Abstract Background The diabetic heart exhibits a high sensitivity to ischaemia/reperfusion (I/R) injury. Diabetes mellitus (DM) can affect the efficacy of cardioprotective interventions and reduce the therapeutic potential of existing treatment options. This study aimed to investigate the feasibility of shifting from monotherapy to combination therapy in diabetic myocardial I/R injury. Methods 6–8 week rats were randomized into 10 groups: sham, I/R, ischaemia postconditioning (I-Post), nicorandil (Nic), combination therapy (I-Post + Nic), DM sham, DM I/R, DM I-Post, DM Nic and DM I-Post + Nic. The extent of myocardial injury was clarified by measuring CK-MB and NO levels in plasma, ROS content in myocardial tissues, and TTC/Evans Blue staining to assess the area of myocardial infarction. Pathological staining of cardiac tissue sections were performed to clarify the structural changes in myocardial histopathology. Finally, Western blotting was performed to detect the phosphorylation levels of some key proteins in the PI3K/Akt signalling pathway in myocardial tissues. Results We confirms that myocardial injury in diabetic I/R rats remained at a high level after treatment with I-Post or nicorandil alone. I-Post combined with nicorandil showed better therapeutic effects in diabetic I/R rats, and the combined treatment further reduced the area of myocardial injury in diabetic I/R rats compared with I-Post or nicorandil treatment alone ( P < 0.001), as well as the levels of the myocardial injury markers CK-MB and ROS ( P < 0.001); it also significantly increased plasma NO levels. Pathological staining also showed that diabetic rats benefited significantly from the combination therapy. Further mechanistic studies confirmed this finding. The protein phosphorylation levels of PI3K/Akt signalling pathway in the heart tissue of diabetic I/R rats were significantly higher after the combination treatment than after one treatment alone (all P < 0.05). Conclusion I-Post combined with nicorandil treatment maintains effective cardioprotection against diabetic myocardial I/R injury by activating the PI3K/Akt signalling pathway.
Objectives. To study trends of utilization, in-hospital outcomes, and short outcomes in patients undergoing transcatheter mitral valve repair (TMVR) vs. surgical mitral valve repair (SMVR) in atrial fibrillation (AF). Background. TMVR is a treatment option in inoperable or high-risk patients with mitral regurgitation (MR). AF is a common comorbidity of MR. Data comparing between TMVR and SMVR in MR patients with AF is lacking. Methods. The National Readmission Database from 2016 to 2019 was utilized to identify hospitalizations undergoing TMVR or SMVR with AF. Outcomes of interest included mortality, postoperative complications, length of stay, and 30-day readmission rate. Results. A total of 9,195 patients underwent TMVR and 16,972 patients underwent SMVR with AF; the number of AF undergoing TMVR was increasing from 1,342 in 2016 to 4,215 in 2019 and SMVR. The incidence of in-hospital mortality decreased from 2.6% in 2016 to 1.8% in 2019. We identified length of stay>5 days, dyslipidemia, cerebrovascular disease, heart failure with reduced ejection fraction, and urgent/emergent admissions as independent risk factors for in-hospital mortality. After matching, we included 4,680 patients in each group; the in-hospital death, transfusion, acute kidney injury, sepsis, stroke, and mechanical ventilation were lower in TMVR compared with SMVR. TMVR was associated with a similar rate of all-cause readmission at 30 days compared with SMVR. Conclusion. Patients with AF receiving TMVR have been increasing along with progressive improvement in in-hospital death and length of stay. Compared to SMVR, AF patients receiving TMVR had a lower rate of in-hospital death and postoperative complications.
