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2.
Lancet ; 394(10207): 1415-1424, 2019 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-31500849

RESUMO

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.


Assuntos
Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea , Idoso , Terapia Combinada , Morte Súbita Cardíaca/prevenção & controle , Feminino , Insuficiência Cardíaca/etiologia , Hospitalização , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/cirurgia , Estudos Prospectivos , Método Simples-Cego , Resultado do Tratamento , Reino Unido
3.
Undersea Hyperb Med ; 46(4): 483-494, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509904

RESUMO

The aim of this study was to establish the effect of combined therapy with hyperbaric oxygen (HBO2) therapy and verapamil, amlodipine or nicorandil on functional recovery and oxidative stress markers after ischemia in the isolated rat heart. The study included 48 rats (Wistar albino, male gender, eight weeks old, body weight 200±50g). All animals were exposed to HBO2 treatment over 14 days. Isolated heart rats were perfused by the Langendorff retrograde method at a constant coronary pressure of 70 cm H2O. After stabilization period the hearts were divided into the following groups: HBO2 group (animals exposed to only HBO2 preconditioning); HBO2 + verapamil; HBO2 + amlodipine; andHBO2 + nicorandil (animals pretreated with HBO2 and appropriate pharmacological agent). Afterward, the hearts in all groups were subjected to 20-minute global ischemia and 30-minute reperfusion. Parameters of heart function were registered, including maximum and minimum rate of pressure development, systolic and diastolic left ventricular pressure, heart rate and coronary flow. Levels of pro-oxidants such as index of lipid peroxidation, measured as thiobarbituric acid-reactive substances, nitrites, levels of superoxide anion radicals and hydrogen peroxide were determined in coronary venous effluent. Changes in cardiac tissue were evaluated by hematoxylin and eosin staining. Obtained results clearly indicate that blockage of calcium channel or the activation of adenosine triphosphate-sensitive potassium (KATP) in combination with HBO2 prevented ischemia/reperfusion-induced cardiac deleterious effects, thus contributing to improvement of functional recovery of the heart. However, future studies are certainly necessary for better understanding the mechanisms through which combination of these two maneuvers of preconditioning triggers cardioprotection.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Oxigenação Hiperbárica , Precondicionamento Isquêmico Miocárdico/métodos , Isquemia Miocárdica/terapia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Bloqueadores dos Canais de Potássio/uso terapêutico , Anlodipino/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Terapia Combinada/métodos , Circulação Coronária , Coração , Frequência Cardíaca/efeitos dos fármacos , Precondicionamento Isquêmico Miocárdico/efeitos adversos , Peroxidação de Lipídeos , Masculino , Miocárdio/patologia , Nicorandil/uso terapêutico , Estresse Oxidativo , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Verapamil/uso terapêutico
5.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052231

RESUMO

We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) (n = 9), or AMI-PostC (n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.


Assuntos
Exossomos/metabolismo , Pós-Condicionamento Isquêmico , Precondicionamento Isquêmico Miocárdico , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Fibrilação Ventricular/metabolismo , Animais , Feminino , Ventrículos do Coração/metabolismo , MicroRNAs/genética , Infarto do Miocárdio/complicações , Infarto do Miocárdio/terapia , Suínos , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/terapia , Função Ventricular
6.
Adv Exp Med Biol ; 1127: 117-130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31140175

RESUMO

Ischemic heart disease is the main cause of morbidity and mortality in the developed world. Although reperfusion therapies are currently the best treatment for this entity, the restoration of blood flow leads, under certain circumstances, to a form of myocardial damage called reperfusion injury. Several studies have shown that age, sex, smoking, diabetes and dyslipidemia are risk factors for cardiovascular diseases. Among these risk factors, dyslipidemias are present in 40% of patients with ischemic heart disease and represent the clinical factor with the greatest impact on the prognosis of patients with cardiovascular diseases. It is known that during reperfusion the increase of the oxidative stress is perhaps one of the most important mechanisms implicated in cell damage. That is why several researchers have studied protective mechanisms against reperfusion injury, such as the ischemic pre- and post- conditioning, making emphasis mainly on the reduction of oxidative stress. However, few of these efforts have been successfully translated into the clinical setting. The controversial results in regards to the relation between cardioprotective mechanisms and dyslipidemia/hypercholesterolemia are mainly due to the difference among quality, composition and the time of administration of hypercholesterolemic diets, as well as the difference in the species used in each of the studies. Therefore, in order to compare results, it is crucial that all variables that could modify the obtained results are taken into consideration.


