RESUMO
BACKGROUND: Accumulating evidence suggests that the ubiquitous anion nitrite (NO2-) is a physiological signaling molecule, with roles in intravascular endocrine nitric oxide transport, hypoxic vasodilation, signaling, and cytoprotection. Thus, nitrite could enhance the efficacy of reperfusion therapy for acute myocardial infarction. The specific aims of this study were (1) to assess the efficacy of nitrite in reducing necrosis and apoptosis in canine myocardial infarction and (2) to determine the relative role of nitrite versus chemical intermediates, such as S-nitrosothiols. METHODS AND RESULTS: We evaluated infarct size, microvascular perfusion, and left ventricular function by histopathology, microspheres, and magnetic resonance imaging in 27 canines subjected to 120 minutes of coronary artery occlusion. This was a blinded, prospective study comparing a saline control group (n=9) with intravenous nitrite during the last 60 minutes of ischemia (n=9) and during the last 5 minutes of ischemia (n=9). In saline-treated control animals, 70+/-10% of the area at risk was infarcted compared with 23+/-5% in animals treated with a 60-minute nitrite infusion. Remarkably, a nitrite infusion in the last 5 minutes of ischemia also limited the extent of infarction (36+/-8% of area at risk). Nitrite improved microvascular perfusion, reduced apoptosis, and improved contractile function. S-Nitrosothiol and iron-nitrosyl-protein adducts did not accumulate in the 5-minute nitrite infusion, suggesting that nitrite is the bioactive intravascular nitric oxide species accounting for cardioprotection. CONCLUSIONS: Nitrite has significant potential as adjunctive therapy to enhance the efficacy of reperfusion therapy for acute myocardial infarction.
Assuntos
Ânions/farmacologia , Cardiotônicos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/patologia , Nitritos/farmacologia , Animais , Ânions/sangue , Apoptose/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Hemoglobinas/metabolismo , Imageamento por Ressonância Magnética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Reperfusão Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Necrose , Óxido Nítrico/sangue , Nitritos/sangue , S-Nitrosotióis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
BACKGROUND: Regional abnormalities in myocardial systolic function can be detected with myocardial strain measurements derived from Doppler tissue echocardiography. We studied longitudinal strain measurements in patients with evidence of myocardial infarction by cardiac magnetic resonance imaging to determine whether end-systolic strain could identify the severity of the infarction. METHODS: A total of 20 patients with chronic myocardial infarctions and 10 healthy volunteers underwent 2-dimensional echocardiography and cardiac magnetic resonance with delayed gadolinium (Gd) gadopentetate dimeglumine (DTPA) contrast hyperenhancement. Delayed Gd hyperenhancement was graded using the following scale: 0 = none, 1 = less than 25%, 2 = 26% to 50%, 3 = 51% to 75%, and 4 = greater than 75%. RESULTS: There was a progressive decrease in peak systolic strain in the infarct segments as the transmural extent of infarction increased. When compared with the peak systolic strain in remote segments without evidence of infarction (-19.7 +/- 0.9), the strain was significantly lower in segments with greater than 25% Gd hyperenhancement (grade 2, -14.8 +/- 1.1, P = .001; grade 3, -12.9 +/- 2.1, P = .001; grade 4, -9.1 +/- 2.0, P < .001). CONCLUSIONS: In patients with chronic myocardial infarctions, strain measurements with echocardiography show a graded response of decreasing regional strain in segments with increasing transmural extent of infarction defined by Gd hyperenhancement.