RESUMO
Although the benefits of using the left internal mammary artery to bypass the left anterior descending artery (LAD) have been extensively ascertained, freedom from major cardiovascular events and survival after coronary artery bypass grafting (CABG) also correlate with the completeness of revascularisation. Hence, careful selection of the second-best graft conduit is crucial for CABG success. The more widespread use of saphenous vein grafts contrasts with the well-known long-term efficacy of multiple arterial grafting, which struggles to emerge as the procedure of choice due to concerns over increased technical difficulties and higher risk of postoperative complications. Conduit choice is at the discretion of the operator instead of being discussed by the heart team, where cardiologists are not usually engaged in such decisions due to a hypothetical lack of technical knowledge. Furthermore, according to the ESC/EACTS guidelines, traditional CABG remains the gold standard for multi-vessel coronary artery disease with complex LAD stenosis, but hybrid procedures using percutaneous coronary intervention for non-LAD targets could combine the best of two worlds. With the aim of raising the cardiologist's awareness of the surgical treatment options, we provide a comprehensive overview of the anatomical, functional and clinical aspects guiding the decision-making process in CABG strategy.
RESUMO
Oxidative stress is a condition in which oxidant metabolites exert their toxic effect because of an increased production or an altered cellular mechanism of protection. The heart needs oxygen avidly and, although it has powerful defence mechanisms, it is susceptible to oxidative stress, which occurs, for instance, during post-ischaemic reperfusion. Ischaemia causes alterations in the defence mechanisms against oxygen free radicals, mainly a reduction in the activity of mitochondrial superoxide dismutase and a depauperation of tissue content of reduced glutathione. At the same time, production of oxygen free radicals increases in the mitochondria and leukocytes and toxic oxygen metabolite production is exacerbated by re-admission of oxygen during reperfusion. Oxidative stress, in turn, causes oxidation of thiol groups and lipid peroxidation leading first to reversible damage, and eventually to necrosis. In man, there is evidence of oxidative stress (determined by release of oxidised glutathione in the coronary sinus) during surgical reperfusion of the whole heart, or after thrombolysis, and it is related to transient left ventricular dysfunction or stunning. Data on oxidative stress in the failing heart are scant. It is not clear whether the defence mechanisms of the myocyte are altered or whether the production of oxygen free radicals is increased, or both. Recent data have shown a close link between oxidative stress and apoptosis. Relevant to heart failure is the finding that tumour necrosis factor, which is found increased in failing patients, induces a rapid rise in intracellular reactive oxygen intermediates and apoptosis. This series of events is not confined to the myocytes, but occurs also at the level of endothelium, where tumour necrosis factor causes expression of inducible nitric oxide synthase, production of the reactive radical nitric oxide, oxidative stress and apoptosis. It is therefore, possible that the immunological response to heart failure results in endothelial and myocyte dysfunction through oxidative stress mediated apoptosis. Clarification of these mechanisms may lead to novel therapeutic strategies.
Assuntos
Insuficiência Cardíaca/metabolismo , Isquemia Miocárdica/metabolismo , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Isquemia Miocárdica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacosRESUMO
BACKGROUND: Left ventricular (LV) dysfunction due to coronary artery disease (CAD) may improve after revascularization in patients with hibernating myocardium (HM). METHODS AND RESULTS: We compared the rate of metabolic (arterial-great cardiac vein differences of lactate, glucose and pyruvate) and functional (intra-operative transesophageal and epicardial echocardiography) recovery and occurrence of oxidative stress (myocardial release of oxidized glutathione (GSSG)) early after surgical revascularization, in patients with CAD, LV dysfunction and HM (n=16) vs those with preserved LV function (n=15). By comparing the two groups, we observed that, after de-clamping, in patients with HM (a) the kinetic of lactate production was converted to extraction (P<0.01 at 1, 5, 10 and 20 min after revascularization), (b) myocardial extraction of pyruvate increased (P<0.01 during the first 5 min after revascularization), (c) GSSG release was less and of shorter duration (P<0.01 at all times), (d) segmental wall motion score improved from 2.4+/-0.3 to 1.7+/-0.5 (P<0.01) as did the thickening of the akinetic territories corresponding to the antero-distal septum and to the distal anterior wall regions (to 36+/-23%, and to 36+/-13%, respectively). There was a correlation between the rate of recovery of metabolic and functional indices. CONCLUSIONS: The contractile and metabolic recovery of HM is more rapid than that of non-HM, and it is not accompanied by oxidative stress.