Assuntos
Dislipidemias/complicações , Isquemia Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/complicações , Estresse Oxidativo , Humanos , Pós-Condicionamento Isquêmico , Precondicionamento Isquêmico Miocárdico , Fatores de Risco
7.
Basic Res Cardiol ; 114(3): 22, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30937537

RESUMO

Ischemic conditioning maneuvers, when induced either locally in the heart or remotely from the heart, reduce infarct size. However, infarct size reduction can be assessed no earlier than hours after established reperfusion. ST-segment elevation and its attenuation might reflect cardioprotection by ischemic conditioning online. Pigs were subjected to regional myocardial ischemia/reperfusion (1 h/3 h). Ischemic conditioning was induced prior to ischemia either locally (preconditioning; IPC; n = 15) or remotely (remote preconditioning; RIPC; n = 21), remotely during ischemia (remote perconditioning; RPER; n = 18), or locally at reperfusion (postconditioning; POCO; n = 9). Pigs without conditioning served as controls (PLA; n = 29). Area at risk and infarct size were measured postmortem, and ST-segment elevation was analyzed in a V2-like electrocardiogram lead. Ischemic conditioning reduced infarct size (PLA 42 ± 11% of area at risk; IPC 18 ± 10%; RIPC 22 ± 12%; RPER 23 ± 12%, POCO 22 ± 11%). With PLA, ST-segment elevation was increased at 5 min ischemia, sustained until 55 min ischemia and further increased at 10 min reperfusion. IPC and RIPC did not impact on ST-segment elevation at 5 min ischemia, but attenuated ST-segment elevation at 55 min ischemia. With RPER, ST-segment elevation was not different from that with PLA at 5 min, but attenuated at 55 min ischemia. POCO abolished the further increase of ST-segment elevation with reperfusion. Cardioprotection by ischemic conditioning is robustly reflected by attenuation of ST-segment elevation online.


Assuntos
Eletrocardiografia , Pós-Condicionamento Isquêmico , Precondicionamento Isquêmico Miocárdico , Infarto do Miocárdio/fisiopatologia , Animais , Circulação Coronária , Masculino , Infarto do Miocárdio/patologia , Miocárdio/patologia , Suínos , Porco Miniatura
8.
Life Sci ; 225: 79-87, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30946838

RESUMO

The different ailments of heart including myocardial infarction (MI) and ischemic heart diseases are the foremost trigger of high mortality across the world which is instigated by sedentary life style, chronic hyperglycaemia and atherosclerosis. Albeit strenuous exercise itself induces temporary hypoxia which causes myocardial damage and this vitiosus circulus is poorly understood and has been assumed difficult to break. Present investigation targets temporal dynamics of aerobic exercise treatment induced preconditioning against diabetes associated pre- and post- myocardial injury. The persisting high blood sugar level leads to several biochemical alterations at pre- and post-MI phase. Here, we present the assessment of temporal expression of cardiac biomarkers (CKMB, LDH, cTnI and serum nitrite/nitrate), oxidative stress (myocardial TBARS and reduced NBT), inflammatory cytokines (IL-6, TNF-α and IL-10), renal biomarkers (BUN, serum creatinine and microproteinuria) and structural alterations of cardio-renal tissue. Aerobic exercise preconditioning significantly downregulate the pathological events or biomarkers and upsurge the physiological biomarkers at both pre- and post-MI phase. The attenuation or returning of pathological makers to lowest level at different time points endorses the therapeutic management of aerobic exercise against diabetic MI. Furthermore, the temporal expression of various cardio-renal biomarkers pattern elucidates that aerobic exercise preconditioning boost the strength and consolidate the cardiac muscles to work under stress. Despite the presence of traditional knowledge about health benefits of aerobic exercise, it is yet to be brought into the clinical arena. In spite of few impending challenges subjected to additional investigations, aerobic exercise preconditioning shows a high degree of promise.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Experimental/fisiopatologia , Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Condicionamento Físico Animal , Animais , Lipídeos/análise , Estresse Oxidativo , Ratos
11.
Basic Res Cardiol ; 114(3): 14, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30838448

