Regional Cardiac Proteome Alterations in a Hypertension-Induced Rat Model for Chronic Heart Failure

Objective: Development of chronic heart failure is promoted by hypertension-induced ventricular stiffening and remodelling. Cardiovascular morbidity and mortality result from a constant rising prevalence in heart failure worldwide. A valuable measure to diagnose heart failure with preserved ejection fraction is speckle-tracking echocardiography to assess cardiac strain. Functional differences in specific cardiac regions can be investigated here. The role of the proteome in these regions remains elusive. Here we hypothesize a distinct proteome signature in intracardiac regions that could explain cardiac functional alterations in different regions of the failing heart. Design and method: Double-transgenic rats, expressing the human renin and angiotensinogen (dTGRs) were included in the study at the age of four weeks. Sprague Dawley wild-type (WT) rats served as controls. Echocardiography and speckle tracking echocardiography were used to evaluate cardiac function. In a label-free mass spectrometry approach, the proteome was analysed from six left-ventricular, intracardiac regions: posterior and anterior/septal base, mid and apex. Results: Vehicle-treated dTGR presented hypertrophy with an increased echocardiographically measured wall thickness of left-ventricular posterior wall in systole and diastole. Speckle tracking echocardiography indicated a diminished global longitudinal strain in vehicle-treated dTGR compared to WT rats. This indicates a reduction of myocardial movement along the longitudinal dimension. Strain analysis in distinct cardiac regions revealed that the myocardial performance of the posterior apex was most affected, followed by posterior base and mid, as well as anterior/septal apex and base. The anterior/septal mid was not significantly different between the groups. Label-free proteomics approach identified 661 and 789 proteins to be significantly different between posterior apex compared to anterior mid or anterior base, respectively. These differences were diminished in the dTGR heart. All six intracardiac regions displayed an altered protein profile in hearts from dTGR compared to WT, with alterations in proteins such as atrial natriuretic peptide, Serpin B3, Xin-Actin-Binding-Repeat-Containing 1 and pyruvate-dehydrogenase-kinase 4. Conclusions: Investigating the shift in cardiac proteome profile can improve our understanding of chronic heart failure and identify potential target proteins. Within this study, we highlight the relevance of intracardiac regions in proteome analysis with respect to chronic heart failure.