The influence of atrial systole on ventricular capture by failing artificial pacemakers. II. Experimental observations

The mechanism by which atrial systole influences the efficacy of ventricular capture by a failing pacemaker was investigated in 12 dogs with atrioventricular heart block. Atrial systole caused facilitation of ventricular capture in eight dogs, and inhibition of capture in 10 dogs. Interpolating atrial extrasystoles caused an enhancement or depression of the hemodynamic performance of the atrial systole that affected the efficacy of the pacemaker stimulus. These interpolation experiments showed that atrial systole influenced the efficacy of capture by a mechanical mechanism and not by an electrotonic mechanism. Atrial systole probably caused motion of the endocardial pacing catheter and/or ventricular myocardium. This motion increased or decreased the contact between the pacing electrode and the endocardium with subsequent changes in the efficacy of capture. In three dogs with pacing through epicardial electrodes, atrial systole had no effect on the efficacy of capture.     

A biologic model of parasystole.

The electrotonic interactions of a parasystolic pacemaker with ventricular responses to the normal pacemaker across an area of depressed excitability were simulated in a model consisting of strands of canine Purkinje fibers mounted in a sucrose gap preparation. Experiments were conducted to study the patterns of ectopic activity that result from entrainment of the "ectopic" pacemaker (EP) on one side of the sucrose gap by evoked responses (sn) on the other side of the gap. When one-way conduction ("entrance block") was established, manipulations of the SN frequency and of the impedance between the two outer chambers resulted in periods of silence, concealed or manifest bigeminy, trigeminy and quadrigeminy, and periods of more complex patterns of group beating as the entrainment ratios changed. The results confirm the predictions of the previously described mathematical model that these patterns depend on the magnitude of the electrotonic influence of SN on the EP cycle length and also on the ratio of the intrinsic frequencies. These studies should help to distinguish between reentrant and parasystolic mechanisms in clinical arrhythmias.     

The influence of atrial activity on ventricular capture by failing artificial pacemakers. I. Report of two new cases and review of the literature.

Atrial activity can influence the ability of a failing artificial pacemaker to excite the heart. An appropriately timed atrial beat may cause failure in excitation by pacemaker stimuli which are usually successful in ventricular capture. Conversely, stimuli which usually fail in excitation may be made to succeed by an appropriately timed atrial beat. Two case reports and a review of the literature are presented. Alternative mechanisms for this influence of atrial activity are electrotonic effects (Wedensky facilitation or inhibition) and mechanical effects (motion of the pacing catheter or ventricular myocardium). The authors consider the latter mechanism preferable.     

Accelerated cardiac escape rhythms caused by ouabain intoxication

In anesthetized dogs treated with ouabain, the ventricular escape intervals were measured after (1) vagally induced atrioventricular block, (2) ventricular premature stimulation, or (3) cessation of a period of regular pacing at various cycle lengths. The escape intervals were a direct function of the basic cycle length and were significantly influenced by the last cycle length, whether premature or postmature. Postpacing acceleration of atrial ectopic responses was also demonstrated. When compared with results obtained in isolated Purkinje tissue, ectopic activity associated with early ouabain toxicity appears to be caused by frequency-related transient depolarizations rather than “true” phase 4 depolarization.     

Human plasma triglyceride labeling after high-sucrose feeding. I. Incorporation of sucrose-U-14 C