RESUMO

Remote ischaemic preconditioning (RIPC) as adjuvant to selective heart surgery attenuates cardiac injury and atrial fibrillation (AF) occurrence. We investigated its effect on sinus rhythm (SR) restoration rate in permanent AF patients undergoing Cox maze (CM) radiofrequency ablation with concomitant mitral valve surgery. From May 2013 to May 2017, 206 patients with rheumatic valve disease concomitant with permanent AF were randomized to receive prosthesis valve replacement and CM radiofrequency ablation procedure with (n = 104) or without (n = 102) RIPC (intermittent arm ischaemia through three cycles of 5-min inflation, followed by 5-min deflation of a blood pressure cuff). The primary end point of the study was freedom from cumulative AF without using antiarrhythmic drugs 1 year after operation; the secondary end points included inflammation reaction index over 48 h postoperatively and clinical outcomes. Baseline characteristics and preoperative data did not differ between groups. The SR restoration rates were significantly higher in the RIPC group, 85.6%, 83.7%, and 82.7%, than those in the control group, 72.5%, 70.6%, and 69.6%, at discharge, 6 months and 12 months, respectively, after the radiofrequency ablation procedure (P < 0.05). The serum concentration of high sensitivity C-reactive protein and neutrophil-lymphocyte ratio were significantly decreased at 12 h, 24 h, and 48 h postoperatively in the RIPC group compared to those in the control group (P < 0.05). RIPC induced by brief ischaemia and reperfusion of the arm ameliorated SR restoration rate in patients with permanent AF through CM radiofrequency ablation procedure and was associated with reduction of postoperative systemic inflammation reaction index.


Assuntos
Ablação por Cateter , Implante de Prótese de Valva Cardíaca , Precondicionamento Isquêmico Miocárdico , Adulto , Idoso , Fibrilação Atrial/cirurgia , Proteína C-Reativa/metabolismo , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Valva Mitral/cirurgia , Cardiopatia Reumática/cirurgia
12.
Basic Res Cardiol ; 114(3): 15, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30838474

RESUMO

Remote ischemic conditioning (RIC) is acutely cardioprotective in ischemia-reperfusion injury. We aimed to evaluate the effect of RIC on septic cardiomyopathy and associated multi-organ failure in a lipopolysaccharide (LPS)-induced sepsis mouse model. Balb/c mice were divided into sham, LPS, and LPS + RIC groups. LPS 10 mg/kg or saline control was injected intraperitoneally. RIC was performed by four cycles of 5 min ischemia and 5 min reperfusion of the left lower limb just before the LPS injection. Cardiac function on echocardiography, circulating mediators, blood biochemistry, and MAPK signalling was assessed. Survival 7 days after LPS injection was evaluated in sham-treated, RIC, and daily repeated RIC groups. An LPS-induced decrease in cardiac output was ameliorated by RIC with preserved left ventricular systolic function. LPS-induced increases in TNF-α, IL-1ß, IL-6, and high-mobility group box 1 protein (HMGB1) were significantly suppressed by RIC. RIC also suppressed increases in plasma cardiac troponin I, aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine with suppressed ERK and JNK phosphorylation in heart, liver, and kidney tissue. RIC significantly improved survival rate (p = 0.0037). Survival rate in the daily repeated RIC group was 100%, and it was higher than that in the RIC group (p = 0.0088). In summary, RIC reduced circulating and myocardial inflammatory mediators associated with septic cardiomyopathy, and led to improved ventricular function, cardiac output, and survival. Our data also revealed that chronic RIC has additional benefit in terms of mortality in sepsis. While further studies are required, RIC may be a clinically useful tool to ameliorate sepsis-induced cardiomyopathy.