Assuntos
Revascularização Miocárdica/métodos , Miocárdio Atordoado/cirurgia , Glicemia/metabolismo , Creatina Quinase/sangue , Ecocardiografia/métodos , Feminino , Hemodinâmica , Humanos , Cuidados Intraoperatórios/métodos , Lactatos/sangue , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Miocárdio Atordoado/metabolismo , Estresse Oxidativo , Ácido Pirúvico/metabolismoRESUMO
BACKGROUND: Apoptosis contributes to cell loss after ischemia/reperfusion injury in the heart. This study describes the time course and level of apoptosis in different cell types in the intact heart during ischemia/reperfusion injury. METHODS AND RESULTS: Isolated Langendorff-perfused rat hearts were subjected to perfusion alone (control) or to 35 minutes of regional ischemia, either alone or followed by 5, 60, or 120 minutes of reperfusion. Sections were stained by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and propidium iodide and with anti-von Willebrand factor, anti-desmin, or anti-active caspase 3 antibodies; they were then visualized by confocal microscopy. Sections were also examined by electron microscopy. No TUNEL-positive cells were seen in control hearts or hearts exposed to ischemia alone. Early in reperfusion, TUNEL staining was colocalized with endothelial cells from small coronary vessels. Endothelial apoptosis peaked at 1 hour of reperfusion and, at this time, there was clear perivascular localization of apoptotic cardiac myocytes, whose number was inversely proportional to their distance from a positive vessel. After 2 hours of reperfusion, apoptotic cardiac myocytes assumed a more homogeneous distribution. Active caspase 3 labeling was seen independent of DNA fragmentation during ischemia alone, but it colocalized with TUNEL staining over the 3 time points of reperfusion. Immunocytochemical findings were confirmed by electron microscopy and Western blotting. CONCLUSIONS: In the very early stages of reperfusion, apoptosis is first seen in the endothelial cells from small coronary vessels. The radial spread of apoptosis to surrounding cardiac myocytes suggests that reperfusion induces the release of soluble pro-apoptotic mediators from endothelial cells that promote myocyte apoptosis.
Assuntos
Apoptose , Endotélio Vascular/patologia , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Animais , Caspase 3 , Caspases/metabolismo , Contagem de Células , Endotélio Vascular/enzimologia , Marcação In Situ das Extremidades Cortadas , Técnicas In Vitro , Masculino , Isquemia Miocárdica/enzimologia , Reperfusão Miocárdica , Traumatismo por Reperfusão Miocárdica/enzimologia , Miocárdio/enzimologia , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
1. Angiotensin converting enzyme (ACE) inhibitors are under study in ischaemic heart diseases, their mechanism of action being still unknown. 2. The anti-ischaemic effect of trandolapril and the possible involvement of a bradykinin-modulation on endothelial constitutive nitric oxide synthase (eNOS) in exerting this effect, were investigated. 3. Three doses of trandolapril, chronically administered in vivo, were studied in isolated perfused rat hearts subjected to global ischaemia followed by reperfusion. 4. Trandolapril has an anti-ischaemic effect. The dose of 0.3 mg kg(-1) exerted the best effect reducing diastolic pressure increase during ischaemia (from 33.0+/-4.5 to 14.0+/-5.2 mmHg; P<0.05 vs control) and reperfusion (from 86.1+/-9.4 to 22.2+/-4.1 mmHg; P<0.01 vs control), improving functional recovery, counteracting creatine phosphokinase release and ameliorating energy metabolism after reperfusion. 5. Trandolapril down-regulated the baseline developed pressure. 6. Trandolapril increased myocardial bradykinin content (from 31.8+/-6.1 to 54.8+/-7.5 fmol/gww; P<0.05, at baseline) and eNOS expression and activity in aortic endothelium (both P<0.01 vs control) and in cardiac myocytes (from 11.3+/-1.5 to 17.0+/-2.0 mUOD microg protein(-1) and from 0.62+/-0.05 to 0.80+/-0.06 pmol mg prot(-1) min(-1); both P<0.05 vs control). 