Differential regional gene expression from cardiac dyssynchrony induced by chronic right ventricular free wall pacing in the mouse.

Routine clinical right ventricular pacing generates left ventricular dyssynchrony manifested by early septal shortening followed by late lateral contraction, which, in turn, reciprocally stretches the septum. Dyssynchrony is disadvantageous to cardiac mechanoenergetics and worsens clinical prognosis, yet little is known about its molecular consequences. Here, we report the influence of cardiac dyssynchrony on regional cardiac gene expression in mice. Mice were implanted with a custom-designed miniature cardiac pacemaker and subjected to 1-wk overdrive right ventricular free wall pacing (720 beats/min, baseline heart rate 520-620 beats/min) to generate dyssynchrony (pacemaker: 3-V lithium battery, rate programmable, 1.5 g, bipolar lead). Electrical capture was confirmed by pulsed-wave Doppler and dyssynchrony by echocardiography. Gene expression from the left ventricular septal and lateral wall myocardium was assessed by microarray (dual-dye method, Agilent) using oligonucleotide probes and dye swap. Identical analysis was applied to four synchronously contracting controls. Of the 22,000 genes surveyed, only 18 genes displayed significant (P < 0.01) differential expression between septal/lateral walls >1.5 times that in synchronous controls. Gene changes were confirmed by quantitative PCR with excellent correlations. Most of the genes (n = 16) showed greater septal expression. Of particular interest were seven genes coding proteins involved with stretch responses, matrix remodeling, stem cell differentiation to myocyte lineage, and Purkinje fiber differentiation. One week of iatrogenic cardiac dyssynchrony triggered regional differential expression in relatively few select genes. Such analysis using a murine implantable pacemaker should facilitate molecular studies of cardiac dyssynchrony and help elucidate novel mechanisms by which stress/stretch stimuli due to dyssynchrony impact the normal and failing heart.

[1]  D. Kass,et al.  Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts. , 2005, Cardiovascular research.

[2]  J. Daubert,et al.  The effect of cardiac resynchronization on morbidity and mortality in heart failure. , 2005, The New England journal of medicine.

[3]  Zhonglin Xie,et al.  Osteopontin Modulates Myocardial Hypertrophy in Response to Chronic Pressure Overload in Mice , 2004, Hypertension.

[4]  M. Schellings,et al.  Matricellular proteins in the heart: possible role during stress and remodeling. , 2004, Cardiovascular research.

[5]  C. McCulloch,et al.  Increased cell death in osteopontin-deficient cardiac fibroblasts occurs by a caspase-3-independent pathway. , 2004, American journal of physiology. Heart and circulatory physiology.

[6]  E. Horwitz.  Dkk-1-mediated expansion of adult stem cells. , 2004, Trends in biotechnology.

[7]  H. Watkins,et al.  Cardiac Myosin Binding Protein C: Its Role in Physiology and Disease , 2004, Circulation research.

[8]  D. DeMets,et al.  Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. , 2004, The New England journal of medicine.

[9]  D. Heinegård,et al.  Altered vascular remodeling in osteopontin-deficient atherosclerotic mice. , 2004, Journal of vascular research.

[10]  Guoxin Zhang,et al.  Growth Factor Signaling Induces Metastasis Genes in Transformed Cells: Molecular Connection between Akt Kinase and Osteopontin in Breast Cancer , 2003, Molecular and Cellular Biology.

[11]  Christophe Leclercq,et al.  Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart , 2003, Circulation.

[12]  D. Prockop,et al.  The Wnt Signaling Inhibitor Dickkopf-1 Is Required for Reentry into the Cell Cycle of Human Adult Stem Cells from Bone Marrow* , 2003, Journal of Biological Chemistry.

[13]  David O. Martin,et al.  Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. , 2002, JAMA.

[14]  A. Maggioni,et al.  Cumulative effect of complete left bundle-branch block and chronic atrial fibrillation on 1-year mortality and hospitalization in patients with congestive heart failure. A report from the Italian network on congestive heart failure (in-CHF database). , 2002, European heart journal.

[15]  D. Kass,et al.  Minimal force‐frequency modulation of inotropy and relaxation of in situ murine heart , 2001, The Journal of physiology.

[16]  Zhonglin Xie,et al.  Exaggerated Left Ventricular Dilation and Reduced Collagen Deposition After Myocardial Infarction in Mice Lacking Osteopontin , 2001, Circulation research.

[17]  Christine Brun,et al.  In silico prediction of protein-protein interactions in human macrophages , 2001, BMC Research Notes.

[18]  F. Deák,et al.  Expression of matrilin-1, -2 and -3 in developing mouse limbs and heart. , 2000, Matrix biology : journal of the International Society for Matrix Biology.

[19]  A. Poustka,et al.  Dickkopf genes are co-ordinately expressed in mesodermal lineages , 1999, Mechanisms of Development.

[20]  I. Morano,et al.  Expression of atrial myosin light chains but not α-myosin heavy chains is correlated in vivo with increased ventricular function in patients with hypertrophic obstructive cardiomyopathy , 1999, Journal of Molecular Medicine.

[21]  J. Taipale,et al.  Latent transforming growth factor-beta binding proteins (LTBPs)--structural extracellular matrix proteins for targeting TGF-beta action. , 1999, Cytokine & growth factor reviews.

[22]  E. Fleck,et al.  Myocardial osteopontin expression is associated with left ventricular hypertrophy. , 1997, Circulation.

[23]  T. Mikawa,et al.  Skeletal muscle-specific myosin binding protein-H is expressed in Purkinje fibers of the cardiac conduction system. , 1997, Circulation research.

[24]  J. Ross,et al.  Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha -/- mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  O. Hess,et al.  Hemodynamic performance and myosin light chain-1 expression of the hypertrophied left ventricle in aortic valve disease before and after valve replacement. , 1992, Circulation research.

[26]  D. Heinegård,et al.  Matrix proteins bound to associatively prepared proteoglycans from bovine cartilage. , 1979, The Biochemical journal.

[27]  Z. Podlubnaya,et al.  Reconstitution of ventricular myosin with atrial light chains 1 improves its functional properties. , 2005, Acta biochimica Polonica.

[28]  P. Krieg,et al.  Molecular regulation of cardiac chamber-specific gene expression. , 2004, Trends in cardiovascular medicine.