Biomechanics of Cardiac Remodelling in Heart Failure

Abstract

Heart failure (HF) occurs when cardiac output does not meet the requirements of the body. HF is the result of maladaptive cardiac remodelling that alters myocardial structure and ventricular function. Current HF treatments were developed targeting patients with systolic dysfunction, but these treatments are ineffective in treating HF patients with diastolic dysfunction. In order to improve treatment of HF, new insights must be gained regarding the multi-scale relationships between myocardial microstructure and ventricular function. This study investigates the structure-function relationship during cardiac remodelling using the spontaneously hypertensive rat (SHR) as a model of HF. The SHR exhibits progressive maladaptive cardiac remodelling, which is similar to that seen in human HF. Groups of SHRs were compared with SHRs treated with angiotensin-converting enzyme inhibitors (TSHRs), as well as Wistar-Kyoto (WKY) controls. These animals were studied at three time-points, 3 months (mo), 14 mo and 21 mo. Each animal underwent cardiac magnetic resonance imaging (MRI) and in vivo pressure measurements, which allowed for assessment of ejection fraction, cardiac output and cardiac minute work. SHRs had similar cardiac output to WKY and TSHR groups, but had greater cardiac minute work than these groups. This high level of cardiac work likely contributes to the progressive decline in ventricular function. At 21 mo, SHRs had significantly lower ejection fraction (EF) than WKYs, indicating systolic dysfunction. However, at 21 mo TSHRs had similar values of EF to WKYs. Measurements of torsion were obtained with the use of tagged MRI. Previous studies have indicated a positive relationship between concentric hypertrophy and ventricular torsion, however this correlation was not observed in this study. To investigate the myocardial microstructure in these animals, a collagen-specific stain was applied to samples of myocardial tissue blocks, which were then imaged using extended-volume confocal microscopy. Previous studies have shown that SHRs have greater deposition of perimysial collagen between sheetlets, and thickening of endomysial collagen compared with control hearts. The samples of TSHR myocardium imaged in this study displayed thickened endomysial collagen, but without deposition of collagen between sheetlets. The microstructural differences between SHRs and TSHRs observed in this study likely contribute to the functional differences. The measurements of myocardial microstructural and ventricular function formed the basis for a conceptual model of the relationship between microstructure and function. In particular, the lack of collagen deposition between sheetlets was proposed to underlie the difference in systolic function between SHRs and TSHRs. Treatments that alter the deposition of collagen between sheetlets may therefore be able to alter the progression of cardiac remodelling in HF.