7. HOE 140 (a bradykinin B(2) receptor antagonist) and NOS inhibitors counteracted the above-reported effects. 8. There was a negative correlation between myocyte's eNOS up-regulation and myocardial contraction down-regulation. 9. Our findings suggest that the down-regulation exerted by trandolapril on baseline cardiac contractility, through a bradykinin-mediated increase in NO production, plays a crucial role in the anti-ischaemic effect of trandolapril by reducing energy breakdown during ischaemia.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bradicinina/metabolismo , Indóis/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Óxido Nítrico Sintase/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Aorta/metabolismo , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/enzimologia , Ventrículos do Coração/metabolismo , Técnicas In Vitro , Indóis/farmacologia , Masculino , Isquemia Miocárdica/enzimologia , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/citologia , Miocárdio/enzimologia , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III , Ratos , Ratos Sprague-Dawley , Pressão Ventricular/efeitos dos fármacosRESUMO
Angiotensin-converting enzyme (ACE) inhibitors exert some cardiovascular benefits by improving endothelial function. We evaluated the effects of chronic treatment with quinapril (Q) on the l -arginine/nitric oxide (NO) pathway in normotensive rats under baseline and inflammatory conditions. The role of bradykinin was also investigated. The animals received for 1 week either the ACE-inhibitor Q (1 and 10 mg/kg/day), the B(2)receptor antagonist HOE 140, Q+HOE 140, or no drug. At the end of chronic treatment, rats underwent either a 6-h placebo or an E. coli endotoxin challenge. The following measurements were made: (i) endothelial and inducible NO synthase (eNOS and iNOS) protein expression; (ii) eNOS/iNOS activity; (iii) serum levels of nitrite/nitrate and tumour necrosis factor (TNF)- alpha; (iv) NO in the expired air (eNO). Q increased baseline aortic eNOS protein expression (up to 99%, P<0.001) and activity (l -citrulline synthesis up to 94%, P<0.01; serum nitrite/nitrate up to 55%, P<0.05). HOE 140 partially reversed Q-induced upregulation of eNOS (P<0.05). Moreover, Q counteracted LPS effects, i.e. increased the impaired eNOS pathway and limited iNOS induction (up to 94 and 24%, respectively), and reduced the increased nitrite/nitrate and TNF- alpha serum levels as well as eNO (up to 25, 38 and 28%, respectively, P<0.01 for all comparisons). HOE 140 did not influence Q effects on iNOS during endotoxaemia. In conclusion, in (patho)physiological conditions in rats, Q up-regulated eNOS with a bradykinin-mediated mechanism, while downregulated iNOS with a possible TNF- alpha -mediated mechanism.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Bradicinina/análogos & derivados , Isoquinolinas/metabolismo , Óxido Nítrico Sintase/biossíntese , Peptidil Dipeptidase A/metabolismo , Transdução de Sinais/fisiologia , Tetra-Hidroisoquinolinas , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/administração & dosagem , Bradicinina/metabolismo , Bradicinina/fisiologia , Antagonistas dos Receptores da Bradicinina , Citrulina/biossíntese , Isoquinolinas/administração & dosagem , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Quinapril , Ratos , Ratos Sprague-Dawley , Receptor B2 da Bradicinina , Fator de Necrose Tumoral alfa/análiseAssuntos
Apoptose/fisiologia , Citocinas/fisiologia , Insuficiência Cardíaca/fisiopatologia , Neurotransmissores/fisiologia , Acetilcolinesterase/metabolismo , Angiotensinas/metabolismo , Endotelinas/metabolismo , Coração/fisiologia , Coração/fisiopatologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Sistema Nervoso Simpático/fisiopatologia , Remodelação Ventricular/fisiologiaRESUMO
