Abstract
Heart failure (HF) development is characterized by huge structural changes that are crucial for disease progression. Analysis of time dependent global proteomic adaptations during HF progression offers the potential to gain deeper insights in the disease development and identify new biomarker candidates. Therefore, hearts of TAC (transverse aortic constriction) and sham mice were examined by cardiac MRI on either day 4, 14, 21, 28, 42, and 56 after surgery (n = 6 per group/time point). At each time point, proteomes of the left (LV) and right ventricles (RV) of TAC and sham mice were analyzed by mass spectrometry (MS). In TAC mice, systolic LV heart function worsened from day 4 to day 14, remained on a stable level from day 14 to day 42, and showed a further pronounced decline at day 56. MS analysis identified in the LV 330 and in RV 246 proteins with altered abundance over time (TAC vs. sham, fc≥±2). Functional categorization of proteins disclosed the time-dependent alteration of different pathways. Heat shock protein beta-7 (HSPB7) displayed differences in abundance in tissue and serum at an early stage of HF. This study not only provides an overview of the time dependent molecular alterations during transition to HF, but also identified HSPB7 as a novel blood biomarker candidate for the onset of cardiac remodeling.
Highlights
Heart failure (HF) is a complex clinical syndrome resulting from structural and functional impairment of ventricular filling or ejection of blood
The decrease in LV ejection fraction (LVEF) was paralleled by an increase in LV end-diastolic volume (LVEDV), end-systolic volume (LVESV), and left ventricular mass-to-tibia-length ratio (LVM/TL) reflecting the time course from compensated LV hypertrophy to development of LV systolic dysfunction and remodeling during the second and the sixth week and, to onset of decompensated HF after 56 days which was demonstrated by the pronounced decrease of LVEF as well as the excessive increase in LVEDV and left ventricular end-systolic volume (LVESV) (Fig 1B, S1 Table [including statistical analyses])
Heart failure is characterized by specific changes in structure, cellular functions, and metabolism, which contribute to the process of remodeling and the phenotype of reduced ventricular contractility
Summary
Heart failure (HF) is a complex clinical syndrome resulting from structural and functional impairment of ventricular filling or ejection of blood. To study the transition from hypertrophy to HF we used the highly reproducible mouse model of transverse aortic constriction (TAC) where a reduced lumen of the ascending aorta induces an increase of left ventricular afterload thereby simulating arterial hypertension as a common cause of HF development. In this model, we were able to examine the different disease stages from left ventricular hypertrophy to ventricular systolic dysfunction and heart failure.
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