George Decherd

THE CHEMICAL NATURE OF HEART FAILURE

Excerpt Heart failure in its commonest and simplest form represents an inadequacy in contraction of a critical number of individual heart muscle cells. Every clinician has witnessed the death of pa...

Response of Plasma Volume to Diuretics

Previous work 1 has led us to conclude that mercurial diuretics act by diminishing tubular reabsorption, while administration of amino-phyllin produces an increase in the volume of the glomerular filtrate. Earlier work 2 suggested a high circulating blood volume in congestive heart failure, but there was no complete agreement as to the change following diuresis. Recent determinations 3 by a more satisfactory method 4 demonstrate a marked elevation of blood and plasma volume in patients with failure, and a decrease towards normal with the development of circulatory compensation. A similar decrease has been noted after the use of mercurial diuretics. 5 We have followed over 12 to 24 hours the changes in plasma volume, determined by the method of Gibson and Evelyn, 4 after the injection intravenously of one of the 3 types of diuretic drugs, salyrgan, aminophyllin, and digoxin. The urinary output has also been carefully followed, and the plasma volume correlated with the degree of diuresis. Data from typical experiments are recorded in Table I. It is to be emphasized that under the conditions of our experiments the plasma volume is influenced by fluid loss through the kidneys and fluid mobilization from the tissues. These factors exert an opposite effect, and their relative magnitude determines the blood volume. When digoxin is injected in a dose of 2 mg there is first noted a slight increase in the plasma volume. This has never been great, 2nd the time of its appearance seems to depend on the attainment of the desired myocardial effect. As the rate of urinary flow accelerates, this increase disappears and is followed by a reduction, the amount of which is determined by the rate of diuresis.

Creatine and Glycogen Content of Normal and Infarcted Heart Muscle of the Dog

In our studies of the effects of perfusing the rabbit hearts with Ringer-Locke solution to which various amino-acids were added, 1 we were struck by the fact that infarction of the myocardium caused a sharp drop in the pH of the perfusate. This was apparently due to the liberation of a non-volatile acid metabolite giving the qualitative test for lactic acid. The inevitable result of the drop in pH was earlier failure, and, furthermore, low heart muscle creatine values. These findings seemed to be a corollary of our previous observation 2 that myocardial infarction in the dog leads to a creatinuria. We therefore decided to undertake chemical studies of the infarcted as compared with the normal heart muscle of the dog. In addition to the creatine content we thought it worth while to determine the glycogen content, since Riesser and Brentano, we found, had demonstrated a close relationship between creatine mobilization and glycogenolysis. 3 Himwich and Goldfarb have demonstrated a decrease in glycogen content and an increase in lactic acid in infarcted heart muscle coincident with a rise in blood lactic acid. 4 Dogs were anesthetized with barbiturates intraperitoneally and the chest opened under artificial pressure respiration. A nick was made in the pericardium over the first part of the main anterior descending branch of the left coronary artery. The artery was isolated and tied off, and the pericardium and chest closed. The heart was then allowed to continue beating for periods varying from 15 minutes to 12 hours. The infarcted beating heart was removed and sections of infarcted and normal muscle were minced in cold alcohol for glycogen determinations; similar portions were removed for creatine and total solid determinations.

Momentary Atrial Electrical Axes in Paroxysmal Tachycardia.

A recent study 1 of our cases of paroxysmal atrial tachycardia has shown the presence of some grade of A-V block with dropped ventricular beats in a large proportion of the group. The block varied in duration as well as degree, and seemed most likely to appear in patients who had either severe myocardial disease or digitalis over-dosage. This led us to the observation 2 , which has also been reported by Barker and his associates 3 , that this group of patients was prone to develop atrial flutter or fibrillation, or both, in close association with the episodes of paroxysmal tachycardia with block. These facts logically raise the question of a possible resemblance between the fundamental disturbances of atrial mechanism in these 3 types of arrhythmia. Barker et al. 4 have suggested, in fact, that a circus movement is probably present in each instance. Others have made similar proposals, which have been reviewed elsewhere. 2 , 5 Lewis, after preliminary animal experiments, reported studies of 3patients, 6 one who had flutter and 2 who had fibrillation. Using simultaneous chest leads placed in 3 planes, he was able to calculate the direction of movement of the atrial electrical axis for each 1/50 second. His results are compatible with the presence of a circus movement in flutter and fibrillation, though they can scarcely be said to supply conclusive proof. One possible approach to the above problem seemed to be the analysis of similar tracings, taken in patients with paroxysmal atrial tachycardia. It is fortunate that the electrocardiograms of the patients most likely to show flutter or fibrillation, i.e., those with A-V block during the paroxysm, are best suited for this type of analysis; while the block is present, at least half of the P waves will avoid superimposition on the preceding T wave.

