Decreasing gut wall glucose as an early marker of impaired intestinal perfusion

OBJECTIVE: The aim of this study was to assess the microcirculatory and metabolic consequences of reduced mesenteric blood flow. DESIGN: Prospective, controlled animal study. SETTING: The surgical research unit of a university hospital. SUBJECTS: A total of 13 anesthetized and mechanically ventilated pigs. INTERVENTIONS: Pigs were subjected to stepwise mesenteric blood flow reduction (15% in each step, n = 8) or served as controls (n = 5). Superior mesenteric arterial blood flow was measured with ultrasonic transit time flowmetry, and mucosal and muscularis microcirculatory perfusion in the small bowel were each measured with three laser Doppler flow probes. Small-bowel intramucosal Pco2 was measured by tonometry, and glucose, lactate (L), and pyruvate (P) were measured by microdialysis. MEASUREMENTS AND MAIN RESULTS: In control animals, superior mesenteric arterial blood flow, mucosal microcirculatory blood flow, intramucosal Pco2, and the lactate/pyruvate ratio remained unchanged. In both groups, mucosal blood flow was better preserved than muscularis blood flow. During stepwise mesenteric blood flow reduction, heterogeneous microcirculatory blood flow remained a prominent feature (coefficient of variation, approximately 45%). A 30% flow reduction from baseline was associated with a decrease in microdialysis glucose concentration from 2.37 (2.10-2.70) mmol/L to 0.57 (0.22-1.60) mmol/L (p < .05). After 75% flow reduction, the microdialysis lactate/pyruvate ratio increased from 8.6 (8.0-14.1) to 27.6 (15.5-37.4, p < .05), and arterial-intramucosal Pco2 gradients increased from 1.3 (0.4-3.5) kPa to 10.8 (8.0-16.0) kPa (p < .05). CONCLUSIONS: Blood flow redistribution and heterogeneous microcirculatory perfusion can explain apparently maintained regional oxidative metabolism during mesenteric hypoperfusion, despite local signs of anaerobic metabolism. Early decreasing glucose concentrations suggest that substrate supply may become crucial before oxygen consumption decreases.

Effect of endotoxin, dobutamine and dopamine on muscle mitochondrial respiration in vitro

INTRODUCTION: Mitochondrial respiration is impaired during endotoxemia. While catecholamines are frequently used in sepsis, their effects on mitochondrial function are controversial. We assessed effects of dobutamine and dopamine endotoxin on isolated muscle mitochondria. MATERIALS AND METHODS: Sternocleidomastoid muscle mitochondria were isolated from six anesthetized pigs. Each sample was divided into six different groups. Three groups were incubated with endotoxin, three with vehicle. After 1 h, dopamine and dobutamine at final concentrations of 100 microM were added to the vehicle and endotoxin groups. After 2 h, state 3 and 4 respiration rates were determined for all mitochondrial complexes. Oxygen consumption was determined with a Clark-type electrode. RESULTS: Endotoxin increased glutamate-dependent state 4 respiration from 9.3 +/- 3.6 to 31.9 +/- 9.1 (P = 0.001) without affecting state 3 respiration. This reduced the efficiency of mitochondrial respiration (RCR; state 3/state 4, 9.9 +/- 1.9 versus 3.6 +/- 0.6; P < 0.001). The other complexes were unaffected. Catecholamine partially restored the endotoxin-induced increase in complex I state 4 respiration rate (31.9 +/- 9.1 versus 17.1 +/- 6.4 and 20.1 +/- 12.2) after dopamine and dobutamine, respectively (P = 0.007), and enhanced the ADP:O ratio (P = 0.033). CONCLUSIONS: Dopamine and dobutamine enhanced the efficiency of mitochondrial respiration after short-term endotoxin exposure.

