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(Circulation. 2001;103:1765.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Differential Profile and Biochemical Effects of Antiautonomic Membrane Receptor Antibodies in Ventricular Arrhythmias and Sinus Node Dysfunction
From the Division of Cardiology, Ramos Mejía Hospital and Institute of Genetic Engineering and Molecular Biology (INGEBI-CONICET), Buenos Aires, Argentina.
Correspondence to Dr Pablo A. Chiale, General Urquiza 609, 1221 Buenos Aires, Argentina. E-mail pchiale{at}sinectis.com.ar
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Abstract |
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Background—The relationship between anti-ß-adrenergic (anti-ßR) and anti-M2-cholinergic (anti-M2R) receptor antibodies (Abs) and cardiac arrhythmias and their biochemical effects have not been systematically investigated.
Methods and Results—We studied 41 patients, 28 with ventricular arrhythmias (primary or due to Chagas’ heart disease or idiopathic dilated cardiomyopathy; group I), 13 with sinus node dysfunction (primary or caused by Chagas’ heart disease; group II), and 10 healthy controls (group III). The chronotropic effects of the IgG and immunopurified anti-ß1RAbs or anti-M2RAbs were assessed on cultured cardiomyocytes before and after exposure to atropine and propranolol. The biochemical effects of the IgG from 9 patients from group I, 6 from group II, and 6 controls were evaluated on COS7 cells transfected with genes encoding for ß1,ß2-adrenergic receptors (cAMP increment) or M2-cholinergic receptors (phosphatidylinositol increment). The IgG from group I patients exerted a positive chronotropic action, with a high prevalence of anti-ßRAbs (75%) and low prevalence of anti-M2RAbs (10.7%) and induced a clear-cut and long-lasting increment in cAMP. The IgG from group II patients depressed chronotropism, with a high prevalence of anti-M2RAbs (76.9%) and low prevalence of anti-ßRAbs (15.4%) and evoked a marked augmentation of phosphatidylinositol.
Conclusions—Our results demonstrate a strong correlation between anti-ßRAbs and ventricular arrhythmias and anti-M2RAbs and sinus node dysfunction. Anti-ßRAbs increase and anti-M2RAbs inhibit cAMP production. These findings offer new insight into the etiology and pathophysiology of cardiac arrhythmias, with therapeutic implications.
Key Words: antibodies • arrhythmia • receptors, adrenergic, beta • receptors
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Introduction |
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Circulating antibodies with agonist-like properties on cardiac autonomic membrane receptors have been reported in heart diseases in which ventricular tachyarrhythmias and bradyarrhythmias are common.1 2 3 4 5 An enhanced sympathetic drive of the heart and catecholamines play a major role in the pathophysiology of ventricular arrhythmias,6 7 whereas an augmented vagal tone and strong vagal stimuli depress sinus node activity and AV nodal propagation.8 9 Thus, it can be hypothesized that the antibodies that stimulate ß-adrenergic and M2-cholinergic receptors might participate in the pathogenesis of ventricular ectopy and bradyarrhythmias, respectively. Anti-ß-adrenergic receptor antibodies were related to ventricular arrhythmias (VAs) in idiopathic dilated cardiomyopathy, whereas anti-M2-cholinergic receptor antibodies were associated with chagasic or idiopathic sinus node dysfunction (SND)4 and other arrhythmias found in Chagas’ heart disease.5 Nevertheless, neither the prevalence nor the functional and biochemical effects of these antibodies in different cardiac arrhythmias have been systematically investigated.
The aim of this study was to explore a link between circulating antiautonomic membrane receptor antibodies and the arrhythmias (ventricular ectopy or SND) observed in selected cardiac disorders and to investigate the functional and biochemical effects of these antibodies.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Population
Forty-one patients and 10 healthy volunteers were studied (Table 1
). Group I consisted of 28 patients with VA
occurring in a structurally normal heart (14 patients) or caused by
chronic Chagas’ heart disease (9 patients) or idiopathic dilated
cardiomyopathy (5 patients). Group II comprised 13 patients with SND,
either primary (4 patients) or chagasic (9 patients). Group III was
composed of 10 healthy controls.
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The evaluation included a clinical and cardiological examination, serological tests for Chagas’ infection, an ECG at rest, a B-mode echocardiogram, 201Tl scintigraphy, and 24-hour ECG Holter monitoring. Coronary angiography was performed in the 5 patients with idiopathic dilated cardiomyopathy, and 25 patients (12 with VA and 13 with SND) underwent an electrophysiological study.