SOME STUDIES IN THE MECHANISM OF CARDIAC HYPERTROPHY

Excerpt Hypertrophy of the heart is a reliable sign of heart disease. A definitely enlarged heart is foredoomed to failure. The functional disadvantages of enlargement of the myocardial fibers have...

Creatine Content of Digitalized Normal and Hypertrophied Rabbit Heart Muscle.

As a preliminary to a study of the effect of digitalization on the progress of experimental cardiac hypertrophy, we administered digalen and digifoline subcutaneously 0.1 C.U. semi-weekly to one series of 10 rabbits for 4 weeks and to 6 other rabbits for 14 to 18 weeks. These animals were then sacrificed and the hearts divided. Muscle from each ventricle was analyzed for creatine by Myers modification 1 of the method of Rose, Helmar and Chanutin. These values were reduced to terms of dried weight by drying one sample at 105°C. to constant weight, then determining the percentage of solids. Large rabbits such as were used in these and subsequent studies on hypertrophy, weighed 2200 to 3200 gm. and showed normal creatine values averaging 180 mg. % with solids averaging 22.3%. Of the 10 rabbits digitalized for 4 weeks, 3 showed essentially normal creatine and total solids content, while the other 7 showed increased levels, as indicated in Table I. In the series in which digitalis injections were continued for 14 to 18 weeks the creatine percentages were slightly higher while the solids had dropped slightly. Simultaneous studies of the vastus lateralis in all of these rabbits revealed values normal for this muscle creatine (400 mg. %) and solids (24%). Thus the digitalis effect in so far as evidenced by the creatine changes is specific for heart muscle. The digitalization evidently produced no change in the heart weight-body weight or left to right ventricular ratios. The normal ratios are recorded in a preceding report. 2

Creatine Content of Hypertrophied Rabbits'Heart Muscle.

In connection with studies on the mechanism of cardiac hypertrophy we have analyzed the muscle from 8 hearts of rabbits in which we have experimentally produced cardiac hypertrophy by section of aortic cusps. These animals were sacrificed 14 to 18 weeks after the valve incompetency had been produced. The hearts were divided and the muscle from each ventricle was analyzed for creatine by Myers modification 1 of the method of Rose, Helmer and Chanutin. These values were reduced to terms of dried weight by drying one sample at 105°C. to a constant weight, thus determining the percentage of solids. The average normal creatine and total solids values for large rabbits such as were used in this series were 180 mg. % and 22.3%. Eight rabbits with varying grades of hypertrophy from moderate to great degree showed creatine levels which were high in a few instances but dropped to normal and definitely low levels as the amount of hypertrophy increased. There is a slight drop in total solids, especially of the left ventricle muscle indicating a slight increase probably in intracellular fluid content. In spite of the relatively lowered creatine concentration in the presence of great work hypertrophy the actual creatine content of the individual heart was distinctly elevated. This type of cardiac hypertrophy is comparable to that of hypertension.