Biologically relevant sex differences for fitness-related parameters in active octogenarians

The number of elderly people is growing in western populations, but only few maximal performance data exist for people >75 years, in particular for European octogenarians. This study was performed to characterize maximal performance of 55 independently living subjects (32 women, 81.1 +/- 3.4 years; 23 men, 81.7 +/- 2.9 years) with a focus on sex differences. Maximal performance was determined in a ramp test to exhaustion on a bicycle ergometer with ergospirometry, electrocardiogram and blood lactate measurements. Maximal isometric extension strength of the legs (MEL) was measured on a force platform in a seated position. Body composition was quantified by X-ray absorptiometry. In >25% of the subjects, serious cardiac abnormalities were detected during the ramp test with men more frequently being affected than women. Maximal oxygen consumption and power output were 18.2 +/- 3.2 versus 25.9 +/- 5.9 ml min(-1) kg(-1) and 66 +/- 12 versus 138 +/- 40 W for women versus men, with a significant sex difference for both parameters. Men outperformed women for MEL with 19.0 +/- 3.8 versus 13.6 +/- 3.3 N kg(-1). Concomitantly, we found a higher proportion of whole body fat in women (32.1 +/- 6.2%) compared to men (20.5 +/- 4.4%). Our study extends previously available maximal performance data for endurance and strength to independently living European octogenarians. As all sex-related differences were still apparent after normalization to lean body mass, it is concluded that it is essential to differentiate between female and male subjects when considering maximal performance parameters in the oldest segment of our population.

Does the beta-blocker nebivolol increase coronary flow reserve?

INTRODUCTION: Nebivolol, a highly selective beta1-adrenergic receptor-blocker, increases basal and stimulated endothelial nitric oxide (NO)-release. It is unknown, whether coronary perfusion is improved by the increase in NO availability. Therefore, we sought to evaluate the effect of nebivolol on coronary flow reserve (CFR) and collateral flow. METHODS: Doppler-flow wire derived coronary flow velocity measurements were obtained in ten controls and eight patients with coronary artery disease (CAD) at rest and after intracoronary nebivolol. CFR was defined as maximal flow during adenosine-induced hyperemia divided by resting flow. In the CAD group, collateral flow was determined after dilatation of a flow-limiting coronary stenosis. Collateral flow index (CFI) was defined as the ratio of flow velocity during balloon inflation divided by resting flow. RESULTS: CFR at rest was 3.0+/-0.6 in controls and 2.1+/-0.4 in CAD patients. After intracoronary doses of 0.1, 0.25, and 0.5 mg nebivolol, CFR increased to 3.4+/-0.7, 3.9+/-0.9, and 4.0+/-0.1 (p<0.01) in controls, and to 2.3+/-0.7, 2.6+/-0.9, and 2.6+/-0.5 (p<0.05) in CAD patients. CFI decreased significantly with intracoronary nebivolol and correlated to changes in heart rate (r=0.75, p<0.001) and rate-pressure product (r=0.59, p=0.001). DISCUSSION: Intracoronary nebivolol is associated with a significant increase in CFR due to reduction in resting flow (controls), or due to an increase in maximal coronary flow (CAD patients). CFI decreased with nebivolol parallel to the reduction in myocardial oxygen consumption.

Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation

A key energy-saving adaptation to chronic hypoxia that enables cardiomyocytes to withstand severe ischemic insults is hibernation, i.e., a reversible arrest of contractile function. Whereas hibernating cardiomyocytes represent the critical reserve of dysfunctional cells that can be potentially rescued, a lack of a suitable animal model has hampered insights on this medically important condition. We developed a transgenic mouse system for conditional induction of long-term hibernation and a system to rescue hibernating cardiomyocytes at will. Via myocardium-specific induction (and, in turn, deinduction) of a VEGF-sequestering soluble receptor, we show that VEGF is indispensable for adjusting the coronary vasculature to match increased oxygen consumption and exploit this finding to generate a hypoperfused heart. Importantly, ensuing ischemia is tunable to a level at which large cohorts of cardiomyocytes are driven to enter a hibernation mode, without cardiac cell death. Relieving the VEGF blockade even months later resulted in rapid revascularization and full recovery of contractile function. Furthermore, we show that left ventricular remodeling associated with hibernation is also fully reversible. The unique opportunity to uncouple hibernation from other ischemic heart phenotypes (e.g., infarction) was used to determine the genetic program of hibernation; uncovering hypoxia-inducible factor target genes associated with metabolic adjustments and induced expression of several cardioprotective genes. Autophagy, specifically self-digestion of mitochondria, was identified as a key prosurvival mechanism in hibernating cardiomyocytes. This system may lend itself for examining the potential utility of treatments to rescue dysfunctional cardiomyocytes and reverse maladaptive remodeling.

