Clinical recovery from myocardial infarction is thwarted, in part, by inability of surviving ventricular myocytes to reconstitute functional cardiac mass through a corresponding, compensatory increase in cell number. This highlights the limited capacity to restore cardiac mass by hypertrophy alone, and deleterious effects associated with hypertrophy that further impair survival. Ongoing myocyte loss also appears likely as an eventual contributor to end-stage heart failure. Conventional therapies for heart failure are aimed at rescuing jeopardized myocardium, optimizing mechanical load, or augmenting the mechanical performance of surviving myocytes. In principle, strategies to increase the number of functional ventricular myocytes have potential for a clinical benefit. Three complementary, gene-based approaches have been brought to bear on the problem of cardiac cell number in this collaborative R01 application-- transdifferentiation, manipulation of cell cycle constraints, and interference with pathways for programmed cell death (apoptosis). Viral delivery of cardiogenic transcription factors and upstream cardiogenic signals will be explored by Dr. Robert Schwartz. Drs. Michael Schneider and Loren Field will use gain- and loss-of-function mutations to dissect the """"""""postmitotic"""""""" phenotype in vivo, and will use co-precipitation or interaction cloning to isolate the endogenous cardiac proteins affecting cell cycle exit. Dr. Konstantin Galaktionov, an expert on Cdc25, will study molecular regulators of the G2/M transition, a second checkpoint that must be overcome for cell number to be increased. Mechanisms and countermeasures for cardiac apoptosis will be tested by Dr. Doug Mann, with emphasis on dilated cardiomyopathy triggered by overexpression of tumor necrosis factor alpha, and on investigations of human myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061543-01
Application #
2737661
Study Section
Special Emphasis Panel (ZHL1-CSR-F (S1))
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
1998-09-30
Budget End
1999-08-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhang, Weili; Lavine, Kory J; Epelman, Slava et al. (2015) Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J Am Heart Assoc 4:e001993
Evans, Sarah; Mann, Douglas L (2013) Circulating p53-responsive microRNAs as predictive biomarkers in heart failure after acute myocardial infarction: the long and arduous road from scientific discovery to clinical utility. Circ Res 113:242-4
Bozkurt, Biykem; Bolos, Mariana; Deswal, Anita et al. (2012) New insights into mechanisms of action of carvedilol treatment in chronic heart failure patients--a matter of time for contractility. J Card Fail 18:183-93
Mann, Douglas L (2012) Sphingosine 1-phosphate as a therapeutic target in heart failure: more questions than answers. Circulation 125:2692-4
Mann, Douglas L; Barger, Philip M; Burkhoff, Daniel (2012) Myocardial recovery and the failing heart: myth, magic, or molecular target? J Am Coll Cardiol 60:2465-72
Divakaran, Vijay; Mehta, Sachin; Yao, David et al. (2011) Hepcidin in anemia of chronic heart failure. Am J Hematol 86:107-9
Mann, Douglas L; Burkhoff, Daniel (2011) Myocardial expression levels of micro-ribonucleic acids in patients with left ventricular assist devices signature of myocardial recovery, signature of reverse remodeling, or signature with no name? J Am Coll Cardiol 58:2279-81
Zhang, Weili; Chancey, Amanda L; Tzeng, Huei-Ping et al. (2011) The development of myocardial fibrosis in transgenic mice with targeted overexpression of tumor necrosis factor requires mast cell-fibroblast interactions. Circulation 124:2106-16
Burchfield, Jana S; Dong, Jian-Wen; Sakata, Yasushi et al. (2010) The cytoprotective effects of tumor necrosis factor are conveyed through tumor necrosis factor receptor-associated factor 2 in the heart. Circ Heart Fail 3:157-64
Topkara, Veli K; Kondareddy, Srikanth; Mann, Douglas L (2009) Modulation of left ventricular dilation remodeling with epicardial restraint devices in postmyocardial infarction heart failure. Curr Heart Fail Rep 6:229-35

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