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1.
EClinicalMedicine ; 72: 102626, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38756107

RESUMO

Background: Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (<140 mmHg). Methods: We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP <140 mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs) × (sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18-65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150 mmHg and ≤180 mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130 mmHg or daytime SBP ≥135 mmHg or nighttime SBP ≥120 mmHg), renal artery stenosis (<50%) and renal function (eGFR >45 mL/min/1.73 m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. After msRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (<140 mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Findings: Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150 mmHg and ≤180 mmHg and met all inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6 M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p = 0.429), achieved non-inferiority margin -10% (2.69%; 95% CI -4.11%, 9.83%, p < 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p = 0.010) and superior to Sham group (-3.25; 95% CI -5.56, -0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP <140 mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p < 0.001 from Baseline; p > 0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. Interpretation: The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP <140 mmHg, with only approximately four targeted ablations per renal main artery, much lower than in previous trials. Funding: SyMap Medical (Suzhou), LTD, Suzhou, China.

2.
Medicine (Baltimore) ; 102(45): e35823, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37960808

RESUMO

RATIONALE: Apical hypertrophic cardiomyopathy (ApHCM) is a phenotypic variant of hypertrophic cardiomyopathy. Endomyocardial fibrosis and endocardial calcification are especially rare in ApHCM. PATIENT CONCERNS: The main symptoms was chest tightness, palpitation, shortness of breath, and fatigue. Echocardiography and imaging examinations found apical hypertrophy along with endocardial calcification and endomyocardial fibrosis. Abnormal structural changes led to thrombosis and made the left ventricle a flat shape resembling an "apple." DIAGNOSES: The typical presentations, hypertrophic apex on echocardiography and an elevated N-terminal pro-brain natriuretic peptide level indicated the diagnosis of ApHCM and heart failure with preserved ejection fraction. INTERVENTIONS: Optimal medical therapy including the administration of ApHCM, heart failure and atrial fibrillation to improve symptoms and life quality. OUTCOMES: Since discharge, the patient could perform normal daily activities and had no discomfort based on the optimal medical therapy. LESSONS: We report a ApHCM patients with unusual presentations of endomyocardial fibrosis and apical calcification. This case highlights the importance of understanding the specific pathological changes of ApHCM for treatment and prognosis.


Assuntos
Miocardiopatia Hipertrófica Apical , Calcinose , Cardiomiopatia Hipertrófica , Fibrose Endomiocárdica , Insuficiência Cardíaca , Humanos , Fibrose Endomiocárdica/diagnóstico , Fibrose Endomiocárdica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Ecocardiografia/métodos , Calcinose/complicações , Calcinose/diagnóstico por imagem
3.
Aging (Albany NY) ; 14(9): 4036-4049, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35522573

RESUMO

BACKGROUND: HF is a common complication of MI. The underlying mechanisms of myocardial fibrosis in HF after MI are incompletely defined. Here, this study aims to investigate the role of PTX3 KD in HF after MI. METHODS: Bioinformatics analysis based on GSE86569 dataset was performed to explore the potential role of PTX3 in HF. Male C57/BL6J mice were administered with lentiviral vector encoding PTX3 KD or empty vector, and then underwent either coronary ligation or sham surgery. Echocardiography, Masson staining, and immunofluorescence counterstaining were conducted to evaluate the cardiac function and fibrosis. Cardiac fibroblasts were isolated and transfected with lentiviral vector encoding PTX3 KD in vitro to verify the in vivo findings. RESULTS: Bioinformatics analysis based on GSE86569 revealed the aberrant expression of PTX3 in HF patients. Echocardiography showed that PTX3 KD reversed the HF-induced cardiac dysfunction with better cardiac function parameters. Masson staining demonstrated that the obvious infarct and high fibrosis ratio in HF mice were remarkably improved after PTX3 KD. Immunofluorescence staining indicated that the HF-induced increase expression of α-SMA was significantly suppressed by PTX3 KD. Additionally, both in vivo and in vitro results confirmed that PTX3 KD decreased the fibrosis-related up-regulation of collagen I, collagen III, and p-STAT3. However, the result was opposite after IL-6 treatment. CONCLUSIONS: PTX3 KD protects the cardiac function and counteracts the myocardial fibrosis by down-regulating IL-6/STAT3 pathway in HF.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Proteína C-Reativa , Colágeno Tipo I/metabolismo , Fibrose , Insuficiência Cardíaca/metabolismo , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Componente Amiloide P Sérico
4.
Biomed Res Int ; 2022: 8866660, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35071601