Few researchers have discussed the differences in gender between the age groups of patients who underwent transcatheter aortic valve implantation (TAVI). We searched the National Readmissions Database from 2012 to 2019 to identify adults who underwent TAVI. We studied hospital outcomes and short- to medium-term outcomes by age stratification (18 to 59, 60 to 69, 70 to 79, and 80 to 90 years) after TAVI and categorized by gender. We included 147,481 patients who underwent TAVI, and 54,802 pairs were matched using propensity score matching separately for each age group. Compared with men, women in all age groups had a similar rate of hospital death. Except the 18- to 59-year-old groups, female patients were less likely to undergo permanent pacemaker implantation and transfusion. Records of readmission at 30 days and 6 months were used as the follow-up outcome according to the presence or absence of readmission. Major adverse cardiovascular events (MACEs) were a composite of cardiovascular readmission, all-cause mortality during readmission, and stroke readmission. At the 30-day follow-up visit, there was no difference in the all-cause readmission and MACE between women and men in any group. At the 6-month follow-up visit, women in the 70- to 79-year-old and 80- to 90-year-old groups had a high risk of all-cause readmission. In conclusion, we reported that female patients have similar in-hospital death rates to male patients who underwent TAVI. During the 30-day follow-up visit, the all-cause readmission and MACE were not different in all age groups between men and women. At 6 months, women in the 70- to 79-year-old and 80- to 90-year-old groups had a higher risk of all-cause readmission.
Diabetes mellitus significantly escalates the risk of accelerated atherosclerosis (AS), severely affecting cardiovascular health. Our research, leveraging Gene Expression Omnibus (GEO) database analysis (GSE118481), revealed diminished TFPI2 expression in diabetic patients' atherosclerotic plaques. Further validation in carotid artery plaques and an AS mouse model confirmed TFPI2's reduced expression in diabetes. Through TFPI2 knockdown in non-diabetic mice, we observed aggravated plaque burden and increased inflammatory M1 macrophage polarization. Conversely, TFPI2 overexpression in diabetic mice improved plaque stability and induced reparative M2 macrophage polarization, countering hyperglycemia's negative effects. Mechanistically, transcription factor activator protein 2α (AP-2α) is a repressor of PPPARg transcription, and the interaction of TFPI2 with the transcription factor AP-2α blocks AP-2α binding to the PPARγ gene promoter, which is essential for PPARγ-mediated transcription and the transition from M1 to M2 macrophages. Additionally, hyperglycemia-induced DNA methyltransferase 1 (DNMT1) upregulation heightens TFPI2 methylation, reducing its expression. Our findings spotlight the TFPI2/AP-2α/PPARγ axis as crucial in diabetic AS modulation, proposing its targeting as a new therapeutic strategy to halt diabetes-driven AS progression, highlighting TFPI2's therapeutic promise in addressing diabetes-related cardiovascular issues.
Abstract BACKGROUND Diabetes mellitus exhibits a high sensitivity to myocardial ischemia-reperfusion injury (MIRI), which can affect the efficacy of cardioprotective interventions, and its complexity significantly reduces the therapeutic potential of existing treatment options. This study was dedicated to investigate the feasibility of shifting from monotherapy to combination therapy in diabetic MIRI. METHODS Rats were randomized into 10 groups: non-diabetic rats included: sham-operated (Sham), ischemia-reperfusion (I/R), ischemia postcondtioning (I-Post), nicorandil (Nic), and combination therapy (I-Post + Nic); diabetic rats included: DM Sham, DM I/R, DM I-Post, DM Nic and DM I-Post + Nic. The T2DM rats were induced by injection of low-dose streptozotocin (30 mg/kg) and supplemented with high-fat and high-sugar chow to establish a myocardial ischemia-reperfusion model. CK-MB, NO levels, ROS content, and myocardial infarct area were measured. HE staining of cardiac tissue sections, TUNEL staining of cardiac tissue sections, WGA immunofluorescence staining, and protein blotting (western blotting) were used to detect myocardial tissue PI3K, Akt, GSK3β, mToR, and eNOS protein phosphorylation levels. RESULTS We found that diabetes impaired the cardioprotective effects of I-Post and nicorandil against MIRI injury compared with non-diabetic I/R rats. Compared with diabetic I/R rats treated with I-Post (41.13% ± 2.17%, 454.64 ± 13.434 µm 2 ) or nicorandil (41.54 ± 1.45%, 439.95 ± 15.087 µm 2 ) alone, I-Post combined with nicorandil treatment (30.67% ± 1.38%, 344.45 ± 13.434 µm 2 ) significantly reduced IS/AAR ( P < 0.001) and cardiac cell cross sectional area ( P < 0.001), reduced the extent of myocardial tissue injury and decreased pathological scores after I/R ( P < 0.001), inhibited myocardial apoptosis ( P < 0.001), decreased plasma central infarct marker CK-MB levels ( P < 0.001), and increased NO levels ( P < 0.001). In addition, combination treatment increased the phosphorylation levels of PI3K, Akt, GSK3β, mToR, and eNOS ( P < 0.001). CONCLUSION I-Post combined with nicorandil treatment maintains effective cardioprotection against diabetic MIRI by activating PI3K/Akt signaling pathway.