OBJECTIVES: To differentiate the impact of the beta-blocking and the anti-oxidant activity of carvedilol in maintaining myocardium viability. METHODS: Isolated rabbit hearts, subjected to aerobic perfusion, or low-flow ischaemia followed by reperfusion, were treated with two doses of carvedilol, one dose (2.0 microM) with marked negative inotropic effect due to beta-blockage and the other (0.1 microM) with no beta-blockage nor negative inotropism. Carvedilol was compared with two doses of propranolol, 1.0 - without - and 5.0 microM - with negative inotropic effect. Anti-oxidant activity was measured as the capacity to counteract the occurrence of oxidative stress and myocardium viability as recovery of left ventricular function on reperfusion, membrane damage and energetic status. RESULTS: Carvedilol counteracted the ischemia and reperfusion induced oxidative stress: myocardial content of reduced glutathione, protein and non-protein sulfhydryl groups after ischaemia and particularly after reperfusion, was higher in hearts treated with carvedilol, while the myocardial content of oxidised glutathione was significantly reduced (0.30+/-0.03 and 0.21+/-0.02 vs. 0.39+/-0.03 nmol/mg prot, both P<0.01, in 0.1 and 2.0 microM). At the same time, carvedilol improved myocardium viability independently from its beta-blocking effect. On the contrary, propranolol maintained viability only at the higher dose, although to a lesser extent than carvedilol. This suggests that the effects of propranolol are dependent on energy saving due to negative inotropism. The extra-protection observed with carvedilol at both doses is likely due to its anti-oxidant effect. CONCLUSIONS: Our data show that the anti-oxidant activity of carvedilol is relevant for the maintenance of myocardium viability.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antioxidantes/uso terapêutico , Carbazóis/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Propanolaminas/uso terapêutico , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Análise de Variância , Animais , Carvedilol , Relação Dose-Resposta a Droga , Masculino , Miocárdio/metabolismo , Perfusão , Fosfocreatina/metabolismo , Propranolol/uso terapêutico , Coelhos , Distribuição AleatóriaRESUMO
OBJECTIVE: to investigate the changes of pyridine nucleotides and thiol redox state in cardiac tissue following ischemia and reperfusion. NADH/NAD and NADPH/NADP redox couples were specifically studied and the influence of NADPH availability on cellular thiol redox was also investigated. METHODS: isolated rabbit hearts were Langendorff perfused and subjected to a protocol of ischemia and reperfusion. An improved technique for extraction and selective quantitation of pyridine nucleotides was applied. RESULTS: ischemia and reperfusion induced an increase in diastolic pressure, limited recovery in developed pressure and loss of creatine phosphokinase. Creatine phosphate and ATP were decreased by ischemia and only partially recovered during reperfusion. NADH was increased (from 0. 36+/-0.04 to 1.96+/-0.15 micromol/g dry wt. in ischemia, P<0.001), whereas NADPH decreased during ischemia (from 0.78+/-0.04 to 0. 50+/-0.06 micromol/g dry wt., P<0.01) and reperfusion (0.45+/-0.03 micromol/g dry wt.). Furthermore, we observed: (a) release of reduced (GSH) and oxidised glutathione (GSSG) during reperfusion; (b) decreased content of reduced sulfhydryl groups during ischemia and reperfusion (GSH: from 10.02+/-0.76 to 7.11+/-0.81 nmol/mg protein, P<0.05, and to 5.48+/-0.57 nmol/mg protein; protein-SH: from 280.42+/-12.16 to 135.11+/-17.00 nmol/mg protein, P<0.001, and to 190.21+/-11.98 nmol/mg protein); (c) increased content in GSSG during reperfusion (from 0.17+/-0.02 to 0.36+/-0.02 nmol/mg protein, P<0.001); (d) increased content in mixed disulphides during ischemia (from 6.14+/-0.13 to 8.31+/-0.44 nmol/mg protein, P<0.01) and reperfusion (to 9.87+/-0.82 nmol/mg protein, P<0.01). CONCLUSIONS: under severe low-flow ischemia, myocardial NADPH levels can decrease despite the accumulation of NADH. The reduced myocardial capacity to maintain NADPH/NADP redox potential can result in thiol redox state changes. These abnormalities may have important consequences on cellular function and viability.
