Instituto de Combate ao Enfarte do Miocárdio
Cardiotonics in Acute Myocardial Infarction
and Chronic Coronaropathy
No part of this book may be reproduced / or transmitted copies by any means,
without the prior permission from Infarct Combat Project.
Note: It should be mentioned that all the information and reasoning contained in this chapter of Dr. Mesquita's book, published 36 years ago, still absolutely valid and undisputed by the current medical thinking
The role of the cardiotonic in acute myocardial infarction should be focused, in first place, from the experimental point of view (54-56). This is due to the widespread fear existing about the cardiotonic use, which came from the concept that when it is administered in acutely ischemic myocardium, would be responsible for the increase in contractility and in oxygen consumption that could develop, as an immediate consequence, the increase of infarction size.
Other aspects that seem to preclude the cardiotonic use are the preconceptions of acting as arrhythmogenic and lead to cardiac rupture.
In addition, prevailed in animal experiments subjective criteria regarding the meaning of the epicardial ECG mapping over the RS-T segment's behavior used in order to predict the severity of myocardial ischemia and resulting damage through the degree of depression of the referred segment and its emphasis on digitalized patients without heart failure. However, recent studies (57-59) on the behavior of the contractile state of the ventricular wall – central ischemic zone, intermediate ischemic zone and non- ischemic areas – in acute ischemic process developed by the usual technique of coronary ligature thereafter submitted to the action of the cardiotonic – digitalis or strophanthin – questions the validity of previous experimental studies, mainly those that highlight the diagnostic and prognostic importance of epicardial electrocardiographic mapping.
It was found that the cardiotonic increased the contractility of the intermediate zone – infarct border – indicating that the ischemic myocardium retains the ability to respond to positive inotropic stimulation of cardiac glycosides. Also it was observed an increase in coronary flow and improvement of the ventricular function and particularly the decrease in the elevation of RS-T segment with the use of strophanthin-G (60). This new experimental technique (57-59) more straightforward in the assessment of the ischemic ventricular wall response, seems to us more objective and should express more faithfully the pharmacological response, mainly indicating the need for a reassessment of old concepts which must be proved or definitely abandoned.
Secondly, the use of cardiotonic drugs in the human model of myocardial infarction (4, 61 - 72) constitutes a clinical experience that always come with the safeguard of a drug administration that lacks experimental support. Nevertheless it always presented recording results that have surprised those who have assessed the cardiotonic effects on acute myocardial infarction without heart failure. With its use purely speculative since all authors did not engage in any contestation circumstance regarding the pathophysiological mechanism of acute myocardial infarction, accepting the concept of coronary thrombosis as the cause of infarction. Even so, these studies provided important inputs to the study we're doing.
On the other hand, devoid of any intrinsic value, we came across new and old references, that do not offer own contribution and just make the chorus to old bias of great fear to increase the risk of causing serious arrhythmias, cardiac rupture and to increase the size of the infarction, thickening the number of those who conveniently only recommend the cardiotonic in heart failure and atrial tachyarrhythmias.
From the literature review carried out by us (4, 61-72), we didn’t found references to the worsening of the human infarction treated by cardiotonics. So, all resistance observed even now can be viewed as the result of outdated or ingrained loyalty to the archaic prejudices developed by experimentation in animals and its clinical implications extrapolated to humans. Therefore, we think be wise to do a detailed presentation about the historical evolution of the cardiotonic use in the myocardial infarction, since the pioneering paper from Herrick (4) to this day.
Previously, we must justify the cardiotonic’s use as a natural consequence of our pathophysiological concept, with special emphasis we declare ourselves convinced that the human model of acute myocardial infarction does not match the experimental model, in which necrosis is an immediate consequence of coronary arterial blockage. In Myogenic Theory the regional myocardial failure - precursor of primary myocardial necrosis - demands the use of cardiotonic.
Herrick was the first to use the cardiotonic – strophanthin or digitalis – in acute myocardial infarction and referred to his clinical experience with great enthusiasm. Apparently, this indication seemed to be due to the great value of the cardiotonic for angina pectoris, especially in patient cases of arterial hypotension. He believed that the timely use of cardiotonic in such cases would be providential and referring quick results with the administration through hypodermic or intravenous route.
