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

George Markousis-Mavrogenis; Waldemar B Minich; Ali A Al-Mubarak; Stefan D Anker; John G F Cleland; Kenneth Dickstein; Chim C Lang; Leong L Ng; Nilesh J Samani; Faiez Zannad; Marco Metra; Petra Seemann; Antonia Hoeg; Patricio Lopez; Dirk J van Veldhuisen; Rudolf A de Boer; Adriaan A Voors; Peter van der Meer; Lutz Schomburg; Nils Bomer

doi:10.1093/cvr/cvad042

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

George Markousis-Mavrogenis, Waldemar B Minich, Ali A Al-Mubarak, Stefan D Anker, John G F Cleland, Kenneth Dickstein, Chim C Lang, Leong L Ng, Nilesh J Samani, Faiez Zannad, Marco Metra, Petra Seemann, Antonia Hoeg, Patricio Lopez, , Dirk J van Veldhuisen, Rudolf A de Boer, Adriaan A Voors, Peter van der Meer, Lutz Schomburg (Lead / Corresponding author)Nils Bomer

Molecular and Clinical Medicine

Research output: Contribution to journal › Article › peer-review

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 analyzed 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, 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.

Original language	English
Article number	cvad042
Journal	Cardiovascular Research
Early online date	8 Mar 2023
DOIs	https://doi.org/10.1093/cvr/cvad042
Publication status	E-pub ahead of print - 8 Mar 2023

Keywords

beta 1
beta 2
beta 3
M2
immune system
autoimmunity

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10.1093/cvr/cvad042Licence: CC BY

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Markousis-Mavrogenis, G., Minich, W. B., Al-Mubarak, A. A., Anker, S. D., Cleland, J. G. F., Dickstein, K., Lang, C. C., Ng, L. L., Samani, N. J., Zannad, F., Metra, M., Seemann, P., Hoeg, A., Lopez, P., van Veldhuisen, D. J., de Boer, R. A., Voors, A. A., van der Meer, P., ... Bomer, N. (2023). Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure. Cardiovascular Research, [cvad042]. https://doi.org/10.1093/cvr/cvad042

@article{bb902e739161478b88e948cad8216963,

title = "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 analyzed 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, 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.",

keywords = "beta 1, beta 2, beta 3, M2, immune system, autoimmunity",

author = "George Markousis-Mavrogenis and Minich, {Waldemar B} and Al-Mubarak, {Ali A} and Anker, {Stefan D} and Cleland, {John G F} and Kenneth Dickstein and Lang, {Chim C} and Ng, {Leong L} and Samani, {Nilesh J} and Faiez Zannad and Marco Metra and Petra Seemann and Antonia Hoeg and Patricio Lopez and {van Veldhuisen}, {Dirk J} and {de Boer}, {Rudolf A} and Voors, {Adriaan A} and {van der Meer}, Peter and Lutz Schomburg and Nils Bomer",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. BIOSTAT-CHF was funded by the European Commission [FP7-242209-BIOSTAT-CHF; 16 EudraCT 2010-020808-29]. The analytical work was supported by the German Federal Ministry for 17 Economic Affairs and Energy (BMWi) and the European Social Fund (ESF); EXIST-Project “Bridge-18 ART”, FKZ: 03EFLBE114.",

year = "2023",

month = mar,

day = "8",

doi = "10.1093/cvr/cvad042",

language = "English",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

}

Markousis-Mavrogenis, G, Minich, WB, Al-Mubarak, AA, Anker, SD, Cleland, JGF, Dickstein, K, Lang, CC, Ng, LL, Samani, NJ, Zannad, F, Metra, M, Seemann, P, Hoeg, A, Lopez, P, van Veldhuisen, DJ, de Boer, RA, Voors, AA, van der Meer, P & Schomburg, L & Bomer, N 2023, 'Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure', Cardiovascular Research. https://doi.org/10.1093/cvr/cvad042

TY - JOUR

T1 - Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure

AU - Markousis-Mavrogenis, George

AU - Minich, Waldemar B

AU - Al-Mubarak, Ali A

AU - Anker, Stefan D

AU - Cleland, John G F

AU - Dickstein, Kenneth

AU - Lang, Chim C

AU - Ng, Leong L

AU - Samani, Nilesh J

AU - Zannad, Faiez

AU - Metra, Marco

AU - Seemann, Petra

AU - Hoeg, Antonia

AU - Lopez, Patricio

AU - van Veldhuisen, Dirk J

AU - de Boer, Rudolf A

AU - Voors, Adriaan A

AU - van der Meer, Peter

AU - Schomburg, Lutz

AU - Bomer, Nils

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. BIOSTAT-CHF was funded by the European Commission [FP7-242209-BIOSTAT-CHF; 16 EudraCT 2010-020808-29]. The analytical work was supported by the German Federal Ministry for 17 Economic Affairs and Energy (BMWi) and the European Social Fund (ESF); EXIST-Project “Bridge-18 ART”, FKZ: 03EFLBE114.

PY - 2023/3/8

Y1 - 2023/3/8

N2 - 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 analyzed 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, 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.

AB - 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 analyzed 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, 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.

KW - beta 1

KW - beta 2

KW - beta 3

KW - M2

KW - immune system

KW - autoimmunity

U2 - 10.1093/cvr/cvad042

DO - 10.1093/cvr/cvad042

M3 - Article

C2 - 36883593

SN - 0008-6363

JO - Cardiovascular Research

JF - Cardiovascular Research

M1 - cvad042

ER -

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

Abstract

Keywords

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