Autoimmune Atrial Fibrillation

BACKGROUND Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF. METHODS Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization. RESULTS A common autoantibody response against K$_{ir}$3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. K$_{ir}$3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K$^{+}$ current, I$_{KACh}$. Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-K$_{ir}$3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of I$_{KACh}$, both key mediators of AF. To establish a causal relationship, we developed a mouse model of K$_{ir}$3.4 autoimmunity. Electrophysiological study in K$_{ir}$3.4-immunized mice showed that K$_{ir}$3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF. CONCLUSIONS To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of K$_{ir}$3.4 autoantibody-mediated AF

Autoimmune Atrial Fibrillation.

BACKGROUND Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF. METHODS Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization. RESULTS A common autoantibody response against Kir3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. Kir3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K+ current, IKACh. Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-Kir3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of IKACh, both key mediators of AF. To establish a causal relationship, we developed a mouse model of Kir3.4 autoimmunity. Electrophysiological study in Kir3.4-immunized mice showed that Kir3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF. CONCLUSIONS To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of Kir3.4 autoantibody-mediated AF

Clinical correlates identify ProBDNF and thrombo-inflammatory markers as key predictors of circulating p75NTR extracellular domain levels in older adults

The p75NTR receptor binds all neurotrophins and is mostly known for its role in neuronal survival and apoptosis. Recently, the extracellular domain (ECD) of p75NTR has been reported in plasma, its levels being dysregulated in numerous neurological diseases. However, the factors associated with p75NTR ECD levels remain unknown. We investigated clinical correlates of plasma p75NTR ECD levels in older adults without clinically manifested neurological disorders. Circulating p75NTR levels were measured by enzyme-linked immunosorbent assay in plasma obtained from participants in the BEL-AGE cohort (n = 1,280). Determinants of plasma p75NTR ECD levels were explored using linear and non-linear statistical models. Plasma p75NTR ECD levels were higher in male participants; were positively correlated with circulating concentrations of pro-brain-derived neurotrophic factor, and inflammatory markers interleukin-6 and CD40 Ligand; and were negatively correlated with the platelet activation marker P-selectin. While most individuals had p75NTR levels ranging from 43 to 358 pg/ml, high p75NTR levels reaching up to 9,000 pg/ml were detectable in a subgroup representing 15% of the individuals studied. In this cohort of older adults without clinically manifested neurological disorders, there was no association between plasma p75NTR ECD levels and cognitive performance, as assessed by the Montreal Cognitive Assessment score. The physiological relevance of high p75NTR ECD levels in plasma warrants further investigation. Further research assessing the source of circulating p75NTR is needed for a deeper understanding of the direction of effect, and to investigate whether high p75NTR ECD levels are predictive biomarkers or consequences of neuropathology

Validating intravascular imaging with serial optical coherence tomography and confocal fluorescence microscopy

Atherosclerotic cardiovascular diseases are characterized by the formation of a plaque in the arterial wall. Intravascular ultrasound (IVUS) provides high-resolution images allowing delineation of atherosclerotic plaques. When combined with near infrared fluorescence (NIRF), the plaque can also be studied at a molecular level with a large variety of biomarkers. In this work, we present a system enabling automated volumetric histology imaging of excised aortas that can spatially correlate results with combined IVUS/NIRF imaging of lipid-rich atheroma in cholesterol-fed rabbits. Pullbacks in the rabbit aortas were performed with a dual modality IVUS/NIRF catheter developed by our group. Ex vivo three-dimensional (3D) histology was performed combining optical coherence tomography (OCT) and confocal fluorescence microscopy, providing high-resolution anatomical and molecular information, respectively, to validate in vivo findings. The microscope was combined with a serial slicer allowing for the imaging of the whole vessel automatically. Colocalization of in vivo and ex vivo results is demonstrated. Slices can then be recovered to be tested in conventional histology