Aortic stenosis and aortic regurgitation express different titin isoforms: Differences and relationships with functional and geometric characteristics.

Background-Titin represents an important biomechanical sensor which determines compliance and diastolic/systolic function of the left ventricle (LV). To assess the different titin-isoform expression and the relationships with functional and geometric patterns, we analyzed titin-isoform expression and cardiomyocytes contractile function in myocardial biopsy samples of patients undergoing aortic valve replacement (AVR) for aortic stenosis (AS) and for aortic regurgitation (AR). Method -Specimens, collected from the LV of 35 with AS and 35 with AR undergoing AVR were analyzed for titin-isoform expression and cardiomyocytes force measurement. Ten donor hearts were analyzed as controls for normal values. Results were implemented with preoperative geometry and function assessed by Doppler echocardiography. Results-Compared to controls, N2BA/N2B titin-isoforms ratio was reduced to 0.24 in AS (p < 0.001) but increased to 0.51 in AR (p < 0.001). N2BA/N2B titin-isoforms ratio was further reduced in 8 patients with severe (restrictive) diastolic dysfunction (0.17 ± 0.03, p < 0.001) but was increased in patients with severe systolic dysfunction (0.58 ± 0.07, p < 0.001). As compared to controls, Fpasive was higher in AS (6.7 ± 0.2 vs 4.4 ± 0.4 kN/m2, p < 0.001) but was lower in AR (3.7 ± 0.2 vs 4.4 ± 0.4 kN/m2, p < 0.001). Total force was comparable. Fpassive was significantly higher in AS patients with severe than with moderate LV diastolic dysfunction (7.1 ± 0.5 vs 6.6. ± 0.6, p = 0.004). Conclusions-titin-isoform expression differs in AS and AR as adaptive response to different pathophysiologic scenarios. Co-expressing isoforms at varying ratios results in modulation of the passive mechanical behavior of the LV at different degree of dysfunction and allows for compensative adjustment of the diastolic/systolic properties of the myocardium.