Hypertensive crises require rapid blood pressure control to prevent stroke and myocardial injury. Despite Cleviprex's efficacy, its high cost limits accessibility in China. This Phase III, multicenter, randomized, double-blind study evaluated the efficacy and safety of a generic clevidipine (China's first injectable generic clevidipine emulsion) versus the branded drug Cleviprex in managing hypertensive emergencies and urgencies among Chinese patients. A total of 377 patients of 33 medical centers from December 2021 to December 2022 were randomized, with 189 in the generic clevidipine group and 188 in the control. As a result, 95.6% of patients in the generic clevidipine group and 93.6% in the control achieved the target systolic blood pressure (SBP) reduction within 30 min (rate difference 0.020, 90% CI: -0.019 to 0.060). The mean area under the curve (AUC) of SBP outside the target range within the first hour was comparable between groups (329.8 ± 238.16 in generic clevidipine vs. 347.9 ± 302.79 in control). The median time to first achieve the target range within 30 min was 12.0 min in both groups. The proportion of patients successfully transitioning to oral therapy within 6 h was 93.4% in the generic clevidipine group and 93.6% in the control group. The incidence of drug-related adverse events (AEs) was reported in 50 patients (27.3%) in the generic clevidipine group and in 48 (27.9%) in the control, with no unexpected safety signals. The generic clevidipine demonstrated comparable efficacy and safety to the branded drug, supporting its potential as an effective and accessible therapeutic alternative for acute hypertension management. Trial Registration: chinadrugtrials.org.cn identifier: ChiCTR20212877.

Aims:The IVUS-ACS trial demonstrated that intravascular ultrasound (IVUS) guidance reduces target-vessel failure (TVF) in patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Whether this benefit applies to all ACS patients across the spectrum of risk is unknown. We sought to develop a new risk score for 1-year TVF after PCI in ACS and determine whether IVUS guidance compared with angiography guidance improves outcomes in both high- and low-risk patients. Methods and results:From the angiography-guided group of the IVUS-ACS trial (n = 1743), the TVF-ACS risk score was developed using the least absolute shrinkage and selection operator method in a derivation group (n = 1288), and its robustness was assessed in an internal validation group (n = 455). External validation was then performed separately in the IVUS-XPL and ULTIMATE trials. Outcomes in high- and low-risk patients randomized to IVUS guidance vs. angiography guidance were then examined. Ten readily available clinical, laboratory, and angiographic variables were selected for inclusion in the TVF-ACS risk score. A cut-off value of 15.64 discriminated angiography-guided PCI patients at high-risk vs. low risk [area under the curve (AUC) 0.715, 95% confidence interval (CI) 0.653-0.777]. The AUC was similar in the validation group [0.709 (95% CI 0.630-0.788)]. High-risk patients exhibited a higher 1-year rate of TVF compared with low-risk patients [19.8 vs. 5.7%, hazard ratio (HR) 3.81, 95% CI 2.06-7.02, P = 0.00002]. Among 3486 randomized patients, IVUS guidance compared with angiography guidance reduced 1-year TVF in high-risk patients (6.9 vs. 17.6%; HR 0.38, 95% CI 0.24-0.59) with a lesser effect in low-risk patients (3.2 vs. 4.3%; HR 0.75, 95% CI 0.51-1.11; P interaction = 0.02). External validation in the IVUS-XPL and ULTIMATE trials confirmed these benefits but with consistent effects in high- and low-risk patients (P interactions = 0.49 and 0.92, respectively). Conclusion:The TVF-ACS risk score reliably stratifies ACS patients undergoing PCI into high- and low-risk groups. The benefits of IVUS guidance during PCI are most pronounced in high-risk ACS patients, although all ACS patients are likely to benefit.

Abstract 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.

