Humoral Immune Response to Cardiac Conducting Tissue
Ulrich Lotze 1 and Bernhard Maisch 2
1 University Hospital of Internal Medicine, Department of Internal Medicine III, University of Saarland, D-6650 Homburg/Saar, Federal Republic of Germany 2 Department of Internal Medicine-Cardiology, Philipps-University Marburg, Baldinger Strasse, D-3550 Marburg, Federal Republic of Germany
Introduction
Wherease autoimmune reactivity is well established in thyroid and other endocrine diseases, in muscular, dermatological and connective tissue diseases [13], only very few investigations have been carried out on humoral immune reactions in cardiac conducting and automaticity disturbances. There are few reports concern- ing the etiology and contributing pathogenetic factors compared to the wealth of literature on the electrophysiology or pharmacotherapy of conduction disorders.
This contribution summarizes data from the literature and our own investiga- tions on the immune response to cardiac conducting tissue [6, 7, 18, 21, 25, 29, 38-41, 44, 51, 56, 61, 62].
The Sick Sinus Syndrome (SSS)
Clinical and Etiological Features
The SSS was first described by Lown [31] and Ferrer [19]. Clinical features are palpitations, angina pectoris, heart failure, dizziness and also, but rarely, systemic emboli. The diagnosis is based on clinical symptoms, conventional ECG or 24 h-Holter monitoring. The SSS presents electrocardiographically with different manifestations, e. g., the sinuatrial (SA) block, the tachycardia-bradycardia syn- drome and the pathological sinusbradycardia [9, 19, 20].
In histopathological studies [15] the sinuatrial disorders were attributed to disproportional ageing of the sinus node and the atrial muscle: according to Davies and coworkers [15] sinus node and atrial tissue possess a higher content of collagen and have lost nodal cells. Idiopathic fibrosis of the sinus node, mostly described as age-related [15], deposits of amyloid staining material [47] or replacement of the sinus node tissue by fat [27] was also observed. Even lymphocytic infiltration
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410 u. Lotze and B. Maisch
may occur [16, 55]. There is still controversy as to whether coronary artery disease should be considered as the main cause leading to SSS [15, 17, 55], since there is evidence of SSS evoked by degenerative processes within the sinus node indepen- dent from a significant stenosis of the sinus node artery or its supplying coronary artery [12, 17, 55, 57, 59].
An overview of the etiological features of sinus node disorders is given in Table 1.
Table 1. Etiological factors in Sick sinus syndrome (SSS)
Antibodies Against the Human Sinus Node (ASN ab). Apart from our own reports on humoral reactions in SSS [30, 39, 40] there are no other communications about antibodies directed against human conducting tissue in sinus node disorders.
By using the indirect immunfluorescence or immunoperoxidase technique as described previously [39-41, 55] in 29 % of 45 patients with SSS (second or third degree SA block, tachycardia-bradycardia syndrome, pathological sinusbradycar- dia) antibodies directed to the human sinuatrial node could be demonstrated (Table 5). The ASN antibodies were primarily of the IgG, rarely of the IgA or IgM type. Complement (C3) fixation was found in 15% of the sero-positive patients.
Circulating autoantibodies were found to react primarily with the membrane of cells. In the cryostate sections antibodies to the interstitial tissue, the ex- tracellular-matrix or to specific surface antigens of the nodal cells could not be distinguished from each other. A typical staining pattern of circulating ASN an- tibodies from a patient with SSS is shown in Fig. 1.
In a separated group with bradyarrhythmia [9] 24% of the 17 patients were positive for ASN antibodies (Table 2). If the sera were used preabsorbed with
Humoral Immune Response to Cardiac Conducting Tissue 411
Fig. 1. Antibodies directed against the human sinuatrial node (indirect immunofluorescence test) giving a membrane staining pattern (oil immersion, 1 : 1250, Leitz Orthoplan)
human ventricular myocardium [39-41] 50% of the positive sera in the group of patients with bradyarrhythmia still showed ASN antibodies, but none in the group with SSS.
