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Pathologic substrates for arrhythmogenesis in chronic chagasic cardiopathy
ELSEVIER
SYMPOSIUM
Pathologic Substrates for Arrhythmogenesis in Chronic Chagasic Cardiopathy Luigi Matturri,
MD
Institute of Pathology, Universiry of Milan, Italy
Here are described the results of a histopathological study on 12 autopsy hearts of subjects deceased secondary to chronic chagasic cardiopathy in order to clarify the nature and the pathogenetic mechanism of its arrhythmogenic potential. The arrhythmogenic hazards of chagasic cardiomyopathy are mainly due to the striking disruptive fibrotic changes with ensuing electrical instability of the ventricular myocardium. Lesions of the conduction system, focal epiperineuritis, and an inconstant and questionable “neuronal depletion” of the cardiac plexuses in the disease play a concomitant role. Cardiovasc Path01 1996;5:221-225
The arrhythmogenic potential of chagasic cardiopathy has long been recognized. The occurrence of ventricular tachycardia and ventricular fibrillatiop in the chronic stage adds to the impending life threat from rupture of the apical left ventricular aneurysm (l-3). Chagasiccardiopathy is characterized in its chronic state by scatteredpatchesof sclerotic replacementof the ventricular walls (2) with thickening of the myocytic basal membrane (2,4). Lesionsof the conduction system (5,6) and an inconstant (7-9) and questionable“neuronal depletion” of the intrinsic cardiac plexusesin the disease(10) also contribute to the arrhythmogenic hazards that are due to the striking disruptive changes and electrical instability of the ventricular myocardium. Recent anatomopathologicinvestigationson chronic chagasic cardiopathy confirm the existence and significance of the blood and lymphatic vascular alterations (6,11,12). The consequencesof the severe obstruction of the arteriolar blood supply and/or lymphatic drainage are particularly serious. These include infarctlike ischemicreperfusion lesions Manuscript received December 15, 1995; accepted January IO, 1996. Presented at an international symposium on Chagas’ heart disease held in Milan, Italy, June 26-28, 199.5. Address for reprints: Luigi Matturri, MD, Institute of Pathology, University of Milan, Via della Commenda, 19, Milan 20122, Italy; telephone: 2-541-9521, fax: 2-55 I-8191.
Cardiovascular Pathology Vol. 5, No. 4, July/August 0 19% by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
and compromisedlymphatic reflux, respectively, especially along the ventricular septum. Thesefindings have helped clarify the nature and pathogenetic mechanismof fibrosis in chagasiccardiopathy and of its arrhythmogenic potential, previously attributed mainly to neurovegetative damage(13).
Material
and Methods
Twelve casesof chronic chagasic cardiopathy were autopsied for an investigation involving the collaboration of the Department of Pathology, University of Milan, the Centro de Enfermedad de Chagas,Fernandez Hospital, University of BuenosAires (Argentina), and the Department of Pathology, University of Ribeifo Preto, San Paolo (Brazil). The heartswere fixed in 10% buffered formalin; the conduction system was removed together with the entire ventricular septum according to our standard procedure (14), and specimensfrom different sitesof the atrial and ventricular free walls were embeddedin paraffin; serial sections every 150 km were stained alternately with hematoxylineosinand Heidenhain’s trichrome (azan).
Compromised
Lymphatic
Reflux
In the chronic stage chagasic cardiopathy is characterized by extensive and marked dilatation of lymphatic capil-
1996: 22 l-225 1054.8807/96/$15.00 PII S 1054~8807(96)OWO2-6
222
MATTURRI .ARRHYTHMOGENESIS
IN CHAGAS’
DISEASE
Cardiovasc Pathol Vol. 5, No. 4 July/August 1996:221-225
Figure 1. Marked dilatationof lymph-
atic capillariesandtrunksin the subendocardiumwith spotty interstitial fibrotic replacementof the myocardium. Azan stainX 100.
