Persistent myocardial ischemia increases GLUT1 glucose transporter expression in both ischemic and non-ischemic heart regions

Persistently ischemic myocardium exhibits increased glucose uptake which may contribute to the preservation of myocardial function and viability. Little is known about the specific molecular events which are responsible for this increase in uptake. Therefore, we investigated whether myocardial ischemia induces the gene expression of the major cardiac facilitative glucose transporters, GLUT4 and GLUT1. We determined the expression of myocardial glucose transporter mRNAs and polypeptides after 6 h of regional ischemia in a dog model by semi-quantitative Northern blotting and immunoblotting. GLUT1 but not GLUT4 expression was significantly increased in both ischemic and non-ischemic regions from the experimental hearts when compared to surgical control and normal hearts. GLUT1 mRNA expression was increased 3.4-fold and GLUT1 polypeptide expression was increased 1.7-fold in ischemic hearts when compared to normal or surgical-control hearts. There were no significant regional differences in GLUT1 expression in either normal or ischemic hearts. However, there was a tendency for GLUT1 mRNA expression to be highest in the non-ischemic regions from the 6-h ischemia hearts. These findings suggest that myocardial ischemia induces a factor or factors which stimulate GLUT1 expression in non-ischemic as well as ischemic myocardial regions. Increased GLUT1 expression may play a role in augmenting glucose uptake during ischemia.     

Abnormality of myocardial oxidative metabolism in noninsulin-dependent diabetes mellitus

The purpose of this study was to evaluate oxidative metabolism and its response by dobutamine in patients with noninsulin-dependent diabetes mellitus (NIDDM) using 11C-acetate PET. METHODS: We studied 16 patients with NIDDM (9 men, 7 women; mean age 53.7 +/- 12.8 yr) and 6 healthy male control subjects (mean age 41.8 +/- 17.2 yr). None of them had an abnormality on stress-perfusion SPECT. The 11C-acetate clearances (Kmono) were compared regionally for five myocardial segments in all subjects at rest and during low-dose dobutamine stress in 13 patients (8 patients with NIDDM, age 51.9 +/- 13.6 yr; 5 healthy male control subjects, age 45.6 +/- 16.3 yr). Correlation between regional Kmono and rate-pressure product (RPP) was also studied. RESULTS: At rest, the clearance of 11C-acetate was slightly heterogeneous for both patients with NIDDM and healthy control subjects, with smaller values in the apex and inferior wall in both groups. The difference became significant during dobutamine stress in the patients. The RPP-to-Kmono (average for five segments) ratio at rest was slightly smaller in the patients (1042.7 +/- 559.1 x 0.01) than in the healthy control subjects (1391.4 +/- 209.6 x 0.01, not significant), and those during dobutamine stress were almost the same in the two groups (1457.3 +/- 737.4 x 0.01 and 1486.0 +/- 211.8 x 0.01, respectively). A significant correlation was seen between regional Kmono and RPP in every segment in the healthy control subjects (average; r = 0.89; p < 0.01), whereas more scattered correlation with greater regional variation was observed in the patients (average; r = 0.31; p value was not significant). CONCLUSION: Patients with NIDDM showed slight regional heterogeneity in myocardial oxidative metabolism. They also had more scattered correlation between myocardial oxidative metabolism and cardiac work (RPP) than healthy control subjects, with the smallest correlation coefficient observed in the inferior wall. These findings may help the understanding of dynamics in myocardial oxidative metabolism of NIDDM hearts.     

