(Circulation. 1999;99:649-654.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Autoantibodies Activating Human ß1-Adrenergic Receptors Are Associated With Reduced Cardiac Function in Chronic Heart Failure
From the Medizinische Poliklinik (R.J., G.I., F.B.) and the Institut für Pharmakologie (R.J., V.B., C.S., M.J.L.), University of Würzburg, Germany.
Correspondence to Dr Fritz Boege, Medizinische Poliklinik der Universität Würzburg, Klinikstraße 6-8, D-97070 Würzburg, Germany. E-mail boege.medpoli{at}mail.uni-wuerzburg.de
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Autoantibodies against synthetic peptides of ß-adrenergic receptors have been observed in human cardiomyopathy. However, it has never been shown that such antibodies really interact with native human ß-adrenergic receptors, nor has the clinical impact of such an interaction been investigated in larger groups of patients.
Methods and Results—We screened 104 patients with dilated or ischemic cardiomyopathy (NYHA functional classes II to IV) and 108 healthy subjects for IgG antibodies reacting with ß-receptor peptides. Such IgGs were further analyzed for binding and functional interactions with native recombinant human ß-adrenergic receptors. Antibodies reacting with synthetic receptor peptides were present in 51% of the patients. However, only a subgroup directed against the second extracellular receptor domain also recognized native human ß-adrenergic receptors situated in a cell membrane. All antibodies of this subgroup impaired receptor ligand binding and enhanced receptor-mediated signaling, which could be blocked by 5 µmol/L bisoprolol in vitro. Their prevalence was 1% in healthy subjects and 10% in ischemic cardiomyopathy, whereas it amounted to 26% in dilated cardiomyopathy and was associated with a significantly poorer left ventricular function.
Conclusions—Our data show that activating autoantibodies against
human ß-adrenergic receptors exist in 
25% of patients with
dilated cardiomyopathy. Counteraction of such
autoantibodies might contribute to the beneficial effects of
ß-adrenergic receptor blockade in chronic heart failure.
Key Words: antibodies • receptors, adrenergic, beta • cardiomyopathy • immune system
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Dilated cardiomyopathy (DCM) is defined by progressive dilation and loss of function of the left ventricle in the absence of known causes.1 Autoimmune responses against various myocardial antigens2 3 have been proposed to be involved in its pathogenesis. Some recent observations indicate that autoimmunity against ß-adrenergic receptors might also play a role: autoantibodies reacting with synthetic peptides derived from ß-adrenergic receptors4 or affecting ß-receptor–mediated functions in animal cells5 6 have been reported, their prevalences varying from 30% to 95% in patients and from 0% to 16% in healthy subjects.6 7 However, it has never been shown that such antibodies really interact with native human ß-adrenergic receptors, nor has the clinical impact of such a direct receptor-antibody interaction been demonstrated in larger groups of patients. Furthermore, it is unclear whether such autoantibodies activate4 6 or inhibit5 8 ß-adrenergic receptors and whether they interfere with ligand binding to the receptor8 or not.9
Several technical developments of the past few years make it possible to address these questions in a more direct manner. These include the cloning of the human receptor cDNAs10 11 and their expression in various cell types, which allows a much more precise definition of autoantibodies than either synthetic peptides or animal cell lines used in earlier studies. Furthermore, the generation of specific and subtype-selective antibodies12 provides positive controls for such experiments. In the present study, we used these instruments in a large number of heart failure patients and healthy control subjects to address the question of autoantibodies against ß-adrenergic receptors in cardiomyopathy.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients and Samples
One hundred four patients were recruited in the course of routine heart catheterization, all suffering from heart failure (NYHA functional classes II to IV), with a left ventricular diastolic volume >110 mL/m2 and an ejection fraction <55% (by ventriculography). DCM (n=65) was diagnosed when coronary heart disease was excluded by angiography and exposure to cardiotoxic substances, myocarditis, or other systemic heart diseases were not evident from clinical history. In ventriculography, all patients of this subgroup exhibited a diffuse reduction in wall motion. ICM (n=39) was diagnosed when a significant stenosis (>75%) of
1 of
the main coronary arteries was ascertained by angiography
and/or myocardial infarction was apparent in the clinical history.