laries and trunks (6). This feature wasparticularly evident in the subepicardium,near the left ventricular aneurysm, and in the ventricular septum(Figure 1). Macroscopic evidence of a seriesef ectatic lymphatics, resulting from drainage obstruction, indicates a pathogenetic mechanismof fibrosis reminiscent of the scleroatrophy of the subcutaneoustissueand dermis found in casesof lymphatic stasisof the lower limbs. As is well-known, lymphatic drainage through the ventricular septumconverges in the lymphatic trunks that cross the central fibrous body to reach the atria1collectors, eventually emerging in the thoracic duct. Extensive dilatations of the lymphatic capillaries of the atrioventricular junctional area are frequently observed, accompanied by marked hypotrophy or even atrophy of the atrioventricular node and of the His bundle, which is also the site of fine fibrosis associatedwith chronic focal lympho-histiocytic inflammation (Figure 2). The presence of autoimmune inflammatory infiltration typical of chronic chagasiccardiopathy near the lymphatic collectors suggeststhat the drainageobstruction is related to chronic myocarditis.
Compromised
Arteriolar
Supply
Alterations of the arteriolae are common in chronic chagasic cardiopathy, and they contribute to the pathogenetic mechanismof the cardiac lesions. These are characterized by concentric subintimal thickening with moderate fibrosis and hypotrophy of the tunica
media. The: lumen of the vessel is reduced by concentric stenosis(<70%). This chronic stenosingarteriolopathy, probably immunopathic in nature, seemsto be more evident in the precapillary segment,sometimeswith the aspectof a luminal fissure due to swelling causedby proliferating endothelia(Figure 3). This picture provides a plausible substratefor the myocardial “decapillarization” underlying chagasic myocardial fibrosis (1;:). The arteriolar lesions are the likely substrate for focal acute ischemic necrosisof the myocardium, with the classic aspectsof anisoinotropismand contraction band necrosis distributed throughout the myocardium (particularly the interventricular septum), and associatedwith more extensive areasof densefibrosis wherein microinfarcts and/or inflammatory sequelaeoverlap (Figure 4). The arrhythmogenic implications of thesemyocardial lesions(particularly the myocardial fibrosis), leadingto disruption and fractionation of both the anatomic texture and the electrical activation of the ventricular wall, are essentially the sameas in postinfarction (1,13). As far asthe cardiac innervation is concerned, alterations were observed in the cardiac nervous system. These consistedof perineuritis, characterized by the presenceof focal lymphohistiocytic infiltrates along the atria1and ventricular nerve ramifications, and to a lesserextent endoneuritis also was found (6,13,15). The vascular (lymphatic and arteriolar) lesionsdescribed confirm the vasculopathic-dystrophic pathogenetic hypothesisof the heart lesionsand ensuingarrhythmias, supervening in the chronic phase.The defective arterial supply and/
Cardiovax July/August
Path01 Vol. 5, No. 4 199632 i-225
ARRHYTHMOGENESIS
IN CHAGAS’
MATTURRI DISEASE
223
2. Pronounceddilatation of the lymphaticcapillariesof the atrioventricularjunctional area,with fibrosisand atrophy of the atrioventricular node. Azan stain X300 (upper) andX600 (lower). Figure
or lympathic drainage is the main cause of the extensive myocardial fibrosis. This refers mainly to the appar.ently “selective” changes of the conduction system(due to 1:ymphatic obstruction) and contributes to the risk of rupture of left ventricular apical de and electromechanical aneurysm (with cardiac tamponac dissociation). The multiple micrcCnfarcted foci associated
with dense fibrotic bands fragment the ventricular wavefront causing dispersionof repolarization and refractoriness reentry ventricular arrhythmias. Our observationsput into a different perspective the prevailing neuropathogenetictheory of dysrhythmias and ventricular apical aneurysm. The recent electrophysiological evidence of M myocells (16) sandwiched in between the
224
MATTURRI ARRHYTHMOGENESIS
IN CHAGAS’
DISEASE
Cardiovasc Path01 Vol. 5, No. 4 July/August 1996:221-225
Figure 3. Concentric subintimal thlickening of arteriolae. Azan stain X 150.
subendocardialand subepicardialmyocardium, exhibiting a prolonged repolarization time and prone to triggered activity, now widens any arrhythmogenic argument in the presence of irregular damageto the ventricular walls, like that presentingin chronic chagasiccardiomyopathy (Figure 5). Chronic chagasiccardiopathy presentsasan autoimmune
damagedependenton and associatedwith acute and chronic cruzi. It vascular myocarditis caused by Trypanosoma evolves into a highly arrhythmogenic fibrosing cardiomyopathy characterized by a hemolymphatic circulatory involvement, with secondarycardioneuropathologicinjury. The arrhythmogenic hazardsof chagasiccardiopathy are
Figure 4. Contraction band degeneration associated with areas of fibrosis. Azan stain X 150.