Medical options for early pregnancy termination

OBJECTIVES: We sought to assess the relation between glucose metabolism, myocardial perfusion and cardiac work after orthotopic heart transplantation. BACKGROUND: The metabolic profile of the transplanted cardiac muscle is affected by the lack of sympathetic innervation, impaired inotropic function, chronic vasculopathy, allograft rejection and immunosuppressive therapy. In relation to myocardial perfusion and cardiac work, glucose metabolism has not previously been studied in heart transplant recipients. METHODS: Regional myocardial blood flow (ml.min-1.g-1) and 18F-2-fluoro-2-deoxyglucose (18FDG) uptake rate (ml.s-1.g-1) were measured after an overnight fast in 9 healthy male volunteers (mean age +/- SD 32 +/- 7 years) and in 10 male patients (mean age 50 +/- 10 years) who had a nonrejecting heart transplant, normal left ventricular function and no angiographic evidence of epicardial coronary sclerosis. Measurements were made by using dynamic positron emission tomography (PET) with 15O-labeled water and 18FDG, respectively. Heart rate and blood pressure were also measured for calculation of rate-pressure product. RESULTS: 18FDG uptake was similar in all heart regions in the patients and volunteers (intrasubject regional variably 12 +/- 8% and 16 +/- 12%, respectively, p = 0.51). Regional myocardial blood flow was similarly evenly distributed (intrasubject regional variability 14 +/- 10% and 12 +/- 8%, respectively, p = 0.67). Mean 18FDG uptake and myocardial blood flow values for the whole heart are given because no regional differences were identified. 18FDG uptake was on average 196% higher in the patients than in the volunteers (2.90 +/- 1.79 x 10(-4) vs. 0.98 +/- 0.38 x 10(-4) ml.s-1.g-1, p = 0.006). Regional myocardial blood flow and rate-pressure product were similarly increased in the patient group, but by only 41% (1.14 +/- 0.3 vs. 0.81 +/- 0.13 ml.min-1.g-1, p = 0.008) and 53% (11,740 +/- 2,830 vs. 7,689 +/- 1,488, p = 0.001), respectively. CONCLUSIONS: 18FDG uptake is homogeneously increased in normally functioning nonrejecting heart transplants. This finding suggests that glucose may be a preferred substrate in the transplanted heart. The magnitude of this observed increase is significantly greater than that observed for myocardial blood flow or cardiac work. In the patient group, the latter two variables were increased to a similar degree over values in control hearts, indicating a coupling between cardiac work load and myocardial blood flow. The disproportionate rise in 18FDG uptake may be accounted for by inefficient metabolic utilization of glucose by the transplanted myocardium or by the influence of circulating catecholamines, which may stimulate glucose uptake independently of changes in cardiac work load.     

Relation of myocardial perfusion at rest and during pharmacologic stress to the PET patterns of tissue viability in patients with severe left ventricular dysfunction

BACKGROUND: Stress perfusion imaging can assess effectively the amount of jeopardized myocardium, but its use for identifying underperfused but viable myocardium has yielded variable results. We evaluated the relation between measurements of myocardial perfusion at rest and during pharmacologic stress and the patterns of tissue viability as determined by positron emission tomographic (PET) imaging. METHODS AND RESULTS: We studied 33 patients with coronary artery disease and left ventricular (LV) dysfunction (LV ejection fraction, 30%+/-8%). PET imaging was used to evaluate regional myocardial perfusion at rest and during pharmacologic stress with [13N]-ammonia as a flow tracer, and to delineate patterns of tissue viability (i.e., perfusion-metabolism mismatch or match) using [18F]-deoxyglucose (FDG). We analyzed 429 myocardial regions, of which 229 were dysfunctional at rest. Of these, 30 had normal perfusion and 199 were hypoperfused. A severe resting defect (deficit >40% below normal) predicted lack of significant tissue viability; 31 of 35 regions (89%) had a PET match pattern denoting transmural fibrosis. Although regions with mild or moderate resting defects (deficit <40% below normal) showed evidence of metabolic activity, perfusion measurements alone failed to identify regions with PET mismatch (reflecting hibernating myocardium). Reversible stress defects were observed with slightly higher frequency in regions with a PET mismatch (10 of 37) than in those with a PET match (36 of 162) pattern of viability. A reversible stress defect was a specific (78%) marker, but was a relatively insensitive marker (27%) of viable myocardium as defined by the PET mismatch pattern. CONCLUSIONS: In patients with LV dysfunction, the severity of regional contractile abnormalities correlates with the severity of flow deficit at rest. Severe reductions in resting blood flow in these dysfunctional regions identify predominantly nonviable myocardium that is unlikely to have improved function after revascularization. Although dysfunctional myocardium with mild to moderate flow reductions contains variable amounts of viable tissue (as assessed by FDG uptake), flow measurements alone do not distinguish between regions with PET mismatch (potentially reversible dysfunction) and PET match (irreversible dysfunction). The presence of an irreversible defect on stress imaging is a relatively specific (78%) marker of PET match, whereas a reversible stress defect is a rather insensitive (27%) marker of viability, as defined by the PET mismatch pattern.     

