Dataset Information

Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure.

ABSTRACT:

Aims

The importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF.

Methods and results

Serum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed using newly established chemiluminescence immunoassays. The primary outcome was a composite of all-cause mortality and HF rehospitalization at 2-year follow-up, and each outcome was also separately investigated. Collectively, 382 (16.9%) patients and 37 (12.4%) controls were seropositive for ≥1 AAB (P = 0.045). Seropositivity occurred more frequently only for anti-M2 AABs (P = 0.025). Amongst patients with HF, seropositivity was associated with the presence of comorbidities (renal disease, chronic obstructive pulmonary disease, stroke, and atrial fibrillation) and with medication use. Only anti-β1 AAB seropositivity was associated with the primary outcome [hazard ratio (95% confidence interval): 1.37 (1.04-1.81), P = 0.024] and HF rehospitalization [1.57 (1.13-2.19), P = 0.010] in univariable analyses but remained associated only with HF rehospitalization after multivariable adjustment for the BIOSTAT-CHF risk model [1.47 (1.05-2.07), P = 0.030]. Principal component analyses showed considerable overlap in B-lymphocyte activity between seropositive and seronegative patients, based on 31 circulating biomarkers related to B-lymphocyte function.

Conclusions

AAB seropositivity was not strongly associated with adverse outcomes in HF and was mostly related to the presence of comorbidities and medication use. Only anti-β1 AABs were independently associated with HF rehospitalization. The exact clinical value of AABs remains to be elucidated.

SUBMITTER: Markousis-Mavrogenis G

PROVIDER: S-EPMC10325696 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure.

Markousis-Mavrogenis George G Minich Waldemar B WB Al-Mubarak Ali A AA Anker Stefan D SD Cleland John G F JGF Dickstein Kenneth K Lang Chim C CC Ng Leong L LL Samani Nilesh J NJ Zannad Faiez F Metra Marco M Seemann Petra P Hoeg Antonia A Lopez Patricio P van Veldhuisen Dirk J DJ de Boer Rudolf A RA Voors Adriaan A AA van der Meer Peter P Schomburg Lutz L Bomer Nils N Bomer Nils N

Cardiovascular research 20230701 8

<h4>Aims</h4>The importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF.<h4>Methods and results</h4>Serum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed u ...[more]

PMID: 36883593

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Project description:BackgroundAmong 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.ObjectivesThe goal of this study was to investigate the role of β1AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy.MethodsPeripheral 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.ResultsAmong 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.ConclusionsIgG3-β1AR-AAbs were associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy.

Project description:Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated. This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity. We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n = 24), only plasma from the second cohort (n = 24) together with plasma samples (n = 24) and CSF (n = 6) from healthy controls. All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1-5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity. Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

Project description:AimsA causal link between non-ischaemic heart failure (HF) and humoral autoimmunity against G-protein-coupled receptors (GPCR) remains unclear except for Chagas' cardiomyopathy. Uncertainty arises from ambiguous reports on incidences of GPCR autoantibodies, spurious correlations of autoantibody levels with disease activity, and lack of standardization and validation of measuring procedures for putatively cardio-pathogenic GPCR autoantibodies. Here, we use validated and certified immune assays presenting native receptors as binding targets. We compared candidate GPCR autoantibody species between HF patients and healthy controls and tested associations of serum autoantibody levels with serological, haemodynamic, metabolic, and functional parameters in HF.MethodsNinety-five non-ischaemic HF patients undergoing transcatheter endomyocardial biopsy and 60 healthy controls were included. GPCR autoantibodies were determined in serum by IgG binding to native receptors or a cyclic peptide (for β1AR autoantibodies). In patients, cardiac function, volumes, and myocardial structural properties were assessed by cardiac magnetic resonance imaging; right heart catheterization served for determination of cardiac haemodynamics; endomyocardial biopsies were used for histological assessment of cardiomyopathy and determination of cardiac mitochondrial oxidative function by high-resolution respirometry.ResultsAutoantibodies against β1 adrenergic (β1 AR) , M5-muscarinic (M5AR), and angiotensin II type 2 receptors (AT2R) were increased in HF (all P < 0.001). Autoantibodies against α1 -adrenergic (α1 AR) and angiotensin II type 1 receptors (AT1R) were decreased in HF (all P < 0.001). Correlation of alterations of GPCR autoantibodies with markers of cardiac or systemic inflammation or cardiac damage, haemodynamics, myocardial histology, or left ventricular inflammation (judged by T2 mapping) were weak, even when corrected for total IgG. β1 AR autoantibodies were related inversely to markers of left ventricular fibrosis indicated by T1 mapping (r = -0.362, P < 0.05) and global longitudinal strain (r = -0.323, P < 0.05). AT2R autoantibodies were associated with improved myocardial mitochondrial coupling as measured by high-resolution respirometry in myocardial biopsies (r = -0.352, P < 0.05). In insulin-resistant HF patients, AT2R autoantibodies were decreased (r = -.240, P < 0.05), and AT1R autoantibodies were increased (r = 0.212, P < 0.05).ConclusionsGPCR autoantibodies are markedly altered in HF. However, they are correlated poorly or even inversely to haemodynamic, metabolic, and functional markers of disease severity, myocardial histology, and myocardial mitochondrial efficiency. These observations do not hint towards a specific cardio-pathogenic role of GPCR autoantibodies and suggest that further investigations are required before specific therapies directed at GPCR autoantibodies can be clinically tested in non-ischaemic HF.

Dataset Information

Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure.

Aims

Methods and results

Conclusions

Publications

Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure.

Similar Datasets

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