A ¹⁴C-labeled sucrose load was given to 23 patients (including 18 obese females) after 1 wk on a low-sucrose, high-starch diet, then again after 1 wk of isocaloric high-sucrose, low-starch diet. Peak radio-activities of total plasma triglycerides (TG-¹⁴C) and of triglyceride-fatty acids (TGFA-¹⁴C) occurred between 3 and 6 hr after the acute oral loading during either dietary period. After high-sucrose diet (HSD) the peak activity of TGFA-¹⁴C appeared to occur earlier than after lowsucrose diet (LSD). On HSD the appearance of sucrose-¹⁴C in plasma TG-¹⁴C was significantly greater up to 12 hr after the acute loading, with maximal increments of 50% or more occurring at 3 hr, compared to a mean increase of merely 13%–14% in the fasting concentration of plasma TG after HSD. The increment results mainly from a greater and earlier appearance of ¹⁴C in TGFA, rather than in the glyceride-glycerol. This implies that enhanced hepatic lipogenesis is responsible, not an increased availability of α-glycerolphosphate, nor any gross defect in removal of plasma TG. On HSD the rate of excretion of breath ¹⁴CO₂ was also slightly but significantly greater during the first 2 hr following the acute loading, though not afterwards. There is a positive correlation of individual changes in excretion of ¹⁴CO₂ with changes in plasma TG-¹⁴C and plasma TGFA-¹⁴C. The individual and temporal relationships between changes in the oxidative and the lipogenic processes, as well as the selectivity of the pathways affected, suggest that important factors are an increased rate of intestinal absorption of sucrose and increased pancreatic insulin secretion. Correlation studies further indicate a lesser response to the high-sucrose feeding in hyperglyceridemic patients, but such patients tend to convert more sucrose to plasma TG even on a low-sucrose diet. Thus, measurement of plasma TG-¹⁴C in the sucrose-¹⁴C loading test on LSD may disclose abnormal lipogenic potential.     

Role of electrophysiologic testing in the diagnosis and treatment of patients with known and suspected bradycardias and tachycardias

Electrophysiologic testing has made possible more accurate diagnosis and treatment of recurrent tachycardias and syncopal episodes. The rapid expansion in clinical electrophysiology is reflected both in the number of reports in the literature and in the texts, monographs, and reviews appearing in recent years.^1–8 The challenge for the 1980s will be the continued refinement of present studies and the identification of high-risk patients for the development of bradycardias or tachycardias who warrant prophylactic treatment.Over the last decade, a battery of tests has been developed to assess the electrophysiologic function of cardiac tissues. The details of these tests vary among investigators. Occasionally, differences in investigator's assumptions, experience, or definitions may result in marked differences in viewpoints or conclusions, much to the consternation of the unwary reader. This article will review some fo the electrophysiologic tests and procedures currently in use, their applications, and reliability.     

Unilateral nodular diabetic glomerulosclerosis (Kimmelstiel-Wilson): report of a case

A unique case of unilateral nodular diabetic glomerulosclerosis is described. It occurred in a patient with arteriosclerotic occlusion of the main renal artery and ischemic atrophy of the uninvolved kidney. The purpose of reporting this case is to draw attention to some factors that seem to be important in the pathogenesis of diabetic glomerulosclerosis.     

Changes in body chemical composition with age measured by total-body neutron activation.

Total-body levels of calcium and phosphorus (reflecting skeletal mass) and total-body levels of potassium (reflecting muscle mass) were measured by neutron activation analysis in 39 men and 40 women ages 30-90 yr. In order to intercompare the total body calcium (TBCa) values in a heterogeneous population, such as this, it was necessary to normalize the data for skeletal size. The normalization consisted of dividing the absolute calcium level by the predicted calcium level for each individual matched to a set of critical parameters. The parameter used in the computation of normal values were age, sex, muscle mass, i.e., total body potassium (TBK) and height. For the calcium data of the women, it was necessary to add an age correction factor after the age of 55 yr. The calcium ratio(mean ratio of the predicted to measured TBCa) in men was 1.000 +/- 7.8% and in women 0.996 +/- 7.1%. The TBCa of normal males and females can thus be predicted to +/- 13% (at the 90% confidence level). An exception to this was found in males (70-90 yr) who exhibited a mean calcium ratio greater than 1.13. The derivative of TBCa with time was determined for this population of men and women by taking into account the dependency of calcium on three time dependent variables, height, TBK, and an explicit age correction factor in the case of the women. The mean rate of loss of TBCa in women was 0.37% and 1.1% per year before and after menopause (50 yr). In the males, the average rate of loss of TBCa was 0.7% per year after 50 yr of age. The pattern of total body phosphorus (TBP) loss with age paralleled that of TBCa as the ratio of TBP/TBCa was rather constant with age. The constancy of the ratio suggests that the mineral composition of bone does not change significantly with age. The rate of loss of TBK with age was also related directly to that of TBCa. The mean ratio of TBK/TBCa was 9.9 in females and 8.0 in males and this ratio remained relatively constant from 30-70 yr. Thus, the mechanism responsible for the loss of bone with age, whether nutritional deficiency or decreased gonadal function and physical activity may also be responsible for the loss of muscle mass with age.     