Cardiovasc Pathol W)l. 5, No. 4 July/Augu?t 1996:22 l--225
ARRHYTHMOGENESIS
IN CHAGAS’
225
MATTURRI DISEASE
Figure 5. Scars from old microinfarcts in between the subendocardial and subepicardial myocardium, arrhythmogenic in nature. Azan stain x 100.
mainly due to the striking disruptive fibrotic changes with ensuing electrical instability of the ventricular myocardium. Lesions of the conduction system and focal epiperineuritis of the intrinsic and extrinsic neuroreceptor glomera including cardiac plexuses play a concomitant role (15).
The authors wish to express their grateful appreciation to Mrs. G. Alfonsi and Mrs. Crippa for invaluable technical-histological help and to Miss G. Randazzo for keen secretarial work all throughout this research. This work was supported by grant 41.115.115237 from the Italian National Research Council (CNR)-Targeted Project “Prevention and control disease factors” subproject “Pathology of arrhythmias and sudden cardiac death.” and by IRCCS Ospedale Maggiore, Milano.
approach
to cardiac
arrhyth-
2. Milei J, Ferrans V, Meira de Oliveira J, Rossi L, Matturri L, Caputi E, SBnchez J, Xi Yu Z. Patologia. In: Storino R, Milei J, eds. Enfermedad de Chagas. Buenos Aires: Mosby Doyma Argentina, 1994;10:141184. 3. Rossi L. Histopathology Febiger 1979.
of Cardiac
6. Rossi L, Matturri L. Cardiomiopatia chagasica. tologico. Federazione Medica 1994: 10:23-26.
Aggiomamento
Arrhythmias.
Philadelphia:
4. Ferrans VJ, Milei J, Tomita Y, Storino R. Basement ening in cardiac myocytes and capillaries in chronic Am J Cardiol 1988;61:1137-1142.
Lea &
membrane thickChagas’ disease.
istopa-
7. Milei J, Storino RA, Beigelman R, Fernandez AG, Matturri L, Rossi L. Histopathology of specialized and ordinary myocardium and nerves in chronic Chagas’ disease, with a morphorrietric study of inflammation and fibrosis. Cardiologia 1991;36:107-114. 8. Kaberle F. Cardiopatia 1959;101:1308-1310.
parasympaticopriva.
9. Olsen GJ. Atlas of cardiovascular 1987;81. Fig. 8.21.
pathology.
Miinch
Med Wochenscrift
Lancaster:
MTP
10. Lopes ER, Tafuri WL. Involvement of the autonomic nervous in Chagas disease. Ret Sot Brasil Med Tropic 1983;16:2G29.
Press system
11. Factor SM, Cho S, Wittner, Tanowitz H. Abnormalities of the coronary microcirculation in acute murine Chagas’ disease. Am J Trop Med Hyg 1985;34:226-253. 12. Rossi M. Microvascular changes as a cause of chronic in Chagas’ disease. Am Heart J 1990: 120:233-236.
References I Rossi L, Matturri L. Clinicopathological mias. Turin: C. Scient Torinese, 1990.
5. Andrade ZA, Andrade GS, Oliveira GB, Alonso DR. Histopathology of the conducting tissue of the heart in Chagas’ myocarditis. Am Heart J 1978;95:31&321.
cardiomyopathy
13. Rossi L, Storino R, Milei J, Matturri L. Depleci6n neuronal en la enfermedad de Chagas: Todo deberia reverse. Revista Argentina de Cardiologia 1994;62:239-246. 14. Rossi L, Pozzato R, Matturri L. L’anatomia patologica della morte improvvisa cardiaca oggi. Riv It Med Leg 1991;13:93-1 10. 15. Rossi L. Histology of cardiac vagal innervation in man. PH Schwartz, eds. Vagal Control of the Heart. Arzmouk, 1994;3-20. 16. Antzelevitch C, Sicouri S. Clinical relevance of cardiac generated by after depolarization. Role of M cells in the U waves, triggered activity and torsade de pointes. J Am 1994;23:259-277.
