March 21, 2026

PO29 Quantification of titin protein isoforms in patients with dilated cardiomyopathy

Key Result

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).

Key Points

The study aims to quantify titin protein expression in the left ventricular myocardium of patients with dilated cardiomyopathy (DCM) compared to controls.
Analyzed 44 LV myocardium samples from heart transplant patients (29 DCM, 15 controls).
Performed echocardiography prior to heart transplant.
Conducted molecular genetic analysis on DCM samples for pathogenic variants.
Assessed titin protein expression using two-phase polyacrylamide gel Western blotting.
Total titin amount was highest in controls and lowest in DCM-TTNtv samples.
T2 expression was higher in controls than in DCM patients regardless of genotype.
N2BA/N2B ratio showed no significant differences across DCM groups but was lower in controls.
Positive correlation found between N2BA/N2B ratio and RVD1 in DCM-TTNtv+ samples.

Structured PICO

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?

Population

44 left ventricular myocardium samples obtained during heart transplant (29 dilated cardiomyopathy (DCM), 15 controls; 38 males, mean age 44 ± 14 years). DCM samples harbored P/LP variants including TTN (19/29), LMNA (3/29), and TNNT2 (2/29).

Comparator

Control left ventricular myocardium samples from organ donors with preserved LV function.

Outcome

Quantification of wild-type (wt) TTN protein expression in the left ventricular (LV) myocardium.surrogate

Wild-type titin protein expression is reduced in heart failure irrespective of TTNtv genotype, suggesting mechanisms of heart failure beyond TTN haploinsufficiency.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

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.

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