during CMD. METHODS: In vivo, CMD in rats was induced by sodium laurate injection. In vitro, rat primary CMECs were stimulated by homocysteine (Hcy). The apoptosis of CMECs was measured using flow cytometry. The inflammation of CMECs was evaluated by the level of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß). The interplay between MIB1 and mitogen-activated protein kinase kinase kinase 5 (map3k5, also called ASK1) was measured using Co-immunoprecipitation. RESULTS: MIB1 expression was decreased and ASK1 expression was increased in the heart tissues of CMD rats and Hcy-treated CMECs. MIB1 overexpression decreased fibrinogen-like protein 2 (FGL2) secretion, inflammation, and apoptosis induced by Hcy in CMECs. Meanwhile, MIB1 overexpression decreased the protein levels of ASK1 and p38, while not affected ASK1 mRNA levels. The following mechanism experiments revealed that MIB1 downregulated ASK1 expression by increasing its ubiquitination. ASK1 overexpression reversed the inhibitory effect of MIB1 on FGL2 secretion, apoptosis, inflammation, and p38 activation in Hcy-treated CMECs. In CMD rats, MIB1 overexpression partly retarded CMD progression, manifesting as increased coronary capillary density and decreased microthrombi formation. CONCLUSION: MIB1 overexpression relieved apoptosis and inflammation of CMECs during CMD by targeting the ASK1/p38 pathway.

Drug-coated balloon in the treatment of coronary left main true bifurcation lesion: A patient-level propensity-matched analysis.

Aims: An increasing body of evidence suggests that drug-coated balloon (DCB) angioplasty represents a valuable option for revascularization in selected patients with coronary bifurcation disease. However, there remains a paucity of real-world observational evidence on the efficacy of DCB in left main (LM) true bifurcation lesion. We compared clinical and angiographic outcomes of hybrid [DCB + drug-eluting stent (DES)] versus DES-only strategy (provisional stenting or two-stent strategies) in de novo LM true bifurcated lesions. Methods: The primary endpoint was the 2-year composite rate of target lesion failure (TLF): cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target lesion revascularization (CD-TLR). A routine 1-year angiographic follow-up was scheduled. Propensity-score matching was utilized to assemble a cohort of patients with similar baseline characteristics. Results: Among 1077 eligible patients, 199 who received DCB treatment and 398 who were assigned to DES therapy had similar propensity scores and were included in the analysis. TLF within 2 years occurred in 13 patients (7.56%) assigned to DCB group, and 52 patients (14.36%) assigned to DES group (odds ratio: 0.487; 95% confidence interval: 0.258-0.922; P = 0.025; Log-rank P = 0.024). Compared with the DES group, the DCB group resulted in a lower rate of CD-TLR (2.91% vs. 9.42%; P = 0.007). Cardiac death, TVMI, all-cause mortality, and stent thrombosis were comparable between both groups. Patients treated with DES-only were associated with a higher late lumen loss (0.42 ± 0.62 mm vs. 0.13 ± 0.42 mm, P < 0.001) compared with the DCB group at 1 year. In sensitivity analysis, the DCB group also presented a lower incidence of TLF, CD-TLR and stent thrombosis both compared to the two-stent strategy and compared to provisional stenting (Ps < 0.05). Conclusion: The 2-year results of PCI utilizing DCB for LM true bifurcation lesions are superior to employing DES alone in terms of safety and effectiveness.

Stentless at ostium: a novel approach for treating ostial left anterior descending or left circumflex coronary artery lesions with drug-coated balloons.

BACKGROUND: Currently, there is no optimal treatment strategy for ostial left anterior descending (LAD) or ostial left circumflex artery (LCx) lesions. This study explored effectiveness and safety of drug-coated balloons (DCB) in individuals presenting with ostial LAD or LCx lesions. METHODS: A total of 137 patients with de novo ostial LAD or LCx lesions scheduled for DCB treatment were prospectively recruited into the study. After mandatory lesion preparation, DCB-only or hybrid strategy [DCB + drug-eluting stent (DES)] were performed on 120 patients (87.59%). The primary endpoint was the rate of 2-year target lesion revascularization (TLR). Rates of major adverse cardiovascular events (MACE), cardiac death, target vessel myocardial infarction (TVMI), and vessel thrombosis were explored as the secondary outcomes. Quantitative coronary angiography software was used to analyze coronary angiograms. RESULTS: Of the participants, 58 were treated with DCB-only and 62 with hybrid strategy. Relative to the DCB-only group, patients in the hybrid group had longer target lesions (15.47 ± 10.08 vs. 36.85 ± 9.46 mm, P<0.001) and higher Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) scores (23.47 ± 5.22 vs. 29.98 ± 3.18, P<0.001). During follow-up (731 ± 64 days), neither the primary endpoint (TLR) nor the secondary endpoints (including MACE, cardiac death, TVMI, and vessel thrombosis) differed statistically between the two groups (all P > 0.05). Treatment strategy (DCB-only or hybrid) was not a significant risk factor for TLR. Patients who underwent DCB-only exhibited less late lumen loss compared with the patients who underwent hybrid strategy (-0.26 ± 0.59 vs. 0.42 ± 0.47 mm, P<0.001) at 1-year angiographic follow-up. CONCLUSIONS: With regards to safety and efficacy, the strategy of DCB as a standalone therapy was similar in comparison with the hybrid strategy of DCB + DES for ostial LAD and ostial LCx lesions. This approach might be effective and technically easy in treating ostial LAD and LCx diseases.

