Highlights of the 2005 scientific sessions of the American Society of Nuclear Cardiology: Seattle, Washington, September 29-October 2, 2005.
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Cardiology↗
Biomedical subjects
Raymond R Russell
Publications and source records attributed to Raymond R Russell.
Nuclear cardiology: present and future.
Nuclear cardiology has made significant advances since the first reports of planar scintigraphy for the evaluation of left ventricular perfusion and function. While the current "state of the art" of gated myocardial perfusion single-photon emission computed tomographic (SPECT) imaging offers invaluable diagnostic and prognostic information for the evaluation of patients with suspected or known coronary artery disease (CAD), advances in the cellular and molecular biology of the cardiovascular system have helped to usher in a new modality in nuclear cardiology, namely, molecular imaging. In this review, we will discuss the current state of the art in nuclear cardiology, which includes SPECT and positron emission tomographic evaluation of myocardial perfusion, evaluation of left ventricular function by gated myocardial perfusion SPECT and gated blood pool SPECT, and the evaluation of myocardial viability with PET and SPECT methods. In addition, we will discuss the future of nuclear cardiology and the role that molecular imaging will play in the early detection of CAD at the level of the vulnerable plaque, the evaluation of cardiac remodeling, and monitoring of important new therapies including gene therapy and stem cell therapy.
Animals↗
AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart.
AMP-activated protein kinase (AMPK) promotes glucose transport, maintains ATP stores, and prevents injury and apoptosis during ischemia. AMPK has several direct molecular targets in the heart but also may interact with other stress-signaling pathways. This study examined the role of AMPK in the activation of the p38 mitogen-activated protein kinase (MAPK). In isolated heart muscles, the AMPK activator 5-aminoimidazole-4-carboxy-amide-1-beta-D-ribofuranoside (AICAR) increased p38 MAPK activation. In AMPK-deficient mouse hearts, expressing a kinase-dead (KD) alpha2 catalytic subunit, p38 MAPK activation was markedly reduced during low-flow ischemia (2.3- versus 7-fold in wild-type hearts, P<0.01) and was similarly reduced during severe no-flow ischemia in KD hearts (P<0.01 versus ischemic wild type). Knockout of the p38 MAPK upstream kinase, MAPK kinase 3 (MKK3), did not affect ischemic activation of either AMPK or p38 MAPK in transgenic mkk3(-/-) mouse hearts. Ischemia increased p38 MAPK recruitment to transforming growth factor-beta-activated protein kinase 1-binding protein 1 (TAB1), a scaffold protein that promotes p38 MAPK autophosphorylation. Moreover, TAB1 was associated with the alpha2 catalytic subunit of AMPK. p38 MAPK recruitment to TAB1/AMPK complexes required AMPK activation and was reduced in ischemic AMPK-deficient transgenic mouse hearts. The potential role of p38 MAPK in mediating the downstream action of AMPK to promote glucose transport was also assessed. The p38 MAPK inhibitor SB203580 partially inhibited both AICAR- and hypoxia-stimulated glucose uptake and GLUT4 translocation. Activation of p38 MAPK by anisomycin also increased glucose transport in heart muscles. Thus, AMPK has an important role in promoting p38 MAPK activation in the ischemic heart by inducing p38 MAPK autophosphorylation through interaction with the scaffold protein TAB1.
AMP-Activated Protein Kinases↗
Dual mechanisms regulating AMPK kinase action in the ischemic heart.
AMP-activated protein kinase (AMPK) is emerging as an important signaling protein during myocardial ischemia. AMPK is a heterotrimeric complex containing an alpha catalytic subunit and beta and gamma regulatory subunits. Phosphorylation of Thr172 in the activation loop of the alpha subunit by upstream AMPK kinase(s) (AMPKK) is a critical determinant of AMPK activity. However, the mechanisms regulating AMPK phosphorylation in the ischemic heart remain uncertain and were therefore investigated. In the isolated working rat heart, low-flow ischemia rapidly activated AMPKK activity when measured using recombinant AMPK (rAMPK) as substrate. The addition of AMP (10 to 200 micromol/L) augmented the ability of heterotrimeric alpha1beta1gamma1 or alpha2beta1gamma1 rAMPK to be phosphorylated by heart AMPKK in vitro, whereas physiologic concentrations of ATP inhibited rAMPK phosphorylation. However, neither AMP nor ATP directly influenced AMPKK activity: they had no effect on AMPKK-mediated phosphorylation of rAMPK substrates lacking normal AMP-binding gamma subunits (isolated truncated alpha1(1-312) or alpha1beta1gamma1 rAMPK containing an R70Q mutation in the gamma1 AMP-binding site). Regional ischemia in vivo also increased AMPKK activity and AMPK phosphorylation in the rat heart. AMPK phosphorylation could also be induced in vivo without activating AMPKK: AICAR infusion increased AMPK phosphorylation without activating AMPKK; however, the AMP-mimetic AICAR metabolite ZMP enhanced the ability of heterotrimeric rAMPK to be phosphorylated by AMPKK. Thus, heart AMPKK activity is increased by ischemia and its ability to phosphorylate AMPK is highly modulated by the interaction of AMP and ATP with the heterotrimeric AMPK complex, indicating that dual mechanisms regulate AMPKK action in the ischemic heart.
AMP-Activated Protein Kinase Kinases↗
AMP-activated protein kinase: a key stress signaling pathway in the heart.
