Gene Profiling Changes in Cytoskeletal Proteins During Clinical Recovery After Left Ventricular–Assist Device Support

Background—After left ventricular–assist device (LVAD) support, a proportion of patients recover sufficient ventricular function to enable explantation of the device. The exact molecular mechanisms involved in myocardial recovery remain unknown. Cytoskeletal proteins are essential for the structure and function of the cardiac myocyte and might play a major role. Methods and Results—A total of 15 patients with nonischemic cardiomyopathy who required LVAD implantation were studied; 6 recovered sufficiently to allow explantation of the device compared with 9 who did not recover and required transplantation. LV myocardial samples were collected at implantation and explantation/transplantation. Affymetrix microarray analysis was performed on the paired samples and analyzed with reference to sarcomeric and nonsarcomeric cytoskeletal proteins. In the recovery group, of the nonsarcomeric proteins, lamin A/C increased 1.5-fold (P<0.05) and spectrin 1.6-fold (P<0.05) between the times of implantation and explantation. Integrins β1, β6, and α7 decreased 1.7-fold (P<0.05), 2.4-fold (P<0.05), and 1.5-fold (P<0.05), respectively, but integrins α5 and β5 increased 2.3-fold (P<0.01) and 1.2-fold (P<0.01) at explantation. The following sarcomeric proteins changed in the recovered group only: β-actin increased 1.4-fold (P<0.05); α-tropomyosin, 1.3-fold (P<0.05); α1-actinin, 1.8-fold (P<0.01); and α-filamin A, 1.6-fold (P<0.05). Both troponin T3 and α2-actinin decreased by 1.6-fold at the time of explantation (P<0.05). Vinculin decreased 1.7-fold (P=0.001) in the recovered group but increased by 1.7-fold (P<0.05) in the nonrecovered group. Vinculin protein levels decreased 4.1-fold in the recovered group. Conclusions—Myocardial recovery was associated with a specific pattern of changes in sarcomeric, nonsarcomeric, and membrane-associated proteins, which could have important implications in understanding the mechanisms involved.

[1]  N. Smedira,et al.  Cytoskeletal structure and recovery in single human cardiac myocytes. , 2004, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[2]  Xinqiang Han,et al.  Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks. , 2004, Physiological genomics.

[3]  Wei Pan,et al.  Modeling the relationship between LVAD support time and gene expression changes in the human heart by penalized partial least squares , 2004, Bioinform..

[4]  J. Towbin,et al.  Molecular normalization of dystrophin in the failing left and right ventricle of patients treated with either pulsatile or continuous flow-type ventricular assist devices. , 2004, Journal of the American College of Cardiology.

[5]  B. Tom,et al.  Endothelial cells preparing to die by apoptosis initiate a program of transcriptome and glycome regulation , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  M. Omary,et al.  Implications of intermediate filament protein phosphorylation , 1996, Cancer and Metastasis Reviews.

[7]  L. Miller,et al.  Alterations of gene expression in failing myocardium following left ventricular assist device support. , 2003, Physiological genomics.

[8]  R. Ross.  The extracellular connections: the role of integrins in myocardial remodeling. , 2002, Journal of cardiac failure.

[9]  C. Pham,et al.  Modulation of integrins and integrin signaling molecules in the pressure-loaded murine ventricle , 2002, Histochemistry and Cell Biology.

[10]  B. M. Christensen,et al.  Characterization of hemocytes from the yellow fever mosquito, Aedes aegypti , 2002, Histochemistry and Cell Biology.

[11]  N. de Jonge,et al.  Left ventricular assist device in end-stage heart failure: persistence of structural myocyte damage after unloading. An immunohistochemical analysis of the contractile myofilaments. , 2002, Journal of the American College of Cardiology.

[12]  J. Towbin,et al.  Molecular remodelling of dystrophin in patients with end-stage cardiomyopathies and reversal in patients on assistance-device therapy , 2002, The Lancet.

[13]  J. Towbin,et al.  The failing heart , 2002, Nature.

[14]  D. Fatkin,et al.  Molecular mechanisms of inherited cardiomyopathies. , 2002, Physiological reviews.

[15]  J. Pepper,et al.  Quantitative Myocardial Cytokine Expression and Activation of the Apoptotic Pathway in Patients Who Require Left Ventricular Assist Devices , 2001, Circulation.

[16]  M. Yacoub.  A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery. , 2001, European heart journal.

[17]  M. Yacoub,et al.  Bridge to recovery: The Harefield Approach , 2001 .

[18]  W. Schaper,et al.  Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. , 2000, Circulation research.

[19]  R. M. Graham,et al.  Pathogenesis of inherited forms of dilated cardiomyopathy. , 1999, The New England journal of medicine.

[20]  J. Seidman,et al.  Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. , 1999, The New England journal of medicine.

[21]  T. Borg,et al.  Regulation of cardiac myocyte protein turnover and myofibrillar structure in vitro by specific directions of stretch. , 1999, Circulation research.

[22]  M Flannery,et al.  Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. , 1998, Circulation.

[23]  C. Pham,et al.  β1 Integrins Participate in the Hypertrophic Response of Rat Ventricular Myocytes , 1998 .

[24]  O. Frazier,et al.  Improved left ventricular function after chronic left ventricular unloading. , 1996, The Annals of thoracic surgery.

[25]  S. Coughlin,et al.  Idiopathic dilated cardiomyopathy. , 1994, The New England journal of medicine.

[26]  P. Poole‐Wilson.  Idiopathic dilated cardiomyopathy. , 1990, BMJ.

[27]  G. Blobel,et al.  cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins. , 1986, Proceedings of the National Academy of Sciences of the United States of America.