"Shades of gray" in cardiac magnetic resonance images of infarcted myocardium: can they tell us what we'd like them to?
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Death, Sudden, Cardiac↗
Biomedical subjects
Daniel C Lee
Publications and source records attributed to Daniel C Lee.
Enhanced cystatin C and lysosomal protease expression following 6-hydroxydopamine exposure.
6-Hydroxydopamine (6-OHDA) is a selective neurotoxin used to induce apoptosis in catecholamine-containing neurons. Although biochemical products and reactive oxygen species (ROS) of 6-OHDA have been well documented, the activation of cellular pathways following exposure are not well understood. Apoptosis in PC12 (Pheochromocytoma) cells was induced by 6-OHDA in a dose (10-150 microM) and time-dependent (24-72 h) manner compared to experimental controls (no treatment). PC 12 cells exposed to 50 microM 6-OHDA demonstrated the involvement of caspase 3 and lysosomal protease alterations. Following 6-OHDA exposure, the caspase 3-like inhibitor Ac-DEVD-CHO significantly decreased 6-OHDA induced cell death. In addition, alterations in expression of the lysosomal cysteine and aspartic proteases, cathepsin B (CB) and cathepsin D (CD) and the endogenous cysteine protease inhibitor cystatin C were observed utilizing immunocytochemical analysis at 24, 48, and 72 h following 6-OHDA exposure. Furthermore, CB and CD and cystatin C immuno-like reactivity was more pronounced in TUNEL positive cells. Moreover, Western blot analysis confirmed a significant increase in protein expression for CB and CD at 72 h and a temporal and concentration dependent increase in cystatin C in response to 6-OHDA. Cells treated with pepstatin A, an inhibitor for CD, showed a significant decrease in cell death, however, CA-074ME, a specific inhibitor for CB, failed to protect cells from 6-OHDA induced cell death. Thus, these results suggest that apoptosis induced by 6-OHDA exposure is mediated in part through caspase 3 activation and lysosomal protease CD.
Animals↗
Magnetic resonance approaches and recent advances in myocardial perfusion imaging.
Myocardial perfusion imaging identifies the presence of coronary artery stenoses and defines the functional significance of those lesions. Single photon emission computed tomography and positron emission tomography have established roles. Cardiac magnetic resonance is evolving as a promising new modality in the evaluation of myocardial perfusion. This article summarizes the current capability and recent advancements in magnetic resonance perfusion imaging.
Animals↗
Contrast-enhanced cardiac magnetic resonance in the evaluation of myocardial infarction and myocardial viability in patients with ischemic heart disease.
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Animals↗
Myosin-binding protein C phosphorylation, myofibril structure, and contractile function during low-flow ischemia.
BACKGROUND: Contractile dysfunction develops in the chronically instrumented canine myocardium after bouts of low-flow ischemia and persists after reperfusion. The objective of this study is to identify whether changes in the phosphorylation state of myosin-binding protein C (MyBP-C) are a potential cause of dysfunction. METHODS AND RESULTS: During low-flow ischemia, MyBP-C is dephosphorylated, and the number of actomyosin cross-bridges in the central core of the sarcomere decreases as thick filaments dissemble from the periphery of the myofibril. During reperfusion, MyBP-C remains dephosphorylated, and its degradation is accelerated. CONCLUSIONS: Dephosphorylation of MyBP-C may initiate changes in myofibril thick filament structure that decrease the interaction of myosin heads with actin thin filaments. Limiting the formation of actomyosin cross-bridges may contribute to the contractile dysfunction that is apparent after low-flow ischemia. Breakdown of MyBP-C during reperfusion may prolong myocardial stunning.
Actins↗
Magnetic resonance versus radionuclide pharmacological stress perfusion imaging for flow-limiting stenoses of varying severity.