Regional wall motion abnormalities and ECG signs of transmural
infarction were evident in all patients of this subgroup. At the time
of sample acquisition, all patients were stable under therapy with
diuretics, ACE inhibitors, digitalis, and nitrates.
None of them were treated with ß-adrenergic receptor agonists or
antagonists. Healthy control subjects (n=108) were matched
for sex and age. Table 1
summarizes basic clinical and hemodynamic data. All
assays were carried out with IgG fractions isolated by caprylic acid
precipitation and normalized to total IgG concentration (µg/mL).
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Immunoassays With Synthetic Antigens
Peptides corresponding to the second extracellular domains or
fusion proteins of aminotermini and carboxytermini of human
ß1- or ß2-adrenergic
receptors12 were coated onto ELISA plates (5 ng/well) or
spotted onto activated nitrocellulose membranes.13
BSA and a nonreceptor peptide served as specificity controls. Antigens
were probed with the IgG preparations (ELISA: 25 and 12.5 µg/mL, 12
hours, 4°C; dot blotting: 50 µg/mL, 2 hours, 37°C), and bound IgG
was detected with biotinylated secondary antibodies,
streptavidin-peroxidase, and
o-phenylenediamine (ELISA) or horseradish
peroxidase–conjugated secondary antibodies and enhanced
chemiluminescence (dot blotting).
Immunoassays With Intact Recombinant Receptors
Human ß1- or
ß2-adrenergic receptors expressed in
baculovirus-infected Sf9 insect cells were used for Western blotting
and indirect immunofluorescence microscopy.
Receptor-specific antibodies raised in rabbits12 served as
positive controls. Cells infected with wild-type baculovirus were used
to define nonspecific staining. Cell lysates were subjected to native
Western blotting14 and incubated with IgG preparations (50
µg/mL, 12 hours, 4°C), and immunoreactive bands were visualized by
enhanced chemiluminescence. For indirect
immunofluorescence microscopy, intact unfixed Sf9
cells were incubated with IgG preparations (167 and 83 µg/mL, 6
hours, 4°C), counterstained with CY3-labeled secondary antibodies
(Dianova), and spotted onto glass slides. Red epifluorescence
was photographed at 400-fold magnification with fixed exposure
times.
Functional Assays
Antibody effects on binding of the radioligand
[3H]CGP 12177 (3 nmol/L, NEN-DuPont) to human
ß-adrenergic receptors expressed in Sf9 cells were
measured12 after the cells had been incubated with IgG
preparations (17, 67, or 167 µg/mL, 30 minutes, 30°C, triplicate
experiments).
Antibody effects on cellular cAMP and the activity of cAMP-dependent
protein kinase were studied in Chinese hamster fibroblasts (CHW cells)
expressing 100 to 120 fmol/mg human ß-adrenergic receptors. Confluent
cells were incubated with human IgG preparations (40 µg/mL, 1 hour,
37°C) in the presence of 0.5 mmol/L
isobutylmethylxanthine. In a second series of
experiments, bisoprolol (5 µmol/L, Merck AG) was added to the
cells together with the IgG preparations. Subsequently, the cells were
either exposed or not exposed to 10 µmol/L (–)isoproterenol and
were incubated further (15 minutes, 37°C). Finally, cellular cAMP was
extracted with boiling water and measured by
125I-labeled cAMP scintillation proximity assay
(Amersham). cAMP-dependent protein kinase activity was determined in
the lysates of cells treated without
isobutylmethylxanthine, with
[
-32P]ATP and 100 µmol/L
kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly, a peptide-based
substrate) as substrate.15 Each series of experiments was
repeated at least 3 times.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Demonstration of ß-Adrenergic Receptor Autoantibodies
Screening With Synthetic Analogues of Selected Receptor Domains
IgG preparations of heart failure patients and healthy control subjects were initially screened for antibodies capable of binding to synthetic domains of human ß1- or ß2-adrenergic receptors (aminoterminus, second extracellular domain, and carboxyterminus) by ELISA. An increased reactivity was assumed for signals above the upper limit of the respective 95% CIs (mean±2 SD) of the healthy subjects. By this criterion, 51% of the patients showed increased reactivity with
1 of
the selected receptor domains (Figure 1a). Of the positive sera, 24% showed
multiple reactivity with >1 receptor domain (Figure 1a, numbers
in parentheses) and 59% revealed cross-reactions between
ß1- and ß2-adrenergic
receptors (Figure 1a, hatched bars).
