Comparison of thallium deposition with segmental perfusion in pigs with chronic hibernating myocardium

Viable, chronically dysfunctional myocardium with reduced resting flow (or hibernating myocardium) is an important prognostic factor in ischemic heart disease. Although thallium-201 imaging is frequently used to assess myocardial viability in patients with ischemic cardiomyopathy, there are limited data regarding its deposition in hibernating myocardium, and this data suggest that thallium retention may be supernormal compared with control myocardium. Accordingly, pigs (n=7) were chronically instrumented with a 1.5 mm Delrin stenosis on the proximal left anterior descending coronary artery (LAD) to produce hibernating myocardium. Four months later, severe anteroapical hypokinesis was documented with contrast ventriculography (wall motion score, 0.7+/-0.8; normal=3), and microsphere measurements confirmed reduced resting flow (LAD subendocardium, 0.78+/-0.34 vs. 0.96+/-0.24 ml.min(-1).g(-1) in remote; P<0.001). Absolute deposition of thallium-201 and insulin-stimulated [18F]-2 fluoro-2-deoxyglucose (FDG) were assessed over 1 h and compared with resting flow (n=704 samples). Thallium-201 deposition was only weakly correlated with perfusion (r2=0.20; P<0.001) and was more homogeneously distributed (relative dispersion, 0.12+/-0.03 vs. 0.29+/-0.10 for microsphere flow; P<0.01). Thus after 1 h relative thallium-201 (subendocardium LAD/remote, 0.96+/-0.16) overestimated relative perfusion (0.78+/-0.32; P<0.0001) and underestimated the relative reduction in flow. Viability was confirmed by both histology and preserved FDG uptake. We conclude that under resting conditions, thallium-201 redistribution in hibernating myocardium is nearly complete within 1 h, with similar deposition to remote myocardium despite regional differences in flow. These data suggest that in this time frame thallium-201 deposition may not discriminate hibernating myocardium from dysfunction myocardium with normal resting flow. Since hibernating myocardium has been associated with a worse prognosis, this limitation could have significant clinical implications.     

Effect of regional hyperemia on myocardial uptake of 2-deoxy-2-[(18)F]fluoro-D-glucose

2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) may be used to predict glucose kinetics when the factor relating differences in transport and phosphorylation between compounds remains constant ("lumped constant"). It is not clear whether hyperemia alters that factor. In anesthetized swine, myocardial FDG uptake was estimated by positron emission tomography, during an intracoronary infusion of either adenosine, ATP, or bradykinin (40 microg x kg(-1) x min(-1), 40 microg x kg(-1) x min(-1), and 2 nmol x kg(-1) x min(-1), respectively; n = 6 for all groups). In controls during normal perfusion (n = 6), FDG uptake was 0.78 +/- 0.32 micromol x g(-1) x min(-1), whereas glucose uptake by Fick was 0.71 +/- 0.25 micromol x g(-1) x min(-1) (r = 0.73; P < 0.05). Adenosine increased blood flow from 1.29 +/- 0.43 to 4.80 +/- 2.19 ml x g(-1) x min(-1) (P < 0.05) and glucose uptake from 1.16 +/- 1.10 to 3.35 +/- 2.12 micromol x g(-1) x min(-1) (P < 0.05), whereas FDG uptake in the hyperemic region was lower than remote regions (0.46 +/- 0.29 and 0.95 +/- 0.55 micromol x g(-1) x min(-1), respectively; P < 0.05). In the ATP and bradykinin groups, blood flow increased four- and twofold, respectively, with no net change in glucose uptake. FDG uptake in the hyperemic region was also significantly lower than remote regions. For all animals, the ratio of blood flow in the hyperemic region relative to remote region was inversely proportional to the ratio of FDG uptake in the same regions (r(2)=0.73; P < 0.001). Because nitric oxide elaboration during hyperemia could potentially alter substrate preference and FDG kinetics, six additional swine were studied during maximal adenosine before and after intracoronary N(G)-monomethyl-L-arginine (1.5 mg/kg). Inhibition of nitric oxide had no effect on either regional myocardial substrate uptake or FDG accumulation. In conclusion, hyperemia decreased regional myocardial FDG uptake relative to normally perfused regions and this effect on the lumped constant was independent of nitric oxide.     

