versão impressa ISSN 0036-4665
Rev. Inst. Med. trop. S. Paulo v. 40 n. 5 São Paulo Set./Out. 1998
José Alberto Mello de OLIVEIRA (1)
This prospective study on 41 autopsy collected human hearts concerns the "apical" lesion in Chagas' disease. Previous report did not show a correlation between lesion frequency and heart weight then discarding a vascular factor in its pathogenesis. The present paper involves other variables besides the heart weight to evaluate the relative coronary insufficiency. Distinct colored gel (green and red) injected through the capillary beds of both coronary arteries defined the extent of both vessels before separating the atria and removing the sub-epicardium fat. The Right Ventricle (RV) and Left Ventricle (LV) free walls furnished the RV/LV mass ratio. The myocardium mass colored green (right coronary artery RC) and the whole Ventricular Weight (VW) determined the RC/VW mass ratio. The heart weight plus these mass ratios, graded and added, composed a score inversely proportional to the myocardium irrigation condition. It intended to be a more sensitive morphologic evaluation of the relative ischaemia to correlate to the apical lesion. This study showed a right deviation for the relative accumulated frequency of lesions plotted as a score function and a significant difference for higher scores in hearts with aneurysm. It suggests a ischaemic factor intervening in the apical lesion pathogenesis in Chagas' cardiopathy.
KEYWORDS: Chagas'disease; Coronary arteries; Heart hypertrophy; Myocardial ischaemia.
The "apical aneurysm" is a very special heart lesion occurring in Chagas' disease whose identification helps in the macroscopic diagnosis of the cardiopathy33. Its location is the left heart apex, less frequently the right side20,21. There are also reports on thinning in the right ventricle wall adjoining the septum37 and the left ventricle posterior wall37,44. Research improved the disease knowledge since the Chagas' discovery10, especially after the fifties6,8,11,18,19,23,24,40,41,44,45 but fails until now to explain many unsolved pathogenic aspects including the heart "apical aneurysm".
Heart lesions in Chagas' disease should be catecholaminogenic36. A similar apical lesion experimentally induced in rats through isoproterenol injection suggests a pathway involving the myocardium cell membrane ß-receptors30,31. These papers support the Köberle's neurogenic theory20-22. That theory supposes Chagas' cardiopathy as a result of the sympathetic dominance after the parasympathetic denervation occurring in the acute phase. There would be a neurocardiopathy with relative coronary insufficiency and hypoxic intervening lesions due to the heart sympathetic dominance. The coronary arteries trunks dilated in Chagas' heart disease as compared to other cardiopathies38 support the concept of a vascular phase in the neurogenic theory. Post mortem coronary arteriography in Chagas' disease showed scarce vascularization in the left apex16. Investigation on the coronary circulation in Chagas' cardiopathy showed apical ventricular regional hypoperfusion28. Most of the hypoxic lesions are mainly microscopic and of scattered distribution. The apical "aneurysm" would be the more conspicuous hypoxic manifestation of such evolution though it is not present in all cases. Heart hypertrophy as a sign of relative coronary insufficiency7,14,25,46 could directly correlate with a higher frequency of the apical lesion. Previous study failed to find such a correlation to support the coronary insufficiency hypothesis in Chagas' heart disease2,37. However heart weight alone is not sufficient to identify heart hypertrophy. It is better discriminated using combined values of heart weight and ventricle mass ratios12,15. Furthermore the anatomic pattern of coronary distribution32,42 may play a role in the coronary artery reserve5. Recent review of Chagas' heart disease implicates a microangiopathy in the pathogenesis of the myocardial lesions41 giving new support to the vascular phase. These reports8,16,28,41 then justify to resume the question of the relative ischaemia since they point out to a vascular factor in the pathogenesis of the Chagas' heart disease.
MATERIAL AND METHODS
This protocol conducted on 41 hearts from autopsies of the Department of Pathology of the School of Medicine of Ribeirão Preto (São Paulo State - Brazil), studied cases that had Chagas' disease as the first or associated cause of death. Positive complement fixation test (Machado-Guerreiro reaction) in autopsy collected blood and pericardium liquid and/or the heart macroscopic aspect33 gave the criteria to accept the diagnosis. They were 28 men (age varying between 19 and 73 years ) and 13 women (age varying between 32 and 80 years). In every case the heart was carefully washed, weighed and examined to identify and register the most characteristic lesion, the wall thinning and bulging in the ventricles, especially in the left side apex.
