Journal of the American College of Cardiology
Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β1-Adrenergic Receptors
Author + information
- Yuji Nagatomo, MDa,b,
- Dennis M. McNamara, MD, MSc,
- Jeffrey D. Alexis, MDd,
- Leslie T. Cooper, MDe,
- G. William Dec, MDf,
- Daniel F. Pauly, MD, PhDg,
- Richard Sheppard, MDh,
- Randall C. Starling, MD, MPHa,
- W.H. Wilson Tang, MDa,∗ (tangw{at}ccf.org),
- IMAC-2 Investigators
- aHeart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio
- bSakakibara Heart Institute, Fuchu, Japan
- cHeart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- dUniversity of Rochester Medical Center School of Medicine and Dentistry, Rochester, New York
- eMayo Clinic Florida, Jacksonville, Florida
- fMassachusetts General Hospital, Boston, Massachusetts
- gTruman Medical Centers, University of Missouri–Kansas City, Kansas City, Missouri
- hJewish General Hospital, Montreal, Quebec, Canada
- ↵∗Address for correspondence:
Dr. W.H. Wilson Tang, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, Ohio 44195.
Central Illustration
Abstract
Background Among various cardiac autoantibodies (AAbs), those recognizing the β1-adrenergic receptor (β1AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption.
Objectives The goal of this study was to investigate the role of β1AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy.
Methods Peripheral blood samples were drawn at enrollment in patients with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; <6 months). The presence of IgG and IgG3-β1AR-AAb was determined, and echocardiograms were assessed, at baseline and 6 months. Patients were followed up for ≤48 months.
Results Among the 353 patients who had blood samples adequate for the analysis, 62 (18%) were positive for IgG3-β1AR-AAbs (IgG3 group), 58 (16%) were positive for IgG but not IgG3 (non-IgG3 group), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. Left ventricular end-diastolic and end-systolic diameters were significantly larger in the non-IgG3 group compared with the other groups (left ventricular end-diastolic diameter, p < 0.01; left ventricular end-systolic diameter, p = 0.03). At 6 months, LVEF was significantly higher in the IgG3 group (p = 0.007). Multiple regression analysis showed that IgG3-β1AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, β = 0.20, p = 0.01; change in LVEF, β = 0.20, p = 0.008). In patients with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had a lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint.
Conclusions IgG3-β1AR-AAbs were associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy.
Idiopathic dilated cardiomyopathy (DCM) has been an important cause of systolic heart failure (HF) and is the most common cause of HF in young people referred for cardiac transplantation (1). It has been believed that this diagnosis comprises diverse etiologies, and patients have highly variable presentations. There has been a longstanding belief that dysregulated autoimmune processes might lead to disease progression in HF. Specifically, several cardiac autoantibodies (AAbs) against specific cardiac antigens have been detected in sera from patients with DCM (2–4). Among the various anticardiac AAbs, autoantibodies against the β1-adrenergic receptor (β1AR-AAbs) have been detected in 30% to 40% of these patients (5–11). Clinical studies conducted in the 1980s and 1990s (before the broad adoption [12] of β-adrenergic blockers) demonstrated associations between detectable β1AR-AAbs and increased rates of mortality (9), fatal ventricular arrhythmias, and sudden death (8,13) in patients with DCM. Mechanistic studies have also shown that β1AR-AAbs may possess agonist-like properties (14–17), which induce some detrimental effects on the heart (18), including receptor uncoupling (12,19,20), myocyte apoptosis (21), and sustained calcium influx resulting in electric instability of the heart (18,22).
These effects can be abolished by β-blockers based on in vitro (17) and in vivo (12) experiments. Indeed, β1AR-AAb–positive patients with HF have demonstrated more favorable recovery of cardiac performance than β1AR-AAb–negative patients in response to β-adrenergic blocker therapy (10). Furthermore, immunoadsorption using columns specific for β1AR-AAbs was effective in alleviating the cardiac dysfunction of an observational series of patients with DCM (23,24). In addition, the elimination of immunoglobin G subclass 3 (IgG3)-AAbs by immunoadsorption was associated with beneficial effects in patients with DCM (25–28). These findings suggest the importance of AAbs of the IgG3 subclass in the pathology of DCM.
The IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study was a multicenter trial that enrolled 373 patients with recent-onset cardiomyopathy and examined the myocardial recovery and clinical prognosis for those patients undergoing contemporary therapy, including β-blockers (29). The objective of the present study was to determine the clinical significance of specific β1AR-AAbs belonging to the IgG3 subclass in patients in the IMAC-2 study.
Patients and Methods
The IMAC-2 study was a prospective, multicenter investigation of myocardial recovery in patients with recent-onset nonischemic DCM and myocarditis that enrolled patients at 16 centers from May 2002 through December 2008 (see the Online Appendix for participating institutions). All patients had a left ventricular ejection fraction (LVEF) ≤0.40 according to echocardiography and symptoms ≤6 months in duration. Informed consent was obtained from all patients, and the protocol was approved by the institutional review boards of all participating centers. Demographic information included self-designated race (white, black, Asian, or other). Patients underwent angiography or noninvasive screening to exclude coronary artery disease, which was defined as a single coronary artery stenosis of a major epicardial vessel >50% or a history of myocardial infarction. Patients also underwent transthoracic echocardiography to rule out valvular disease.
The following patients were excluded: those with significant diabetes (requiring therapy with insulin or an oral agent for >1 year), uncontrolled hypertension (diastolic blood pressure >95 mm Hg or systolic blood pressure >160 mm Hg), suspected alcoholism, tachycardia-induced cardiomyopathy, uncorrected thyroid disease, or systemic disorders with associated cardiomyopathy (e.g., lupus erythematosus, hemochromatosis, sarcoidosis). Right ventricular endomyocardial biopsy was not required according to current practice guidelines (30). LVEF was assessed by using transthoracic echocardiography at entry and at 6 months. Patients were followed up for ≤48 months. All deaths and hospitalizations were adjudicated by an independent events committee.
Imaging and assays
Echocardiographic studies were reviewed in a blinded fashion by a core laboratory at the University of Pittsburgh. Digital routine grayscale 2-dimensional cine loops were obtained at frame rates of 40 to 90 Hz (mean 60 ± 15 Hz) from standard apical 4-chamber, 2-chamber, and long-axis views. Left ventricular volume and LVEF were assessed by using biplane Simpson’s rule with manual tracing of digital images. Left ventricular end-diastolic and end-systolic diameters (LVEDD and LVESD, respectively) were assessed in the parasternal long-axis view.
The presence of β1AR-AAbs was determined by enzyme-linked immunosorbent assay using a synthetic peptide corresponding to the putative sequence of the second extracellular loop of human β1AR (amino acid sequence number 197 to 222; H-W-W-R-A-E-S-D-E-A-R-R-C-Y-N-D-P-K-C-C-D-F-V-T-N-R) as an epitope peptide. Anti-human IgG antibody or IgG3 antibody was used as a secondary antibody to detect β1AR-AAbs belonging to the IgG or IgG3 subclass. Positivity was defined as 2.5 times the background density, consistent with earlier reports (8,10,28,31). IgG β1AR-AAb–positive but IgG3 β1AR-AAb–negative patients were classified as the non-IgG3 group.
Statistical analysis
All values are expressed as mean ± SD. Demographic and clinical characteristics were compared according to the status of β1AR-AAb (i.e., negative/non-IgG3/IgG3) at baseline. Differences among the 3 groups were compared by using analysis of variance or the Kruskal-Wallis test. When it was significant, multiple comparisons were performed by using the Tukey-Kramer test or Steel-Dwass method. For myocardial recovery, LVEF at 6 months and change in LVEF over 6 months were compared. In multivariate analysis, multiple linear regression was used to identify independent predictors of change in LVEF at 6 months (i.e., verified as approximately normally distributed). In addition to the covariates chosen in the main study (29) for use for stepwise selection (forward) with an entry and retainment p value of 0.05, the status of β1AR-AAb at baseline was included in the present study.