While Herrick did apology to the cardiotonic use in acute myocardial infarction he advocated the infarct as due to coronary thrombosis. This mechanism besides logical and pathophysiologically representing cause and effect passed to be replicated experimentally, with rapid consolidation. However, the experimental procedure reinforcing the pathophysiological mechanism of Herrick gave rise to the controversy about the true role of the cardiotonic in the human model of acute myocardial infarction. Since it was gaining consistency the suggestion that the cardiotonic, by increasing myocardial contractility, would lead to higher consumption of oxygen and therefore would appear as harmful, because the region affected by ischemia, without other sources of blood supply and obviously lacking oxygen, would tend to increase in size, besides its direct arrhythmogenic effect on ischemic myocardium.
Chronologically we record the paper from Hamman (61) on the use of the cardiotonic in myocardial infarction, participating in the concepts of Herrick, advocating the rest as a valuable therapeutic measure, besides the use of morphine and immediate digitalization, according to Eggleston’s method, which would prepare the heart to face arrhythmias and efforts support.
Such conduct, in the spirit of the cardiologic orthodoxy, would represent an unnecessary risk, due to the lack of experimental support. This, in our view, lacked pathophysiological concept to lend more strength to the results.
However, long after those pioneers, the clinical experience of Edens (62) with intravenously strophanthin administered before, during and after acute myocardial infarction, was only interrupted by his death in 1944, but the results were valid and consistent with those that follows.
Schemm (63), escaping from the rules of theoretical conjectures, advocated the convenience of free use of digitalis, in the presence of acute myocardial infarction, as suggested by the fact that almost 2/3 of patients who survive from the infarction develop congestive heart failure during the time of hospitalization or soon after discharge. Moreover, according to the clinical history of the considerable number of these patients already have heart failure in the beginning of infarction. In the absence of congestive heart failure signals Schemm do not hesitated to use digitalis when the pulse was rapid and weak or irregular pulse and in case of persisting dyspnea, not relieved by oxygen or morphine. He administered digitalis slowly or quickly, oral or intravenously if necessary, as it would be in the common heart failure without complications. The action of the drug on the non-necrotic portion of the myocardium seemed to lead to a clear improvement and could in advance not only prevent heart failure, but also the development of arrhythmias.
Schemm used digitalis in 265 patients with myocardial infarction and recorded mortality of 10%; in a control group of 286 patients, without digitalis use, he found the mortality was 16%. In practice, Schemm observed that instead of myocardial damage, the cardiotonic was compatible with the acute infarction, reason of benefic effects and lower mortality.
Askey (64), refers to his own clinical experience with the use of digitalis that started in the first week after the heart attack, administering digitoxin 0.2 mg, three times daily for 2 days and then 0,2 mg, once daily, for the remainder of the hospital stay. In our view, this interval of one week to start the digitalis treatment could give opportunity for the happening of secondary coronary thrombosis and therefore, its use in this manner would not appear very advisable in our view, because it could be facing the usual conditions developed in experimentation trials. However, we shouldn’t forget that the acute myocardial processes, left on their own fate, did not record mandatorily the secondary coronary thrombosis.
The objective from Askey was to evaluate the effects of digitalis on the total number of deaths, sudden deaths and frequency of arrhythmias.Askey noticed that the incidence of extrasystoles in cases treated with digitalis was lower than in the control group. In 50 patients with acute infarction, digitalis in effective doses did not have developed any dangerous ventricular rhythms and the incidence of death was not different in the 2 groups. Askey added that the exact time for the use of digitalis needs to be found, questioning derivative results of animal experiments with normal coronaries and hearts. As well if the results obtained could be extrapolated to humans without further critical considerations. He also thought doubtfully that animal experiments can respond appropriately to the raised questions and solve the problems that clinicians usually face. He thought, ultimately, that meaningful data should be logically obtained by observing the effect of digitalis on the men who has spontaneously suffered myocardial infarction.
Askey admitted to be justified the use more liberal of digitalis in acute infarction, until more comprehensive studies were realized. He told that instead of staying digitalis with a restricted indication to the treatment of congestive heart failure it would be better use it looking to avoid heart failure. Citing the paper from Schemm he unburden, saying his belief that the medical profession has been unable to provide the benefits of this valuable drug and providing Thoreau’s thought: "It is never too late to give up our prejudices. No way of thinking, however ancient, can be trusted without proof." Askey said this after presenting his results and to assess the clinical and experimental studies of the time, demonstrating healthy concern in front of the accommodation and lack of interest for so palpitating subject, which still persists until today.
