Abstract
In patients with myocardial infarction (MI), cardiac rupture is an uncommon but catastrophic complication. In the mouse model of nonreperfused MI, reported rupture rates are highly variable and depend not only on the genetic background and sex of animals but also on the method used for documentation of rupture. In most studies, diagnosis of cardiac rupture is based on visual inspection during autopsy; however, criteria are poorly defined. We performed systematic histopathological analysis of whole hearts from C57BL/6J mice dying after nonreperfused MI and evaluated the reliability of autopsy-based criteria in identification of rupture. Moreover, we compared the cell biological environment of the infarct between rupture-related and rupture-independent deaths. Histopathological analysis documented rupture in 50% of mice dying during the first week post-MI. Identification of a gross rupture site was highly specific but had low sensitivity; in contrast, hemothorax had high sensitivity but low specificity. Mice with rupture had lower myofibroblast infiltration, accentuated macrophage influx, and a trend toward reduced collagen content in the infarct. Male mice had increased mortality and higher incidence of rupture. However, infarct myeloid cells harvested from male and female mice at the peak of the incidence of rupture had comparable inflammatory gene expression. In conclusion, the reliability of autopsy in documentation of rupture in infarcted mice is dependent on the specific criteria used. Macrophage-driven inflammation and reduced activation of collagen-secreting reparative myofibroblasts may be involved in the pathogenesis of post-MI cardiac rupture.NEW & NOTEWORTHY We show that cardiac rupture accounts for 50% of deaths in C57BL/6J mice undergoing nonreperfused myocardial infarction protocols. Overestimation of rupture events in published studies likely reflects the low specificity of hemothorax as a criterion for documentation of rupture. In contrast, identification of a gross rupture site has high specificity and low sensitivity. We also show that mice dying of rupture have increased macrophage influx and attenuated myofibroblast infiltration in the infarct. These findings are consistent with a role for perturbations in the balance between inflammatory and reparative responses in the pathogenesis of postinfarction cardiac rupture. We also report that the male predilection for rupture in infarcted mice is not associated with increased inflammatory activation of myeloid cells.