Titin modulation and left ventricular remodelling in chronic primary mitral regurgitation

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Background Left ventricular (LV) remodelling in mitral valve prolapse (MVP) is usually induced by chronic mitral regurgitation (MR), however it can also be disproportionate to the volume load, generating the hypothesis of MVP cardiomyopathy. Changes in the sarcomeric protein titin could contribute to its underlying pathophysiology. Objectives To investigate the role of titin modulation as a mechanism of disproportionate LV remodelling in MVP patients. Methods Myocardial biopsies from 16 patients with MVP and severe MR were compared with 6 controls. All patients underwent pre-operative transthoracic echocardiography and cardiac magnetic resonance imaging. Titin modifications were analyzed by gel electrophoresis and western blotting. Results Five patients had disproportionate LV remodelling. Compared to controls, the larger N2BA isoform was significantly upregulated in MVP patients, displaying a significantly higher N2BA/N2B isoform ratio (0.589 ± 0.055 vs. 0.479 ± 0.024, p < 0.001). The proportion of total N2B-phosphorylated titin was significantly lower in MVP patients with normal vs. disproportionate LV remodelling (0.709 ± 0.142 vs. 0.971 ± 0.084, p = 0.008) and controls (1.246 ± 0.147, p < 0.001). Furthermore, titin oxidation was significantly higher in MVP patients vs. controls (0.635 ± 0.104 vs. 0.481 ± 0.105, p = 0.006). Finally, there was less N2B-titin ubiquitination in MVP compared to controls (0.607 ± 0.138 vs. 0.989 ± 0.102, p < 0.001). Univariate linear regression showed that corrected LV end-diastolic volume index was correlated with total N2B-titin phosphorylation (R 2 = 0.362, p = 0.014), suggesting lower passive stiffness in disproportionate LV remodelling. Conclusions MVP patients with severe MR demonstrate significant changes in titin isoform ratio, phosphorylation, oxidation and ubiquitination compared to controls. Disproportionate LV remodelling was correlated with increased phosphorylation and showed a trend towards increased N2BA titin, both markers of decreased myocardial stiffness.

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