The preparation of the 41 hearts followed the protocol described in a previous report32. They were part of a wider sample gathered for the study of the anatomic pattern of coronary arteries in human hearts with and without hypertrophy. In that protocol the simultaneous perfusion of the capillary beds of both coronary arteries with a gelatin-salt mixture allowed to color the myocardium green for right side and red for left side. Then the ventricle myocardium was divided into three parts the right ventricle (RV) and left ventricle (LV) free walls and the interventricular septum (IVS) after separating the atria and carefully removing the sub-epicardium fat 12, 17, 32. The weights of the RV and LV free walls allowed to obtain the "Right Ventricle/Left Ventricle" mass ratio (RV/LV). The extent of the right coronary (RC) artery territory was also identified in each heart, either restricts to the RV free wall or reaching the posterior half of the IVS and/or the LV free wall. These parts separated again for muscle masses colored green and red determined the distinctly colored myocardium weights. These data furnished the RC fraction in the whole ventricular mass, i.e. the "Right Coronary/ Ventricular Weight" mass ratio (RC/VW). The present report deals only with the left and right ventricular weights and the ventricular RC and the left coronary (LC) arteries dependent territories.
The heart weight, the RV/LV and RC/VW mass ratios graded or graded and added composed scores related to the presence or absence of the left apical lesion in the examined hearts. The criterion for hearts without weight hypertrophy was the heart weight limited of 350g and 300g for men and women, respectively. The standard values for the RV/LV and RC/VW mass ratios in hearts without weight hypertrophy were those previously reported 32, respectively RV/LV = 0.56 ± 0.07 and RC/VW = 0.38 ± 0.11. That study showed no differences between sexes for both ratios.
The grades for heart weight were "I" for cases up to 350g for men and 300g for woman; "II" for hearts weights more than 350 and 300g and up to 450g and 400g, respectively; and "III" for cases over these limits. The grades for RV/LV mass ratio were "I" for hearts within one standard deviation around the mean value referred above for cases without weight hypertrophy; "II" for hearts with greater values and up to two standard deviation and "III" for cases exceeding two standard deviation around that mean. The grades for RC/VW mass ratio were "I" for hearts within one standard deviation around that referred mean value for cases without hypertrophy; "II" for hearts with greater values and up to two standard deviation around the mean and "III" for hearts exceeding two standard deviation around that mean. The scores to be obtained could vary between 1 and 3 minimum for one variable and 3 to 9 maximum for combined variables, being further correlated to hearts with and without the apical lesion. The two-tailed Fisher Exact Test43 gave the probability at a 5% level to accept the Ho hypothesis that scores did not directly correlate to the lesion frequency.
Table 1 lists the studied cases including sex, age, heart weight, RV/LV and RC/VW mass ratios, the grades for each variable, the maximum heart scores and the presence or absence of the left ventricle apical lesion on each heart. They are 41 cases of Chagas' disease but 29 with apical aneurysm. Minimal and maximal values were respectively 180 and 740g for heart weights; 0.32 and 0.81 for the RV/LV mass ratio; 0.29 and 0.63 for the RC/VW mass ratio.
Table 2 summarizes these data. There was 3 aneurysms in 8 cases grade I for the variable "Heart Weight", 16 aneurysms in 20 cases grade II and 10 aneurysms in 13 cases grade III. There was 9 aneurysms in 16 cases grade I for "RV/LV", 10 aneurysms in 15 cases grade II and 10 aneurysms in 10 cases grade III. There was 21 aneurysms in 33 cases grade I for "RC/VW", 7 aneurysms in 7 cases grade II and 1 aneurysm in the only case grade III. The two-tailed Fisher Exact Test showed a p<0.05 concerning the RV/LV mass ratio and no significant differences for the other variables.
Table 3 shows the distribution of the 41 hearts for the presence of the apical lesion related to scores obtained by adding pairs of variables. The two-tailed Fisher Exact Test for the paired variables showed a p=0.047 for "Heart Weight + RV/LV". Furthermore it showed a p=0.012 for "Heart Weight + RC/VW" and p=0.039 for "RV/LV + RC/VW". The "p" value in every case, lower than the 5% limit allowed to reject Ho for all the combinations of variables.
Table 4 shows the frequency distribution of cases as related to the heart scores calculated by adding the "Heart Weight + RV/LV + RC/VW" grades. The table also shows the accumulated frequencies (AF) equalized through the Relative Accumulated Frequency (RAF) logarithm. RAF is calculated throughout the formula [(N+1)/(N-AF+1)] where N is the total number of cases in each group; AF is the absolute accumulated frequency. The Fisher Exact Test applied to the contingence table 2x5 (score versus lesion present or absent) showed a two-tailed probability p=0.033 associated with its occurrence under Ho. The values for the logRAF in both groups are graphically displayed in the Figure 1 as a score function showing a right deviation for the greater scores from cases with the apical aneurysm.
