Time-Warped Comparison of Gene Expression in Adaptive and Maladaptive Cardiac Hypertrophy

Abstract

Background— Cardiac hypertrophy is classically regarded as a compensatory response, yet the active tissue remodeling processes triggered by various types of mechanical stress can enhance or diminish the function of the heart. Despite the disparity in outcomes, there are similarities in the hypertrophic responses. We hypothesized that a generic genetic response that is not dependent on the particular nature of the hypertrophic stimulus exists. To test our hypothesis, we compared the temporal evolution of transcriptomes measured in hearts subjected to either adaptive (exercise-induced) or maladaptive (aortic banding–induced) hypertrophy. Methods and Results— Generic hypertrophy-associated genes were identified and distinguished from stimulus-dependent transcripts by coupling a metric of cardiac growth with a dynamic time-warping algorithm to align transcriptome changes with respect to the hypertrophy response. The major differences in expression between the adaptive and maladaptive hypertrophy models were centered around the genes involved in metabolism, fibrosis, and immune response. Conversely, transcripts with common expression patterns in both hypertrophy models were associated with signal transduction, cytoskeletal development, and muscle contraction. Thus, despite the apparent differences in the expression response of the heart to either athletic conditioning or pressure overload, there is a set of genes that displays similar expression profiles. Conclusions— This finding lends support to the notion of a generalized cardiac growth mechanism that is activated in response to mechanical perturbation. The common and unique genetic signatures of adaptive and maladaptive hypertrophy may be useful in the diagnosis and treatment of pathological myocardial remodeling.