Myocardial infarction (MI) is a major cause of heart failure (HF) with the progressive worsening of cardiac performance due to structural and functional alterations. Therefore, we studied cardiac function in adult mice following MI using the Millar pressure-volume (P-V) conductance catheter system in vivo during the later phase of compensatory remodeling and decompensation to HF. We evaluated load dependent and independent parameters in control and 2, 4, 6 and 10 wk post-MI mice and integrated changes in function with changes in gene expression. Our results indicated a significant deterioration of cardiac function in post-MI mice over time reflected first by systolic dysfunction followed by a transient improvement, before further decline in both systolic and diastolic function. Associated with the function and adaptive remodeling phases were transient changes in fetal gene and extracellular matrix gene expression. However undermining the compensatory remodeling response was a continual decline in cardiac contractility, which promoted the transition into failure. Our study provided a scheme of integrated cardiac function and gene expression changes occurring during the adaptive and maladaptive response of the heart independent of systemic vascular properties during the transition to HF following MI in mice. P-V loop analysis was used to quantitatively evaluate the gradual deterioration in cardiac function post-MI. P-V loop analysis was found to be an appropriate method for assessment of global cardiac function under varying load dependent and independent conditions in the murine model with many similarities to data obtained from larger animals and humans.