The impact of pericardial disruption on heart function and remodeling after myocardial infarction in mice
Sara Munk Laursen1,2, Ditte Gry Ellman1,2, Charlotte Harken Jensen1,2
1Andersen Group, Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark.
Abstract:
Myocardial infarction (MI) remains a leading cause of deaths globally. Thus, reliable and relevant animal MI models are crucial to understand underlying disease mechanisms and develop new therapies. Generally, MI in rodents is induced by ligation of the left anterior descending artery (LAD) leaving a ruptured pericardium. This contrasts MI in man, where the pericardium remains intact. Herein, we therefore determined in adult mice whether pericardial disruption along MI influences left ventricular (LV) heart function, remodeling, and scar formation. Baseline heart function was assessed in 30 C57BL/6J adult, female mice, using state-of-the-art ultra-high-resolution ultrasound imaging (Vevo F2). After one week, MI was randomly introduced by LAD in two groups of mice with or without rupturing the pericardium. Functional heart recovery was evaluated 1- and 10 weeks post-MI, whereas success of MI introduction, animal survival, and scarring were quantified at week 10 by Masson's Trichrome histology and compared between groups. The success of MI introduction as well as mouse survival was equal between groups (p > 0.05). Cohort baseline data revealed normal heart function (55.9 ± 4.5% ejection fraction (EF), 33.3 ± 3.2% fractional shortening (FS), 23.3 ± 4.2 µL end-systolic volume (ESV), 52.5 ± 5.1 µL end-diastolic volume (EDV) and 29.2 ± 2.1 µL stroke volume (SV) (mean, SD, n = 21)). At 1-week post-MI, all mice exhibited significant (all p < 0.05) systolic dysfunction, which persisted at 10-weeks post-MI (46.8 ± 7.4%- vs. 49.3 ± 10.0% EF, 24.7 ± 6.3%- vs. 24.7 ± 5.6% FS, and 35.7 ± 12.8 µL- vs. 37.0 ± 14.9 µL ESV for intact and ruptured pericardium, respectively (mean, SD, n = 9 and 12)) with no major differences between groups (all p > 0.05). For ruptured pericardium, we did see a slight increase in EF and SV from week 1 to 10. Ventricular remodeling was equally evident in both groups, with increased (all p > 0.05) LV mass and end-systolic- and end-diastolic area, but no difference (all p > 0.05) between groups. A mild increase in LV posterior wall thickness was exclusively apparent for ruptured pericardium, whereas anterior wall thickness was similar between groups. In line, infarct size was similar between groups (p > 0.05). Pericardial integrity does not universally alter heart function and scar size following LAD ligation in adult female mice, but may have some previously unnoticed compensatory effects not present after MI in man and that should be considered when modeling MI in the mouse.
Insights
Investigating myocardial infarction (MI) models in mice, this study found that pericardial integrity during left anterior descending artery ligation did not significantly alter heart function or infarct size. These findings suggest potential compensatory effects in mice not seen in humans.
Area of Science:
- Cardiovascular Research
- Animal Models of Disease
- Cardiac Surgery
Background:
- Myocardial infarction (MI) is a leading global cause of death, necessitating reliable animal models for research.
- Current rodent models of MI often involve ligating the left anterior descending artery (LAD) with a ruptured pericardium, unlike the intact pericardium in human MI patients.
Purpose of the Study:
- To investigate the influence of pericardial integrity during LAD ligation-induced MI on left ventricular (LV) heart function, remodeling, and scar formation in adult female mice.
- To compare the outcomes of MI in mice with intact versus ruptured pericardium to better understand the relevance of current animal models.
Main Methods:
- Adult female C57BL/6J mice underwent baseline echocardiography to assess heart function.
- Myocardial infarction was induced by LAD ligation, with mice randomly assigned to groups with either an intact or ruptured pericardium.
- Cardiac function, ventricular remodeling, and infarct size were evaluated at 1 and 10 weeks post-MI using ultrasound imaging and Masson's Trichrome histology.
Main Results:
- Both intact and ruptured pericardium groups showed similar MI induction success, survival rates, and persistent systolic dysfunction at 10 weeks post-MI.
- No significant differences in left ventricular ejection fraction, fractional shortening, or end-systolic volume were observed between the groups at 10 weeks.
- Ventricular remodeling, including increased LV mass and chamber area, was comparable between groups, although a mild increase in posterior wall thickness was noted in the ruptured pericardium group.
Conclusions:
- Pericardial integrity does not universally impact heart function and scar size following LAD ligation in adult female mice.
- The intact pericardium in mice may exhibit compensatory effects not present in human MI, highlighting a potential limitation in current MI modeling.
- These findings underscore the importance of considering pericardial integrity when interpreting results from mouse models of myocardial infarction.