BACKGROUND: Although magnetic resonance first-pass imaging (MRFP) has potential advantages in pharmacological stress perfusion imaging, direct comparisons of current MRFP and established radionuclide techniques are not available. METHODS AND RESULTS: Graded regional differences in coronary flow were produced during global coronary vasodilation in chronically instrumented dogs by partially occluding the left circumflex artery. Regional differences in full-thickness flow quantified using microspheres were compared with regional differences obtained with MRFP and radionuclide SPECT imaging (99mTc-sestamibi and 201Tl). Relative regional flows (RRFs) derived from the initial areas under MRFP signal intensity-time curves were linearly related to reference microsphere RRFs over the full range of vasodilation (y=0.93x+4.3; r2=0.77). Relationships between 99mTc-sestamibi and 201Tl RRFs and microsphere RRFs were curvilinear, plateauing as flows increased. The high spatial resolution of the MRI enabled transmural flow to be evaluated in 3 to 5 layers across the myocardial wall. Reductions in subendocardial flow were visually apparent in MRFP images for > or =50% reductions in full-thickness flow. Endocardial-to-epicardial gradients in MRFP flow increased progressively with stenosis severity, whereas transmural flow patterns in remote normally perfused myocardium remained normal. Flow reductions of > or =50% not identified by radionuclide imaging were apparent in MRFP full-thickness and transmural analyses. CONCLUSIONS: High-resolution MRFP can identify regional reductions in full-thickness myocardial blood flow during global coronary vasodilation over a wider range than current SPECT imaging. Transmural flow gradients can also be identified; their magnitude increases progressively as flow limitations become more severe and endocardial flow is compromised increasingly.
Animals↗
Functional insights revealed by the crystal structures of Escherichia coli glucose-1-phosphatase.
The Escherichia coli periplasmic glucose-1-phosphatase is a member of the histidine acid phosphatase family and acts primarily as a glucose scavenger. Previous substrate profiling studies have demonstrated some of the intriguing properties of the enzyme, including its unique and highly selective inositol phosphatase activity. The enzyme is also potentially involved in pathogenic inositol phosphate signal transduction pathways via type III secretion into the host cell. We have determined the crystal structure of E. coli glucose-1-phosphatase in an effort to unveil the structural mechanism underlying such unique substrate specificity. The structure was determined by the method of multiwavelength anomalous dispersion using a tungstate derivative together with the H18A inactive mutant complex structure with glucose 1-phosphate at 2.4-A resolution. In the active site of glucose-1-phosphatase, there are two unique gating residues, Glu-196 and Leu-24, in addition to the conserved features of histidine acid phosphatases. Together they create steric and electrostatic constraints responsible for the unique selectivity of the enzyme toward phytate and glucose-1-phosphate as well as its unusually high pH optimum for the latter. Based on the structural characterization, we were able to derive simple structural principles that not only precisely explains the substrate specificity of glucose-1-phosphatase and the hydrolysis products of various inositol phosphate substrates but also rationalizes similar general characteristics across the histidine acid phosphatase family.
Binding Sites↗
Gastric hypercarbia and adverse outcome after cardiac surgery.
OBJECTIVE: It has been postulated that splanchnic ischemia, as manifested by gastric hypercarbia, helps to trigger excessive systemic inflammation, which has been linked to the development of adverse postoperative outcome. This study examined whether gastric PCO(2) values are associated with adverse outcome in cardiac surgical patients. DESIGN AND SETTING: Prospective cohort study in a tertiary-care hospital. PATIENTS: 43 patients undergoing elective cardiac surgery. INTERVENTIONS: Simultaneous measurements of gastric PCO(2) (using automated air tonometry) and arterial PCO(2) were obtained at the beginning and end of surgery. The difference (gap) between regional PCO(2) and arterial PCO(2) (corrected for temperature) was calculated. Adverse outcome was defined as in-hospital death or prolonged (>10 days) postoperative hospitalization. MEASUREMENTS AND RESULTS: Fourteen patients fulfilled the predefined definition for adverse outcome. Postoperative ICU stay and postoperative hospital length of stay were significantly longer in these patients. At the end of surgery gastric minus arterial PCO(2) gap was significantly larger in patients with adverse outcome. Global hemodynamic and perfusion related variables were not associated with adverse outcome (cardiac index, mean arterial pressure, mixed venous oxygen saturation, arterial lactate, arterial base excess). CONCLUSIONS: Gastric minus arterial PCO(2) gap after surgery is larger in patients with adverse postoperative outcome, which supports the theory that gastrointestinal reduced perfusion is relevant to the pathogenesis of postoperative morbidity.
Aged↗
Appropriate timing of surgical intervention after transmural acute myocardial infarction.
