optimization-transesophageal-atrial-pacing-to-assess-atrial

Optimization of Transesophageal Atrial Pacing to Assess Atrial Fibrillation Susceptibility in Mice

Mouse models of genetic and acquired risk factors for atrial fibrillation (AF) have proven valuable in investigating the molecular determinants of AF. ...

Vanderbilt University School of Medicine

Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we used an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown.

Cardiomyocyte Homeodomain-Interacting Protein Kinase 2 Maintains Basal Cardiac Function via Extracellular Signal-Regulated Kinase Signaling.

Mice are routinely used to investigate molecular mechanisms underlying the atrial fibrillation (AF) substrate. We sought to optimize transesophageal rapid atrial pacing (RAP) protocols for the detection of AF susceptibility in mouse models. Hypertensive and control C57Bl/6J mice were subjected to burst RAP at a fixed stimulus amplitude. The role of parasympathetic involvement in pacing-related atrioventricular (AV) block and AF was examined using an intraperitoneal injection of atropine. In a crossover study, burst and decremental RAP at twice diastolic threshold were compared for induction of AV block during pacing. The efficacy of burst and decremental RAP to elicit an AF phenotype was subsequently investigated in mice deficient in the lymphocyte adaptor protein () resulting in systemic inflammation, or the paired-like homeodomain-2 transcription factor () as a positive control. When pacing at a fixed stimulus intensity, pacing-induced AV block with AF induction occurred frequently, so that there was no difference in AF burden between hypertensive and control mice. These effects were prevented by atropine administration, implicating parasympathetic activation due to ganglionic stimulation as the etiology. When mice with AV block during pacing were eliminated from the analysis, male  mice displayed an AF phenotype only during burst RAP compared with controls, whereas male  mice showed AF susceptibility during burst and decremental RAP. Notably,  and  females exhibited no AF phenotype. Our data support the conclusion that multiple parameters should be used to ascertain AF inducibility and facilitate reproducibility across models and studies. Methods were developed to optimize transesophageal rapid atrial pacing (RAP) to detect AF susceptibility in new and established mouse models. High stimulus intensity and pacing rates caused parasympathetic stimulation, with pacing-induced AV block and excessive AF induction in normal mice. For a given model, pacing at twice TH enabled improved phenotype discrimination in a pacing mode and sex-specific manner. Transesophageal RAP should be individually optimized when developing a mouse model of AF.

Optimizing transesophageal atrial pacing in mice to detect atrial fibrillation.

With aging, the human atrium invariably develops amyloid composed of ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide). Preamyloid oligomers are the primary cytotoxic species in amyloidosis, and they accumulate in the atrium during human hypertension and a murine hypertensive model of atrial fibrillation susceptibility. We tested the hypothesis that preamyloid oligomers derived from natriuretic peptides cause cytotoxic and electrophysiological effects in atrial cells that promote arrhythmia susceptibility and that oligomer formation is enhanced for a mutant form of ANP linked to familial atrial fibrillation.

Article	Year
Cardiomyocyte Homeodomain-Interacting Protein Kinase 2 Maintains Basal Cardiac Function via Extracellular Signal-Regulated Kinase Signaling. Circulation\| PubMed ID: 31581792	2019
Optimizing transesophageal atrial pacing in mice to detect atrial fibrillation. American journal of physiology. Heart and circulatory physiology\| PubMed ID: 34767487	2022
Natriuretic Peptide Oligomers Cause Proarrhythmic Metabolic and Electrophysiological Effects in Atrial Myocytes. Circulation. Arrhythmia and electrophysiology\| PubMed ID: 35212578	2022

Kyungsoo Kim

Biography

JoVE Journal Publications

Other Publications