Abstract: To detect the methylation level of genome-wide DNA and total RNA in the process of heart failure, we established the method of ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to observe the change and synchronization of methylation rate of myocardial infarction (MI) tissue and peripheral blood. Animal welfare and experimental process were in accordance with the regulations of the Animal Ethics Committee of Guangzhou Medical University. The rats with myocardial infarction were divided into three groups:1^st, 4^th, and 8^th week to simulate different levels of cardiac function. And they were euthanized at the same time to keep the same age. DNA and RNA were extracted from infarct marginal tissues and peripheral blood lymphocytes, and then decomposed into single nucleosides by enzymolysis. The methylation rate of DNA and RNA was measured and calculated quantitatively. The results showed a concordant methylation changes in tissue and blood, and the methylation level of genome-wide DNA and total RNA was increased after myocardial infarction in rats. In this study, we obtained the preliminary data of DNA and RNA methylation during the occurrence and development of heart failure, further indicating that epigenetic changes can be used as biomarkers for early diagnosis of heart failure.