Abstract 3217: Diastolic Dysfunction is Associated With Cardiac Fibrosis in the Senescence-Accelerated Mouse
Approximately half of all heart failure patients in the United States suffer from diastolic heart failure (DHF), and it is a major cause of mortality in the elderly population. Diastolic dysfunction (DD) often precedes DHF and is characterized by impaired active relaxation and increased stiffness. We have used the senescence-accelerated mouse model (SAM) to investigate age-related DD. Cardiac function was examined in 6 month old senescence-prone (SAMP8) and senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging was used to measure the ratio of blood flow velocity through the mitral valve during early (E) versus late (A) diastole, and E/A was reduced from 1.33±0.03 in SAMR1 mice to 1.17±0.03 in SAMP 8 mice. Tissue Doppler imaging was used to measure mitral annulus velocity during early diastole (E′) as well as the ratio of the early to late mitral annulus velocities (E′/A′). E′ was reduced from 25.7±0.9 mm/s in SAMR1 to 21.14±0.8 mm/s in SAMP8 mice, and E′/A′ was similarly reduced from 1.11±0.02 to 0.82±0.03 in SAMR1 vs. SAMP8 mice, respectively (p<0.05 for all). Using M-mode echocardiography, there were no differences in cardiac dimensions or systolic function between SAMR1 and SAMP8 mice. Using mice instrumented with telemetry, we found no difference in mean arterial pressure between SAMP8 and SAMR1 between the ages of 3 and 6 months. Picrosirius red and Masson’s trichrome staining showed increased fibrosis in the hearts of SAMP8 mice compared to SAMR1 counterparts. In SAMR1 versus SAMP8 mice, interstitial collagen area was increased from 0.31±0.04% to 0.78±0.09% and perivascular collagen area was increased from 0.95±0.11% to 1.60±0.14%, respectively. Additionally, collagen 1A1, collagen 3A, fibronectin 1, TGF-β and connective tissue growth factor (CTGF) gene expression were all significantly increased 1.94-, 1.65-, 1.65-, 1.75-, and 1.80-fold, respectively, in SAMP8 mice, suggestive of age-related fibrosis. Together, these data indicate that aging is associated with DD and that DD observed in this model is not associated with hypertension, but instead correlates with the presence of fibrosis. Therefore, the SAM model may be useful in elucidating molecular mechanisms behind age-associated DD and the fibrotic pathways that may be involved.
This research has received full or partial funding support from the American Heart Association, National Center.