Characterising myocardial remodelling in hypertensive heart disease. Structural and functional changes in the Spontaneously Hypertensive Rat

Abstract

Myocytes of varying orientation across the ventricular wall are grouped into layers, separated by cleavage planes. The role of extracellular matrix, in particular collagen, in this laminar organisation has not been fully delineated due to an inability to truly appreciate its 3D relationships. This thesis utilised an unique laser confocal scanning microscopy system to produce high resolution 3D images of normal adult rat myocardium to elucidate the arrangement of collagen with respect to myocytes. Perimysium was shown to have an ordered arrangement that played a direct role in laminar organisation. There were three distinct forms of perimysial structures seen in the midwall: an extensive meshwork on laminar surfaces, convoluted fibres connecting adjacent layers, and longitudinal cords. The subepicardium had a different structure that lacks distinct layers and the only perimysial collagen present was as longitudinal cords. Changes in perimysial collagen organisation were then studied using a rat model of hypertensive heart disease. Spontaneously Hypertensive Rats were studied at 3 months (hypertensive), 12 months (associated hypertrophy), 18 months (compensated failure) and 24 months or when determined to be in decompensated heart failure. Age-matched Wistar Kyoto rats were used as controls. Clinically used assessments, namely blood pressure measurements, echocardiography measurement of active left ventricular (LV) function and neurohormone BNP measurements were carried out on each rat to demonstrate disease progression. Hearts were then removed and passive LV function was determined using pressure-volume loop measurements on a Langendorff apparatus. Finally, hearts were then imaged as above. High resolution imaging of the diseased hearts showed the expected increased fibrosis. Moreover, there were distinct changes in perimysial and endomysial collagen that disrupted and in some places eradicated the myocardial laminar organisation. These changes persisted into LV decompensation along with LV hypertrophy and passive compliance, which is contrary to the current understanding of HHD. The mechanical and electrical consequences of this remodelling are likely to contribute to the transition from compensated to decompensated heart failure.