Autoimmune myocarditis, which falls within the broad spectrum of myocarditis, is characterized by an excessive inflammatory response in the heart, and can progress into dilated cardiomyopathy and irreversible heart failure in all possibility. However, effective clinical therapeutics are limited due to its complex inflammatory reactions. Empagliflozin (EMPA) has been previously demonstrated to possess anti-inflammatory properties. This study aimed to determine the improvement effects of EMPA on cardiac dysfunction under the condition of autoimmune myocarditis, and to further investigate the potential mechanisms. In vivo, all male Balb/c mice were randomly divided into four groups: control, experimental autoimmune myocarditis (EAM), EAM+EMPA and EMPA. In vitro, the effects of EMPA on IL-18-stimulated H9C2 cells were explored and the underlying molecular mechanisms were further determined. EMPA treatment significantly inhibited the development of autoimmune myocarditis, and mice treated with EMPA exhibited improved cardiac function compared with that in the EAM group, potentially through modulating pyroptosis of myocardium. Specifically, the NF-κB pathway was activated in the hearts of the EAM mice, which further activated NLRP3 inflammasome-dependent pyroptosis. EMPA treatment significantly inhibited such activation, thus alleviating inflammatory reactions in the context of EAM. Moreover, in vitro, we also observed that EMPA significantly inhibited pyroptosis of IL-18-stimulated H9C2 cells, and reduced nuclear translocation of NF-κB and degradation of activated IκBα. This work provides the first direct evidence that EMPA can inhibit myocardial inflammation and improve cardiac function in EAM mice, partly attributed to the drug-induced suppression of cardiomyocyte pyroptosis via disrupting the NF-κB pathway.

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium. It is characterized by acute onset, rapid progress and high risk of death. Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm. According to China's practical experience, the adoption of the "life support-based comprehensive treatment regimen" (with mechanical circulation support and immunomodulation therapy as the core) can significantly improve the survival rate and long-term prognosis. Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.

BACKGROUND:Intravascular ultrasound-guided percutaneous coronary intervention has been shown to result in superior clinical outcomes compared with angiography-guided percutaneous coronary intervention. However, insufficient data are available concerning the advantages of intravascular ultrasound guidance for patients with an acute coronary syndrome. This trial aimed to investigate whether the use of intravascular ultrasound guidance, as compared with angiography guidance, improves the outcomes of percutaneous coronary intervention with contemporary drug-eluting stents in patients presenting with an acute coronary syndrome. METHODS:In this two-stage, multicentre, randomised trial, patients aged 18 years or older and presenting with an acute coronary syndrome at 58 centres in China, Italy, Pakistan, and the UK were randomly assigned to intravascular ultrasound-guided percutaneous coronary intervention or angiography-guided percutaneous coronary intervention. Patients, follow-up health-care providers, and assessors were masked to random assignment; however, staff in the catheterisation laboratory were not. The primary endpoint was target vessel failure, a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularisation at 1 year after randomisation. This trial is registered at ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS:Between Aug 20, 2019 and Oct 27, 2022, 3505 patients with an acute coronary syndrome were randomly assigned to intravascular ultrasound-guided percutaneous coronary intervention (n=1753) or angiography-guided percutaneous coronary intervention (n=1752). 1-year follow-up was completed in 3504 (>99·9%) patients. The primary endpoint occurred in 70 patients in the intravascular ultrasound group and 128 patients in the angiography group (Kaplan-Meier rate 4·0% vs 7·3%; hazard ratio 0·55 [95% CI 0·41-0·74]; p=0·0001), driven by reductions in target vessel myocardial infarction or target vessel revascularisation. There were no significant differences in all-cause death or stent thrombosis between groups. Safety endpoints were also similar in the two groups. INTERPRETATION:In patients with an acute coronary syndrome, intravascular ultrasound-guided implantation of contemporary drug-eluting stents resulted in a lower 1-year rate of the composite outcome of cardiac death, target vessel myocardial infarction, or clinically driven revascularisation compared with angiography guidance alone. FUNDING:The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION:For the Mandarin translation of the abstract see Supplementary Materials section.

