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Cardiovascular Club I 11:00 PM Thursday, February 17, 2011

1 MYOCARDIAL AGING, FIBROSIS AND DYSFUNCTION AND ITS RELATIONSHIP TO PLASMA C-TYPE NATRIURETIC PEPTIDE AND THE CLEARANCE RECEPTOR

Sangaralingham J, Huntley B, McKie P, Bellavia D, Ichiki T, Martin F, Chen H, Burnett Jr. JC Mayo Clinic, Rochester, MN.

Purpose of Study: Myocardial aging is characterized by left ventricular (LV) fibrosis due to an increase in cardiac fibroblast (CF) proliferation and LV collagen deposition leading to LV dysfunction. Studies have established the potent anti-fibrotic and -proliferative actions of C-type natriuretic peptide (CNP), however the relationship between plasma CNP, LV fibrosis and changes in LV function during aging are undefined. We hypothesized that aging results in a progressive loss in plasma CNP, which would lead to an increase in LV fibrosis and LV impairment. We also tested the hypothesis that CNP's anti-proliferative action involves the clearance receptor NPR-C.

Methods Used: Studies were performed in 2, 11 and 20 month old rats. LV structure and function was assessed by standard and strain echocardiography. LV was harvested for analysis and plasma CNP was measured. Adult human CFs were used to assess the anti-proliferative actions of 10-8 M CNP by BrdU treated with and without NPR-A/B receptor antagonist, HS-142-1 and NPR-C ligand,cANF(4 -23).

Summary of Results: Aging from 2 to 20 months was characterized by a progressive decline in plasma CNP (from 29±3 to 20±1 to 9±1 pg/ml,p<0.01) and a progressive rise in LV fibrosis (from 9±1 to 15±1 to 22±1%,p<0.01). Importantly, there was a strong negative correlation between LV fibrosis and plasma CNP. The aging fibrotic heart was also associated with a reduction in LV ejection fraction (88±1 to 80±1%,p<0.01), while strain analysis revealed significant reductions in circumferential systolic strain (-23±1 to -18±1%,p<0.01) and systolic and diastolic strain rate (-6.1±0.2 to -4.8±0.21/s,p<0.01 & 7.1±0.6 to 5.6±0.21/s, p<0.05,respectively). The anti-proliferative response to CNP was significantly blocked by the NPR-C ligand, but not with blockade of NPR-A/B.

Conclusions: We demonstrate that aging …

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