Postexercise fat intake repletes intramyocellular lipids but no faster in trained than in sedentary subjects

The hypotheses that postexercise replenishment of intramyocellular lipids (IMCL) is enhanced by endurance training and that it depends on fat intake were tested. Trained and untrained subjects exercised on a treadmill for 2 h at 50% peak oxygen consumption, reducing IMCL by 26-22%. During recovery, they were fed 55% (high fat) or 15% (low fat) lipid energy diets. Muscle substrate stores were estimated by (1)H (IMCL)- and (13)C (glycogen)-magnetic resonance spectroscopy in tibialis anterior muscle before and after exercise. Resting IMCL content was 71% higher in trained than untrained subjects and correlated significantly with glycogen content. Both correlated positively with indexes of insulin sensitivity. After 30 h on the high-fat diet, IMCL concentration was 30-45% higher than preexercise, whereas it remained 5-17% lower on the low-fat diet. Training status had no significant influence on IMCL replenishment. Glycogen was restored within a day with both diets. We conclude that fat intake postexercise strongly promotes IMCL repletion independently of training status. Furthermore, replenishment of IMCL can be completed within a day when fat intake is sufficient.

Quantitative (1)H magnetic resonance spectroscopy of myoglobin de- and reoxygenation in skeletal muscle: reproducibility and effects of location and disease

1H-magnetic resonance spectroscopy ((1)H-MRS) of deoxymyoglobin (DMb) provides a means to noninvasively monitor the oxygenation state of human skeletal muscle in work and disease. As shown in this work, it also offers the opportunity to measure the absolute tissue content of DMb, the basic oxygen consumption of resting muscle, and the reperfusion characteristics after release of a pressure cuff. The methodology to determine these tissue properties simultaneously at two positions along the calf is presented. The obtained values are in agreement with invasive determinations. The reproducibility of the (1)H-MRS measurements is established for healthy controls and patients with peripheral arterial disease (PAD). A location dependence in axial direction, as well as differences between controls and patients are demonstrated for all parameters. The reoxygenation time in particular is expected to provide a means to quantitatively monitor therapies aimed at improving muscular perfusion in these patients.

Meperidine and skin surface warming additively reduce the shivering threshold: a volunteer study

INTRODUCTION: Mild therapeutic hypothermia has been shown to improve outcome for patients after cardiac arrest and may be beneficial for ischaemic stroke and myocardial ischaemia patients. However, in the awake patient, even a small decrease of core temperature provokes vigorous autonomic reactions-vasoconstriction and shivering-which both inhibit efficient core cooling. Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds. We tested whether a combination of skin warming and a medium dose of meperidine additively would reduce the shivering threshold to below 34 degrees C without producing significant sedation or respiratory depression. METHODS: Eight healthy volunteers participated on four study days: (1) control, (2) skin warming (with forced air and warming mattress), (3) meperidine (target plasma level: 0.9 mug/ml), and (4) skin warming plus meperidine (target plasma level: 0.9 mug/ml). Volunteers were cooled with 4 degrees C cold Ringer lactate infused over a central venous catheter (rate asymptotically equal to 2.4 degrees C/hour core temperature drop). Shivering threshold was identified by an increase of oxygen consumption (+20% of baseline). Sedation was assessed with the Observer's Assessment of Alertness/Sedation scale. RESULTS: Control shivering threshold was 35.5 degrees C +/- 0.2 degrees C. Skin warming reduced the shivering threshold to 34.9 degrees C +/- 0.5 degrees C (p = 0.01). Meperidine reduced the shivering threshold to 34.2 degrees C +/- 0.3 degrees C (p < 0.01). The combination of meperidine and skin warming reduced the shivering threshold to 33.8 degrees C +/- 0.2 degrees C (p < 0.01). There were no synergistic or antagonistic effects of meperidine and skin warming (p = 0.59). Only very mild sedation occurred on meperidine days. CONCLUSION: A combination of meperidine and skin surface warming reduced the shivering threshold to 33.8 degrees C +/- 0.2 degrees C via an additive interaction and produced only very mild sedation and no respiratory toxicity.