Long-term outcomes of drug-coated balloons in patients with diffuse coronary lesions.

Background: Drug-coated balloons (DCB), alone or in combination with drug-eluting stents (DES), may be used to treat diffuse coronary lesions. We aimed to explore the efficacy and safety of DCB in patients with diffuse coronary lesions. Methods: Consecutive patients with diffuse coronary lesions (lesion length > 25 mm) who underwent DCB and/or DES between January 2015 and December 2019 were included in this prospective, observational, multicenter study. The DCB group included 355 patients (360 lesions), of which 142 patients (143 lesions, 39.7%) received the DCB-only strategy and 213 patients (217 lesions, 60.3%) received the hybrid strategy (DCB combined with DES). The DES group included 672 patients (831 lesions) treated with DES alone. Target lesion revascularization (TLR) during 3-year follow-up was the primary outcome of interest. The secondary outcome was major adverse cardiac events (MACE), defined as a composite of all-cause death, non-fatal myocardial infarction, and target vessel revascularization. Results: The two groups had comparable baseline clinical and lesion characteristics. Lesion length was similar (43.52 ± 16.46 mm vs. 44.87 ± 15.80 mm, P = 0.181), but the stent length in the DCB group was significantly shorter (24.02 ± 23.62 mm vs. 51.89 ± 15.81 mm, P < 0.001). Ten lesions (2.8%) in the DCB group received bailout stents. Over 3 years of follow-up, no significant difference in TLR incidence between the groups (7.3 vs. 8.3%, log-rank P = 0.636) was observed. Incidence of MACE also did not differ significantly (11.3 vs. 13.7%, log-rank P = 0.324). No thrombosis events occurred in the DCB group, while four patients (0.6%) in the DES group experienced stent thrombosis (log-rank P = 0.193). Moreover, similar TLR and MACE rates were observed between DCB-only and hybrid strategies (TLR: 6.4 vs. 8.0%, log-rank P = 0.651; MACE: 11.4 vs. 11.2%, log-rank P = 0.884). Conclusion: Long-term outcomes show that the efficacy and safety of the DCB strategy (DCB alone or combined with DES) are similar to those of DES alone in diffuse coronary lesions. These findings suggest that this strategy is a promising alternative for select patients with diffuse coronary lesions.

Clinical outcomes of drug-coated balloon in coronary lesions: a real-world, all-comers study.

BACKGROUNDS: Although drug-eluting stents are the most common interventional devices for patients with coronary disease, drug-coated balloons (DCBs) represent a novel therapeutic alternative in certain scenarios. This prospective, observational all-comers study explored the clinical outcomes of DCB use in patients with coronary lesions. METHODS AND RESULTS: All patients treated with DCBs were enrolled in this study, including patients with in-stent restenosis (ISR) or de novo lesions. The primary outcome was the target lesion revascularization (TLR) rate at one year. We enrolled 2306 patients with 2660 lesions and performed DCB angioplasty in 399 patients (17.3%) with ISR and 1907 patients (82.7%) with de novo lesions. During follow-up (366 ± 46 days), the TLR rate was lower in the de novo lesion group (1.31%) compared to the ISR group (7.02%) [odds ratio (OR) 0.176, 95% confidence interval (CI) 0.101-0.305, p < 0.001]. Patients with de novo lesions had a lower yearly incidence of MACE compared to ISR patients (2.73 vs. 9.27%, respectively, OR 0.274, 95% CI 0.177-0.424, p < 0.001) and a lower incidence of any revascularization (5.09 vs. 13.03%, OR 0.358, 95% CI 0.251-0.510, p < 0.001). No significant differences between groups were observed in the rates of cardiac death (OR 0.783, 95% CI 0.258-2.371, p = 0.655) or MI (OR 0.696, 95% CI 0.191-2.540, p = 0.573). CONCLUSIONS: DCB angioplasty in this all-comers, real-world, prospective study was safe and efficient with low TLR and MACE rates. Thus, DCB appears to be an attractive alternative for the stent-less treatment of de novo coronary lesions. ISR in-stent restenosis; OR odds ratio; CI confidence interval; TLR target lesion revascularization; MACE major adverse cardiovascular events; MI myocardial infraction. MACE defined as the composite outcome of cardiac death, myocardial infarction, and target vessel revascularization. Any revascularization includes any percutaneous coronary intervention, and coronary artery bypass grafting.