RESUMO

AIM: Trastuzumab (TZM) is a monoclonal antibody drug for HER2-positive breast cancer by targeting epidermal growth factor 2, but it has significant cardiotoxicity. Ginsenoside Rg2 has shown a variety of biological activities. This study was aimed at investigating whether Rg2 attenuates TZM-induced cardiotoxicity. METHODS: A model of TZM-induced cardiotoxicity was established in Wistar rats, and the rats were pretreated with Rg2. After echocardiography analysis, the rats were killed and the hearts were dissected for RNAseq analysis. Primary human cardiomyocytes (HCMs) were treated with TZM with or without pretreatment with Rg2 and then subjected to a colony formation assay, flow cytometry analysis, and Western blot analysis for the detection of caspase-3, caspase-9, and BAX. RESULTS: TZM induced LV dysfunction in rats, but Rg2 could attenuate TZM-induced LV dysfunction. The mRNA levels of caspase-3, caspase-9, and BAX were significantly higher in TZM-treated rats. The colony formation ability of HCMs was significantly lower in TZM-treated cells but was recovered after pretreatment with Rg2. The apoptosis rate of HCMs was significantly higher in TZM-treated cells but was significantly lower after pretreatment with Rg2. Moreover, protein levels of caspase-3, caspase-9, and BAX were significantly higher in TZM-treated cells but were significantly lower after pretreatment with Rg2. CONCLUSION: Ginsenoside Rg2 inhibited TZM-induced cardiotoxicity, and the mechanism may be related to the downregulation of the expression of proapoptotic proteins caspase-3, caspase-9, and BAX and the inhibition of TZM-induced apoptosis in cardiomyocytes. Ginsenoside Rg2 has a potential to be applied in patients with breast cancer to prevent TZM-induced cardiotoxicity.


Assuntos
Neoplasias da Mama , Ginsenosídeos , Animais , Apoptose , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/tratamento farmacológico , Caspase 3/metabolismo , Caspase 9/metabolismo , Feminino , Ginsenosídeos/farmacologia , Humanos , Ratos , Ratos Wistar , Trastuzumab/efeitos adversos , Proteína X Associada a bcl-2/metabolismo
5.
Acta Biochim Pol ; 68(4): 705-710, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34730924

RESUMO

This study was conducted to investigate the roles of ferritin in atherosclerosis. The mouse model of atherosclerosis was established by feeding ApoE knockout mice with a high-fat diet. The mice were then treated with ferritin-overexpressing and -silencing constructs, and assessed for interleukins (ILs) and matrix metalloproteinases (MMPs) levels using ELISA and Western blot analysis. After being fed with a high-fat diet, the ApoE knockout mice developed pro-atherogenic lipid profiles with elevated total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). They also showed increased atherosclerotic lesions including narrowed lumen diameter, reduced lumen area, and increased plaque size. Following injection of the overexpression and silencing constructs, mRNA levels of ferritin were increased and decreased, respectively, and at the same time the atherosclerotic lesions were aggravated and alleviated, respectively. Further analysis indicated that silencing of ferritin gene reduced IL-1ß and IL-10 levels while overexpressing ferritin increased them. On other hand, the TNF-α levels showed an opposite trend. MMP8, MMP12 and MMP13 levels were increased or decreased significantly after the mice were injected with ferritin over-expression or silencing vectors, respectively. Western blot analysis showed that compared to the control, overexpressing ferritin resulted in increased expression of p-JNK while silencing ferritin decreased the expression. Meanwhile, the levels of pc-Jun remained unchanged. Our work demonstrates that ferritin can regulate the progress of atherosclerosis via regulating the expression levels of MMPs and interleukins. Silencing ferritin inhibits the development of atherosclerosis and is, therefore, worth being further investigated as a potential therapeutic approach for this disease.


Assuntos
Aterosclerose/metabolismo , Ferritinas/genética , Ferritinas/metabolismo , Interleucinas/metabolismo , Metaloproteinases da Matriz/metabolismo , Animais , Aterosclerose/genética , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Inativação Gênica , Inflamação/metabolismo , Lipídeos/sangue , Lipoproteínas LDL/sangue , Masculino , Camundongos , Camundongos Knockout para ApoE , Placa Aterosclerótica/metabolismo , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/metabolismo
6.
Exp Ther Med ; 21(5): 473, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33767768

RESUMO

Trastuzumab (TZM) significantly improves the outcomes of patients with breast cancer; however, it is associated with severe cardiotoxicity. Ginsenoside Rg2 was reported to exert protective effects against myocardial injury and apoptosis in human cardiomyocytes (HCMs). However, whether ginsenoside Rg2 protects HCMs against TZM-induced toxicity remains unclear. The present study investigated the proliferation of HCMs using a Cell Counting Kit-8 assay and Ki67 immunofluorescence staining. Apoptotic cells were detected by Annexin V/propidium iodide staining and flow cytometry. Furthermore, monodansylcadaverine staining was performed to detect cell autophagy. In addition, western blotting was used to detect the expression levels of phosphorylated (p)-Akt, p-mTOR, beclin 1, microtubule associated protein 1 light chain 3α (LC3) and autophagy protein 5 (ATG5) in HCMs. Pretreatment with ginsenoside Rg2 significantly protected HCMs against TZM-induced cytotoxicity by inhibiting apoptosis. Furthermore, pretreatment with ginsenoside Rg2 induced autophagy in HCMs by upregulating the expression levels of p-Akt, p-mTOR, beclin 1, LC3 and ATG5. The results obtained in the present study suggested that ginsenoside Rg2 could protect HCMs against TZM-induced cardiotoxicity by activating autophagy. Therefore, ginsenoside Rg2 may serve as a potential therapeutic agent to prevent TZM-related cardiotoxicity in patients with breast cancer.