Assuntos
Metabolismo Energético , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/enzimologia , NADP/metabolismo , NAD/metabolismo , Compostos de Sulfidrila/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Creatina Quinase/metabolismo , Glucose-6-Fosfato/metabolismo , Glutationa/metabolismo , Masculino , Oxirredução , Perfusão , Fosfocreatina/metabolismo , CoelhosRESUMO
BACKGROUND: Cytokine activation and endothelial dysfunction are typical phenomena of congestive heart failure (CHF). We tested the hypothesis that incubating human umbilical vein endothelial cells with serum from patients with CHF will downregulate endothelial constitutive nitric oxide synthase (eNOS) and induce apoptosis. METHODS AND RESULTS: We studied 21 patients with severe CHF. Levels of tumor necrosis factor-alpha (TNF-alpha) and several neuroendocrine parameters were assessed. eNOS was measured by Western Blot analysis and apoptosis by optical microscopy and flow cytometry. We observed (1) eNOS downregulation (difference versus healthy subjects at 24 hours [P<0.05] and 48 hours [P<0.001]), (2) nuclear morphological changes typical of apoptosis; and (3) a high apoptotic rate with propidium iodide (increasing from 2.1+/-0.4% to 11.3+/-1.2% at 48 hours; P<0.001 versus healthy subjects) and annexin V. An anti-human TNF-alpha antibody did not completely counteract these effects. A strong correlation existed between eNOS downregulation and apoptosis (r = -0.89; P<0.001). CONCLUSIONS: Serum from patients with severe CHF downregulates eNOS expression and increases apoptosis. High levels of TNF-alpha likely play a role, but they cannot be the only factor responsible.
Assuntos
Apoptose , Insuficiência Cardíaca/sangue , Óxido Nítrico Sintase/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia , Idoso , Células Cultivadas , Regulação para Baixo , Endotélio Vascular/fisiologia , Citometria de Fluxo , Humanos , Pessoa de Meia-Idade , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo IIIRESUMO
AIMS: We studied the induction of monocytic inducible nitric oxide synthase expression and the tumour necrosis factor-alpha system in patients with congestive heart failure. METHODS AND RESULTS: Forty-three congestive heart failure patients and 15 healthy subjects were studied. Antigenic tumour necrosis factor-alpha and its soluble receptors, measured by ELISA, were increased in chronic heart failure and the increase was related to the clinical severity of the syndrome (tumour necrosis factor-alpha from 8.2+/-5.2 in NYHA class II to 18.2+/-7.2 in class III and 26.9+/-13.2 pg. ml(-1)in class IV, P<0.0001 classes III and IV vs class II; soluble tumour necrosis factor receptor I from 1.0+/-0.2 in class II to 2.3+/-1.1 in class III and 5.5+/-3.2 ng. ml(-1)in class IV, P<0.0001 classes III and IV vs class II; soluble tumour necrosis factor receptor II from 2.7+/-0.7 in class II to 4.9+/-1.9 in class III and 8.4+/-5.0 ng. ml(-1)in class IV, P<0.002 classes III and IV vs class II). Monocytic inducible nitric oxide synthase assessed by Western blot, was expressed only in congestive heart failure patients (13 out of 43). The association among monocytic inducible nitric oxide synthase expression, tumour necrosis factor-alpha system activation, neurohormones and other clinical parameters was studied. The univariate logistic regression showed that inducible nitric oxide synthase expression was strictly associated with NYHA class (P<0.05), antigenic tumour necrosis factor-alpha (P<0.01) and its soluble receptors (P<0.05). The multivariate analysis showed that antigenic tumour necrosis factor-alpha was the only predictor for monocytic inducible nitric oxide synthase expression (P<0.05, RR=2.75, CI 1. 34-5.43). CONCLUSIONS: Inducible nitric oxide synthase is expressed in circulating monocytes of patients with severe congestive heart failure. This phenomenon is linked to the activation of the tumour necrosis factor-alpha system.