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Control for Nonspecific Hyperreactivity
The high prevalence (24%) of multiple reactions with several
receptor domains could indicate either polyclonal immune responses
against the whole receptor molecule or high levels of nonspecific
binding. To differentiate between these possibilities, IgG preparations
with increased reactivity toward synthetic ß-adrenergic receptor
domains were also checked for binding to albumin and a
nonreceptor control peptide by dot blotting, which allowed a clear
differentiation between specific binding to 1 or several receptor
domains (Figure 2a, lanes 1 to 3),
negative results (Figure 2a, lane 4), or nonspecific binding to
all protein spots on the membrane (Figure 2a, lane 5). The
prevalences of truly specific antibodies remaining after elimination of
nonspecific reactions are summarized in Figure 1b
: 34% and 31%
of the patients with DCM and ICM, respectively, but only 4% of the
healthy subjects had circulating IgG specific for synthetic
ß-receptor domains. In DCM, 83% of these antibodies were directed
against the second extracellular domains, 86% recognized the
ß1-adrenergic receptor, 41% recognized
ß1- and ß2-receptor
subtypes, and only 14% were selective for
ß2-adrenergic receptors. In ICM, in contrast,
these antibodies were directed with similar frequency against all 3
receptor domains tested and both receptor subtypes (Figure 1b).
Multiple reactivity with several receptor domains appeared to be mostly
due to nonspecific binding (compare numbers in parenthesis between
Figure 1a and 1b). Only 1 patient in each group showed specific
reactions with the aminoterminus and the second extracellular domain of
the ß1-adrenergic receptor.
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Demonstration of IgG Binding to Native Human ß-Adrenergic
Receptors
To analyze binding of human IgG preparations to
ß-adrenergic receptors presented in their native conformation
in a cell membrane, we performed immunofluorescence
experiments with unfixed Sf9 cells transiently overexpressing intact
human ß-adrenergic receptors. A representative result
is shown in Figure 2c: in cells infected with recombined
baculovirus coding for human ß1- (top) or
ß2-adrenergic receptors (middle), a pattern
typical for membrane proteins could be visualized by receptor-specific
antibodies raised in rabbits (Figure 2c, Rabbit). Cells devoid
of ß-receptors were not stained (bottom). A similar receptor-specific
immunofluorescence pattern was obtained with 87%
of those IgG preparations, which according to ELISA and dot blotting
were specific for the second extracellular domains of ß-adrenergic
receptors (Figure 2c, Patients). For some of these antibodies,
we could also demonstrate specific staining of ß-adrenergic receptors
in renatured Western blots of Sf9 cell lysates (Figure 2b).
However, this was not possible for all antibodies exhibiting a
receptor-specific staining pattern in microscopy, suggesting either a
lower sensitivity of the Western blot or a requirement for a specific
native conformation of the receptor, which cannot be completely
restored by renaturation. None of the IgG preparations from healthy
subjects that did not react with synthetic receptor domains in ELISA
(Figure 2c, Healthy) or of the patient IgG preparations
recognizing aminotermini or carboxytermini of ß-receptors (not shown)
stained native ß-adrenergic receptors expressed in Sf9 cell
membranes.
These observations show that a native epitope within the second
extracellular domain of ß-adrenergic receptors can be targeted by
autoantibodies under physiological conditions. As
summarized in Figure 1c, we detected such autoantibodies in 26%
(17 of 65) of the patients with DCM, 10% (4 of 39) of the patients
with ICM, and only 1% (1 of 108) of the healthy subjects. It can also
be seen that all these antibodies recognized the
ß1-subtype of the receptor (Figure 1c, open boxes), and only a small subgroup cross-reacted with the
ß2-subtype (Figure 1c, hatched
boxes).
