Comparison of supine and erect bicycle exercise electrocardiography in coronary heart disease: Accentuation of exercise-induced ischemic ST depression by supine posture

Exercise-induced electrocardiographic ST depression was compared during supine and erect graded bicycle exercise in 43 patients with chest pain but no prior myocardial infarct; all had ≥1 mm of ST depression during either erect or supine exercise; 16 had multivessel, 24 had 1-vessel and 3 had no coronary artery disease. Supine exercise used 4 minutes/stage and erect exercise used either 4 minutes or 3 minutes/stage with identical graded work loads for both postures. Chest pain occurred in 31 patients during erect and in 29 during supine exercise. ST depression was ≥1 mm in 28 patients during erect exercise and in all 43 during supine exercise (p <0.001); mean maximal ST depression was 1.3 ± 0.2 mm during erect and 2.6 ± 0.2 mm during supine exercise (p <0.001). Maximal work load was higher during erect than supine exercise (745 ± 32 versus 678 ± 32 kpm/min; p <0.001). The accentuation of ST depression by supine posture was not attributable to the changes in heart rate, rate-pressure product or mean blood pressure during supine versus erect exercise. In the 10 patients who had 2 erect bicycle tests using work load durations of 3 and 4 minutes, the maximal ST depression was not significantly different (erect 3 minutes 1.3 ± 0.5 mm and erect 4 minutes 1.4 ± 0.4 mm). In 7 patients who also had a maximal treadmill exercise test, the maximal ST depression was significantly greater during supine exercise (2.3 ± 0.4 mm) than during either an erect bicycle test (0.6 ± 0.4 mm) or treadmill exercise (0.7 ± 0.4 mm) (p <0.05). Supine posture should be considered as an important potentiator of exercise-induced myocardial ischemia whem comparing indicators such as electrocardiography, radionuclide ventriculography and thallium-201 myocardial perfusion imaging during exercise.     

Incremental value of clinical assessment, supine exercise electrocardiography, and biplane exercise radionuclide ventriculography in the prediction of coronary artery disease in men with chest pain

The incremental value of clinical assessment, exercise electrocardiography (ECG) and biplane radionuclide ventriculography (RVG) in the prediction of coronary artery disease (CAD) was assessed in 105 men without myocardial infarction who were undergoing coronary angiography for investigation of chest pain. Independent clinical assessment of chest pain was made prospectively by 2 physicians. Graded supine bicycle exercise testing was symptom-limited. Right anterior oblique ECG-gated first-pass RVG and left anterior oblique ECG-gated equilibrium RVG were performed at rest and exercise. Regional wall motion abnormalities were defined by agreement of 2 of 3 blinded observers. A combined strongly positive exercise ECG response was defined as greater than or equal to 2 mm ST depression or 1.0 to 1.9 mm ST depression with exercise-induced chest pain. A multivariate logistic regression model for the preexercise prediction of CAD was derived from the clinical data and selected 2 variables: chest pain class and cholesterol level. A second model assessed the incremental value of the exercise test in prediction of CAD and found 2 exercise variables that improved prediction: RVG wall motion abnormalities, and a combined strongly positive ECG response. Applying the derived predictive models, 37 of the 58 patients (64%) with preexercise probabilities of 10 to 90% crossed either below the 10% probability threshold or above the 90% threshold and 28 (48%) also moved across the 5 and 95% thresholds. Supine exercise testing with ECG and biplane RVG together, but neither test alone, effectively adds to clinical prediction of CAD. It is most useful in men with atypical chest pain and when the ECG and RVG results are concordant.     

Low dose heparin in the prevention of deepvein thromboses in patients with acute myocardial infarction

Patients with acute myocardial infarction of less than 48 hours duration were randomized into three groups. The “fully anticoagulated” group received heparin by intravenous infusion and warfarin sodium to maintain a whole blood clotting time of 30 to 90 minutes and a prothrombin index of 10% to 35%. The “low dose” heparin group received 500 units by intravenous infusion every 12 hours. The control group received no anticoagulants. The radioactive fibrinogen test was used to diagnose the presence of leg vein thromboses.The control group had an incidence of venous thrombosis of 29.7% compared with 13.9% in the low dose group and 11.3% in the fully anticoagulated group. Patients in the control group who had cardiac failure had a significantly higher incidence of venous thromboses (71.4%) when compared with patients not in failure (20.0%). In the two treatment groups no significant difference was observed in patients with and without cardiac failure.Patients with cardiac failure complicating an acute myocardial infarction have a high incidence of venous thromboses. Anticoagulants significantly reduce this incidence and low dose intravenous heparin is as efficacious as full anticoagulation.     