Three-dimensional 31P magnetic resonance spectroscopic imaging of regional high-energy phosphate metabolism in injured rat heart

The purpose of this study was to measure the spatially varying 31P MR signals in global and regional ischemic injury in the isolated, perfused rat heart. Chronic myocardial infarcts were induced by occluding the left anterior descending coronary artery eight weeks before the MR examination. The effects of acute global low-flow ischemia were observed by reducing the perfusate flow. Chemical shift imaging (CSI) with three spatial dimensions was used to obtain 31P spectra in 54-microl voxels. Multislice 1H imaging with magnetization transfer contrast enhancement provided anatomical information. In normal hearts (n = 8), a homogeneous distribution of high-energy phosphate metabolites (HEP) was found. In chronic myocardial infarction (n = 6), scar tissue contained negligible amounts of HEP, but their distribution in residual myocardium was uniform. The size of the infarcted area could be measured from the metabolic images; the correlation of infarct sizes determined by histology and 31P MR CSI was excellent (P < 0.006). In global low-flow ischemia (n = 8), changes of HEP showed substantial regional heterogeneity. Three-dimensional 31P MR CSI should yield new insights into the regionally distinct metabolic consequences of various forms of myocardial injury.     

Human nickel exposure in an area polluted by nickel refining: the S?r-Varanger study

BACKGROUND: Because myocardial wall thickness is smaller than the spatial resolution of single photon emission computed tomography (SPECT) imaging, changes in myocardial wall thickness are related to changes in maximum pixel counts via the partial volume effect, allowing for quantification of regional systolic wall thickening. We have developed a new gated SPECT method for computing the global left ventricular ejection fraction (LVEF) based entirely on changes in maximum regional myocardial counts during systolic contraction. This new method is independent of endocardial edge detection or other geometric measurements. METHODS AND RESULTS: In 23 patients the gated SPECT method was validated by comparison with radionuclide angiography. The correlation between computed LVEFs was excellent (slope = 0.97, r = 0.91). The measurement of LVEF by gated SPECT was highly reproducible, with minimal intraoperator (slope = 0.97, r = 0.97) or interoperator (slope = 1.00, r = 0.97) variability. Measurements of regional thickening indexes were also reproducible, with a mean intraoperator correlation coefficient of 0.89 +/- 0.05 (range 0.79 to 0.95) for the 14 myocardial regions. Finally, the measurement of LVEF was not significantly influenced by changes in reconstruction filter parameters over a range of cutoff frequencies from 0.16 to 0.28. CONCLUSIONS: This new counts-based gated SPECT method for measuring global left ventricular systolic function correlates well with radionuclide angiography, is highly reproducible, and has theoretic advantages over geometric methods.     

Rapid genomic changes in newly synthesized amphiploids of Triticum and Aegilops. II. Changes in low-copy coding DNA sequences

Postischemic myocardium possesses considerable contractile and metabolic reserves, but their mobilization could result in increased cell death. We tested the hypothesis that beta-adrenergic stimulation of reperfused myocardium would increase segment work more than O2 consumption, thereby improving efficiency without increased cell death. In 16 open-chest anesthetized dogs, the left anterior descending coronary artery (LAD) was ligated for 2 h; during the reperfusion period, isoproterenol (ISO; 0.1 microg/kg/min, i.v.) was administered to nine of the animals. Regional myocardial segment length and force were measured in the anterior (LAD) and posterior circumflex coronary artery (CFX) regions of the left ventricular myocardium. Work was calculated as the integrated products of force and shortening for each region. Regional myocardial O2 consumption was obtained from LAD flow and arterial and local venous O2 saturations. Infarct size (tetrazolium) was measured in the treated and untreated hearts at the end of the experiment. In untreated hearts, the first derivative of left ventricular pressure, cardiac output, and external work were significantly depressed during reperfusion; ISO restored all values to preocclusion levels. Regional myocardial work in both LAD and CFX regions was significantly increased by ISO (from 564 +/- 207 to 1,635 +/- 543 g/mm/min in LAD, and from 753 +/- 90 to 1,426 +/- 245 g/mm/min in CFX). Efficiency (work/oxygen consumption) of the reperfused region was similarly increased. LAD flow was significantly increased by ISO, and O2 extraction was unchanged. Infarct size was 28.2 +/- 4.7% in untreated hearts and 29.0 +/- 3.5% in ISO hearts. Thus isoproterenol stimulation significantly improved both regional and global function without subsequent evidence of increased cell death.     