Antibody Effects on Receptor Function
Interference With Ligand Binding
Binding of the radioligand
[3H] CGP 12177 to human ß-adrenergic
receptors expressed in Sf9 cells was determined after the cells had
been incubated with various concentrations of human IgG preparations.
In repeated experiments, none of the antibodies directed against
aminoterminal or carboxyterminal receptor domains affected ligand
binding. In contrast, antibodies directed against the second
extracellular domains and capable of immunostaining
native ß-adrenergic receptors (ie, the subgroup shown in Figure 1c) decreased radioligand binding in a
concentration-dependent manner by decreasing
[3H]CGP 12177 affinity by up to 3-fold (data
not shown), indicating some degree of competition between these
autoantibodies and ligand binding. However, the maximum of inhibition
at IgG concentrations as high as 167 µg/mL was 
19±3.5%
(mean±SEM, single values ranging from 10% to 35% inhibition).
Stimulation of ß1-Adrenergic Receptor
Activity
Antibody effects on cellular cAMP production mediated by
human ß1-adrenergic receptors are summarized in
Figure 3. Antibodies directed against the
second extracellular domain of the
ß1-adrenergic receptor and capable of binding
to native human ß-receptors (ie, again as in Figure 1c) (1)
increased basal cAMP levels (1.25±0.27-fold, P<0.05), (2)
enhanced isoproterenol stimulation of cellular cAMP production
(1.27±0.11-fold, P<0.0001), and (3) increased basal and
isoproterenol-stimulated activities of cAMP-dependent protein kinase by
1.55±0.18- and 1.20±0.04-fold, respectively (P<0.005, not
shown). In patients with DCM, there was a modest positive correlation
(R=0.59) between immunoreactivity in ELISA and the increase
in isoproterenol-stimulated cAMP (Figure 3, inset). For the 4
autoantibody-positive patients with ICM, such an analysis was
not meaningful. The data clearly show that these antibodies act as
activators and sensitizers of ß-adrenergic receptors and
that the degree of stimulation attainable with isoproterenol in the
presence of such antibodies exceeds the maximum effect of the full
agonist alone. We detected such sensitizing antibodies not only in
patients with DCM (Figure 3, open circles) but also in those
with ICM (Figure 3, solid circles) and even in 1 of the healthy
subjects (Figure 3, triangle). In contrast, IgG preparations
from healthy subjects (Figure 3, hatched box) or patients
(Figure 3, open box), which had no reactivity against receptor
domains other than the second extracellular domain and/or did not stain
native ß-adrenergic receptors, had no effect on basal or stimulated
cAMP production. A mediation of these activating effects via
the ß1-adrenergic receptor was further
supported by 2 observations: (1) maximal cAMP levels after stimulation
of G proteins with NaF were not altered by sensitizing antibodies (data
not shown), excluding a postreceptor effect; and (2) antibody-mediated
increases in basal and agonist-stimulated cAMP concentration were
blocked by bisoprolol, a selective ß1-receptor
antagonist (Table 2):
preincubation of ß1-receptor–expressing CHW
cells with 5 µmol/L bisoprolol abolished not only the
stimulation of cellular cAMP production by 10 µmol/L
isoproterenol alone but also the increases in basal and (maximally)
isoproterenol-stimulated cAMP effected by receptor autoantibodies.
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) or ICM (
) and the only positive healthy
individual (triangle). Squares and error bars indicate mean values
±SEM of all antibody-positive patients with DCM (
, n=17) or ICM
(
, n=4). Boxes indicate 95% CIs of patients (
, n=9) who were autoantibody-negative. Inset: Correlation
of antipeptide signal in ELISA (Figure 1b
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ß-Adrenergic Receptor Autoantibodies and Left Ventricular
Function
Table 1 compares left ventricular function
between patients with and without ß-receptor autoantibodies (as
defined by binding to native ß-adrenergic receptors and enhancement
of cAMP responses). In DCM, autoantibody-positive patients clearly had
a poorer left ventricular function than antibody-negative
patients. Their peak systolic contraction force (derived from
left ventricular time-pressure curves), their left
ventricular ejection fraction, and most notably their
cardiac index (Figure 4) were
significantly lower than in the antibody-negative subgroup. Table 1 also shows that autoantibody-positive patients had a higher
heart rate (P<0.05), which could result from a direct
autoantibody-mediated stimulation of
ß1-adrenergic receptors but could also reflect
an adaptation to the more severely impaired cardiac function in these
patients. In contrast, the antibody-positive and -negative (DCM-)
subgroups did not differ significantly with respect to duration of the
disease, onset of clinical symptoms, ECG abnormalities (left
bundle-branch block and/or atrial fibrillation), and/or the medication
at the time of sample acquisition.