Kaplan-Meier survival curves for the composite endpoint of all-cause death, cardiac transplantation, or hospitalization due to the exacerbation of HF were calculated, and log-rank tests were performed by dividing the study cohort into 3 groups: IgG3 β1AR-AAb–positive, non-IgG3 β1AR-AAb–positive, and β1AR-AAb–negative groups. The differences among groups were analyzed by using the log-rank test. A p value <0.05 was considered statistically significant. All statistical analyses were performed in JMP version 10.0.2 (SAS Institute, Inc., Cary, North Carolina).
Results
Among 373 patients enrolled in IMAC-2, a total of 353 had adequate blood samples for analysis. In this cohort, 120 (34%) patients had detectable β1AR-AAbs: 62 (18%) patients were in the IgG3 group; 58 (19%) patients were in the non-IgG3 group; and the remaining 233 (66%) patients were in the negative group.
Patient characteristics
According to baseline characteristics of the study population based on β1AR-AAb status (Table 1), there were no significant differences in demographic characteristics, vital signs, or specified laboratory data (hematocrit, serum creatinine, and serum sodium) among the 3 groups. In addition, there were no significant differences in medication use, including β-blockers, or the proportion of patients who underwent therapeutic device implantation among the 3 groups. Of note, most patients (82%) were treated with β-blockers at baseline. There were no significant differences in the proportion of patients treated with β-blockers among the 3 groups or mean dose converted to carvedilol units (negative: 18 ± 16 mg; non-IgG3: 18 ± 14 mg; IgG3: 20 ± 17 mg; p = NS). The proportion of patients who were administered β-blockers increased to 94% (294 of 313) at 6 months. There was no significant difference in the rate of β-blocker use (negative: 202 [96%] of 211; non-IgG3: 45 [94%] of 48; IgG3: 47 [87%] of 54; p = NS) or mean dose (negative: 33 ± 21 mg; non-IgG3: 36 ± 25 mg; IgG3: 38 ± 27 mg; p = NS).
Baseline Characteristics
Change of LVEF and left ventricular size
When the population was divided into 2 groups on the basis of total IgG-β1AR-AAb positivity, there was no significant difference in LVEF at baseline (negative: 0.24 ± 0.08; positive: 0.23 ± 0.08; p = 0.92), LVEF at 6 months (negative: 0.40 ± 0.12; positive: 0.41 ± 0.12; p = 0.96) (Central Illustration), or change in LVEF over 6 months (negative: 0.17 ± 0.13; positive: 0.18 ± 0.13; p = 0.97). However, when the population was divided into 2 groups on the basis of IgG3-β1AR-AAb positivity, LVEF at 6 months was significantly higher in the IgG3-positive group (negative: 0.40 ± 0.12; positive 0.46 ± 0.10; p = 0.002), whereas there was no significant difference at baseline (negative: 0.23 ± 0.08; positive: 0.26 ± 0.08; p = 0.06). LVEF increased in the IgG3 group to a greater degree than the negative group (p < 0.001 by repeated measures analysis of variance). The absolute change in LVEF was higher in the IgG3-positive group compared with the IgG3-negative group with borderline significance (IgG3 negative: 0.17 ± 0.13; IgG3 positive: 0.20 ± 0.11; p = 0.10).
Autoantibodies Specifically Against β1ARs in Cardiomyopathy
(A) In investigating the role of β1-adrenergic receptor autoantibodies (β1AR-AAbs) belonging to the immunoglobulin G3 (IgG3) subclass in patients with recent-onset cardiomyopathy, we found no significant difference in left ventricular ejection fraction (LVEF) at baseline and 6 months based on presence or absence of total immunoglobulin G (IgG). (B) However, when the population was divided on the basis of IgG3 positivity, a significant difference in LVEF emerged at 6 months. (C) When the population was further divided into patients who were β1AR-AAb negative, non–IgG3-β1AR-AAb positive, and IgG3-β1AR-AAb positive, the IgG3 groups demonstrated significantly higher LVEF compared with each of the other cohorts.
