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Articles by G. W Dorn
Total Records ( 2 ) for G. W Dorn
  D. E Sosnovik , M Nahrendorf , P Panizzi , T Matsui , E Aikawa , G Dai , L Li , F Reynolds , G. W Dorn , R Weissleder , L Josephson and A. Rosenzweig
 

Background— The ability to image cardiomyocyte (CM) apoptosis in heart failure could facilitate more accurate diagnostics and optimize targeted therapeutics. We thus aimed to develop a platform to image CM apoptosis quantitatively and specifically in heart failure in vivo. The myocardium in heart failure, however, is characterized by very low levels of CM apoptosis and normal vascular permeability, factors thought to preclude the use of molecular MRI.

Methods and Results— Female mice with overexpression of Gaq were studied. Two weeks postpartum, these mice develop a cardiomyopathy characterized by low levels of CM apoptosis and minimal myocardial necrosis or inflammation. The mice were injected with the annexin-labeled nanoparticle (AnxCLIO-Cy5.5) or a control probe (CLIO-Cy5.5) and imaged in vivo at 9.4 T. Uptake of AnxCLIO-Cy5.5 occurred in isolated clusters, frequently in the subendocardium. Myocardial T2* was significantly lower (7.6±1.5 versus 16.8±2.7 ms, P<0.05) in the mice injected with AnxCLIO-Cy5.5 versus CLIO-Cy5.5, consistent with the uptake of AnxCLIO-Cy5.5 by apoptotic CMs. A strong correlation (r2=0.86, P<0.05) was seen between in vivo T2* (AnxCLIO-Cy5.5 uptake) and myocardial caspase-3 activity.

Conclusions— The ability of molecular MRI to image sparsely expressed targets in the myocardium is demonstrated in this study. Moreover, a novel platform for high-resolution and specific imaging of CM apoptosis in heart failure is established. In addition to providing novel insights into the pathogenesis of CM apoptosis, the developed platform could facilitate the development of novel antiapoptotic therapies in heart failure.

  F Qin , S Lennon Edwards , S Lancel , A Biolo , D. A Siwik , D. R Pimentel , G. W Dorn , Y. J Kang and W. S. Colucci
 

Background— Although it seems that reactive oxygen species contribute to chronic myocardial remodeling, questions remain about (1) the specific types of reactive oxygen species involved, (2) the role of reactive oxygen species in mediating specific cellular events, and (3) the cause-and-effect relationship between myocardial reactive oxygen species and the progression to heart failure. Transgenic mice with myocyte-specific overexpression of Gq develop a dilated cardiomyopathy that progresses to heart failure. We used this model to examine the role of H2O2 in mediating myocardial remodeling and the progression to failure.

Methods and Results— In Gq myocardium, markers of oxidative stress were increased at 4 weeks and increased further at 20 weeks. Gq mice were crossbred with transgenic mice having myocyte-specific overexpression of catalase. At 4 weeks of age, left ventricular end-diastolic dimension was increased and left ventricular fractional shortening decreased in Gq mice and deteriorated further through 20 weeks. In Gq mice, myocardial catalase overexpression had no effect on left ventricular end-diastolic dimension or fractional shortening at 4 weeks but prevented the subsequent deterioration in both. In Gq mice, myocyte hypertrophy; myocyte apoptosis; interstitial fibrosis; and the progression to overt heart failure, as reflected by lung congestion and exercise intolerance, were prevented by catalase overexpression.

Conclusion— In Gq mice, myocyte-specific overexpression of catalase had no effect on the initial phenotype of left ventricular dilation and contractile dysfunction but prevented the subsequent progressive remodeling phase leading to heart failure. Catalase prevented the cellular hallmarks of adverse remodeling (myocyte hypertrophy, myocyte apoptosis, and interstitial fibrosis) and the progression to overt heart failure. Thus, H2O2, associated oxidant pathways, or both play a critical role in adverse myocardial remodeling and the progression to failure.

 
 
 
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