Comparative skeletal mass and radial bone mineral content in black and white women

The age-related changes in both skeletal mass and muscle mass were directly measured in normal black women ages 30–80 yr. The levels of total-body calcium (TBCa) were determined with the use of in vivo neutron activation. The muscle mass was measured by whole-body counting of ⁴⁰K. In the same population, the bone mineral content of the radius was measured using a photon absorptiometric technique. Although there was no significant difference in stature, black women had a greater skeletal mass and bone mineral content of the radius than age-matched white female subjects. When the TBCa values were normalized for body size (i.e., corrected for height and lean body mass), the TBCa was still higher for the black women but not as high as the absolute TBCa values. Clearly, it is the larger muscle mass (as reflected by the ⁴⁰K measure) in relation to weight and height that accounts for this difference. The lower prevalence of fracture and osteoporosis observed in black women relative to white women is due in part to this greater quantity of skeleton. American black women with a higher bone density (i.e., skeletal mass) maintain mechanical integrity of the skeleton longer than individuals with a lower bone density. It is suggested that the larger muscle mass in black women is, in part, a determinant of their increased skeletal mass and is partly responsible for their apparent resistance to osteoporosis and fracture of the skeleton.     

Captopril (SQ 14,225) (d-3-mercapto-2-methylpropanoyl-l-proline): A novel orally active inhibitor of angiotensin-converting enzyme and antihypertensive agent

Relatively potent and specific in vitro and in vivo (oral or intravenous) inhibition of angiotensin-converting enzyme by a nonpeptidic compound, captopril (SQ 14,225; d-3-mercapto-2-methylpropanoyl-l-poline), was demonstrated in excised guinea pig ileum and in rats, rabbits, cats, dogs, and monkeys. The design of captopril was based on a hypothetical model of the active site of the enzyme. Captopril, in vitro or in vivo, was about ten times as potent as teprotide. Inhibition of angiotensin-converting enzyme was evaluated in vitro and in vivo by inhibition of the contractile or vasopressor activity of angiotensin I or by augmentation of the contractile or vasodepressor activity of bradykinin. Acute of subacute dosage with captopril moderately to markedly lowered the blood pressure of the renin-dependent aorticligated and the conscious two-kidney Goldblatt hypertensive rat; in the latter, the effect was intensified by concomitant dosage with a thiazide diuretic. Furthermore, the life-prolonging effects of captopril in renal hypertensive rats were augmented by a thiazide diuretic. In the two-kidney Goldblatt rat, acute captopril (p.o.) was about ten times as potent as teprotide (s.c.) in lowering blood pressure. Acute or subacute oral doses of captopril moderately reduced the blood pressure of the spontaneously hypertensive Wistar-Kyoto rat; chronic dosage almost normalized blood pressure. Captopril produced little or no hypotension in the saltreplete normotensive Wistar-Kyoto rat. Bilateral nephrectomy virtually abolished the hypotensive activity of captopril in the spontaneous hypertensive rat. The results suggest that captopril acts in large part by inhibiting the renin-angiotensin-aldosterone system to reduce elevated blood pressure, especially in renindependent models of hypertension; the roles of the kallikrein-kinin-prostaglandin systems and sodium balance remain to be elucidated. Captopril also lowers blood pressure in apparently non-renin-dependent types of hypertension by mechanisms that are as yet undefined.     

Renal glycosuria in normoglycemic glysoduric pregnancy: a quantitative study

The prevalence and quantitation of renal glycosuria was determined in a total of 309 normoglycemic patients in the second and third trimesters of pregnancy. A 2-hr glucose tolerance test, using 1.75 g of glucose per kg of ideal body weight as the test load, was performed in each patient. A two-drop quantitative Clinitest method for urinary glucose showed that 26.9% of 104 patients in the second trimester and 42.8% of 205 patients in the third trimester were glycosuric during the course of the glucose tolerance test. The maximum frequency of glycosuria appeared at the 1-hr period in both groups. The increased prevalence of glycosuria observed in the third trimester is consistent with known alterations in renal hemodynamics occurring at that time. A wide variance in the quantitative excretion of glucose can occur with blood sugars between $\text{69}\text{mg}\text{100}\text{ml}$ and $\text{175 mg}\text{100}\text{ml}$. Although not calculated, the data indicates that the renal threshold for glucose can be lower than previously considered. There is nothing to suggest that normoglycemic glycosuria in pregnancy is hazardous.     