Objective: Despite the widespread use of doxorubicin (DOX) in chemotherapy, it can cause cardiotoxicity, which severely limits its potential clinical use. CYP2J2-derived epoxyeicosatrienoic acids (EETs) exert cardioprotective effects by maintaining cardiac homeostasis. The roles and latent mechanisms of EETs in DOX cardiotoxicity remain uncertain. We investigated these aspects using mouse tissue and cell culture models. Methods: C57BL/6J mice were injected with rAAV9-CYP2J2 or a control vector via the caudal vein. A five-week intraperitoneal course of DOX (5 mg/kg per week) was administered. After pretreatment with 14,15-EET, H9C2 cells were treated for 24-h with DOX, to use as a cell model to verify the role of EETs in cardiotoxicity in vitro. Results: CYP2J2 overexpression mitigated DOX-induced cardiotoxicity, as shown by the diminished cardiac injury marker levels, improved heart function, reduced oxidative stress, and inhibition of myocardial apoptosis in vivo. These protective roles are associated with the enhancement of antioxidant and anti-apoptotic abilities and the activation of the AMPK pathway. 14,15-EET suppresses DOX-induced oxidative stress, mitochondrial dysfunction, and apoptosis in H9C2 cells. AMPK knockdown partially abolished the cardioprotective effects of 14,15-EET against oxidative damage and apoptosis in DOX-treated cells, suggesting that AMPK is responsible for EET-mediated protection against cardiotoxicity. Conclusion: CYP2J2-derived EETs confer myocardial protection against DOX-induced toxicity by activating the AMPK pathway, which reduces oxidative stress, mitochondrial dysfunction, and apoptosis.

Background: Long-term clinical outcomes after pulmonary artery denervation (PADN) in patients with Group 1 pulmonary arterial hypertension (PAH) have not been reported.Aims: We aimed to investigate the effect of PADN on 1-year outcomes in patients with PAH.Methods: In the multicentre PADN-CFDA trial, 128 patients with Group 1 PAH were randomly assigned to PADN plus a phosphodiesterase-5 inhibitor (PDE-5i) versus a sham PADN procedure plus a PDE-5i. The principal endpoint of interest for the present study was clinical worsening at 1 year after randomisation, the composite of worsening of PAH (increase in WHO functional class, need for additional PAH treatments or PAH-related hospitalisation), atrial septostomy, listing for lung transplantation, or all-cause death.Results: One-year clinical follow-up was available in all patients. At 1 year, clinical worsening had occurred in 3 (4.8%) patients in the PADN plus PDE-5i group and in 15 patients (23.1%) in the sham plus PDE-5i group (adjusted hazard ratio: 0.17; 95% confidence interval [CI]: 0.05-0.60; p=0.006), driven by significantly increased rates of PAH-related hospitalisations, worsening functional class and the requirement for additional PAH treatments in the sham group. Results were consistent in high-risk, intermediate-risk and low-risk patients (p(interaction)=0.186). Patients treated with PADN plus PDE-5i had an improvement in the between-group change in the six-minute walking distance (6MWD) from baseline to 1 year of 81.2 m (95% CI: 50.3-112.2; p<0.001) compared with PDE-5i treatment alone.Conclusions: In this multicentre sham-controlled randomised trial, PADN treatment for Group 1 PAH significantly reduced clinical worsening and improved the 6MWD during 1-year follow-up in patients treated with a PDE-5i.

BACKGROUND:The differential treatment effect of pulmonary artery denervation (PADN) in pulmonary arterial hypertension (PAH) patients with different risk burdens remains unclear. This study aimed to determine the effectiveness of PADN in low vs intermediate-high-risk PAH patients. METHODS:In total, 128 patients with treatment naive PAH included in the PADN-CFDA trial were categorized into low-risk and intermediate-high-risk patients. The primary endpoint was the between-group difference in the change in 6-min walk distance (6 MWD) from baseline to 6 months. RESULTS:In the intermediate-high-risk group, those treated with PADN and PDE-5i had a greater improvement in 6 MWD from baseline to 6 months as compared to those treated with sham plus PDE-5i. From baseline to 6 months, pulmonary vascular resistance (PVR) was reduced by -6.1 ± 0.6 and -2.0 ± 0.7 Wood units following PADN plus PDE-5i and sham plus PDE-5i, respectively, along with the significant reduction of NT-proBNP in the intermediate-high-risk group. However, there were no significant differences in 6 MWD, PVR, and NT-proBNP between the PADN plus PDE-5i and sham plus PDE-5i groups among low-risk patients. Moreover, the right ventricular function was equally improved by PADN treatment across the low-, intermediate-, and high-risk groups. Clinical worsening was less with PADN plus PDE-5i treatment during the 6-month follow-up. CONCLUSIONS:In patients with pulmonary arterial hypertension, pulmonary artery denervation plus PDE-5i improved exercise capacity, NT-proBNP, hemodynamic, and clinical outcomes during the 6-month follow-up among intermediate-high risk patients.

