RESUMEN
AIMS/HYPOTHESIS: AMP-activated protein kinase (AMPK) has a broad role in the regulation of glucose and lipid metabolism making it a promising target in the treatment of type 2 diabetes mellitus. We therefore sought to characterise for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding AMPKgamma(3) subunit, PRKAG3 R225W. METHODS: Aspects of fuel metabolism were studied in vitro in myocytes isolated from vastus lateralis of PRKAG3 R225W carriers and matched control participants. In vivo, muscular strength and fatigue were evaluated by isokinetic dynamometer and surface electromyography, respectively. Glucose uptake in exercising quadriceps was determined using [(18)F]fluorodeoxyglucose and positron emission tomography. RESULTS: Myotubes from PRKAG3 R225W carriers had threefold higher mitochondrial content (p < 0.01) and oxidative capacity, higher leak-dependent respiration (1.6-fold, p < 0.05), higher basal glucose uptake (twofold, p < 0.01) and higher glycogen synthesis rates (twofold, p < 0.05) than control myotubes. They also had higher levels of intracellular glycogen (p < 0.01) and a trend for lower intramuscular triacylglycerol stores. R225W carriers showed remarkable resistance to muscular fatigue and a trend for increased glucose uptake in exercising muscle in vivo. CONCLUSIONS/INTERPRETATION: Through the enhancement of skeletal muscle glucose uptake and increased mitochondrial content, the R225W mutation may significantly enhance exercise performance. These findings are also consistent with the hypothesis that the gamma(3) subunit of AMPK is a promising tissue-specific target for the treatment of type 2 diabetes mellitus, a condition in which glucose uptake and mitochondrial function are impaired.
Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Glucosa/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Adulto , Transporte Biológico/genética , Transporte Biológico/fisiología , Western Blotting , Células Cultivadas , Ácidos Grasos/metabolismo , Glucógeno/metabolismo , Humanos , Técnicas In Vitro , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Mutación , Consumo de Oxígeno/genética , Consumo de Oxígeno/fisiología , Tomografía de Emisión de Positrones , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Impairment of myocardial flow reserve (MFR) in aortic stenosis (AS) with normal left ventricular function relates to the haemodynamic severity. OBJECTIVES: To investigate whether myocardial blood flow (MBF) and MFR differ in low-flow, low-gradient AS depending on whether there is underlying true-severe AS (TSAS) or pseudo-severe AS (PSAS). METHODS: In 36 patients with low-flow, low-gradient AS, dynamic [13N]ammonia PET perfusion imaging was performed at rest (n = 36) and during dipyridamole stress (n = 20) to quantify MBF and MFR. Dobutamine echocardiography was used to classify patients as TSAS (n = 18) or PSAS (n = 18) based on the indexed projected effective orifice area (EOA) at a normal flow rate of 250 ml/s (EOAI(proj )
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Estenosis de la Válvula Aórtica/diagnóstico , Circulación Coronaria/fisiología , Adulto , Anciano , Estenosis de la Válvula Aórtica/fisiopatología , Velocidad del Flujo Sanguíneo/fisiología , Estudios de Casos y Controles , Ecocardiografía de Estrés , Femenino , Humanos , Masculino , Tomografía de Emisión de Positrones , Adulto JovenRESUMEN
BACKGROUND: Over the past few decades, advanced imaging modalities with excellent diagnostic capabilities have emerged. The aim of the present position statement was to systematically review existing literature to define Canadian recommendations for their clinical use. METHODS: A systematic literature review to 2005 was conducted for positron emission tomography (PET), multidetector computed tomographic angiography and magnetic resonance imaging (MRI) in ischemic heart disease. Papers that met the criteria were reviewed for accuracy, prognosis data and study quality. Recommendations were presented to primary and secondary panels of experts, and consensus was achieved. RESULTS: Indications for PET include detection of coronary artery disease (CAD) with perfusion imaging, and defining viability using fluorodeoxyglucose to determine left ventricular function recovery and/or prognosis after revascularization (class I). Detection of CAD in patients, vessel segments and grafts using computed tomographic angiography was considered class IIa at the time of the literature review. Dobutamine MRI is class I for CAD detection and, along with late gadolinium enhancement MRI, class I for viability detection to predict left ventricular function recovery. Imaging must be performed at institutions and interpreted by physicians with adequate experience and training. CONCLUSIONS: Cardiac imaging using advanced modalities (PET, multidetector computed tomographic angiography and MRI) is useful for CAD detection, viability definition and, in some cases, prognosis. These modalities complement the more widespread single photon emission computed tomography and echocardiography. Given the rapid evolution of technology, initial guidelines for clinical use will require regular updates. Evaluation of their integration in clinical practice should be ongoing; optimal use will require proper training. A joint effort among specialties is recommended to achieve these goals.
Asunto(s)
Angiografía Coronaria , Imagen por Resonancia Magnética , Isquemia Miocárdica/diagnóstico , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , HumanosRESUMEN
BACKGROUND: Standard perfusion imaging may underestimate the extent of disease in 3-vessel coronary atherosclerosis. This study determined whether positron emission tomography quantification of perfusion reserve by use of rubidium 82 net retention defined a greater extent of disease than the standard approach in patients with 3-vessel disease. METHODS AND RESULTS: Rb-82 net retention was quantified as an estimation of absolute perfusion at rest and with dipyridamole stress by use of dynamic positron emission tomography imaging. The percent of abnormal myocardial sectors, as compared with a normal database, for a standard and quantification approach was determined. Twenty-three patients were evaluated. Defect sizes were larger in patients with 3-vessel disease (n = 13) by use of quantification methods: 44% +/- 18% of the myocardial sectors were abnormal by use of the standard approach versus 69% +/- 24% of sectors when measured by quantification of the stress-rest perfusion difference (P =.008). In patients with single-vessel disease (n = 10), defect sizes were smaller with quantification methods. CONCLUSIONS: Quantification of Rb-82 net retention to measure the stress-rest perfusion difference in the myocardium defined a greater extent of disease than the standard approach in this group of patients with triple-vessel disease. More accurate measurement of the extent of coronary artery disease could facilitate better risk stratification and identify more high-risk patients in whom aggressive intervention is required.