Clinical Outcomes of Drug-Coated Balloon in Coronary Patients with and without Diabetes Mellitus: A Multicenter, Propensity Score Study.

BACKGROUND: Relative to nondiabetic patients, percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM) is associated with inferior clinical outcomes. We aimed to evaluate the outcomes of drug-coated balloon (DCB) in diabetic versus nondiabetic patients. METHODS AND RESULTS: In this observational, prospective, multicenter study, we compared the outcomes of patients with and without DM after undergoing PCI with DCBs. Target lesion failure (TLF) was analyzed as primary endpoint. Secondary endpoints were the rates of target lesion revascularization (TLR), major adverse cardiovascular events (MACE), cardiac death, myocardial infarction (MI), and any revascularization. Propensity score matching was used to assemble a cohort of patients with similar baseline characteristics. Among 2,306 eligible patients, 578 with DM and 578 without DM had similar propensity scores and were included in the analyses. During follow-up (366 ± 46 days), compared with DM patients, patients without DM were associated with a lower yearly incidence of TLF (2.77% vs. 5.36%; OR, 1.991; 95% CI, 1.077 to 3.681; P = 0.025) and TLR (1.90% vs. 4.15%; OR, 2.233; 95% CI, 1.083 to 4.602; P = 0.026). No significant differences were observed with regards to rates of MACE (OR: 1.580, 95% CI: 0.912-2.735; P = 0.100), cardiac death (OR: 1.608, 95% CI: 0.523-4.946; P = 0.403), MI (OR: 4.042, 95% CI: 0.855-19.117; P = 0.057), and any revascularization (OR: 1.534, 95% CI: 0.983-2.393; P = 0.058). CONCLUSIONS: Diabetic patients experience higher TLF and TLR rates following DCB angioplasty without substantial increase in the risk of MACE, cardiac death, MI, or revascularization.

Drug-coated balloon angioplasty: predicting outcomes based on different patterns of drug-eluting stent restenosis.

Although drug-coated balloon (DCB) angioplasty is an effective therapy for drug-eluting stent- in stent restenosis (DES-ISR) after coronary stenting, recurrent ISR after DCB angioplasty still occurs. Different patterns of DES-ISR responding to DCB are largely unknown. This study sought to assess outcomes of different patterns of DES-ISR treated with DCB. From December 2014 to December 2016, a total of 160 DES-ISR lesions treated with DCB were retrospectively evaluated. Restenosis patterns were classified into two groups according to Mehran classification: focal, defined as < 10 mm, 58 lesions (36.3%); non-focal, which were diffuse, proliferative, or obstructive, 102 lesions (63.7%). The primary endpoint was binary restenosis rate at 9-month angiographic follow-up. Secondary endpoint was major adverse cardiac events (MACE) at 24-month follow-up. Baseline characteristics were comparable between the two groups. Angiographic follow-up rate was 93.7% (93.1% in the focal group and 94.1% in the non-focal group). The focal group had a lower recurrent restenosis rate compared to the non-focal group (3.7% vs. 33.3%, respectively; P = 0.003) at an average angiographic follow-up of 10 (10.4 ± 6.2) months. There was no difference in MACE between the two groups (6.9% vs. 11.8%, respectively; P = 0.70) at (22.7 ± 9.1) months clinical follow-up. On multivariate logistic regression analysis, focal pattern (OR 13.033; 95% CI 2.441-69.573, P = 0.003) and post-procedure DS% (OR 1.142; 95% CI 1.070-1.218, P = 0.000) were predictive factors of binary restenosis after DCB angioplasty. On multivariate analysis, focal pattern of ISR was a predictive factor of MACE (OR 0.260; 95% CI 0.071-0.959, P = 0.043), and diabetes mellitus (DM) was an independent predictor of MACE after DCB angioplasty (OR 5.045; 95% CI 1.179-21.590, P = 0.029). The present study suggests that DCB provides much better clinical, angiographic outcomes in patients with focal DES-ISR than non-focal DES-ISR.

CTRP3 Protects against High Glucose-Induced Cell Injury in Human Umbilical Vein Endothelial Cells.