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In ICM, hemodynamic differences between autoantibody-positive and -negative patients had a similar trend but were not significant, because only 4 patients in this group were positive for ß-receptor autoantibodies.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Using the molecular tools developed during recent years,10 11 12 we present here evidence for human autoantibodies, which bind to native ß-adrenergic receptors under physiological conditions. Their overall prevalence was 20% in patients with chronic heart failure and 1% in healthy subjects, which is clearly less than in most previous reports.4 6 7 We believe that these differences are essentially due to the more stringent criteria for such autoantibodies, which have become available by recombinant techniques. In agreement with previous reports,7 9 we found a high prevalence (51%) of IgG antibodies directed against various synthetic ß-receptor domains when a similar peptide-based ELISA approach was used (compare Figure 1a
). However, most of these antibodies were
nonspecific; they did not react with native ß-adrenergic receptors
and had no effect on receptor function. Only half of the antibodies
detected by binding to receptor fragments also recognized the native
membrane-bound ß-adrenergic receptor. All of these antibodies were
directed against the second extracellular domain, which is known to
affect ligand binding16 and suggested to induce immune
responses.17 All of them increased basal and
agonist-stimulated cAMP production in a receptor-mediated
fashion, probably by stabilizing an active conformation of the
receptor, which is also favored by binding of agonists. The possible relation of such sensitizing ß-receptor autoantibodies to the clinical course of chronic heart failure remains open to speculation: some recent transgenic animal models overexpressing ß-adrenergic receptors and/or constitutively active ß-adrenergic receptor mutants18 suggest that amplification of receptor-mediated myocardial signaling increases cardiac contractility and thus (transiently) improves left ventricular function. However, it is also possible that chronically enhanced ß-receptor activity potentiates the vicious circle of adrenergic overdrive, thereby promoting the clinical manifestations of heart failure. Thus, antibodies that stabilize an active receptor state and sensitize the ß-adrenergic system for catecholamines could cause adverse long-term effects in the failing heart, an argument supported by their relatively high prevalence in DCM and their association with a more severely reduced left ventricular function. However, these coincidences do not necessarily imply a cause-and-effect relation: immunologically3 or genetically determined muscle damage19 might be responsible for both the depression of cardiac function and the elaboration of receptor autoantibodies, although in our study, a familiar basis for sensitizing ß-receptor autoantibodies was not evident. The clinical effects of ß-receptor autoantibodies could also be triggered and/or enhanced by autoimmune responses against other myocardial antigens,2 3 which were not examined in this study.
We could block the stimulatory antibody effects by bisoprolol in vitro. This observation might provide a mechanistic explanation for the recent beneficial effects of ß1-adrenergic receptor antagonists in the treatment of DCM.20 21 Although a preliminary reanalysis of some of the patients of the Metoprolol in Dilated Cardiomyopathy trial has not shown a clear correlation between ß-blocker benefit and prevalence of ß-receptor autoantibodies,22 this analysis may be difficult to interpret because the ß-receptor autoantibodies were defined solely by their binding to synthetic receptor peptides, which, as shown here, results in a large fraction of false-positive sera. Future trials on the therapeutic effects of cardioselective ß-receptor antagonists could take advantage of the newly available tools to define antibodies that recognize and activate native human ß-adrenergic receptors.
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Acknowledgments |
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This study was supported by the Deutsche Forschungsgemeinschaft, SFB 355/C4. We are grateful to Nicola Röthlein for excellent technical assistance.
