Cardiac extrinsic neuropathy: Lesions of the mediastinal paraganglia in chronic chagasic cardiomyopathy

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Cardiac Extrinsic Neuropathy: Lesions of the Mediastinal Paraganglia in Chronic Chagasic Cardiomyopathy Simone G. Ramos, MD,*

Luigi Matturri,

MD,+ Lino Rossi, MD,’

and Marcos A. Rossi, MD, PhD*

*Department of Pathology, Faculty of Medicine of Ribeirrlo Preto, University of So Paula, Brazil; and iInstitute of Anatomical Pathology, University qf Milan, Italy

The pathologyof cardiacinnervation,both intrinsicandexternalto the heart(mediastinalparaganglia included),is scarcelyknown,yet it canbecritical to life-threateningdisordersin cardiacperformanceor to reflexes dischargingoutside the heart, or both. This article focuseson such a fundamentalandill-understoodsubjectthroughan anatomoclinical outlookof mediastinal paraganglia lesionsin the settingof suddendeathin chronicchagasiccardiomyopathy.Cardiovasc Pathol 1996;5:227-231

Malignant ventricular tachyarrhythmias (ventricular tachycardia and ventricular fibrillation) are major causesof sudden death among patients with chronic Chagas’ heart disease (1,2). Given the magnitude of the problem and the limited progressin reducing mortality, there is a pressing needto identify more clearly the patient at high risk and to delineate the processesthat initiate or facilitate these arrhythmias, so that high-risk patients can be more effectively managed. Different hypotheseshave been proposedto explain the pathogenesisof the myocardial changesin chronic Chagas’ disease(3-6): (1) direct myocardial tissue destruction by Trypanosoma cruzi; (2) neurogenic theory; (3) altered immune responsesin chronic Chagas’ diseaseand autoimmune myocarditis; and (4) infection-associatedevents and development of microvascular disease.The mechanismsalleged to induce ventricular arrhythmias is chronic chagasic cardiomyopathy are still controversial. According to the “neurogenic theory,” the pathogenesisof all manifestations Manuscript received December 15, 1995; accepted January 10, 1996. Presented at an international symposium on Chagas’ disease held in Milan, Italy, June 26-28, 1995. Address for reprints: Marcos A. Rossi, MD, PhD, Professor of Pathology and Chairman, Department of Pathology, Faculty of Medicine of Ribeirlo Preto, University of Sgo Paula, 14049-900 RibeiGo Preto, S.P., Brazil; telephone (55) 16 633-3035; fax: (55) 16 633-1068. Cardiovascular Pathology Vol. 5, No. 4, July/August 0 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York. NY 10010

1996:227-23

of Chagas’ diseasedependson denervation of the central and/or peripheral nervous system (7,8). A reduction in the number of ganglion cells of the intrinsic nervous system of all the organs studied thus far (heart, esophagus,sigmoid, colon, cerebellum, spinal cord, bronchi) has been reported in chronic Chagas’ disease(7,8). In the heart, the alleged destruction of the intrinsic nervous system (chiefly parasympatheticganglioncells) could induce an increasedsympathetic tone that might have an important role in arrhythmogenesis. The main dilemma of the “neurogenic theory” remains in the uncertainty of its physiopathologic mechanism (6). On the other hand, the consistency of the heart denervation in chronic Chagas’ disease has been challenged. Some investigators have found neither neuronal damagein the early stageof the diseasenor a relationship between neuronal counting and progressionof the disease (9,lO). The morphologic and functional basisof the “neurogenie theory” was initially obtained from chagasicpatients in very advancedstagesof the disease,most of the reduction of vagal neurons being detected in casesof patients who died of severecardiac failure (11). Previous studiesshowed that the reduction in the number of cardiac parasympathetic neuronswas minimal in chagasichearts without ventricular hypertrophy and/or dilatation and that the myocardial damage may precede functional parasympathetic abnormalities in chagasic patients (12). Cardiac epiperiganglioneuritis