Abstract Background Diabetes mellitus is one of the causes of poor ventricular remodelling and poor cardiac recovery after myocardial infarction (MI). We previously reported that tissue factor pathway inhibitor-2 (TFPI2) was downregulated in response to hyperglycaemia and that it played a pivotal role in extracellular matrix (ECM) degradation and cell migration. Nonetheless, the function and mechanism of TFPI2 in post-MI remodelling under diabetic conditions remain unclear. Therefore, in the present study, we investigated the role of TFPI2 in post-MI effects in a diabetic mouse model. Results TFPI2 expression was markedly decreased in the infarcted myocardium of diabetic MI mice compared with that in non-diabetic mice. TFPI2 knockdown in the MI mouse model promoted fibroblast activation and migration as well as matrix metalloproteinase (MMP) expression, leading to disproportionate fibrosis remodelling and poor cardiac recovery. TFPI2 silencing promoted pro-inflammatory M1 macrophage polarization, which is consistent with the results of TFPI2 downregulation and M1 polarization under diabetic conditions. In contrast, TFPI2 overexpression in diabetic MI mice protected against adverse cardiac remodelling and functional deterioration. TFPI2 overexpression also inhibited MMP2 and MMP9 expression and attenuated fibroblast activation and migration, as well as excessive collagen production, in the infarcted myocardium of diabetic mice. TFPI2 promoted an earlier phenotype transition of pro-inflammatory M1 macrophages to reparative M2 macrophages via activation of peroxisome proliferator-activated receptor gamma. Conclusions This study highlights TFPI2 as a promising therapeutic target for early resolution of post-MI inflammation and disproportionate ECM remodelling under diabetic conditions.
Objective: To establish 3-{4-[2-hydroxyl-(1-methylethylamino) propoxy] phenyl} propionic acid cetylesters (PAC) modified nanoparticles, and preliminarily explore its cardiomyocyte-targeting function and protection effects on myocardium. Methods: (1) HL-1 myocardial cells were divided into cyanidin-3 (Cy3) marked non-targeted small interference RNA (Cy3-siNC) group and Cy3 marked small interference RNA designed for the nuclear factor kappa B (NF-κB)-p65 gene (Cy3-si435) group according to the random number table, with 3 wells in each group. Cells in Cy3-siNC group were transfected with Cy3-siNC, while cells in Cy3-si435 group were transfected with Cy3-si435. At transfection hour 24, the mRNA expression of NF-κB-p65 of cells was determined by real-time fluorescent quantitative polymerase chain reaction. (2) Multiple emulsificating solvent evaporating method was adopted to prepare PAC modified nanoparticles carried with Cy3-siNC (Cy3-siNC-PAC) and PAC modified nanoparticles carried with Cy3-si435 (Cy3-si435-PAC). The morphology of Cy3-si435-PAC nanoparticles was