Boyer (65) cites an accidental experience with the use of intravenous Lanatoside-C (digitalis lanata) with starting dose of 1.2 mg and then with 0.4 mg every 4 hours, amounting within few hours in the dosage of 3,6 mg followed by the patient recovery of extensive acute myocardial. The patient had poor physical conditions (sinus tachycardia, progressive drop in blood pressure, paleness and sweating). Boyer points out that after this unexpected and providential experience ceased his fears about the digitalis use and since then he has used freely without any adverse effects attributable to the drug. In a series of 50 consecutive patients with myocardial infarction and under digitalis treatment, the mortality was 16%. It was a heterogeneous group and included patients with cardiogenic shock, congestive heart failure, atrial fibrillation, as well as others with less evidence of heart failure. The group presented by Boyer is entirely similar to ours, also treated with Lanatoside-C and equal in the incidence of death.
Malmcrona et al (66) studied from the hemodynamic point of view the effects of digitalis in 10 patients with acute myocardial infarction, transmural, during sinus rhythm and without heart failure or cardiogenic shock. The study was conducted within the first 4 days of onset. They have administered Lanatoside-C of 0.80 mg in a single dose, and concluded that a moderate digitalis dose given intravenously to patients with acute infarction may be more beneficial than dangerous, even in the absence of heart failure.
Constant (67), in a review of the literature reveals that no clinical studies have demonstrated increased incidence of mortality or arrhythmias caused by digitalis, when used in acute infarction.
Pizzarello et al (68) in speculative basis, sought to assess the effects of administration of Digoxin 0.50 mg, intravenously, on the extent of acute infarction, and subsequent mortality, among 18 patients in the acute infarction period and during 4 months observation. The infarct size was predicted by the CPK changes within the first 7 hours of the infarcting process and taking pulmonary arterial pressure (average of 20 mm Hg. variation of 16 - 26 mm Hg). Completed the infarction its size was calculated through all changes of CPK (90-160 hours). In 28 control patients with acute infarction, there was a close correlation between the predicted infarct size and the calculated infarction. In the 18 patients receiving digoxin, the calculated infarct size was significantly smaller than the size of the expected infarct. They found these data suggested that the digoxin in some patients with acute infarction, with great size predicted and high pulmonary pressure is responsible for the salvage of ischemic myocardial fibers. According to the current prognostic significance of enzymatic repercussion in acute infarction, this study was the first to think about the enzymatic behavior and about the possible influence of digitalis on infarct size, recorded by us as highly significant.
Morrison et al. (69) in new clinical research with the previous goal (68), making the enzymatic evaluation grounded in overall planning of CPK and also CPK-MB. The effect of administration of intravenously digoxin 0.50 mg on the extent of acute myocardial infarction was studied in 8 patients after infarct size was predicted by the early changes in CPK and CPK-MB, and the determination of the pulmonary artery pressure (average 23 mm Hg, 21-28 mm Hg variation). Completed the infarction its size was calculated by the findings of CPK and CPK-MB. In 21 control patients with acute infarction, there was a close correlation between the predicted infarct size and the calculated one with the record of an average difference of - 3%. In the treated group, of 8 patients, the size of the calculated infarction was significantly lower than the predicted infarction, registering an average difference of 16%. These data suggest that intravenously digoxin use in patients with large infarction predicted and high pulmonary artery pressure (greater than 20 mm Hg) produces the apparent salvage of the ischemic myocardium fibers.
Reicansky et al. (70), using intravenous digoxin in patients with acute myocardial infarction, complicated by incipient left ventricular failure, not registered ventricular tachyarrhythmias, thus demonstrating the absence of increased myocardial sensitivity in front of the therapeutic dosage of digoxin. Their results showed that digoxin did not increase the occurrence of any type of ventricular tachyarrhythmia. Therefore, the sensitivity of digoxin in experimental infarction was not confirmed by these authors.
In the last published paper on the effects of strophanthin in acute myocardial infarction and especially as to the behavior of enzymatic reactions, Varonkov et al. (71) reported increased enzyme release, coinciding with the administration of cardiotonic drugs in cases of acute myocardial infarction, 14 hours following the initiation of the painful crisis and also with the repetition of the half dose of strophanthin 4 hours after. This observation appreciated within our view and based on our experience with similar clinical cases followed routinely for 6 days with daily use of intravenously strophanthin, rather than to establish itself as a contradictory fact, seems in fact to represent a common and expected response, after the administration of the cardiotonic during a period relatively long of gradual and slow release of myocardial enzymes and accumulation at myocardial level, blood vessels and lymphatics, which exerting increased myocardial contractility would act precipitating the release of enzymes deposited at the myocardium, in this manner squeezed and activated.