Magnetic resonance imaging of perfusion in the isolated rat heart using spin inversion of arterial water

Measurement of regional myocardial perfusion is important for the diagnosis and treatment of coronary artery disease. Currently used methods for the measurement of myocardial tissue perfusion are either invasive or not quantitative. Here, we demonstrate a technique for the measurement of myocardial perfusion using magnetic resonance imaging (MRI) with spin tagging of arterial water. In addition, it is shown that changes in perfusion can be quantitated by measuring changes in tissue T1. Perfusion images are obtained in Langendorff-perfused, isolated rat hearts for perfusion rates ranging from 5 to 22 ml/g/min. The MRI-determined perfusion rates are in excellent agreement with perfusion rates determined from measurement of bulk perfusate flow (r = 0.98). The predicted linear dependence of the measured T1 (T1app) on perfusion is also demonstrated. The ability of perfusion imaging to measure regional variations in flow is demonstrated with hearts in which perfusion defects were created by ligation of a coronary artery. These results indicate that MRI of perfusion using spin inversion of arterial water gives quantitative maps of cardiac perfusion.     

Randomized trial of a home-based family intervention for children who have deliberately poisoned themselves

OBJECTIVE: Intraoperative myocardial contrast echocardiography was used to determine whether the identification of regional myocardial flow patterns during revascularization could predict myocardial contractile function immediately after separation from cardiopulmonary bypass (CPB) and at 1 month after coronary artery bypass grafting (CABG) surgery. DESIGN: A prospective, open-labeled, longitudinal analysis. SETTING: Two independent university hospitals. PARTICIPANTS: Twenty patients, during and up to 1 month after CABG. INTERVENTIONS: The contrast agent Albunex (Mallenckrodt Medical, Inc, St Louis, MO) was injected into the aortic root during CPB. MEASUREMENTS AND MAIN RESULTS: Myocardial contrast echocardiography opacification of flow was graded from intraoperative transesophageal echocardiographic images of the left ventricle in the short-axis, midpapillary view. The same myocardial images were also evaluated for regional wall motion abnormalities at 15, 30, and 60 minutes, 24 hours, 5 to 8 days, and 1 month after CPB. Logistic regression analysis was used to analyze the flow scores and regional function data from identical segments. Regional flow represented by contrast enhancement was assessed in 70% of the myocardial regions (55 of 80 possible segments; 95% confidence interval [CI], 61 to 76). Flow was more easily evaluated in the posterior region (95%) than in the anterior (70%) or septal regions (60%), and least likely evaluated in the lateral regions (50%). Regional wall motion was scored in 84% of the myocardial regions (469 of 560 possible regions). Function (segmental wall motion) was assessed in all regions with equal success. Segmental function and flow scores were matched to the same regions 66% of the time (53 of 80 possible series; 95% CI, 55 to 76). Regional myocardial contrast flow patterns did not predict myocardial function at 15, 30, or 60 minutes after separation from CPB. However, contrast opacification of flow did predict regional myocardial function at 1 week (p < or = 0.05) and at 1 month (p < or = 0.01) after CABG surgery. The probability that myocardial function would be normal at 1 month was 0.62 when intraoperative flow opacification was abnormal and 0.98 when flow opacification was normal. For patients with normal flow, the estimated odds of having normal myocardial function were 3.33 times those of patients with abnormal flow at 1 week (odds ratio, 3.33; 95% CI, 1.09 to 10.19) and 18.5 times those of patients with abnormal flow at 1 month (95% CI, 2.44 to 140.48). CONCLUSION: Intraoperative application of myocardial contrast echocardiography to determine regional flow patterns after revascularization may help differentiate conditions of left ventricular systolic dysfunction immediately after separation from CPB for CABG surgery and appear to predict myocardial function at 1 month.     