observed with scanning electron microscope, and the size and potential of Cy3-si435-PAC nanoparticles were detected by nanometer particle size and zeta potential analyzer. The entrapment efficiency and drug loadings of Cy3-si435-PAC nanoparticle were determined with ultraviolet spectrophotometer. The release of Cy3-si435 of Cy3-si435-PAC nanoparticles was determined by dialysis method. (3) Another batch of HL-1 cells were divided into 4 groups according to the random number table, with 9 wells in each group. Cells in negative control group were added with 5 μL phosphate buffer. Cells in 25, 50, and 100 mg/mL Cy3-si435-PAC nanoparticles groups were added with 5 μL 25, 50, and 100 mg/mL Cy3-si435-PAC nanoparticles, respectively. At transfection hour 6, 12, and 24, proliferation activity of cells in 3 wells of each group was detected by methyl thiazolyl tetrazolium method, respectively. (4) Another batch of HL-1 cells were cultured for 24 h, and then treated with 100 μL Cy3-si435-PAC nanoparticles. At transfection hour 0, 4, 8, 12, and 24, the percentage of cells uptaking Cy3-si435-PAC nanoparticles in 3 wells were detected by flow cytometry, respectively. (5) Another batch of HL-1 cells were divided into 2 groups according to the random number table, with 3 wells in each group. Cells in Cy3-siNC-PAC group were added with 100 μL Cy3-siNC-PAC nanoparticles, while cells in Cy3-si435-PAC group were added with 100 μL Cy3-si435-PAC nanoparticles. At transfection hour 24, the mRNA expression of NF-κB-p65 of cells was determined by real-time fluorescent quantitative polymerase chain reaction. (6) Six male C57BL/6J mice were divided into 2 groups according to the random number table, with 3 mice in each group. Mice in Cy3-siNC-lipopolysaccharide (LPS) group and Cy3-si435-LPS group were respectively injected with 500 μL Cy3-siNC-PAC nanoparticles and Cy3-si435-PAC nanoparticles (50 mg/mL) in the tail vein. At injection hour 24, mice in the two groups were intraperitoneally injected with 10 mg/kg LPS to induce myocardial injury. At post injury hour 24, the distribution of nanoparticles in mice was detected with small animal imager. (7) Another 9 male C57BL/6J mice were divided into 3 groups according to the random number table, with 3 mice in each group. Mice in Cy3-siNC-normal saline (NS) group and Cy3-siNC-LPS group were injected with 500 μL 50 mg/mL Cy3-siNC-PAC nanoparticles in the tail vein, while mice in Cy3-si435-LPS group were injected with 500 μL 50 mg/mL Cy3-si435-PAC nanoparticles. At injection hour 24, mice in Cy3-siNC-NS group were intraperitoneally injected with NS, while mice in Cy3-siNC-LPS group and Cy3-si435-LPS group were injected with 10 mg/kg LPS to induce myocardial injury. At post injury hour 24, pathological changes of myocardium of mice in each group were observed with HE staining. Data were processed with t test and one-way