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Angiotensin receptor/neprilysin inhibitor (ARNI) is a novel combination drug that is a dual inhibitor of angiotensin receptor and neprilysin. In June 2021, the National Medical Products Administration approved ARNI for hypertension indications. This review provides an update of current literature on ARNI in elderly hypertension.
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β2 microglobulin (β2-MG) is a key component I molecule of the major histocompatibility complex class that assists in the cytotoxic T lymphocyte (CTL) immune response. Serum β2-MG content is dynamically correlated with many diseases. Most studies on β2-MG mainly focus on the pathogenesis of kidney disease, tumor and amyloid fibrils. In recent years, some studies have found that β2-MG is also involved in the adverse prognosis of cardiovascular system, cognitive impairment of aging and antibacterial effects. This paper summarized the domestic and foreign studies on β2-MG in recent years, and proposed the possible role of β2-MG in multi-system human body and its potential application prospect of drug molecular targeting.
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Cardiomyopathy is a disease with abnormal myocardial structure and function. For a long time, due to the limited understanding of cardiomyopathies, cardiomyopathies are treated empirically based on symptoms (such as heart failure, arrhythmia, etc.). Over years, with the improvement of diagnosis technology and the discover of disease mechanism, a variety of drugs have been approved, such as tafamidis, patisiran and Inotersen. Many more drugs have completed preliminary safety and efficacy verification and entered Phase III trials. In addition, some cutting-edge technologies are also being developed, such as siRNA drug patisiran, CRISPR/Cas9 gene editing technology drug NTLA-2001, stem cell therapy, etc. This article discusses two cardiac problems that may be caused by cardiomyopathy: myocardial hypertrophy and cardiac remodeling, and introduces the pharmacology and related research of the latest drugs for these diseases.
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Heart failure is the terminal stage of all kinds of heart diseases. Despite the use of a variety of traditional drug standard treatment, the prognosis is still not ideal, and there is an urgent need for the update and improvement of new drugs and treatment methods. In recent years, angiotensin receptor-enkephalase inhibitors (Sacubitril/Valsartan), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), soluble guanoside cyclase agonists (Vericiguat) and myocardial myosin activators omecamtiv mecarbil have been developed successively. SGLT2 inhibitors can improve ventricular load, reduce fibrosis and affect myocardial metabolism. sGC agonists play an anti-heart failure role by enhancing l-ARg-No-SGC-CGMP signaling pathway, improving myocardial and vascular function, reversing ventricular hypertrophy and fibrosis, slowing ventricular remodeling, and reducing ventricular afterload through systemic and pulmonary vasodilation. In addition, fineridone, a novel salt corticosteroid receptor antagonist, has also been reported in clinical studies in the field of heart failure. Therefore, it is the direction and hope for the development of heart failure in the future to select appropriate drugs for different types of patients with heart failure and carry out individualized treatment according to the optimized process of heart failure.
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Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Lack of the activating enzyme in skeletal muscle may prevent the muscular adverse effects associated with statins. In this review, we summarize the latest advances in bempedoic acid, and review the phase 2 and phase 3 clinical trials results, adverse events, and the clinical trials results in progress of Bempedoic acid. Finally, we discuss the current status of bempedoic acid in the clinical works.
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Because of high rate of nonadherence to statins, the subcutaneously injection of Inclisiran therapy intervals are from 3 months to 6 months, which will increase the patients' adherence to the Inclisiran therapy. In this review, we summarize the latest advances of Inclisiran, and review the phase 2 and phase 3 clinical trials results, adverse events, and the clinical trials results in progress of Inclisiran. Finally, we discuss the current status of Inclisiran in the clinical works.
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Homozygous familial hypercholesterolemia is a rare genetic disorder of lipid metabolism, traditional lipid-lowering therapies such as statins and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have little efficacy in these patients. Evinacumab can reduce the levels of LDL-C effectively. In this review, we summarize the latest advances in Evinacumab, and review the phase 2 and phase 3 clinical trials results, adverse events, and the clinical trials results in progress of Evinacumab. Finally, we discuss the current status of Evinacumab in the clinical works.