Effects of verapamil on the electrophysiologic properties of the accessory pathway in patients with the Wolff-Parkinson-White syndrome

The effects of intravenous verapamil on the electrophysiologic properties of the accessory pathway in 12 patients with symptomatic Wolff-Parkinson-White syndrome were studied using intracardiac electrical recordings. In 11 of the 12 patients it was possible to induce a reentrant supraventricular tachycardia with programmed atrial or ventricular pacing. After verapamil it was still possible to induce supraventricular tachycardia in 6 of the 11 patients; however, the mean cycle of length of the tachycardia increased from a control value of 330 ± 20 ms (mean ± standard error of mean) to 369 ± 21 ms (p < 0.05). Although verapamil had no significant effect on the anterograde refractory period of the accessory pathway as measured by the extrastimulus technique, it significantly increased maximal 1:1 atrioventricular (AV) conduction through the accessory pathway to incremental high rate atrial pacing in 10 of the 12 patients (control value 227 ± 10 beats/min, value after verapamil 258 ± 14 beats/min, p < 0.001). In 4 patients in whom episodes of atrial fibrillation could be compared before and after verapamil, the drug decreased the average R-R interval from a control value of 327 ± 27 ms to 282 ± 28 ms (p < 0.05) and decreased the shortest R-R interval between preexcited beats from a control value of 237 ± 21 ms to 209 ± 18 ms (p < 0.05).

It is concluded that in patients with symptomatic Wolff-Parkinson-White syndrome, verapamil may increase the ventricular response through the accessory pathway if atrial fibrillation occurs. This finding, which is of potential clinical significance, could not have been predicted from conventional anterograde refractory period estimations.     

The mechanism of adaptive hyperlipogenesis: Insulin receptor binding and glucokinase activity in rat liver during fasting and refeeding

In the present study, rats were fasted for 3 days and subsequently refed for 1, 3, or 5 days. Measurements of insulin binding to its receptors on liver plasma membranes were carried out in conjunction with measurements of the activity of an insulin-regulated enzyme from liver cytosol, glucokinase. In response to the 3-day fast (chronic hypoinsulinemia), the insulin receptor number almost tripled, whereas the glucokinase activity was halved. The insulin receptor number slowly fell to control values during the 5 days of refeeding. In contrast, glucokinase activity rose to levels 2.5 times higher than control (5 times higher than the fasting values) after 1 day of refeeding. Although the activity fell off somewhat during refeeding it was still double control values after 5 days refeeding. It was concluded that in the fasted rat there was a dissociation between insulin receptor concentration and the activity of the insulin-regulated enzyme glucokinase. However, the fasting-induced increase in receptor concentration appeared to play a permissive role in the rapid overshoot of glucokinase activity observed in the early stages of refeeding. Such a scheme would explain the metabolic changes occurring in the fasted-refed rat.     

Sucrose-induced changes in VLDL- and LDL-B apoprotein removal rates.

Dietary sucrose has been shown to increase triglyceride transport in very-low-density lipoproteins (VLDL), but it is not known whether the metabolism of the entire particle is affected. Measurements were therefore carried out on VLDL-B apoprotein flux and removal rate before and after the consumption of high sucrose diets (55% of calories). Autologous 125I-labeled VLDL were injected and the specific activity-time curves analyzed by two-pool kinetics. Two kinds of response to sucrose were seen. In two subjects, the pool of VLDL-B apoprotein decreased by 20% and 14% (despite increased fluxes) due to substantial increases in removal rates of 42% and 116%. In four subjects, pool size expanded by 154%, 426%, 50% and 105%, primarily as the result of decreased removal rates (decreases of 55%, 67%, 30%, and 43%). Changes in flux were inconstant, suggesting that accumulation of VLDL particles was related to delayed clearance rather than to increased formation. This may reflect the longer time required to remove the larger load of triglyceride from each particle. The catabolic rate of low-density lipoprotein (LDL) was also measured in five subjects: in four, the clearance of LDL increased with sucrose and was associated with decreases in LDL-B apoprotein and plasma cholesterol.     

