Key result
In the context of pressure overload, Z-disc TTNtv in rats is associated with cardiac fibrosis, diastolic dysfunction (dp/dt min -3435 vs -6497 mmHg/s, p<0.01), and capillary rarefaction without overt systolic dysfunction.
Why the study?
Does pressure overload via trans-aortic constriction induce a heart failure phenotype in rats with titin Z-disc truncating variants?
Does pressure overload via trans-aortic constriction induce a heart failure phenotype in rats with titin Z-disc truncating variants?
Truncating variants in the titin Z-disc predispose to a heart failure with preserved ejection fraction (HFpEF) phenotype characterized by diastolic dysfunction, fibrosis, and capillary rarefaction under pressure overload.
Z-disc TTNtv may model HFpEF under pressure overload in rats; leaves open relevance to human diastolic disease.
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.
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Ye et al. (2018) studied Heart failure with preserved ejection fraction (HFpEF) (n=30). Trans-aortic constriction (TAC) in Z-disc TTNtv rats vs. Sham surgery and wildtype littermates was evaluated on Diastolic function (dp/dt min, mmHg/s) (p=<0.01). In the context of pressure overload, Z-disc TTNtv in rats is associated with cardiac fibrosis, diastolic dysfunction (dp/dt min -3435 vs -6497 mmHg/s, p<0.01), and capillary rarefaction without overt systolic dysfunction.
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