Similarities and differences of myocardial metabolic characteristics between HFpEF and HFrEF mice based on LC-MS/MS metabolomics / 中华心血管病杂志

Objective: To reveal the similarities and differences in myocardial metabolic characteristics between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) mice using metabolomics. Methods: The experimental mice were divided into 4 groups, including control, HFpEF, sham and HFrEF groups (10 mice in each group). High fat diet and Nω-nitroarginine methyl ester hydrochloride (L-NAME) were applied to construct a"two-hit"HFpEF mouse model. Transverse aortic constriction (TAC) surgery was used to construct the HFrEF mouse model. The differential expression of metabolites in the myocardium of HFpEF and HFrEF mice was detected by untargeted metabolomics (UHPLC-QE-MS). Variable importance in projection>1 and P<0.05 were used as criteria to screen and classify the differentially expressed metabolites between the mice models. KEGG functional enrichment and pathway impact analysis demonstrated significantly altered metabolic pathways in both HFpEF and HFrEF mice. Results: One hundred and nine differentially expressed metabolites were detected in HFpEF mice, and 270 differentially expressed metabolites were detected in HFrEF mice. Compared with the control group, the most significantly changed metabolite in HFpEF mice was glycerophospholipids, while HFrEF mice presented with the largest proportion of carboxylic acids and their derivatives. KEGG enrichment and pathway impact analysis showed that the differentially expressed metabolites in HFpEF mice were mainly enriched in pathways such as biosynthesis of unsaturated fatty acids, ether lipid metabolism, amino sugar and nucleotide sugar metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and arginine and proline metabolism. The differentially expressed metabolites in HFrEF mice were mainly enriched in arginine and proline metabolism, glycine, serine and threonine metabolism, pantothenate and CoA biosynthesis, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism and arachidonic acid metabolism, etc. Conclusions: HFpEF mice have a significantly different myocardial metabolite expression profile compared with HFrEF mice. In addition, biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, glycerophospholipid metabolism and arginine and proline metabolism are significantly altered in both HFpEF and HFrEF mice, suggesting that these metabolic pathways may play an important role in disease progression in both types of heart failure.

Association between cardiometabolic diseases and quality of life and the mediation effect of perceived stress / 中华心血管病杂志

Objective: To explore the association between cardiometabolic diseases (CMD) and quality of life, the association between CMD and perceived stress, and the mediation effect of perceived stress on the association between CMD and quality of life, and to provide evidence for the prevention and treatment of CMD and the improvement of quality of life in these patients. Methods: This is a cross-sectional study. Data were collected by the employees' physical examination of a company in Xi'an in 2021. Multiple linear regression models were used to analyze the association between the status of CMD (divided into three categories: no CMD, presence of one kind of CMD, and with≥2 kinds of CMD (≥2 kinds of CMD were defined as cardiometabolic multimorbidity (CMM)), quality of life, and perceived stress. Mediation analysis with a multi-categorical independent variable was conducted to determine the mediation effect of perceived stress on the association between CMD and quality of life. Results: Among all 4 272 participants, 1 457 (34.1%) participants had one kind of CMD and 677 (15.8%) participants had CMM. The average scores for quality of life and perceived stress were (57.5±15.7) and (16.9±7.9), respectively. Compared with participants without CMD, after adjusting for demographic and lifestyle factors, no statistically significant associations were observed between one kind of CMD and perceived stress or quality of life (both P>0.05). Perceived stress did not mediate the association between one kind of CMD and quality of life. However, participants with CMM had lower quality of life and higher perceived stress than participants without CMD. The relative total effect coefficient c (95%CI) and the relative direct effect coefficient c' (95%CI) between CMM and quality of life were -3.71 (-5.04--2.37) and -2.52 (-3.81--1.24) (both P<0.05), respectively. The relative indirect effect coefficient a2b (95%CI) of perceived stress on the association between CMM and quality of life was -1.18 (-1.62--0.77) (P<0.05). The mediation effect size was 31.8%. Conclusions: CMM is negatively associated with quality of life and positively associated with perceived stress. Perceived stress partially mediates the association between CMM and quality of life. Our results suggest that, in addition to preventing and treating CMM actively, efforts should be taken to relieve the perceived stress of people with CMM to improve their quality of life.