7.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786624

RESUMO

The therapeutic effect of sacubitril/valsartan (S/V) on heart failure has been confirmed, while its role in atherosclerosis remains largely unexplored. The present study aimed to investigate the effects of S/V on the expression of metastasis­associated lung adenocarcinoma transcript 1 (MALAT1), inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) induced by oxidized low­density lipoprotein (ox­LDL) and to elucidate its possible mechanism. Cell Counting Kit­8 assay was used to detect cell viability. Reverse transcription­quantitative PCR was performed to detect the MALAT1 expression. ELISA was performed to detect the levels of IL­1ß, IL­6 and TNF­α. Flow cytometry was conducted to detect the apoptotic rate of cells. A nitric oxide (NO) detection kit was used to determine the concentration of NO. Western blotting analysis was performed to determine the levels of intercellular cell adhesion molecule (ICAM)­1, vascular cell adhesion molecule (VCAM)­1, endothelin­1, caspase­3, Bax, Bcl­2, Toll­like receptor 4 (TLR4), p65 and p­p65. Compared with the ox­LDL group, S/V treatment significantly increased the cell viability, NO concentration and Bcl­2 expression, decreased the levels of IL­1ß, IL­6 and TNF­α and reduced the expressions of MALAT1, ICAM­1, VCAM­1, cleaved­caspase­3, Bax, TLR4 and p­p65. Overall, the findings suggested that S/V could downregulate the expression of MALAT1, inhibit inflammation and apoptosis and improve endothelial function in ox­LDL­induced HUVECs via inactivating the TLR4/NF­κB signaling pathway. Therefore, S/V might be utilized as a promising therapeutic strategy for the prevention and treatment of atherosclerosis.


Assuntos
Aminobutiratos/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , RNA Longo não Codificante/genética , Tetrazóis/farmacologia , Valsartana/farmacologia , Compostos de Bifenilo , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
8.
Biomed Res Int ; 2020: 1625362, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998779

RESUMO

The Akt plays an important role in regulating cardiac growth, myocardial angiogenesis, and cell death in cardiac myocytes. However, there are few studies to focus on the responses of the Akt pathway to cardiac contractility modulation (CCM) in a chronic heart failure (HF) model. In this study, the effects of CCM on the treatment of HF in a rabbit model were investigated. Thirty six-month-old rabbits were randomly separated into control, HF, and CCM groups. The rabbits in HF and CCM groups were pressure uploaded, which can cause an aortic constriction. Then, CCM was gradually injected to the myocardium of rabbits in the CCM group, and this process lasted for four weeks with six hours per day. Rabbit body weight, heart weight, and heart beating rates were recorded during the experiment. To assess the CCM impacts, rabbit myocardial histology was examined as well. Additionally, western blot analysis was employed to measure the protein levels of Akt, FOXO3, Beclin, Pi3k, mTOR, GSK-3ß, and TORC2 in the myocardial histology of rabbits. Results showed that the body and heart weight of rabbits decreased significantly after suffering HF when compared with those in the control group. However, they gradually recovered after CCM application. The CCM significantly decreased collagen volume fraction in myocardial histology of HF rabbits, indicating that CCM therapy attenuated myocardial fibrosis and collagen deposition. The levels of Akt, FOXO3, Beclin, mTOR, GSK-3ß, and TORC2 were significantly downregulated, but Pi3k concentration was greatly upregulated after CCM utilization. Based on these findings, it was concluded that CCM could elicit positive effects on HF therapy, which was potentially due to the variation in the Pi3k/Akt signaling pathway.


Assuntos
Insuficiência Cardíaca , Proteínas Musculares/metabolismo , Contração Miocárdica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Doença Crônica , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Coelhos
9.
Med Sci Monit ; 25: 2633-2639, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30968846