In MN Levy, NY, Futura, arrhythmias generation of Co11 Cardiol
SYMPOSIUM
Pathologic Substrates for Arrhythmogenesis in Chronic Chagasic Cardiopathy Luigi Matturri,
MD
Institute of Pathology, Universiry of Milan, Italy
Here are described the results of a histopathological study on 12 autopsy hearts of subjects deceased secondary to chronic chagasic cardiopathy in order to clarify the nature and the pathogenetic mechanism of its arrhythmogenic potential. The arrhythmogenic hazards of chagasic cardiomyopathy are mainly due to the striking disruptive fibrotic changes with ensuing electrical instability of the ventricular myocardium. Lesions of the conduction system, focal epiperineuritis, and an inconstant and questionable “neuronal depletion” of the cardiac plexuses in the disease play a concomitant role. Cardiovasc Path01 1996;5:221-225
The arrhythmogenic potential of chagasic cardiopathy has long been recognized. The occurrence of ventricular tachycardia and ventricular fibrillatiop in the chronic stage adds to the impending life threat from rupture of the apical left ventricular aneurysm (l-3). Chagasiccardiopathy is characterized in its chronic state by scatteredpatchesof sclerotic replacementof the ventricular walls (2) with thickening of the myocytic basal membrane (2,4). Lesionsof the conduction system (5,6) and an inconstant (7-9) and questionable“neuronal depletion” of the intrinsic cardiac plexusesin the disease(10) also contribute to the arrhythmogenic hazards that are due to the striking disruptive changes and electrical instability of the ventricular myocardium. Recent anatomopathologicinvestigationson chronic chagasic cardiopathy confirm the existence and significance of the blood and lymphatic vascular alterations (6,11,12). The consequencesof the severe obstruction of the arteriolar blood supply and/or lymphatic drainage are particularly serious. These include infarctlike ischemicreperfusion lesions Manuscript received December 15, 1995; accepted January IO, 1996. Presented at an international symposium on Chagas’ heart disease held in Milan, Italy, June 26-28, 199.5. Address for reprints: Luigi Matturri, MD, Institute of Pathology, University of Milan, Via della Commenda, 19, Milan 20122, Italy; telephone: 2-541-9521, fax: 2-55 I-8191.
Cardiovascular Pathology Vol. 5, No. 4, July/August 0 19% by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
and compromisedlymphatic reflux, respectively, especially along the ventricular septum. Thesefindings have helped clarify the nature and pathogenetic mechanismof fibrosis in chagasiccardiopathy and of its arrhythmogenic potential, previously attributed mainly to neurovegetative damage(13).
Material
and Methods
Twelve casesof chronic chagasic cardiopathy were autopsied for an investigation involving the collaboration of the Department of Pathology, University of Milan, the Centro de Enfermedad de Chagas,Fernandez Hospital, University of BuenosAires (Argentina), and the Department of Pathology, University of Ribeifo Preto, San Paolo (Brazil). The heartswere fixed in 10% buffered formalin; the conduction system was removed together with the entire ventricular septum according to our standard procedure (14), and specimensfrom different sitesof the atrial and ventricular free walls were embeddedin paraffin; serial sections every 150 km were stained alternately with hematoxylineosinand Heidenhain’s trichrome (azan).
Compromised
Lymphatic
Reflux
In the chronic stage chagasic cardiopathy is characterized by extensive and marked dilatation of lymphatic capil-
1996: 22 l-225 1054.8807/96/$15.00 PII S 1054~8807(96)OWO2-6
222
MATTURRI .ARRHYTHMOGENESIS
IN CHAGAS’
DISEASE
Cardiovasc Pathol Vol. 5, No. 4 July/August 1996:221-225
Figure 1. Marked dilatationof lymph-
atic capillariesandtrunksin the subendocardiumwith spotty interstitial fibrotic replacementof the myocardium. Azan stainX 100.
laries and trunks (6). This feature wasparticularly evident in the subepicardium,near the left ventricular aneurysm, and in the ventricular septum(Figure 1). Macroscopic evidence of a seriesef ectatic lymphatics, resulting from drainage obstruction, indicates a pathogenetic mechanismof fibrosis reminiscent of the scleroatrophy of the subcutaneoustissueand dermis found in casesof lymphatic stasisof the lower limbs. As is well-known, lymphatic drainage through the ventricular septumconverges in the lymphatic trunks that cross the central fibrous body to reach the atria1collectors, eventually emerging in the thoracic duct. Extensive dilatations of the lymphatic capillaries of the atrioventricular junctional area are frequently observed, accompanied by marked hypotrophy or even atrophy of the atrioventricular node and of the His bundle, which is also the site of fine fibrosis associatedwith chronic focal lympho-histiocytic inflammation (Figure 2). The presence of autoimmune inflammatory infiltration typical of chronic chagasiccardiopathy near the lymphatic collectors suggeststhat the drainageobstruction is related to chronic myocarditis.