Determinants of contractile reserve in viable, chronically dysfunctional myocardium

There is considerable variability in the sensitivity of inotropic reserve to identify viability in chronically dysfunctional myocardium. This is partially related to the underlying pathophysiology, with more frequent contractile reserve in chronically stunned (with normal resting perfusion) than hibernating myocardium (with reduced flow). This study was undertaken to determine the physiological responses to transient and graded stimulation in chronically stunned and hibernating myocardium to define the relative roles of acute catecholamine desensitization and biphasic responses. Pigs were chronically instrumented with a fixed left anterior descending artery stenosis that resulted in chronically stunned myocardium after 2 mo. One month later, hibernating myocardium was confirmed by regional dysfunction (wall thickening, 3.2 +/- 0.3 vs. 5.5 +/- 5 mm in remote, P=0.01) with reduced resting flow (0.70 +/- 0.07 vs. 0.92 +/- 0.09 ml x min(-1) x g(-1) in remote, P=0.01) without infarction. Wall thickening in dysfunctional regions significantly increased during both graded and transient epinephrine stimulation in chronically stunned (from 3.6 +/- 0.3 to 5.6 +/- 0.5 and 4.9 +/- 0.5 mm, respectively) and hibernating myocardium (from 3.3 +/- 0.3 to 5.4 +/- 0.6 and 5.0 +/- 0.7 mm, respectively) and returned to baseline within 15 min. Although a biphasic response during graded stimulation was common, the subsequent decrement in function was small and similar in both groups (stunned, 0.7 +/- 0.2 mm; hibernating, 1.1 +/- 0.3 mm, P=0.25). We conclude that 1) the extent of contractile reserve during beta-adrenergic stimulation is similar in chronically stunned and hibernating myocardium, 2) there are no significant differences between the responses to transient compared with graded catecholamine stimulation, and 3) submaximal catecholamine stimulation does not induce additional stunning in either chronically stunned or hibernating myocardium.     

Dobutamine responsiveness,PET mismatch,and lack of necrosis in low-flow ischemia: is this hibernation in the isolated rat heart?

The clinical hallmarks of hibernating myocardium include hypocontractility while retaining an inotropic reserve (using dobutamine echocardiography), having normal or increased [18F]fluoro-2-deoxyglucose-6-phosphate (18FDG6P) accumulation associated with decreased coronary flow [flow-metabolism mismatch by positron emission tomography (PET)], and recovering completely postrevascularization. In this study, we investigated an isolated rat heart model of hibernation using experimental equivalents of these clinical techniques. Rat hearts (n = 5 hearts/group) were perfused with Krebs-Henseleit buffer for 40 min at 100% flow and 3 h at 10% flow and reperfused at 100% flow for 30 min (paced at 300 beats/min throughout). Left ventricular developed pressure fell to 30 +/- 8% during 10% flow and recovered to 90 +/- 7% after reperfusion. In an additional group, this recovery of function was found to be preserved over 2 h of reperfusion. Electron microscopic examination of hearts fixed at the end of the hibernation period demonstrated a lack of ischemic injury and an accumulation of glycogen granules, a phenomenon observed clinically. In a further group, hearts were challenged with dobutamine during the low-flow period. Hearts demonstrated an inotropic reserve at the expense of increased lactate leakage, with no appreciable creatine kinase release. PET studies used the same basic protocol in both dual- and globally perfused hearts (with 250MBq 18FDG in Krebs buffer +/- 0.4 mmol/l oleate). PET data showed flow-metabolism "mismatch;" whether regional or global, 18FDG6P accumulation in ischemic tissue was the same as (glucose only) or significantly higher than (glucose + oleate) control tissue (0.023 +/- 0.002 vs. 0.011 +/- 0.002 normalized counts. s-1x g-1x min-1, P < 0.05) despite receiving 10% of the flow. This isolated rat heart model of acute hibernation exhibits many of the same characteristics demonstrated clinically in hibernating myocardium.     

