[A new paradigm for the progression of advanced heart failure].
To clarify the precise mechanism for the progression of advanced heart failure (AdHF), we assessed the scheme in two HF models, using (I) TO-2 strain hamsters sharing common genetic and clinical features to human families with the delta-sarcoglycan (SG) gene mutation and (II) administration of a high-dose (HD) of isoproterenol (Isp) to normal rats. Delta-SG is a component in dystrophin (Dys)-related proteins that stabilize the sarcolemma (SL) during repeated heart beats. In TO-2, we followed time course of hemodynamics, immunostaining and Western blotting of Dys and in situ SL permeability by Evans blue uptake with or without the gene therapy. Dys was age-dependently translocated from the SL to myoplasm (MP) where the SL instability accompanied the fragmentation of Dys. By gene therapy to supplement the normal delta-SG gene in hearts in vivo, we found that Dys translocation was selectively improved in cardiomyocytes expressing the delta-SG transgene, where the SL fragility was ameliorated. Most importantly, the survival period of the animals was prolonged. Furthermore, Dys but not delta-SG was also time-dependently shifted with a HD of Isp from the SL to MP and fragmented, while delta-SG was preserved intact. We present a novel paradigm that disruption of Dys, but not delta-SG per se, leads to AdHF irrespective of hereditary or acquired origin.
Kawada
Tomie
T
Division of Pharmacy, Niigata University Medical & Dental Hospital, Japan.
Nakazawa
Mikio
M
Toyo-oka
Teruhiko
T
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000150:complications; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D016189:Dystrophin / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D009203:Myocardial Infarction / Q000150:complications; D051381:Rats; D049031:Sarcoglycans
D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D049031:Sarcoglycans