VEGF-A splice variants and related receptor expression in human skeletal muscle following submaximal exercise.

VEGF-A contributes to muscle tissue angiogenesis following aerobic exercise training. The temporal response of the VEGF-A isoforms and their target receptors has not been comprehensively profiled in human skeletal muscle. We combined submaximal exercise with and without reduced leg blood flow to establish whether ischemia-induced metabolic stress was an important physiological stimuli responsible for regulating the VEGF-A system in humans. Nine healthy men performed two 45-min bouts of one-leg knee-extension exercise, with and without blood flow restriction. Muscle biopsies were obtained at rest and 2 and 6 h after exercise. Expression (mRNA) of the VEGF-A splice variants and related receptors [VEGF receptor (VEGFR)-1, VEGFR-2, and neuropilin-1] was determined by using qPCR. VEGF-A(total) expression increased more robustly after exercise with reduced blood flow, and initially this principally reflected an increase in VEGF-A(165). Six hours after exercise, there was a relatively greater increase in VEGF-A(189), and this response was not influenced by blood flow conditions. VEGFR-1 mRNA expression increased 2 h after exercise, and neuropilin-1 expression was transiently reduced, while all three receptors increased by 6 h. There was no evidence for the expression of the inhibitory VEGF-A(165B) variant in human skeletal muscle. Our study, reflecting both VEGF-A ligand and receptors, implicates metabolic perturbation as a regulator of human muscle angiogenesis and demonstrates that VEGF-A splice variants are distinctly regulated. Our findings also indicate that all three receptor genes exhibit different pretranslational regulation, in response to exercise in humans.

Acute alterations of pre- and afterload: are Doppler-derived diastolic filling patterns able to differentiate the loading condition?

The net effects of acute changes in pre- and afterload on left ventricular filling, were examined by altering loading conditions in normal subjects. The specific purpose of this study was to investigate whether Doppler-derived transmitral flow patterns are able to differentiate the type of loading conditions. In 24 normal subjects (13 females, 11 males, mean age 44.1 +/- 11.5 years), the following Doppler variables were determined at baseline, after rapid volume infusion (preload increase), after nitroglycerin administration (preload decrease), during isometric exercise (afterload increase), and after application of a converting enzyme inhibitor (afterload decrease): the peak and integrated early (E, Ei) and late (A, Ai) diastolic flow velocities, their ratios (E/A, Ei/Ai), the percentage of atrial contribution (ACON), and the acceleration and deceleration times (Ac, Dc) of early filling. Reduced preload and increased afterload led to similar filling patterns characterized by a significant E and Ei decrease (p < 0.05, compared to baseline) accompanied by an A and Ai increase with a resultant reduction of E/A and Ei/Ai. Both changes increased the atrial contribution to filling and reduced Ac and Dc. Increased preload only significantly increased E and Ei, while reduced afterload did not induce any significant changes. Different loading conditions alter Doppler-derived diastolic filling patterns. However, the transmitral flow profile is not specific enough to distinguish the manner in which loading conditions have been altered.

Sudden increase of the ST segment elevation at time of reperfusion predicts extensive infarcts in patients with intravenous thrombolysis.

Within 4 hours from the onset of symptoms in 61 patients with myocardial infarction and intravenous thrombolysis, ST segment elevation and creatine phosphokinase (CK) were measured every 15 minutes. Because of a premature enzyme rise, 42 patients (69%) were reperfused early (group 1). Immediately following reperfusion, eight of them (13%, group 1a) showed a marked increase of the ST elevation, in six of whom it was associated with clearly intensified chest pain. These patients exhibited a much steeper enzyme release and developed a larger enzymatic infarct size than patients (group 1b) without an additional transient ST elevation at reperfusion (CK peak 5.1 +/- 1.6 vs 9.8 +/- 4.2 hours after the start of thrombolysis; CK release 48 +/- 22 vs 19 +/- 18 IU/ml x hours, both p < 0.005). At angiography 11 days later, left ventricular function was significantly worse in group 1a than in group 1b (regional dyssynergic area 51 +/- 24 vs 21 +/- 18, global ejection fraction 39 +/- 14 vs 58 +/- 11; both p < 0.0005). During intravenous thrombolysis in acute myocardial infarction, some patients show a marked transient increase of the ST segment elevation at reperfusion. Their enzyme rise is very rapid and suggests a special reperfusion pattern. Most of these patients suffered large infarcts.