Antibodies Against Human Atrioventricular (A V) node (AA VN ab), HIS-bundle (AHIS ab) and Bovine Cardiac Purkinje Cells (ACPC ab). Apart from the an- tibodies directed to the human sinus node also circulating AAVN (18%), AHIS (22%) and ACPC [18] (11%) antibodies were found (Table 2). In the group of patients with bradyarrhythmia, 29 % showed AAVN antibodies. The relatively high incidence of AAVN antibodies in the group with sinus node disorders may be explained by a binodal disease (first to third degree AV-block) in five out of eight sero-positive patients with SSS and two out of four sero-positive patients with bradyarrhythmia, respectively. AHIS antibodies were present in 6 % of the patients with bradyarrhythmia which is comparable to the age-matched control group. In 35 % of this group antibodies to bovine Purkinje-fibers were detected (Table 2).
The incidence of anti-myolemmal (AMLA) and anti-sarcolemmal (ASA) an- tibodies [33] in sinus node dysfunction can also be derived from Table 2. Anti- SSA/Ro- or anti-SS-B/La-antibodies could not be found. Although in some patients antibodies directed to single- and double-stranded DNA were observed in low titers (< 25 U/ml) there was no clinical evidence of lupus erythematosus.
The Diagnostic and Prognostic Relevance of the ASN Antibodies. From our data a tenfold risk of developing SSS for patients with ASN antibodies can be postulated when compared to age-matched controls without rhythm disturbances. In com- parism to normal controls without any heart disease the calculated risk may be even higher (Table 2).
ASN antibodies are, therefore, highly specific for sinus node disorders, their sensitivity for identifying patients with SSS is lower, however.
412 U. Lotze and B. Maisch
Table 2. Antibodies in cardiac conduction disturbances and arrhythmias
Statistical significance by X 2 s q u a r e analysis with Yates correction factor a 2 P < 0.05 when compared to non cardiac controls (n = 23) b 2 P < 0.05 when compared to age-matched controls without rhythm disturbances (n = 31) c p < 0.008 when compared to healthy normals (n = 100) d p < 0.04 when compared to age-matched controls (n = 34)
P < 0.006 when compared to healthy normals (n = 100) f not significant g P < 0.001 when compared to the patients with rheumatoid arthritis, but without RBBB h p < 0.001 when compared to the patients with rheumatoid arthritis, but without RBBB Antibodies against: ASN = human sinus node; AAVN = atrioventricular node; AHIS = HIS bundle; ACPC = bovine cardiac Purkinje cells AMLA: Anti-myolemmal antibodies; ASA: anti-sarcolemmal antibodies; RBBB: right bundle branch block; LBBB: left bundle branch block
Humoral Immune Response to Cardiac Conducting Tissue 413
Based on absorption experiments [39-41] and the simultaneous prevalence of ASN antibodies and homologous AMLA (60 % - 100 %) and ASA (25 %-50 %) in the patients with SSS and bradyarrhythmia, a microheterogeneity of antibodies directed to human sinus node can be assumed. It is likely that ASA and AMLA are cross-reactive with sinus node tissue, but, by the absorption of the patients sera with human ventricular myocardium, it could be demonstrated that at least one unabsorbable antibody specific for the sinus node can be identified.
These observations are in accordance with previous investigations by Helander et al. [21] and Szabo et al. [58]. Using biochemical analysis they detected antigens specific for the cardiac conducting system which are not present in the working myocardium.
The two- to threefold higher incidence of anti-sinus node antibodies in patients with SSS and bradyarrhythmia associated with previous rheumatic fever or myocarditis in comparison to patients without a biography of these cardiac diseases indicates that patients with former inflammatory heart disease and circulating ASN antibodies have a high risk of developing, or already suffer from, SSS. ASN an- tibodies can, therefore, be considered not only as diagnostic but also as prognostic markers.
The Pathogenetic Relevance of the ASN Antibodies. The incidence of the ASN antibodies does not increase with the severity of heart disease (NYHA classifica- tion) nor from exact analysis of the patients biography with the time elapsed after the pacemaker implantation. Thus, these antibodies do not seem to be an epiphenomen in sinus node disorders. On the other hand it cannot be seen from the existing data whether these antibodies are essential for a possible immunopathogenesis of sinus node dysfunction [39, 40].
The AV Block
Clinical and Etiological Features
The AV conduction disturbances are divided in three groups: the rare first-degree AV block (PR) interval in the ECG prolonged over 0.20 s), the second-degree AV block Mobitz type I or Wenckebach block (progressive PR interval prolonga- tion prior to block of an atrial impuls), the Mobitz type II second-degree AV block (conduction fails suddenly without a preceeding prolongation of the PR intervals) and the third-degree AV block (no atrial impulse is conducted into the ventricles).