Efficacy and safety of various doses of hybutimibe monotherapy or in combination with atorvastatin for primary hypercholesterolemia: a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial / 中华心血管病杂志

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.

Renal protective and anti-apoptotic functions of erythropoietin in ze-brafish embryonic development / 中国病理生理杂志

AIM:To analyze zebrafish embryos and to identify erythropoietin (Epo) as an active renal anti-apoptotic factor in an Epo receptor (EpoR)-dependent manner. METHODS:For transient knockdown of Epo and EpoR in renal Tg (wt1b:EGFP) zebrafish reporter lines, the morpholino antisense oligonucleotide technique was used. Morphant zebrafish embryos were phenotypically analyzed using fluorescence microscopy. Apoptosis was determined by TUNEL assay and Annexin V staining. Western blot was used to identify Akt phosphorylation in Epo and EpoR knockdown zebrafish. RE-SULTS:Epo and EpoR zebrafish morphants exhibited pathophysiological changes within the pronephros, adversely affecting pronephric structure. Zebrafish embryos upon silencing of Epoa and EpoR showed a significant increase in the apoptosis within the zebrafish pronephros, consequently leading to renal pathophysiological effects. Decreased p-Akt was identified in Epo and EpoR knockdown zebrafish embryos. CONCLUSION:Epo is an essential regulator of renal development and function by interacting with its receptor EpoR and thereby repressing apoptosis, mechanistically by promoting Akt phospho-rylation.

Pioglitazone ameliorates atherosclerosis in apoE knockout mice through transforming growth factor-β/Smad signaling and adaptive T cell immunity / 南方医科大学学报

<p><b>OBJECTIVE</b>To examine whether transforming growth factor-β (TGF-β) pathway and adaptive T cell immunity play roles in the anti-atherosclerotic effects of pioglitazone (PIO) in ApoEmice.</p><p><b>METHODS</b>ApoEmice with atherosclerosis induced by high-fat feeding were treated daily with PIO (20 mg/kg) or vehicle for 8 weeks. The protein expressions of TGF-β pathway in the atheromatous lesions of the aorta and the percentages of IFN-γand Foxp3cells in the spleen of the mice were examined with immunohistochemical staining. In the in vitro experiment, primary cultured splenocytes were stimulated with oxidized low-density lipoproteins (oxLDL) and treated with PIO either alone or in combination with the PPARγ antagonist GW9662, after which the changes in percentages of CD4IFN-γcells and CD4CD25Foxp3cells were analyzed with flow cytometry.</p><p><b>RESULTS</b>PIO treatment of ApoEmice with high-fat feeding significantly attenuated the progression of atheromatous lesions (P<0.05) and resulted in increased expressions of TGFβ1 (P<0.01), TGFβRII (P<0.05), and p-Smad3 (P<0.05) and a decreased expression of Smad7 (P<0.05) in the lesions. PIO treatment also led to decreased percentage of IFN-γcells (P<0.05) and increased percentage of Foxp3cells (P<0.01) in the spleen of the mice. In primary cultured splenocytes, PIO treatment caused significant down-regulation of IFN-γ mRNA (P<0.05) and up-regulation of Foxp3 mRNA (P<0.05) and obviously increased the percentages of CD4IFN-γcells (P<0.05) and CD4CD25Foxp3(P<0.05); the effects of PIO on CD4IFN-γand CD4CD25Foxp3cells were abolished by treatment of the cells with GW9662.</p><p><b>CONCLUSION</b>The anti-atherosclerotic effect of PIO is probably mediated by the TGF-β/Smad signaling pathway and PPAR-γ-dependent modulation of Th1/Treg population.</p>

