Reductions in systemic and skeletal muscle blood flow and oxygen delivery limit maximal aerobic capacity in humans

[EN] BACKGROUND: A classic, unresolved physiological question is whether central cardiorespiratory and/or local skeletal muscle circulatory factors limit maximal aerobic capacity (VO2max) in humans. Severe heat stress drastically reduces VO2max, but the mechanisms have never been studied. METHODS AND RESULTS: To determine the main contributing factor that limits VO2max with and without heat stress, we measured hemodynamics in 8 healthy males performing intense upright cycling exercise until exhaustion starting with either high or normal skin and core temperatures (+10 degrees C and +1 degrees C). Heat stress reduced VO2max, 2-legged VO2, and time to fatigue by 0.4+/-0.1 L/min (8%), 0.5+/-0.2 L/min (11%), and 2.2+/-0.4 minutes (28%), respectively (all P<0.05), despite heart rate and core temperature reaching similar peak values. However, before exhaustion in both heat stress and normal conditions, cardiac output, leg blood flow, mean arterial pressure, and systemic and leg O2 delivery declined significantly (all 5% to 11%, P<0.05), yet arterial O2 content and leg vascular conductance remained unchanged. Despite increasing leg O2 extraction, leg VO2 declined 5% to 6% before exhaustion in both heat stress and normal conditions, accompanied by enhanced muscle lactate accumulation and ATP and creatine phosphate hydrolysis. CONCLUSIONS: These results demonstrate that in trained humans, severe heat stress reduces VO2max by accelerating the declines in cardiac output and mean arterial pressure that lead to decrements in exercising muscle blood flow, O2 delivery, and O2 uptake. Furthermore, the impaired systemic and skeletal muscle aerobic capacity that precedes fatigue with or without heat stress is largely related to the failure of the heart to maintain cardiac output and O2 delivery to locomotive muscle.

Metabolic and thermodynamic responses to dehydration-induced reductions in muscle blood flow in exercising humans

[EN] 1. The present study examined whether reductions in muscle blood flow with exercise-induced dehydration would reduce substrate delivery and metabolite and heat removal to and from active skeletal muscles during prolonged exercise in the heat. A second aim was to examine the effects of dehydration on fuel utilisation across the exercising leg and identify factors related to fatigue. 2. Seven cyclists performed two cycle ergometer exercise trials in the heat (35 C; 61 +/- 2 % of maximal oxygen consumption rate, VO2,max), separated by 1 week. During the first trial (dehydration, DE), they cycled until volitional exhaustion (135 +/- 4 min, mean +/- s.e.m.), while developing progressive DE and hyperthermia (3.9 +/- 0.3 % body weight loss and 39.7 +/- 0.2 C oesophageal temperature, Toes). On the second trial (control), they cycled for the same period of time maintaining euhydration by ingesting fluids and stabilising Toes at 38.2 +/- 0.1 degrees C. 3. After 20 min of exercise in both trials, leg blood flow (LBF) and leg exchange of lactate, glucose, free fatty acids (FFA) and glycerol were similar. During the 20 to 135 +/- 4 min period of exercise, LBF declined significantly in DE but tended to increase in control. Therefore, after 120 and 135 +/- 4 min of DE, LBF was 0.6 +/- 0.2 and 1.0 +/- 0.3 l min-1 lower (P < 0.05), respectively, compared with control. 4. The lower LBF after 2 h in DE did not alter glucose or FFA delivery compared with control. However, DE resulted in lower (P < 0.05) net FFA uptake and higher (P < 0.05) muscle glycogen utilisation (45 %), muscle lactate accumulation (4.6-fold) and net lactate release (52 %), without altering net glycerol release or net glucose uptake. 5. In both trials, the mean convective heat transfer from the exercising legs to the body core ranged from 6.3 +/- 1.7 to 7.2 +/- 1.3 kJ min-1, thereby accounting for 35-40 % of the estimated rate of heat production ( approximately 18 kJ min-1). 6. At exhaustion in DE, blood lactate values were low whereas blood glucose and muscle glycogen levels were still high. Exhaustion coincided with high body temperature ( approximately 40 C). 7. In conclusion, the present results demonstrate that reductions in exercising muscle blood flow with dehydration do not impair either the delivery of glucose and FFA or the removal of lactate during moderately intense prolonged exercise in the heat. However, dehydration during exercise in the heat elevates carbohydrate oxidation and lactate production. A major finding is that more than one-half of the metabolic heat liberated in the contracting leg muscles is dissipated directly to the surrounding environment. The present results indicate that hyperthermia, rather than altered metabolism, is the main factor underlying the early fatigue with dehydration during prolonged exercise in the heat.

Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans

[EN] A universal O2 sensor presumes that compensation for impaired O2 delivery is triggered by low O2 tension, but in humans, comparisons of compensatory responses to altered arterial O2 content (CaO2) or tension (PaO2) have not been reported. To directly compare cardiac output (QTOT) and leg blood flow (LBF) responses to a range of CaO2 and PaO2, seven healthy young men were studied during two-legged knee extension exercise with control hemoglobin concentration ([Hb] = 144.4 +/- 4 g/l) and at least 1 wk later after isovolemic hemodilution ([Hb] = 115 +/- 2 g/l). On each study day, subjects exercised twice at 30 W and on to voluntary exhaustion with an FIO2 of 0.21 or 0.11. The interventions resulted in two conditions with matched CaO2 but markedly different PaO2 (hypoxia and anemia) and two conditions with matched PaO2 and different CaO2 (hypoxia and anemia + hypoxia). PaO2 varied from 46 +/- 3 Torr in hypoxia to 95 +/- 3 Torr (range 37 to >100) in anemia (P < 0.001), yet LBF at exercise was nearly identical. However, as CaO2 dropped from 190 +/- 5 ml/l in control to 132 +/- 2 ml/l in anemia + hypoxia (P < 0.001), QTOT and LBF at 30 W rose to 12.8 +/- 0.8 and 7.2 +/- 0.3 l/min, respectively, values 23 and 47% above control (P < 0.01). Thus regulation of QTOT, LBF, and arterial O2 delivery to contracting intact human skeletal muscle is dependent for signaling primarily on CaO2, not PaO2. This finding suggests that factors related to CaO2 or [Hb] may play an important role in the regulation of blood flow during exercise in humans.

Muscle blood flow is reduced with dehydration during prolonged exercise in humans

[EN] 1. The present study examined whether the blood flow to exercising muscles becomes reduced when cardiac output and systemic vascular conductance decline with dehydration during prolonged exercise in the heat. A secondary aim was to determine whether the upward drift in oxygen consumption (VO2) during prolonged exercise is confined to the active muscles. 2. Seven euhydrated, endurance-trained cyclists performed two bicycle exercise trials in the heat (35 C; 40-50 % relative humidity; 61 +/- 2 % of maximal VO2), separated by 1 week. During the first trial (dehydration trial, DE), they bicycled until volitional exhaustion (135 +/- 4 min, mean +/- s.e.m.), while developing progressive dehydration and hyperthermia (3.9 +/- 0.3 % body weight loss; 39.7 +/- 0.2 C oesophageal temperature, Toes). In the second trial (control trial), they bicycled for the same period of time while maintaining euhydration by ingesting fluids and stabilizing Toes at 38.2 +/- 0.1 C after 30 min exercise. 3. In both trials, cardiac output, leg blood flow (LBF), vascular conductance and VO2 were similar after 20 min exercise. During the 20 min-exhaustion period of DE, cardiac output, LBF and systemic vascular conductance declined significantly (8-14 %; P < 0.05) yet muscle vascular conductance was unaltered. In contrast, during the same period of control, all these cardiovascular variables tended to increase. After 135 +/- 4 min of DE, the 2.0 +/- 0.6 l min-1 lower blood flow to the exercising legs accounted for approximately two-thirds of the reduction in cardiac output. Blood flow to the skin also declined markedly as forearm blood flow was 39 +/- 8 % (P < 0.05) lower in DE vs. control after 135 +/- 4 min. 4. In both trials, whole body VO2 and leg VO2 increased in parallel and were similar throughout exercise. The reduced leg blood flow in DE was accompanied by an even greater increase in femoral arterial-venous O2 (a-vO2) difference. 5. It is concluded that blood flow to the exercising muscles declines significantly with dehydration, due to a lowering in perfusion pressure and systemic blood flow rather than increased vasoconstriction. Furthermore, the progressive increase in oxygen consumption during exercise is confined to the exercising skeletal muscles.

