The prevalence of atrial fibrillation (AF), the most common cardiac arrhythmia, increases from 0.1% of the US population at age 40 to 10% by age 80. AF increases the chance of a stroke by five times and doubles the mortality rate compared to patients without AF. The slowing of propagation velocity of wave fronts in the atria is an important mechanism of AF. Atrial gap junctions, which are composed of three distinct proteins, connexin (cX) 40, 43, and 45, are a primary determinant of propagation velocity. The objective of this proposal is to test the hypothesis that propagation velocity in the human atria slows with aging. Furthermore, the slowing is associated with an age dependent decrease in expression of gap junction proteins. Propagation velocity and whole tissue resistivity will be measured in the longitudinal and transverse axis of muscle bundles taken from the human right atrial appendage, routinely removed during cardiac surgery. In the same tissue, the amount of Cx40, 43, and 45 mRNA and protein will be determined using Northern and Western blot analysis. The size, shape and distribution of immunofluorescently labeled gap junction will be quantified by laser confocal microscopy. Light microscopy will be used to reconstruct the 3-dimensional distribution of myocyte interconnections and the volume of the extracellular space. The number and size of individual gap junctions will be characterized with electron microscopy. Identification of an age-dependent decrease in propagation velocity, along with a concomitant down regulation of gap junction protein expression, will provide a basis for a comprehensive research proposal to elucidate the underlying mechanisms responsible for the age dependent increase in AF.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG014542-01
Application #
2002446
Study Section
Special Emphasis Panel (SRC (14))
Project Start
1997-03-15
Project End
1999-02-28
Budget Start
1997-03-15
Budget End
1999-02-28
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130