Purpose: To study the role of heart and neural crest derivatives expressed 1 (HAND1) and cystathionine-beta-synthase (CBS) in the maintenance of cardiac architecture following high fat dietinduced obesity. Methods: Mouse models of initial and critical heart disease were established by continuous feeding of high fat diet for 7 and 12 months, respectively. The expression of HAND1 and CBS were assayed using immunohistochemistry and Western blotting. Results: Obesity led to mild and severe forms of heart disease which were confirmed through histological imaging. Initial obesity resulted in cardiac tissue remodeling along with initial degeneration, while critical obesity resulted in tissue hardening. The expression of HAND1 was upregulated 4.3 folds in the mild form of cardiac failure, relative to marginal expression pattern of HAND1 in control tissue. However, as the disease progressed, the expression of HAND1 was limited in serve form of cardiac failure. Moreover, the expression of cystathionine beta-synthase (CBS) was upregulated 3.7-fold in the initial form of heart failure, but was subsequently reduced in serve form of heart disease. Conclusion: These results reveal that in high fat diet-induced cardiac stress, the over-expressions of HAND1 and CBS at the initial stages induce extensive alterations in cardiac architecture.