When the population was divided into 3 groups of negative, non-IgG3, and IgG3, there was no significant difference in LVEF among the groups at baseline (negative: 0.23 ± 0.08; non-IgG3: 0.22 ± 0.08; IgG3: 0.26 ± 0.08; p = NS). However, at 6 months, LVEF was significantly higher in the IgG3 group compared with the non-IgG3 or negative group (negative: 0.40 ± 0.12; non-IgG3: 0.38 ± 0.13; IgG3: 0.46 ± 0.10; p = 0.007 by Kruskal-Wallis test; p = 0.01 between negative and IgG3; p = 0.01 between non-IgG3 and IgG3 by the Steel-Dwass method) (Central Illustration). LVEF significantly increased over 6 months in all groups (p < 0.0001) (Online Figure 1) but increased in the IgG3 group to a greater degree than in the negative or non-IgG3 group (p < 0.01 by repeated measures analysis of variance). There was no significant difference in the absolute change in LVEF among the 3 groups (negative: 0.17 ± 0.13; non-IgG3: 0.17 ± 0.14; IgG3: 0.20 ± 0.11; p = 0.25). Baseline echocardiography showed that LVEDD and LVESD were significantly larger in the non-IgG3 group compared with the negative and IgG3 groups (LVEDD: p = 0.028; LVESD: p = 0.025) (Table 2). Both LVEDD and LVESD significantly decreased at 6 months in all 3 groups (LVEDD: p < 0.005; LVESD: p < 0.0001), but they remained larger in the non-IgG3 group compared with the negative and IgG3 groups (LVEDD: p = 0.012; LVESD: p = 0.010).
Echocardiographic Change of LV and LA Dimension
Although the total IgG titer did not show any significant correlation with LVEF at baseline (r = –0.038; p = 0.94) or at 6 months (r = –0.001; p = 0.99) (Figure 1A), the IgG3 titer at baseline exhibited a modest positive correlation with LVEF at 6 months (r = 0.17; p = 0.002) (Figure 1B), although there was no significant correlation with LVEF at baseline (r = 0.10; p = 0.06). Multiple regression analysis was performed to identify independent predictors of LVEF at 6 months and change in LVEF during the same period. As shown in Table 3, β1AR-AAb was an independent predictor of LVEF at 6 months as well as for 6-month change in LVEF even after adjusting for covariates that were used for stepwise selection in the main study (30).
6-Month LVEF Correlated With Baseline IgG
(A) At 6 months, there was no significant correlation between left ventricular ejection fraction (LVEF) and the baseline (BL) titer of immunoglobulin G3 β1-adrenergic receptor autoantibodies (IgG-β1AR-AAbs). (B) The correlation became significant in the presence of the immunoglobulin G3 subclass β1AR-AAb (IgG3). IgG = immunoglobulin G.
Independent Predictors for LVEF at 6 Months and Change in LVEF
Clinical events based on β1AR-AAb status
During 3.8 ± 1.5 years of follow-up, there was no significant difference in the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to HF among patients based on β1AR-AAb status, a point replicated in the population with low New York Heart Association (NYHA) functional class (I or II) at baseline (Figure 2A). However, in the population with high NYHA functional class (III or IV) at baseline, IgG3 patients had the lowest rate of adverse clinical events, and non-IgG3 patients had the highest rate (log-rank test p = 0.03) (Figure 2B). Specifically, within the β1AR-AAb–positive cohort, the difference in adverse event rates between the IgG3 versus non-IgG3 groups was statistically significant (log-rank test p = 0.02). In patients with β-blocker use at baseline and continued at 6 months or with β-blocker use by 6 months (n = 322), the presence of non-IgG3 was associated with worse overall survival from HF hospitalization (log-rank test p = 0.021), whereas no differences were observed between the IgG3 and negative groups (p = 0.64) (Figure 3).
Composite Endpoint: NYHA Functional Class
When divided into populations on the basis of baseline New York Heart Association (NYHA) functional class status (I–II vs. III–IV), (A) there were no significant differences in the 3 groups of β1AR-AAb–negative, non-IgG3-β1AR-AAb–positive (non-IgG), and IgG3 for the composite endpoint of all-cause death, cardiac transplantation, or hospitalization due to exacerbation of heart failure in patients with low NYHA functional class, but (B) significance was seen in sicker patients. *p = 0.02 versus negative group; †p = 0.02 versus non-IgG3. Abbreviations as in Figure 1.