Assuntos
Cardiomiopatias/terapia , Endotoxemia/complicações , Precondicionamento Isquêmico Miocárdico , Animais , Débito Cardíaco , Cardiomiopatias/etiologia , Cardiomiopatias/mortalidade , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos BALB C , Função Ventricular
13.
Biomed Pharmacother ; 112: 108584, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784910

RESUMO

Stem cell therapy represents a promising therapeutic avenue for cardiac disorders, including heart failure. Although stem cell transplantation showed encouraging preliminary results, the outcomes of clinical studies are still unsatisfactory. This study aimed to compare the outcomes of two therapeutic approaches, in vivo co-delivery of sodium hydrogen sulfide (NaHS) concomitant with bone marrow-derived mesenchymal stem cell (BMSC) transplantation and in vitro preconditioning of BMSCs with NaHS, both of which are intended to promote the success of stem cell therapy in rats with isoprenaline-induced heart failure. Heart failure developed 4 weeks after the subcutaneous injection of isoprenaline (170 mg/kg) for 4 consecutive days. The in vivo approach involved the co-delivery of intraperitoneally administered NaHS concomitant with BMSC transplantation for a period of 14 days. The in vitro approach involved preconditioning BMSCs with NaHS for 30 min before transplantation. Compared to treatment with BMSCs alone, in vitro preconditioning of BMSCs with NaHS improved left ventricular function as measured by echocardiography and electrocardiography and enhanced stem cell homing, proliferation and differentiation as manifested by higher cardiac expression of GATA-4 and myocyte enhancer factor 2. Moreover, the measurement of cardiac transforming growth factor beta 1 levels and histopathological investigation revealed mitigated fibrosis and myocardial injury scores. Compared with BMSC therapy alone, the in vivo approach enhanced stem cell homing and differentiation, alleviated fibrosis and augmented vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression. In conclusion, NaHS can potentiate the efficiency of BMSC therapy for heart failure by in vitro preconditioning or in vivo co-delivery. The in vitro approach is superior with regard to improving cardiac function in addition to enhancing stem cell proliferation, while the in vivo approach is superior with regard to increasing cardiac VEGF and eNOS expression.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/terapia , Sulfeto de Hidrogênio/administração & dosagem , Precondicionamento Isquêmico Miocárdico/métodos , Animais , Terapia Combinada , Insuficiência Cardíaca/fisiopatologia , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
14.
Int Heart J ; 60(2): 419-428, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30745541

RESUMO

The role of autophagy in the cardioprotection conferred by ischemic preconditioning (IPC) has been well described. This study aimed to investigate the changes in autophagy levels during the cardioprotective effects initiated by exercise preconditioning (EP).Rats were randomly divided into 4 groups: group C (control), group EP, group EE (exhaustive exercise), and group EP + EE (EP pretreatment at 0.5 hours before EE). The EP protocol included 4 periods of 10 minutes of treadmill running each at 30 m/minute with intervening 10 minute periods of rest. Hematoxylin-basic fuchsin-picric acid (HBFP) staining and plasma levels of cardiac troponin I (cTnI) were used to evaluate the ischemia-hypoxia injury in rat myocardium. Alteration levels in several autophagy proteins in the left ventricular myocardium were analyzed by Western blot. The phasic alterations of autophagy levels during EP-initiated cardioprotective phase were also examined.Compared with group C, the ischemia-hypoxia positive areas and IOD value in HBFP-staining and cTnI plasma levels increased significantly in group EE. Compared with group EE, the ischemia-hypoxia injury was markedly attenuated in group EP + EE. Compared with group C, the LC3-II/LC3-I ratio, a marker of autophagosome formation, was reduced in group EE, but the LC3-II/LC3-I ratio remained unaltered in group EP + EE. Furthermore, the LC3-II/LC3-I ratio increased significantly at 2 hours during the cardioprotective phase after EP.These results suggest that the activated autophagy level during the EP-initiated cardioprotective phase may be partly involved in the cardioprotective effects by maintaining a normal autophagy basal level during the subsequent exhaustive exercise in rat myocardium.