RESUMO

BACKGROUND This study investigated the expression of the BCL2 and BAX mRNA, inflammatory cytokines, interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-alpha), and cardiac function in patients with chronic heart failure (CHF). The New York Heart Association (NYHA) Functional Classification and measurement of the left ventricular ejection fraction (LVEF) evaluated cardiac function. MATERIAL AND METHODS Patients with CHF (n=60) due to coronary heart disease, hypertensive heart disease, and cardiomyopathy, and healthy controls (n=30) were studied. Enzyme-linked immunosorbent assay (ELISA) measured serum levels of IL-1ß, IL-6, and TNF-alpha. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected mRNA expression of BCL2 and BAX in peripheral blood mononuclear cells (PBMCs). Color Doppler ultrasound measured the LVEF, and the NYHA classification of CHF was used. RESULTS In patients with CHF, levels of IL-1ß, IL-6 and TNF-alpha, and mRNA expression of BAX were significantly increased compared with the control group (p<0.01); BCL2 mRNA level was significantly lower (p<0.01). There were no significant differences in the expression levels of inflammatory cytokines, or BCL2 or BAX mRNA in patients with CHF due to coronary heart disease, hypertensive heart disease, or cardiomyopathy. Expression levels of IL-1ß, IL-6, TNF-alpha, and BAX mRNA were significantly associated with the degree of CHF. Cardiac function was negatively correlated with LVEF (p<0.05). Expression levels of BCL2 mRNA level were negatively correlated with cardiac function (p<0.05), and positively correlated with LVEF (p<0.05). CONCLUSIONS Levels of IL-1ß, IL-6, TNF-alpha, and BAX mRNA were negatively correlated with cardiac function, and BCL2 mRNA expression was positively associated with CHF.


Assuntos
Citocinas/sangue , Regulação da Expressão Gênica , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , Mediadores da Inflamação/sangue , Leucócitos Mononucleares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Idoso , Cardiomiopatias/sangue , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Doença Crônica , Doença das Coronárias/sangue , Doença das Coronárias/genética , Doença das Coronárias/fisiopatologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Humanos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Volume Sistólico , Proteína X Associada a bcl-2/sangue
10.
Oncol Lett ; 13(1): 89-98, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28123527

RESUMO

We investigated the possible implication of miR-23a in anoxia-induced phenotypic transformation of the pulmonary arterial smooth muscle and studied the mechanism of upregulation of miR-23a expression in anoxia. The collagenase digestion method was used for preparing rat primary pulmonary artery smooth muscle cell (PASMC) culture. SM-MHC, SM-α-actin, calponin-1 and SM22α protein expression levels were evaluated using western blot analysis after the ASMCs were subjected to anoxia treatment (3% O2). Transfection with miR-23a mimics were conducted when PASMCs were under normoxia and anoxia conditions. EdU staining was used to detect the proliferative activity of PASMCs. Cells were transfected with HIF-1α specific siRNA under anoxia condition. RT-qPCR was used to detect miR-23a expression in PASMCs. Chromatin immunoprecipitation method was employed to verify the binding sites of HIF-1α. The dual-luciferase reporter gene was used to study the role of HIF-1 and its binding sites. Rat hypoxic pulmonary hypertension models were established to study the expression of miR-23a using RT-qPCR method and to verify the expression of miR-23a in the arteriole of the rat pulmonary. Our results showed that compared with normoxia condition, under anoxia condition (3% O2), the expression levels of the contractile phenotype marker proteins decreased significantly after 24 and 48 h. The positive rate of the EdU staining increased significantly and the expression of miR-23a increased. Transfection with miR-23a-mimic downregulated the expression of contractile marker proteins and improved the positive rate of the EdU staining under normoxia. Anoxia and transfection with HIF-1α enhanced the activity of the wild-type Luc-miR-23a-1 (WT) reporter gene. We concluded that miR-23a participated in the anoxia-induced phenotypic transformation of PASMCs. Increased expression of miR-23a under anoxia may primarily be due to miR-23a-1 and miR-23a-3 upregulation. The anoxia-induced upregulation of miR-23a was regulated by HIF-1.

11.
Am J Med Sci ; 349(5): 406-12, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25723884

RESUMO

BACKGROUND: To evaluate the cardioprotective effect of dexrazoxane (DEX) on chemotherapy in patients with breast cancer with concurrent type 2 diabetes mellitus (DM2). METHODS: Eighty female patients with breast cancer with DM2 were randomly assigned to receive chemotherapy only or chemotherapy plus DEX. All patients received 80 mg/m epirubicin and 500 mg/m cyclophosphamide by intravenous infusion every 3 weeks for a total of 6 cycles. The group assigned to receive chemotherapy alone received placebo 30 minutes before epirubicin administration. The group assigned to receive chemotherapy plus DEX received 800 mg/m DEX 30 minutes before epirubicin administration. Cardiac function and hematology before and after 6 cycles of chemotherapy were analyzed. RESULTS: There was no difference in baseline systole or diastole function between the 2 DM2 groups. Patients receiving chemotherapy alone experienced significantly greater reductions in Ea and significantly greater elevations in E/Ea and Tei index in comparison with patients receiving chemotherapy plus DEX. After chemotherapy, superoxide dismutase was significantly reduced, and serum malondialdehyde (MDA) was significantly increased in patients with DM2. Serum superoxide dismutase levels were comparable between the 2 groups before and after chemotherapy, MDA levels were comparable between the 2 groups before chemotherapy, whereas serum MDA was significantly higher after chemotherapy in the chemotherapy alone group in comparison with the group that received DEX. CONCULSIONS: DEX protects against cardiotoxicity induced by chemotherapy in patients with breast cancer with concurrent DM2.