Functional imaging of the parotid glands using blood oxygenation level dependent (BOLD)-MRI at 1.5T and 3T

PURPOSE: To evaluate the function of the parotid glands before and during gustatory stimulation, using an intrinsic susceptibility-weighted MRI method (blood oxygenation level dependent, BOLD-MRI) at 1.5T and 3T. MATERIALS AND METHODS: A total of 10 and 13 volunteers were investigated at 1.5T and 3T, respectively. Measurements were performed before and during gustatory stimulation using ascorbate. Circular regions of interest (ROIs) were delineated in the left and right parotid glands, and in the masseter muscle for comparison. The effects of stimulation were evaluated by calculating the difference between the relaxation rates, DeltaR(2)*. Baseline and stimulation were statistically compared (Student's t-tests), merging both parotid glands. RESULTS: The averaged DeltaR(2)* values prestimulation obtained in all parotid glands were stable (-0.61 to 0.38 x 10(-3) seconds(-1)). At 3T, these values were characterized by an initial drop (to -2.7 x 10(-3) seconds(-1)) followed by a progressive increase toward the baseline. No significant difference was observed between baseline and parotid gland stimulation at 1.5T, neither for the masseter muscle at both field strengths. A considerable interindividual variability (over 76%) was noticed at both magnetic fields. CONCLUSION: BOLD-MRI at 3T was able to detect DeltaR(2)* changes in the parotid glands during gustatory stimulation, consistent with an increase in oxygen consumption during saliva production.

Norepinephrine to increase blood pressure in endotoxaemic pigs is associated with improved hepatic mitochondrial respiration

ABSTRACT: INTRODUCTION: Low blood pressure, inadequate tissue oxygen delivery and mitochondrial dysfunction have all been implicated in the development of sepsis-induced organ failure. This study evaluated the effect on liver mitochondrial function of using norepinephrine to increase blood pressure in experimental sepsis. METHODS: Thirteen anaesthetized pigs received endotoxin (Escherichia coli lipopolysaccharide B0111:B4; 0.4 mug/kg per hour) and were subsequently randomly assigned to norepinephrine treatment or placebo for 10 hours. Norepinephrine dose was adjusted at 2-hour intervals to achieve 15 mmHg increases in mean arterial blood pressure up to 95 mmHg. Systemic (thermodilution) and hepatosplanchnic (ultrasound Doppler) blood flow were measured at each step. At the end of the experiment, hepatic mitochondrial oxygen consumption (high-resolution respirometry) and citrate synthase activity (spectrophotometry) were assessed. RESULTS: Mean arterial pressure (mmHg) increased only in norepinephrine-treated animals (from 73 [median; range 69 to 81] to 63 [60 to 68] in controls [P = 0.09] and from 83 [69 to 93] to 96 [86 to 108] in norepinephrine-treated animals [P = 0.019]). Cardiac index and systemic oxygen delivery (DO2) increased in both groups, but significantly more in the norepinephrine group (P < 0.03 for both). Cardiac index (ml/min per.kg) increased from 99 (range: 72 to 112) to 117 (110 to 232) in controls (P = 0.002), and from 107 (84 to 132) to 161 (147 to 340) in norepinephrine-treated animals (P = 0.001). DO2 (ml/min per.kg) increased from 13 (range: 11 to 15) to 16 (15 to 24) in controls (P = 0.028), and from 16 (12 to 19) to 29 (25 to 52) in norepinephrine-treated animals (P = 0.018). Systemic oxygen consumption (systemic VO2) increased in both groups (P < 0.05), whereas hepatosplanchnic flows, DO2 and VO2 remained stable. The hepatic lactate extraction ratio decreased in both groups (P = 0.05). Liver mitochondria complex I-dependent and II-dependent respiratory control ratios were increased in the norepinephrine group (complex I: 3.5 [range: 2.1 to 5.7] in controls versus 5.8 [4.8 to 6.4] in norepinephrine-treated animals [P = 0.015]; complex II: 3.1 [2.3 to 3.8] in controls versus 3.7 [3.3 to 4.6] in norepinephrine-treated animals [P = 0.09]). No differences were observed in citrate synthase activity. CONCLUSION: Norepinephrine treatment during endotoxaemia does not increase hepatosplanchnic flow, oxygen delivery or consumption, and does not improve the hepatic lactate extraction ratio. However, norepinephrine increases the liver mitochondria complex I-dependent and II-dependent respiratory control ratios. This effect was probably mediated by a direct effect of norepinephrine on liver cells.