Assuntos
Autofagia/fisiologia , Precondicionamento Isquêmico Miocárdico/métodos , Proteínas Associadas aos Microtúbulos/metabolismo , Isquemia Miocárdica , Miocárdio/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Autofagossomos/metabolismo , Vasos Coronários , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Isquemia Miocárdica/prevenção & controle , Ratos , Ratos Sprague-Dawley , Troponina I/sangue
15.
J Physiol Biochem ; 75(1): 19-28, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30729392

RESUMO

Diabetes mellitus significantly hampers the development of cardioprotective response to remote pre/post/perconditioning stimuli by impairing the activation of cardioprotective signaling pathways. Among the different pathways, the impairment in O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling and release of cardioprotective humoral factor may contribute in attenuating remote preconditioning-induced cardioprotection. Moreover, the failure to phosphorylate extracellular signal related kinase (ERK), phosphoinositide-3-kinase (PI3K), and AKT along with up-regulation of mechanistic target of rapamycin (mTOR) and decrease in autophagy may also attenuate remote preconditioning-induced cardioprotection. Remote perconditioning stimulus also fails to phosphorylate AKT kinase in diabetic heart. In addition, diabetes may increase the oxidative stress, reactive oxygen species (ROS) production, decrease the beclin expression, and inhibit autophagy to attenuate remote perconditioning-induced cardioprotection. Moreover, diabetes-induced increase in the Rho-associated kinase (ROCK) activity, decrease in the arginase activity, and reduction in nitric oxide (NO) bioavailability may also contribute in decreasing remote perconditioning-induced cardioprotection. Diabetes may reduce the phosphorylation of adenosine 5'-monophosphate activated protein kinase (AMPKα) and increase the phosphorylation of mTOR to attenuate cardioprotection of remote postconditioning. The present review describes the role of diabetes in attenuating remote ischemic conditioning-induced cardioprotection along with the possible mechanisms.


Assuntos
Acetilglucosamina/metabolismo , Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica , Precondicionamento Isquêmico Miocárdico , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/terapia , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Autofagia , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
16.
PLoS One ; 14(1): e0211238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682140

RESUMO

Sevoflurane postconditioning (sevo postC) is an attractive and amenable approach that can protect the myocardium against ischemia/reperfusion (I/R)-injury. Unlike ischemic preconditioning (IPC), sevo postC does not require additional induced ischemic periods to a heart that is already at risk. IPC was previously shown to generate myocardial protection against I/R-injury through regulation of iron homeostasis and de novo ferritin synthesis, a process found to be impaired in the diabetic state. The current study investigated whether alterations in iron homeostasis and ferritin mRNA and protein accumulation are also involved in the cardioprotective effects generated by sevo postC. It was also investigated whether the protective effects of sevo postC in the diabetic state can be salvaged by simvastatin, through inducing nitric oxide (NO) bioavailability/activity, in isolated streptozotocin (STZ)-induced diabetic hearts (DH). Isolated rat hearts from healthy Controls and diabetic animals were retrogradely perfused using the Langendorff configuration and subjected to prolonged ischemia and reperfusion, with and without (2.4 and 3.6%) sevo postC and/or pre-treatment with simvastatin (0.5 mg/kg). Sevo postC significantly reduced infarct size and improved myocardial function in healthy Controls but not in isolated DH. The sevo postC mediated myocardial protection against I/R-injury was not associated with de novo ferrtin synthesis. Furthermore, simvastatin aggravated myocardial injury after sevo postC in STZ-induced DHs, likely due to increasing NO levels. Despite the known mechanistic overlaps between PC and postC stimuli, distinct differences underlie the cardioprotective interventions against myocardial I/R-injury and are impaired in the DH. Sevo postC mediated cardioprotection, unlike IPC, does not involve de novo ferritin accumulation and cannot be rescued by simvastatin in STZ-induced DHs.