Diabetic neuropathy: Clinical aspects

The importance of diabetic neuropathy derives from its remarkable frequency and its clinical impact. In view of the varying underlying pathogenetic mechanisms and the resulting diversity of clinical representations, it becomes apparent that there are diabetic neuropathies, rather than a single entity of diabetic neuropathy. The scope of involvement is widespread with virtually every system at risk. Although peripheral neuropathy is by far the most common expression, visceral neuropathy is also highly significant. It may affect every part of the gastrointestinal tract, the genitourinary tract, and sexual function, as well as direct autonomic nerve pathology. Clearly, neuropathy in diabetes offers a specific and important diagnostic challenge to the clinician and plays a definitive role in differential diagnosis. The problem is heightened by the fact that any and all of the diabetic neuropathic syndromes may be the initial clinical manifestation of diabetes in the absence of covert manifestations of carbohydrate metabolic disorder. It is to be stressed that the diagnosis is more than an academic exercise, since each diabetic neuropathic syndrome carries with it some beneficial therapeutic modality to aid the patient.     

Skeletal turnover and total body elemental composition during extended calcitonin treatment of Paget's disease

Twenty patients with generalized symptomatic Paget's disease had serial measurements of radiocalcium turnover and/or total body elemental composition by in vivo neutron activation analysis during long-term calcitonin therapy. Despite maintained clinical improvement, seven of 15 patients showed partial or total loss of the initial decelerating effect of calcitonin on skeletal turnover, whereas the remaining eight patients maintained the calcitonin-induced deceleration. The changes in skeletal turnover were roughly proportional to the induced changes in serum alkaline phosphatase and urinary hydroxyproline. However, disparities in the magnitude of the changes among the three parameters were not uncommon. Total body calcium was increased by a mean of 22% above predicted prior to calcitonin and decreased significantly by 4% during long-term calcitonin treatment. Total body phosphorus, nitrogen, and sodium also decreased. The phosphorus and sodium losses appeared to be mostly from the skeleton. These data confirm histologic evidence of the disappearance of pagetic bone, resumption of normal lamellar bone formation, and radiographic evidence of a decrease in bone volume during calcitonin treatment and indicate the relative magnitude of this effect. The action of calcitonin in this regard possibly represents a specific effect on Paget's disease beyond its general skeletal effect to reduce cellular activity.     

Effect of physical training on esterification of glycerol-3-phosphate by homogenates of liver,skeletal muscle,heart, and adipose tissue of rats

The effect of a physical training program on glyceride synthesis by homogenates of rat adipose tissue, muscle, heart, and liver was studied. One group of rats was trained by a 12-wk program of treadmill running, while another group served as sedentary controls. Training increased glycerol-3-phosphate esterification in adipose tissue (59%), skeletal muscle (27%), and heart (16%) but had no effect in liver. The results of this study indicate that training increased a synthetic pathway of lipid metabolism in muscle, providing further evidence that endogenous glycerides may provide a source of fatty acids during exercise. The effect of training on glyceride synthesis in adipose tissue indicates that an enhanced ability to esterify fatty acids in times of inactivity may be a biochemical adaptation enabling a trained animal to replenish an energy reserve that can be called upon in time of need.     