Effect of MCI-154, a cardiotonic agent, on regional contractile function and myocardial oxygen consumption in the presence and absence of coronary artery stenosis in dogs

The effects of MCI-154 (6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)- pyridazinone hydrochloride.3H2O), a cardiotonic agent with calcium sensitizing actions, on regional contractile function and myocardial oxygen consumption (MVO2) were studied in the dog hearts with and without partial occlusion of the left anterior descending coronary artery and compared with those of dobutamine. Segment shortening by sonomicrometry, regional myocardial blood flow by microspheres and the oxygen content of coronary venous blood drawn from the ischemic left anterior descending coronary artery area were simultaneously measured. The ischemic zone segment shortening and left ventricular (LV) dP/dtmax were decreased after partial occlusion. The infusion of MCI-154 starting 20 min after ischemia improved the depressed segment shortening and LV dP/dtmax without increasing the ischemic zone MVO2 and regional myocardial blood flow. In the nonischemic hearts, MCI-154 did not increase MVO2 and coronary blood flow despite the augmentation of myocardial contractility. MCI-154 decreased LV end-diastolic pressure and systemic blood pressure. On the other hand, dobutamine failed to increase the ischemic zone segment shortening, but the drug increased MVO2, coronary blood flow and LV dP/dtmax in both ischemic and nonischemic hearts. These results indicate that MCI-154 alleviates the ischemic contractile failure without increasing myocardial oxygen demand. Thus, MCI-154 may be useful in the management of heart failure with reduced coronary reserve.     

Fractal analysis of striatal dopamine re-uptake sites

Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT). The mean fractal dimension was 1.15+/-0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19+/-0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions.     

Interventional hemodynamics in pediatric cardiology

A new color Doppler myocardial imaging (CDMI) system with high spatial and temporal resolution and novel postprocessing modalities has been developed that could allow quantifiable stress echocardiography. The purpose of this study was to determine whether regional myocardial systolic velocities could be accurately and reproducibly measured both at rest and during bicycle ergometry by using CDMI. Thirty normal subjects were examined with CDMI at rest, and peak mean systolic myocardial velocities (MSV) were measured for 34 predetermined left ventricular myocardial segments. Interobserver variability and intraobserver variability were established for all segments. Submaximal bicycle ergometry was performed in 20 normal subjects by using standardized weight-related increases in workload. MSV were measured at each step of exercise for 16 left ventricular stress echo segments. At rest, a base-apex gradient in regional MSV was recorded with highest longitudinal shortening velocities at the base. A similar pattern was noted for circumferential shortening MSV. Measurements were predictable and highly reproducible with low interobserver and intraobserver variability for 26 of 34 segments. Reproducibility was poor for basal anteroseptal segments in all views and mid anterior, anteroseptal, and septal segments in the short-axis views. During exercise, mid and basal segments of all walls showed a significant increase of MSV between each workload step and for apical segments between alternate steps. The resting base-apex velocity gradient observed at rest remained in all walls throughout ergometry. Thus a CDMI system with improved spatial and temporal resolution and postprocessing analysis modalities provided reproducible and accurate quantification of segmental left ventricular circumferential and longitudinal contraction both at rest and during exercise.     

Assessment of transmyocardial perfusion in alligator hearts

BACKGROUND: Techniques for achieving myocardial perfusion directly from the left ventricular chamber are currently under investigation. Although originally based on the anatomy of reptilian hearts, which are rich in transmural channels and reported to have a poorly developed coronary vasculature, the blood flow capacity of a transmyocardial blood supply has not been studied in these hearts. With the ultimate goal of providing insight into the potential for achieving transmyocardial perfusion in human hearts, we studied the relative contribution of transmyocardial and coronary perfusion in alligator hearts. METHODS AND RESULTS: After explanation from six American alligators, the left ventricle was instrumented, and coronary arteries were perfused with oxygenated physiological solution. Using microspheres to estimate regional myocardial perfusion in the beating hearts, we show that although the epicardium was well perfused by the coronary arteries (0.20 +/- 0.08 versus 0.07 +/- 0.01 mL.min-1.g-1 owing to flow from the ventricular chamber), a significant proportion of endocardial perfusion was from the ventricular chamber (0.21 +/- 0.07 mL.min-1.g-1 from the left ventricle versus 0.13 +/- 0.04 mL.min-1.g-1 from coronary arteries). CONCLUSIONS: A significant amount of direct transmyocardial perfusion is present in alligator hearts. The conditions that apparently permit this situation in reptilian hearts are reviewed, and their implications for aiding in the optimization of techniques for achieving transmyocardial flow in humans are discussed.     

