Abstract P603: Age and Angiotensin-(1-12) Expression in Human Atrial Tissue of Patients with Left Heart Disease

Abstract

In the human heart formation of angiotensin (Ang) II results from the hydrolysis of an alternate angiotensin substrate, -Ang-(1-12)-, by chymase rather than angiotensin converting enzyme. In our recent study a higher Ang-(1-12) expression and upregulation of chymase mRNA and enzymatic activity was found in left (LAA) versus right atrial appendages (RAA) of subjects with left heart disease. Since aging is associated with prominent changes in cardiac structure and function, we assessed the relationships among age, Ang-(1-12), and chymase gene expression and activity in both LAA and RAA in 44 patients undergoing cardiac surgery for the correction of valvular heart disease, resistant atrial fibrillation or ischemic heart disease. Immunohistochemistry for Ang-(1-12) detection was performed using an affinity purified polyclonal antibody directed to the COOH terminus of the full length of the sequence of human Ang-(1-12). Quantitative real-time polymerase chain reaction was used to detect chymase mRNA levels whereas chymase activity was assessed by HPLC. We report that Ang-(1-12) immunostaining in atrial appendages (r=0.30; p<0.05), but not chymase mRNA expression or activity, correlated directly with patients age. While a tendency for higher Ang-(1-12) expression in LAA (Intensity: 5.88 ± 0.91 units; n=11) when compared to RAA (Intensity: 3.948 ± 0.55 units; n=15) was noted in patients younger than 65 yrs, this difference was more prominent and statistically significant in patients older than 65 yrs of age (LAA Intensity: (n=12): 7.39 ± 1.06 units versus RAA Intensity (n=13): 4.74 ±0.54 units; p < 0.05). The results of the present study suggest an age-related increase in Ang-(1-12) expression in human atrial tissue that may be more prominent in the LAA of patients with left heart disease. We suggest that higher availability of Ang-(1-12) for direct Ang II formation may be an underlying mechanism responsible, at least in part, for age- and disease-related atrial and ventricular remodeling and dysfunction.