Hemodynamic response to exercise-induced myocardial ischemia detected by transmitral filling patterns derived from Doppler echocardiography.

There is still controversy as to the manner in which Doppler-derived transmitral filling patterns change because of myocardial ischemia. To evaluate the effects of exercise-induced ischemia on Doppler-derived filling patterns, 28 patients were examined at rest and during three stages of supine bicycle exercise (0.5, 1.0, and 1.5 W/kg). The peak early (E) and integrated early (Ei) and peak late (A) and integrated late (Ai) diastolic flow velocities, as well as their ratios (E/A, Ei/Ai), were compared between patients with exercise-induced ischemia but no wall-motion abnormalities at rest (ischemia group, n = 13) and those with akinetic scars from previous infarction but no exercise ischemia (scar group, n = 15). Normal subjects with no evidence of heart disease served as a control group (n = 11). At maximal workload the ischemia group showed a significantly lower peak flow velocity at atrial contraction than the control and scar group (0.74 +/- 0.18 vs 1.08 +/- 0.25 and 0.89 +/- 0.19 m/sec, respectively; p < 0.05) and also a significantly lower flow velocity integral at atrial contraction (8.24 +/- 2.2 vs 12.81 +/- 4.8 and 11.32 +/- 3.6 cm, respectively; p < 0.05). Therefore, the atrial contribution to filling was diminished during ischemia (36.2% +/- 9.2% vs 47.3% +/- 6.4% and 48.4% +/- 13.8%, respectively; p < 0.05). By maintaining the early filling rate during ischemia, the reduced atrial contribution resulted in a significantly higher E/A ratio (1.48 +/- 0.31 vs 1.05 +/- 0.15 and 1.16 +/- 0.44, respectively) and Ei/Ai ratio (2.0 +/- 1.06 vs 1.09 +/- 0.26 and 1.24 +/- 0.79, respectively). The assessment of Doppler-derived transmitral filling during exercise-induced ischemia shows mainly early diastolic filling, which is in contrast to the profile of impaired relaxation usually associated with ischemia. Evidence of exercise-induced ischemia leading to greater increases in left atrial pressure suggests that transmitral filling patterns are more closely related to hemodynamic status than to diastolic function.

[Detection of early reperfusion and prediction of left ventricular damage from the course of increased ST values in acute myocardial infarct with thrombolysis]. / Erkennung der frühen Reperfusion und Vorhersage der linksventrikulären Schädigung aus dem Verlauf der ST-Strecken-Hebung beim akuten Myokardinfarkt mit Thrombolyse.

In 60 patients with acute myocardial infarction (pain < or = 4 h), we examined the value of ST segment monitoring in predicting early reperfusion, resulting left ventricular damage, and complications during hospitalization. Two criteria were determined by observation of the ST segment elevation during the first 4 h following initiation of thrombolysis. Early reperfusion was assessed by an early increase of the creatine phosphokinase (CK) with measurements taken in 15-min intervals. Cardiac catheterization was performed on days 11 +/- 5. According to the CK measurements, a reduction of the ST elevation > or = 50% within 1 h of serial ECG follow-up (ST criterion A) was the best indicator of early reperfusion (sensitivity 84%, specificity 80%, positive predictive value 93%, negative predictive value 67%). Simple comparison of the ST segment in the initial ECG and an ECG recorded 3 h later (ST criterion B) was less accurate according to the detection of early reperfusion (sensitivity 68%, specitivity 93%, positive predictive value 97%, negative predictive value 50%). However, contrary to ST criterion A, criterion B was useful in predicting subsequent left ventricular damage. Patients with a resolution of the initial ST elevation > or = 70%/3 h showed smaller regional wall motion abnormalities (dyssynergic area 21.3 +/- 20.3 vs 33.8 +/- 18.4, p < 0.01) and a better left ventricular ejection fraction (57.7 +/- 11.6 vs 50.2 +/- 12.6, p < 0.05). Patients with early reduction of the ST elevation following either criterion experienced fewer critical events (reinfarction, reischemia, death). In conclusion, the investigated criteria are useful in assessing reperfusion of the infarcted artery following thrombolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Doppler echocardiography measurement of diastolic filling parameters in acute changes of pre- and afterload in healthy probands]. / Doppler-echokardiographische Messung diastolischer Füllungsparameter während akuter Vor- und Nachlaständerungen bei Herzgesunden.

