Abstract 12597: Progressive Induction of Pressure Overload in a Large Animal Model Causes a Unique Matrix Signature and Remodeling: Relation to LV Function and Stiffness
Background: Patients with severe pressure overload (PO), secondary to aortic stenosis often present with signs and symptoms of heart failure secondary to LV hypertrophy (LVH), matrix remodeling and diastolic dysfunction (DD). However, these events are end-stage, and the temporal sequence of molecular and functional events which lead to this presentation remain unclear. Accordingly, a progressive model of PO in pigs (serial proximal aortic cuff inflation) was created in order to identify early structural milestones in the progression to DD.
Methods and Results: Adult pigs (n=23) were randomized to progressive PO (n=11) or sham (n=12) where LV mass (echo) and plasma collagen I degradation product (ICTP; ELISA) were determined weekly for 4 weeks (Figure). A clear transition in LV mass and ICTP occurred between 7–14 days with PO, which corresponded to an LV-aortic gradient of 62±5 mmHg. At terminal study, regional LV myocardial stiffness (rKm; sonomicrometry) was 3-fold higher in PO compared to sham (11.6±0.8 vs 3.9±0.3, p<0.05), and was directly related to increased LV myocardial collagen content (60.3±6.1 vs 38.7±4.7 ng/g wet weight, p<0.05; inset in figure). At terminal study, soluble collagen content was higher with PO (14.5±2.3 vs. 2.0±1.2 ng/g wet weight, p<0.05) as was active matrix metalloproteinase-2 (157±33 vs. 100%, p<0.05).
Conclusions: In this clinically relevant model of PO, the progressive increase in LV hypertrophy was associated with a persistent increase in collagen turn over facilitated by the induction of protease activation. These protease-dependent changes likely limited the extent of matrix remodeling and diastolic dysfunction present at 4 weeks.
- © 2010 by American Heart Association, Inc.