Effects of glucose-insulin-potassium infusion on the angina response during treadmill exercise.

The effects of glucose-insulin-potassium (GIK) and placebo normal saline (S) infusion on treadmill-walking time to angina, ST depression, heart rate (HR), systolic blood pressure (SBP), rate pressure product (RPP), blood glucose (G), lactate (L) and free fatty acids (FFA) were studied in 14 non diabetic patients with exertional angina. For the whole group, the post-GIK walking time to angina (393 +/- 33 sec, mean +/- SEM) was greater than the values during control GIK (319 +/- 20 sec, p less than 0.02) and post-S infusion (334 +/- sec, p less than 0.05), but circulatory and ST responses were similar in post-GIK and post-S studies. 7 of the 14 patients experienced significantly greater improvement in exercise tolerance following GIK (467 +/- 39 sec) in comparison to control GIK (313 +/- 29 sec, p less than 0.001) and post-S infusion (334 +/- 32 sec, p less than 0.005) and exercised to a higher HR, SBP and RPP after GIK than after S infusion. At the onset of angina these patients had similar ST-segment depression before and after GIK but when ST segments were assessed after GIK at the same exercise duration when angina had occurred during the control and post-S studies, there was significantly less ST depression (p less than 0.01). Of the remaining 7 patients exercise tolerance following GIK deteriorated in 3, remained unchanged in 2 and increased by 12 and 48 sec in 2 patients in comparison to post-S values. Comparison of post-GUK and post-S values for G, L and FFA for the whole group showed significantly lower resting values of FFA and post-exercise values of G following GIK infusion. The differences in clinical and circulatory responses between patients who improved and those who did not improve following GIK were not related to the angiographically determined severity of coronary artery disease or to GIK-induced metabolic changes. Results suggest that some patients with angina pectoris do benefit from GIK infusion but the response in a given patient to this therapeutic modality is unpredictable.     

Fibrinolytic response to exercise in women using third-generation oral contraceptives.

The use of oral contraceptives (OC) is associated with an increased risk of thrombosis, suggesting OC exert procoagulant and/or antifibrinolytic effects. Given that physical exercise physiologically leads to an activation of blood coagulation and fibrinolysis, this study tested the hypothesis that OC might compromise the fibrinolytic response to exercise. Fibrinolytic variables were measured in 10 women (24 +/- 2 years) using OC (a formulation containing 30 micro g ethinylestradiol and 150 micro g desogestrel) and in 11 women without OC (mean +/- SD, 27 +/- 3 years) before, during and after a 1-h run on a treadmill at a velocity corresponding to an oxygen demand of 75-80% of maximum (anaerobic threshold). Exercise testing gave rise to considerable increases of tissue-type plasminogen activator antigen by seven-fold to eight-fold in women taking and not taking OC alike. In the presence of unchanged plasma levels of plasminogen activator inhibitor-1, exercise-induced release of tissue-type plasminogen activator led to enhanced plasmin formation with respect to plasmin-antiplasmin complexes, rising by (mean +/- standard error) 701 +/- 77 ng/ml (P < 0.001) in women using OC and by 695 +/- 117 ng/ml (P < 0.001 versus baseline; NS versus OC users) in controls. The fibrinolytic response to intensive physical exercise is preserved in women using OC and is similar to women not using OC.     

Fibrinolytic response to moderate exercise and platelet adhesiveness in diabetes mellitus

Summary The fibrinolytic response to moderate exercise has been studied in 15 diabetics and compared with 32 controls. Platelet adhesiveness has been studied in 18 diabetic subjects and compared with 37 controls. Increased platelet adhesiveness, lower levels of resting spontaneous fibrinolysis and impaired fibrinolytic response have been demonstrated in diabetic subjects as compared to controls. The significance of these findings is discussed. Traduzione a cura di G. U.     

Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol in healthy subjects

Introduction: Catecholamines are known to affect cardiac repolarization, and provocation with either isoproterenol or epinephrine has been proposed as a tool for uncovering latent repolarization abnormalities. This study systematically compares the effects of isoproterenol and epinephrine infusions on QT interval (QT), T waves and U waves in normal subjects.
Methods and Results: Twenty-four normal subjects (29 ± 8 years) were evaluated during graded infusions of up to 0.30 μg/kg/minute epinephrine and 5.0 μg/minute isoproterenol. Heart rates at peak doses were 81 ± 13 bpm at 0.28 ± 0.04 μg/kg/minute epinephrine and 104 ± 5 bpm at 2.4 μg/minute isoproterenol. The longest absolute QT increase was 4 ± 5 msec above baseline during isoproterenol (P < 0.001) and 12 ± 23 msec during epinephrine (P = 0.07), while the longest corrected QT interval (QTc) increase was 67 ± 28 msec (P < 0.0001) and 79 ± 40 msec (P < 0.0001) above baseline during isoproterenol and epinephrine, respectively (P = 0.12 for difference). There was a 2-fold increase in U-wave amplitude during each intervention (P < 0.001). The specificity of paradoxical QT prolongation (≥30 msec at 0.05 μg/kg/minute or ≥35 msec at 0.10 μg/kg/minute epinephrine) and an increase in QTc ≥600 msec at any dose epinephrine were 100%. However, the specificity of other proposed criteria that utilized QTc measurement (≥30 msec at 0.10 μg/kg/minute or ≥65 msec at any dose) was poor whether all leads or only lead II were assessed.
Conclusion: Both epinephrine and isoproterenol are associated with QTc prolongation and amplification of the U wave in normal subjects. The specificity of proposed criteria for epinephrine provocation in diagnosis of the long-QT syndrome is variable; however, paradoxical QT prolongation at low-dose epinephrine or a QTc ≥600 msec is highly specific.     

Ventriculoarterial coupling during exercise in normal human subjects.

To examine the relative roles of ventricular contractility and loading conditions for cardiovascular adjustment during exercise, 10 normal human subjects were studied using a framework of ventriculoarterial coupling. Anaerobic threshold was evaluated to determine the work rates of aerobic and anaerobic exercise. Ventricular contractile properties were quantified by the slope of the end-systolic pressure-volume relationship (ventricular elastance) and arterial system properties were expressed by the end-systolic pressure-stroke volume relationship (arterial elastance). During aerobic exercise, left ventricular end-diastolic volume and stroke volume were increased by 14 and 33%, with plasma norepinephrine levels being doubled. Arterial elastance was reduced by 30%, but ventricular elastance did not change significantly. During anaerobic exercise, ventricular end-diastolic volume returned to the resting value, while stroke volume remained increased by 31%. In contrast to aerobic exercise, ventricular elastance rose substantially by 89% in association with about a 10 times increase in plasma norepinephrine. Arterial elastance remained the same as in aerobic exercise. Thus, the increase in stroke volume was primarily mediated by changes in loading conditions during aerobic exercise and by enhanced contractility during anaerobic exercise.     

A kinetic model of the circulatory regulation of tissue plasminogen activator during exercise, epinephrine infusion, and endurance training

A computer simulation of the circulatory system was used to kinetically model secretion, inhibition, and clearance of tissue plasminogen activator (t-PA) during three different processes that increase active t-PA levels: epinephrine infusion, exercise, and endurance training. Infusion of epinephrine stimulated an increase in t-PA secretion that was proportional to the plasma epinephrine concentration. In addition, epinephrine infusion increased hepatic blood flow and t-PA clearance, thus slowing the increase of plasma t-PA levels. During exercise, t-PA levels increased due both to increased t-PA secretion and to decreased clearance secondary to reduced hepatic blood flow. The increase in t-PA secretion during exercise was directly proportional to the epinephrine concentration in blood with the same ratio of t-PA secretion to epinephrine as found during epinephrine infusion, suggesting that increased plasma epinephrine during exercise was the primary stimulus for t-PA secretion. Lastly, the simulation predicted that 6 months of endurance training produced a decrease in resting plasminogen activator inhibitor type 1 (PAI-1) secretion, resulting in less t-PA inhibition and an overall increase in active t-PA after training. Accurate analysis of the regulation of active t-PA levels in blood required simultaneous modeling of t-PA and PAI-1 secretion, hepatic clearance, and inhibition of t-PA by PAI-1.     