[Is resting heart rate a cardiovascular risk factor?]

During recent years, resting heart rate was not considered as a cardiovascular risk factor. However, new evidences have showed that resting heart rate is an important prognostic factor for sudden cardiac death and heart failure in the general population, and especially among patients with known cardiac disease. Interestingly, resting heart rate not only predicts cardiac mortality but also all-cause mortality. The most common pathophysiological explanation is related to the fact that increased heart rate increases myocardial oxygen consumption and in parallel reduces coronary blood flow (reduction in the diastolic duration).

Influence of exertional oscillatory ventilation on exercise performance in heart failure

BACKGROUND: Exertional oscillatory ventilation (EOV) in heart failure may potentiate the negative effects of low cardiac output and high ventilation on exercise performance. We hypothesized that the presence of EOV might, per se, influence exercise capacity as evaluated by maximal cardiopulmonary exercise test. METHODS AND RESULTS: We identified 78 severe chronic heart failure patient pairs with and without EOV. Patients were matched for sex, age and peak oxygen consumption (VO2). Patients with EOV showed, for the same peak VO2, a lower workload (WL) at peak (DeltaWatts=5.8+/-23.0, P=0.027), a less efficient ventilation (higher VE/VCO2 slope: 38.0+/-8.3 vs. 32.8+/-6.3, P<0.001), lower peak exercise tidal volume (1.49+/-0.36 L vs. 1.61+/-0.46 L, P=0.015) and higher peak respiratory rate (34+/-7/min vs. 31+/-6/min, P=0.002). In 33 patients, EOV disappeared during exercise, whereas in 45 patients EOV persisted. Fifty percent of EOV disappearing patients had an increase in the VO2/WL relationship after EOV regression, consistent with a more efficient oxygen delivery to muscles. No cardiopulmonary exercise test parameter was associated with the different behaviour of VO2/WL. CONCLUSION: The presence of EOV negatively influences exercise performance of chronic heart failure patients likely because of an increased cost of breathing. EOV disappearance during exercise is associated with a more efficient oxygen delivery in several cases.

Exercise capacity and biventricular function in adult patients with repaired tetralogy of Fallot

BACKGROUND: Adult patients with repaired tetralogy of Fallot (rTOF) often have diminished exercise capacity. The primary objective of this study was to examine whether abnormalities of biventricular function play a role in exercise limitation in patients with rTOF. METHODS: This was a retrospective review of 99 adult patients with rTOF. Right ventricular (RV) and left ventricular (LV) function were assessed echocardiographically using the myocardial performance index (MPI). Maximal oxygen consumption (VO(2) Max) was measured during a level 1 cardiopulmonary exercise test. RESULTS: The mean age of the cohort was 34 +/- 11 years (50% females). Although most of the patients reported good functional capacity, the peak Vo(2)max was decreased at 22 +/- 6 mL/kg per minute (66% +/- 13% predicted Vo(2)max for age and sex). The mean RV and LV MPI were 0.30 +/- 0.07 and 0.42 +/- 0.09, respectively. In the multivariate model, higher RV MPI (P = .04) and LV MPI (P = .005) values, representing impaired ventricular function, were associated with diminished Vo(2)max. There was a significant correlation between the RV and LV MPI (r = 0.54, P = .001). CONCLUSIONS: Impairment of RV and LV function, as measured by MPI, is associated with diminished exercise capacity in patients with repaired tetralogy of Fallot. Furthermore, there is a linear relationship between the RV and LV function suggesting that ventricular interactions are contributing to the limited exercise capacity in this group of patients. Strategies aimed at preserving biventricular function or improving adverse ventricular interactions could help to improve functional capacity in these patients.

