Cardiovascular disease is the leading cause of death in the US and other parts of the world. Various concurrent risk factors are associated with the ever-rising prevalence of heart diseases. Cardiovascular diseases are resulted from a complex interaction between environmental and genetic factors. Although environmental factors play an important role in heart disease, genetic factors are key determinants as well. In this dissertation research, I examined compromised cardiac geometric and contractile function in particular in the form of cardiomyopathies caused by environmental toxic stress, genetic mutation-induced insulin resistance and maternal obesity. Environmental risk factors are known to contribute to heart diseases. Among the environmental toxins, paraquat, a widely used non-selective herbicide, induces cardiotoxicity leading to myocardial injury and contractile dysfunction. Ablation of the essential post-receptor insulin signaling molecule Akt2 ablation conferred insulin resistance which is associated with high incidence of heart disease. Finally, maternal overnutrition and maternal obesity have been shown to contribute to the obesity pandemics in the 21st century and represent a good example for the interaction between environment and genetics, which negatively impact fetal heart development and cardiac health later on in life. Autophagy is a highly regulated intracellular lysosomal-mediated catabolic process which degrades aged, damaged or dysfunctional proteins, intracellular organelles and cytoplasmic components for maintaining cellular homeostasis. Autophagy is a double-edged sword, in some cases it acts as an adaptive response to stress for organismal survival, whereas in other cases it may promote cell death. Autophagy plays an essential role in cardiac homeostasis. Under normal conditions, basal level of autophagy is crucial for organelle turnover. Autophagy levels may be either up- or down-regulated in response to stresses such as ischemia/reperfusion, environmental toxins, insulin resistance and high caloric intake, contributing to cardiac remodeling and heart failure. Thus, the overall aim for my PhD research was to use autophagy as a cellular survival/death regulatory mechanism to examine the role of environmental and genetic factors in myocardial dysfunction and ultimately heart disease under various pathological conditions including paraquat toxicity and Akt2 deletion-induced insulin resistance. In order to examine the influence of maternal obesity on fetal sheep cardiomyocyte contractile and intracellular Ca2+ transient function, I established a novel method of assessment on fetal sheep cardiomyocyte function. First, my data indicated that paraquat-induced cardiac dysfunction was associated with excessive autophagy, which was ameliorated by AMPK deficiency. Furthermore, my data revealed that downregulation of autophagy from AMPK deficiency was mediated through AMPK-TSC2-mTORC1-ULK1 pathway. Secondly, I evaluated the effect of Akt2 ablation induced insulin resistance on diabetic cardiomyopathy, with a focus on the role of apoptosis and autophagy. I found that Akt2 knockout-induced insulin resistance caused cardiac anomalies was mediated via suppressed autophagy and activated apoptosis by decreased FOXO1 and increased p38 MAPK activity, which was effectively attenuated by the mTOR-independent inducer of autophagy trehalose. More intriguingly, activation of FOXO1 which facilitates the expression of autophagy related genes; and inhibition of p38 MAPK which suppresses the activity of Atg9, seem to be involved in trehalose-induced autophagy, in an mTOR-independent fashion. Finally, I successfully established a novel method for measuring mechanical and intracellular Ca2+ properties in fetal sheep cardiomyocytes. My data indicated that maternal obesity caused fetal sheep cardiomyocyte contractile dysfunction and disrupted intracellular Ca2+ homeostasis. Taken together, these findings provide some evidence to suggest that environmental and genetic factors play an important role in heart disease.