The cardiovascular response at rest and during exercise in hypothyroid subjects to thyroxine substitution

Rapid and intense thyroxine substitution can lead to heart failure and myocardial infarction in hypothyroid patients. We have analyzed the normalization of the circulatory system in hypothyroid subjects on a gradual thyroxine substitution. Fourteen hypothyroid patients were studied repeatedly with an orthostatic test and a standardized symptom-limited exercise test during substitution. ST and T abnormalities were observed in 51 and 33%, respectively, before substitution. Many of these changes were normalized upon substitution at a dose level of 0.15 mg/d thyroxine. The pulse reaction to standing was enhanced early during substitution. The capacity to perform work, on the other hand, responded more slowly to thyroxine substitution, and was significantly increased only after six months of full substitution. This difference in the time course of recovery may be of clinical importance when substituting patients with hypothyroidism and ischemic heart disease.     

Cardiovagal response to acute mild exercise in young healthy subjects.

BACKGROUND: The aim of the present study was to investigate the effect of a single bout of mild exercise on autonomic nervous system activity in healthy subjects. METHODS AND RESULTS: The study group comprised 18 healthy males, aged between 20 and 24 years, who had not been training regularly for the last 3 months. A supine recording of systolic arterial pressure (SAP) and RR interval and the administration of the phenylephrine test were performed at baseline and repeated after a 60-min recovery period following treadmill exercise training for 30 min at 65% of maximal heart rate. Mean SAP and RR interval, heart rate variability (HRV) indices (the standard deviation of normal-to-normal RR intervals (SDNN), the square root of the mean of squared differences between successive intervals and the percentage of adjacent RR intervals differing more than 50 ms), noninvasive spectral baroreflex sensitivity (Spe-BRS) and phenylephrine baroreflex sensitivity (Phe-BRS) were assessed before and after training. Mean SAP measured after exercise was lower than baseline (120+/-12 mmHg vs 128+/-12 mmHg, p = 0.05). Spe-BRS and Phe-BRS increased significantly after exercise, from 11.8+/-6.1 ms/mmHg to 16.0+/-7.8 ms/mmHg (p = 0.034), and from 16.0+/-8.8 ms/mmHg to 21.9+/-9.3 ms/mmHg (p = 0.022), respectively. A parallel increase was also observed in SDNN (from 81+/-44 ms to 96+/-53 ms, p = 0.02), but the other HRV indices showed no significant differences between pre- and post-exercise. CONCLUSIONS: A single session of mild exercise performed by sedentary young men leads to significant autonomic nervous system improvement, which suggests that even mild physical activity is beneficial for neural cardiac regulation and should be recommended to sedentary healthy subjects.     

Electrophysiologic effects of mental stress in healthy subjects: a comparison with epinephrine infusion

Mental stress has been associated with serious cardiac arrhythmias, including ventricular tachycardia and ventricular fibrillation. The purpose of this study was to assess cardiac electrophysiologic effects of mental stress and compare them with those of epinephrine infusion. Ten healthy male volunteers participated. Electrophysiologic and hemodynamic variables were measured at baseline, during mental stress produced by Stroop's color word conflict test and during epinephrine infusion at 2 rates (0.025 micromol/kg/min and 0.3 micromol/kg/min). Mental stress produced significant effects on the electrophysiologic properties of the heart with shortening of all measured electrophysiologic variables except atrial, most markedly those of the sinus and the atrioventricular nodes. The effects on the right ventricular myocardium and the His-Purkinje conduction system were less pronounced. During infusion of epinephrine, corresponding effects could only be reproduced at a much higher plasma level. Circulating epinephrine apparently plays a minor role as a mediator of mental stress effects on the heart.     