AV conduction disturbances do not become symptomatic before there is evidence of a second-degree AV block with 2 : 1 block and a slow escape rhythm (< 40 beats/rain) or a complete AV block. The clinical characteristics of third- degree AV block are similar to those of SSS. They include syncopal (Stokes-Adams attacks), dizziness, palpitations, congestive heart failure with dyspnoe, and in two thirds of all cases cardiomegaly. According to Davies et al. [15], data from 200 autotopsies of patients with chronic AV block demonstrate that the main cause of permanent AV block is bundle branch fibrosis [26, 29] in ca. 50%, followed by ischemic heart disease in 20 %-30%, and by calcification of the AV node in 10% of cases. A synopsis of etiological factors in AV block is given in Table 3.
414
T a b l e 3 . E t i o l o g i c a l factors in AV b l o c k
U. Lotze and B. Maisch
(modified according t o L a n d e g r e n and Bj6rck [24]) - C o n g e n i t a l with or without cardiac malformation [56] - Acute rheumatic fever [15] - Myocarditis
- a s s o c i a t e d t o ' rheumatic ' or collagen diseases: - HLA B 27 associated diseases [8], Reiter 's syndrome [43], rheumatoid arthritis [1, 61],
- Diphtheria [11] - Syphilis [15] - Chronic Chagas disease [54] - Sarcoidosis [48] - Other forms of myocarditis or pericarditis [14, 15]
- Valvular disease: - I n c l u d i n g chronic rheumatic heart disease [15]
- N o n - i s c h e m i c d e g e n e r a t i v e disorders: - Idiopathic bilateral bundle branch fibrosis in AV b l o c k :
- Lev 's disease [29] - L6n6gre's disease [26]
- Amyloidosis [47] - Haematochromatosis [15]
- Other cardiomyopathies: - Hypertrophic [60] - D e g e n e r a t i v e neuromuscular disease [45] - Friedreich's ataxia [15]
- Acute myocardial infarction, coronary artery disease [15] - T u m o r s o f t h e heart, metastatic disease [15] - Aortic and mitral valve surgery [23] - C a l c i f i c a t i o n o f t h e anulus fibrosus [15] - Carotid sinus syndrome, others [24] - Pharmacologic causes: Hyperpotassaemia; digitalis, quinidine, procainamide, others [24]
Immunological Findings
Anti-SS-A/Ro and Anti-SS-B/La Antibodies. As far as cardiac conduction distur- bances are concerned, anti-SS-A/Ro and anti-SS-B/La antibodies of the IgG type, diagnostic markers of the lupus erythmematosus (SLE) and the sicca syndrome, have been found both in mothers, often showing clinical signs of SLE, and tem- porarily in the neonates suffering from congenital complete heart block [25, 51, 56]. From the immunological and pathological studies in complete heart block (Table 2) it can be concluded, that anti-SSA/Ro and anti-SS-B/La antibodies are specific diagnostic markers for congenital AV block. Since SLE will often develop in later life [56], these anti-rubonuclein antibodies are also of prognostic value for the mother. In conformation of the serological data, Ro-IgG- and C3-deposits around the conduction system were described by Lee et al. [25] in a neonate who died of congenital complete heart block. It should be noted from other reports [51, 56] that anti-SS-A/Ro- and anti-SS-B/La-antibodies are not only diagnostic markers in congenital complete heart block, but may also be involved in the immunopathogenesis of congenital heart block itself.
Humoral Immune Response to Cardiac Conducting Tissue 415
In patients with acquired first to third degree AV block associated to polymyositis, Behan et al. [7] detected circulating anti-SS-A/Ro-antibodies of the IgG-type in 77.8 % (Table 2). However, we could not find La- and Ro-antibodies in acquired AV block unassociated to rheumatic disorders. The diagnostic relevance of these antibodies is, therefore, limited to AV block in patients with polymyositis or SLE. In analogy to the data from the congenital complete AV block it can be assumed that the A-SS-A/Ro-antibodies in patients with AV block associated to polymyositis are operative in the pathogenesis of acquired heart block in certain collagen diseases.