Association of individual resting state EEG alpha frequency and cerebral blood flow

Cognitive task performance differs considerably between individuals. Besides cognitive capacities, attention might be a source of such differences. The individual's EEG alpha frequency (IAF) is a putative marker of the subject's state of arousal and attention, and was found to be associated with task performance and cognitive capacities. However, little is known about the metabolic substrate (i.e. the network) underlying IAF. Here we aimed to identify this network. Correlation of IAF with regional Cerebral Blood Flow (rCBF) in fifteen young healthy subjects revealed a network of brain areas that are associated with the modulation of attention and preparedness for external input, which are relevant for task execution. We hypothesize that subjects with higher IAF have pre-activated task-relevant networks and thus are both more efficient in the task-execution, and show a reduced fMRI-BOLD response to the stimulus, not because the absolute amount of activation is smaller, but because the additional activation by processing of external input is limited due to the higher baseline.

Right ventricular absolute myocardial blood flow in complex congenital heart disease

A consequence in patients with d-transposition of the great arteries (d-TGA) and tetralogy of Fallot (TOF) is right ventricular hypertrophy (RVH) and right ventricular failure. Myocardial contrast echocardiography (MCE) permits the determination of the myocardial microvascular density reflected by the relative myocardial blood volume (rBV; ml/ml). This study was conducted to elucidate the relationship between RVH and myocardial microvascular changes by quantitative MCE in patients with d-TGA and TOF.

Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia

Reduced motor activity has been reported in schizophrenia and was associated with subtype, psychopathology and medication. Still, little is known about the neurobiology of motor retardation. To identify neural correlates of motor activity, resting state cerebral blood flow (CBF) was correlated with objective motor activity of the same day. Participants comprised 11 schizophrenia patients and 14 controls who underwent magnetic resonance imaging with arterial spin labeling and wrist actigraphy. Patients had reduced activity levels and reduced perfusion of the left parahippocampal gyrus, left middle temporal gyrus, right thalamus, and right prefrontal cortex. In controls, but not in schizophrenia, CBF was correlated with activity in the right thalamic ventral anterior (VA) nucleus, a key module within basal ganglia-cortical motor circuits. In contrast, only in schizophrenia patients positive correlations of CBF and motor activity were found in bilateral prefrontal areas and in the right rostral cingulate motor area (rCMA). Grey matter volume correlated with motor activity only in the left posterior cingulate cortex of the patients. The findings suggest that basal ganglia motor control is impaired in schizophrenia. In addition, CBF of cortical areas critical for motor control was associated with volitional motor behavior, which may be a compensatory mechanism for basal ganglia dysfunction.

Intussusceptive angiogenesis: pillars against the blood flow

Adaptation of vascular networks to functional demands needs vessel growth, vessel regression and vascular remodelling. Biomechanical forces resulting from blood flow play a key role in these processes. It is well-known that metabolic stimuli, mechanical forces and flow patterns can affect gene expression and remodelling of vascular networks in different ways. For instance, in the sprouting type of angiogenesis related to hypoxia, there is no blood flow in the rising capillary sprout. In contrast, it has been shown that an increase of wall shear stress initiates the splitting type of angiogenesis in skeletal muscle. Otherwise, during development, both sprouting and intussusception act in parallel in building the vascular network, although with differences in spatiotemporal distribution. Thereby, in addition to regulatory molecules, flow dynamics support the patterning and remodelling of the rising vascular tree. Herewith, we present an overview of angiogenic processes with respect to intussusceptive angiogenesis as related to local haemodynamics.