AMP-activated protein kinase (AMPK) is activated during exercise and ischemia and is emerging as an important regulatory mechanism in the heart. AMPK promotes adenosine triphosphate-generating pathways, including glucose transport, glycolysis, and fatty acid oxidation, while inhibiting energy-consuming anabolic pathways. After ischemia-reperfusion, AMPK-deficient hearts from transgenic mice have severe left ventricular contractile dysfunction with increased apoptosis and necrosis. Mutations in the AMPKgamma(2) subunit lead to cardiac glycogen overload, Wolff-Parkinson-White syndrome, arrhythmias, and heart failure. This review focuses on the molecular mechanisms of activation and cardiovascular actions of AMPK in the heart.
AMP-Activated Protein Kinases↗
Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle.
AMP-activated protein kinase (AMPK) is a serine-threonine kinase that regulates cellular metabolism and has an essential role in activating glucose transport during hypoxia and ischemia. The mechanisms responsible for AMPK stimulation of glucose transport are uncertain, but may involve interaction with other signaling pathways or direct effects on GLUT vesicular trafficking. One potential downstream mediator of AMPK signaling is the nitric oxide pathway. The aim of this study was to examine the extent to which AMPK mediates glucose transport through activation of the nitric oxide (NO)-signaling pathway in isolated heart muscles. Incubation with 1 mM 5-amino-4-imidazole-1-beta-carboxamide ribofuranoside (AICAR) activated AMPK (P < 0.01) and stimulated glucose uptake (P < 0.05) and translocation of the cardiomyocyte glucose transporter GLUT4 to the cell surface (P < 0.05). AICAR treatment increased phosphorylation of endothelial NO synthase (eNOS) approximately 1.8-fold (P < 0.05). eNOS, but not neuronal NOS, coimmunoprecipitated with both the alpha(2) and alpha(1) AMPK catalytic subunits in heart muscle. NO donors also increased glucose uptake and GLUT4 translocation (P < 0.05). Inhibition of NOS with N(omega)-nitro-l-arginine and N(omega)-methyl-l-arginine reduced AICAR-stimulated glucose uptake by 21 +/- 3% (P < 0.05) and 25 +/- 4% (P < 0.05), respectively. Inhibition of guanylate cyclase with ODQ and LY-83583 reduced AICAR-stimulated glucose uptake by 31 +/- 4% (P < 0.05) and 22 +/- 3% (P < 0.05), respectively, as well as GLUT4 translocation to the cell surface (P < 0.05). Taken together, these results indicate that activation of the NO-guanylate cyclase pathway contributes to, but is not the sole mediator of, AMPK stimulation of glucose uptake and GLUT4 translocation in heart muscle.
AMP-Activated Protein Kinases↗
Experience with the continuous glucose monitoring system in a medical intensive care unit.
Strict glycemic control improves clinical outcomes in critically ill patients. However, practical tools for frequent monitoring of blood glucose (BG) levels in the intensive care unit (ICU) are limited. The Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA) is currently approved for detecting glycemic excursions in outpatients with diabetes mellitus. The use of this device has never been carefully examined in the inpatient setting. This preliminary study was designed to investigate the accuracy of the CGMS in critically ill patients admitted to a medical ICU (MICU). Subjects at risk for hyperglycemia were recruited from among all patients admitted to our MICU. CGMS sensors were implanted for up to 72 h. Study subjects wore between one and five consecutive sensors. Four or more standard capillary BG readings were recorded per 24 h. All paired meter-sensor (M-S) readings were used both for CGMS calibration and for data analysis. Twenty-two MICU patients wore 41 CGMS sensors, yielding 546 M-S BG pairs. Overall, the Pearson correlation coefficient ( r ) was 0.88, with a mean M-S difference of 3.3 +/- 26.7 mg/dL (0.6 +/- 17.4%) and a mean absolute M-S difference of 19.7 +/- 18.3 mg/dL (12.8 +/- 11.9%). Clarke Error Grid analysis categorized 98.7% of the M-S pairs within "clinically acceptable" zones A and B. The CGMS is promising for potential use in critically ill patients. If validated in larger studies, the device could serve as a useful research tool for investigating the role of hyperglycemia (and strict glycemic control) in ICU patients. If further developed as a "real-time" glucose sensor, CGMS technology could ultimately prove clinically useful in the ICU, by decreasing nursing workload and/or by providing alarm signals for impending glycemic excursions.
APACHE↗
AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury.
AMP-activated protein kinase (AMPK) is an important regulator of diverse cellular pathways in the setting of energetic stress. Whether AMPK plays a critical role in the metabolic and functional responses to myocardial ischemia and reperfusion remains uncertain. We examined the cardiac consequences of long-term inhibition of AMPK activity in transgenic mice expressing a kinase dead (KD) form of the enzyme. The KD mice had normal fractional shortening and no heart failure, cardiac hypertrophy, or fibrosis, although the in vivo left ventricular (LV) dP/dt was lower than that in WT hearts. During low-flow ischemia and postischemic reperfusion in vitro, KD hearts failed to augment glucose uptake and glycolysis, although glucose transporter content and insulin-stimulated glucose uptake were normal. KD hearts also failed to increase fatty acid oxidation during reperfusion. Furthermore, KD hearts demonstrated significantly impaired recovery of LV contractile function during postischemic reperfusion that was associated with a lower ATP content and increased injury compared with WT hearts. Caspase-3 activity and TUNEL-staining were increased in KD hearts after ischemia and reperfusion. Thus, AMPK is responsible for activation of glucose uptake and glycolysis during low-flow ischemia and plays an important protective role in limiting damage and apoptotic activity associated with ischemia and reperfusion in the heart.
AMP-Activated Protein Kinases↗
Coronary vasospasm during an adenosine stress test.
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Adenosine↗