Figure 1 - Chagas' disease: LogRAF (Relative Accumulated Frequency) of the apical aneurysm in the left ventricle for 12 hearts without and 29 with the lesion plotted as a function of heart scores in 41 human cases.
Chagas' heart disease is a complex and still now poorly understood cardiopathy. The main facts well established are the identification of the etiologic agent (Trypanosoma cruzi, Chagas 1909), scattered focal myocytolysis27 and fibrosis, disturbances of the electric stimulus generation and conduction4,13, the post-ganglionic autonomic nervous cells wasting22, the presence of mural "aneurysms" either in the left and/or right apex20-22 or more infrequently elsewhere37,44, the inflammatory infiltration by immunologically competent45 and phagocytic cells, congestive cardiac insufficiency13 and sudden death22. How to gather all these facts in an unitary concept is still now debatable and far from being reached. The heart macroscopic aspect at autopsy may show a global cardiac hypertrophy and dilation (cardiomegaly) suggesting a functional congestive cardiopathy. However ventricle hypertrophy without dilation or even a small heart are not infrequent. Bulging of the conus arteriosus, the presence of tiny delicate granules linearly disposed along the coronary vessels (fibrous pericarditis "in rosary") or a lymphnode between the aorta and pulmonary artery trunks are also macroscopic findings. In every situation the diagnosis is easier if the characteristic apical "aneurysm" is present with or without mural thrombi. The apical aneurysm of the Chagas' cardiopathy differs from the post-infarct aneurysm. It does not display the typical thick collagen infiltration of the healed infarct though some people designated it "apical infarct"35. Usually the wall becomes so thin as to be translucent suggesting that the myocells are lost through a mechanism scarcely eliciting the repair process. It seems as to the epicardium and endocardium become face to face without myocardium interposed. The collagen quality in the apical lesion reparative process in Chagas' heart disease is different as compared to that from the myocardium infarct9. The healing aspect changes when mural thrombosis intervene and the collagen may be found as part of the thrombus organization. Previous reports dealing with this lesion considered inflammatory8,34, mechanical1,39, neurogenic20,21, vascular3,20,21,26,27,29 and ß-receptor stimulating30,31 factors implicated in its pathogenesis. Recently, other observations41 showed lesions at the microvasculature level corroborating the presence of vascular factors in its pathogenesis. An in vivo study of the coronary circulation28 using specific markers of myocardial flow showed regional ventricular hypoperfusion especially in the apex and lateral view of the left ventricle free wall. KÖBERLE20-22 considered Chagas' heart disease as a neurocardiopathy beginning in the acute period of the T.cruzi infection, when mural autonomic neurocytes are destroyed. Later follow the vascular and myogenic phases. The autonomic control lost by parasympathetic denervation causes hypertrophy because of the sympathetic dominance. In this theory the vascular phase is consequence of a relative coronary insufficiency to attend the myocardial metabolic needs in the denervated heart. In this phase there should be scattered focal necrosis from hypoxic origin. Finally follows the myogenic phase with continuing focal myocardial necrosis, inflammation and fibrosis.
There is a consensus about the efficiency of the coronary arterial system for a good irrigation of the normal heart but there is also a bulk and broad clue about its limitations face to heart hypertrophy7,14, 25,46. Coronary artery dilation demonstrated in Chagas' heart disease may reflect the sustained coronary insufficiency38. Many reports refer a relative coronary insufficiency7,14,25,46 when heart hypertrophy induces a loss of adequate proportion between myocardium mass and irrigation then causing a relative ischaemia. This mechanism has been supposed to be involved in this cardiopathy24. However previous report studying the heart weight and the frequency of the apical lesion2,37 in Chagas' heart disease failed to demonstrate a direct correlation between them. This study on 41 hearts in autopsies that had Chagas' disease as the first or associated cause of death shows the apical lesion distributed along with all the heart weight range (Table 1) confirming previous reports 2,37. Table 1 displays a case weighing 740g without the apical lesion. Scores taken from the variable "Heart Weight" alone (Table 2) did not show significant difference between the heart groups with and without aneurysm.