Hypotension during fluid-restricted abdominal surgery: effects of norepinephrine treatment on regional and microcirculatory blood flow in the intestinal tract

Vasopressors, such as norepinephrine, are frequently used to treat perioperative hypotension. Increasing perfusion pressure with norepinephrine may increase blood flow in regions at risk. However, the resulting vasoconstriction could deteriorate microcirculatory blood flow in the intestinal tract and kidneys. This animal study was designed to investigate the effects of treating perioperative hypotension with norepinephrine during laparotomy with low fluid volume replacement.

Effects of cardiac preload reduction and dobutamine on hepatosplanchnic blood flow regulation in porcine endotoxemia

Insufficient cardiac preload and impaired contractility are frequent in early sepsis. We explored the effects of acute cardiac preload reduction and dobutamine on hepatic arterial (Qha) and portal venous (Qpv) blood flows during endotoxin infusion. We hypothesized that the hepatic arterial buffer response (HABR) is absent during preload reduction and reduced by dobutamine. In anesthetized pigs, endotoxin or vehicle (n = 12, each) was randomly infused for 18 h. HABR was tested sequentially by constricting superior mesenteric artery (SMA) or inferior vena cava (IVC). Afterward, dobutamine at 2.5, 5.0, and 10.0 μg/kg per minute or another vehicle (n = 6, each) was randomly administered in endotoxemic and control animals, and SMA was constricted during each dose. Systemic (cardiac output, thermodilution) and carotid, splanchnic, and renal blood flows (ultrasound Doppler) and blood pressures were measured before and during administration of each dobutamine dose. HABR was expressed as hepatic arterial pressure/flow ratio. Compared with controls, 18 h of endotoxin infusion was associated with decreased mean arterial blood pressure [49 ± 11 mmHg vs. 58 ± 8 mmHg (mean ± SD); P = 0.034], decreased renal blood flow, metabolic acidosis, and impaired HABR during SMA constriction [0.32 (0.18-1.32) mmHg/ml vs. 0.22 (0.08-0.60) mmHg/ml; P = 0.043]. IVC constriction resulted in decreased Qpv in both groups; whereas Qha remained unchanged in controls, it decreased after 18 h of endotoxemia (P = 0.031; constriction-time-group interaction). One control and four endotoxemic animals died during the subsequent 6 h. The maximal increase of cardiac output during dobutamine infusion was 47% (22-134%) in controls vs. 53% (37-85%) in endotoxemic animals. The maximal Qpv increase was significant only in controls [24% (12-47%) of baseline (P = 0.043) vs. 17% (-7-32%) in endotoxemia (P = 0.109)]. Dobutamine influenced neither Qha nor HABR. Our data suggest that acute cardiac preload reduction is associated with preferential hepatic arterial perfusion initially but not after established endotoxemia. Dobutamine had no effect on the HABR.

Outer skull landmark-based coordinates for measurement of cerebral blood flow and intracranial pressure in rabbits

Despite the increased use of intracranial neuromonitoring during experimental subarachnoid hemorrhage (SAH), coordinates for probe placement in rabbits are lacking. This study evaluates the safety and reliability of using outer skull landmarks to identify locations for placement of cerebral blood flow (CBF) and intraparenchymal intracranial pressure (ICP) probes. Experimental SAH was performed in 17 rabbits using an extracranial-intracranial shunt model. ICP probes were placed in the frontal lobe and compared to measurements recorded from the olfactory bulb. CBF probes were placed in various locations in the frontal cortex anterior to the coronary suture. Insertion depth, relation to the ventricular system, and ideal placement location were determined by post-mortem examination. ICP recordings at the time of SAH from the frontal lobe did not differ significantly from those obtained from the right olfactory bulb. Ideal coordinates for intraparenchymal CBF probes in the left and right frontal lobe were found to be located 4.6±0.9 and 4.5±1.2 anterior to the bregma, 4.7±0.7mm and 4.7±0.5mm parasagittal, and at depths of 4±0.5mm and 3.9±0.5mm, respectively. The results demonstrate that the presented coordinates based on skull landmarks allow reliable placement of intraparenchymal ICP and CBF probes in rabbit brains without the use of a stereotactic frame.

