Background: Despite major advances in the treatment of heart failure (HF), it remains the major cause of mortality and morbidity worldwide. Experimental models of HF typically utilize acute myocardial infarction. However, the majority of clinical HFs occur gradually by a chronic progressive mechanism. Thus, more relevant models are required to aid identification, quantification, and characterization of HF, and its underlying mechanisms. Methods and findings: We developed a model of progressive chronic heart failure (CHF) in the mini-swine by placement of an ameroid constrictor on the left anterior descending coronary artery (LAD). This model demonstrated a steady decline in the cardiac function from 8 to 12 weeks, with a 50% reduction in the ejection fraction. Further, the proteomic, metabolomic and bioinformatic analyses of ischemic tissue and plasma revealed a significant alteration of the mitochondrial respiratory chain mediated by nicotinamide adenine dinucleotide (NADH), which resulted in down-regulation of malate dehydrogenase (MDH) and insufficient energy supply to support cardiac contractility and relaxation. Furthermore, significant changes in apolipoprotein A-I, low density lipoprotein (LDL), and very LDL (VLDL) in plasma indicated that lipid metabolism disorders occurred in mini-swines with myocardial ischemia via glycerolipid metabolism. Conclusions: We describe a stable and easily reproducible CHF model using an ameroid constrictor placed on the LAD. We found that the NADH-mediated tricarboxylic acid cycle and energy metabolism disorders are key pathophysiological mechanisms underlying CHF. These data will provide potential biomarkers for monitoring the therapeutic intervention of CHF.