AAVN Antibodies. Apart from our own reports [38-41] investigations on the presence of circulating antibodies against human conducting tissue in chronic AV block were not undertaken. The immunological methods and the preparation of cryostate sections from human conducting tissue (sinus node, AV node and HIS bundle) are described elsewhere [39-41, 55]. AAVN antibodies were detected in the sera of 12 from 55 (22%) pacemaker patients with first- to third-degree AV block (Table 2). The first-degree AV block was either associated with distal bifascicular block (40%) or binodal disease (60%). The AAVN antibodies were primarily of the IgG, rarely of the IgM or IgA class. Complement (C3) fixation was observed in ca. 30%. The statistical significance of these observations is shown in Table 2, including the incidences of circulating AMLA and ASA [33] in AV block. When the sera were preabsorbed with human ventricular-myocar- dium [39-41] only one patient with third-degree AV block showed AAVN an- tibodies. A typical membraneous staining of AAVN antibodies can be seen in Fig. 2.
AAVNAntibodies as Diagnostic Markers. Based on the incidence of AAVN an- tibodies in 22% of patients with AV block and the positive sera in 10% of the age-matched controls without heart block (but including those with different forms
Fig. 2. Antibodies directed against the human atrioventricular (AV) node (indirect immuno- fluorescence test): a membrane staining is characteristic for the anti-AV node antibody; (oil immer- sion, i : 1250, Leitz Orthoplan)
416 U. Lotze and B. Maisch
of heart disease) a 2.2-fold risk of acquiring or already having an AV block can be calculated [39, 40]. In comparison with non-cardiac controls, who showed no AAVN antibodies, these antibodies are specific and prognostic markers for AV node disorders (Table 2). Our absorption experiments [39-41] and the simultaneous staining of the AV node and the human myolemma or human sar- colemma [33] in 50% of the sera containing AAVN antibodies show that a microheterogenity or a cross-reactivity of the AAVN antibodies exists. Since not all of the antibodies could be absorbed by ventricular myocardium, including Purkinje cells, at least two types of antibodies exist: one is a specific antibody directed to the AV node, the other is an absorbable, cross-reacting antibody.
Pathogenetic and Prognostic Relevance of the AAVN Antibodies. The threefold higher incidence of AAVN antibodies in patients with AV block and previous rheumatic fever or myocarditis compared to the patients with AV block (but without these inflammatory heart disease in their biography) indicates both the diagnostic and prognostic value of the AAVN antibodies. However, no pathogenetic role in the primary or secondary immunopathogenesis of AV conduc- tion disturbances, although ca. 30% of these antibodies fix complement [39, 40] can be derived just from the mere existence of the AAVN antibodies.
ASN and HIS Bundle Antibodies. ASN antibodies could be detected in 24 % of the patients with AV block (Table 2). In seven (54%) of the patients with AV block and ASN antibodies binodal disease was present. The incidence of AHIS antibodies was low (13 %) and statistically not significant when compared either to the non-cardiac or the age-matched controls (Table 2). Using sera preabsorbed with human ventricular myocardium [39-41] all sera of patients with AV block became negative for AHIS antibodies.
Fig. 3. A submembraneous or, more often, a cytoplasmic staining is typical for the antibodies directed against the bovine cardiac Purkinje fibers (indirect immunofluorescence test; oil immersion, 1 : 1250, Leitz Orthoplan)
Humoral Immune Response to Cardiac Conducting Tissue 417
ACPC Antibodies. ACPC antibodies were tested using the ox heart false tendon prepared according to Doniach and Fairfax [18]. A characteristic pattern of the mostly diffuse cytoplasmic, sometimes also of membrane-associated, staining can be seen in Fig. 3. Since sera containing anti-myosin or anti-mitochondrial an- tibodies could also be react with Purkinje cells, diagnosis of a specific ACPC an- tibody in the indirect immunofluorescence technique (IFT) must rule out anti- muscle or anti-mitochondrial antibodies, the former expressing a cross-striated, the latter a diffuse cytoplasmic pattern (unpublished data). Whereas other authors [44] who recently found circulating ACPC antibodies in chronic non-ischemic SA and AV block or in idiopathic heart block at or below the ,bundle of HIS in a range from 30 % to 45.5 % (Table 2), we found these antibodies not only in 27 % of patients with AV block, but also in a similar range in the age-matched control population. From our data the ACPC antibodies, therefore, cannot be considered as specific diagnostic or prognostic markers in AV conduction disturbances [39-41].
