Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110␣ isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exerciseinduced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110␣) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiacspecific transgenic mice with increased or decreased PI3K(p110␣) activity to the DCM model, and subjected PI3K(p110␣) transgenics to acute pressure overload (ascending aortic constriction). Lifespan, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110␣) activity prolonged survival in the DCM model by 15-20%. In contrast, reduced PI3K(p110␣) activity drastically shortened lifespan by Ϸ50%. Increased PI3K(p110␣) activity had a favorable effect on cardiac function and fibrosis in the pressureoverload model and attenuated pathological growth. PI3K(p110␣) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110␥) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110␣) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.heart failure ͉ signal transduction ͉ heart growth ͉ athlete's heart

Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause atrioventricular conduction defects in humans by unknown mechanisms. We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage. Null mutant embryos appear to lack the primordium of the atrioventricular node. In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells. In addition, an entire population of connexin40 -/connexin45 + cells is missing in the atrioventricular node of Nkx2-5 heterozygous KO mice. Specific functional defects associated with Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system. Surprisingly, the cellular expression of connexin40, the major gap junction isoform of Purkinje fibers and a putative Nkx2-5 target, is unaffected, consistent with normal conduction times through the His-Purkinje system measured in vivo. Postnatal conduction defects in Nkx2-5 mutation may result at least in part from a defect in the genetic program that governs the recruitment or retention of embryonic cardiac myocytes in the conduction system. 1130The Nonstandard abbreviations used: AV nodal effective refractory period (AVERP); connexin40 (Cx40); embryonic day (E); interventricular septum (IVS); intracardiac electrogram (IEGM); stimulus (S).

No abstract

Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause atrioventricular conduction defects in humans by unknown mechanisms. We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage. Null mutant embryos appear to lack the primordium of the atrioventricular node. In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells. In addition, an entire population of connexin40 -/connexin45 + cells is missing in the atrioventricular node of Nkx2-5 heterozygous KO mice. Specific functional defects associated with Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system. Surprisingly, the cellular expression of connexin40, the major gap junction isoform of Purkinje fibers and a putative Nkx2-5 target, is unaffected, consistent with normal conduction times through the His-Purkinje system measured in vivo. Postnatal conduction defects in Nkx2-5 mutation may result at least in part from a defect in the genetic program that governs the recruitment or retention of embryonic cardiac myocytes in the conduction system. 1130The Nonstandard abbreviations used: AV nodal effective refractory period (AVERP); connexin40 (Cx40); embryonic day (E); interventricular septum (IVS); intracardiac electrogram (IEGM); stimulus (S).