Assuntos
Diabetes Mellitus Experimental/complicações , Ferritinas/genética , Ferritinas/metabolismo , Infarto do Miocárdio/prevenção & controle , Sevoflurano/administração & dosagem , Sinvastatina/farmacologia , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Ferro , Precondicionamento Isquêmico Miocárdico , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Óxido Nítrico/metabolismo , Ratos , Sevoflurano/farmacologia , Estreptozocina
17.
J Cardiothorac Surg ; 14(1): 22, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683137

RESUMO

BACKGROUND: Grafting vessel with LIMA to the left anterior descending coronary artery plays a most important role in the long-term prognosis of OPCABG surgery. The aim of this study was to compare the effects of isoflurane preconditioning on miRs and mRNAs levels in the left internal mammary arterie (LIMA) graft with propofol in patients undergoing off-pump coronary artery bypass surgery (OPCABG). METHODS: Patients were randomly assigned to receive either propofol (n = 15), or interrupted isoflurane (n = 15). In group P, propofol administration was continued at 3-5 mg/kg/h intravenous injection for the duration of surgery. Five minutes prior to incision, patients of the isoflurane group (group Iso) received 2 cycles of 1 MAC isoflurane. RESULTS: miR-221 were significantly lower in group Iso (P < 0 .05). E-selectin mRNA, RhoA mRNA and ROK mRNA were significantly lower at specimens of LIMA in group Iso compared with those in group P patients (P < 0 .05). The expression of NOS3 mRNA was significantly higher in group Iso patients (P < 0 .05). CONCLUSION: Our findings provide some insight that prior interrupted isoflurane administration could regulate miR-221, and downstream effectors (mRNAs) and resulted in actual attenuation of inflammation and spasm of LIMA in patients undergoing OPCABG surgery. TRIAL REGISTRATION: NCT No. ( ClinicalTrials.gov ): NCT02678650; Registration date: January 23, 2016.


Assuntos
Ponte de Artéria Coronária sem Circulação Extracorpórea/métodos , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/metabolismo , Precondicionamento Isquêmico Miocárdico/métodos , Isoflurano/farmacologia , Óxido Nítrico/genética , Quinases Associadas a rho/genética , Idoso , Anestésicos Inalatórios/farmacologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Artéria Torácica Interna/metabolismo , Pessoa de Meia-Idade , Óxido Nítrico/biossíntese , Estudos Prospectivos , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Quinases Associadas a rho/biossíntese
18.
Int J Legal Med ; 133(2): 529-538, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30353364

RESUMO

The immunohistochemical detection of dityrosine, troponins I (cTNI) and T (cTnT), and connexin 43 has been proposed as a tool for the diagnosis of myocardial infarction with short survival times. Results of clinical and experimental studies reveal that gender and/or ischemic preconditioning of the heart may have an influence on severity and magnitude of myocardial infarction. To clarify the question, if the above-mentioned markers are influenced by sex or ischemic preconditioning, experiments on isolated rat hearts using the Langendorff technique were performed. Using the hearts of 12 male and 12 female Wistar rats a local ischemia was induced through ligation of the left coronary artery. Furthermore, 12 male rat hearts underwent ischemic preconditioning of the heart by stopping the perfusion of the whole heart for 30 min and subsequently reperfusing the heart for another 60 min, before inducing local ischemia. The perfusion time after ligation varied from 10 to 60 min. A control group was comprised out of 6 male and 2 female rat hearts. These were placed in the Langendorff system for 60 min without further manipulation or received ischemic preconditioning without subsequent local ischemia or were excised without being mounted on the Langendorff system at all. All hearts were fixed in formalin and stained immunohistochemically. Depletion of the marker cTnT appeared to be less in females when compared to male hearts, for all other markers tested, no apparent difference in staining results were seen when comparing male and female rat hearts. Male rat hearts with ischemic preconditioning showed no difference compared to male rat hearts without ischemic preconditioning when stained fort dityrosine. Connexin 43 staining was less pronounced in hearts with ischemic preconditioning, whereas cTnI as well as cTnT depletion was more pronounced in preconditioned hearts. The presented findings indicate to some extent the vulnerability of the investigated markers for the influencing factors tested.