Blunted functional responses to pre- and postjunctional sympathetic stimulation in hibernating myocardium

Regional reductions in norepinephrine-tracer uptake are found in pigs with hibernating myocardium. Clinical studies would suggest that this is evidence for denervation; however, the functional responses to sympathetic stimulation have not been evaluated, and our previous studies with beta-adrenergic stimulation have not suggested denervation hypersensitivity. Therefore, pigs were chronically instrumented to produce hibernating myocardium characterized by chronic regional dysfunction and histological viability. Open-chest studies were performed to determine changes in regional function in response to both pre- and postjunctional stimulation. Regional segment shortening was reduced at rest in hibernating myocardium compared with controls (13 +/- 3% vs. 27 +/- 3%, P = 0.004). During stellate ganglion stimulation, regional function increased in both groups of animals (P = 0.008 vs. baseline), but the increase in hibernating myocardium was blunted compared with controls (Delta%, 3 +/- 2% vs. 8 +/- 3%, P = 0.04). Similar results occurred with intracoronary tyramine (10 mug/kg). Functional improvement during intravenous epinephrine infusion (0.35 mug.kg(-1).min(-1)) was also blunted in hibernating myocardium compared with controls (Delta%, 7 +/- 1% vs. 15 +/- 2%, P = 0.04). Even when the improvement in function was expressed relative to the reduced baseline, there was no evidence for catecholamine-mediated hypersensitivity in hibernating myocardium. We therefore conclude that functional responses to both pre- and postjunctional sympathetic stimulation are blunted in pigs with hibernating myocardium. In contrast to previous studies of infarcted, denervated, and acutely stunned myocardium, there is no catecholamine-induced hypersensitivity in hibernating myocardium. These data suggest a downregulation in functional responses to stimulation that would protect hibernating myocardium from demand-induced ischemia at the expense of contractile reserve during sympathetic stimulation.     

Positron emission tomography with [18F]fluorodeoxyglucose to evaluate neutrophil kinetics during acute lung injury

We measured neutrophil glucose uptake with positron emission tomographic imaging and [18F]fluorodeoxyglucose ([18F]FDG-PET) in anesthetized dogs after intravenous oleic acid-induced acute lung injury (ALI; OA group, n = 6) or after low-dose intravenous endotoxin (known to activate neutrophils without causing lung injury) followed by OA (Etx + OA group, n = 7). The following two other groups were studied as controls: one that received no intervention (n = 5) and a group treated with Etx only (n = 6). PET imaging was performed 1.5 h after initiating experimental interventions. The rate of [3H]deoxyglucose ([3H]DG) uptake was also measured in vitro in cells recovered from bronchoalveolar lavage (BAL) performed after PET imaging. Circulating neutrophil counts fell significantly in animals treated with Etx but not in the other two groups. The rate of [18F]FDG uptake, measured by the influx constant Ki, was significantly elevated (P < 0.05) in both Etx-treated groups (7.9 +/- 2.6 x 10(-3) ml blood x ml lung(-1) x min(-1) in the Etx group, 9.3 +/- 4.8 x 10(-3) ml blood x ml lung(-1) x min(-1) in the Etx + OA group) but not in the group treated only with OA (3.4 +/- 0.8 x 10-3 ml blood x ml lung(-1) x min(-1)) when compared with the normal control (1.6 +/- 0.4 x 10(-3) ml blood x ml lung(-1) x min(-1)). [3H]DG uptake was increased (73 +/- 7%) in BAL neutrophils recovered from the Etx + OA group (P < 0.05) but not in the OA group. Ki and [3H]DG uptake rates were linearly correlated (R2 = 0.65). We conclude that the rate of [18F]FDG uptake in the lungs during ALI reflects the state of neutrophil activation. [18F]FDG-PET imaging can detect pulmonary sequestration of activated neutrophils, despite the absence of alveolar neutrophilia. Thus [18F]FDG-PET imaging may be a useful tool to study neutrophil kinetics during ALI.     

The effect of dynamic knee-extension exercise on patellar tendon and quadriceps femoris muscle glucose uptake in humans studied by positron emission tomography.

Both tendon and peritendinous tissue show evidence of metabolic activity, but the effect of acute exercise on substrate turnover is unknown. We therefore examined the influence of acute exercise on glucose uptake in the patellar and quadriceps tendons during dynamic exercise in humans. Glucose uptake was measured in five healthy men in the patellar and quadriceps tendons and the quadriceps femoris muscle at rest and during dynamic knee-extension exercise (25 W) using positron emission tomography and [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Glucose uptake index was calculated by dividing the tissue activity with blood activity of [18F]FDG. Exercise increased glucose uptake index by 77% in the patellar tendon (from 0.30 +/- 0.09 to 0.51 +/- 0.16, P = 0.03), by 106% in the quadriceps tendon (from 0.37 +/- 0.15 to 0.75 +/- 0.36, P = 0.02), and by 15-fold in the quadriceps femoris muscle (from 0.31 +/- 0.11 to 4.5 +/- 1.7, P = 0.005). The exercise-induced increase in the glucose uptake in neither tendon correlated with the increase in glucose uptake in the quadriceps muscle (r = -0.10, P = 0.87 for the patellar tendon and r = -0.30, P = 0.62 for the quadriceps tendon). These results show that tendon glucose uptake is increased during exercise. However, the increase in tendon glucose uptake is less pronounced than in muscle and the increases are uncorrelated. Thus tendon glucose uptake is likely to be regulated by mechanisms independently of those regulating skeletal muscle glucose uptake.     

Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy

Pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy are at high risk of sudden cardiac death (SCD). We sought to identify the arrhythmic mechanism of SCD, the relation to changes in left ventricular (LV) function, and inducibility of malignant arrhythmias before SCD. Juvenile pigs (n = 72) were instrumented with chronic stenoses on proximal left anterior descending and circumflex arteries. Survival was only 29% 3 mo after instrumentation, and all deaths were sudden and without prodromal symptoms of heart failure. Triphenyltetrazolium chloride staining demonstrated necrosis in only nine animals averaging 2.3 +/- 0.9% of the LV, with no difference between SCD animals and survivors. Implantable loop recorders (n = 13) documented both ventricular fibrillation (n = 6) and bradyasystole (n = 2) as the arrhythmic mechanism of death. Although regional and global function were depressed [anteroseptal wall thickening 1.8 +/- 0.2 vs. 4.2 +/- 0.2 mm in Sham animals (P < 0.001); fractional shortening 21 +/- 2 vs. 31 +/- 1% in Sham animals (P < 0.01)], there were no differences between SCD animals and survivors. LV mass increased in animals with ischemic cardiomyopathy and was greater in animals with SCD (4.0 +/- 0.2 vs. 3.1 +/- 0.1 g/kg in survivors; P < 0.001). Serial programmed ventricular stimulation failed to induce any sustained arrhythmias. We conclude that pigs with viable dysfunctional myocardium and globally reduced LV function have a high rate of SCD with a spectrum of arrhythmias similar to patients with ischemic cardiomyopathy. The risk is independent of necrosis but appears to increase with LV hypertrophy. Like patients with ischemic cardiomyopathy, programmed stimulation is insensitive to predict SCD when viable dysfunctional myocardium is the pathological substrate.     

Regional myocardial blood flow and glucose utilization during fasting and physiological hyperinsulinemia in humans

We investigated the effect of insulin on total and regional myocardial blood flow (MBF) and glucose uptake (MGU) in healthy subjects (50 +/- 5 yr) by means of positron emission tomography (PET) with oxygen-15-labeled water (H(2)(15)O) and fluorine-18 labeled fluorodeoxyglucose ((18)FDG) before and during physiological hyperinsulinemia (40 mU.min(-1).m(-2)). Twelve male subjects were included in the study. During hyperinsulinemia, MBF increased from 0.91 +/- 0.28 to 1.01 +/- 0.31 ml.min(-1).g(-1) (n = 7 patients, P = 0.05; n = 112 regions, P < 0.005). Intersubject variability ranged from -3.0 to +41%. MGU increased from 0.11 +/- 0.08 (n = 5) to 0.56 +/- 0.08 micromol.min(-1).g(-1) (P < 0.0001, n = 7). MBF and insulin-mediated MGU were higher in the septum and anterior and lateral wall along short-axis regions of the heart. During hyperinsulinemia, MBF was also higher in the apex and midventricle compared with the base. MBF and MGU were positively correlated before (r = 0.66, P < 0.0001) and during hyperinsulinemia (r = 0.24, P < 0.05). These results provide evidence that insulin stimulates MBF in normal human hearts and appears to involve mainly those regions of the heart where insulin-mediated MGU is higher. Furthermore, regional distribution of insulin-stimulated MBF and MGU does not appear to be uniform across the left ventricular wall of healthy subjects.     

