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MicroRNAs are recently discovered regulators of gene expression and are becoming increasingly recognized as important regulators of heart function. Genome-wide profiling of microRNAs in human heart failure has not been reported previously. We measured expression of 428 microRNAs in 67 human left ventricular samples belonging to control ( n = 10), ischemic cardiomyopathy (ICM, n = 19), dilated cardiomyopathy (DCM, n = 25), or aortic stenosis (AS, n = 13) diagnostic groups. miRNA expression between disease and control groups was compared by ANOVA with Dunnett's post hoc test. We controlled for multiple testing by estimating the false discovery rate. Out of 428 microRNAs measured, 87 were confidently detected; 43 were differentially expressed in at least one disease group. In supervised clustering, microRNA expression profiles correctly grouped samples by their clinical diagnosis, indicating that microRNA expression profiles are distinct between diagnostic groups. This was further supported by class prediction approaches, in which the class (control, ICM, DCM, AS) predicted by a microRNA-based classifier matched the clinical diagnosis 69% of the time ( P < 0.001). These data show that expression of many microRNAs is altered in heart disease and that different types of heart disease are associated with distinct changes in microRNA expression. These data will guide further studies of the contribution of microRNAs to heart disease pathogenesis.

Cardiac hypertrophy is a complex and nonhomogenous response to various stimuli. In this study, we used high-density oligonucleotide microarray to examine gene expression profiles during physiological hypertrophy, pathological hypertrophy, and heart failure in Dahl salt-sensitive rats. There were changes in 404/3,160 and 874/3,160 genes between physiological and pathological hypertrophy and the transition from hypertrophy to heart failure, respectively. There were increases in stress response genes (e.g., heat shock proteins) and inflammation-related genes (e.g., pancreatitis-associated protein and arachidonate 12-lipoxygenase) in pathological processes but not in physiological hypertrophy. Furthermore, atrial natriuretic factor and brain natriuretic protein showed distinctive changes that are very specific to different conditions. In addition, we used a resampling-based gene score-calculating method to define significantly altered gene clusters, based on Gene Ontology classification. It revealed significant alterations in genes involved in the apoptosis pathway during pathological hypertrophy, suggesting that the apoptosis pathway may play a role during the transition to heart failure. In addition, there were significant changes in glucose/insulin signaling, protein biosynthesis, and epidermal growth factor signaling during physiological hypertrophy but not during pathological hypertrophy.

Mouse models mimicking human diseases are important tools in trying to understand the underlying mechanisms of many disease states. Several surgical models have been described that mimic human myocardial infarction (MI) and pressure-overload-induced cardiac hypertrophy. However, there are very few detailed descriptions for performing these surgical techniques in mice. Consequently, the number of laboratories that are proficient in performing cardiac surgical procedures in mice has been limited. Microarray technologies measure the expression of thousands of genes simultaneously, allowing for the identification of genes and pathways that may potentially be involved in the disease process. The statistical analysis of microarray experiments is highly influenced by the amount of variability in the experiment. To keep the number of required independent biological replicates and the associated costs of the study to a minimum, it is critical to minimize experimental variability by optimizing the surgical procedures. The aim of this publication was to provide a detailed description of techniques required to perform mouse cardiac surgery, such that these models can be utilized for genomic studies. A description of three major surgical procedures has been provided: 1) aortic constriction, 2) pulmonary artery banding, 3) MI (including ischemia-reperfusion). Emphasis has been placed on technical procedures with the inclusion of thorough descriptions of all equipment and devices employed in surgery, as well as the application of such techniques for expression profiling studies. The cardiac surgical techniques described have been, and will continue to be, important for elucidating the molecular mechanisms of cardiac hypertrophy and failure with high-throughput technology.