OBJECTIVE: Recommended timing of coronary revascularization after transmural acute myocardial infarction ranges from immediate surgical intervention to repair 4 weeks after infarction. Such wide variation has created a dilemma in the management of these patients. The objective of this study was to delineate the optimal timing of revascularization after transmural acute myocardial infarction in a large and contemporary patient population. METHODS: We performed a retrospective multicenter analysis of 32,099 patients who underwent coronary artery bypass grafting as the sole procedure after transmural myocardial infarction between 1991 and 1996 by 179 surgeons at 33 hospitals in New York State. RESULTS: Overall hospital mortality for all patients who underwent coronary revascularization with a history of transmural myocardial infarction was 3.3%. Hospital mortality decreased with increasing time interval between revascularization and transmural acute myocardial infarction: 14.2%, 13.8%, 7.9%, 3.8%, 2.9%, and 2.7% for less than 6 hours, 6 hours to 1 day, 1 to 3 days, 4 to 7 days, 7 to 14 days, and greater than 15 days, respectively. Multivariate analyses of 43 potential risk factors suggests that revascularization within 3 days of transmural acute myocardial infarction is independently associated with mortality. CONCLUSIONS: Coronary revascularization within 3 days of a transmural acute myocardial infarction might be an added risk for mortality. In the absence of absolute indications for emergency surgical intervention, such as structural complications and ongoing ischemia, a 3-day waiting period before surgical revascularization should be considered.
Aged↗
RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice.
BACKGROUND: Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice. METHODS AND RESULTS: Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed. CONCLUSIONS: RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.
Animals↗
Diurnal heart rate reactivity: a predictor of severity of experimental coronary and carotid atherosclerosis.
BACKGROUND: Elevated awake resting heart rate (HR) has been shown to be a major risk factor for cardiovascular disease. Since coronary ischaemic events appear to peak during transition from sleep to awake HR, we sought to determine whether the degree of diurnal HR fluctuation (dHRV) is an independent predictor of coronary and peripheral atherogenesis. In this study, we varied both baseline HR and dHRV using sino-atrial node ablation (SNA) in a primate model of diet-induced atherogenesis and determined the degree of plaque formation relative to both HR parameters. METHODS: HR was recorded continuously for 6 months by an implantable intraaortic sensor/transmitter in 17 active unrestricted male cynomolgus monkeys. In nine monkeys, SNA was employed to create a wide spectrum of dHRV, and the power amplitude of dHRV was determined for the daily HRV cycle with power spectral analysis. After a 6-month diet induction period, percent coronary and carotid stenosis, intimal thickness and area were quantitated in each animal. RESULTS: Total serum cholesterol and mean HR were no different between high ( n= 10) and low ( n= 7) dHRV groups (866 mg% vs. 740 mg%, P> 0.2 and 130 +/- 22 and 115 +/- 13, P> 0.1, respectively). Percent carotid stenosis was markedly greater in both high HR and dHRV animals ([HR], 54 +/- 19 vs. 35 +/- 10, P< 0.04) and ([dHRV], 54 +/- 17 vs. 32 +/- 10, P< 0.01). Significant increases in all measures of coronary atherogenesis were found in high dHRV animals when compared with those with low dHRV (percent stenosis: 48% +/- 22 vs. 23% +/- 16, P< 0.02), (lesion area: 1.2 +/- 0.8 vs. 0.3 +/- 0.3, P< 0.02), and (intimal thickness: 0.3 +/- 0.1 vs. 0.1 +/- 0.1, P< 0.01), respectively. While there was a trend towards greater coronary atherogenesis in animals with high HR, this did not reach statistical significance. CONCLUSION: Elevated HR and dHRV are both associated with enhanced experimental atherosclerotic plaque formation. However, a greater degree of carotid and coronary atherogenesis is observed in animals with high dHRV. These findings suggest that elevated dHRV is a stronger predictor for susceptibility to atherogenesis than elevated HR alone. Such a relationship may be attributed to the potential role of dHRV in modulating the frequency of adverse near wall haemodynamic forces, which have been shown to induce atherosclerotic plaques. Lowering of dHRV in humans by exercise or pharmacological agents may have a beneficial role in retarding atherosclerotic plaque induction, progression and complication.
Animals↗