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Diabetic cardiomyopathy is described as the existence of abnormal myocardial structure and function caused by diabetes, which is considered to be an underlying cause of increased heart failure in diabetic patients. The pathophysiological mechanisms of diabetic cardiomyopathy are complex and the detailed molecular networks remain obscure. Mitochondrial oxidative stress is the main pathogenic factor of cardiovascular and metabolic diseases, and it is one of the important factors that affect the heart function of diabetes. This review aims to discuss the recent advances of the mechanisms of mitochondrial oxidative stress in diabetic cardiomyopathy, to provide new thoughts for the treatment of diabetic cardiomyopathy.
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Objective@#To investigate the feasibility of echocardiography-guided closed-chest repeated intraventricular blood sampling in mice, and to clarify the maximum blood volume that can be collected by this method, and whether the method can be used for long-term repeated blood collection in mice.@*Methods@#Twenty-four male C57BL/6J mice (10-14 weeks old) were divided into the terminal experiment group (n=4, for investigating the maximum blood amount that could be sampled at one time), the repeated 0.5 ml blood collection group (n=10, sampling 0.5 ml whole blood each time, once every two days for consecutive 4 weeks), and the repeated 0.75 ml blood collection group (n=10, sampling 0.75 ml whole blood each time, once every two days for consecutive 4 weeks). High-frequency echocardiography was used to display the largest section of the left ventricle, guiding the insulin syringe needle through the thorax into the left ventricle for blood collection. In the repeated 0.5 ml blood collection group, echocardiography was used to detect the cardiac structure and function before blood collection, three minutes after blood collection, and one week after the last (the 14th) blood collection.@*Results@#We successfully performed echocardiography-guided closed-chest intraventricular blood sampling, with an average operating time (88±19)s per mouse, and a maximum blood volume (1.43±0.11)ml per mouse. In the repeated 0.5 ml blood collection group, heart rate, left ventricular ejection fraction, left ventricular fractional shortening, left ventricular end-diastolic dimension and left ventricular posterior wall end-diastolic thickness remained uncganged before the first blood collection and after 4 weeks of repeated blood collection (all P>0.05). No death in the repeated 0.5 ml blood collection group. However, in the 0.75 ml blood collection group, two mice died before the end point.@*Conclusions@#The echocardiography-guided closed-chest intraventricular blood sampling is a safe, minimally invasive, convenient and efficient method, and can be used repeatedly for long-term blood collection in mice.
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Qili-Qiangxin capsules have been wildly used for the cardiovascular diseases. Qili-Qiangxin capsules have good effect on the myocardial infarction, dilated cardiomyopathy, congestive heart failure, diastolic heart failure and HFPEF patients. Patients' cardiac function and quality of life can be improved after treatment. In the basic researches, we concluded the mechanisms of Qili-Qiangxin capsules'effect on the heart failure that Qili-Qiangxin capsules could effectively restrain the cardiac remodeling, improve cardiac function.Although the Qili-Qiangxin capsules were wild used in the clinic, its precise molecular mechanisms for cardiovascular diseases remained unknown.
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AIM:We investigated how AT 1-R stimulated by mechanical stresses induces cardiac fibrosis .METHODS:We produced in vivo cardiac pressure overload model in angiotensinogen knockout ( ATG-/-) mice and in vitro mechanically-stretched cell model in cultured neonatal cardiac cells of ATG-/-mice both lack the participation of Ang II .RESULTS: Pressure overload for 4 weeks in ATG-/-mice induced myocardial hypertrophy accompanied by the significant interstitial fibrosis , however , the TGF-β, a key regulatory factor of fibrosis, was not significantly increased in these ATG-/-mice.Meanwhile, the inhibitor for AT1-R significantly inhibited mechani-cal stress-induced cardiac fibrosis in these ATG-/-models whereas inhibition of TGF-βdid not.CONCLUSION:The results showed that mechanical stress-induced fibrotic responses through AT 1-R required the phosphorylation of Smad 2 but not the involvement of TGF-β.