Hemodynamic response to isometric exercise in elderly subjects

The haemodynamic responses to isometric exercise (handgrip) performed during right cardiac catheterization were tested in 9 elderly patients (1 female, 8 males) with average age of 67.8 +/- 2.3 years, without clinical and instrumental signs of cardiovascular disease. The parameters tested before and after handgrip were: heart rate (FC), systolic blood pressure (PAS), diastolic blood pressure (PAD), mean blood pressure (PAM), cardiac output (PC), cardiac index (IC), systolic index (IS), mean pulmonary pressure (PPM), end-diastolic pulmonary pressure (PPTD), systemic arterial resistance (RST), pulmonary arterial resistance (RPT), stroke volume (GS), left ventricular systolic stress index (ILS). Statistical analysis was carried out using the Student test. Stress produced a highly significant increase (p less than 0.001) of PPM (+28%) of PPTD (+ 33.1%), a modestly significant increase (p less than 0.01) of PAD (+ 15.6%), PAM (+ 18.2%), ILS (+ 24%,), RPT (+ 25%), a weakly significant increase (p less than 0.05) of PAS (+ 20%), RST (+ 15.6%). No significant variation attributable to FC, IC, IS, GS was observed. Our subjects presented a reduced tolerance to isometric exercise.     

Ventilatory efficiency during exercise in healthy subjects

When evaluating dyspnea in patients with heart or lung disease it is useful to measure the quantity of ventilation needed to eliminate metabolically produced CO2 (i.e., the ventilatory efficiency). Mathematically, the relationship between ventilation (VE) and CO2 output is determined by the arterial CO2 pressure and the physiologic dead space-tidal volume ratio. We decided to determine how age, sex, size, fitness, and the type of ergometer influenced ventilatory efficiency in normal subjects. Three methods were compared for expressing this relationship: (1) the VE versus CO2 output slope below the ventilatory compensation point, commonly used by cardiologists for estimating the severity of heart failure; (2) the VE/CO2 output ratio at the anaerobic threshold, commonly used by pulmonologists; and (3) the lowest VE/CO2 output ratio during exercise, the latter parameter not previously reported. We studied 474 healthy adults, between 17 and 78 years of age during incremental cycle and treadmill cardiopulmonary exercise tests at three test sites, correcting the total VE for the equipment dead space. The lowest VE/CO2 output ratio was insignificantly different from the ratio at the anaerobic threshold, less variable than that for the slope relationship, and unaffected by the site, ergometer, and gas exchange measurement systems. The regression equation for the lowest VE/CO2 output ratio was 27.94 + 0.108 x age + (0.97 = F, 0.0 = M) - 0.0376 x height, where age is in years and height is in centimeters. We conclude that the lowest VE/CO2 output ratio is the preferred noninvasive method to estimate ventilatory inefficiency.     

Reliability of noninvasive oximetry in black subjects during exercise and hypoxia.

The effect of skin pigmentation on the reliability of noninvasive oximetry, especially during exercise and hypoxia, has not been thoroughly investigated. This is the first study, to our knowledge, that specifically addresses this question. Thirty-three young black men performed multistage, steady-state cycle ergometry, breathing gas mixtures simulating different altitudes: 33 breathed gas simulating sea level (PIO2 = 146 mm Hg), 11 breathed gas simulating 2,300 m (PIO2 = 110 mm Hg), and 22 breathed gas simulating 4,000 m (PIO2 = 85 mm Hg). Co-oximeter SaO2 determinations were performed in arterial blood samples obtained concurrently with ear oximetry that was measured using Hewlett-Packard 47201A (HP) and Blox IIA oximeters. The mean error or bias for the [HP - SaO2] and for [Biox IIA - SaO2] +/- 95% CI were: at simulated sea level (SaO2 greater than 96%): -0.4 +/- 0.3% and 2.1 +/- 0.3%; at simulated 2,300 m (range of SaO2 means, 89 to 94%): -0.8 +/- 0.5% and 3.5 +/- 0.9%; for simulated 4,000 m (range of SaO2 means, 75 to 84%): -4.8 +/- 1.6% and 9.8 +/- 1.8%, respectively. A better coefficient correlation was observed for all the pairs between SaO2 versus HP (r = 0.94, p less than 0.001, n = 279) than for the SaO2 versus Biox IIA (r = 0.80, p less than 0.001, n = 242). In conclusion, the HP oximeter appears to estimate SaO2 more accurately than the Biox IIA oximeter. The previously described overestimation for the Biox IIA ear oximeter and the underestimation for the HP ear oximeter at low SaO2 values in whites is exaggerated in blacks.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to physical exercise and tyramine infusion in hypertensive and normotensive subjects