Effects of dobutamine stress on myocardial blood flow, 99mTc sestamibi uptake, and systolic wall thickening in the presence of coronary artery stenoses: implications for dobutamine stress testing

BACKGROUND: Although dobutamine stress is used with both 99mTc sestamibi (sestamibi) myocardial perfusion imaging and echocardiography for detecting coronary artery stenoses, the impact of stenosis severity on test end points (myocardial sestamibi uptake and systolic thickening, respectively) has not been clearly defined. METHODS AND RESULTS: In 15 open-chest dogs, dobutamine (2.5 to 30 microg x kg(-1) x min(-1)) was infused after placement of an LAD stenosis that reduced (n=8) or abolished (n=7) flow reserve. In dogs with reduced flow reserve, the stenotic-to-normal sestamibi activity ratio (0.86+/-0.03) significantly underestimated the approximately 2-to-1 dobutamine-induced flow disparity at the time of sestamibi injection (flow ratio, 0.53+/-0.04; P<.001). Stenotic-zone thickening increased at low but not at higher doses of dobutamine (2.9+/-0.4 versus 4.2+/-0.4 mm in normal zone at peak dobutamine; P=.055) but did not fall below baseline (2.7+/-0.3 mm). Similarly, in dogs with absent flow reserve, the sestamibi activity ratio (0.78+/-0.02) underestimated the approximately 2.5-to-1 dobutamine-induced flow disparity (flow ratio, 0.41+/-0.05; P<.001), and failure to increase systolic thickening was observed in the stenotic zone (2.7+/-0.4 versus 4.6+/-0.3 mm in the normal zone at peak stress, P<.01). In both groups of dogs, myocardial sestamibi uptake and image defect magnitudes were less than expected for the dobutamine-induced hyperemia, suggesting that dobutamine adversely affects myocardial sestamibi binding. Finally, a significant reduction in stenotic-zone thickening was seen during postdobutamine recovery, consistent with myocardial stunning. CONCLUSIONS: In the presence of stenoses that reduced or abolished regional flow reserve, (1) myocardial sestamibi uptake significantly underestimated the dobutamine-induced flow heterogeneity, (2) a "failure to increase systolic thickening" rather than a reduction in thickening was observed during dobutamine stress, and (3) myocardial stunning was observed during postdobutamine recovery.     

Physiologic and clinical significance of myocardial blood flow quantitation: what is expected from these measurements in the clinical ward and in the physiology laboratory?

In this essay we review data on absolute quantitation of myocardial blood flow (MBF) in humans. Earlier work established that coronary heart disease (CAD) can be detected by coronary angiography and that this disease has characteristic features at rest and during stress, which indicate the linkage between regional metabolic needs and myocardial perfusion. In the 1970s myocardial perfusion was mapped in patients with radioxenon, but this method had significant technical limitations. About the same time, radioactive microspheres were introduced for cardiovascular research and investigations; these particles provided insights on MBF in acute infarction and ischemia, myocardial reperfusion, collateral circulation, myocardial blood flow during exercise, coronary flow reserve (CFR), and layer-to-layer distribution of MBF. Studies with microspheres also permitted investigators to establish the presence in the heart of MBF heterogeneity. Currently, there are several techniques that aim at extending these concepts into clinical investigation. Two of these techniques, i.e. Doppler coronary flow velocity and fast magnetic resonance imaging assess epicardial flow dynamics and CFR. Contrast myocardial echocardiography is another novel technique which has been useful in mapping the area at risk, reperfusion, myocardial viability and collateral circulation. This essay also considers the emerging technique of intracoronary ultrasound which has shown evidence of disease underestimation by conventional contrast angiography. Positron emission tomography (PET) is a noninvasive technique that uniquely and quantitatively maps myocardial perfusion and CFR. The latter can be computed before and after angioplasty. PET studies have further demonstrated that chronic myocardial ischemia does not exist as a distinct state in patients with CAD. From the above investigations the concept has arisen that not only is CAD an entity involving epicardial vessels but also, in a significant portion of patients, an abnormal microcirculation plays an important role in the pathogenesis of ischemic syndromes. PET studies have relatively low spatial resolution since they cannot resolve layer-to-layer absolute MBF.     