Regression analysis of red cell distribution width and mean platelet volume in patients with acute myocardial infarction / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate clinical implications of changes in red cell distribution width (RDW) and mean platelet volume (MPV) in patients with acute myocardial infarction.</p><p><b>METHODS</b>A total of 127 patients (90 men and 37 women) were enrolled in this analysis, including 66 with acute myocardial infarction (AMI) and 61 with unstable angina (UA). The patients' baseline demographic and clinical data were compared between the two groups including age, hypertension, diabetes, smoking, BMI, blood biochemical profiles, cardiac functions and platelet and red blood cell parameters. The patients were further divided into subgroups according to the RDW 50% cumulative frequency, and the MPV, P-LCR, hsCRP, NT-proBNP, RBC, Dimer and MCV were compared. The correlations between platelet and erythrocyte test results were evaluated in both the AMI and UA patients. Regression analysis was performed to identify the factors affecting the RDW in the AMI group and a regression model was established.</p><p><b>RESULTS</b>The platelet and red blood cell test results, P-LCR, MPV, and RDW differed significantly between AMI and UA groups (P<0.01 or 0.05). Correlation analysis showed a significant positive correlation between RDW and MPV in AMI group (r=0.34, P<0.01). Between the subgroups with different RDW 50% cumulative frequencies, MPV, P-LCR, hsCRP, D-Dimer, and NT-proBNP all differed significantly (P<0.05 or 0.01). In AMI group, with RDW as the dependent variable, we established a multivariate regression model of RDW=0.19MPV+10.83.</p><p><b>CONCLUSION</b>RDW and MPV are closely correlated in patients with AMI. In multiple regression analysis, MPV can explain the changes in RDW in patients with AMI.</p>

Effect of metallothionein on myocyte apoptosis and energy supply of isolated rabbit heart muscle during perfusion with ropivacaine / 南方医科大学学报

<p><b>OBJECTIVE</b>[corrected] To assess the effects of metallothionein on myocyte apoptosis and energy supply of isolated rabbit heart muscle during perfusion with ropivacaine..</p><p><b>METHODS</b>Sixty New Zealand white male rabbits were randomized into 3 equal groups. In group I, the rabbits received a intreaperitioneal injection of distilled water 24 h before isolation of the heart with perfusion by Langendoff model; in group II, distilled water was injected intreaperitioneally, and 24 h later the heart was isolated and perfused with Langendoff model and ropivacaine; in group III, 3.6% ZnSO(4) was injected intreaperitioneally and the isolated heart was perfused with Langendoff model and ropivacaine. The myocardial metallothionein content, myocyte apoptosis, and myocardial ATP, ADP and AMP content were detected.</p><p><b>RESULTS</b>The myocardial metallothionein content was significantly higher in group III than in the other two groups; the percent of myocyte apoptosis was the highest in group II, and was significantly higher in group III than in group I. The myocardial content of ATP was the highest in group I, and was significantly higher in group III than in group II.</p><p><b>CONCLUSION</b>Metallothionein can significantly inhibit myocyte apoptosis and alleviate energy supply disorder induced by ropivacaine.</p>

Relationship between accelerated artherosclerosis and Treg/Teff balance in uremic apoE-/- mice / 南方医科大学学报

<p><b>OBJECTIVE</b>To establish a uremic apolipoprotein E knockout (apoE-/-) mouse model and explore the relationship between accelerated atherosclerosis and Treg/Teff balance.</p><p><b>METHODS</b>Using apoE-/- mice with C57BL/6J background, uremic apoE-/- mice were created by electrocautery of the right kidney and nephrectomy of the left, and the control apoE-/- mice received a sham-operation. Two weeks after inducing uremia, the renal function of the mice were evaluated to assess the validity of the model. Ten weeks after the operation, blood samples were obtained from the mice to assess the renal function and serum total cholesterol (TCH); the serum concentrations of transforming growth factor-beta(1) (TGF-beta(1)) and interferon-gamma (IFN-gamma) were detected by ELISA, and CD4(+)CD25(+)Foxp3(+)Treg ratio in the spleen was determined by flow cytometry. RT-PCR was used to detect the expression of Foxp3 and IFN-gamma mRNA in the aorta, and oil red O staining used to investigate the relative atherosclerotic area on the frozen sections of the aortic root. The correlation between the renal function parameters and Treg quantity was analyzed.</p><p><b>RESULTS</b>Renal function detection confirmed successful establishment of the uremic apoE-/- mouse model. Ten weeks after the operation, the relative atherosclerotic plaque area in the aortic root plaque increased significantly, the spleen Treg ratio decreased, the serum concentrations of TGF-beta(1) decreased and IFN-gamma and TCH increased, the expression of aortic Foxp3 mRNA decreased and IFN-gamma mRNA increased as compared with those in the control apoE-/- mice. A significant inverse correlation was found between the renal function parameters and Treg quantity in uremic apoE-/- mice.</p><p><b>CONCLUSION</b>In uremic apoE-/- mice, accelerated aortic atherosclerosis is correlated to the T cell subset (Treg/Teff) imbalance shown by decreased quantity and impaired function of Treg and enhanced activity of Teff.</p>

