Abstract 14408: Lack of Collagen Type 8 in Pressure Overload Causes Left Ventricular Dilatation and Overt Heart Failure in Mice, Suggesting a Role in Transition to Heart Failure in Patients With Aortic Stenosis
Background: Aortic stenosis causes left ventricular (LV) pressure overload resulting in LV remodeling. A key step in the transition from compensated hypertrophy to overt heart failure (HF) is LV dilatation. Collagen type 8 (col8) is a non-fibrillar collagen bridging extracellular matrix molecules and lack of col8 might therefore result in LV dilatation. Importantly, we have previously reported that pressure overload reduces col8, correlating to LV dilatation. Here we examined the role of col8 in LV dilatation and failure progression using col8 knock-out (KO) mice and aortic banding (AB) to induce pressure overload.
Methods: We induced pressure overload in wild type (WT) and KO mice. Echocardiography and lung weights were used to evaluate LV geometry and degree of HF. Collagen composition was analyzed by real-time PCR and hydroxyproline HPLC. The study was performed in a blinded manner. The gradient across AB was comparable in both groups of mice.
Results: In contrast to WT mice developing concentric hypertrophy, already 24h after AB there was a LV dilatation in KO mice (LVIDd=4.90±0.06mm) compared to WT (LVIDd=4.58±0.06mm, p<0.05) which was also present 16 weeks after AB (LVIDd=6.34±0.17mm in KO mice vs. LVIDd=5.80±0.09mm in WT mice, p<0.05). Furthermore, early mortality due to signs of pulmonary congestion was higher in KO mice (39.4%) than in WT (25.0%, p<0.05), where lung weight was 26.0% higher in KO mice compared to WT. At 48h, AB KO mice did not show any increase in mRNA expression of fibrillar collagens type 1 and 3 (col1/3) in contrast to an 193% increase of col1 and 168% increase of col3 mRNA in WT mice. After six weeks of AB, increases in col1 and col3 mRNA were significantly less pronounced in KO mice compared to WT (163% and 279%, 160% and 223%, for col1/3 respectively). In accordance with attenuated col1/3 mRNA expression 48h after AB, after six weeks of AB, total collagen was increased by only 84% in KO compared to 164% in WT mice.
Conclusion: Since lack of col8 caused reduced production of the main structural collagens 1 and 3, we suggest an important role for the non-fibrillar col8 in synthesis and regulation of fibrillar collagens and proper structure of the extracellular matrix in the heart, preventing LV dilatation and transition to HF in pressure overload.
- © 2013 by American Heart Association, Inc.