Attenuation of myocardial reperfusion injury by reducing intracellular calcium overloading with dihydropyridines

The effects of three different dihydropyridine (DHP) calcium channel antagonists, nisoldipine, nimodipine, and nifedipine, on myocardial ischemic and reperfusion injury were studied using isolated rat hearts subjected to ischemia and reperfusion. Hearts were perfused with Krebs-Henseleit bicarbonate buffer containing 0, 4, 16, 64 and 100 nM concentrations of the above dihydropyridines for 15 min. Global ischemia was then induced by terminating the aortic flow for 30 min at 37 degrees, followed by 30 min of reperfusion. Left ventricular (LV) functional (LV developed pressure, its first derivative and coronary flow) and biochemical parameters (creatine kinase release) were monitored prior to ischemia and during reperfusion. In separate group of hearts, intracellular free Ca2+ ([Ca2+]i) was monitored with an intracellular calcium analyzer using a fluorescent Ca2+ indicator (Fura-2 AM). Tissue Ca2+ was also measured by atomic absorption spectroscopy after perfusing the hearts with ion-free cold buffer to wash out extracellular Ca2+. Significant recovery of the coronary flow was observed in all hearts treated with a high concentration (100 nM) of DHPs compared with the control group (P < 0.05), while a lower dose of nisoldipine (16 nM) and nifedipine (64 nM) also improved the coronary flow effectively. Reduction of myocardial creatine kinase release and improvement of the recovery of LV developed pressure, dp/dtmax, were achieved by DHPs in a concentration-dependent manner. A higher concentration of DHPs also decreased the formation of myocardial thiobarbituric acid reactive substances, although these compounds did not possess direct free radical scavenging effects in vitro. Tissue Ca2+ content was reduced significantly in treated groups. The rise of [Ca2+]i during ischemia and reperfusion appeared to be attenuated by these DHPs. The concentration-response study of the three DHPs showed the effective concentrations for reducing [Ca2+]i to be 16, 64 and 100 nM nisoldipine, nifedipine and nimodipine, respectively, in this experimental setting. The above results indicate that pretreatment with DHPs can attenuate the myocardial reperfusion injury by modulating Ca2+ overloading and decreasing the susceptibility of the membrane to free radical attack.     

Strength and pain measures associated with lateral epicondylitis bracing

BACKGROUND: In the experiment described here, we investigated the effects of the immunosuppressants FK506 and leflunomide (Lef) on the survival of hamster hearts and liver xenografts in Lewis rats. METHODS: Lewis rats were used as recipients of hamster heart or liver grafts using different regimens of FK506 and Lef. Donor-matched heart grafts were transplanted into long-term surviving Lewis rat recipients of hamster xenografts to test donor-specific prolongation of xenograft survival. Hyperimmune, late xenograft rejection, and naive sera were transferred into long-term surviving Lewis rat recipients of hamster heart xenografts to determine whether these sera could inhibit the efficacy of donor-specific long-term survival. Anti-donor-specific antibodies were analyzed by flow cytometry. RESULTS: After a short induction with FK506 plus Lef, maintenance treatment with FK506 alone was sufficient to prolong survival of hamster xenografts. All hamster heart and four of six hamster liver xenografts survived for more than 3 months. Second hamster hearts were permanently accepted by Lewis rats bearing long-term surviving hamster heart xenografts when rats were treated with FK506 monotherapy (mean survival time >60 days, n=4). Long-term surviving hamster heart grafts were rejected after transfer of hyperimmune serum but not late xenograft rejection serum or naive serum. Lef and FK506 significantly reduced the production of anti-donor-specific antibodies in Lewis rats transplanted with hamster liver and heart xenografts. CONCLUSION: Long-term survival of hamster liver and heart xenografts in Lewis rats could be induced by a regimen of short-term FK506 in combination with Lef followed by FK506 monotherapy. The acquired sensitivity of late xenoreactivity to FK506 reflects primarily a modification in the host immune response to the hamster graft.     