Compromised
Arteriolar
Supply
Alterations of the arteriolae are common in chronic chagasic cardiopathy, and they contribute to the pathogenetic mechanismof the cardiac lesions. These are characterized by concentric subintimal thickening with moderate fibrosis and hypotrophy of the tunica
media. The: lumen of the vessel is reduced by concentric stenosis(<70%). This chronic stenosingarteriolopathy, probably immunopathic in nature, seemsto be more evident in the precapillary segment,sometimeswith the aspectof a luminal fissure due to swelling causedby proliferating endothelia(Figure 3). This picture provides a plausible substratefor the myocardial “decapillarization” underlying chagasic myocardial fibrosis (1;:). The arteriolar lesions are the likely substrate for focal acute ischemic necrosisof the myocardium, with the classic aspectsof anisoinotropismand contraction band necrosis distributed throughout the myocardium (particularly the interventricular septum), and associatedwith more extensive areasof densefibrosis wherein microinfarcts and/or inflammatory sequelaeoverlap (Figure 4). The arrhythmogenic implications of thesemyocardial lesions(particularly the myocardial fibrosis), leadingto disruption and fractionation of both the anatomic texture and the electrical activation of the ventricular wall, are essentially the sameas in postinfarction (1,13). As far asthe cardiac innervation is concerned, alterations were observed in the cardiac nervous system. These consistedof perineuritis, characterized by the presenceof focal lymphohistiocytic infiltrates along the atria1and ventricular nerve ramifications, and to a lesserextent endoneuritis also was found (6,13,15). The vascular (lymphatic and arteriolar) lesionsdescribed confirm the vasculopathic-dystrophic pathogenetic hypothesisof the heart lesionsand ensuingarrhythmias, supervening in the chronic phase.The defective arterial supply and/
Cardiovax July/August
Path01 Vol. 5, No. 4 199632 i-225
ARRHYTHMOGENESIS
IN CHAGAS’
MATTURRI DISEASE
223
2. Pronounceddilatation of the lymphaticcapillariesof the atrioventricularjunctional area,with fibrosisand atrophy of the atrioventricular node. Azan stain X300 (upper) andX600 (lower). Figure
or lympathic drainage is the main cause of the extensive myocardial fibrosis. This refers mainly to the appar.ently “selective” changes of the conduction system(due to 1:ymphatic obstruction) and contributes to the risk of rupture of left ventricular apical de and electromechanical aneurysm (with cardiac tamponac dissociation). The multiple micrcCnfarcted foci associated
with dense fibrotic bands fragment the ventricular wavefront causing dispersionof repolarization and refractoriness reentry ventricular arrhythmias. Our observationsput into a different perspective the prevailing neuropathogenetictheory of dysrhythmias and ventricular apical aneurysm. The recent electrophysiological evidence of M myocells (16) sandwiched in between the
224
MATTURRI ARRHYTHMOGENESIS
IN CHAGAS’
DISEASE
Cardiovasc Path01 Vol. 5, No. 4 July/August 1996:221-225
Figure 3. Concentric subintimal thlickening of arteriolae. Azan stain X 150.
subendocardialand subepicardialmyocardium, exhibiting a prolonged repolarization time and prone to triggered activity, now widens any arrhythmogenic argument in the presence of irregular damageto the ventricular walls, like that presentingin chronic chagasiccardiomyopathy (Figure 5). Chronic chagasiccardiopathy presentsasan autoimmune
damagedependenton and associatedwith acute and chronic cruzi. It vascular myocarditis caused by Trypanosoma evolves into a highly arrhythmogenic fibrosing cardiomyopathy characterized by a hemolymphatic circulatory involvement, with secondarycardioneuropathologicinjury. The arrhythmogenic hazardsof chagasiccardiopathy are
Figure 4. Contraction band degeneration associated with areas of fibrosis. Azan stain X 150.