HF Hospitalization and β-Blocker Use
In 322 patients who used β-blockers at baseline (BL) and continued at 6 months or were taking β-blockers at 6 months, there was no significant difference in overall survival from heart failure (HF) hospitalization in patients (A) whether IgG3 was present but (B) the presence of non-IgG3 was associated with worse overall survival. (C) No differences were observed in the negative group. Abbreviations as in Figures 1 and 2.
Discussion
The present study reports 3 main findings. First, the myocardial recovery represented by LVEF at 6 months after enrollment was more evident in the IgG3 group compared with the negative or non-IgG3 groups. Second, LVEF at 6 months was positively correlated with IgG3-β1AR-AAb titer but not with IgG-β1AR-AAb titer. The IgG3-β1AR-AAb titer was an independent predictor of LVEF at 6 months and increased in LVEF over 6 months even after adjusting for some confounding factors. Third, in patients with higher NYHA functional class (III or IV), patients with IgG3-β1AR-AAbs had the lowest incidence of the composite endpoint and patients with non–IgG3-β1AR-AAbs had the highest incidence. Of note, this finding is consistent with our single-center pilot study, which enrolled a population with stable HF (31). Taken together, these findings imply the possibility that β1AR-AAb IgG subclasses might play differential roles in the pathophysiology of cardiomyopathies. Specifically, it is conceivable that the β1AR-AAb IgG3 subclass may exert a more direct pathological effect related to a primary autoimmune process, such as failure of self-tolerance, than other non–IgG3-β1AR-AAbs that are more dependent on secondary autoimmune responses to self-antigens released as a result of cardiac damage.
Previous studies suggested that some types of AAbs exert their effect by binding to the Fc receptor as well as its epitope. Often referred to as “cardiodepressant” AAbs, certain types of AAbs purified from patients with DCM have been found to induce a negative inotropy in vitro (32) and ex vivo (27,33). Interestingly, patients with cardiodepressant AAbs exhibited an acute increase in cardiac index and LVEF after immunoadsorption therapy (27,32). Staudt et al. (34) reported that the cardiodepressant effects of these AAbs are unlikely to be induced by either the F(ab′)2 or Fc fragment alone. Therefore, the effects of the AAb may vary depending on the structure of the Fc fragment, the very factor that determines IgG subclasses. IgG subclasses 1 and 3 are most likely to trigger effector function and be involved in immunoregulatory activities and complement activation (33,35,36). The presence of AAbs against β1AR and muscarinic M2 receptors belonging to the IgG3 subclass has been shown to be an independent predictor of the presence of cardiodepressant AAbs (27).
The importance of IgG3 AAbs was further supported when immunoadsorption via antihuman IgG columns (high affinity for all IgG subclasses) resulted in additional improvement of cardiac function compared with using protein A (high affinity for IgG1, 2, and 4 but low affinity for IgG3) (24). Alternatively using the tryptophan column, the IgG3 subclass was eliminated effectively by immunoadsorption and to a greater extent than other subclasses (28), although these findings must be confirmed. Furthermore, in a pilot study, direct administration of the cyclic peptide against β1AR-AAbs improved LVEF (37). The increase in LVEF after immunoadsorption was better correlated with AAb titers belonging to the IgG3 subclass than total IgG, which also suggested that the removal of IgG3-AAb is important to maximize the effect of immunoadsorption in patients with DCM (27). Interestingly, in the Myocarditis Treatment Trial, an association between cardiac IgG and better LVEF was observed (38), suggesting that the timing of interpretation of AAb data (acute vs. chronic) might also be a factor.
There is emerging appreciation that only a subset of β1AR-AAbs may be functionally active (39,40). Interestingly, in the analysis of weaned DCM patients who tested positive for β1AR-AAbs before implantation of a left ventricular assist device, β1AR-AAbs became undetectable after left ventricular unloading by mechanical circulatory assist support (41). This finding suggests that certain β1AR-AAbs can be generated, at least partly, by cardiac loading or damage. The notion that IgG3-β1AR-AAbs might serve as a potential pathogenic factor that can be counteracted with β-blockers raises an exciting possibility that their detection in patients at risk of developing cardiomyopathies might provide a potential indication for preventive β-blocker therapy. Further investigations are warranted into the presence of IgG3-β1AR-AAbs in at-risk patients.