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AIM:To examine and compare the effects of several ARBs that are widely used in clinics , on the ACE-Ang II-AT1 receptor and the ACE2-Ang(1-7)-Mas axis during the development of cardiac remodeling after pressure overload .METHODS: All of the mice used in the study underwent transverse aortic constriction (TAC) or sham operation for 2 or 4 weeks.A solution of either ARBs or sa-line was administered through a stomach tube 3 days before the operation .Meanwhile , to eliminate the influence of Ang II , a recombi-nant adenovirus expressing small interfering RNAs targeting angiotensinogen ( Ad-ATG siRNA) was injected via the tail vein .The sur-gery was then performed and the drug was administered as mentioned above .Cardiac function and remodeling were evaluated by echo-cardiography , hemodynamic measurements and cardiac histology .Western blotting was used to determine the protein expression levels . Meanwhile , we performed similar experiments using ARBs with or without ATG siRNA in cardiomyocytes induced by mechanical stretch.RESULTS:Although all of the six ARBs , none of which repressed the elevation of left ventricular pressure after TAC , attenu-ated the development of cardiac hypertrophy and heart failure in the wild-type mice, the degree of attenuation by Olmesartan , Candesar-tan and Losartan tended to be larger than that of the other three drugs tested .Additionally , the degree of downregulation of the ACE-Ang II-AT1 axis and upregulation of the ACE2-Ang(1-7)-Mas axis was higher in response to Olmesartan, Candesartan and Losartan administration in vivo and in vitro.Additionally, Olmesartan had a larger influence when administered long term .However, the expres-sion of ACE was not influenced by the administration of ARBs in vivo and in vitro.Moreover, in angiotensinogen-knockdown mice, TAC-induced cardiac hypertrophy and heart failure were inhibited by Olmesartan , Candesartan and Losartan but not by Telmisartan , Valsartan and Irbesartan administration .Furthermore , only Olmesartan and Candesartan could downregulate the ACE-Ang II-AT1 axis and upregulate the ACE2-Ang(1-7)-Mas axis in vitro.CONCLUSION: Olmesartan, Candesartan and Losartan could effectively in-hibit pressure overload-induced cardiac remodeling even when with knockdown of Ang II , possibly through upregulation of the expres-sion of the ACE2-Ang(1-7)-Mas axis and downregulation of the expression of the ACE-Ang II-AT1 axis.In contrast, Telmisartan, Valsartan and Irbesartan only played a role in the presence of Ang II , and Losartan had no effect in the presence of Ang II in vitro.
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AIM:To investigate the effects of angiotensin II ( Ang II) on the immune maturation and the oxi-dized low-density lipoprotein (Ox-LDL)-uptaking capacity of human monocyte-derived dendritic cells (DCs).METH-ODS:Human peripheral blood mononuclear cells were isolated by density gradient centrifugation , and the monocytes were purified by positive selection with anti-CD14 magnetic beads.After cultured with rhGM-CSF (100 μg/L) and rhIL-4 (50μg/L) for 5 d, the monocytes differentiated into immature DCs .On the 6th day of the culture, the cells were treated with various concentration levels of Ang II or pretreated with losartan .The immunophenotypic expression of HLA-DR and CD83 was analyzed by flow cytometry .The secretion levels of IL-12 and IFN-γin the culture supernatants were measured by ELISA.Furthermore, DCs were incubated with DiI-labelled Ox-LDL.The DiI-Ox-LDL-incorporated fraction was investiga-ted by flow cytometry .The mRNA expression of 3 scavenger receptors , scavenger receptor A ( SR-A) , CD36 and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), was examined by real-time PCR.RESULTS: Ang II induced the maturation of human monocyte-derived DCs, stimulated the expression of CD83 and HLA-DR, and promoted the secre-tion of IL-12 and IFN-γ, which were suppressed by losartan .Furthermore, Ang II increased the Ox-LDL-uptaking capacity of DCs, which was partially reduced by losartan .The incubation of DCs with Ang II enhanced the mRNA expression of LOX-1 in a dose-dependent manner , which was reduced by losartan .However, the expression of SR-A and CD36 was not changed .CONCLUSION:Ang II promotes the immune maturation of human monocyte-derived DCs and increases the up-take of Ox-LDL probably through the up-regulation of LOX-1 expression.