Chronic Chagas’ heart disease and idiopathic dilated cardiomyopathy were diagnosed according to reported criteria.10 11 The arrhythmias were regarded as primary whenever no structural abnormalities of the heart were detected and serological tests for Chagas’ disease were negative.
Patients with >30 ventricular extrasystoles per hour were included (range 866 to 18 615/24 hours). Ventricular ectopy was uniform in 14 patients and multiform in the other 14. Repetitive ventricular activity was documented in 20 patients. Five patients had experienced 1 or more episodes of sustained ventricular tachycardia, and in 4 of them, the arrhythmia was induced by programmed ventricular stimulation.
SND was diagnosed as reported previously,12 either when VAs were absent (10 patients) or when a nonsignificant number of ventricular extrasystoles (<1/hour; 3 patients) were recorded.
After clinical evaluation, blood samples were drawn, and sera were obtained and coded. The IgG fractions and antiautonomic receptor antibodies were purified and their functional and biochemical effects evaluated.
The study protocol was approved by the Ramos Mejía Hospital Ethical Board. Each patient was informed about the study characteristics and signed a written consent form.
IgG Fractionation
IgG fractions were separated by ammonium sulfate
precipitation13 and dialyzed
against PBS. Less than 10% contamination with IgM was demonstrated by
an enzyme immunoassay.
Antibody Immunopurification
Antibodies against
M2-cholinergic and
ß1-adrenergic receptors were affinity purified
from the IgG with synthetic peptides corresponding to the second
extracellular loop of the receptors (M2:
VRTVEDGECYIQFFSNAAVTFGTAI; ß1:
HWWRAESDEARRCYNDPKCCDFVTNR) coupled to activated CNBr
Sepharose.13
Functional Assay
The chronotropic effects of IgG and immunopurified
antibodies were assessed on spontaneously beating cultured
cardiomyocytes.13 The
baseline beating rate, measured in 10 fields at 37°C, was 120±24
bpm. Measurements were repeated 1 hour after exposure to IgG at a 1:50
dilution and subsequent addition of atropine
(10-7 mol/L), propranolol
(10-7 mol/L), and isoproterenol
(10-5 mol/L). Functional tests were
performed in a blinded manner 3 times for reproducibility.
The functional test was considered positive for the presence of anti-ß-adrenergic receptor antibodies if addition of IgG induced a statistically significant increase in the beating rate (compared with the control IgG) that was neutralized by propranolol. It was considered positive for the presence of anti-M2-cholinergic receptor antibodies whenever addition of IgG led to a statistically significant reduction in the beating rate (compared with the control IgG) that was antagonized by atropine.
IgG from a single patient may contain both anti-M2-cholinergic and anti-ß-adrenergic receptor antibodies, whose chronotropic effects may counteract each other. Therefore, a significant increase in the beating rate of cardiomyocytes after exposure to atropine that was in turn antagonized by propranolol, even in the absence of any initial significant change induced by the IgG alone, was interpreted as an indication of the presence of both types of antiautonomic receptor antibodies.
Biochemical Studies
Expression Vectors and Transfection
COS7 cells were transfected with pBC expression
vector containing cDNA encoding for the human
ß1-adrenergic
receptor,14 pSVL containing
the gene of the rat ß2-adrenergic receptor.
For phosphatidylinositol (PI) turnover, cells were cotransfected with
OB vector containing M2-cholinergic receptor
cDNA plus pcDNAI vector having the cDNA encoding for a chimera of
murine Gi+Gq transduction
proteins15 or with pCEFL
containing the M1-cholinergic receptor cDNA as
control. The pCMV-ß-Gal plasmid was used to evaluate basal receptor
expression and transfection efficiency, estimated as 75% by a ß-Gal
colorimetric method.15
Plasmids were amplified in Escherichia
coli XL1 Blue (Stratagene) and purified by column
chromatography (Qiagen Maxiprep kits). One microgram of the expression
plasmid was used to transfect COS7 cells, as described
previously.15 16
Measurement of cAMP and PI Hydrolysis
The principle of competitive protein binding was used
to assess cAMP production in ß1- and
ß2-adrenergic transfectants after incubation
with 10-5 mol/L isoproterenol for 10
minutes or with a 1:50 final dilution of the IgG for up to 60 minutes,
and finally expressed as
pmol/tube.15
M2+Gi/q cotransfectants
and M1 transfectants (control) incubated 1 hour
with 50 µmol/L carbachol or the IgG were used to evaluate PI
hydrolysis, as described
previously.17 ß-Gal
transfectants were used as controls for each
experiment.