Assuntos
Insuficiência Cardíaca/sangue , Monócitos/enzimologia , Óxido Nítrico Sintase/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Idoso , Antígenos CD/sangue , Biomarcadores/sangue , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurotransmissores/sangue , Óxido Nítrico Sintase Tipo II , Receptores do Fator de Necrose Tumoral/sangue , Receptores Tipo I de Fatores de Necrose Tumoral , Receptores Tipo II do Fator de Necrose TumoralAssuntos
Precondicionamento Isquêmico Miocárdico , Miocárdio Atordoado/fisiopatologia , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Radicais Livres , Humanos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/prevenção & controle , Miocárdio Atordoado/metabolismo , Miocárdio Atordoado/patologia , Miocárdio Atordoado/prevenção & controle , Miocárdio/metabolismo , Miocárdio/patologia , Espécies Reativas de OxigênioRESUMO
BACKGROUND: Cardioplegic solutions assure only a sub-optimal myocardial protection during prolonged storage for transplantation. The ultimate cause of myocardial damage during storage is unknown, but oxygen free radicals might be involved. We evaluated the occurrence of oxidative stress and changes in cellular redox potential after different periods of hypothermic storage. METHODS: Langendorff-perfused rabbit hearts were subjected to a protocol mimicking each stage of a cardiac transplantation procedure: explantation, storage and reperfusion. Three periods of storage were considered: Group A = 5 hours, Group B = 15 hours, and Group C = 24 hours. Oxidative stress was determined in terms of myocardial content and release of reduced (GSH) and oxidized (GSSG) glutathione, and cellular redox potential as oxidized and reduced pyridine nucleotides ratio (NAD/NADH). Data on mechanical function, cellular integrity and myocardial energetic status were collected. RESULTS: At the end of reperfusion, despite the different timings of storage, recovery of left ventricular developed pressure (46.1+/-7.0, 54.7+/-6.7, and 45.7+/-7.4% of the baseline pre-ischaemic value), energy charge (0.81+/-0.02, 0.81+/-0.02, and 0.77+/-0.01) and NAD/NADH ratio (8.87+/-1.08, 9.39+/-1.72, and 10.26+/-1.98) were similar in all groups (A, B and C). On the contrary, the rise in left ventricular resting pressure (LVRP) and GSH/GSSG ratio were significantly different between Group C, and Groups A and B (p<0.0001, analyzed by Generalized Estimating Equations model for repeated measures, and p<0.05, respectively). CONCLUSIONS: The pathophysiology of myocardial damage during hypothermic storage cannot be considered as a normothermic ischaemic injury and parameters other than energetic metabolism, such as thiolic redox state, are more predictive of functional recovery upon reperfusion.
Assuntos
Criopreservação , Transplante de Coração , Miocárdio/metabolismo , Preservação de Órgãos , Estresse Oxidativo/fisiologia , Animais , Soluções Cardioplégicas/administração & dosagem , Creatina Quinase/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Coração/efeitos dos fármacos , Masculino , Contração Miocárdica , Oxirredução , Coelhos , Pressão VentricularRESUMO
Adenosine protects myocardium from ischemia and reperfusion damage; however, the mechanism of action is still under discussion. We investigated whether (a) adenosine protects isolated crystalloid-perfused rabbit heart from ischemia/ reperfusion injury; (b) this action is receptor mediated and what receptor subtypes are involved, and (c) this action is dependent on an enhanced nitric oxide production. Our results showed a cardioprotective effect of adenosine (10(-4) M), of nonselective adenosine-receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA; 5 x 10(-6) M), and of A2A agonists CGS 21680 (10(-8) and 10(-6) M), 2-hexynylNECA (10(-7) M). On the contrary, A1 agonist CCPA (10(-8) and 10(-6) M) does not provide any protection. The effect has been achieved in terms of significant reduction in contracture development during reperfusion [diastolic pressure was 46.8 +/- 7.1 mm Hg (p < 0.01); 46.1 +/- 7.8 mm Hg (p < 0.01); 46.9 +/- 5.5 mm Hg (p < 0.01); and 59.3 +/- 6.7 mm Hg (p < 0.05) with 10(-4) M adenosine, 5 x 10(-6) M NECA, 10(-6) M CGS 21680, and 10(-7) M 2-hexynylNECA, respectively, versus 77.6 +/- 5.0 mm Hg in control]; reduced creatine phosphokinase release (13.5 +/- 1.6, 22.2 +/- 7.9, 14.2 +/- 3.3, and 14.1 +/- 4.5 U/gww in treated hearts vs. 34.6 +/- 7.2 U/gww in controls; p < 0.05); improved energy metabolism [adenosine triphosphate (ATP) content is 9.9 +/- 0.5, 10.4 +/- 0.6, 9.8 +/- 0.5, and 10.5 +/- 0.5 micromol/gdw in treated hearts vs. 7.6 +/- 0.2 micromol/gdw; p < 0.05]. Moreover, our data indirectly show a functional presence of A2A receptors on cardiomyocytes as the protection is A2A mediated and exerted only during reperfusion, although in the absence of blood and coronary flow changes. These activities appear independent of nitric oxide pathways, as adenosine and 2-hexynylNECA effects are not affected by the presence of a nitric oxide-synthase inhibitor (10(-4) M L-NNA).
Assuntos
Adenosina/farmacologia , Isquemia Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Receptores Purinérgicos P1/classificação , Traumatismo por Reperfusão/prevenção & controle , Animais , Creatina Quinase/análise , Coração/efeitos dos fármacos , Técnicas In Vitro , Masculino , Miocárdio/enzimologia , Nucleotídeos/análise , Perfusão/métodos , Fosfocreatina/análise , Coelhos , Receptores Purinérgicos P1/fisiologiaRESUMO
It has recently been suggested that inflammation may play an important role in the pathogenesis of acute ischemic syndromes. It may therefore be important to relate their clinical features with plasma indexes of inflammation. We have studied leukocyte, platelet and fibrinogen blood levels in 57 consecutive patients with acute myocardial infarction admitted to our Intensive Care Unit within 90 min after the onset of chest pain and treated with primary coronary angioplasty. Patients were divided into two groups on the basis of blood leukocyte levels: Group A, 24 patients, 17 males, mean age 54.2 +/- 13.7 years, with high blood leukocytes and Group B, 33 patients, 28 males, mean age 60.9 +/- 10.3 years, with normal blood leukocytes. Group A patients also had higher serum fibrinogen (p = 0.05) and blood platelet levels (p < 0.05). The stenosis observed after guidewire advancement was significant (> 75%) in 33% of the patients with leukocytosis vs 94% of the others (p < 0.01). No difference between the two groups was observed in the success rate of coronary angioplasty and prevalence of stent placement (100 vs 97%, and 43 vs 42% of the patients of Group A and B, respectively). In contrast, a tendency to rethrombosis requiring Rheopro administration was observed in 62% Group A patients vs 21% Group B patients (p < 0.01). In conclusion, the finding of leukocytosis in the acute phase of myocardial infarction suggests that coronary occlusion is mainly caused by a coronary thrombus occurring at the site of a non significant stenosis. In contrast, when blood leukocytes are normal, the underlying coronary stenosis is more often critical and the thrombotic process is less important. The high blood leukocytes, platelet and fibrinogen levels of Group A patients are consistent with a significant role of inflammation in the pathogenesis of the thrombotic process while hemodynamic and local mechanical factors are probably more important in patients with normal blood leukocytes.