The aim of our investigation was to assess blood pressure and heart rate variations in 20 essential hypertensive male in-patients (WHO class I and II) and in 20 normotensive healthy volunteers submitted to three provocation tests: isometric handgrip (IHG), bicycle ergometric exercise (BEE) and tyramine infusion (TI) given as i.v. boluses alternating with saline in a single-blind fashion. According to our data IHG induced a comparable rise of systolic BP, diastolic BP and heart rate both in hypertensive and normotensive subjects. BEE, compared with IHG, caused a more significant (P less than 0.01) rise in SBP and heart rate in both groups. By contrast, DBP during BEE was significantly increased in hypertensive (P less than 0.01), but slightly decreased in normotensive subjects (P = NS). TI caused a dose dependent SBP rise in both groups studied, while DBP and HR were unaffected. BP elevation was, however, more marked in hypertensive subjects. Confirming this finding significantly lower tyramine doses were required to produce the same SBP increase in hypertensives than in the normotensive volunteers. In short, SBP rise during TI and DBP rise during BEE may be the markers of an enhanced cardiovascular reactivity of hypertensive subjects. Our study suggests that BP reactivity to stress may be different according to the laboratory stress employed and also that BEE and TI are more useful than IHG for the assessment of an enhanced cardiovascular response to stress in hypertensive subjects.     

Thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone during infusion of epinephrine and propranolol in man.

Male volunteers were administered 100 microgram thyrotropin-releasing hormone (TRH) intravenously during control (saline) and drug (epinephrine-propranolol) infusions. There were no differences in the thyroid-stimulating hormone (TSH) or prolactin responses to TRH during the epinephrine-propranolol infusion periods. There were no significant differences in growth hormone (GH) responses to epinephrine-propranolol infusions. Epinephrine-propranolol had no detectable effect on basal TSH, prolactin and GH concentrations. We conclude that the alpha-adrenergic system does not play any role at the pituitary level in modulating the effect of TRH-stimulated TSH or prolactin secretion in male volunteers.     

Impact of acute epinephrine removal on hepatic glucose metabolism during stress hormone infusion.

We examined the effect of acute discontinuation of an epinephrine (EPI) infusion on hepatic glucose metabolism during stress hormone infusion (SHI). Glucose metabolism was assessed in 11 conscious, 20-hour fasted dogs using tracer and arteriovenous techniques after a 3-day exposure to SHI. SHI increased EPI, norepinephrine, cortisol, and glucagon levels (approximately sixfold to 10-fold), which led to marked hyperglycemia, hyperinsulinemia, and accelerated glucose metabolism. On day 3, EPI infusion was acutely discontinued for 180 minutes in five dogs while infusion of the other hormones was continued (SHI - EPI). In the remaining six dogs, all hormones were continued for the duration of the study (SHI + EPI). In SHI - EPI, EPI levels decreased from 1,678+/-191 to 161+/-47 pg/mL. Isoglycemia (183+/-10 to 185+/-15 mg/dL) was maintained with an exogenous glucose infusion. Arterial insulin levels increased from 41+/-8 to 64+/-8 microU/mL. Whole-body glucose utilization increased from 3.5+/-0.5 to 9.4+/-1.9 mg/kg/min. Nonesterified fatty acids ([NEFAs] 763+/-292 to 147+/-32 micromol/L) decreased. Net hepatic glucose output decreased (2.6+/-0.6 to 0.1+/-0.3 mg/kg/min). In SHI + EPI, hepatic glucose metabolism remained unaltered. In summary, EPI plays a pivotal role during SHI by stimulating glucose production and inhibiting glucose utilization. In part, these effects are mediated by restraining pancreatic insulin secretion.     

The response to intravenous glucose infusion in normal and diabetic subjects

Summary Data from single injection studies on 23 normal subjects led to development of an intravenous primed — constant infusion test. The plasma glucose response to this test was determined in 48 normal and 24 diabetic subjects. Variation in plasma glucose concentration at equilibrium was minimal in normal and marked in diabetic subjects — assessed by the difference between maximum and minimum glucose concentration over the final 25 min of a 50 min infusion. This parameter was used successfully in predicting the course of 16 pregnant women with clinical suspicion of prediabetes unresolved by oral glucose tolerance tests.Submitted as part fulfillment of the requirements for Doctor of Medicine, Monash University, Melbourne, 1967.