Document Detail


Focal but reversible diastolic sheet dysfunction reflects regional calcium mishandling in dystrophic mdx mouse hearts.
MedLine Citation:
PMID:  22777417     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cardiac dysfunction is a primary cause of patient mortality in Duchenne muscular dystrophy, potentially related to elevated cytosolic calcium. However, the regional versus global functional consequences of cellular calcium mishandling have not been defined in the whole heart. Here we sought for the first time to elucidate potential regional dependencies between calcium mishandling and myocardial fiber/sheet function as a manifestation of dystrophin-deficient (mdx) cardiomyopathy. Isolated-perfused hearts from 16-mo-old mdx (N = 10) and wild-type (WT; N = 10) were arrested sequentially in diastole and systole for diffusion tensor MRI quantification of myocardial sheet architecture and function. When compared with WT hearts, mdx hearts exhibited normal systolic sheet architecture but a lower diastolic sheet angle magnitude (|β|) in the basal region. The regional diastolic sheet dysfunction was normalized by reducing perfusate calcium concentrations. Optical mapping of calcium transients in isolated hearts (3 mdx and 4 WT) revealed a stretch-inducible regional defect of intracellular calcium reuptake, reflected by a 25% increase of decay times (T(50)) and decay constants, at the base of mdx hearts. The basal region of mdx hearts also exhibited greater fibrosis than did the apex, which matched the regional sheet dysfunction. We conclude that myocardial diastolic sheet dysfunction is observed initially in basal segments along with calcium mishandling, ultimately culminating in increased fibrosis. The preservation of relatively normal calcium reuptake and diastolic/systolic sheet mechanics throughout the rest of the heart, together with the rapid reversibility of functional defects by reducing cytosolic calcium, points to the significance of regional mechanical factors in the progression of the disease.
Authors:
Ya-Jian Cheng; Di Lang; Shelton D Caruthers; Igor R Efimov; Junjie Chen; Samuel A Wickline
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-09
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  303     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-03     Completed Date:  2012-11-07     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H559-68     Citation Subset:  IM    
Affiliation:
Cardiovascular Division, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
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MeSH Terms
Descriptor/Qualifier:
Action Potentials
Animals
Biomechanics
Calcium Signaling*
Diffusion Tensor Imaging
Disease Models, Animal
Disease Progression
Excitation Contraction Coupling
Fibrosis
Heart Failure / etiology*,  metabolism,  pathology,  physiopathology
Male
Mice
Mice, Inbred mdx
Muscular Dystrophy, Animal / complications*,  genetics,  metabolism
Muscular Dystrophy, Duchenne / complications*,  genetics,  metabolism
Myocardial Contraction*
Myocardium / metabolism*,  pathology
Perfusion
Recovery of Function
Time Factors
Ventricular Dysfunction / etiology*,  metabolism,  pathology,  physiopathology
Ventricular Function*
Voltage-Sensitive Dye Imaging
Grant Support
ID/Acronym/Agency:
R01 AR056223/AR/NIAMS NIH HHS; R01 HL073646/HL/NHLBI NIH HHS; R01-AR-056223/AR/NIAMS NIH HHS; R01-HL-085369/HL/NHLBI NIH HHS; R21-HL-108617/HL/NHLBI NIH HHS
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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