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Atrial fibrillation: villain or bystander in vascular brain injury.

ABSTRACT: Atrial fibrillation (AF) and stroke are inextricably connected, with classical Virchow pathophysiology explaining thromboembolism through blood stasis in the fibrillating left atrium. This conceptualization has been reinforced by the remarkable efficacy of oral anticoagulant (OAC) for stroke prevention in AF. A number of observations showing that the presence of AF is neither necessary nor sufficient for stroke, cast doubt on the causal role of AF as a villain in vascular brain injury (VBI). The requirement for additional risk factors before AF increases stroke risk; temporal disconnect of AF from a stroke in patients with no AF for months before stroke during continuous ECG monitoring but manifesting AF only after stroke; and increasing recognition of the role of atrial cardiomyopathy and atrial substrate in AF-related stroke, and also stroke without AF, have led to rethinking the pathogenetic model of cardioembolic stroke. This is quite separate from recognition that in AF, shared cardiovascular risk factors can lead both to non-embolic stroke, or emboli from the aorta and carotid arteries. Meanwhile, VBI is now expanded to include dementia and cognitive decline: research is required to see if reduced by OAC. A changed conceptual model with less focus on the arrhythmia, and more on atrial substrate/cardiomyopathy causing VBI both in the presence or absence of AF, is required to allow us to better prevent AF-related VBI. It could direct focus towards prevention of the atrial cardiomyopathy though much work is required to better define this entity before the balance between AF as villain or bystander can be determined.

SUBMITTER: Freedman B

PROVIDER: S-EPMC7916423 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Atrial fibrillation: villain or bystander in vascular brain injury.

Freedman Ben B Kamel Hooman H Van Gelder Isabelle C IC Schnabel Renate B RB

European heart journal supplements : journal of the European Society of Cardiology 20201101 Suppl M

Atrial fibrillation (AF) and stroke are inextricably connected, with classical Virchow pathophysiology explaining thromboembolism through blood stasis in the fibrillating left atrium. This conceptualization has been reinforced by the remarkable efficacy of oral anticoagulant (OAC) for stroke prevention in AF. A number of observations showing that the presence of AF is neither necessary nor sufficient for stroke, cast doubt on the causal role of AF as a villain in vascular brain injury (VBI). The ...[more]

PMID: 33664640

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Project description:ImportanceAccumulating evidence links inflammation and atrial fibrillation (AF).ObjectiveTo assess whether markers of systemic and atrial inflammation are associated with incident AF in the general population.Design, setting, and participantsThe Bruneck Study is a prospective, population-based cohort study with a 20-year follow-up (n = 909). The population included a random sample of the general community aged 40 to 79 years. Levels of 13 inflammation markers were measured at baseline in 1990. Findings were replicated in a case-control sample nested within the prospective Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1770). Data analysis was performed from February to May 2016.ExposuresLevels of 13 inflammation markers.Main outcomes and measuresIncident AF over a 20-year follow-up period in the Bruneck Study.ResultsOf the 909 participants included in the Bruneck Study, mean [SD] age was 58.8 (11.4) years and 448 (49.3%) were women. Among the 880 participants free of prevalent AF (n = 29) at baseline, 117 developed AF during the 20-year follow-up period (incidence rate, 8.2; 95% CI, 6.8-9.6 per 1000 person-years). The levels of soluble vascular cell adhesion molecule 1 (VCAM-1) and osteoprotegerin were significantly associated with incident AF (hazard ratio [HR], 1.49; 95% CI, 1.26-1.78; and 1.46; 95% CI, 1.25-1.69, respectively; P < .001 with Bonferroni correction for both), but osteoprotegerin lost significance after age and sex adjustment (HR, 1.05; 95% CI, 0.87-1.27; P > .99 with Bonferroni correction). Matrix metalloproteinase 9, metalloproteinase inhibitor 1, monocyte chemoattractant protein-1, P-selectin, fibrinogen, receptor activator of nuclear factor-κB ligand, high-sensitivity C-reactive protein, adiponectin, leptin, soluble intercellular adhesion molecule 1, and E-selectin all fell short of significance (after Bonferroni correction in unadjusted and age- and sex-adjusted analyses). The HR for a 1-SD higher soluble VCAM-1 level was 1.34 (95% CI, 1.11-1.62; Bonferroni-corrected P = .03) in a multivariable model. The association was of a dose-response type, at least as strong as that obtained for N-terminal pro-B-type natriuretic peptide (multivariable HR for a 1-SD higher N-terminal pro-B-type natriuretic peptide level, 1.15; 95% CI, 1.04-1.26), internally consistent in various subgroups, and successfully replicated in the SAPHIR Study (age- and sex-adjusted, and multivariable odds ratios for a 1-SD higher soluble VCAM-1 level, 1.91; 95% CI, 1.24-2.96, P = .003; and 2.59; 95% CI, 1.45-4.60; P = .001).Conclusions and relevanceLevels of soluble VCAM-1, but not other inflammation markers, are significantly associated with new-onset AF in the general community. Future studies should address whether soluble VCAM-1 is capable of improving AF risk classification beyond the information provided by standard risk scores.

Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Experiment Overall Design: HL-1 cell expression profile in vitro with and without rapid electric stimulation

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Atrial fibrillation: villain or bystander in vascular brain injury.

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Atrial fibrillation: villain or bystander in vascular brain injury.

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