Ca(2+) handling in isolated human atrial myocardium

Physiologically, human atrial and ventricular myocardium are coupled by an identical beating rate and rhythm. However, contractile behavior in atrial myocardium may be different from that in ventricular myocardium, and little is known about intracellular Ca(2+) handling in human atrium under physiological conditions. We used rapid cooling contractures (RCCs) to assess sarcoplasmic reticulum (SR) Ca(2+) content and the photoprotein aequorin to assess intracellular Ca(2+) transients in atrial and ventricular muscle strips isolated from nonfailing human hearts. In atrial myocardium (n = 19), isometric twitch force frequency dependently (0. 25-3 Hz) increased by 78 +/- 25% (at 3 Hz; P < 0.05). In parallel, aequorin light signals increased by 111 +/- 57% (P < 0.05) and RCC amplitudes by 49 +/- 13% (P < 0.05). Similar results were obtained in ventricular myocardium (n = 13). SR Ca(2+) uptake (relative to Na(+)/Ca(2+) exchange) frequency dependently increased in atrial and ventricular myocardium (P < 0.05). With increasing rest intervals (1-240 s), atrial myocardium (n = 7) exhibited a parallel decrease in postrest twitch force (at 240 s by 68 +/- 5%, P < 0.05) and RCCs (by 49 +/- 10%, P < 0.05). In contrast, postrest twitch force and RCCs significantly increased in ventricular myocardium (n = 6). We conclude that in human atrial and ventricular myocardium the positive force-frequency relation results from increased SR Ca(2+) turnover. In contrast, rest intervals in atrial myocardium are associated with depressed contractility and intracellular Ca(2+) handling, which may be due to rest-dependent SR Ca(2+) loss (Ca(2+) leak) and subsequent Ca(2+) extrusion via Na(+)/Ca(2+) exchange. Therefore, the influence of rate and rhythm on mechanical performance is not uniform in atrial and ventricular myocardium.     

Interdependence of bronchial circulation and clearance of 99mTc-DTPA from the airway surface.

The extent to which the systemic vasculature is involved in soluble-particle uptake in the conducting airways has not been studied extensively. In anesthetized, ventilated sheep, 6-10 microl of technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) was delivered through a microspray nozzle to a fourth-generation airway. Perfusion of the cannulated bronchial artery was varied between control flow (0.6 ml x min(-1) x kg(-1)), high flow (1.8 ml x min(-1) x kg(-1)) or no flow (the infusion pump was stopped). Airway retention of the radioactive tracer was monitored using gamma camera imaging, and venous blood was sampled. During control perfusion, tracer retention at the site of deposition at 30 min averaged 20 +/- 6% (n = 7). With no flow, retention was significantly elevated to 32 +/- 8% (P = 0.03). In another group of sheep (n = 5) with a control retention of 13 +/- 4%, high flow resulted in an increase in tracer (25 +/- 4%; P = 0.04). Maximum blood uptake of tracer was calculated by estimating circulating blood volume and averaged 16% of total activity during control flow. Only during high-flow conditions was 99mTc-DTPA in the blood decreased (10%; P = 0.04). Most of the tracer was cleared by mucociliary clearance as visualized by imaging. This component was substantially decreased during no flow. The results demonstrate that both decreased and increased airway perfusion limit removal of soluble tracer applied to the conducting airways.     

Internal carotid flow velocity with exercise before and after acclimatization to 4,300 m.

Cerebral blood flow and O2 delivery during exercise are important for well-being at altitude but have not been studied. We expected flow to increase on arrival at altitude and then to fall as O2 saturation and hemoglobin increased, thereby maintaining cerebral O2 delivery. We used Doppler ultrasound to measure internal carotid artery flow velocity at sea level and on Pikes Peak, CO (4,300 m). In an initial study (1987, n = 7 men) done to determine the effect of brief (5-min) exercises of increasing intensity, we found at sea level that velocity [24.8 +/- 1.4 (SE) cm/s rest] increased by 15 +/- 7, 30 +/- 6, and 22 +/- 8% for cycle exercises at 33, 71, and 96% of maximal O2 uptake, respectively. During acute hypobaric hypoxia in a decompression chamber (inspired PO2 = 83 Torr), velocity (23.2 +/- 1.4 cm/s rest) increased by 33 +/- 6, 20 +/- 5, and 17 +/- 9% for exercises at 45, 72, and 98% of maximal O2 uptake, respectively. After 18 days on Pikes Peak (inspired PO2 = 87 Torr), velocity (26.6 +/- 1.5 cm/s rest) did not increase with exercise. A subsequent study (1988, n = 7 men) of the effect of prolonged exercise (45 min at approximately 100 W) found at sea level that velocity (24.8 +/- 1.7 cm/s rest) increased by 22 +/- 6, 13 +/- 5, 17 +/- 4, and 12 +/- 3% at 5, 15, 30, and 45 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lumped constant for [(18)F]fluorodeoxyglucose in skeletal muscles of obese and nonobese humans