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without neuroganglionalalterationsor intrinsic neuronaldepletion could be demonstratedin chronic chagasic hearts (13). On the other hand, vagal denervation hasalso been observed in other heart diseases,such as, in idiopathic dilated cardiomyopathy, clearly indicating that the association of cardiac denervation in advanced Chagas’ diseasedoes not inexorably imply a primary role (14). Hence, in the absence of a sensitive method of analysis, the precise relation between aganglionosisand chronic chagasiccardiomyopathy remainsto be determined. In other words, the cardiac parasympathetic impairment as cause or consequenceof Chagas’ heart diseasehasto be settled. Neural abnormalitieswithin the heart in various forms of cardiac arrhythmias have been emphasizedby a few investigators (15-19). Isolated reports of sudden death in developed countries have shown lesionsof the intrinsic nervous system of the heart characterized by ganglionitis and periganglionitis (20,21) closely similar to those detected in casesof Chagas’heart disease(8). The presenceof mild sinoatrial ganglionitis without neuronal depletion hasbeen reported to occur in infantile dilated cardiomyopathy (17). Cardioneuropathic changescould be observed in a number of casespresentingwith atria1arrhythmia, such assustained sinustachycardia and sinusarrhythmia, atria1fibrillation, sinoatrial block, and sick sinussyndrome. In the latter, intrinsic nerves changes alone were occasionally seento cause pacemaker dysfunction (15). Cardiac autonomic dysfunction expressedby reduced baroreflex bradycardia responsivenesswas detected in rats chronically infected with the Y, Sgo Felipe, and Colombia strains of Z cruzi. Predominant impaired efferent parasympathetic action on the heart, causedby intrinsic neuroganglionar inflammatory lesions, was the mechanismsuggestedto be directly involved (22). Studies on the physiopathology of the extrinsic nervous system of the heart are scarcein the literature. Beat-to-beat variability of heart rate dependson instantaneousvariations of the balance of the two limbs of the autonomic nervous system and it is thought to represent a reliable marker of cardiac vagal tone (23,24). Thus, preservation of barochemoreflex responsivenessis an important determinant of the autonomic control of the heart. The barochemoreflex arc representsthe most important neural mechanismfor cardiovascular control (25); it configurates a classical structure modulating and conveying vagosympathetic reciprocal discharges to modify heartbeat and arterial patency (18). As such, the testing of the barochemoreflex responsiveness standsamong the most credited proceduresto diagnoseautonomic neural derangements(26). The classic barochemoreceptors located in the carotid bifurcation and in the aortopulmonary troncus are stimulated by the mechanical and chemical influences exerted by the circulating blood; so, theseneuroreceptorsplay a.fundamental role in the homeostatic control of the cardiovascular system through regulatory adjustments of the arterial diameter and intracardiac pressure,attended by modifications of the heart rate (21).

On the neurophysiological plane, the barochemoreceptorreflex is a major mechanismto regroup afferent impulsesinto the efferent (motor) fibers of the vagus, thereby exerting a strong cardioinhibitory-vasodilatatory action (18,27,28). Little is known about disorderedparasympatheticaction on the heart from diseaseof the cardiac plexus (mainly vagal) with involvement of aortopulmonary juxta or intravagal paraganglia. A patient with mediastinal invasion due to bronchogenic carcinoma died from refractory paroxysms of ventricular tachycardia/fibrillation (17). Besides, mediastinitis with focal mflammation of mediastinal nerve plexus and paragangliawas observedin acute myocardial infarction associated with suddendeath due to ventricular tachycardial fibrillation ((17). This mediastinitis would impair the equilibrium of the autonomic control of the heart and interfere with barochemoreflex regulation of the systemic and/or coronary circulation. Basedon thesefacts, we carried out a study of aortopulmonary paraganglia in five patients who died from chronic chagasic cardiomyopathy after marked disturbancesof the rhythm.

Materials

and Methods

Five casesof Chagas’heart diseasewere selectedfrom autopsies (ranging from 43 to 74 years of age) performed at the Faculty of Medicine of Ribeirgo Preto, University of SZo Paulo, Brazil. The diagnosis was basedon previously establishedcriteria: macroscopic (cardiomegaly, apical aneurysm, rosary-bead type epicarditis, dilatation of the subpulmonary infundibulum) and microscopic features(chronic fibrosing myocarditis) and clinical and laboratory findings (positive complement-fixation and/or immunofluorescence testsfor Chagas’diseasedone before death or in serousfluids collected at autopsy). All patients studied here showed typical electrocardiographic changesand died suddenly following an episode of ventricular tachyarrhythmia degenerating in ventricular fibrillation. To obtain somebaselinevalues, two autopsy cases of adult patients without heart pathology were examined. The hearts were openedaccording to the recommendationsof one of the authors (LR) and fixed in 10% formalin for a few days. Representative sections taken from several areasof both atria and ventricles were studiedby conventional methods.Blocks including the sinus atria1 node (SAN) and the atrioventricular node (AVN) were studied as describedelsewhere(29) and correlated to the electrocardiographic tracings. The mediastinal paraganglia were obtained by accurately decorticating the adventitial and subadventitial structures, removing the fibroadiposetissueinterposedbetween the aortic arc and the pulmonary troncus. Since the receptors can be clearly seen grossly, the removed fibroadipose tissuewas stretched to be presentedon the cut surface. Serial sectioning was carried out, and sire5-p,m-thick sectionswere obtained and stained with hematoxylin and eosin, azan-Heidenhain, and Grime-

