Gao Z, Barth AS, DiSilvestre D, Akar FG, Tian Y, Tanskanen A, Kass DA, Winslow RL, Tomaselli GF. Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling. Physiol Genomics 35: 222-230, 2008. First published September 9, 2008 doi:10.1152/physiolgenomics.00100.2007.-Heart failure (HF) is the leading cause of morbidity and mortality in the industrialized world. While the transcriptomic changes in end-stage failing myocardium have received much attention, no information is available on the gene expression patterns associated with the development of HF in large mammals. Therefore, we used a well-controlled canine model of tachycardia-induced HF to examine global gene expression in left ventricular myocardium with Affymetrix canine oligonucleotide arrays at various stages after initiation of rapid ventricular pacing (days 3, 7, 14, and 21). The gene expression data were complemented with measurements of action potential duration, conduction velocity, and left ventricular end diastolic pressure, and dP/dt(max) over the time course of rapid ventricular pacing. As a result, we present a phenotypecentered gene association network, defining molecular systems that correspond temporally to hemodynamic and electrical remodeling processes. Gene Ontology analysis revealed an orchestrated regulation of oxidative phosphorylation, ATP synthesis, cell signaling pathways, and extracellular matrix components, which occurred as early as 3 days after the initiation of ventricular pacing, coinciding with the early decline in left ventricular pump function and prolongation of action potential duration. The development of clinically overt left ventricular dysfunction was associated with few additional changes in the myocardial transcriptome. We conclude that the majority of tachypacing-induced transcriptional changes occur early after initiation of rapid ventricular pacing. As the transition to overt HF is characterized by few additional transcriptional changes, posttranscriptional modifications may be more critical in regulating myocardial structure and function during later stages of HF. transcriptional remodeling; microarray; oxidative phosphorylation; action potential HEART FAILURE (HF) is the leading cause of morbidity and mortality in the industrialized world, with an estimated 5 million HF patients in the United States alone (5). Virtually any form of cardiovascular disease may culminate in HF, a final common pathway to mortality, through maladaptive left ventricular remodeling, which may begin before clinical symptoms become apparent (14, 29). Hence, early diagnosis of asymptomatic left ventricular dysfunction and timely intervention are critical to slowing or arresting the development of HF. While the clinical symptoms of decompensated HF are well described, it is difficult, if not impossible, for a physician to make a diagnosis when left ventricular dysfunction is in its earliest stages. Limited understanding of the molecular systems underlying ventricular dysfunction an...