The present paper considered that other variables (RV/LV and RC/VW mass ratios) rather than the heart weight alone could help in evaluating the coronary insufficiency intervening in the apical lesion pathogenesis in Chagas' heart disease. The heart weight as unique criterium for heart hypertrophy masks some aspects that become evident when one takes into account an isolated ventricular hypertrophy even in hearts with small weight12,15. Otherwise the anatomic pattern of coronary distribution32,42 may play a role in the coronary artery reserve5 then justifying the RC/VW mass ratio inclusion in this study. The values of these mass ratios have a normal distribution around the mean. It justifies to assign grades I to III to individuals as they deviate from the most frequent mean values. In the case of the RV/LV mass ratio these deviations correspond to right or left ventricle hypertrophy. In the case of the RC/VW mass ratio it corresponds to right or left coronary artery dominance. The grades of the isolated RV/LV mass ratio here analyzed showed a significant difference in the lesion frequency related to the heart groups (Table 2). However there was no difference between the same groups when considered the isolated RC/VW mass ratio. This sample is probably too small to show a significant difference concerning this variable alone, since the great majority of hearts (33 cases) are RC/VW grade I (Table 2). The concentration of cases in grade I hearts reflects the narrow variation range of the RC fraction irrigating the ventricles as shown in a previous paper32. It is to be noticed that all the other 8 cases had the apical lesion (7 cases graded II and 1 graded III). Furthermore scores obtained by adding pairs of variables showed for all their combinations a significant difference for the lesion frequency in both groups (Table 3).
These 41 cases were furthest separated using a score calculated by adding all the variables grades. This score intended to be more sensitive in evaluating through a morphological criterion the proportion between myocardial mass and the irrigation condition. It means that greater the score worse the irrigation condition. Table 4 shows no cases with apical lesion in hearts with the smaller score 3. Otherwise the frequency of hearts with the apical lesion is greater in the higher scores with a significant statistical difference. The logRAF for both groups put in a graphical form shows a right deviation for the hearts with the apical lesion and indicate that it has a higher incidence as far as worse is the heart irrigation. Nevertheless the overlap among cases with and without aneurysm in the intermediate scores (4 to 6) deserves further investigation as well as the capricious locations of the ventricular wall thinning in the apex and elsewhere. The heart apex is usually irrigated by the LC artery in its frontiers with the RC territory. Even the other locations of ventricular wall thinning referred in previous reports37,44 are in the frontiers between both territories. The nature of this histotoxic anoxy still remains to be investigated. There is no obstruction of the main trunks and branches of the coronary arteries1,2. Arteritis referred in Chagas' patients for intramural vessels in oesophagus biopsies6 are not conspicuous in the Chagas' heart disease44. Microangiopathy with microthrombus in the capillary vessels41 could explain the hypoxidosis, myocell necrosis and fibrosis.
In summary this macroscopic study suggests that all the variables combinations here used were more effective than the heart weight alone for the morphologic evaluation of the relative coronary insufficiency. It corroborates the vascular phase20 in the evolution of Chagas' heart disease pointed out by other reports28,41 suggesting hypoxic factors intervening in the pathogenesis of the apical lesion.
Aneurisma cardíaco na doença de Chagas
Trata-se de estudo prospectivo referente à lesão apical da cardiopatia chagásica em 41 corações humanos. A relatada falta de correlação entre freqüência da lesão e peso do coração, descartou o fator patogênico vascular. Neste trabalho avalia-se a insuficiência coronária relativa incluindo outras variáveis além do peso do coração. A perfusão do leito capilar com gel de cores diferentes para cada coronária (verde e vermelho) permitiu delimitar seus territórios antes de separar os átrios e a gordura sub-epicárdica. As paredes livres dos ventrículos direito (RV) e esquerdo (LV) definiram o índice RV/LV. O peso do miocárdio ventricular corado em verde (artéria coronária direita-RC) e o peso ventricular total (VW) definiram o índice RC/VW. O peso do coração e esses dois índices, graduados e somados, compuseram um "score" de valor inversamente proporcional à condição de irrigação do miocárdio. Tencionou-se, com este "score", obter uma avaliação morfológica da isquemia relativa, a ser relacionada com a frequência do aneurisma da ponta. A frequência acumulada relativa das lesões obtida para dois grupos de corações (sem e com aneurisma) revelou valores maiores dos "scores" para os chagásicos com a lesão, corroborando a existência de uma fase vascular interveniente na patogênese da lesão apical.
Grant support by the Comissão de Aperfeiçoamento de Pessoal de Nível Superior - CAPES - (Bolsa de Dedicação Acadêmica) and the Fundação de Apoio ao Ensino, Pesquisa e Assistência (Hospital das Clínicas - FMRPUSP) .
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(1) Professor of Pathology, Department of Pathology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
Correspondence to: José Alberto Mello de Oliveira, Department of Pathology, School of Medicine of Ribeirão Preto. Av. Bandeirantes 3900. 14049-900 Ribeirão Preto, SP, Brazil. Phone/fax: 55 16 633 1068. E-mail: email@example.com
Received: 7 April 1998
Accepted: 4 September 1998