Risk factors and coronary angiographic findings in young and elderly patients with acute myocardial infarction: a comparative analysis / 南方医科大学学报

<p><b>OBJECTIVE</b>To identify the risk factors for acute myocardial infarction (AMI) and summarize the features of coronary angiographic (CAG) findings in young and elderly patients.</p><p><b>METHODS</b>A case-control study was conducted involving 53 young (below 40 years) and 438 elderly (60 years and over) patients with clinical diagnosis of AMI. The differences in the risk factors, clinical characteristics and CAG findings were analyzed between the two groups.</p><p><b>RESULTS</b>Compared with the elderly patients, the risk factors of smoking and positive family history was more frequently found among the young patients, but the rates of hypertension and diabetes were lower. The levels of triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) were significantly higher, while high-density lipoprotein cholesterol (HDL-C) lower in the young patients than in the elderly patients. Angiography identified higher incidence of one-vessel disease in the young patients (73.33% vs 25.09%), but the incidence of double-vessel and multi-vessel diseases was more frequent in the elderly patients (11.11% vs 27.49%, and 8.89% vs 47.01%), most commonly compromising the left anterior descending (LAD) coronary artery in both groups. Modified Gensini score of coronary angiography was lower in the young patients (7.69-/+5.23 vs 16.08-/+7.81). Correlation analysis showed that LDL-C (r=0.289, P=0.046) was positively correlated, while HDL-C (r=-0.589, P=0.01), ApoA-I(r=-0.395, P=0.023) were inversely correlated to the angiographic score. Multiple regression analysis showed a significant inverse linear correlation between HDL-C level and coronary artery stenosis.</p><p><b>CONCLUSION</b>Smoking, metabolic disorders and positive family history are the major risk factors for AMI among individuals below the age of forty, who often have milder coronary artery stenosis than elderly patients. HDL-C variation is significantly correlated to the degree of coronary artery stenosis in young patients with AMI.</p>

High glucose suppresses ABCG1 expression by increasing oxidative stress and inducing nuclear factor-kappaB activation in vascular smooth muscle cells / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the role of high glucose in the expression of ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1 (ABCG1) in human vascular smooth muscle cells (VSMCs) and its possible mechanisms.</p><p><b>METHODS</b>VSMCs were incubated in the presence of glucose at the concentrations ranging from 5 to 30 mmol/L for 1 to 7 days, and real-time PCR and Western blotting were used to measure the mRNA and protein expressions of ABCA1 and ABCG1. The effects of cells pretreatment with antioxidant NAC (10 mmol/L) and nuclear factor-kappaB (NF-kappaB) inhibitors BAY 11-7085 (10 micromol/L) and TPCK (10 micromol/L) were also tested on ABCA1 and ABCG1 expressions.</p><p><b>RESULTS</b>High glucose suppressed, in a time- and dose-dependent manner, ABCG1 expression in incubated human VSMCs, and this effect was abolished by pretreatment with the antioxidant and nuclear factor-kappaB (NF-kappaB) inhibitors, but ABCA1 expression was not significantly decreased in the presence of high glucose.</p><p><b>CONCLUSION</b>High glucose suppresses ABCG1 expression in human VSMCs possibly due to increased oxidative stress and NF-kappaB activation induced by high glucose.</p>