Regionally different vascular response to vasoactive substances in the remodelled infarcted rat heart; aberrant vasculature in the infarct scar

Remodelling after myocardial infarction (MI) is associated with vascular adaption, increasing vascular capacity of non-infarcted myocardium, and angiogenesis in the infarcted part during wound healing and scarring. We investigated regional vascular reactivity in the infarcted rat heart. Transmural infarction of the left ventricular free wall was induced by coronary artery ligation. After 3 weeks, regional flow during maximal vasodilation (nitroprusside, NPR) and submaximal vasoconstriction (arginine-vasopressin, AVP) were studied in buffer-perfused hearts. The main findings were: (1) a reduced vasodilator response (NPR) in the viable part of the left ventricular free wall, where hypertrophy was most pronounced, resulting in reduced maximal tissue perfusion of the myocardium bordering the scar (19.7 + 0.6 v 25.7 + 1.2 ml/min.g), whereas perfusion of other non-infarcted regions was preserved. (2) A 54% lower vasodilator response (NPR) and a 25% stronger vasoconstriction (AVP) in scar tissue compared to viable parts of MI hearts. Microscopy showed thicker walls of resistance arteries in scar tissue than in viable parts of MI hearts or in sham hearts, morphometrically substantiated by two- to three-fold greater wall/lumen ratios. These data indicate a deviant response of scar vessels of MI hearts, and in the non-infarcted part, a reduced coronary reserve in the most hypertrophied region. Whereas the former may be caused by different vessel structure, the reduced vasodilator reserve of the spared part of the left ventricular free wall may indicate vasodilation at rest due to insufficient vascular growth. Thus, the most hypertrophied region would be at the highest risk of further ischemic damage.     

Synergism between platelets and neutrophils in provoking cardiac dysfunction after ischemia and reperfusion: role of selectins

BACKGROUND: Neutrophils (PMNs) are known to contribute to both cardiac dysfunction and myocardial necrosis after reperfusion of an ischemic heart. Moreover, platelets are also important blood cells that can aggravate myocardial ischemic injury. This study was designed to test the effects of PMNs and platelets separately and together in provoking cardiac dysfunction in isolated perfused rat hearts after ischemia and reperfusion. METHODS AND RESULTS: Control rat hearts not subjected to ischemia were perfused without blood cells for 80 minutes. Additional control rat hearts were perfused with 75x106 PMNs, with 100x106 platelets, or with 75x106 PMNs+100x106 platelets over a 5-minute perfusion followed by a 75-minute observation period. No significant reduction in coronary flow, left ventricular developed pressure (LVDP), or the first derivative of LVDP (dP/dtmax) was observed at the end of the observation period in any nonischemic group. Similarly, global ischemia (I) for 20 minutes followed by 45 minutes of reperfusion (R) produced no sustained effects on the final recovery of any of these parameters in any group of hearts perfused in the absence of blood cells. However, I/R hearts perfused with either PMNs or platelets alone exhibited decreases in these variables of 10% to 12% (P<0.05 from control). Furthermore, I/R hearts perfused with both PMNs and platelets exhibited decreases of 50% to 60% in all measurements of cardiac function (P<0.001). These dual-cell-perfused I/R hearts also exhibited marked increases in cardiac myeloperoxidase (MPO) activity, indicating a significant PMN infiltration, and enhanced P-selectin expression on the coronary microvascular endothelium. All cardiodynamic effects as well as MPO accumulation and PMN infiltration were markedly attenuated by a sialyl LewisX-oligosaccharide or a recombinant soluble P-selectin ligand, which inhibits selectin-mediated cell adhesion. CONCLUSIONS: These results provide evidence that platelets and neutrophils act synergistically in provoking postreperfusion cardiac dysfunction and that this may be largely due to cell-to-cell interactions mediated by P-selectin. These findings may help explain the reperfusion injury phenomenon.