Substrate delivery and ionic balance disturbance after severe human head injury

The most important early pathomechanism in traumatic brain injury (TBI) is alteration of the resting membrane potential. This may be mediated via voltage, or agonist-dependent ion channels (e.g. glutamate-dependent channels). This may result in a consequent increase in metabolism with increased oxygen consumption, in order to try to restore ionic balance via the ATP-dependent pumps. We hypothesize that glutamate is an important agonist in this process and may induce an increase in lactate, potassium and brain tissue CO2, and hence a decrease in brain pH. Further we propose that an increase in lactate is thus not an indicator of anaerobic metabolic conditions as has been thought for many years. We therefore analyzed a total of 85 patients with TBI, Glasgow Coma Scale (GCS) < 8 using microdialysis, brain tissue oxygen, CO2 and pH monitoring. Cerebral blood flow studies (CBF) were performed to test the relationship between regional cerebral blood flow (rCBF) and the metabolic determinants. Glutamate was significantly correlated with lactate (p < 0.0001), potassium (p < 0.0001), brain tissue pH (p = 0.0005), and brain tissue CO2 (p = 0.006). rCBF was inversely correlated with glutamate, lactate and potassium. 44% of high lactate values were observed in brain with tissue oxygen values, above the threshold level for cell damage. These results support the hypothesis of a glutamate driven increase in metabolism, with secondary traumatic depolarization and possibly hyperglycolysis. Further, we demonstrate evidence for lactate production in aerobic conditions in humans after TBI. Finally, when reduced regional cerebral blood flow (rCBF) is observed, high dialysate glutamate, lactate and potassium values are usually seen, suggesting ischemia worsens these TBI-induced changes.

Haemodynamic and arrhythmic effects of moderately cold (22 degrees C) water immersion and swimming in patients with stable coronary artery disease and heart failure

AIMS: Data on moderately cold water immersion and occurrence of arrhythmias in chronic heart failure (CHF) patients are scarce. METHODS AND RESULTS: We examined 22 male patients, 12 with CHF [mean age 59 years, ejection fraction (EF) 32%, NYHA class II] and 10 patients with stable coronary artery disease (CAD) without CHF (mean age 65 years, EF 52%). Haemodynamic effects of water immersion and swimming in warm (32 degrees C) and moderately cold (22 degrees C) water were measured using an inert gas rebreathing method. The occurrence of arrhythmias during water activities was compared with those measured during a 24 h ECG recording. Rate pressure product during water immersion up to the chest was significantly higher in moderately cold (P = 0.043 in CHF, P = 0.028 in CAD patients) compared with warm water, but not during swimming. Rate pressure product reached 14200 in CAD and 12 400 in CHF patients during swimming. Changes in cardiac index (increase by 5-15%) and oxygen consumption (increase up to 20%) were of similar magnitude in moderately cold and warm water. Premature ventricular contractions (PVCs) increased significantly in moderately cold water from 15 +/- 41 to 76 +/- 163 beats per 30 min in CHF (P = 0.013) but not in CAD patients (20 +/- 33 vs. 42 +/- 125 beats per 30 min, P = 0.480). No ventricular tachycardia was noted. CONCLUSION: Patients with compensated CHF tolerate water immersion and swimming in moderately cold water well. However, the increase in PVCs raises concerns about the potential danger of high-grade ventricular arrhythmias.