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Objective: To observe the changes of circulating fractalkine and its receptor CX3CR1 level in patients with chronic congestive heart failure (CHF). Methods: Our work included 2 group, CHF group, n=55 patients and Control group, n=25 healthy subjects. Plasma level of soluble fractalkine (sFKN) was measured by ELISA, CX3CR1 in peripheral blood mononuclear cell was examined by lfow cytometry method. The relationship between sFKN and NT-proBNP was studied. Results: Compared with Control group, CHF group had increased sFKN level, P=0.004, and the patients with NYHY III, IV were more than NYHY II, and CHF group also had the higher CX3CR1 expression (14.7 ± 8.1), P Conclusion: The circulating FKN l and its receptor CX3CR1 might be involved in pathogenesis of immune-inlfammatory pathogenesis in CHF patients.
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Objective To explore the change of multiple electrocardiogram(ECG) parameters and their impact on P-R interval in pregnant women.Methods Healthy women aged 20-40 years were enrolled and divided into 4 groups:control group (n =194),early-pregnant group (n =172),mediate-stage group (n =105)and late-phase group(111).The following data were collected for analysis:heart rate (HR),axis,rotation,P-R interval(on lead V3),and p wave duration(on lead Ⅱ).Between-group analysis and multiple liner regression analysis were conducted.Results Compared with the control group,we found no significant difference in the early-pregnant group,but HR significantly increased in the mediate-stage group and late-phase group((77.76 ± 14.75) beat/min vs.(78.12 ± 11.24) beat/min vs.(84.21 ± 11.91) beat/min vs.(88.15 ± 15.05) beat/min,P ＜ 0.05).BP increased with the duration of pregnancy.Axis and P wave duration decreased with the duration of pregnancy.We found no significant difference in the early-pregnant group,but significantly decreased axis and P wave duration in the mediate-stage group and late-phase group (axis:(61.11 ± 225.84) ° vs.(56.97 ±25.17)° vs.(50.11 ±21.78)° vs.(41.72 ±28.36)°,P ＜0.05;P wave duration:(0.100 ±0.015)s vs.(0.099 ± 0.012) s vs.(0.095 ± 0.013) s vs.(0.093 ± 0.013) s,P ＜ 0.05).P-R interval was significantly shorter in women at all the three stages of pregnancy than in the healthy controls ((0.145 ± 0.021)) svs.(0.138±0.019) s vs.(0.133 ±0.020) s vs.(0.131 ±0.019) s,P ＜0.05).There was no significant difference found in heart rotation proportion among the four groups.Multiple liner regression analysis indicated that only pregnancy factors (t =-4.607,P =0.000) and p wave duration (t =9.339,P =0.000) had significant influences on P-R interval.Conclusion P-R interval is negatively correlated to pregnancy stage and positively correlated to p wave duration,but irrelevant to HR and axis in pregnant women.
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Objective To investigate the effects of apolipoproteinA1 (apoA1) on levels of cholesterol, cholesteryl ester (CE), and expression of ATP-bindiag cassette transporter A1 (ABCA1) in human acute monocytie leukemia cell line (THP-1) macrophage-derived foam cells.Methods The cultured THP-1 cells were induced into foam cells by exposing first to phorbol myristate acetate (PMA, 50 ng/ml) for 48 h, and then to oxidized-low density lipoprotein (ox-LDL, 50μg/ml) for 48 h.Under treatment of apoA1 in different doses (5, 10, 15 and 20 μg/ml) and one simple dose (10 μg/ml) for different time (6, 12 and 24 h), THP-1 macrophage-derived foam cells were incubated to observe the expression of cholesterol and ABCA1.The concentrations of cellular total cholesterol (TC), free cholesterol (FC) and CE were determined by oxidization enzymatic methods.Oil red O dyeing experiment was used to show the cellular lipid droplets in the cells.The expression of ABCA1 was tested by immunofluorescence method.Reverse transcription-polymerase chain reaction was applied to investigate mRNA expression of ABCA1.Results The THP-1 cells turned into typical foam cells after treated with PMA (50 ng/ml) for 48 h, and ox-LDL (50 μg/ml) for 48 h.apoA1 could lower the levels of TC, FC and CE in THP-1 macrophage-derived foam cells in a dose-dependent and a time-dependant manner, apoA1 could increase the expression of ABCA1 protein in THP-1maerophage-derived foam cells without up-regulation of mRNA.Antibody of ABCA1 could up- regulate the expression of ABCA1.Conclusions apoA1 may decrease the levels of cholesterols in THP-1 macrophage-derived foam cells, by promoting the expression of ABCA1 and the reverse cholesterol transport of high density lipoprotein.