Assuntos
Neoplasias da Mama , Cardiotoxicidade , Ciclofosfamida , Dexrazoxano/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Epirubicina , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Cardiotônicos/administração & dosagem , Cardiotoxicidade/sangue , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Monitoramento de Medicamentos , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Feminino , Testes de Função Cardíaca , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento
12.
BMC Cardiovasc Disord ; 14: 99, 2014 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-25117689

RESUMO

BACKGROUND: A number of clinical and experimental studies have investigated the effect of atorvastatin on atrial fibrillation (AF), but the results are equivocal. This meta-analysis was performed to evaluate whether atorvastatin can reduce the risk of AF in different populations. METHODS: We searched PubMed, EMBASE and the Cochrane Database for all published studies that examined the effect of atorvastatin therapy on AF up to April 2014. A random effects model was used when there was substantial heterogeneity and a fixed effects model when there was negligible heterogeneity. RESULTS: Eighteen published studies including 9952 patients with sinus rhythm were identified for inclusion in the analysis. Ten studies investigated primary prevention of AF by atorvastatin in patients without AF, seven studies investigated secondary prevention of atorvastatin in patients with AF, and one study investigated mixed populations of patients. Overall, atorvastatin was associated with a decreased risk of AF (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.36-0.70, P < 0.0001). However, subgroup analyses showed that in the primary prevention subgroup (OR 0.55, 95% CI 0.38-0.81, P = 0.002), atorvastatin reduced the risk of new-onset AF in patients after coronary surgery (OR 0.44, 95% CI 0.29-0.68, P = 0.0002), but had no beneficial effect in patients without coronary surgery (OR 0.97, 95% CI 0.59-1.58, P = 0.89); in the secondary prevention subgroup, atorvastatin had no beneficial effect on AF recurrence in patients with electrical cardioversion (EC) (OR 0.57, 95% CI 0.25-1.32, P = 0.19) or without EC (OR 0.38, 95% CI 0.14-1.06, P = 0.06). CONCLUSIONS: This meta-analysis suggests that atorvastatin has an overall protective effect against AF. However, this preventive effect was not seen in all types of AF. Atorvastatin was significantly associated with a decreased risk of new-onset AF in patients after coronary surgery. Moreover, atorvastatin did not prove to exert a significant protective effect against the AF recurrences in both patients who had experienced sinus rhythm restoration by means of EC and those who had obtained cardioversion by means of drug therapy. Thus, further prospective studies are warranted.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/prevenção & controle , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Prevenção Primária/métodos , Pirróis/uso terapêutico , Prevenção Secundária/métodos , Atorvastatina , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Distribuição de Qui-Quadrado , Humanos , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Fatores de Risco , Resultado do Tratamento
13.
Cell Physiol Biochem ; 33(5): 1389-99, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24853498

RESUMO

OBJECTIVE: To compare the effects of biventricular electrical pacing and conventional single-ventricular pacing for cardiac contractility modulation (CCM) on cardiac contractile function and to delineate the underlying molecular mechanisms. METHODS: Forty rabbits were divided into four groups before surgery: healthy control, HF sham, HF left ventricular pacing CCM (LVP-CCM), and HF biventricular pacing CCM (BVP-CCM) groups with n=10 for each group. A rabbit model of chronic heart failure was established by ligating ascending aortic root of rabbits. Then electrical stimulations during the absolute refractory period were delivered to the anterior wall of left ventricle in the LVP-CCM group and on the anterior wall of both left and right ventricles in the BVP-CCM group lasting six hours per day for seven days. Changes in ventricular structure, cardiac function and electrocardiogram were monitored before and after CCM stimulation. RESULTS: Compared with the sham-operated group, heart weight, heart weight index, LV end-systolic diameter (LVESD), LV end-diastolic diameter (LVEDD) in the LVP-CCM and BVP-CCM groups were significantly decreased (p<0.05), while LV ejection fraction (LVEF) and fractional shortening fraction (FS) were increased (p<0.05). Notably all these changes were consistently found to be greater in BVP-CCM than in LVP-CCM. Moreover, plasma BNP levels were highest in the HF sham-control group, followed by the LVP-CCM group, and lowest in the BVP-CCM group (p<0.05). Furthermore, sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) protein levels were upregulated by 1.7 and 2.4 fold, along with simultaneous upregulation of a cardiac-enriched microRNA miR-133 levels by 2.6 and 3.3 fold, in LVP-CCM and BVP-CCM, respectively, compared to sham. CONCLUSIONS: Biventricular pacing CCM is superior to conventional monoventricular pacing CCM, producing greater improvement cardiac contractile function. Greater upregulation of SERCA2 and miR-133 may account, at least partially, for the improvement by BVP-CCM.