We interpret this release as a mechanical phenomenon, like squeezing a sponge, regardless of myocardial injury by direct cardiotonic action.Thist because the continuation of the cardiotonic use has revealed enzyme levels that inscribe a curve with increasing and decreasing peaks, whose climax is recorded in the first 48 hours, returning to normal despite continuous administration of the cardiotonic. Incidentally, this phenomenon of increased enzyme release, during acute myocardial infarction, has been observed in experimental myocardial reperfusion (119) and would result from the myocardial washing and motion of accumulated enzymes. We believe that the clinical experiment conducted by those authors was started late and ended early, probably motivating the assessment of incomplete and inconclusive phenomenology.
Loeb et al. (72) using intravenously ouabain, for acute myocardial infarction observed that the reduction in the left ventricular diastolic pressure is related to the improvement of contractility.
Recently, we have appreciated the publication of clinical studies investigating the behavior of ischemic ventricular wall, chronic, in cases with coronaropathy without heart failure, studied through echocardiographic, hemodynamic and scintigraphic records in patients taking cardiotonics.
Chronologically, we must record as the first in this line of research the paper from O'Rourke et al. (73) on the favorable effects of orally administered digoxin, related to the size of the left ventricle and ventricular wall motion in patients with previous myocardial infarction, demonstrating that the cardiotonic decreases the cardiomegaly, increases the course and the maximum shortening velocity of the myocardial fiber in normal ventricular segments and often reduces the extent of abnormal wall motion, at rest and during exercise. Therefore, the oral maintenance of digoxin (O, 5O mg / daily) may be beneficial in patients who have persistent increase in left ventricular wall or large motion abnormalities or both, after infarction, particularly when these wall motion disorders are associated with decreased left ventricular reserve and decreased tolerance in face of efforts. They acknowledge the importance of further studies to evaluate the effects of the therapy maintenance by digitalis on morbidity and mortality in such patients.
They reviewed the great current controversy regarding the use of digitalis in patients with myocardial infarction and refer that any benefit in the use of agents that increase the contractility and myocardial oxygen demand in the presence of acute myocardial necrosis, remains to be demonstrated. However, there is general agreement that digitalis maintenance therapy is indicated in patients with recent myocardial infarction, with symptoms and signs of congestive heart failure. They make special reference to the experimental papers on myocardial infarction, that demonstrate the improvement of regional myocardial function by digitalis use on the normal myocardium and intermediate zone, and the marked increase in contractility in these regions (57-59).
Amsterdam et al. (74) trying to evaluate the effect of strophanthin on regional function of the ischemic myocardium observed improvement of segmental ventricular wall and mechanical function of the entire left ventricle in patients with chronic stable coronary disease. The segmental movement was improved in both normal myocardial segments as well in asynergic segments.
Ferlinz et al. (75), attempting to identify the effects of rapid strophanthin use on left ventricular function and ventricular asynergy of patients with chronic coronary artery disease concluded that the strophanthin not only improves ventricular function in normal and in coronaropathy cases, but also dramatically reduces the extent of asynergy of the left ventricle. This paper represents the first effort of combined research of coronary angiography and hemodynamic in order to determine the response of the asynergic myocardium of man submitted to the cardiotonic use and verified the agreement with the results of noninvasive experimental studies, indicating improved left ventricular asynergy under digitalis or strophanthin.
Vogel et al. (76) observed improvement in ventricular function as immediate effect of intravenous strophanthin, and during the long term with oral digoxin use, in patients with chronic coronary artery disease during rest and exercise, undergoing hemodynamic studies.
Vogel et al. (77), studying the myocardial perfusion with thallium-201 in patients with chronic coronary artery disease and ventricular dysfunction, treated with digitalis, observed improvement in myocardial perfusion and left ventricular hemodynamic at rest and after exercise.
Koetter et al. (78), in a more recent publication, mentioned the existence of impairment in left ventricular function in patients with chronic coronary artery disease but without evidence of heart failure. They recorded a significant decline in diastolic pressure and residual volume of the left ventricle under the action of digitalis glycosides. The decrease in ventricular volume and left ventricular parietal tension could prevent or at least reduce the increased oxygen demand caused by the improvement in contractility.
They didn’t observe any changes in myocardial oxygen consumption before and after digoxin, either at rest or during atrial rhythm stimulation. Likewise, the myocardial lactate extraction showed no changes. They also do not have recorded abnormal metabolism of lactate, as anaerobic index and result of digitalization.
