Heart failure (HF) is a common condition that affects approximately 6.7 million adults in the United States alone. Although extensively studied, the mechanisms underlying cardiac metabolism in HF patients remain incomplete. Creatine is essential for maintaining proper cardiac function, as the creatine-phosphocreatine buffer allows for sufficient energy storage and heart contraction. In HF patients, reduced creatine levels and increased levels of its precursor, guanidinoacetate (GAA), are observed. Transporters Crt1 and Crt2 facilitate the translocation of creatine across the plasma membrane, and decreased transporter expression may cause reduced creatine levels in heart failure. Previously we have shown that Methionine adenosyltransferase 2A cardiac knockout (Mat2a cKO) mice exhibit heart failure with decreased creatine. In this study, we aimed to rescue heart failure symptoms in Mat2a cKO mice by increasing creatine via overexpression of Crt1 and Crt2. Because traditional AAVs do not allow sufficient delivery to cardiac muscles, we designed and validated a myofibril-AAV under the control of the cardiac troponin promoter. Through western blots and qPCR, our findings demonstrate that the myo-AAV effectively increases Crt1 and Crt2 expression in cardiomyocytes. Surprisingly, compared to the control, Crt1 OE did not alter survival or creatine levels. However, Crt2 overexpression mice exhibit increased survival and ejection fraction. Interestingly, metabolomics results showed decreased creatine levels, indicating Crt2 overexpression has a creatine independent survival mechanism. Given Crt2 has a GAA efflux role in the kidney, in human heart failure samples GAA levels are increased, and GAA accumulation is associated with unfavorable cardiometabolic risk, we hypothesize the protective role of overexpression is due to a release of GAA buildup. Overall, these findings show cardiac specific Crt2 overexpression can mitigate heart failure and increase survival, and in the future we aim to overexpress Crt2 in a mouse heart failure model and conduct metabolomics to understand the mechanism behind this cardioprotection.