Abstract Body: Introduction: Mixed lineage kinase 3 (MLK3) is required for preservation of cardiac function in experimental HF models. In mice, cardiomyocyte (CM) specific MLK3 deletion leads to left ventricular (LV) dysfunction and eccentric remodeling after 4 weeks of transaortic constriction (TAC) induced pressure overload. Physiological mechanisms by which MLK3 controls the cardiac response to pressure overload remain unknown.

Hypothesis: MLK3 preserves LV function in pressure overload through an early compensatory function in the CM.

Methods: We generated mice with loxP sites flanking exons 4-10 of the Map3k11 gene encoding MLK3, crossing with αMHC-Cre transgenic mice to generate MLK3 CM-specific deletion (CMKO) mice. We subjected 12-week-old male MLK3 CMKO and control MLK3fl/fl Cre- (MLK3 intact) littermates to TAC or sham for 1 week. Echocardiography, hemodynamic analysis and tissue harvest were performed at day 7. Left ventricular wall stress (LVWS) was calculated from echocardiographic and hemodynamic measurements in both 4- and 1-week TAC.

Results: MLK3 CMKO mice developed increased systolic and diastolic LVWS after 4-week TAC, compared with MLK3 intact littermates. Consistent with our prior 4-week TAC study, we found that after 1 week of TAC, MLK3 CMKO mice exhibited decreased ejection fraction and rate of ventricular relaxation compared to intact littermates. Both genotypes developed comparable LV hypertrophy after TAC, but MLK3 CMKO mice showed decreased systolic and diastolic LV wall thickness and increased systolic LV chamber dimension compared to intact littermates, consistent with a more eccentric remodeling phenotype. Systolic LV wall stress in TAC was significantly increased in MLK3 CMKO vs. MLK3 intact, with a trend toward increased diastolic wall stress.

Conclusions: MLK3 CMKO mice develop more severe LV dysfunction and eccentric remodeling during the early stages of pressure overload. We conclude that MLK3 maintains normal, compensated LV WS in chronic pressure overload by preserving normal LV function and concentric geometry. Since increased LV WS is a key, but poorly understood driver of worsening heart failure and mortality, these findings support further investigation of mechanisms CM through which MLK3 normalizes this variable.