Abstract:
Conduction of electrical impulse in the heart is heavily reliant on its structure. At the cellular level, close apposition of cells determines the local conduction properties. At the tissue level, the orientation of myofibre bundles and their organisation dictates conduction pathways in the heart. Structural heart disease results in changes in the structure of the myocardium, known as structural remodelling, which includes disruption in cell-to-cell coupling, changes in myofibre bundle organisation, as well as changes in chamber geometry. Structural remodelling has been correlated with increased risk of arrhythmias, but the extent of remodelling and its role in the progression of electrical dysfunction in the atria remains unclear. In this study, we use a hypertensive heart disease animal model to characterise electrical dysfunction and structural remodelling in the atria during the progression to heart failure. Hypertensive rats were studied at three time points: 6, 12, and 18 months to fully represent the progression of the disease from onset of hypertension to failure. A novel preparation of isolated intact atria was developed and used for optical mapping experiments to study the extent of electrical dysfunction. Techniques for high resolution micro-computed tomography imaging were developed to study the changes in geometry of the atria and novel tissue clearing techniques to facilitate 3D reconstruction of cellular architecture. The progression towards heart failure was characterised by marked changes in electrical properties. Conduction pathways were significantly altered by regions of inactive tissue in the left atrium of older animals. This was also accompanied by prolonged action potential duration, activation, and repolarisation of the atria, resulting in an increased vulnerability to arrhythmias. A significant increase in atrial chamber volume, tissue volume, and wall thickness, together with disruption of cellular architecture due to interstitial fibrosis and patches of replacement fibrosis were all evident in older animals. The results of this study demonstrate that the progression of hypertensive heart disease to failure is accompanied by an increased propensity to atrial arrhythmias. The fact that electrical dysfunction is significantly more pronounced in the left atrium reinforces the idea that structural remodelling is the main contributor to arrhythmogenesis in the atria.