Diminished plasma free fatty acid clearance in obese subjects

Obese subjects were compared with lean subjects to define the previously reported disturbance of plasma free fatty acid (FFA) kinetics in terms of altered net transport (lipolysis) or clearance (esterification). These measurements were made during prolonged constant infusions of 1 — ¹⁴C-palmitate toward the end of sustained glucose ingestion and again 6–8 hr after stopping glucose. Net transport of FFA was suppressed to equally low levels in obese and lean subjects, though at the expense of higher insulin concentrations in the obese. Whereas in the lean subjects the clearance of FFA was significantly stimulated with glucose, the obese subjects showed low clearance rates both during and after stopping glucose. When glucose was stopped, net transport rose more rapidly and to a greater extent in some obese than in the lean subjects. The increased influx of FFA led to a rise in the plasma triglyceride level only in the lean subjects. These studies suggest that clearance of plasma FFA, probably denoting esterification in tissues such as muscle and adipose tissue, is impared in obesity and cannot be readily stimulated with glucose and insulin. Lipolysis, measured as net transport of FFA, however, is suppressible with glucose and insulin in the obese, though this might be achieved only at insulin levels that are higher than those in lean subjects.     

Renin and renin substrate in primary adrenal insufficiency: contrasting effects of glucocorticoid and mineralocorticoid deficiency.

Overactivity of the renin-angiotensin system has recently been shown to be important in circulatory homeostasis in adrenocortical failure. However, renin substrate levels decrease in experimentally induced glucocorticoid deficiency, and this can impair both the function of the renin-angiotensin system and its accurate assessment by measurement of renin activity. In order to define the effects of spontaneous steroid deficiency, renin concentration activity and renin substrate were assessed before and after treatment in seven patients with Addison's disease who showed varying degrees of aldosterone and cortisol deficiency.Severe adrenocortical failure, affecting both aldosterone and cortisol, resulted in a gross increase in renin concentration with substrate levels reduced to less than 10 per cent of the mean normal level. Renin excess was poorly reflected by measurement of renin activity when substrate depletion was severe. Substrate deficiency was closely related to the degree of cortisol lack, i.e., renin substrate showed a positive correlation with the level of plasma cortisol before treatment (r = 0.94, p < 0.005). In severe glucocorticoid deficiency, with preservation of normal aldosterone secretion, substrate was very low without renin excess, indicating that severe substrate depletion can occur without increased utilization. With marked renin excess in predominant mineralocorticoid deficiency and in untreated diabetic ketoacidosis, substrate remained normal, indicating that renin excess per se does not lead to substrate depletion.These findings indicate that although mineralocorticoid failure stimulates renin release, adequate glucocorticoid production is crucial in preventing substrate depletion. The homeostatic role of the renin-angiotensin system may be impaired in severe adrenal failure despite an appropriate renin response to mineralocorticoid deficiency. Depletion of substrate may be a factor which contributes to circulatory failure in glucocorticoid deficiency.     

Turnover of apoproteins A-I and A-II of high density lipoprotein and the relationship to other lipoproteins in normal and hyperlipidemic individuals