Postoperative splanchnic blood flow redistribution in response to fluid challenges in the presence and absence of endotoxemia in a porcine model

We hypothesized that fluid administration may increase regional splanchnic perfusion after abdominal surgery-even in the absence of a cardiac stroke volume (SV) increase and independent of accompanying endotoxemia. Sixteen anesthetized pigs underwent abdominal surgery with flow probe fitting around splanchnic vessels and carotid arteries. They were randomized to continuous placebo or endotoxin infusion, and when clinical signs of hypovolemia (mean arterial pressure, <60 mmHg; heart rate, >100 beats · min(-1); urine production, <0.5 mL · kg(-1) · h(-1); arterial lactate concentration, >2 mmol · L(-1)) and/or low pulmonary artery occlusion pressure (target 5-8 mmHg) were present, they received repeated boli of colloids (50 mL) as long as SV increased 10% or greater. Stroke volume and regional blood flows were monitored 2 min before and 30 min after fluid challenges. Of 132 fluid challenges, 45 (34%) resulted in an SV increase of 10% or greater, whereas 82 (62%) resulted in an increase of 10% or greater in one or more of the abdominal flows (P < 0.001). During blood flow redistribution, celiac trunk (19% of all measurements) and hepatic artery flow (15%) most often decreased, whereas portal vein (10%) and carotid artery (7%) flow decreased less frequently (P = 0.015, between regions). In control animals, celiac trunk (30% vs. 9%, P = 0.004) and hepatic artery (25% vs. 11%, P = 0.040) flow decreased more often than in endotoxin-infused pigs. Accordingly, blood flow redistribution is a common phenomenon in the postoperative period and is only marginally influenced by endotoxemia. Fluid management based on SV changes may not be useful for improving regional abdominal perfusion.

Anterior knee pain after total knee arthroplasty: does it correlate with patellar blood flow?

Total knee arthroplasty (TKA) disturbs patellar blood flow, an unintended accompaniment to TKA that may be a cause of postoperative anterior knee pain. We examine whether disrupted patellar blood flow correlates with anterior knee pain following TKA.

[Blood flow assessment with magnetic resonance imaging after 1.9 μm diode laser assisted arterial micronastomoses]

The most important factor for successful free-flap transfer and replantations is a well-executed anastomosis. The aim of this study is to assess blood flow after laser assisted arterial microanastomosis (LAMA) using a 1.9 μm diode laser.

Theta burst TMS increases cerebral blood flow in the primary motor cortex during motor performance as assessed by arterial spin labeling (ASL)

Theta burst stimulation (TBS) is a novel variant of repetitive transcranial magnetic stimulation (rTMS), which induces changes in neuronal excitability persisting up to 1h. When elicited in the primary motor cortex, such physiological modulations might also have an impact on motor behavior. In the present study, we applied TBS in combination with pseudo continuous arterial spin labeling (pCASL) in order to address the question of whether TBS effects are measurable by means of changes in physiological parameters such as cerebral blood flow (CBF) and if TBS-induced plasticity can modify motor behavior. Twelve right-handed healthy subjects were stimulated using an inhibitory TBS protocol at subthreshold stimulation intensity targeted over the right motor cortex. The control condition consisted of within-subject Sham treatment in a crossover design. PCASL was performed before (pre TBS/pre Sham) and immediately after treatment (post TBS/post Sham). During the pCASL runs, the subjects performed a sequential fingertapping task with the left hand at individual maximum speed. There was a significant increase of CBF in the primary motor cortex after TBS, but not after Sham. It is assumed that inhibitory TBS induced a "local virtual lesion" which leads to the mobilization of more neuronal resources. There was no TBS-specific modulation in motor behavior, which might indicate that acute changes in brain plasticity caused by TBS are immediately compensated. This compensatory reaction seems to be observable at the metabolic, but not at the behavioral level.