Objective: Obesity is a significant risk factor for metabolic syndrome, type 2 diabetes mellitus, hypertension, nonalcoholic fatty liver disease, and cardiovascular disorders. As a well-known Chinese tea product, Besunyen Slimming Tea (BST) is believed to effectively reduce body weight (BW) and lipid profile. In this study, we aimed to elucidate the mechanisms and effects of BST on treating obesity and hepatic steatosis using a rat model fed with a high-fat diet (HFD). Methods: Sprague-Dawley rats were subjected to random separation into three categories: Animals were fed (1) a normal diet food (ND); (2) HFD, and (3) HFD + BST (n = 12/category). After successfully establishing the obesity model at week 8, the HFD + BST received BST (0.6 g/0.6 kg) orally, and the ND and HFD received the same amount (2 ml) of distilled water orally. Results: HFD + BST reduced waist circumference (7.84%, P = 0.015), food intake (14.66%, P = 0.011), final BW (12.73%, P = 0.010), BW gain (964.16%, P < 0.001), and body mass index (8.97%, P = 0.044) compared with the HFD. BST supplementation also decreased hyperlipidemia, inflammation, and insulin resistance in rats with HFD. Furthermore, BST suppressed hepatic lipidosis by decreasing de novo lipogenesis and increasing fatty acid oxidation. Conclusions: The results of this study offer evidence supporting the potential health benefits of BST in the management of metabolic disorders and obesity.

目的:探讨Stanford B型急性主动脉夹层(AAD)的临床特点及不同治疗方式对预后的影响.方法:回顾性分析947例Stanford B型主动脉夹层患者的临床资料,根据治疗方式分为非介入手术组(单纯药物治疗457例)和介入手术组(490例).统计并比较2组院内死亡率.结果:947例患者中,男789例,平均年龄(55.9±12.6)岁,女158例,平均年龄(56.8±11.4)岁.住院死亡40例(4.22％);其中非介入手术组死亡39例;介入手术组死亡1例;非介入手术组院内病死率明显高于介入手术组(8.53％vs 0.20％,P＜0.01).结论:Stanford B型AAD患者病情急,进展快,死亡风险大,尽早确诊并行适宜的介入手术治疗可明显提高患者的生存率.

Sepsis is a dysregulated systemic inflammatory response that often leads to cardiac dysfunction, which is termed sepsis-induced cardiomyopathy (SIC). Harmine, a natural β-carboline alkaloid compound, has been shown to exert pharmacological effects on several diseases. Here, we investigated whether harmine protected against SIC development and the underlying mechanisms. In vitro, the expression of the M1 phenotype markers iNOS and COX-2 was increased in RAW 264.7 cells stimulated with lipopolysaccharide (LPS), but this effect was reversed by the harmine intervention. Furthermore, LPS-induced increases in the levels of inflammatory cytokines, including IL-1β, IL-6, TNF-α, iNOS, COX-2, PGE2 and TXB2, generated by macrophages were suppressed when the cells were pretreated with harmine. Meanwhile, our findings showed that harmine administration effectively attenuated inflammation and apoptosis in H9c2 cells in the proinflammatory environment produced by macrophages, as evidenced by reductions in NLRP3 and cleaved caspase 3 levels and the p-NF-κB/NF-κB ratio. The western blot results indicated that the mechanisms underlying harmine-mediated inhibition of M1 polarization might be associated with suppression of STAT1/3, NF-κB and MAPK activation. Furthermore, an LPS injection induced cardiac dysfunction and decreased the survival rate of mice, which were alleviated by harmine treatment, and the relevant mechanism was possibly attributed to a drug-induced attenuation of the inflammatory and apoptotic processes in cardiomyocytes. Collectively, these results implied that harmine treatment protected against SIC by suppressing M1 phenotypic polarization and inflammation in macrophages.