Effect of Myocardial Destructive Agents on Creatine Content of the Rabbit's Heart

For a further experimental study of the creatine changes in damaged heart muscle we have employed the method of Fleischer and Loeb 1 for the production of myocarditis. This involves the intravenous administration of caffeine or sparteine, followed in a few minutes by adrenalin intravenously. Caffeine-sodio-benzoate (25 mg./kilo) was injected intravenously in the marginal ear vein of rabbits; after a wait of 3 minutes this was followed by the adrenalin (0.1 mg./kilo), given very slowly, taking 3 or 4 minutes for the injection. Some of the animals died within a few minutes. Of those that survived, 15-20% were found dead the following morning, with fluid in their pleural and pericardial cavities. A few more succumbed in the following days, but most of those alive 24 hours after the injection survived until sacrificed. In a series of 69 rabbits the chemical changes have been followed at time intervals up to 31 days. The creatine content of the heart was determined by Myers modification 2 of the method of Rose, Helmer and Chanutin; these values were reduced to terms of dried weight by drying one sample to a constant weight at 105°C. and calculating the percentage of solids. Normal Values. The total creatine value for the normal rabbit determined on 25 comparable hearts, i. e., from animals 1200-1500 gm., was found to be 165 mg.% with a standard deviation of 14.7. The dried weight averaged 21.7% of the moist weight.

Creatine Content of Human Hearts

Even before the important rôle of phosphocreatine in muscular contraction was recognized, Constabel 1 noted that there was a decreased total creatine content in those human hearts that showed either clinical or post-mortem evidence of damage. Recently Cowan 2 has examined a larger group of hearts, and found that myocardial failure is accompanied by a creatine content that is markedly below normal. Seecof, Linegar and Myers 3 , whose method for determining myocardial creatine we have employed, have also examined a series of human hearts, emphasizing particularly the higher creatine concentration in the left ventricular muscle as compared to the right ventricle. In our laboratory we have approached from several experimental angles the question of the chemical changes that initiate or accompany heart failure. Since our primary interest is clinical, we have also analyzed muscle from the left ventricle of human hearts, as this material became available from time to time. 4 In Table I we have summarized creatine determinations on 105 additional human hearts. The total creatine has been determined, the total solids, and from this calculated the percentage of creatine on a dry basis. The normal values have been determined in hearts from patients that died a traumatic or surgical death, and in hearts from those who died from an infectious disease, yet showed no gross or microscopic evidence of myocardial involvement. We list the mean value, with the standard deviation from the mean. In hypertrophied hearts, which have not failed, the values for total creatine are elevated; in those with myocardial change secondary to coronary sclerosis, the averages are low. The creatine content of hearts that have failed is reduced, averaging 30% below normal. Low values were also obtained in hearts that showed microscopic changes, inflammatory or degenerative, from patients that had died of infectious disease.

Further Rabbit Heart Perfusion Experiments with Amino-Acids

We have previously reported 1 our studies on the creatine content of rabbit heart muscle after perfusion of the coronary system with oxygenated Ringer-Locke solution plus glycocoll in a Dawson-Gunn-Locke apparatus. We found that a further modification of the method was necessary in order to maintain the perfusate at a satisfactory pH level. The cause of the greater part of the fall in pH was found to be the CO2 produced by the hearts metabolism. In order to remove this absorbed and diffusible CO2, an aerating agitating lift for the perfusate was devised with the use of a suction pump instead of oxygen pressure. The perfusate was then reoxygenated in the reservoir in the constant temperature bath just above the heart cannulae. It was found that the creatine content of the heart muscle dropped when the pH of the perfusion fluid was allowed to fall below 7.3–7.5 (Table I). When the estimated pH of the fluid in the myocardial vessels was maintained within these limits, however, failure was postponed for several hours. Eventually there accumulated in the perfusate a non-volatile acid metabolite, lactic acid on the basis of the qualitative test, which caused an agitation-irreversible drop in the pH. In the presence of myocardial infarcts the non-volatile acid metabolites early forced down the pH and lead to a sharp loss in creatine and early failure. We have previously 1 noted that perfusion of the isolated rabbit heart with Ringer-Locke solution, until it stopped in failure after several hours, resulted in a uniform drop in the creatine content of he heart muscle. Furthermore, we found that under similar circumstances the addition of glycocoll failed to prevent this creatine loss. This finding has been confirmed in a larger series of hearts perfused under more constant conditions made possible by the modified method described above.