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Objective To investigate whether timing of image acquisition influenced infarct size estimation using delayed CeMRI,and the association of left ventricular ejection fraction between magnetic resol3anee imaging and left ventrieulography Was also studied.Method From Junary 2005 to April 2006,27 first,onset AMI patients [23 male,mean age(54.3±10.5)years]were enrolledinthistudr.Allpatients receivedleft ventrictdographyas well as coronary angiography.The average checking time was(13.2±5.2)clays after the onset of AMI.MR imaging was performed with a 1.5-T magnet(SIMENS).After breath-hold eine images were acquired,patients re.ceived afI intravenous bolus of 0.05 mmol/kg Gd-DTPA at a rate of 5 ml/8.A first-pass perfusion scan was ac.qllired.Then a second bolus of 0.15 mmoVkg Gd-DTPA was give.at a rate of 2 mE/Is.After the hyperenhancement localized,the typical short axis slice with hyperenhancement WaS chosen to repeat imaging for IlleasuriIin.farct size every5minutesfrom5minutes after secondinjection ofcontrast until 20minutes.Results Twexty-seren patients showed hyperenhancement at the delayed CeMRI and hypoenhancement at the first pass enhancement(FPE).The average infarct size estimated by CeMRI WaS(17.9士9.8)%of LV nlass.Myocardial enhancement at a repesentative short-axis slice WIllS(7.2±6.2)%of LV Imss at 5 minutes,(8.5±7.4)%at 10 minutes,(7.3±6.3)%at 15 minutes and(6.9-t-6.4)%at 20 minutes respectively.There WltlS significant difference be-tween lmfninmes and 20-minutes enhancement size(P<0.05).Correlations of EF obtained by cineventriculo-grapIIy and MR irr,lg were significant(r=0.867,P<0.01).There were also correlations between infarction size and pe.k CK(r:O.819,P<O.01),a8 well ills peaI[cTNT(r=0.517,P<0.05)levels.Tuning of image acquisition iufluenced infarct size quantification using delayed CeMRI when TI Was kept constant.
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Objective To observe the effects of eluting stents coated with arsenic trioxide(As2O3)and suspended in poly-L-lactic acid(PLLA)on expression of monocyte chemoattractant protein-1 (MCP-1)and interleukin-6(IL-6)and to assess the effects of As2O3 eluting stents on local inflammatory reaction in injured coronary arteries in pigs. Methods Bare metal stents,rapamycin eluting stents and As2O3-eluting stents were randomly and double-blindly implanted into the anterior descending branches,circumflex branches and right coronary arteries in eight pigs.Animals were sacrificed and coronary arteries were isolated 7 days after stents implantation.The expression levels of protein and mRNA of MCP-1 and IL-6 were determined by Western blot analysis and reverse transcription polymerase chain reaction(RT-PCR),and the inflammatory cell infiltration was observed by HE staining and immunohistochemistry. Results Compared to bare metal stents,As2O3-eluting stents and rapamycin-eluting stents identically and markedly inhibited the protein expression level of MCP-1(0.421±0.055 and 0.406±0.042 vs.0.857±0.053,P＜0.01)and IL-6(0.151±0.032 and 0.146±0.051 vs.0.551±0.032,P＜0.01)and correspondingly lowered the mRNA expression level of MCP-1(0.338±0.047 and 0.327±0.051 vs.0.724±0.027,P＜0.01)and IL-6(0.531±0.052 and 0.523±0.061 vs.1.015±0.041,P＜0.01),and significantly reduced the inflammatory cell infiltration of injured coronary arteries in pigs. Conclusions As2O3-eluting stents can effectively inhibit the expressions of MCp-1 and IL-6 and reduce the inflammatory cell infiltration of injured coronary arteries in pigs.