Statistical Analysis
Changes in the beating rate were assessed by ANOVA
and Tukey test. A MANOVA test was used to compare the results between
groups (Software Statistica 5.1, 1997).
P<0.05 was chosen as the least
significant difference. Changes in cAMP and PI production were
evaluated by nonparametric tests (Kruskal-Wallis and Dums) and
the Mann-Whitney rank sum test,
respectively.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Prevalence of Antiautonomic Membrane Receptor Antibodies in Relation to Cardiac Arrhythmias
Figure 1
depicts the chronotropic effects of the IgG
fractions. The beating rate was not modified by the IgG from the
healthy controls, whereas it was increased by the IgG from patients
with VA and decreased by the IgG from patients with SND
(P<0.001 between groups),
irrespective of the origin of the arrhythmias.
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Figure 2 shows the prevalence of antiautonomic membrane
receptor antibodies in the different study groups and according to the
cause of the arrhythmias. No antiautonomic membrane receptor antibodies
were detected in the healthy controls. Patients with VA showed a high
prevalence of anti-ß-adrenergic receptor antibodies (75%;
P<0.001 versus groups II and
III) and a relatively low prevalence of
anti-M2-cholinergic receptor antibodies (10.7%;
P<0.05 versus group III). The
prevalence of anti-ß-adrenergic receptor antibodies was similar for
patients with primary VA (72%), Chagas’ heart disease (78%), and
idiopathic dilated cardiomyopathy (80%), whereas
anti-M2-cholinergic receptor antibodies occurred
only in the first subgroup (22%). In marked contrast, patients with
SND had a high prevalence (76.5%) of
anti-M2-cholinergic receptor antibodies (75%
for the subgroup with primary SND and 78% for chagasic patients;
P<0.001 versus groups I and
III) and a low prevalence (15.4%) of anti-ß-adrenergic receptor
antibodies, which were present only in chagasic patients (22%;
P<0.10 versus group III).
Thus, anti-ß-adrenergic receptor antibodies were significantly more
prevalent in patients with VA than in those with SND, whereas the
opposite occurred regarding anti-M2-cholinergic
receptor antibodies.
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Table 2 shows the effects of atropine on the
electrocardiographic and electrophysiological manifestations of SND as
related to the presence of antiautonomic membrane receptor antibodies.
Although the number of patients did not allow reliable statistical
analysis, the prevalence of anti-M2-cholinergic
receptor antibodies did not differ substantially in patients in whom
atropine corrected the manifestations of SND totally or in part. The
same occurred regarding anti-ß-adrenergic receptor antibodies in
patients with inducible versus noninducible sustained ventricular
tachycardia.
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Figure 3 illustrates the correlation of the
electrocardiographic findings with the in vitro effects of the IgG from
2 patients, 1 with a "pure" primary SND (A) and the other with
chagasic VA (B). In
Figure 3A, a pronounced sinus bradycardia that was corrected
by atropine (top) and the chronotropic effect of the IgG fraction on
cultured cardiomyocytes before and after addition of atropine (bottom)
were concordant with the clinical findings. The marked slowing of the
beating rate induced by the IgG was neutralized by atropine, indicating
the existence of anti-M2-cholinergic receptor
antibodies. In B, a selected strip from a 24-hour ECG Holter monitoring
shows the characteristics of the ventricular ectopy (top). A 95%
suppression of ventricular extrasystoles was achieved with nadolol at a
daily dose of 80 mg (from 3765 at baseline to 188 after 7 weeks of
treatment), suggesting that the arrhythmia was adrenergically driven.
Furthermore, the chronotropic action of the IgG from this patient was
abolished by propranolol (bottom), denoting the presence of
anti-ß-adrenergic receptor antibodies.
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Analysis of the effects of the IgG on an individual basis
revealed a broad spectrum of quantitative and qualitative chronotropic
changes
(Figure 4). Furthermore, the chronotropic effects of the IgG
fractions from 9 patients having anti-ß-adrenergic receptor
antibodies and from 2 with anti-M2-cholinergic
receptor antibodies were not totally abolished by the corresponding
autonomic receptor antagonist. This was not due to low concentrations
of atropine or propranolol in the assay, because concentrations >1
µmol/L caused a toxic effect (absence of chronotropic activity or
slow and irregular rhythm). Therefore, persistence of a mild or
moderate, but still significant, chronotropic effect of an IgG after
addition of atropine or propranolol would suggest the presence of
antibodies acting on membrane receptors other than the
M2-cholinergic or the ß-adrenergic receptor
and/or on ionic channels that influence cardiomyocyte
automatism.