AIMS: Inflammation was closely associated with diabetes-related endothelial dysfunction. C1q/tumor necrosis factor-related protein 3 (CTRP3) is a member of the CTRP family and can provide cardioprotection in many cardiovascular diseases via suppressing the production of inflammatory factors. However, the role of CTRP3 in high glucose- (HG-) related endothelial dysfunction remains unclear. This study evaluates the effects of CTRP3 on HG-induced cell inflammation and apoptosis. MATERIALS AND METHODS: To prevent high glucose-induced cell injury, human umbilical vein endothelial cells (HUVECs) were pretreated with recombinant CTRP3 for 1 hour followed by normal glucose (5.5 mmol/l) or high glucose (33 mmol/l) treatment. After that, cell apoptosis and inflammatory factors were determined. RESULTS: Our results demonstrated that CTRP3 mRNA and protein expression were significantly decreased after HG exposure in HUVECs. Recombinant human CTRP3 inhibited HG-induced accumulation of inflammatory factors and cell loss in HUVECs. CTRP3 treatment also increased the phosphorylation levels of protein kinase B (AKT/PKB) and the mammalian target of rapamycin (mTOR) in HUVECs. CTRP3 lost its inhibitory effects on HG-induced cell inflammation and apoptosis after AKT inhibition. Knockdown of endogenous CTRP3 in HUVECs resulted in increased inflammation and decreased cell viability in vitro. CONCLUSIONS: Taken together, these findings indicated that CTRP3 treatment blocked the accumulation of inflammatory factors and cell loss in HUVECs after HG exposure through the activation of AKT-mTOR signaling pathway. Thus, CTRP3 may be a potential therapeutic drug for the prevention of diabetes-related endothelial dysfunction.

Bailcalin Protects against Diabetic Cardiomyopathy through Keap1/Nrf2/AMPK-Mediated Antioxidative and Lipid-Lowering Effects.

Previous studies demonstrated that Bailcalin (BAI) prevented cardiac injuries under different disease models. Whether BAI protected against type 2 diabetes mellitus- (T2DM-) associated cardiomyopathy was investigated in this study. T2DM was established by the combination of streptozotocin injection and high-fat diet in mice. BAI was administered daily for 6 months. After evaluating cardiac functions, mice hearts were removed and processed for morphological, biochemical, and molecular mechanism analyses. Neonatal rat cardiomyocytes (NRCM) were isolated and treated with high glucose and palmitate (HG/Pal) for in vitro investigation. BAI significantly ameliorated T2DM-induced cardiomyocyte hypertrophy, interstitial fibrosis, and lipid accumulation accompanied by markedly improved cardiac functions in diabetic mice. Mechanically, BAI restored decreased phosphorylation of AMPK and enhanced expression and nuclei translocation of Nrf2. In in vitro experiments, BAI also prevented NRCM from HG/Pal-induced apoptosis and oxidative stress injuries by increasing p-AMPK and Nrf2 accumulation. The means by which BAI restored p-AMPK seemed to be related to the antioxidative effects of Nrf2 after silencing AMPK or Nrf2 in NRCM. Furthermore, BAI regulated Nrf2 by inhibiting Nrf2 ubiquitination and consequent degradation mediated by Keap1. This study showed that BAI alleviated diabetes-associated cardiac dysfunction and cardiomyocyte injuries in vivo and in vitro via Keap1/Nrf2/AMPK-mediated antioxidation and lipid-lowering effects. BAI might be a potential adjuvant drug for diabetes cardiomyopathy treatment.

The Glp-1 Analog Liraglutide Protects Against Angiotensin II and Pressure Overload-Induced Cardiac Hypertrophy via PI3K/Akt1 and AMPKa Signaling.

The Glp-1 analog, liraglutide (Lir), has been shown to reduce infarct size and improve cardiac function after myocardial ischemia in rodents with or without diabetes. However, the effect of Lir on angiotensin II (AngII) and pressure overload induced cardiac hypertrophy in nondiabetic mice and the underlying mechanisms are unclear. The aim of this study was to investigate the effect of Lir on cardiac hypertrophy induced by AngII infusion and pressure overload and to explore its possible mechanism. Mice were subjected to AngII as well as thoracic aorta coarctation (TAC) to induce a cardiac hypertrophy model. Mice were daily injected with either liraglutide or saline for 2 weeks after AngII infusion. Mice were also subjected to either liraglutide or saline for 25 days after TAC surgery. Neonatal rat cardiomyocytes and human AC cell lines were stimulated with AngII to induce a cardiomyocytes hypertrophy model. The results indicated Lir significantly inhibited cardiac hypertrophy and fibrosis and improved cardiac function in both the AngII and pressure overload induced model. The in vitro study showed that Lir inhibits AngII induced cell hypertrophy. Mechanistically, Lir directly suppressing the activation of PI3K/Akt1 and stimulated AMPKα signaling pathways in cardiomyocytes, which was confirmed by use of an mTOR activator (MHY1485), overexpression of constitutively active Akt, and the knockdown of AMPKa2 expression. Moreover, the protective effects of Lir were lost in AMPKa2 knockout mice. Taken together, Lir inhibits AngII and pressure overload induced cardiac remodeling via regulating PI3K/Akt1 and AMPKα signaling.