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Truncations of the titin Z-disc predispose to a heart failure with preserved ejection phenotype in the context of pressure overload.
- Source :
-
PloS one [PLoS One] 2018 Jul 31; Vol. 13 (7), pp. e0201498. Date of Electronic Publication: 2018 Jul 31 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- Titin (TTN) Truncating variants (TTNtv) in the A-band of TTN predispose the mouse heart to systolic dysfunction when subjected to pressure-loading. However, the effects of TTNtv of the Z-disc are largely unexplored. A rat model of pressure-loaded heart is developed by trans-aortic constriction (TAC). Rats with TTNtv of the Z-disc were randomly assigned to TAC (Z-TAC) or sham-surgery (Z-Sham) and wildtype (WT) littermates served as controls (WT-TAC or WT-Sham). Left ventricular (LV) function was assessed by echocardiography. Pressure volume (PV) loops, histology and molecular profiling were performed eight months after surgery. Pressure-load by TAC increased LV mass in all cases when compared with Sham animals. Notably, systolic function was preserved in TAC animals throughout the study period, which was confirmed by terminal PV loops. Diastolic function was impaired in Z-disc TTNtv rats at baseline as compared to WT and became impaired further after TAC (dp/dtmin, mmHg/s): Z-TAC = -3435±763, WT-TAC = -6497±1299 (p<0.01). Z-TAC animals had greater cardiac fibrosis, with elevated collagen content and decreased vascular density as compared to WT-TAC animals associated with enhanced apoptosis of myocyte and non-myocyte populations. In the context of pressure overload, Z-disc TTNtv is associated with cardiac fibrosis, diastolic dysfunction, and capillary rarefaction in the absence of overt systolic dysfunction.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Aortic Valve Stenosis complications
Aortic Valve Stenosis genetics
Aortic Valve Stenosis physiopathology
Fibrosis genetics
Fibrosis physiopathology
Genetic Predisposition to Disease
Heart Failure complications
Hypertension complications
Male
Phenotype
Polymorphism, Genetic
Protein Interaction Domains and Motifs genetics
Protein Isoforms genetics
Rats
Rats, Inbred F344
Rats, Transgenic
Ventricular Dysfunction, Left genetics
Ventricular Dysfunction, Left physiopathology
Connectin chemistry
Connectin genetics
Heart Failure genetics
Hypertension genetics
Ventricular Function, Left genetics
Ventricular Function, Left physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 13
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 30063764
- Full Text :
- https://doi.org/10.1371/journal.pone.0201498