For a more precise understanding of the net effects of acute alterations of pre- and afterload on left-ventricular filling, loading conditions were altered in normal subjects. The specific purpose of this study was to investigate if Dopplerechocardiographically derived transmitral flow patterns are able to differentiate the manner of loading condition. In 24 normal subjects (13 female, 11 male, mean age 44.1 +/- 11.5 years) the following Doppler variables were analyzed at baseline, after rapid infusion of volume (preload increase), nitroglycerine (preload decrease), isometric exercise (afterload increase) and converting enzyme inhibitor (afterload decrease): peak and integrated early (E, Ei) and late (A, Ai) diastolic flow velocities, their ratios (E/A, Ei/Ai), the percentage of atrial contribution (ACON) and the times of acceleration (Az) and deceleration (Dz) of early filling. Preload reduction as well as afterload increase led to a similar filling pattern with a significant decrease (p < 0.05 from baseline) of E and Ei, increase of A and Ai, and, consequently, a reduction of E/A and Ei/Ai. The atrial contribution to filling increased during both alterations; Az and Dz were reduced. Following the increase of preload, only the increase of E and Ei was statistically significant, while afterload reduction showed no significant differences. Different loading conditions alter Doppler-derived diastolic filling patterns. But the transmitral flow profile is not specific enough to differentiate in which manner loading conditions have been altered.

The cardiac filling pressure following exercise and thermal stress.

Under heat stress, a decrease of the central venous pressure (CVP) was regularly observed, raising the question of whether this reaction is a limiting factor for the circulation. In animal experiments it could be shown, however, that despite a lowered CVP, which depended on the elevated body temperatures, a high cardiac output (CO), as well as an elevated stroke volume could be maintained. A low CVP went hand in hand with a low total peripheral resistance. It was argued that under these circumstances the low CVP was not limiting because the intrinsic factors of the heart (sympathetic stimulation) were capable of maintaining a high CO. In human experiments the lowered CVP had to be seen in relation to the degree of dehydration. Regardless of whether the plasma volume remained constant, as in exercise, or declined, as in thermal stress (sauna), the CVP followed the volume depletion of the vascular and extravascular space, and it might well be that under these circumstances CVP is limiting. In this case, however, the altered CVP must be seen first as a monitor for the fluid deficit and not as a factor controlling cardiac function.

Effects of dehydration on the vasopressin response to immersion.

Nine healthy volunteers underwent three experimental procedures in random order. The protocols were 4 h of thermal dehydration followed by 2 h of head-out water immersion, 4 h of thermal dehydration followed by 2 h of chair rest, and 6 h of rest in the supine position. Four hours of heat exposure (50 degrees C) resulted in a body weight loss of approximately 3.5%. Plasma osmolality rose by approximately 5 mosmol/kg, mean arterial pressure (MAP) decreased from 85 to 78 mmHg, and body temperature increased from 36.8 to 38.6 degrees C. As a consequence of the combined action of hypertonicity, hypovolemia, hypotension, and hyperthermia, plasma arginine vasopressin (AVP) increased from 2.1 to 8.1 pg/ml after 4 h thermal dehydration. Changes in body weight, plasma osmolality, body temperature, and MAP were similar after either a subsequent 2 h of water immersion or 2 h of chair rest. However, during chair rest plasma AVP remained elevated (8.4 pg/ml), whereas during immersion plasma AVP decreased from 8.1 to 4.7 pg/ml. This was probably due to the central hypervolemia induced by immersion. Our results support the hypothesis that central hypervolemia rather than hypotonicity is the primary stimulus for AVP suppression during water immersion in dehydrated subjects. During the early immersion period hypoosmolality might contribute to the AVP suppression.

Current views and future programs in cardiovascular physiology in space.