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The results obtained with the IgG before and after addition
of atropine and propranolol indicate indirectly the presence of
antiautonomic receptor antibodies. Functional testing of the
immunopurified antibodies in 10 selected cases was perfectly concordant
with that performed with the IgG
(Table 3).
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Changes in Second Messenger Production
In
Figure 5, the biochemical effects of the IgG containing
ß1- and/or
ß2-adrenergic receptor antibodies or
anti-M2-cholinergic receptor antibodies were
compared with those of the IgG from healthy controls. The latter did
not modify cAMP or PI production. The IgG from patients with VAs
increased cAMP in COS7 cells transfected with either
ß1-adrenergic receptors (2.8±1.1-fold versus
0.25±0.36-fold in patients with SND;
P<0.001) or
ß2-adrenergic receptors (7.4±5.4-fold versus
0.55±0.26-fold in patients with SND;
P<0.001) without affecting PI
concentration. In contrast, the IgG from patients with SND only
increased PI production (5.8±4.5-fold versus 0.13±0.12-fold in
patients with VAs; P<0.01).
Thus, anti-ß1- and
anti-ß2-adrenergic receptor antibodies
stimulate the corresponding membrane receptor that interacts with the
Gs protein to induce an increment of cAMP.
Anti-M2-cholinergic receptor antibodies
stimulate the corresponding receptor that interacts with the
Gi protein, inhibiting cAMP production. These
actions explain the chronotropic action of the antibodies on
cardiomyocytes. The long-lasting increment of cAMP induced by the
anti-ß-adrenergic receptor antibodies contrasts with the ephemeral
action of isoproterenol
(Figure 6).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our results demonstrate a strong correlation between circulating anti-ß-adrenergic receptor antibodies and VA in the setting of a structurally normal heart, idiopathic dilated cardiomyopathy, and Chagas’ heart disease, as well as between circulating anti-M2-cholinergic receptor antibodies and primary or chagasic SND. Anti-ß-adrenergic receptor antibodies are rare in patients without VA, whereas anti-M2-cholinergic receptor antibodies are rare in patients with normal sinus node function. Furthermore, anti-M2-cholinergic receptor antibodies are uncommon in patients with "pure" VA, whereas anti-ß-adrenergic receptor antibodies are rarely present in patients with "pure" SND.
IgG from a number of patients with either VA or SND contains both anti-ß-adrenergic receptor and anti-M2-cholinergic receptor antibodies, whose functional effects on cardiac cells may neutralize each other. In 5 patients (not included in this study) who had both VA and SND, the prevalence of anti-M2-cholinergic and anti-ß-adrenergic receptor antibodies was 80% and 40%, respectively. Under such circumstances, the antibodies should not show any potential arrhythmogenic action, thus invalidating the relationship between arrhythmias and antibodies. However, it may be postulated that the net functional effect of the IgG on cardiac tissues is dependent not only on the relative concentration of each type of antiautonomic membrane receptor antibody but also on the relative density of ß-adrenergic and M2-cholinergic receptors in the different heart tissues. The functional actions of anti-M2-cholinergic receptor antibodies should prevail in the sinus and AV nodes, rich in cholinergic innervation and receptors. In fact, the inhibitory action of the vagal stimulation on the sinus node prevails over the sympathetic stimulation when both systems are activated simultaneously.18 19 Conversely, the functional effects of ß-adrenergic receptor antibodies should predominate in the ventricle, where ß-adrenergic innervation and receptors are prevalent.20 Accordingly, the presence of both types of antiautonomic membrane receptor antibodies demonstrated in patients with Chagas’ heart disease13 may explain the coexistence of SND and complex VA, as well as the fact that the heart rate is often slow in chagasic patients with heart failure.10 Matsui et al21 reported that rabbits immunized simultaneously with M2-cholinergic and ß1-adrenergic peptides developed a cardiomyopathy with left ventricular hypertrophy, mild inflammatory cell infiltrates, and interstitial fibrosis.
