Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction

Abstract

Rationale: We previously reported that type VI collagen deposition increases in the infarcted myocardium in vivo. To date, a specific role for this nonfibrillar collagen has not been explored in the setting of myocardial infarction (MI).

Objective: To determine whether deletion of type VI collagen in an in vivo model of post-MI wound healing would alter cardiac function and remodeling in the days to weeks after injury.

Methods and results: Wild-type and Col6a1(-/-) mice were subjected to MI, followed by serial echocardiographic and histological assessments. At 8 weeks after MI, infarct size was significantly reduced, ejection fraction was significantly preserved (43.9% ± 3.3% versus 29.1% ± 4.3% for wild-type), and left ventricular chamber dilation was attenuated in the Col6a1(-/-) MI group (25.8% ± 7.9% increase versus 62.6% ± 16.5% for wild-type). The improvement in cardiac remodeling was evident as early as 10 days after MI in the Col6a1(-/-) mice. Myocyte apoptosis within the infarcted zones was initially greater in the Col6a1(-/-) group 3 days after MI, but by day 14 this was significantly reduced. Collagen deposition also was reduced in the infarcted and remote areas of the Col6a1(-/-) hearts. The reductions in chronic myocyte apoptosis and fibrosis are critical events leading to improved long-term remodeling and functional outcomes.

Conclusions: These unexpected results demonstrate for the first time that deletion of type VI collagen in this knockout model plays a critical protective role after MI by limiting infarct size, chronic apoptosis, aberrant remodeling, and fibrosis, leading to preservation of cardiac function.

Figure 1. Cardiac structure and function are preserved in Col6^-/- mice following MI

(A and B) Representative images taken at 8 weeks post-MI demonstrate preservation of LV wall integrity, greater wall kinesis, and reduced chamber size in Col6^-/- hearts (n=8). (C and D) TTC staining performed on 3 day post-MI hearts revealed no significant differences in Inf/LV area ratio in Col6^-/- versus WT mice, however infarct size at 8 weeks is significantly greater in WT (n=4/group). *p<0.05.

Figure 2. Decreased collagen content in Col6^-/- mice and temporal apoptotic responses post-MI

(A) Representative images (2x) of 8 week post-MI WT and Col6^-/- hearts stained with Masson’s trichrome illustrates a reduction in infarct size, chamber dilation, and remote fibrosis in Col6^-/- mice. Magnified images (4x) of serial sections stained with Masson’s trichrome, PSR, and PSR using polarized microscopy reveal increased collagen deposition and more densely packed collagen in infarct scars of WT mice 8 weeks post-MI. (B) Quantification of collagen volume from stained sections of WT and Col6^-/- 8 week post-MI hearts (% stained/LV area). (C) TUNEL positive cells (per field) at 3 days and 14 days post-MI revealed an initial increase in apoptosis in Col6^-/- mice at 3 days which was reversed by 14 days. (C) The ratio of myocyte/non-myocyte apoptosis increased at 14 days post-MI in WT mice (n=3/group, 5 fields per heart). *p<0.05.

Figure 3. Function and geometry of post-MI hearts are improved in Col6^-/- mice from 3 days to 8 weeks post-MI

(A and B) Echocardiographic assessment of sham and MI groups at 3 days post-MI show similar function and geometry between MI groups (n=8). (C and D) Echocardiography at 8 weeks post-MI revealed preserved systolic function in Col6^-/- MI mice compared to WT MI. Diastolic LV chamber dilation was significantly attenuated in the post-MI Col6^-/- MI mice compared WT MI mice (n=8). (E and F) Improved remodeling and cardiac function were evident at 10 days and 3 weeks post-MI, respectively, as measured by serial echocardiography at the indicated post-MI time points. *p<0.05.