Cardiac remodelling in obesity- and angiotensin II-mediated heart failure: Morphological, functional and metabolic alterations

Abstract

Heart failure is associated with altered myocardial substrate utilization and reduced cardiac efficiency - changes that are hallmarks in heart failure independent of disease aetiology. This thesis describes remodelling in two distinct models of heart failure, namely obesity-mediated cardiomyopathy and early failure induced using a low dose angiotensin II (AngII). The reported cardiac phenotype in obese mouse models varies, and methods used for cardiac functional assessment may influence these discrepancies. This thesis shows that ex vivo cardiac examination (isolated perfused working hearts) using prediabetic and diabetic mice, reveals a more severe dysfunction than in vivo measurements (echocardiography), suggesting that systemic changes contribute to sustain cardiac function in vivo. Hence, the ex vivo heart preparation provides valuable additional information in cardiac phenotyping, unmasking changes that might be compensated in vivo. Furthermore, when exposing obese mouse hearts to high fatty acid levels (mimicking stressful conditions, such as myocardial infarction), they did not display the adverse effects that were seen in hearts from normal mice. In fact, ischemic tolerance was increased with high fat in obese hearts. This suggests that, despite contributing to the progression of diabetic cardiomyopathy, chronic hyperlipidaemia induces cardiac adaptation making these hearts able to handle an acute exposure to high levels of fat. Conversely, a low-dose of AngII did not change cardiac metabolism or efficiency, despite causing hypertrophy. However, the same dose of AngII induced cardiac dysfunction in mice with cardiac-specific NOX2 overexpression, with a concomitant change in substrate utilization. Thus, in AngII-induced heart failure, substrate utilization is not altered prior to dysfunction and NOX2 aggravates AngII-mediated effects. In conclusion, although both obesity and early angiotensin II-induced heart failure are associated with altered substrate metabolism, these changes might be beneficial adaptations.