Quantitative 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) positron emission tomography (PET) has been widely used to calculate glucose utilization in skeletal muscle. FDG-PET results depend partly on the lumped constant (LC), which accounts for the differences in the transport and phosphorylation between [(18)F]FDG and glucose. In this study, we estimated the LC for [(18)F]FDG directly in normal and in insulin-resistant obese subjects by combining FDG PET with the microdialysis technique. Eight obese [age 29.4 +/- 1.0 yr, body mass index (BMI) 33.6 +/- 1.0 kg/m(2)] and eight nonobese (age 25.0 +/- 1.0 yr, BMI 23.1 +/- 1.0 kg/m(2)) males were studied during euglycemic hyperinsulinemia (1 mU. kg(-1).min(-1) for 150 min). Muscle blood flow was measured using (15)O-labeled water and PET. Muscle [(18)F]FDG uptake (rGU(FDG)) was calculated with Patlak graphic analysis. Interstitial glucose concentration of the quadriceps femoris muscle was measured simultaneously with [(18)F]FDG scanning using microdialysis. Muscle glucose uptake (by microdialysis, rGU(MD)) was calculated by multiplying glucose extraction by regional muscle blood flow. A significant correlation was found between rGU(MD) and rGU(FDG) (r = 0.78, P < 0.01). The LC was determined as the ratio of the rGU(FDG) to the rGU(MD). The LC averaged 1.16 +/- 0.16 and was similar in the obese and nonobese subjects (1.15 +/- 0.11 vs. 1.16 +/- 0.07, respectively, not significant). In conclusion, the microdialysis technique can be reliably combined with FDG PET to measure glucose uptake in skeletal muscle. Direct measurements with these two independent techniques suggest an LC value of 1.2 for [(18)F]FDG in human skeletal muscle during insulin stimulation, and the LC appears not to be sensitive to insulin resistance.     

Changes in the myocardial area at risk, infarct size, and collateral flow following nicardipine infusion in dogs.

The area at risk of infarction after an acute occlusion of the left anterior descending coronary artery was defined in anesthetized dogs using the distribution of 99mTc-labelled albumin microaggregates and Monastral blue dye. In thirteen dogs, it was determined that these two particulate labels identified identical areas of unperfused myocardium. In a second group of dogs (n = 12), the risk areas determined at 10 (99mTc-labelled macroaggregates) and at 180 min (Monastral blue dye) were found to be identical, with no change in collateral blood flow, indicating the absence of a spontaneous change in underperfused myocardium over this time. In a third group of dogs (n = 17) nicardipine was infused (10 micrograms.kg-1.min-1 for 5 min, followed by 8 micrograms.kg-1.min-1 for 165 min). This resulted in a significant and sustained fall (32 +/- 4 mmHg; 1 mmHg = 133.32 Pa) in mean arterial blood pressure but no significant change in collateral blood flow was found, except for a marginal increase in the center of the ischemic zone. Area at risk and infarct sizes were also not significantly different between the latter two groups (18.2 +/- 4.1 vs. 21.6 +/- 4.0% of left ventricle). In this model, the magnitude of the area at risk appears to be determined early after a coronary occlusion and appears to be unmodified by treatment with nicardipine begun after the occlusion.     

Effects of gestational age on myocardial blood flow and coronary flow reserve in pressure-loaded ovine fetal hearts