Assuntos
Estimulação Cardíaca Artificial , Insuficiência Cardíaca/metabolismo , MicroRNAs/biossíntese , Contração Miocárdica , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Regulação para Cima , Animais , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/genética , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Coelhos
14.
Artif Cells Nanomed Biotechnol ; 42(6): 400-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24059532

RESUMO

Recent research suggested that cardiac stem cells (CSCs) may have the clinical application for cardiac repair. However, their characteristics and the regulatory mechanisms of their growth and differentiation have not been fully investigated. Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. But the homing role of VEGF for CSCs is unclear. In this report, CSCs were isolated, purified, and expanded in vitro from rat heart. VEGF, SU5416 (VEGF receptor blocker), and Wortmannin (PI3K/Akt signaling pathway inhibitor) were used for differentiation into vascular endothelial cells (VECs). Real-time qPCR was selected to confirm the role of PI3K/Akt signaling pathway in VECs differentiation from rat CSCs. The result of real-time qPCR demonstrated that PI3K/Akt signaling pathway plays an important role in rat CSCs differentiated into VECs. So, our research provides a theoretical basis and experimental evidence for therapeutic application of rat CSCs to treat cardiac repair.


Assuntos
Células-Tronco Adultas/fisiologia , Diferenciação Celular , Endotélio Vascular/fisiologia , Mioblastos Cardíacos/citologia , Miocárdio/citologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Células Cultivadas , Indóis/farmacologia , Proteína Oncogênica v-akt/metabolismo , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Pirróis/farmacologia , Ratos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Transdução de Sinais , Transplante de Células-Tronco , Cicatrização
15.
Chin Med J (Engl) ; 121(23): 2403-9, 2008 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-19102957

RESUMO

BACKGROUND: The necrosis of a large number of myocardial cells after acute myocardial infarction (AMI) results in a decrease of cardiac function and ventricle remodeling. Stem cell transplantation could improve cardiac function after AMI, but the involving mechanisms have not been completely understood. The present study aimed to investigate the effects of transplantation of autologous bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells (MSCs) via the coronary artery on the ventricle remodeling after AMI as well as the mechanisms of the effects of transplantation of different stem cells on ventricle remodeling. METHODS: A total of 36 male pigs were enrolled in this study, which were divided into 4 groups: control group, simple infarct model group, BM-MNC transplantation group, and MSCs transplantation group. At 90 minutes when a miniature porcine model with AMI was established, transplantation of autologous BM-MNC ((4.7 +/- 1.7) x 10(7)) and MSCs ((6.2 +/- 1.6) x 10(5)) was performed in the coronary artery via a catheter. Ultrasound, electron microscope, immunohistochemical examination and real time reverse transcriptase-polymerase chain reaction were used respectively to observe cardiac functions, counts of blood vessels of cardiac muscle, cardiac muscle nuclear factor (NF)-kappaB, myocardial cell apoptosis, and the expression of the mRNA of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cardiac muscles. Multivariate Logistic regression was used to analyze the correlation factors of left ventricular end-diastolic diameter (EDD). RESULTS: The number of blood vessels in the infarct zone and around its border in the BM-MNC transplantation group was more than those in the infarct model group and MSCs group (P = 0.0001) and there was less myocardial cell apoptosis in the stem cell transplantation group than that in the infarct model group (all P < 0.01). The positive rate of NF-kappaB in the stem cell transplantation group was lower than that in the infarct model group (P = 0.001). The gene expression of VEGF in the infarct border zone of the BM-MNC group was higher than that in the MSCs group (P = 0.0001). The gene expression of bFGF in the infarct border zone in the MSCs transplantation group was higher than that in the infarct model group and the BM-MNC group (P = 0.0001). Left ventricular ejection fraction was inversely proportional to the apoptotic rate of myocardial cells and cardiac muscle NF-kappaB but positively correlated with the number of blood vessels and the expression of VEGF and bFGF in the infarct zone and infarct border zone. The Multivariate Logistic regression analysis on the factors influencing the left ventricular end-diastolic diameter after stem cell transplantation showed that the expression of VEGF mRNA in the cardiac muscles in the infarct zone, the number of apoptotic myocardial cells and the expression of NF-kappaB in the infarct border zone were independent factors for predicting the inhibitory effect on the dilation of left ventricular EDD after stem cell transplantation. CONCLUSIONS: Transplantation of autologous BM-MNC and MSCs in pigs can improve the condition of left ventricular remodeling and recover the cardiac functions after AMI. The improvement of cardiac functions is related to the increase of blood vessels, the increased expression of VEGF and bFGF, the reduction of myocardial cell apoptosis, and the decrease of NF-kappaB level in cardiac muscle tissues after stem cell transplantation.


