Feasibility of high-density electrophysiological study using multiple-electrode array in isolated small animal atria.

1. High-density cardiac electrophysiological study (EPS) of small animal atria has been limited to optical mapping techniques, which require complex and expensive equipment setup. We aim to evaluate the feasibility of carrying out EPS in isolated atrial tissues using a custom made high-density multiple-electrode array (MEA). 2. Isolated rat atrial preparations were studied. The MEA (4 × 5 mm) consisted of 90 silver chloride coated electrodes (0.1 mm diameter, 0.5 mm pitch) and was connected to a conventional EP system yielding 80 bipolar signals. Atrial tissues were placed over the MEA in a dish bubbled with 100% oxygen and superfused with modified HEPES solution at pH 7.35 and 37°C. Then, 1 mmol of 2,3-butanedione monoxime was added to suppress motion artifacts from muscle contractions. Custom plaque analysis software was used for offline conduction analysis. 3. Isolated atrial tissues showed good viability of > 30 min, allowing ample time for complete EPS. High quality electrograms with excellent signal to noise ratio were obtained. All electrophysiological parameters showed good reproducibility: effective refractory period, conduction velocity and heterogeneity index. Tachycardia was also inducible in these normal atria. 4. The present study shows the feasibility of performing high-density EPS of small isolated atrial tissues with a conventional electrode-based technique. The MEA system is compatible with standard electrophysiology recording systems and provides a novel, inexpensive option for detailed EPS in small animal models. In particular, it presents new research avenues to further explore the mechanisms of atrial arrhythmias in various transgenic and knockout rodent models.

Hypertension and atrial fibrillation: evidence of progressive atrial remodeling with electrostructural correlate in a conscious chronically instrumented ovine model.

BACKGROUND: Hypertension accounts for more atrial fibrillation (AF) than any other predisposing factor. OBJECTIVE: The purpose of this study was to characterize the time course, extent, and electrostructural correlation of atrial remodeling in chronic hypertension. METHODS: Thirty-two sheep were studied: 21 with induced "one-kidney, one-clip" hypertension and 11 controls. Sequential closed-chest electrophysiologic studies were performed in 12 conscious animals (6 hypertensive, 6 controls) to evaluate progressive remodeling over 15 weeks. Additional atrial structural/functional analyses were performed in 5 controls and at 5, 10, and 15 weeks of hypertension (five per time point) via histology/cardiac magnetic resonance imaging to correlate with open-chest electrophysiologic parameters. RESULTS: The hypertensive group developed a progressive increase in mean arterial pressure (P <.001). Mean effective refractory periods were uniformly higher at all time points (P <.001). Progressive biatrial hypertrophy (P = .003), left atrial dysfunction (P <.05) and greater AF inducibility were seen early with increased inflammation from 5 weeks of hypertension. In contrast, significant conduction slowing (P <.001) with increased heterogeneity (P <.001) along with increased interstitial fibrosis resulted in longer and more fractionated AF episodes only from 10 weeks of hypertension. Significant electrostructural correlation was seen in conduction abnormalities and AF inducibility with both atrial inflammation and fibrosis. CONCLUSION: Hypertension is associated with early and progressive changes in atrial remodeling. Atrial remodeling occurs at different time domains in chronic hypertension with significant electrostructural correlation of the remodeling cascade. Early institution of antihypertensive treatment may prevent formation of substrate capable of maintaining AF.

Characterization of cardiac remodeling in a large animal "one-kidney, one-clip" hypertensive model.

OBJECTIVE: The aim of this study is to characterize cardiac remodeling in a large animal model of hypertension. METHODS: 23 sheep were subjected to unilateral nephrectomy followed by clamping of the remaining renal artery to 60% ("one kidney-one clip", 1K1C) 3 weeks later. Blood pressure (BP) was monitored invasively over 73+/-28 days. Cardiac function was assessed with magnetic resonance imaging and compared with 12 size-matched controls. Detailed atrial histopathological analysis was performed. RESULTS: In the 1K1C animals, BP rose from baseline to reach a plateau by 4 weeks (systolic BP: 107+/-12 to 169+/-27, diastolic BP: 71+/-10 to 118+/-29 mmHg, both p< 0.0001); cardiac hypertrophy was significant when compared with controls with increased left ventricular weight [left ventricular (LV)/body wt: 2.7+/-0.5 vs 2.1+/-0.2 g/kg, p=0.01] as well as bi-atrial enlargement (right atrial, RA: 22.9+/-4.9 vs 15.7+/-2.8g, p=0.003; left atrial, LA: 35.5+/-6.7 vs 20.9+/-4.1g, p=0.0003); cardiac magnetic imaging demonstrated significantly increased LA volumes (end-diastolic volume: 42.9+/-6.8 vs 28.7+/-6.3 ml, p< 0.0001) and reduced LA ejection fraction (24.1+/-3.6 vs 31.6+/-3.0%, p=0.001) while LV function was relatively preserved (42.3+/-4.7 vs 46.4+/-4.1%, p=0.1); degeneration and necrosis of atrial myocytes were evident with increased atrial lymphocytic infiltration and interstitial fibrosis. CONCLUSIONS: The ovine 1K1C model produces reliable and reproducible hypertension with demonstrable cardiac end-organ damage.

Short-term hypertension is associated with the development of atrial fibrillation substrate: a study in an ovine hypertensive model.

BACKGROUND: Hypertension is frequently complicated by the development of atrial fibrillation (AF). However, the mechanisms of this link remain poorly understood. In addition, whether short-term hypertension can result in a substrate for AF is not known. OBJECTIVE: The purpose of this study was to characterize the atrial substrate predisposing to AF due to short-duration hypertension. METHODS: Sixteen sheep were studied: 10 had induced hypertension for 7 +/- 4 weeks via the "one-kidney, one-clip" model, and six were controls. Cardiac magnetic resonance imaging was used to assess functional changes. Open-chest electrophysiological study was performed using a custom-made 128-electrode epicardial plaque applied to both right (RA) and left atria (LA), including the Bachmann's bundle, to determine effective refractory periods (ERPs) and conduction velocity at four pacing cycle lengths from six sites. Tissue specimens were harvested for structural analysis. RESULTS: The hypertensive group demonstrated the following compared with controls: higher blood pressure (P <.0001), enlarged LA (P <.05), reduced LA ejection fraction (P <.05), uniformly higher mean ERP (P <.001), slower mean conduction velocity (P <.001), higher conduction heterogeneity index (P <.0001), greater AF inducibility (P = .03), and increased AF durations (P = .04). Picrosirius red staining of atrial tissues revealed increased interstitial fibrosis (P <.0001). There was also evidence of increased inflammatory cell infiltrates (P <.0001). CONCLUSION: Short-duration hypertension is associated with significant atrial remodeling characterized by atrial enlargement/dysfunction, interstitial fibrosis, inflammation, slowed/heterogeneous conduction, increased ERP, and greater propensity for AF.