To test the hypothesis that coronary flow and coronary flow reserve are developmentally regulated, we used fluorescent microspheres to investigate the effects of acute (6 h) pulmonary artery banding (PAB) on baseline and adenosine-enhanced right (RV) and left ventricular (LV) blood flow in two groups of twin ovine fetuses (100 and 128 days of gestation, term 145 days, n = 6 fetuses/group). Within each group, one fetus underwent PAB to constrict the main pulmonary artery diameter by 50%, and the other twin served as a nonbanded control. Physiological measurements were made 6 h after the surgery was completed; tissues were then harvested for analysis of selected genes that may be involved in the early phase of coronary vascular remodeling. Within each age group, arterial blood gas values, heart rate, and mean arterial blood pressure were similar between control and PAB fetuses. Baseline endocardial blood flow in both ventricles was greater in 100 than 128-day fetuses (RV: 341 +/- 20 vs. 230 +/- 17 ml*min(-1)*100 g(-1); LV: 258 +/- 18 vs. 172 +/- 23 ml*min(-1)*100 g(-1), both P < 0.05). In both age groups, RV and LV endocardial blood flows increased significantly in control animals during adenosine infusion and were greater in PAB compared with control fetuses. After PAB, adenosine further increased RV blood flow in 128-day fetuses (from 416 +/- 30 to 598 +/- 33 ml*min(-1)*g(-1), P < 0.05) but did not enhance blood flow in 100-day animals (490 +/- 59 to 545 +/- 42 ml*min(-1)*100 g(-1), P > 0.2). RV vascular endothelial growth factor and Flk-1 mRNA levels were increased relative to controls (P < 0.05) in 128 but not 100-day PAB fetuses. We conclude that in the ovine fetus, developmentally related differences exist in 1) baseline myocardial blood flows, 2) the adaptive response of myocardial blood flow to acute systolic pressure load, and 3) the responses of selected genes involved in vasculogenesis to increased load in the fetal myocardium.     

Impact of testosterone on cardiac L-type calcium channels and Ca2+ sparks: acute actions antagonize chronic effects

While androgens generally have been associated with an increased cardiovascular risk, recent studies indicate potential beneficial acute effects of testosterone. However, detailed evaluation of chronic and acute actions of testosterone on the function of cardiac I(Ca,L) and intracellular Ca2+ handling is limited. To clarify this situation we performed whole-cell and single-channel analysis of I(Ca,L), recordings of Ca2+ sparks, measurements of contractility and quantitative real-time RT-PCR in rat cardiomyocytes following testosterone pretreatment and acute testosterone application. Pretreatment with testosterone 100 nM for 24-30 h increased whole-cell I(Ca,L) from 3.8+/-0.8 pA/pF (n=10) to 10.1+/-0.31 pA/pF (n=9) at +10 mV (p<0.001). Increase of I(Ca,L) density was caused by both, increased expression levels of the alpha 1C subunit of L-type calcium channel and a pronounced increment of the single-channel activity (availability 81.8+/-3.15% versus 37.1+/-7.01%; open probability 12.8+/-3.09% versus 1.0+/-0.62%, p<0.01). Moreover, testosterone pretreatment significantly increased the frequency of Ca2+ sparks and improved myocytes contractility without altering SR Ca2+ load. All chronic effects could be inhibited by flutamide. In contrast acute testosterone administration significantly reduced I(Ca,L) density. Indeed, on the single-channel level acute testosterone application completely reversed the chronic testosterone-mediated effects, and antagonized the chronic testosterone effects on Ca2+ spark frequency, which was unaffected by flutamide. Thus, testosterone pretreatment activates I(Ca,L) via nuclear receptor-mediated pathways, while testosterone acutely blocks I(Ca,L) in a direct manner. Thus, testosterone chronically affects the basal level of intracellular Ca2+ handling, which in addition rapidly may be modulated by acute changes of hormone levels.     

Glucose uptake patterns in exercised skeletal muscles of elite male long-distance and short-distance runners

The aim of this study was to determine glucose uptake patterns in exercised skeletal muscles of elite male long-distance and short-distance runners. Positron emission tomography (PET) using 18F-fluoro-2-deoxyglucose (FDG) was performed to determine the patterns of glucose uptake in lower limbs of short-distance (SD group, n=8) and long-distance (LD group, n=8) male runners after a modified 20 min Bruce treadmill test. Magnetic resonance imaging (MRI) was used to delineate the muscle groups in lower limbs. Muscle groups from hip, knee, and ankle movers were measured. The total FDG uptake and the standard uptake value (SUV) for each muscle group were compared between the 2 groups. For the SD and LD runners, the 2 major muscle groups utilizing glucose during running were knee extensors and ankle plantarflexors, which accounted for 49.3 +/- 8.1% (25.1 +/- 4.7% and 24.2 +/- 6.0%) of overall lower extremity glucose uptake for SD group, and 51.3 +/- 8.0% (27.2 +/- 2.7% and 24.0 +/- 8.1%) for LD group. No difference in muscle glucose uptake was noted for other muscle groups. For SD runners, the SUVs for the muscle groups varied from 0.49 +/- 0.27 for the ankle plantarflexors, to 0.20 +/- 0.08 for the hip flexor. For the LD runners, the highest and lowest SUVs were 0.43 +/- 0.15 for the ankle dorsiflexors and 0.21 +/- 0.19 for the hip. For SD and LD groups, no difference in muscle SUV was noted for the muscle groups. However, the SUV ratio between the ankle dorsiflexors and plantarflexors in the LD group was significantly greater than that in the SD group. We thus conclude that the major propelling muscle groups account for approximately 50% of lower limb glucose utilization during running. Thus, the other muscle groups involving maintenance of balance, limb deceleration, and shock absorption utilize an equal amount. This result provides a new insight into glucose distribution in skeletal muscle, suggesting that propellers and supporters are both energetically important during running. Furthermore, for each unit muscle volume, movers of ankle are more glucose-demanding than those of hip.     