They found reasonable to use digitalis in patients with coronaropathy, with no evidence of congestive heart failure, but showing limited tolerance to efforts, probably caused by decreased contractile reserve.
They stressed that despite the beneficial effects on left ventricular function, the digitalization definitely do not alter the degree of tolerance to efforts, in which angina occurs. So, they do not admitted digoxin as anti-anginal agent and stood as close goal of digitalis therapy the left ventricular failure, as frequent consequence of chronic coronaropathy.
DeMots et al. (79) observed that treatment by intravenous ouabain increased ejection fraction, improved the left ventricular function and contractility and reduced diastolic residual volume of the left ventricle, even when initially normal, in patients with chronic coronary artery disease without changing the oxygen consumption by compensatory mechanisms.
Kleiman et al. (80), underwent patients with stable chronic coronary artery disease, with no evidence of heart failure, to a careful hemodynamic study during the control period, after rapid digitalization with intravenous digoxin, and also, for a few weeks on oral digoxin. The patients showed persistent improvement in contractility and of left ventricular function as response to both conditions under the cardiotonic.
At the beginning of our clinical experience with the use of the cardiotonic in acute myocardial infarction, contrary to orthodox cardiology that is based on experimental concepts, we heard again the very old refrain that the cardiotonic by increasing myocardial contractility would lead to the increase in oxygen consumption in ischemic area and, consequently, would be harmful, by increasing the infarct size and trigger serious arrhythmias, and increase the risk of myocardial rupture in the infarct area.
We have faced this apparent contraindication discouraging about the cardiotonic use in acute myocardial infarction, motivated by our new pathophysiological concept based on myogenic phenomenology that would lack the essential use of cardiotonic as evidence. Right from the beginning, we got the strengthening of our concepts through the easy resolution of intermediate syndrome, under this new therapeutic approach.
Strengthened our spirit the pathological contributions (16, 29-53) that were being added to coronary angiographic findings of acute myocardial infarction (12-15) and the few clinical trials in human infarction using the cardiotonic in AMI (4, 61-72).
The experimentally recordings obtained by Puri (57), Kerber et al. (58) and Banka et al. (59), marked the beginning of a new era, when was shown that the cardiotonic retrieves the contractility of ischemic and hypocontractile area and keep its well for a long time, contrary to old concepts of myocardial injury and possible increase of the necrotic area.
It is likely that these contributions have something to do with the latest researches on cardiotonic in men with acute infarction (68, 69, 70) and also with the most recent papers on the effect of cardiotonic in chronic ischemic myocardium, cardiomegaly and ventricular dyssynergy (73- 80).
The results obtained with the cardiotonic in human model of myocardial infarction have been peaceful and with real benefits over morbidity and mortality, as compared to control groups (61 -72).
All that concerns to acute myocardial infarction, pathophysiologically and therapeutically, require a serious reassessment, mainly because the increasing doubts about the primary process of coronary thrombosis, are strengthened by coronary arteriographic studies, conducted in acute myocardial infarction (12-15) and also by pathological findings (l6, 29-53).
Similarly, as regards to results referred as cardiotonic effects in chronic stable coronary artery disease (73-80), especially on the segmental dysfunction of the ventricular wall and the global left ventricular function, at rest and after exercise, there has been no further reference to that old refrain that the cardiotonic by increasing contractility and oxygen consumption, would represent a harmful effect.
It was observed, in generalized way, an agreement on the advantage of its action by providing better conditions of contractility and of ventricular function to withstand the physical loads of programmed exercises or resulting from common activity, despite the natural evolution be characterized by ischemic phenomenon in front to efforts. Furthermore, it is encouraging the finding that the cardiotonic also improves myocardial perfusion in chronic coronary artery disease with ventricular segmental dysfunction (77). This improvement of myocardial perfusion in coronary artery disease seems to contradict the suspicion that in acute ischemia the cardiotonic have coronary constrictor effect. Accordingly, the thallium-201 could provide to the human model of infarction decisive information, once between experimentation in animals with induced myocardial infarction and spontaneous infarct in human, seem to be major differences which, for us, arise from the pathophysiological disparity in the two mechanisms at play.
For us, it has been very important the series of recent papers on the action of the cardiotonic in stable chronic coronary artery disease, seeking to objectively record of their effects in man and assuming the true scientific attitude of clinical proof, safely, assessing controversial clinical conditions, still based on questionable experimental assumptions.
It is necessary to re-examine with precise technology and true critical spirit, the real position of the cardiotonic in acute myocardial infarction in man and especially within our justified preference for the use of strophanthin.
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