It is also possible that anti-HF therapy including β-blockers can suppress the production of AAbs in patients with recent-onset DCM. A previous report showed that β1AR-AAbs enhanced proliferation of rat CD3+ T lymphocytes in vitro, which was blocked by the selective β1AR antagonist metoprolol (42). β1AR-AAbs also inhibited the secretion of interferon gamma while promoting an increase in interleukin-4 levels. These findings suggest that β1AR-AAbs promote humoral immunity, possibly through the agonistic effect on β1AR expressed on T lymphocytes. It might be the important mechanism by which β-blockers are especially effective for patients with IgG3-β1AR-AAbs. Although we evaluated β1AR-AAb status at baseline and at 6 months by using an enzyme-linked immunosorbent assay and examined clinical outcomes in this study, we found no significant associations between change in β1AR-AAb status and the clinical outcome mechanism that differentiated IgG3- and non–IgG3-β1AR-AAbs (data not shown).
Study limitations
Patients with non–IgG3-β1AR-AAbs had larger left ventricular size at baseline. Previous studies showed that the presence of β1AR-AAbs was associated with reduced cardiac function at baseline (7,9,10), but these studies did not examine the IgG subclasses of β1AR-AAbs. Although our findings might support these previous findings, this factor may affect the findings in the present study. We have no data that support the proposed mechanisms previously mentioned that differentiate the IgG3- and non–IgG3-β1AR-AAbs because the enzyme-linked immunosorbent assay do not include a functional bioassay (e.g., protein kinase A activity). Moreover, we did not further determine the IgG subclasses of β1AR-AAb IgG due to limited sample availability. Meanwhile, targeting of the β1AR first extracellular loop by the IgG3 was not directly tested. In addition, although the administration of β-blockers has been speculated as a mechanism that might have yielded more favorable outcomes in patients with IgG3-β1AR-AAbs, the observational nature of our study did not allow further clarification regarding the interrelationship between β-blockers and IgG3-β1AR-AAbs.
Conclusions
The presence of the IgG3 subclass of β1AR-AAbs was associated with favorable myocardial recovery in patients with recent-onset cardiomyopathy. Future investigations will be necessary to better elucidate the detailed mechanisms that differentiate the effects of IgG3- and non–IgG3-β1AR-AAbs.
COMPETENCY IN MEDICAL KNOWLEDGE: In patients with HF, β1AR-AAbs may be antagonized by administration of β-blocker drugs. Immunoabsorption studies suggest that antibody subclasses may differ in terms of pathogenicity and potential for recovery of myocardial function in response to β-blocker therapy.
TRANSLATIONAL OUTLOOK: Detection of pathogenetic subclasses of β1-adrenoceptor autoantibodies responsive to β-blocker therapy may have implications for treatment to prevent progression of cardiomyopathy.
Appendix
Appendix
For a list of the IMAC-2 investigators and institutions and a supplemental figure, please see the online version of this article.
Footnotes
The IMAC-2 study was supported by National Heart, Lung, and Blood Institute contracts HL075038, HL086918, and HL69912, and the National Institutes of Health. This study was also supported by funding from the Cleveland Clinic Research Programs Committee. Dr. Nagatomo is supported by the Postdoctoral Fellowship award from the Myocarditis Foundation (MYF1401MF). Dr. Tang is supported by a grant from the National Institutes of Health (1R01HL103931). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Barry H. Greenberg, MD, served as Guest Editor for this paper.
Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
- Abbreviations and Acronyms
- AAb
- autoantibody
- β1AR
- β1-adrenergic receptor
- β1AR-AAb
- β1-adrenergic receptor autoantibody
- DCM
- dilated cardiomyopathy
- HF
- heart failure
- IgG3
- immunoglobin G subclass 3
- LVEDD
- left ventricular end-diastolic diameter
- LVESD
- left ventricular end-systolic diameter
- LVEF
- left ventricular ejection fraction
- NYHA
- New York Heart Association
- Received October 19, 2016.
- Revision received November 15, 2016.
- Accepted November 29, 2016.
- American College of Cardiology Foundation
References
Figures in Article
Figures
Supplementary Materials
- Online Appendix and Online Figure 1[S0735109717300049_mmc1.doc]
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