analysis of variance. Results: (1) The mRNA expression of NF-κB-p65 of cells in Cy3-si435 group was 0.183±0.004, significantly lower than 1.003±0.092 in Cy3-siNC group (t=15.46, P<0.01). (2) The form of prepared Cy3-si435-PAC nanoparticles was good, with particle size of 146.0 nm, potential of -29.2 mV, entrapment efficiency of (86.9±1.1) %, drug loadings of (25.4±0.9) %, and stable Cy3-si435 release. (3) At transfection hour 6, 12, and 24, there were no statistically significant differences in proliferation activity of cells in the 4 groups (with F values from 0.129 to 2.512, P values above 0.05). (4) At transfection hour 0, 4, 8, 12, and 24, the percentages of cells uptaking Cy3-si435-PAC nanoparticles were (0.79±0.06)%, (31.04±1.59)%, (51.64±2.67)%, (68.15±2.60)%, and (83.68±4.67)%, respectively. (5) The mRNA expression of NF-κB-p65 of cells in Cy3-si435-PAC group was 0.286±0.015, significantly lower than 1.002±0.073 in Cy3-siNC-PAC group (t=16.62, P<0.01). (6) At post injury hour 24, uniform distribution of nanoparticles could be observed in cardiomyocytes of mice in Cy3-siNC-LPS group and Cy3-si435-LPS group. (7) The structure of myocardial fibers of mice in Cy3-siNC-NS group was dense, with no inflammatory cells infiltration and uniform distribution of cytoplasm. The structure of myocardial fibers of mice in Cy3-siNC-LPS group were loose, with inflammatory cells infiltration and scattered distribution of cytoplasm. The structure of myocardial fibers of mice in Cy3-si435-LPS group was denser, with no obvious inflammatory cells infiltration and uniform distribution of cytoplasm. Conclusions: Cy3-si435-PAC nanoparticles have good morphology, uniform particle size, normal potential distribution, and no cell cytotoxicity. Cy3-si435-PAC nanoparticles can be effectively uptaked by HL-1 cells and suppress NF-κB-p65 mRNA expression. They also can effectively target to mice cardiomyocytes to reduce inflammatory cells infiltration and alleviate the myocardial injury of mice induced by LPS.目的： 制备3－{ 4－[ 2－羟基－ (1－甲基乙胺基) 丙氧基]苯基}丙酸十六醇酯 (PAC) 修饰的纳米粒，观察其对心肌细胞的靶向性及对心肌的保护作用。 方法： (1)将HL－1心肌细胞按随机数字表法分成花青素Cy3标记的非靶向小干扰RNA(Cy3－siNC)组和针对NF－κB－p65基因设计的花青素Cy3标记的小干扰RNA(Cy3－si435)组，每组3孔。Cy3－siNC组细胞转染Cy3－siNC，Cy3－si435组细胞转染Cy3－si435。转染24 h，实时荧光定量PCR检测细胞NF－κB－p65 mRNA的表达。(2)采用复乳溶剂挥发法制备PAC修饰且载有Cy3－siNC(Cy3－siNC－PAC)的纳米粒和PAC修饰且载有Cy3－si435(Cy3－si435－PAC)的纳米粒。扫描电镜观察Cy3－si435－PAC纳米粒的形态，纳米粒度及zeta电位仪检测Cy3－si435－PAC纳米粒的粒径和电势，紫外分光光度计测定Cy3－si435－PAC纳米粒的包封率、载药量，透析法测定Cy3－si435－PAC纳米粒的Cy3－si435释放量。(3)另取HL－1细胞，按随机数字表法分成4组，每组9孔。阴性对照组加入5 μL PBS；25、50、100 mg/mL Cy3－si435－PAC纳米粒组分别加入5 μL 25、50、100 mg/mL的Cy3－si435－PAC纳米粒。分别于转染6、12、24 h时，每组各取3孔，噻唑蓝法检测细胞的增殖活性。(4)另取HL－1细胞，培养24 h后加入100 μL Cy3－si435－PAC纳米粒。分别于转染0、4、8、12、24 h时各取3孔细胞，流式细胞仪检测摄取Cy3－si435－PAC纳米粒的细胞百分比。(5)另取HL－1细胞，按随机数字表法将细胞分成2组，每组3孔。Cy3－siNC－PAC组加入100 μL Cy3－siNC－PAC纳米粒，Cy3－si435－PAC组加入100 μL Cy3－si435－PAC纳米粒。