BackgroundTo evaluate the safety and efficacy of hybutimibe plus atorvastatin for lipid control in hypercholesterolemia patients with atherosclerotic cardiovascular disease risk equivalent.MethodsIn this double-blind phase III study, we 1:1 randomly assigned 255 hypercholesterolemia patients with atherosclerotic cardiovascular disease to receive hybutimibe plus atorvastatin or placebo plus atorvastatin. The primary endpoint was the rate of change of plasma low-density lipoprotein-cholesterol (LDL-C) level at 12 weeks from baseline. The secondary endpoints were plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), non-HDL-C, apoprotein (Apo) B, and 2-, 4-, 8-, and 12-week Apo A1 levels change rate and rates of change of plasma LDL-C levels at 2, 4, and 8 weeks from baseline.ResultsFrom April 2016 to January 2018, 128 in the hybutimibe plus atorvastatin group and 125 in the atorvastatin group were included in modified intention-to-treat (mITT) analysis. After 12 weeks of treatment, LDL-C level changed from 2.61 mmol/L (±0.30) at baseline to 2.18 mmol/L (±0.45) in the hybutimibe plus atorvastatin group and from 2.58 (±0.31) mmol/L to 2.40 (± 0.46) mmol/L in the atorvastatin group (P < 0.0001), in mITT. The change rate in the hybutimibe plus atorvastatin group was significantly higher than that in the atorvastatin group (P < 0.0001); the estimated mean rates of change were −16.39 (95% confidence interval: −19.04, −13.74) and −6.75 (−9.48, −4.02), respectively. Consistently, in per-protocol set (PPS) analysis, the rate of change of LDL-C in the hybutimibe plus atorvastatin group was significantly higher than that in atorvastatin group. Significant decreases in the change rates of non-HDL-C, TC, and Apo B at 2, 4, 8, and 12 weeks (all P < 0.05) were observed for hybutimibe plus atorvastatin, while the differences were not significant for HDL-C, TG, and Apo-A1 (all P > 0.05). During the study period, no additional side effects were reported.ConclusionsHybutimibe combined with atorvastatin resulted in significant improvements in LDL-C, non-HDL-C, TC, and Apo B compared with atorvastatin alone. The safety and tolerability were also acceptable, although additional benefits of hybutimibe plus atorvastatin were not observed compared with atorvastatin alone in HDL-C, TG, and Apo-A1.

Aims:This study aimed to assess the long-term effects of pulmonary artery denervation (PADN) on mortality in patients with pulmonary arterial hypertension (PAH). Methods and results:Between March 2012 and March 2018, a total of 120 patients with PAH, who underwent PADN treatment and were prospectively followed up, were analysed. Patients were classified into World Health Organization (WHO) Functional Class I and II (FC 1-2; n=46) and Functional Class III and IV (FC 3-4; n=74) according to their FC prior to PADN. The primary endpoint was lung transplantation-free mortality until March 2021. The secondary endpoint was a change in the six-minute walk distance (6MWD). During the median of 4.8 years of follow-up, 23 (19.2%) patients died, predominantly from the FC 3-4 group (25.7%), compared to 8.7% in the FC 1-2 group (p=0.034). The mortality rate at one year (2.2% vs 12.2%, p=0.087) and three years (6.5% vs 17.6%, p=0.102) was numerically low in the FC 1-2 group versus the FC 3-4 group, respectively. The median net increase of 6MWD was +29 m in the FC 1-2 group, compared to +60.5 m in the FC 3-4 group (p=0.037). Conclusions:PADN results in significant improvements in survival at long-term follow-up, especially in patients with PAH in FC 3-4. This study was the continuation of the PADN-1 study which was registered at URL: http://www.chictr.trc.com.cn. Unique identifier: chiCTR-ONC-12002085.

