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Cardiotoxicity is a serious complication of antineoplastic drugs. With the continuous development of antineoplastic drugs, immune checkpoint inhibitors have been used in the treatment of a variety of cancers. PD-1/PD-L1 immune checkpoint inhibitors have been widely concerned in recent years. This article reviews the manifestations and possible mechanisms of cardiotoxicity induced by PD-1/PD-L1 immune checkpoint inhibitors, and the detection methods and treatment of cardiotoxicity.
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Objective To investigate the potential effects and mechanism on peroxisome proliferator-activated receptor γ-toll-like receptor 4-tumor necrosis factor-α (PPARγ-TLR4-TNF-α) targeted pathway on hyperglycemia induced myocardium inflammation and oxidative stress. Methods Thirty-two Japanese healthy adult rabbits were randomly divided into four groups with 8 rabbits in each group: normal control group (NC group), diabetes mellitus group (DM group), diabetes mellitus + pioglitazone 4 mg·kg-1·d-1 and 8 mg·kg-1·d-1 groups (DM+PGZ 4 mg and 8 mg groups). DM model was reproduced by alloxan of 150 mg/kg through auricular vein injection. On the same day of successful DM model reproduction, the diabetic rabbits were fed with corresponding dose of pioglitazone in DM+PGZ 4 mg and 8 mg groups, but the rabbits in NC group were not challenged. After 8 weeks of feeding, venous blood of left jugular vein bifurcation and myocardium tissue were harvested respectively for the determination of inflammation and oxidative stress parameters. TNF-α, interleukin-1 (IL-1), adiponectin (ADP), nitric oxide (NO) and total nitric oxide synthase (NOS) levels were determined by enzyme linked immunosorbent assay (ELISA), myeloperoxidase (MPO) activity was determined by colorimetric method, superoxide dismutase (SOD) activity was determined by hydroxylamine method, malondialdehyde (MDA) was determined by thiobarbituric acid colorimetric method, and catalase (CAT) activity was determined by UV spectrophotometry method. In addition, the mRNA expressions of TNF-α and TLR4 were determined by real-time quantitate reverse transcription-polymerase chain reaction (RT-qPCR). Results ① IL-1 and TNF-α in serum and myocardium of model rabbits were significantly increased, ADP was significantly decreased, and the mRNA expressions of TNF-α and TLR4 in myocardium were significantly increased, indicating a significant inflammatory reaction. The inflammatory reaction in pioglitazone intervention groups was significantly reduced, TNF-αand IL-1 levels in serum and myocardium of DM+PGZ 4 mg and 8 mg groups were significantly decreased as compared with those of DM group [serum: TNF-α(ng/L) was 268.33±46.57, 261.34±33.73 vs. 331.40±69.05, myocardium: TNF-α (ng/L) was 144.72±26.90, 139.59±14.59 vs. 177.48±27.40; serum: IL-1 (ng/L) was 24.40±2.56, 23.35±3.13 vs. 30.08±5.44, myocardium: IL-1 (ng/L) was 21.26±2.85, 20.54±2.75 vs. 24.78±3.60, all P < 0.05], and ADP levels were significantly increased [serum (μg/L): 19.64±8.85, 20.54±7.47 vs. 15.45±3.06, myocardium (μg/L): 10.31±2.22, 11.49±3.42 vs. 7.76±1.77, all P < 0.05], and the mRNA expressions of TNF-α and TLR4 in myocardium were significantly decreased (TNF-αmRNA: 0.15±0.05, 0.14±0.06 vs. 0.25±0.09; TLR4 mRNA: 0.57±0.17, 0.40±0.18 vs. 0.75±0.35, all P < 0.05). ②Oxidative stress in serum and myocardium of model rabbits was significantly increased, SOD, NO, and total NOS levels were significantly decreased while the serum CAT and MDA levels were significantly increased without effect on MPO. Compared with the DM group, SOD and NO levels in serum and myocardium were significantly increased in DM+PGZ 4 mg and 8 mg groups [serum: SOD (U/L) was 571.39±40.85, 609.28±54.47 vs. 535.10±37.08, myocardium:SOD (U/mg) was 55.74±8.12, 53.60±9.87 vs. 42.26±12.34; serum: NO (μmol/L) was 2.95±0.51, 2.99±0.43 vs. 2.03±0.78, myocardium: NO (nmol/mg) was 1.95±0.37, 2.11±0.26 vs. 1.56±0.33, all P < 0.05], the serum MDA levels were significantly decreased (μmol/L: 20.11±2.34, 19.70±2.02 vs. 23.07±3.06, both P < 0.05), while no significant effect on CAT. There was no significant difference in parameter of inflammatory and oxidative stress between the two pioglitazone intervention groups. Conclusion 4 mg·kg-1·d-1 pioglitazone could activate PPARγ-TLR4-TNF-α targeted pathway, thus inhibit inflammatory and oxidative stress factors expression, and down-regulate hyperglycemia induced myocardium inflammatory and oxidative stress level, but the effect did not show a dose dependent manner.