转染24 h，实时荧光定量PCR检测细胞NF－κB－p65 mRNA的表达。(6)取6只雄性C57BL/6J小鼠，按随机数字表法分为2组，每组3只。Cy3－siNC－LPS组和Cy3－si435－LPS组小鼠尾静脉分别注射500 μL Cy3－siNC－PAC纳米粒和Cy3－si435－PAC纳米粒(50 mg/mL)，注射后24 h，再分别腹腔注射LPS(10 mg/kg)，诱导心肌损伤。伤后24 h，小动物成像仪检测纳米粒在小鼠体内的分布情况。(7)另取9只雄性C57BL/6J小鼠，按随机数字表法分为3组，每组3只。Cy3－siNC－生理盐水(NS)组和Cy3－siNC－LPS组小鼠尾静脉注射500 μL 50 mg/mL的Cy3－siNC－PAC纳米粒，Cy3－si435－LPS组小鼠注射500 μL 50 mg/mL的Cy3－si435－PAC纳米粒。注射后24 h，Cy3－siNC－NS组小鼠腹腔注射NS；Cy3－siNC－LPS组和Cy3－si435－LPS组小鼠腹腔注射10 mg/kg LPS，诱导心肌损伤。伤后24 h，取各组小鼠心肌组织，HE染色观察心肌病理变化。对数据行t检验、单因素方差分析。 结果： (1)Cy3－si435组细胞NF－κB－p65 mRNA表达量为0.183±0.004，明显低于Cy3－siNC组的1.003±0.092(t＝15.46，P<0.01)。(2)制备的Cy3－si435－PAC纳米粒形态良好，粒径大小为146.0 nm，电势为－29.2 mV，包封率为(86.9±1.1)%，载药量为(25.4±0.9)%，Cy3－si435释放稳定。(3)转染6、12、24 h，4组细胞增殖活性总体比较，差异均无统计学意义(F值为0.129～2.512，P值均大于0.05)。(4)转染0、4、8、12、24 h时，摄取Cy3－si435－PAC纳米粒的细胞百分比分别为(0.79±0.06)%、(31.04±1.59)%、(51.64±2.67)%、(68.15±2.60)%、(83.68±4.67)%。(5)Cy3－si435－PAC组细胞NF－κB－p65 mRNA的表达量为0.286±0.015，明显低于Cy3－siNC－PAC组细胞的1.002±0.073(t＝16.62，P<0.01)。(6)伤后24 h，Cy3－siNC－LPS组和Cy3－si435－LPS组小鼠心肌细胞都能够观察到分布均匀的纳米粒。(7)Cy3－siNC－NS组小鼠心肌纤维结构致密，无炎性细胞浸润，胞质分布均匀；Cy3－siNC－LPS组小鼠心肌纤维结构疏松，炎性细胞浸润，胞质分布散乱；Cy3－si435－LPS组小鼠心肌纤维结构较致密，未见明显炎性细胞浸润，胞质分布均匀。 结论： Cy3－si435－PAC纳米粒形态良好，粒径大小均一，电势分布正常，无细胞毒性；能够被HL－1细胞有效摄取并抑制细胞NF－κB－p65 mRNA的表达；能够有效靶向到小鼠心肌细胞并减少炎性细胞浸润，减轻LPS诱导的小鼠心肌损伤。.
This study aimed to analyze in-hospital and early-to-interim outcomes of pure aortic regurgitation (AR) using transcatheter aortic valve replacement (TAVR) vs. surgical aortic valve replacement (SAVR).Few studies have discussed and compared the safety and short-term prognosis of TAVR and SAVR in pure AR patients. As such, we looked to the National Readmissions Database (NRD) for records between 2016 and 2019 in order to identify patients diagnosed with pure AR who underwent SAVR or TAVR. We used the propensity score matching to minimize disparities between two groups. We included 23,276 pure AR patients: 1983 (8.5%) who underwent TAVR and 21,293 (91.5%) who underwent SAVR. We found 1820 matched pairs using propensity score matching. In the matching cohort, TAVR was associated with a low risk of in-hospital mortality. Although TAVR had lower incidences of 30-day all-cause readmission (hazard ratio (HR):0.73, 95% confidence interval (CI): 0.61-0.87; P < 0.01) and 6-month all-cause readmission (HR: 0.81, 95% CI: 0.67-0.97; P = 0.03), while TAVR had high incidences of 30-day permanent pacemaker implantation incidence (HR: 3.54, 95% CI: 1.62-7.74; P < 0.01) and 6-month permanent pacemaker implantation incidence (HR: 4.12, 95% CI: 1.17-14.4; P = 0.03).In conclusion, TAVR and SAVR had similar risks of hospital death and lower rates of 30-day and 6-month all-cause and cardiovascular readmission. But TAVR had a higher risk of permanent pacemaker implantation than SAVR in AR patients, suggesting that TAVR can be performed safely in pure AR patients.
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