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 functioninmyocardialbiopsysamplesofpatientsundergoingaorticvalvereplacement(AVR)foraorticstenosis (AS)and for aorticregurgitation (AR). Method-Specimens,collectedfromtheLVof35withASand35withARundergoingAVRwereanalyzedfortitinisoform 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-Comparedtocontrols,N2BA/N2Btitin-isoformsratiowasreducedto0.24inAS(p b 0.001)butincreased to 0.51 in AR (p b 0.001). N2BA/N2B titin-isoforms ratio was further reduced in 8 patients with severe (restrictive) diastolic dysfunction (0.17 ± 0.03, p b 0.001) but was increased in patients with severe systolic dysfunction (0.58 ± 0.07, p b 0.001). As compared to controls, Fpasive was higher in AS (6.7 ± 0.2 vs 4.4 ± 0.4kN/m2,p b 0.001)butwaslowerinAR(3.7±0.2vs4.4±0.4kN/m2,p b 0.001).Totalforcewascomparable. FpassivewassignificantlyhigherinAS patientswithseverethanwithmoderateLVdiastolicdysfunction(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.