目的:评估海博麦布治疗原发性高胆固醇血症的有效性和安全性.方法:本研究为多中心、随机、双盲、安慰剂平行对照的Ⅲ期临床试验.共纳入分析原发性高胆固醇血症患者373例,按2:1随机接受海博麦布(试验组,n=248)或安慰剂(对照组,n=125)20 mg/d治疗12周(治疗评价期).延伸期持续40周,两组均口服海博麦布20 mg/d.主要疗效终点为第12周低密度脂蛋白胆固醇(LDL-C)较基线的变化率,次要疗效终点为治疗评价期和延伸期其他血脂指标的变化率,同时观察用药安全性.结果:第12周试验组LDL-C较基线的变化率为(-10.23±13.58)％,显著优于对照组(4.34±15.88)％,P<0.05.试验组非高密度脂蛋白胆固醇(non-HDL-C)、总胆固醇(TC)和载脂蛋白B(Apo B)的变化率分别为(-10.81±12.28)％、(-7.92±9.88)％和(-12.06±11.32)％,均显著优于对照组的(3.22±15.90)％、(2.18±11.68)％和(0.51±13.37)％(P均<0.05),而高密度脂蛋白胆固醇、甘油三酯和载脂蛋白AI变化率的差异无统计学意义.试验组与对照组不良反应的发生率在第12周分别为4.55％和8.40％,在延伸期分别为4.43％和7.07％,未发现新的或加重的与海博麦布可能相关的不良事件.结论:海博麦布可以有效降低原发性高胆固醇血症患者的LDL-C、non-HDL-C、TC和Apo B水平,降脂效果可长期持续,不良反应发生率低,耐受性好.

BACKGROUND:World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH) is a progressive, debilitating disease. Previous observational studies have demonstrated that pulmonary artery denervation (PADN) reduces pulmonary artery pressures in PAH. However, the safety and effectiveness of PADN have not been established in a randomized trial. OBJECTIVES:The aim of this study was to determine the treatment effects of PADN in patients with group 1 PAH. METHODS:Patients with WHO group 1 PAH not taking PAH-specific drugs for at least 30 days were enrolled in a multicenter, sham-controlled, single-blind, randomized trial. Patients were assigned to receive PADN plus a phosphodiesterase-5 inhibitor or a sham procedure plus a phosphodiesterase-5 inhibitor. The primary endpoint was the between-group difference in the change in 6-minute walk distance from baseline to 6 months. RESULTS:Among 128 randomized patients, those treated with PADN compared with sham had a greater improvement in 6-minute walk distance from baseline to 6 months (mean adjusted between-group difference 33.8 m; 95% CI: 16.7-50.9 m; P < 0.001). From baseline to 6 months, pulmonary vascular resistance was reduced by -3.0 ± 0.3 WU after PADN and -1.9 ± 0.3 WU after sham (adjusted difference -1.4; 95% CI: -2.6 to -0.2). PADN also improved right ventricular function, reduced tricuspid regurgitation, and decreased N-terminal pro-brain natriuretic peptide. Clinical worsening was less (1.6% vs 13.8%; OR: 0.11; 95% CI: 0.01-0.87), and a satisfactory clinical response was greater (57.1% vs 32.3%; OR: 2.79; 95% CI: 1.37-5.82) with PADN treatment during 6-month follow-up. CONCLUSIONS:In patients with WHO group 1 PAH, PADN improved exercise capacity, hemodynamic status, and clinical outcomes during 6-month follow-up. (Safety and Efficacy of Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension [PADN-CFDA]; NCT03282266).

