Wild-type titin protein expression is reduced in dilated cardiomyopathy compared to controls, with comparable levels in patients with and without TTN truncating variants (p=0.3176).
Does wild-type TTN protein expression differ in the left ventricular myocardium of patients with advanced heart failure compared to controls, and does it depend on TTNtv genotype?
Wild-type titin protein expression is reduced in heart failure irrespective of TTNtv genotype, suggesting mechanisms of heart failure beyond TTN haploinsufficiency.
Absolute Event Rate: 0% vs 0%
Abstract Background Genetic variants in the TTN gene represent the most frequent genetic cause for inherited heart failure (HF) in the general population. Still, pathogenic mechanisms of HF in carriers with heterozygous truncating variants (TTNtv) in the TTN gene remain unclear. Purpose We aimed to quantify wild-type (wt) TTN protein expression in the left ventricular (LV) myocardium of patients with advanced HF and controls. Methods We analyzed 44 LV myocardium samples obtained during heart transplant (29 dilated cardiomyopathy (DCM), 15 controls; 38 males, mean age 44 ± 14 years). The echocardiography was performed closely before the heart transplant. All DCM samples underwent molecular genetic analysis, harboring the P/LP variants TTN (19/29), LMNA (3/29), TNNT2 (2/29), as well as FLNC, BAG3, SGCD, MYH7, and PLN. Control LV myocardium samples were from organ donors with preserved LV function, not used due to other reasons. Protein expression of titin, T2, and isoforms (N2BA, N2B, Cronos) were assessed by two-phase polyacrylamide gel Western blotting, normalized to total or sarcomeric protein (MHC). Results The total titin amount was the highest in the controls and the lowest in the DCM-TTNtv samples, while the DCM-TTNtv+ and DCM-TTNtv- samples did not show significant differences (p = 0.3176). N2BA and N2B expression did not differ between groups, whereas T2, as a known degradation product of TTN, was more expressed in controls than in DCM, independent of genotype. The N2BA/N2B ratio was comparable across DCM groups but lower in controls. Regarding clinical and echocardiography parameters, the N2BA/N2B ratio showed a positive correlation with RVD1 in DCM-TTNtv+ samples. Conclusions Wt TTN protein expression is reduced in HF irrespective of genotype compared to controls. Notably, titin wt levels were comparable in DCM-TTNtv+ and DCM-TTNtv- samples, which indicates other mechanisms of HF, beyond TTN haploinsufficiency. The association with RVD1 highlights potential titin-related mechanisms of right ventricular remodeling.
Adamová et al. (Sun,) reported a other. Wild-type titin protein expression is reduced in dilated cardiomyopathy compared to controls, with comparable levels in patients with and without TTN truncating variants (p=0.3176).