Cardiovasc Pathol W)l. 5, No. 4 July/Augu?t 1996:22 l--225
ARRHYTHMOGENESIS
IN CHAGAS’
225
MATTURRI DISEASE
Figure 5. Scars from old microinfarcts in between the subendocardial and subepicardial myocardium, arrhythmogenic in nature. Azan stain x 100.
mainly due to the striking disruptive fibrotic changes with ensuing electrical instability of the ventricular myocardium. Lesions of the conduction system and focal epiperineuritis of the intrinsic and extrinsic neuroreceptor glomera including cardiac plexuses play a concomitant role (15).
The authors wish to express their grateful appreciation to Mrs. G. Alfonsi and Mrs. Crippa for invaluable technical-histological help and to Miss G. Randazzo for keen secretarial work all throughout this research. This work was supported by grant 41.115.115237 from the Italian National Research Council (CNR)-Targeted Project “Prevention and control disease factors” subproject “Pathology of arrhythmias and sudden cardiac death.” and by IRCCS Ospedale Maggiore, Milano.
approach
to cardiac
arrhyth-
2. Milei J, Ferrans V, Meira de Oliveira J, Rossi L, Matturri L, Caputi E, SBnchez J, Xi Yu Z. Patologia. In: Storino R, Milei J, eds. Enfermedad de Chagas. Buenos Aires: Mosby Doyma Argentina, 1994;10:141184. 3. Rossi L. Histopathology Febiger 1979.
of Cardiac
6. Rossi L, Matturri L. Cardiomiopatia chagasica. tologico. Federazione Medica 1994: 10:23-26.
Aggiomamento
Arrhythmias.
Philadelphia:
4. Ferrans VJ, Milei J, Tomita Y, Storino R. Basement ening in cardiac myocytes and capillaries in chronic Am J Cardiol 1988;61:1137-1142.
Lea &
membrane thickChagas’ disease.
istopa-
7. Milei J, Storino RA, Beigelman R, Fernandez AG, Matturri L, Rossi L. Histopathology of specialized and ordinary myocardium and nerves in chronic Chagas’ disease, with a morphorrietric study of inflammation and fibrosis. Cardiologia 1991;36:107-114. 8. Kaberle F. Cardiopatia 1959;101:1308-1310.
parasympaticopriva.
9. Olsen GJ. Atlas of cardiovascular 1987;81. Fig. 8.21.
pathology.
Miinch
Med Wochenscrift
Lancaster:
MTP
10. Lopes ER, Tafuri WL. Involvement of the autonomic nervous in Chagas disease. Ret Sot Brasil Med Tropic 1983;16:2G29.
Press system
11. Factor SM, Cho S, Wittner, Tanowitz H. Abnormalities of the coronary microcirculation in acute murine Chagas’ disease. Am J Trop Med Hyg 1985;34:226-253. 12. Rossi M. Microvascular changes as a cause of chronic in Chagas’ disease. Am Heart J 1990: 120:233-236.
References I Rossi L, Matturri L. Clinicopathological mias. Turin: C. Scient Torinese, 1990.
5. Andrade ZA, Andrade GS, Oliveira GB, Alonso DR. Histopathology of the conducting tissue of the heart in Chagas’ myocarditis. Am Heart J 1978;95:31&321.
cardiomyopathy
13. Rossi L, Storino R, Milei J, Matturri L. Depleci6n neuronal en la enfermedad de Chagas: Todo deberia reverse. Revista Argentina de Cardiologia 1994;62:239-246. 14. Rossi L, Pozzato R, Matturri L. L’anatomia patologica della morte improvvisa cardiaca oggi. Riv It Med Leg 1991;13:93-1 10. 15. Rossi L. Histology of cardiac vagal innervation in man. PH Schwartz, eds. Vagal Control of the Heart. Arzmouk, 1994;3-20. 16. Antzelevitch C, Sicouri S. Clinical relevance of cardiac generated by after depolarization. Role of M cells in the U waves, triggered activity and torsade de pointes. J Am 1994;23:259-277.
In MN Levy, NY, Futura, arrhythmias generation of Co11 Cardiol