Assuntos
Transplante de Medula Óssea/métodos , Transplante de Células-Tronco/métodos , Remodelação Ventricular , Animais , Modelos Animais de Doenças , Testes de Função Cardíaca , Masculino , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/cirurgia , Suínos , Resultado do Tratamento
16.
Zhonghua Xin Xue Guan Bing Za Zhi ; 36(6): 546-50, 2008 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-19100071

RESUMO

OBJECTIVE: To investigate the effects of autologous bone mesenchymal stem cells (MSC) transplantation on malignant arrhythmia induced by electrophysiological (EP) stimulation and cardiomyocyte ion channels remodeling in a mini-swine model of acute myocardial infarction (AMI). METHODS: Immediately after AMI (LAD occluded for 120 min), MSC (10 x 10(7), labeled by colloidal gold and co-cultivated with 5-azacytidine, 5-aza, n = 12) or equal volume saline (n = 10) were injected through over-the-wire (OTW) balloon in LAD at distal over D(1). EP stimulation is performed after 2 hours and 4 weeks in both groups to induce arrhythmia. The variance of heterogeneity of sodium currents (I(Na)) and I(Na) steady-state inactivation curves in different zones of infracted wall were investigated by patch clamp technology and the relationship between ionic channel and ventricular arrhythmia is analyzed. RESULTS: EP induced malignant ventricular arrhythmia (VT) rate was similar (MSC 75% vs. saline 90%, P = 0.455) at 2 hours post AMI and was significantly lower in MSC group (25% vs. 80%, P = 0.012) at 4 weeks post AMI. The Peak I(Na) current densities of the Endo, Media and Epi were significantly lower in MSC group [(-14.04 +/- 3.82) pA/pF, (-29.26 +/- 5.70) pA/pF, (-12.43 +/- 3.04) pA/pF] compared those in saline group [(-9.71 +/- 3.38) pA/pF, (-18.98 +/- 4.05) pA/pF, (-8.47 +/- 3.34) pA/pF, all P < 0.05]. The I(Na) steady-state inactivation curves of the Epi, Endo and Media in mini-swine with VT in MSC group [(-126.2 +/- 10.9) mV, (-106.7 +/- 11.9) mV, (-105.4 +/- 11.0) mV] were similar as those in saline group with VT [(-129.1 +/- 10.9) mV, (-112.2 +/- 9.9) mV, (-109.7 +/- 9.2) mV, all P > 0.05] while significantly lower compared to MSC group without VT [(-93.1 +/- 13.8) mV, (-95.2 +/- 15.5) mV, (-103.4 +/- 8.7) mV, all P < 0.05]. The multiple logistic regression analysis showed that I(Na) current density (RR = 1.449, 95% CI 1.276 - 2.079, P = 0.029) and I(Na) steady-state inactivation curves (RR = 1.092, 95% CI 1.008 - 1.917, P = 0.012) were the independent factors for reduced VT. CONCLUSIONS: Autologous MSC attenuated malignant ventricular arrhythmia induced by EP at 4 weeks in mini-swine with AMI which might due to altered cardiomyocyte ion channels remodeling induced by MSC.


Assuntos
Arritmias Cardíacas/etiologia , Transplante de Células-Tronco Mesenquimais , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/cirurgia , Animais , Transplante de Medula Óssea , Modelos Animais de Doenças , Feminino , Masculino , Técnicas de Patch-Clamp , Suínos , Porco Miniatura , Transplante Autólogo
17.
Clin Exp Pharmacol Physiol ; 33(3): 227-31, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16487266

RESUMO

Although the importance of elevated circulating plasma catecholamines on cardiac structural and functional remodelling of hypertension is well documented, it is unclear whether the catecholamine-beta-adrenoreceptor (beta AR)-cAMP system can predict different cardiovascular events. 2. A total of 601 identified hypertensive patients with baseline and follow-up plasma levels of noradrenaline (NA) and adrenaline (Adr), lymphocyte beta AR density (B(max)) and intra-lymphocyte cAMP levels in peripheral blood (last examination 60+/-26 months apart) were followed up for an additional 24+/-12 months. 3. After the last follow up, a composite end-point of cardiovascular death, non-fatal myocardial infarction (MI) and stroke occurred in 139 patients (23.1%). In Cox analyses, adjusting for other standard factors as well as treatment effect, NA (hazard ratio 1.22; 95% confidence interval (CI) 1.17-1.28; P=0.0008), Adr (hazard ratio 1.53; 95% CI 1.18-2.00; P=0.002), beta AR (hazard ratio 1.12; 95% CI 1.06-1.17; P=0.007) and cAMP (hazard ratio 1.15; 95% CI 1.09-1.21; P=0.005) separately predicted cardiovascular mortality. Noradrenaline, Adr, beta AR and intra-lymphocyte cAMP separately predicted fatal/non-fatal MI; NA and Adr predicted fatal/non-fatal stroke, whereas B(max) and intra-lymphocyte cAMP levels were not a significant predictor of fatal/non-fatal stroke. When stratifying the study population by NA or Adr (median 4 nmol/L), B(max) (median 600 fmol/10(7) cells) and cAMP (median 5.0 pmol/mg protein) above and below the median values in both parameters categories, patients above the median had composite cardiovascular end-point (all P<0.001) and high cardiovascular death (all P<0.01, log-rank test). 4. These results suggest that plasma NA and Adr are significant predictors of cardiovascular mortality, MI and stroke. The B(max) and intra-lymphocyte cAMP levels are significant predictors of cardiovascular mortality and MI, but not stroke.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Catecolaminas/fisiologia , AMP Cíclico/fisiologia , Hipertensão/fisiopatologia , Receptores Adrenérgicos beta/fisiologia , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Catecolaminas/sangue , AMP Cíclico/sangue , Epinefrina/sangue , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Hipertensão/mortalidade , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Norepinefrina/sangue , Receptores Adrenérgicos beta/metabolismo , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Análise de Sobrevida
18.
Chin Med J (Engl) ; 116(10): 1459-63, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14570600