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ObjectiveTo investigate the relationship between aging-induced neointimal formation and Jagged 1 dynamic expression in endothelium after arterial injury in rats. MethodsForty healthy male Sprague-Dawley rats aged 3 months (young adult) and 22 months (old) were selected, and thirty of them were subjected to balloon catheter injury at the thoracic aorta. Morphometry analysis was applied to evaluate neointima/media ratio at 28 days after arterial injury. Immunohistochemistry was used to observe the dynamic expressions of Jaggedl in endothelium and the proliferating cell nuclear antigen (PCNA) in neointima at 7 days, 14 days and 28 days after arterial injury respectively. Cell co-culture system was developed by inoculating endothelial cells(EC) in the upper chamber and smooth musele eells(SMC) in the lower chamber. Fluorescence activated cell sorter (FACS) was used to assay the effect of aging on the expression of Jagged 1 in EC. ＜'3＞H-TdR incorporation and cells counting were used to determine the influence of EC of different ages of rats on platelet derived growth factor (PDGF)-induced proliferation and migration of SMC. ResultsThe neointima/media ratio were obviously higher in old rats than in young rats (0.35±0.02 vs. 0.28±0.01, n=5, P＜0.01). Compared with the young counterparts, old rats showed in immunohistochemistry that the Jaggedl in endothelium displayed a delayed up-regulation and quickly diminished evolvement pattern. The maximal enhancing level of Jaggedl in old rats was much lower than that in young ones. However, the increased extent of PCNA in neointima was significantly higher in old rats than that in young ones. Jagged 1 expression in EC in old rats was significantly lower than that in young one[(46.6±6.3)% vs. (85.4±4.0)%,n=3, P＜0.05]. The SMC co-cultured with EC in old rats exhibited higher proliferation and migration capability than those in young ones after exposure to PDGF of 10ng/ml[2H-TdR incorporation: (26 438±1857) cpm/well vs. (16 698±2076)cpm/well, n=5, P＜0.05. migration:(32±4) cells/field vs. (18±5) cells/field, n=5, P＜0. 05]ConclusionsThe up-regulation of Jaggedl in EC is impaired in aged rats, which is closely related to aging-indueed SMC proliferation and migration. It also suggests that Jagged1 might be involved in the process of aging-exaggerated neointima formation.
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AIM: To investigate the effect of paclitaxel on the quantitative growth of rabbit's vascular smooth muscle cells (SMCs) and endothelial cells (ECs) and their relationship in vitro. METHODS: An ex vivo model of endothelium repair was developed in which rabbit's SMCs were inoculated in the upper chamber and rabbit's ECs in the lower chamber of a co-culture system. 3 H-TdR incorporation and cell counting were used to determine the effect of paclitaxel on the quantitative proliferation of rabbit's vascular ECs and SMCs. The migration rate was analyzed to determine the effect of paclitaxel on the migration of rabbit's vascular ECs and SMCs. The IC50 of paclitaxel on ECs and SMCs was calculated. RESULTS: The 3 H-TdR incorporation, cell counting and migration of rabbit's vascular SMCs were inhibited by paclitaxel of 1 nmol·L-1-1 μmol·L-1 in a concentration-dependent manner (n=6, P<0.01). The 3 H-TdR incorporation and cell counting of rabbit's vascular ECs were inhibited by paclitaxel of 10 nmol·L-1-1 μmol·L-1 and migration by paclitaxel of 1 nmol·L-1-1 μmol·L-1 in a concentration-dependent manner (n=6, P<0.01). The 3 H-TdR incorporation assay resulted in the IC50 of 10.09±0.47 nmol·L-1 on SMCs and 19.06±0.35 nmol·L-1 on ECs proliferation. The migration assay resulted in the IC50 of 9.16±0.54 nmol·L-1 on SMCs and 5.37±0.51 nmol·L-1 on ECs migration. Paclitaxel (10 nmol·L-1, 20 min) inhibited SMCs growth of the confluent ECs group during the observed period. However, increased SMCs growth was observed in the proliferative ECs group 10 days after paclitaxel intervention. CONCLUSION: Paclitaxel inhibits not only SMCs but also ECs growth in rabbit's vascular. The delayed SMCs proliferation is closely related with the delayed ECs regeneration induced by paclitaxel.