Introduction: Heart failure is a major complication of hypertension and metabolic syndrome and the most common condition requiring hospitalization. The molecular mechanisms underlying pathogenesis of heart failure remain unclear. Recent advances in genomic technology have provided novel insights in understanding the pathophysiology and signaling mechanisms that could lead to failing myocardium. Using the Next Gen RNA sequencing of the heart in a rat model of metabolic syndrome that develops florid heart failure, we investigated the genes and pathways differentially expressed. Methods: Obese ZSF1 rats, which were developed by crossing Zucker Diabetic Fatty (ZDF) rats with spontaneously hypertensive heart failure (SHHF) rats exhibit full blown metabolic syndrome with obesity, hypertension, hyperlipidemia, hyperglycemia and progressive heart failure by the age of 20 weeks. We used lean littermates of ZSF rats as controls as they do not develop diabetes or heart failure. All rats were maintained for 23 weeks from 8th week and euthanized and hearts were harvested. Total RNA was isolated from the hearts and processed for transcriptome analysis using Illumina HiSeq 2500. Hearts from obese ZSF1 rats were compared to those from lean ZSF rats. The differential gene list from this analysis was imported into Ingenuity Pathway Analysis (IPA) for global transcriptome analysis and pathway mapping. Results: The top canonical pathways that were differentially affected include cardiac β adrenergic signaling, mitochondrial dysfunction, dopamine receptor signaling, creatinine phosphate biosynthesis, superoxide degradation and CDK5 signaling. Overall about 400 genes demonstrated a significant change of at least 2 fold change on log 2 fluorescence intensity values with majority of these genes down regulated. The important downregulated molecules included PPP2RIA (protein phosphatase 2regulatory subunit A alpha), PPP2R14C, AKAP7 (A Kinase anchoring protein 7), SLC8A2 (solute carrier family 8 Na-Ca) SOD 2 (superoxide dismutase 2), CKM (creatinine kinase muscle) CITED 2 (cbp/p300 interacting transactivator) and ALDH8A1 ( aldehyde dehydrogenase 8). Conclusions: Our data indicates that Next Gen sequencing of hearts from ZSF1 rats identified several pathways and molecules which are involved in myocardial function and failure. A number of these specific proteins and molecules are incriminated in biochemical and signaling cascades that result in myocardial inflammation, oxidative stress, apoptosis and fibrosis. These observations provide new insights into understanding the pathogenic pathways resulting in heart failure.