RESUMO

OBJECTIVE: To investigate the association between catecholamine-beta-adrenoceptor (beta-AR)-adenosine 3', 5'-monophosphate (cAMP) system and long-term prognosis in patients with chronic heart failure (CHF). METHODS: The study population comprised 73 patients with CHF (EF: 23% +/- 10%) with a mean follow-up of 3.8 +/- 1.9 years. Plasma levels of norepinephrine (NE) were measured using high performance lipid chromatography, beta-adrenergic receptor density (Bmax) and the content of cAMP in peripheral lymphocytes were calculated using 3H-dihydroalpneolo as ligand and competitive immunoassay, respectively. Deaths due to cardiovascular events within the follow-up period were registered. RESULTS: The total mortality was 64.7%, 57.4% of which was for cardiogenic (worsening heart failure: 32.4%; sudden death: 25.0%). In the cardiogenic death group, plasma levels of NE and epinephrine (E) (3.74 nmol/L +/- 0.09 nmol/L and 3.17 nmol/L +/- 1.0 nmol/L) and the contents of peripheral lymphocyte cAMP (3.64 pmol/mg protein +/- 1.4 pmol/mg protein) were significantly increased as compared with the survival group (2.68 nmol/L +/- 0.07 nmol/L, 2.41 nmol/L +/- 0.24 nmol/L and 2.73 pmol/mg protein +/- 0.9 pmol/mg protein, respectively, all P < 0.01). In the sudden death group, plasma levels of NE and E (5.01 nmol/L +/- 0.06 nmol/L and 4.13 nmol/L +/- 0.08 nmol/L) were significantly increased as compared with the worsening heart failure group (2.49 nmol/L +/- 0.07 nmol/L and 2.33 nmol/L +/- 0.8 nmol/L, all P < 0.001) and to the survival group (2.68 nmol/L +/- 0.07 nmol/L and 2.41 nmol/L +/- 0.14 nmol/L, all P < 0.01). The incidences of sudden death were 0%, 75%, and 100% (chi(2) = 16.018, P < 0.01) in patients with plasma NE < 2.5 nmol/L, NE 2.5 nmol/L - 4.5 nmol/L, and NE > 4.5 nmol/L, respectively. In the worsening heart failure group, the content of peripheral lymphocyte cAMP (4.46 pmol/mg protein +/- 0.18 pmol/mg protein) was significantly increased compared with the sudden death group (2.39 pmol/mg protein +/- 0.9 pmol/mg protein, P < 0.001) and to the survival group (2.73 pmol/mg protein +/- 1.1 pmol/mg protein, P < 0.001). The worsening heart failure death occurences were 5.0%, 72.2%, and 100% (chi(2) = 14.26, P < 0.01) in patients with a content of peripheral lymphocyte cAMP < 2.5 nmol/L, cAMP 2.5 nmol/L - 4.5 nmol/L, and cAMP > 4.5 nmol/L, respectively. Bmax in peripheral lymphocyte was not significantly different (P > 0.05) among the sudden death, worsening heart failure, and survival groups in CHF patients. CONCLUSIONS: Plasma levels of catecholamine increase significantly, and Bmax and the contents of cAMP in peripheral lymphocytes decrease significantly in patients with CHF. High plasma catecholamine levels may be associated with sudden death, and high intralymphocyte cAMP content may be associated with worsening heart failure in CHF patients.


Assuntos
Catecolaminas/sangue , AMP Cíclico/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Receptores Adrenérgicos beta/sangue , Adulto , Idoso , Morte Súbita Cardíaca , Feminino , Humanos , Linfócitos/química , Masculino , Pessoa de Meia-Idade
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