The kinetics of the major apoproteins of high density lipoproteins (HDL), A-I(apoA-I) and A-II(apoA-II), were studied from the specific activity-time curves of these apoproteins, after reinjection of radioiodine-labeled HDL. In all 20 subjects, HDL apoprotein kinetics conformed to a two-pool model. The total fractional removal rates for the two apoproteins were similar, although the irreversible fractional removal rate appeared to be slightly greater for apoA-I. The mean transport for A-I and A-II was 12.2 mg/kg/day and 5.0 mg/kg/day, respectively. The mass of the apoprotein pools was strongly correlated with apoprotein production rate and also, to a lesser degree and inversely, with the irreversible fractional catabolic rate. Transport was directly correlated with body weight. Higher fractional catabolic rates, including the transfer rates between the two pools, were observed in five hypertriglyceridemic subjects; in contrast, five subjects with familial hypercholesterolemia tended to show lower fractional catabolic rates. These findings were supported by (1) a strongly positive correlation between the transport rates of HDL A-I and of very low density lipoprotein (VLDL) apoB, determined simultaneously in 10 subjects; and (2) a significant inverse correlation between the irreversible fractional removal rate of HDLA-I and the concentration of low density lipoprotein (LDL) apoB, measured in 15 subjects. These observations underline the metabolic interrelationships of the major lipoprotein classes. Two subjects with familial hyperalphalipoproteinemia showed enlarged pool sizes, but normal transport, with irreversible fractional removal rates that were in the lower range for the group of 20 subjects.     

Metabolism of apolipoproteins CII,CIII1, CIII2 and VLDL-B in human subjects consuming high carbohydrate diets

Simultaneous kinetics of apoproteins CII, CIII₁ and CIII₂ and VLDL-B were determined in six normal subjects initially while consuming a control diet and subsequently while consuming a high carbohydrate diet. Mean triglyceride levels in plasma and VLDL were significantly increased, from 110 to 173 mg/dl and 40 to 114 mg/dl respectively, by the high carbohydrate diet. Specific radioactivity of each C peptide was determined, following injection of ¹²⁵I-VLDL, in both VLDL and HDL from plasma samples taken over 48 hr using a technique involving analytical isoelectric focusing. Specific activity vs time curves for VLDL and HDL were almost superimposable on either diet, suggesting that CII, CIII₁ and CIII₂ were catabolized as a group. The high carbohydrate diet resulted in a significant increase in the mass of each C peptide which was brought about by an increase in production since no change in fractional removal rate (FRR) was observed. The pool size of VLDL apo B was also significantly increased and was a function of both increased production as well as decreased FRR. The proportion of CIII₂ mass relative to those of CII and CIII₁ was lower in both VLDL and HDL with the high carbohydrate diet. These observations indicate that the metabolism of the B and C apoproteins are independent of each other and do not respond in the same manner to changes in VLDL triglyceride and that increased triglyceride synthesis and secretion stimulates C apoprotein production.     

Responses of dog large coronary arteries to constrictor and dilator substances: implications for the cause and treatment of variant angina pectoris

Canine circumflex coronary artery ring segments were mounted in organ baths and contracted by ergonovine (ergometrine), serotonin, phenylephrine, norepinephrine (in the presence of propranolol), potassium (K⁺) and a thromboxane A₂ mimetic, U46619. Ergometrine was classified as a serotonin agonist since concentration-response curves were competitively inhibited by methysergide but not by alpha-adrenoceptor antagonists. Arteries precontracted to 80% of maximum were relaxed by verapamil, nifedipine and glyceryl trinitrate. However, nifedipine was 100-fold more potent against K⁺ than either serotonin- or phenylephrine-contracted vessels. Verapamil showed some selectivity for K⁺ and serotonin contractions compared with phenylephrine and was almost ineffective against U46619. Glyceryl trinitrate was without selectivity. Electrical field stimulation (2 and 20 Hz, 10-second) caused a weak contraction or relaxation or biphasic response in the isolated coronary ring. Contraction was amplified by propranolol (up to 1 μM) or metoprolol (50 ng/ml) and inhibited by alpha-adrenoceptor antagonists. In a blood-perfused left anterior descending coronary artery preparation, external diameter was measured by sonomicrometry under conditions of controlled flow and resistance. Intraarterial serotonin, U46619 and ergometrine infusions decreased the diameter by up to 18% without causing spasm (0 lumen diameter). Lowering the perfusion pressure from 90 to 60 mm Hg increased the decrease in diameter during serotonin infusions. Verapamil (50 to 150 ng/ml) and nifedipine (15 to 45 ng/ml) inhibited, to a similar degree, the decrease in coronary artery diameter in response to serotonin infusions. However, verapamil was more effective than nifedipine in depressing the sinoatrial node, abolishing reflex tachycardia and lengthening the atrioventricular conduction time. These studies suggest that verapamil and nifedipine are only selective antagonists of constrictor agents in the dog coronary artery, that both low perfusion pressure and beta-adrenoceptor blockade may amplify constrictor responses, and that nifedipine has fewer cardiotoxic effects than verapamil.     