The volume shift of 2000 cm3 from the lower to the upper part of the human body during weightlessness gave rise to theoretical and practical questions which are addressed in this communication. The analysis revealed that the mobilized fluid reduced the interstitial fluid of the lower extremities by 40%. Applying the current ideas in the field of interstitial tissue physiology to these problems, one must conclude that the fluid displacement can only be brought about by a change of the interstitial tissue compliance. Based on the observations made by the astronauts and on our working hypothesis, a method was proposed to follow the fluid migration and to measure the tissue compliance in man. Results are reported from experiments under terrestrial conditions. They show that the tissue compliance indeed can be modulated. Applying the method in space can eventually help to clarify several concepts in terrestrial physiology.

Feeding patterns of endurance athletes.

Feeding pattern was studied in 13 long distance runners, eight cyclists and eight sedentary men. The timing of the food and fluid intakes, the kind and the amount of food and fluids taken, the body weight (BW), and the exercise schedules were recorded on 3 or 4 successive days under ad libitum conditions of feeding and drinking. The subjects remained in energy and water balance, since the BW measured in the morning during the observation periods did not change significantly. The total caloric intake was 13 876 kJ per day in the runners and 26 282 kJ per day in the cyclists, exceeding the estimated basic metabolic rate by 103% and 250% respectively. The total water intakes were 33 and 36 ml . kg-1 . 24 h-1. The athletes consistently showed a nibbling pattern, characterized by frequent eating and drinking (average 8-10 per day). In the runners 63% of eating and drinking were synchronized, in the cyclists only 49% (p less than 0.01). In both groups drinking occurred most frequently in the morning, at noontime and in the evening. After 8 p.m. 45% of the total daily fluid intake occurred. In all likelihood the fluid intake followed an underlying circadian rhythm. The total intake frequency was determined by the total caloric needs.

Fluid control mechanisms after exercise dehydration.

Since the osmocontrol- (osmolality), the renin-angiotensin-(PRA), and the volume control-(central venous pressure, CVP) systems are involved in the maintainance of the salt-water balance, we investigated the pattern of these parameters in the recovery period after exercise dehydration in 13 well trained long-distance runners. On average, after exercise the athletes had lost 3.1% of their body weight (BW). After eating and drinking the BW was still 1.3% below control value, indicative of continuing deficits. Plasma osmolality increased, however, from an average value of 286-290 mosmol/kg after exercise as well as postprandially, but the change was not significant. PRA-Levels rose significantly from 0.167-0.599 ng/ml . h after exercise and decreased to 0.333 ng/ml . h postprandially. CVP was significantly altered after exercise (-3.5 cm H20) as well as postprandially (-2.4 cm H20). The results suggest that the salt-water balance is maintained by the interplay of all the three systems. In conflicting situations, however, as when intercompartmental water- and solute-shifts take place during the recovery period, the volume control system triggered off by the CVP is the dominant corrective response to the prevailing deficits.U

Extracellular fluid volume and central circulation after long lasting exercise and dehydration in conscious dogs.

Two aspects of the recovery period after endurance exercise were investigated: a) the fluid distribution between the intra- and extravascular parts of the extracellular fluid volume (ECFV) induced by exercise dehydration, b) the cardiovascular response pattern [blood pressure (BP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), and central venous pressure (CVP)] to the heat load which results from the preceding exercise. Seven conscious dogs performed endurance exercise in a cool environment (16 degrees C) on a horizontal treadmill till 4% of the body weight was lost. It was found that about 70% of the total fluid loss of the body came from intracellular water. During exercise sodium and chloride concentrations rose by 6 mMol and 7 mMol respectively (P less than 0.005) and remained elevated throughout the early recovery period indicating a fluid loss of about 100-200 ml out of the ECFV. Direct measurements of the ECFV as sulfate space confirmed these values. Since the plasma volume remained unchanged, this fluid loss was carried totally by the interstitial fluid volume. Immediately after exercise body temperature was elevated by 1.5 degrees C and returned towards control within 90 min. Cardiac output was above control level for 2 h after the end of exercise, at first due to an increased HR and thereafter to an elevated stroke volume (SV) (P less than 0.02). CVP and TPR were below control levels for at least 2 h (P less than 0.01). A linear correlation was found between CVP and TPR. A close correlation existed between the body temperature and the cardiovascular parameters. It can be concluded that even long after exercise the cardiovascular system has to serve thermoregulatory needs.