Received June 1, 1998; revision received October 14, 1998; accepted October 22, 1998.
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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A. Yndestad, A. M Holm, F. Muller, S. Simonsen, S. S Froland, L. Gullestad, and P. Aukrust Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure Cardiovasc Res, October 15, 2003; 60(1): 141 - 146. [Abstract] [Full Text] [PDF]
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C. C. Q. Hernandez, L. C. Barcellos, L. E. D. Gimenez, R. A. B. Cabarcas, S. Garcia, R. C. Pedrosa, J. H. M. Nascimento, E. Kurtenbach, M. O. Masuda, and A. C. Campos de Carvalho Human chagasic IgGs bind to cardiac muscarinic receptors and impair L-type Ca2+ currents Cardiovasc Res, April 1, 2003; 58(1): 55 - 65. [Abstract] [Full Text] [PDF]
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 A. Staudt, M. Bohm, F. Knebel, Y. Grosse, C. Bischoff, A. Hummel, J. B. Dahm, A. Borges, N. Jochmann, K. D. Wernecke, et al. Potential Role of Autoantibodies Belonging to the Immunoglobulin G-3 Subclass in Cardiac Dysfunction Among Patients With Dilated Cardiomyopathy Circulation, November 5, 2002; 106(19): 2448 - 2453. [Abstract] [Full Text] [PDF]
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M. Brede, F. Wiesmann, R. Jahns, K. Hadamek, C. Arnolt, S. Neubauer, M. J. Lohse, and L. Hein Feedback Inhibition of Catecholamine Release by Two Different {alpha}2-Adrenoceptor Subtypes Prevents Progression of Heart Failure Circulation, November 5, 2002; 106(19): 2491 - 2496. [Abstract] [Full Text] [PDF]
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S. B. Felix, A. Staudt, M. Landsberger, Y. Grosse, V. Stangl, T. Spielhagen, G. Wallukat, K. D. Wernecke, G. Baumann, and K. Stangl Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption J. Am. Coll. Cardiol., February 20, 2002; 39(4): 646 - 652. [Abstract] [Full Text] [PDF]
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 S. Engelhardt, Y. Grimmer, G.-H. Fan, and M. J. Lohse Constitutive Activity of the Human beta 1-Adrenergic Receptor in beta 1-Receptor Transgenic Mice Mol. Pharmacol., October 1, 2001; 60(4): 712 - 717. [Abstract] [Full Text] [PDF]
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P. A. Chiale, I. Ferrari, E. Mahler, M. A. Vallazza, M. V. Elizari, M. B. Rosenbaum, and M. J. Levin Differential Profile and Biochemical Effects of Antiautonomic Membrane Receptor Antibodies in Ventricular Arrhythmias and Sinus Node Dysfunction Circulation, April 3, 2001; 103(13): 1765 - 1771. [Abstract] [Full Text] [PDF]
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M. Iwata, T. Yoshikawa, A. Baba, T. Anzai, H. Mitamura, and S. Ogawa Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy J. Am. Coll. Cardiol., February 1, 2001; 37(2): 418 - 424. [Abstract] [Full Text] [PDF]
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R. Jahns, V. Boivin, T. Krapf, G. Wallukat, F. Boege, and M. J. Lohse Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1280 - 1287. [Abstract] [Full Text] [PDF]
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 R. H Halfmann Immunoadsorption as a new treatment option for patients with idiopathic dilated cardiomyopathy Perfusion, July 1, 2000; 15(4): 333 - 336. [PDF]
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 O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
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R. Jahns, V. Boivin, C. Siegmund, F. Boege, M. J. Lohse, and G. Inselmann Activating beta-1-adrenoceptor antibodies are not associated with cardiomyopathies secondary to valvular or hypertensive heart disease J. Am. Coll. Cardiol., November 1, 1999; 34(5): 1545 - 1551. [Abstract] [Full Text] [PDF]
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 C.H. Davies and Y. Bashir Beta-blockers for heart failure-time to think the unthinkable? QJM, November 1, 1999; 92(11): 673 - 678. [Full Text] [PDF]
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