Assuntos
Leucocitose/complicações , Infarto do Miocárdio/etiologia , Adulto , Idoso , Angioplastia Coronária com Balão , Angiografia Coronária , Feminino , Fibrinogênio/análise , Hemodinâmica , Humanos , Leucocitose/diagnóstico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/terapia , Contagem de Plaquetas , Stents , Terapia Trombolítica , Fatores de TempoRESUMO
Abnormalities of cytosolic calcium handling and myocyte energetics appear to play an important role in mediating contractile dysfunction in heart failure. Systolic and diastolic dysfunction in the failing heart are related to abnormalities of the excitation-contraction mechanism as well as myofilament calcium sensitivity. These abnormalities can be viewed as a compensatory mechanism as the myocytes by down regulating its function and metabolic activity preserve energy consumption and allow better maintenance of basal cellular homeostasis. The end point of myocyte dysfunction, however, is a reduced contraction, which, in turn, might cause a reduced cardiac output and a threatening of arterial pressure. This causes a second level of adaptation, which implies a neuroendocrine response of the whole organism. Consequently, the syndrome of congestive heart failure is characterized not only by impaired ventricular function, but also by an increase in some endogenous substances leading to vasoconstriction and water and salt retention. Although activation of the systems that release these substances is presumed to be compensatory, the sympathetic nervous system and renin-angiotensin-aldosterone system as well as the endothelins may contribute to the pathogenesis of the syndrome. Opposite to the effects of these systems are those evoked by the release of atrial natriuretic peptides. The peptides exert a potent direct vasodilatation and natriuresis. In addition, atrial natriuretic peptides inhibit the release of norepinephrine from nerve terminals and suppress the formation of renin. However, the natriuretic and vasodilator effects of these peptides in patients with congestive heart failure are outweighed by the sodium retention and vasoconstriction caused by sympathetic stimulation and activation of the renin-angiotensin-aldosterone system. The reasons for this are not entirely known. The atrial stretch receptors that are responsible for the release of the atrial peptides become impaired, and it has been suggested that patient with heart failure may adapt to the physiologic effects of atrial natriuretic peptides. The possibility that congestive heart failure is in part a humoral disease is reviewed here and consequently pharmacologic treatment aimed at reducing the effects of the neuroendocrine response as to be advantageous for patients with heart failure.
Assuntos
Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/terapia , Animais , Cálcio/metabolismo , Citosol/metabolismo , Metabolismo Energético , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Miocárdio/metabolismo , Sistema Renina-Angiotensina/fisiologiaRESUMO
Altered endothelium-dependent vasodilation has been observed in congestive heart failure (CHF), a disease characterized by a sustained adrenergic activation. The purpose of our study was to test the hypothesis that chronically elevated catecholamines influence the nitric oxide (NO) pathway in the human endothelium. Human umbilical vein endothelial cells (HUVEC) were exposed for 7 days to a concentration of noradrenaline (NA, 1 ng/mL) similar to that found in the blood of patients with CHF. Kinetics of endothelial constitutive NO synthase (ecNOS) and inducible NO synthase (iNOS) activity, measured by [3H]L-arginine to [3H]L-citrulline conversion, and protein expression of ecNOS and iNOS, assessed by Western blot analysis, were unaffected by chronic NA treatment. Furthermore, no changes in subcellular fraction-associated ecNOS were found; this indirectly shows that chronic NA did not cause phosphorylation of the enzyme. Moreover, [3H]L-arginine transport through the plasma membrane was conserved in chronically NA-treated cells. The data demonstrate that prolonged in vitro exposure to pathologic CHF-like NA does not affect the L-arginine: NO pathway in human endothelial cells.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Norepinefrina/farmacologia , Vasoconstritores/farmacologia , Arginina/metabolismo , Transporte Biológico/efeitos dos fármacos , Western Blotting , Células Cultivadas , Endotélio Vascular/enzimologia , Endotélio Vascular/metabolismo , Humanos , Cinética , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo IIIRESUMO
There are several potential outcomes of myocardial ischaemia. When ischaemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. Interventions aimed at reducing mechanical activity and oxygen demand either before ischaemia or during reperfusion have been shown to delay the onset of ischaemic damage and to improve recovery during reperfusion. When myocardial ischaemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischaemia leading to a reversible, chronic left ventricular dysfunction has been termed 'hibernating myocardium'. It is important clinically recognize hibernation as reperfusion of hibernating myocardium by angioplasty or heart surgery restores contraction and this correlates with long term survival. A third possible outcome after a short period of myocardial ischaemia is a transient post-ischaemic ventricular dysfunction, a situation termed 'stunned myocardium'.