Assuntos
Conexina 43/metabolismo , Precondicionamento Isquêmico Miocárdico , Miocárdio/metabolismo , Troponina I/metabolismo , Tirosina/análogos & derivados , Animais , Biomarcadores/metabolismo , Feminino , Medicina Legal , Imuno-Histoquímica , Masculino , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica , Ratos Wistar , Fatores Sexuais , Tirosina/metabolismo
19.
Int J Cardiol ; 275: 36-38, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30309681

RESUMO

BACKGROUND: We recently reported a new approach for cardioprotection, postconditioning with lactate-enriched blood (PCLeB), and a patient with ST-segment elevation myocardial infarction (STEMI), in whom muscle squeezing of the culprit coronary artery was observed immediately after reperfusion with PCLeB. In this study, we examined the prevalence of muscle squeezing immediately after reperfusion in patients with anterior STEMI treated using PCLeB. METHODS AND RESULTS: PCLeB is a modified postconditioning protocol that comprises intermittent reperfusion and timely coronary injections of lactated Ringer's solution. We treated 30 consecutive patients with anterior STEMI using PCLeB. Among the 30 patients, 4 patients exhibited muscle squeezing of the left anterior descending artery (LAD) immediately after reperfusion. We performed follow-up coronary angiography in 23 patients and found another patient who exhibited muscle squeezing of the LAD. Thus, of 30 patients, 5 were confirmed to have myocardial bridging and 4 exhibited muscle squeezing immediately after reperfusion with PCLeB. No patient died or experienced re-hospitalization for heart failure or recurrent ischemic events at 6 months except for one patient with malignancy. CONCLUSION: Muscle squeezing immediately after reperfusion therapy is not a rare phenomenon in patients with anterior STEMI treated using PCLeB.


Assuntos
Circulação Coronária/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Precondicionamento Isquêmico Miocárdico/métodos , Lactato de Ringer/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Vasos Coronários/efeitos dos fármacos , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Fatores de Tempo
20.
Eur J Pharmacol ; 842: 79-88, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30401629

RESUMO

The present study was designed to investigate the effect of late phase of whole body hypoxic preconditioning on endothelial-dependent vasorelaxation and cardioprotection from ischemia-reperfusion injury in spontaneously hypertensive rats (SHR). Hypoxic preconditioning was performed by subjecting rats to four episodes of alternate exposure to low O2 (8%) and normal air O2 of 10 min each. After 24 h, the mesenteric arteries and hearts were isolated to determine the vascular function and cardioprotection from ischemia-reperfusion (I/R) injury on the Langendorff apparatus. There was a significant impairment in acetylcholine-induced relaxation in norepinephrine precontracted arteries (endothelium-dependent function) and increase in I/R-induced myocardial injury in SHR in comparison to Wistar Kyoto rats (WKY). However, hypoxic preconditioning significantly restored endothelium-dependent relaxation in SHR and attenuated I/R injury in both SHR and WKY. Hypoxic preconditioning also led to an increase in the levels of endothelin-1 (not endothelin-2 or -3), vascular endothelial growth factor-A (VEGF-A) and HIF-1α levels. Pretreatment with bevacizumab (anti-VEGF-A) and bosentan (endothelin receptor blocker) significantly attenuated hypoxic preconditioning-induced restoration of endothelium-dependent relaxation and cardioprotection from I/R injury. These interventions also attenuated the levels of VEGF-A and HIF-1α without modulating the endothelin-1 levels. It may be concluded that an increase in the endothelin-1 levels with a subsequent increase in HIF-1α and VEGF expression may possibly contribute in improving endothelium-dependent vasorelaxation and protecting hearts from I/R injury in SHR during late phase of whole body hypoxic preconditioning.


Assuntos
Endotelina-1/metabolismo , Endotélio/patologia , Precondicionamento Isquêmico Miocárdico , Miocárdio/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vasodilatação , Animais , Pressão Sanguínea , Hipóxia Celular , Endotélio/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos SHR , Transdução de Sinais , Fatores de Tempo
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