Aims: This study aimed to assess the long-term effects of pulmonary artery denervation (PADN) on mortality in patients with pulmonary arterial hypertension (PAH). Methods and results: Between March 2012 and March 2018, a total of 120 patients with PAH, who underwent PADN treatment and were prospectively followed up, were analysed. Patients were classified into World Health Organization (WHO) Functional Class I and II (FC 1-2; n=46) and Functional Class III and IV (FC 3-4; n=74) according to their FC prior to PADN. The primary endpoint was lung transplantation-free mortality until March 2021. The secondary endpoint was a change in the six-minute walk distance (6MWD). During the median of 4.8 years of follow-up, 23 (19.2%) patients died, predominantly from the FC 3-4 group (25.7%), compared to 8.7% in the FC 1-2 group (p=0.034). The mortality rate at one year (2.2% vs 12.2%, p=0.087) and three years (6.5% vs 17.6%, p=0.102) was numerically low in the FC 1-2 group versus the FC 3-4 group, respectively. The median net increase of 6MWD was +29 m in the FC 1-2 group, compared to +60.5 m in the FC 3-4 group (p=0.037). Conclusions: PADN results in significant improvements in survival at long-term follow-up, especially in patients with PAH in FC 3-4. This study was the continuation of the PADN-1 study which was registered at URL: http://www.chictr.trc.com.cn. Unique identifier: chiCTR-ONC-12002085.

Background. Doxorubicin (DOX) is one of the most potent and widely prescribed antitumor agents; however, its clinical use is limited by cardiac side effects. In this study, we aimed to clarify the protective effects of Qiliqiangxin (QL), a traditional Chinese medicine formulation, on DOX-induced cardiotoxicity and to explore the underlying mechanisms in a rat model. Methods. Male Sprague-Dawley rats were randomly assigned to three groups with different interventions (control, DOX, and DOX plus QL) for 31 days. Cardiac function was monitored. The levels of oxidative stress in plasm were detected, the activities of autophagy and apoptosis in rat hearts were determined, and then, the related PI3K/AKT/mTOR signal pathway regulating apoptosis and autophagy was investigated. Results. QL improved cardiac dysfunction and decreased the increased level of cardiac enzymes in plasm caused by DOX. Moreover, DOX exposure resulted in oxidative stress enhancement, which was suppressed by QL treatment. Then, we discovered that DOX intervention caused the apoptosis of cardiomyocytes by activating the mitochondrial-dependent apoptotic pathway which was strongly inhibited by QL treatment. Furthermore, there was a significant increase in autophagic activities in the DOX-stimulated myocardium. Administration of QL substantially inhibited the enhanced autophagic activities, which might be attributed to the activation of PI3K/AKT/mTOR cascade, followed by suppression of ULK1 activity. Conclusions. QL exhibited protective roles against DOX-induced cardiotoxicity possibly via mediating the PI3K/AKT/mTOR pathway, leading to inhibition of autophagy and subsequent apoptosis activities.

Abstract Background and purpose: Hybutimibe is proved to be safe in healthy adults by a phase I study. A multi-center, randomized, double-blind phase II clinical trial evaluated its effectiveness and safety of Hybutimibe in the treatment of primary hypercholesterolemia. Methods: A total of 244 patients between August 2014 and August 2015, with primary hypercholesterolemia from 15 centers in China were enrolled and randomly assigned to receive placebo, ezetimibe, or hybutimibe 5, 10, or 20 mg/day in a 1:1:1:1:1 ratio. The primary outcome was evaluated from the change rate of low-density lipoprotein cholesterol (LDL-C) at week 8 from baseline, whereas secondary outcomes were evaluated from the change rates of LDL-C, TC, TG, HDL-C, non-HDL-C, APO-B, APO-A1 at weeks 1, 2, 4, and 8 from baseline. Results: After 8 weeks of treatment, the average decrease rate of LDL-C was −20.01% for ezetimibe, −10.84% (95% CI: −14.67, −7.00) for hybutimibe 5 mg/day, −17.06% (95% CI: −20.83, −13.29) for hybutimibe 10 mg/day, and −17.04% (95% CI: −20.30, −13.79) for hybutimibe 20 mg/day, respectively. The change rates of TC, non-HDL-C, and APO-B levels were significantly improved in all treatments compared with placebo (P < 0.05), whereas changes in the above lipid profiles of hybutimibe 20 mg/day were similar with ezetimibe. In terms of safety, the most common adverse events were elevation in ALT, gastrointestinal reaction, dizziness, and headache. Conclusions: This clinical study found that hybutimibe with the least dose of 5 mg/day effectively improved the LDL-C, TC, non-HDL-C, and APO-B levels in patients with primary hyperlipidemia with good tolerance and safety with no significant effect on TG levels.