The Bundle Branch Block
By analysis of the electrocardiographical patterns, a left and a right bundle branch block (LBBB/RBBB) can be distinguished. In contrast to sinus node disorders (SSS, bradyarrhythmia) or AV block, LBBB or RBBB are not related to clinical symptoms like syncope or dizziness. In a few cases, however, a progression from bifascicular block to a trifascicular or complete AV block can be observed.
Clinical and Etiological Aspects in the LBBB
The LBBB is characterized by a prolonged ventricular complex (QRS) duration of > 0.12 s and a more generalized change of QRS morphology. It is found in nearly 0.2 %-1.2 % in young healthy persons and increases with age to 2.0 % [15]. Dependant on the degree of damage in the conducting tissue two forms can be distinguished from each other: the left anterior hemiblock (LAH) and the left posterior hemiblock (LPH). The pathological process leading to the LBBB is nonspecific and was first described by Lev [28] as a loss of the left bundle branch fascicles exceeding the usual changes with age and a number of other degenerative factors developing in the ageing heart.
The major diseases to which the LBBB is associated, according to [15], are: ischemia; hypertension with ventricular hypertrophy; aortic valve disease, par- ticularly stenosis; cardiomyopathies (congestive, hypertrophic); surgical trauma of the septum.
Immunological Findings (LBBB)
ACPC Antibodies. Circulating ACPC antibodies in idiopathic bundle branch fibrosis were first detected by Fairfax and Doniach [18] in 8.6% of the patients. This finding was not statistically significant (Table 2).
In our investigations we did not especially look for ACPC antibodies in LBBB, however, 60% of the patients with first-degree AV block and ACPC antibodies
418 u. Lotze and B. Maisch
simultaneously showed either a LAH or a bifacicular bundle branch block. Based on the heterologous nature of these antibodies and the low incidence when com- pared to controls (Table 2), they seem to be an epiphenomen and not a diagnostic, prognostic or even pathogenetic marker of LBBB.
Anti-SS-A/Ro antibodies. Circulating anti-SS-A/Ro antibodies were demonstrated in one of two patients with LBBB associated to polymyositis [7]. In analogy to other connective tissue diseases with heart block [56, 61, 62] it can be concluded that the anti-SS-A/Ro antibody is a specific diagnostic marker only for a small groups of patients with LBBB in association with polymyositis. The number of patients with LBBB and collagen diseases tested for these antibodies is to small to permit final conclusions.
Clinical and Etiological Features in the RBBB
The incidence of the RBBB (prolongation of the QRS complex > 0.12 s with delayed excitation of the right ventricle) in a normal population of elderly in- dividuals over 65 years is comparable to the incidence of the LBBB [15].
The following processes may lead to RBBB [15]: complete interruption of the proximal right branch; a progressive loss of conduction fibers with the risk of developing third-degree AV block in the familial and congenital form: an ischemic lesion of the right bundle branch during acute myocardial infarction; and a nonspecific fibrous, mostly proximal disruption of the main stem within the septum in the acquired non-ischemic RBBB.
The major etiological factors of RBBB, according to Davies et al. [15], are: ischemic heart disease; chronic lung disease with pulmonary hypertension; con- genital heart disease with cardiac or valve malformation (Ebstein's anomaly); familial; and chest trauma.
Immunological Findings (RBBB)
ACPC Antibodies. In 69% to 76% of patients with RBBB and simultaneous rheumatoid arthritis circulating ACPC antibodies of the IgG class could be detected [61, 62]. Since this incidence of the ACPC antibodies is only statistically signifi- cant in a selected group with RBBB associated to rheumatoid arthritis (Table 2), the ACPC antibodies are only considered to be diagnostic markers for RBBB in patients with rheumatoid arthritis. Whether the antibodies are also involved in the primary or secondary immunopathogenesis of the RBBB remains an open question.
Anti-SS-A/Ro antibodies. As in patients with LBBB and polymyositis, a circulating A-SS-A/Ro antibody could be demonstrated [6, 7] in one of two patients with RBBB associated to polymyositis and in one patient (case report) with RBBB and dermatomyositis who died from cardiac failure. The latter showed a decrease in peripheral suppressor lymphocytes and myocarditis with severe inflammation and fibrosis of the conduction system.
From these data it is likely that the A-SS-A/Ro-antibodies are also operative in the immunopathogenesis of RBBB in patients with connective tissue diseases, as previously described for congenital complete heart block [56].
