Dataset Information

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β₁-Adrenergic Receptors.

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.

SUBMITTER: Nagatomo Y

PROVIDER: S-EPMC5330212 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β<sub>1</sub>-Adrenergic Receptors.

Nagatomo Yuji Y McNamara Dennis M DM Alexis Jeffrey D JD Cooper Leslie T LT Dec G William GW Pauly Daniel F DF Sheppard Richard R Starling Randall C RC Tang W H Wilson WH

Journal of the American College of Cardiology 20170201 8

<h4>Background</h4>Among various cardiac autoantibodies (AAbs), those recognizing the β<sub>1</sub>-adrenergic receptor (β<sub>1</sub>AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption.<h4>Objectives</h4>The goal of this study was to investigate the role of β<sub>1</sub>AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy.<h4>Methods</h4>Peripheral blood samples were dra ...[more]

PMID: 28231950

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Project description:BackgroundTransverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca2+.MethodsHF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca2+, and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure.ResultsAtrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca2+ release in the cell interior. Systolic Ca2+, ICa-L, sarcoplasmic reticulum Ca2+ content, and sarcoendoplasmic reticulum Ca2+ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca2+ transient, the rate of Ca2+ removal, and the peak L-type Ca2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria.ConclusionsWe show that recovery from HF restores atrial t-tubules, and this promotes recovery of ICa-L, sarcoplasmic reticulum Ca2+ content, and systolic Ca2+. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.

Project description:AimsChronic heart failure (CHF) can be caused by autoantibodies stimulating the heart via binding to first and/or second extracellular loops of cardiac β1 -adrenoceptors. Allosteric receptor activation depends on conformational features of the autoantibody binding site. Elucidating these features will pave the way for the development of specific diagnostics and therapeutics. Our aim was (i) to fine-map the conformational epitope within the second extracellular loop of the human β1 -adrenoceptor (β1 ECII ) that is targeted by stimulating β1 -receptor (auto)antibodies and (ii) to generate competitive cyclopeptide inhibitors of allosteric receptor activation, which faithfully conserve the conformational auto-epitope.Methods and resultsNon-conserved amino acids within the β1 ECII loop (compared with the amino acids constituting the ECII loop of the β2 -adrenoceptor) were one by one replaced with alanine; potential intra-loop disulfide bridges were probed by cysteine-serine exchanges. Effects on antibody binding and allosteric receptor activation were assessed (i) by (auto)antibody neutralization using cyclopeptides mimicking β1 ECII ± the above replacements, and (ii) by (auto)antibody stimulation of human β1 -adrenoceptors bearing corresponding point mutations. With the use of stimulating β1 -receptor (auto)antibodies raised in mice, rats, or rabbits and isolated from exemplary dilated cardiomyopathy patients, our series of experiments unmasked two features of the β1 ECII loop essential for (auto)antibody binding and allosteric receptor activation: (i) the NDPK211-214 motif and (ii) the intra-loop disulfide bond C209 ↔C215 . Of note, aberrant intra-loop disulfide bond C209 ↔C216 almost fully disrupted the functional auto-epitope in cyclopeptides.ConclusionsThe conformational auto-epitope targeted by cardio-pathogenic β1 -receptor autoantibodies is faithfully conserved in cyclopeptide homologues of the β1 ECII loop bearing the NDPK211-214 motif and the C209 ↔C215 bridge while lacking cysteine C216 . Such molecules provide promising tools for novel diagnostic and therapeutic approaches in β1 -autoantibody-positive CHF.

Dataset Information

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β₁-Adrenergic Receptors.

Background

Objectives

Methods

Results

Conclusions

Publications

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β<sub>1</sub>-Adrenergic Receptors.

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Dataset Information

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β1-Adrenergic Receptors.

Background

Objectives

Methods

Results

Conclusions

Publications

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β<sub>1</sub>-Adrenergic Receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β₁-Adrenergic Receptors.