Mesenchymal stem cells from ischemic heart disease patients improve left ventricular function after acute myocardial infarction

Mesenchymal stem cells (MSCs) from healthy donors improve cardiac function in experimental acute myocardial infarction (AMI) models. However, little is known about the therapeutic capacity of human MSCs (hMSCs) from patients with ischemic heart disease (IHD). Therefore, the behavior of hMSCs from IHD patients in an immune-compromised mouse AMI model was studied. Enhanced green fluorescent protein-labeled hMSCs from IHD patients (hMSC group: 2 x 10(5) cells in 20 microl, n = 12) or vehicle only (medium group: n = 14) were injected into infarcted myocardium of NOD/scid mice. Sham-operated mice were used as the control (n = 10). Cardiac anatomy and function were serially assessed using 9.4-T magnetic resonance imaging (MRI); 2 wk after cell transplantation, immunohistological analysis was performed. At day 2, delayed-enhancement MRI showed no difference in myocardial infarction (MI) size between the hMSC and medium groups (33 +/- 2% vs. 36 +/- 2%; P = not significant). A comparable increase in left ventricular (LV) volume and decrease in ejection fraction (EF) was observed in both MI groups. However, at day 14, EF was higher in the hMSC than in the medium group (24 +/- 3% vs. 16 +/- 2%; P < 0.05). This was accompanied by increased vascularity and reduced thinning of the infarct scar. Engrafted hMSCs (4.1 +/- 0.3% of injected cells) expressed von Willebrand factor (16.9 +/- 2.7%) but no stringent cardiac or smooth muscle markers. hMSCs from patients with IHD engraft in infarcted mouse myocardium and preserve LV function 2 wk after AMI, potentially through an enhancement of scar vascularity and a reduction of wall thinning.     

Stroma-free hemoglobin: its presence in plasma does not improve oxygen supply to the resting hindlimb vascular bed of hemodiluted dogs.

In hemodilution, red cell spacing in the microcirculation is increased, flow distribution may become more heterogeneous, and, as a result, oxygen supply to tissues may suffer. We tested the hypothesis that oxygen extraction from diluted blood may be enhanced by the presence of hemoglobin in the plasma phase in relatively low concentrations. In anesthetized dogs, the hindlimb vascular bed was isolated and perfused with the animal's own blood by a roller pump. One group of dogs (n = 6) was hemodiluted (hematocrit = 15.0 +/- 1.0%) with a 6% solution of dextran. A second group of dogs (n = 6) was similarly hemodiluted (hematocrit = 16.0 +/- 0.4%) with dextran containing stroma-free hemoglobin solution whereby plasma-phase hemoglobin concentration was raised to 1.1 +/- 0.1 g.dL-1. Systemic hemodynamic observations were made repeatedly over the subsequent 2.5 h, while blood flow to the hindlimb was progressively reduced in stepwise decrements. The hemoglobin-hemodiluted group showed increased systemic arterial blood pressure and total peripheral resistance when compared with the control (dextran diluted) group. The isolated hindlimb also showed evidence of increased vascular resistance in the hemoglobin-treated group. In each individual animal, critical oxygen delivery and extraction were determined by finding the intercept of the supply-independent and supply-dependent portions of the oxygen uptake/oxygen delivery relationship. Neither the critical oxygen delivery rates (5.75 +/- 0.83 vs. 6.41 +/- 0.53 mL.kg-1.min-1) nor critical oxygen extraction ratios (0.75 +/- 0.03 vs. 0.76 +/- 0.04) were found to be significantly different in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)