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Objective To investigate changes in the number and function of endothelial progenitor cells (EPCs) in elderly patients with permanent atrial fibrillation(AF).Methods This prospective study included 35 elderly patients in each the permanent atrial fibrillation group and the control group.The numbers of circulating CD34+/KDR+ cells in the two groups were determined by flow cytometry.After two sets of peripheral blood samples were taken,mononuclear cells were isolated through density gradient centrifugation and cultured in vitro.EPC colonies were identified by the methylthiazolyldipheny-tetrazolium(MTT) assay and adhesion assay.The proliferation,adhesion and vasculogenesis of EPC colonies were determined by Matrigel culture.Enzyme-linked immunosorbent assay and nitric acid reductase assay were used to measure the secretion of vascular endothelial growth factor (VEGF) and nitric oxide (NO) in EPCs.Results The numbers of CD34+/KDR+ cells were lower in the AF group than in the control group (20.0±12.7)/104 vs.(77.9±58.9)/104 (P＜0.05).The number of EPC colonies in the atrial fibrillation group was significantly lower than that in the control group (1.8 ± 0.6) CFU vs.(3.5 ± 0.8) CFU (P ＜ 0.01).The proliferation,adhesion and vasculogenesis of EPC colonies in the AF group decreased,compared with the control group (each P＜0.01 or 0.05).Paracrine secretion of VEGF in the AF group (27.4±9.9)ng/L was lower than that in the control group (41.9±7.3)ng/L (P＜0.01) and paracrine production of NO in the AF group also decreased (P＜0.05).Conclusions EPCs In elderly patients with permanent atrial fibrillation show decreased numbers and reduced proliferation,adhesion and vasculogenesis.Paracrine VEGF and NO secretion is down as well.
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Objective To construct vectors expressing small interfering RNA targeting the Toll like receptor-4 (TLR4) gene and obtain TLR4 knock downed vascular smooth muscle cells (SMC). Methods Three small hairpin RNA (shRNA) targeting the TLR4 gene were designed, synthesized and cloned into the pSilence 2.1-U6 neo vector. Positive clones were verified with double enzyme digestion and sequencing. Then the recombinants were transfected to SMC by the cationic lipid method respectively.SMC were stably transfected with an expression plasmid and screened by G418. TLR4 mRNA and protein expression were detected by RT-PCR and Western blot methods. Results The pSilence2.1-siTLR4 ex-pression vectors were successfully constructed and a TLR4 knock-downed SMC cell line was established. RT-PCR and Western blot analysis confirmed that the expression of TLR4 was significantly down-regulated in the infected SMC cell line, and pSilence2.1-siTLR4-1was the most efficacious recombinant vector.Conclusion Recombinant vectors carrying shRNA targeting the TLR4 gene were successfully constructed and the TLR4 expression in vascular SMCs was inhibited.
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Objective To investigate the effects of pioglitazone on atrial ionic channel remodeling in alloxan-induced diabetic rabbit models.Methods A total of 32 rabbits were randomly (random number) divided into control (CN) group,diabetes mellitus (DM) group,diabetes mellitus + pioglitazone 4 mg/ (d · kg) (DPG) group and diabetes mellitus + double pioglitazone 8 mg/ (d · kg) (DPI) group.The diabetic state was examined by quantitative determination of blood glucose levels of ≥ 14 mmol/L.Langendorff-perfused rabbit hearts were used to isolate single atrial myocyte,and whole-cell patch-clamp technique was used to record action potential duration (APD) and atrial ionic channel currents (ICa,L and INa).Variables with normal distribution were compared with One-way ANOVA and LSD-t test.Results Compared with controls,APD90 and APDS0 of left atrial myocytes were significantly prolonged in DM group (P ＜0.05 vs.CN),and there was no significant difference in APD90 frequency adaptation between them (P ＞0.05 vs.CN).The densities of INa were reduced and the densities of ICa,L were increased in DM group (P ＜ 0.01 vs.CN).The above variables were markedly attenuated in DPG and DPI group.Conclusions Pioglitazone may inhibits atrial ionic channel remodeling in diabetic rabbit models.
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Objective:To evaluate the changes of the left atrial systolic function in patients with acute myocardial infarction(AMI)using quantitative tissue velocity imaging(QTVI).Methods:The systolic velocities of the middle of left atrial lateral wall,anterior wall,inferior wall and atrial septum were measured with QTV1 in 45 patients with AMI.The left atrial volume and active atrial emptying fraction(AA-EF)were measured using single-plane Simpson method.Results:(1)Compared with the control group(30 normal subjects),the diameter and volume of the left atrium,as well as AA-EF,increased obviously in patients with AMI(P ＜ 0.01).(2)Compared with the control group,the systolic velocities of the middle of left atrial lateral wall,anterior wall,inferior wall and atrial septum,as well as the average value,increased significantly in patients with AMI (P ＜ 0.05 or P ＜ 0.01).In addition,the average value of left atrial systolic velocity was closely correlated with AA-EF(r=-0.906,tr=14.001,P ＜ 0.01).Conclusion:QTVI could be used to evaluate the left atrial systolic function accurately in patients with AMI.
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Objective To observation the changes of left atrium and pulmonary veins(PV)in patients with atrial fibrillation(AF) by transthoracic two-and three-dimensional echocardiography. Methods Transthoracic echocardiography were applied in 126 patients,which were divided into sinus rhythm(SR) group(64 cases)and AF group(62 cases),AF group were further divided into two subgroups:the paroxysmal AF and non-paroxysmal AF group.Left atrial area(LAA),left atrial volume(LAV),left atrial diameter(LAD)were measured by 2-dimensional echocardiography imaging.PV diameters were measured by three-dimensional echocardiography. Results Compared with SR group,PV diameters were significantly increased in AF group(P＜0.05).In patients with AF,PV diameters in non-paroxysmal AF group were larger than paroxysmal AF group.The four PV diameters in SR,paroxysmal AF and non-paroxysmal AF group did not show statisticant difference(P＞0.05).Compared with SR group,LAD,LAA,LAV were increased in AF group.LAD,LAA,LAV were larger in non-paroxysmal AF group than SR group and paroxysmal AF group(P＜0.05).Conclusions Left atrium and PV dilate significantly in patients with AF,transthoracic echocardiography could be a non-invasive method to observe left atrium and PV.