Humoral Immune Response to Cardiac Conducting Tissue 419
Arrhythmias of Supraventricular Origin
Clinical and Etiological Features
There are different forms of tachycardia with originate from atrial excitation: AV- re-entrant (paroxysmal supraventricular) tachycardia, atrial fibrillation, atrial flut- ter, atrial tachycardia, junctional tachycardia. Because of their origin from the bundle branches, these supraventricular tachycardias show narrow QRS in the ECG.
The main causes of atrial tachycardia including flutter and fibrillation are myocarditis, rheumatic heart disease, pericarditis, coronary heart or mitral valve disease, acute myocardial infarction, hyperthyreodism, hypertensive heart disease, cardiac surgery and several pulmonary disease [46].
Immunological Findings
Immunological investigations on circulating antibodies directed to cardiac conducting tissue, especially in arrhythmias of supraventricular origin, have yet to be carried out.
Ventricular Arrhythmias
Clinical and Etiological Features
The ventricular tachycardia, characterized by QRS duration > 0.12 s and a fre- quency from 150-200 beats/min, originates from ventricular epitopic loci or the HIS bundle. It is a life-threatening rhythm disturbance, because there can be a sudden change into ventricular flutter or fibrillation. The clinical symptoms in- clude hypotension, shock, angina pectoris, heart failure or cardiac arest. Sudden cardiac death has often been attributed to ventricular tachycardias, flutter or fibrillation especially associated to congestive heart failure [5].
Ventricular arrhythmias are mostly described in acute myocardial infarction, coronary heart or valvular diseases, myocarditis, dilated cardiomyopathy, secondary heart muscle diseases and, less frequently, after hereditary prolongation of the QT interval (Romano-Ward syndrome, Jervell and Lange-Nielson syn- drome). Sudden cardiac death may occur from the latter, usually induced by exer- cise or stress. Moreover, the toxic side effects of drugs, electrolyte imbalance or proarrhythmic effects of antiarrhythmic therapy may cause ventricular ar- rhythmias.
Immunological Findings
The inflammatory process in myocarditis as well as the secondary im- munopathogenesis by humoral or cellular effector mechanisms may induce ven- tricular arrhythmias. In vitro, antibodies directed against the cardiac myolemma cause spherical contraction of myocytes in the presence of (and sometimes also without) complement [33], indicating a pathogenetic mechanism which has still to be proven to operate in vivo.
420 U. Lotze and B. Maisch
Conclusions
Whereas the immunopathogenesis of congenital heart block in neonates of mothers with latent or manifest connective tissue disease and in RBBB associated to der- matomyositis or polymyositis [6, 7, 25, 51, 56] is a well-established hypothesis which attributes relevance to anti-Ro or anti-La-antibodies, the true significance of circulating ACPC antibodies in either chronic heart or bundle branch block is controversial [18, 39-41, 61, 62]. The higher prevalence of ACPC antibodies in conduction disturbances associated to systemic autoimmune diseases may be interpreted as polyclonal B cell activation, which can be regularly observed in these diseases [44].
From our data a tenfold risk of developing SSS for patients with ASN an- tibodies and a two-to threefold risk of acquiring an AV block for patients with AAVN antibodies can be postulated when compared to age-matched controls without rhythm disturbances [39-41]. At least two different antibodies were detected by absorption experiments; one, which is cross-reactive or absorbable with ventricular myocardium and another, which is specific for the sinus or AV node. The simultaneous staining of the sinus and AV node in patients with binodal disease suggests, that the underlying pathogenetic process may not only affect the sinus node but also the AV node or other parts of the conducting tissue [12, 15, 16, 55, 57].
Former myocarditis and rheumatic fever are predisposing factors for the ex- istence of circulating antibodies directed against the conducting tissue in patients with SSS and AV block. The ASN and AAVN antibodies in patients with former inflammatory heart disease define a group of patients at risk for developing or already suffering from conduction disturbances and are, therefore, considered diagnostic and prognostic markers [39-41].
The concept of immunopathogenesis of conduction disorders may also be applied to postmyocarditic heart diseases [32, 37, 42], perimyocarditis [32, 35, 36, 37, 42] and post-pericardiotomy syndrome [34] in the future. It indicates that not only the myocardium but also the cardiac conducting system can be the target in the secondary immunopathogenesis.
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