Biochemical, Arrhythmogenic, and
Cardiomyopathic Effects of Antiautonomic Membrane Receptor
Antibodies
The functional and biochemical tests indicate that
antiautonomic membrane receptor antibodies stimulate the corresponding
cardiac receptors. IgG containing anti-ß-adrenergic receptor
antibodies induces a long-lasting increment of cAMP in
ß1- and
ß2-transfectants, as demonstrated in CHW cells
for anti-ß1-adrenergic receptor antibodies
from patients with idiopathic dilated
cardiomyopathy.22 In
contrast, IgG containing anti-M2-cholinergic
receptor antibodies decreased cAMP production in
M2 transfectants, as shown in membranes of rat
heart ventricles.23 The
catecholamine-like and acetylcholine-like actions of the antibodies
might play a major role in the pathophysiology of VA and SND,
respectively. Nevertheless, no direct or conclusive proofs of the
potential arrhythmogenic properties of antiautonomic membrane receptor
antibodies are available. A recent report by Farias de Olivera et
al5 showed that the IgG from
chagasic patients causes bradycardia and AV block in a Langendorff
preparation of the rabbit heart. Interestingly, in our patients with
SND and anti-M2-cholinergic receptor antibodies,
the electrophysiological abnormalities were totally or partially
corrected by atropine. Furthermore, in 4 of our patients with VA and
anti-ß-adrenergic receptor antibodies, nadolol (80 to 160 mg/d
orally) suppressed ventricular ectopy by >90% (baseline 2515 to 7085
per 24 hours, nadolol 51 to 564 per 24 hours).
The antiautonomic membrane receptor antibodies might play a role in the pathogenesis of cardiac arrhythmias not only via their functional effects on the receptors and changes in the electrophysiological properties of cardiac tissues, but also by causing structural damage to the myocardial cells. Matsui et al24 reported that chronic immunization of rabbits with ß1- or M2-peptides induces a cardiomyopathy with ventricular dilation and the histological pattern of chronic myocarditis and that 2 of 8 rabbits immunized with the ß1-peptide died suddenly. The cardiomyopathic effects of immunization with the peptides may be prevented by simultaneous treatment with specific antagonists. In addition, immunoadsorption dramatically improves myocardial performance and left ventricular dimensions in patients with heart failure due to idiopathic dilated cardiomyopathy and circulating anti-ß1-adrenergic receptor antibodies.25 26
The Nature of the Immunologic Disorder Causing
Antiautonomic Membrane Receptor Antibodies
Experimental evidence indicates that ß-adrenergic and
M2-cholinergic receptors may be
immunogenic.24 27
However, the factors that trigger the immunoregulatory abnormality
involving the autonomic membrane receptors in cardiac diseases are
unknown. The observations of Kaplan et
al28 shed light on the
nature of the antibodies that recognize and stimulate the autonomic
membrane receptors of cardiac cells in patients with Chagas’ heart
disease. They demonstrated that the antibodies directed against a
ribosomal P protein of Trypanosoma
cruzi cross-react with and stimulate the
ß1-adrenergic receptors. This was attributed
to a stretch of acidic residues present in the R13 peptide of the
parasite (EEEDDD), which is homologous to an epitope of the second
extracellular loop of the ß1-adrenergic
receptor (AESDE). Therefore, antiautonomic receptor antibodies may
actually be directed against antigens of an infectious agent and may
not be the result of an autoimmune reaction involving the
ß-adrenergic and/or M2-cholinergic
receptors.
Implications
In accordance with our results, it is possible to
speculate about a potential pathogenic link between antiautonomic
membrane receptor antibodies and cardiac arrhythmias found in diverse
heart diseases. This approach may open new research avenues and
contribute to the knowledge of the etiology and pathophysiology of
cardiac arrhythmias, which may have therapeutic consequences.
Demonstration of the arrhythmogenic activity of these antibodies
remains an issue that merits further clinical and experimental
investigations.
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Acknowledgments |
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This study was supported by the Fundación de Investigaciones Cardiológicas Einthoven, the European Commission, the WHO/TDR, the University of Buenos Aires (project 01/TW18), and ANPC-Foncyt-SECyT-Argentina (project BID802/OC-AR-PICT05-00103-02030).
Received August 28, 2000; revision received December 1, 2000; accepted December 14, 2000.
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P. LOPEZ BERGAMI, J. SCAGLIONE, and M. J. LEVIN Antibodies against the carboxyl-terminal end of the Trypanosoma cruzi ribosomal P proteins are pathogenic FASEB J, December 1, 2001; 15(14): 2602 - 2612. [Abstract] [Full Text] [PDF]
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