Effects of aminoglutethimide, metyrapone, and ascorbic acid on testicular metabolism of cholesterol

The effects of aminoglutethimide (AG), metyrapone (MET), and ascorbic acid (AA) on the conversion of labeled cholesterol to testosterone (T) by the mature rat testis were examined and compared under identical in vitro conditions. In cell-free testicular homogenates, formation of labeled T from cholesterol-4-¹⁴C was depressed in a dose-related manner by AG and MET in concentrations ranging from 0.03 to 1.0 mM; AG was the more potent inhibitor at each concentration tested. Within this range of concentrations, AA induced a slight stimulation of the conversion of cholesterol-4-¹⁴C to T, with inhibition demonstrable only above 5.0 mM. Halfmaximal inhibition of T formation was attained with 0.1, 0.3, and 6.4 mM concentrations of AG, MET, and AA, respectively. When the synthesis of T was almost completely prevented by any of these agents, no accumulation of known intermediates between cholesterol and T could be demonstrated. Under these conditions, MET had no effect on the conversion of pregnenolone-4-¹⁴C to T or several T precursors or on the rate of metabolic degradation of testosterone-4-¹⁴C. Since the generation of the six-carbon fragment resulting from side chain cleavage of cholesterol-26-¹⁴C by rat testicular mitochondrial suspensions was also inhibited by AG, MET, and AA, the depression of steroid production affected by these agents in the testis appears to be related to their capacity to block the reaction cholesterol pregnenolone, as previously demonstrated in the adrenal and ovary. AG, MET, and AA thus inhibit cholesterol cleavage in adrenal and gonadal tissues as well as 11β-hydroxylation in the adrenal. In view of the similarities between the enzyme systems affected, it is likely that AG, MET, and AA exert their inhibitory effects on steroid-forming tissues through similar mechanisms.     

Evaluation of ethanol hypoglycemia in man: turnover studies with C-6 14C glucose

Glucose turnover (supply and utilization) was studied prior to and following the administration of alcohol to obese human subjects and human subjects of normal weight fasted for 3 days. Hypoglycemia was observed in all subjects. The rate of decrease in glucose concentration was significantly greater in subjects of normal weight than in obese subjects. It has been demonstrated that this difference is due to an average increase in the rate of glucose utilization in subjects of normal weight versus an average decline in the rate of glucose utilization in obese subjects during the production of hypoglycemia. The alterations observed in glucose supply and utilization were complex. Immediately following the initiation of the ethanol infusion, the rate of glucose utilization rose sharply in every individual. During this same period (0–35 min following alcohol) the rate of glucose supply rose in all but one individual in each group. In the subsequent portion of the period of production of hypoglycemia, glucose supply (presumably gluconeogenesis) was inhibited in every case. During this period, the rate of glucose utilization was observed to be greater than prealcohol rates in the individuals of normal weight, while in the obese individuals a decline was observed in the rate of glucose utilization compared to that observed prior to alcohol. In the final hours of these studies, a second steady state (constant low blood glucose concentration) was observed. The kinetics of glucose supply and utilization in the transition from progressive hypoglycemia to this terminal phase were again complex. All, but one individual, were found to have increased their rates of glucose supply over the inhibited rates observed during the production of hypoglycemia. At the same time, the rate of peripheral glucose utilization fell in every individual, ranging from a barely perceptible fall in the obese group to an average decrease of 40% in the individuals whose weight was normal. These studies indicate that there are factors other than inhibition of gluconeogenesis that contribute to the degree of hypoglycemia after alcohol in man fasted 72 hr.     

Advanced ventricular arrhythmias during bedside pulmonary artery catheterization

To determine the incidence of advanced arrhythmias and acute right bundle branch block during beside pulmonary artery catheterization, 119 critically ill patients undergoing 150 pulmonary artery catheterizations were prospectively studied using continuous electrocardiographic monitoring with permanent recordings. Ventricular arrhythmias other than isolated premature ventricular contractions, couplets or bigeminy occurred during 80 of the 150 catheterizations (53 percent). These included ventricular salvos (three to five consecutive premature ventricular contractions) in 30 percent, non-sustained ventricular tachycardia (five to 30 premature ventricular contractions) in 20 percent and sustained ventricular tachycardia (more than 30 consective premature ventricular contractions) in 3 percent. In two patients, ventricular fibrillation developed; in another three patients, lidocaine or a precordial thump was required to terminate the episodes of ventricular tachycardia. The incidence of advanced ventricular arrhythmias was statistically correlated with either the presence of predisposing risk factors for ventricular ectopy (p < 0.05) or prolonged catheterization time (p < 0.01). A new right bundle branch block developed in seven patients (5 percent) and persisted for a mean of 9.5 hours.