Atrial structure, function and arrhythmogenesis in aged and frail mice

Abstract

Atrial fibrillation (AF) is prevalent in aging populations; however not all individuals age at the same rate. Instead, individuals of the same chronological age can vary in health status from fit to frail. Our objective was to determine the impacts of age and frailty on atrial function and arrhythmogenesis in mice using a frailty index (FI). Aged mice were more frail and demonstrated longer lasting AF compared to young mice. Consistent with this, aged mice showed longer P wave duration and PR intervals; however, both parameters showed substantial variability suggesting differences in health status among mice of similar chronological age. In agreement with this, P wave duration and PR interval were highly correlated with FI score. High resolution optical mapping of the atria demonstrated reduced conduction velocity and action potential duration in aged hearts that were also graded by FI score. Furthermore, aged mice had increased interstitial fibrosis along with changes in regulators of extracellular matrix remodelling, which also correlated with frailty. These experiments demonstrate that aging results in changes in atrial structure and function that create a substrate for atrial arrhythmias. Importantly, these changes were heterogeneous due to differences in health status, which could be identified using an FI.

Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes

“…Surface electrocardiograms (ECGs) were measured in anesthetized mice (2% isoflurane inhalation) using 30-gauge subdermal needle electrodes (Grass Technologies). In conjunction, a 1.2F octapolar electrophysiology catheter (Transonic) was inserted into the right heart via an incision in the jugular vein and used to assess inducibility of AF during burst pacing as we have done previously (57,58). Burst pacing protocols were standardized so that all mice were stimulated in identical fashion using the same pacing protocols.…”

“…Changes in fluorescence were captured using the voltage-sensitive dye Di-4-ANEPPS (10 µM) and a high-speed electron multiplying charge-coupled device camera at ∼900 frames per 1 s. Spatial resolution was 67 × 67 µM per pixel. Conduction velocity was measured locally in the right and left atria using approaches described previously (21,22,57,58). In some instances, optical APs were measured by measuring the change in fluorescence as a function of time at individual pixels in the right and left atria as previously described (21,22).…”

Sex Differences in Healthspan Predict Lifespan in the 3xTg-AD Mouse Model of Alzheimer’s Disease

“…Tools to assess frailty in mice have been developed and validated (Parks et al, 2012 ; Liu et al, 2014 ; Whitehead et al, 2014 ; Feridooni et al, 2015 ; Antoch et al, 2017 ; Gomez-Cabrera et al, 2017 ; Rockwood et al, 2017 ). The mouse clinical frailty index (MCFI) was the first of these tools, and has been used in a variety of studies (Whitehead et al, 2014 ; Kane et al, 2016a , b ; Huizer-Pajkos et al, 2016 ; Moghtadaei et al, 2016 ; Jansen et al, 2017 ). The MCFI is based on the FI approach that is commonly used to quantify frailty in humans (Kane and Howlett, 2018 ).…”

Isolation of Atrial Myocytes from Adult Mice

“…These are highly prevalent, yet poorly understood, atrial arrhythmias that lead to significant morbidity and mortality. Atrial fibrillation can occur in association with genetic mutations, in association with aging or in the setting of acquired forms of heart disease, including hypertension, heart failure and diabetes 2,4,5,6 . These conditions can alter the electrical properties of atrial myocytes which can create a substrate that increases the prevalence of arrhythmogenesis 1,2 .…”

“…While we describe our approach here using atrial appendage tissue, the approach can be used on any region of the atrial myocardium (i.e., right or left atrial appendages, free walls, posterior walls) that the investigator chooses. This approach is ideal for studies of atrial myocyte electrophysiology in genetically modified mice, in mouse models of cardiovascular disease, or for studying the effects of pharmacological compounds 5,6,17,18,19 .…”