Heterogeneity of very-low-density lipoprotein metabolism in hyperlipidemic subjects

Very-low-density lipoproteins (VLDL) are triglyceride-rich lipoporteins that have been shown, by physicochemical means, to comprise more than one group of particles. Because of the potential atherogenicity of catabolized VLDL, we used the technique of heparin-affinity chromatography to separate VLDL into two classes of particles, one of which appears to contain partly catabolized VLDL. This observation is based on the higher cholesterol/triglyceride and higher apoprotein E/apoprotein C ratios in VLDL particles that are bound to heparin, resembling in this way intermediate-density lipoproteins (IDL), which are certainly derived in the main through VLDL catabolism. Further studies showed separate metabolic characteristics for the unbound and heparin-bound VLDL particles. Radiolabeled whole VLDL or unbound particles were reinjected into seven hypertriglyceridemic subjects and the kinetics studied in serial samples of plasma over the next 18–48 hours. The specific radioactivity-time curves of apoprotein B in the unbound and bound particles showed that the bound particles were derived wholly or partly from the unbound particles and in turn, were the precursors of IDL. This confirmed that heparin-bound VLDL particles represented VLDL undergoing catabolism, although in one subject about one-half of the bound particles appeared to have an origin other than through VLDL catabolism. These studies show that VLDL metabolism is heterogeneous, that the kinetics of total VLDL must be interpreted accordingly, and that the technique of heparin-affinity chromatography can be used for more detailed studies of VLDL.     

Blunted norepinephrine responsiveness to changing energy states in obese subjects

We have previously reported in lean subjects a significant relationship between plasma norepinephrine metabolism and energy state. The present study has examined in six obese men the response in plasma norepinephrine flux to ten day periods of overeating (+ 1000 kcal/m2 above isocaloric requirements) or undereating (400 kcal/d). Despite significant gains or losses in body weight, norepinephrine flux, measured during constant infusions of 3H-l-norepinephrine, failed to change significantly. Measurements of glucose utilization during constant infusions of insulin, showed significant changes with changing energy state, falling with overeating and rising with undereating. Insulin sensitivity was not correlated with plasma norepinephrine metabolism.     

Initiation,duration and dissipation of diet-induced changes in sympathetic nervous system activity in the rat

Previous studies in this laboratory have demonstrated that 48 hr of fasting suppresses and 72 hr of sucrose feeding (a model of voluntary overfeeding) stimulates sympathetic nervous system activity in rats. The experiments described here were undertaken to establish whether these diet-induced changes in sympathetic activity occur in the early phases of a fast and whether they persist beyond a 3 day period of overfeeding. The results indicate that changes in cardiac norepinephrine turnover can be detected during the first 24 hr of fasting or overfeeding, and that the increase in cardiac norepinephrine turnover induced by sucrose overfeeding is sustained over 8 days of sucrose administration.     

Noradrenaline turnover during under- and over-eating in normal weight subjects

Adjustments to sympathetic nervous system activity may regulate constant body weight despite wide variations in energy intake. To test this six normal weight subjects were studied at three different energy intakes (low, weight maintaining and high). Noradrenaline turnover was measured on the tenth day of each diet. Both noradrenaline appearance rate and noradrenaline clearance increased significantly with increasing energy intake and were more sensitive indices than the plasma noradrenaline concentrations which rose, but not significantly. Fasting triiodothyronine (T₃) rose and reverse T₃ fell with increasing energy intake, while thyroxine (T₄) concentrations did not change. Systolic blood pressure also rose signficantly. Underfeeding resulted in reductions in noradrenaline appearance and clearance rates and in the T₃ level. These results demonstrate that sympathetic nervous system activity, as determined by noradrenaline turnover in plasma, varies in response to short-term changes in energy intake in normal weight subjects. These changes may partly explain why some individuals maintain body weight constant despite large differences in food intake. The present findings may also be relevant to the variability in susceptibility to become obese.