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Figure 1. Fibroadipose tissueof the aortopulmonarytroncusshowingan inflammatoryinfiltrate composed of lymphomononuclear cellsaroundsmallvessels(A) andnerves(B). The fibroustissue is augmented.Paragangliashowmarkedinflammatoryinfiltrate composed of lymphomononuclear cells (C), interstitialfibrosis(D), and capillary microthrombi(arrows)in the Zellballenstructures (E). An apparentdegranulation of the cytoplasmiccomponents of the chief cells(arrows) associated with proliferationof Schwann-typesustentacular cells(arrow heads)canbe seen(F). A, hematoxylin and eosin X57; B, hematoxylinand eosin X90; C, hematoxylinand eosin X145; D, AzanHeidenhaintrichromeX 145;E, hematoxylinandeosinX145;F, Grimelius,X290.

lius. Following establishedconventions, the next eight sections (40 p,m in thickness) were discarded. All laboratory studieswere conducted at the Cardiovascular Laboratory of the Institute of Anatomical Pathology of the University of Milan.

Results All caseshad positive complement-fixation and/or immunofluorescencetestsfor Chagas’disease.The heart weights ranged from 360 to 570 g (mean 492 g). The micropathology revealed in all casesa mild to moderatechronic fibros-

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ing myocarditis associated with right atria1 pericarditis. The tibroadipose tissue of the aortopulmonary truncus showed a chronic inflammatory infiltrate characterized by multiple foci of mononuclear cells diffusely spread in the adipose tissue or around small vessels and nerves. The fibrous tissue was markedly increased. Besides, and importantly, capillary and arteriolar microthrombi were observed in three out of five cases. The paraganglia, immersed in the fibroadipose tissue from all cases studied showed marked inflammatory changes characterized by mononuclear infiltrates, interstitial fibrosis, and capillary microthrombi in the Zellballen structures. An apparent degranulation of the cytoplasmatic contents of the chief cells, as demonstrated by Grimelius silver impregnation, could also be observed usually associated with proliferation of Schwann-type sustentacular cells (Figure 1). The conduction system showed nonspecific chronic inflammatory and fibrotic lesions similar to those found in the myocardium, but not correlated to the electrocardiographic tracings, as previously reported (30,31).

Discussion In most cases, the cause of sudden death in chronic chagasic cardiomyopathy is believed to be ventricular tachycardia or fibrillation (1,2). Our lack of understanding of the problem is undoubtedly related to its heterogenous nature and our inability to identify the majority of the patients at highest risk for sudden cardiac death. Basic and clinical studies suggest that four factors interact in a complex fashion to generate ventricular tachyarrhythmias: myocardial infarction and dysfunction, myocardial ischemia, electrical instability as suggested by complex ventricular ectopy, and potentially adverse modulating factors such as altered autonomic tone, electrolyte imbalance, and pharmacologic therapy (32). This interaction greatly complicates the study of mechanisms in vivo and the identification of independently predictive risk factors. On the other hand, the autonomic nervous system responds to changes in left ventricular function, ischemia, and rhythm, modulates the electrophysiologic properties of the myocardium, and appears to be a major determinant of a patient’s susceptibility to sudden cardiac death (32). The testing of barochemoreflex responsiveness stands among the most credited procedures to diagnose autonomic neural derangements (18). The structures studied are well known to be neuroreceptor in nature (19), carrying out a complex afferent activity in the arc of vasomotor barochemoreflexes. Considering that barochemoreceptor responsiveness may influence arrhythmogenesis, the presence of morphologic changes in the mediastinal paraganglia of chagasic patients suggests that these alterations could act as factors predisposing one to an increased risk of sudden death. Therefore, we focused on and enhanced such a fundamental and ill-understood subject through an anatomoclinical look at medias-

tinal paraglanglia lesions in sudden death in chronic chagasic cardiomyopathy.

We thank Marina Crippa, Gioacchina Randazzo, and Graziella Alfonsi, from the University of Milan and Maria E. Rim, from the University of Sao Paulo, for their friendship and their excellent technical and secretarial assistance. Supported by a grant from the Fundacb de Amparo a Pesquisa do Estado de Sao Paul0 (Proc. 95/1634-3). The research was conducted under the auspices of the Scientific Cooperation between the University of Sao Paulo, Brazil, and the University of Milan, Italy. Simone G. Ramos was recipient of a Scholarship from the Fundacao Coordenacao de Aperfeicoamento de Pessoal de Nfvel Superior (CAPES). Professor Marcos A. Rossi is Chairman :md Professor of Pathology and Senior Investigator of the Conselho National de Desenvolvimento Cientffico e Tecnol6gico (CNPq).

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