Background:
Our analysis in a clinical cohort of patients with first ST-elevation myocardial infarction (MI) showed a negative correlation between left ventricular function early after MI and body mass index (BMI). Among individuals with high BMI most are characterized by obesity which comes along with a systemic low-grade inflammatory state due to the activation of the innate immune system. The impact of this so called “meta-inflammation” state on healing, left-ventricular function, and survival after MI remains to be studied.

Rationale:
An experimental model of obesity that replicates the negative association of BMI and early negative outcome after MI might allow to mechanistically study the role of the innate immune system for the healing after MI in obese vs. lean individuals. Hence, the study aims to analyse if diet-induced obesity impacts left ventricular function and survival in an experimental mouse model of MI.

Methods and Results:
 Starting at an age of 8 weeks, male and female wild-type C57B6/J mice were either feeded with a high (60 kJ %) or low fat (10 kJ %) diet. After 16-weeks on high-fat diet (HFD) mice showed significant increase body weights compared to mice on control diet. Weight gain was less in female than in male mice (male: 46.6 ± 0.8 vs. 34.7 ± 0.7g, p<0.0001; female: 33.5 ± 1.9 vs. 25.7 ± 0.5g, p<0.0001). Mice on HFD showed significant increased level of triglycerides (males: 121.6 ± 8.1 vs. 84.05 ± 8.4mg/dI, p<0.01; females: 77.3 ± 1.8 vs. 49.3 ± 8.0mg/dl, p<0.05) and cholesterol (males: 254.1 ± 8.4 vs. 231.4 ± 9.3 mg/dl, p<0.05; females: 248.2 ± 27.4 vs. 171.0 ± 21mg/dl, p<0.05). Male mice on HFD showed significant higher leukocyte counts (males: 11,775 ± 1,783 vs. 4,671 ± 556, p<0.01; females: 13,100 ± 1,775 vs. 14,280 ± 2,296, p=0.69), whereby monocytes, lymphocytes and granulocytes were significant higher in obese male mice compared to lean mice and female obese mice. Moreover, myelopoiesis in the spleen was increased in male obese vs lean mice. Obesity did not affect baseline systolic function and left ventricular dimensions assessed by echocardiography. However, after MI obese mice showed worse survival rates than mice on control diet (63.3% vs. 78.9% males; 62.5% vs. 100% females). Left-ventricular function in surviving obese male or female mice was not different from lean mice. Five days after MI, myelopoiesis in the spleen as measured by proliferation activity and cell numbers of progenitors was more increased in male obese mice than in female obese and lean mice (multipotent haematopoietic progenitors: 65,586 ± 1,688 vs. 1,065 ± 1,004 males; p<0.05, granulocyte-monocyte progenitors: 13,850 ± 3,092 vs. 3,659 ± 1,875; p<0.05). In the bone marrow, no differences in myelopoiesis between lean and obese male mice at baseline and 5 days after MI were detected.

Summary:
Male mice develop a more pronounced obesity-like phenotype and show impaired survival as compared to lean mice. The model will allow to mechanistically study the role of innate immunity on the impaired outcome after MI in obese mice.