Abstract
Background: Residual lesions in repaired tetralogy of Fallot and other congenital heart diseases induce chronic right ventricular (RV) pressure and/or volume loading. These activate cardiac fibroblasts (CFs) resulting in pathological myocardial remodelling, including fibrosis, contributing to eventual RV diastolic dysfunction, failure, and mortality. Transforming growth factor (TGF)β1 and platelet-derived growth factor (PDGF) are implicated in generating a hyper-fibrotic response to ventricular pressure-loading through synergistic activation and proliferation of CFs. Hypothesis: Dual TGFβ1 and PDGF inhibition will effectively reduce fibrosis in response to RV pressure-loading and thereby improve RV function. Methods: Sprague-Dawley rats underwent pulmonary artery banding (PAB) to induce RV pressure-loading or sham surgery (n=10-12/group). One-week post-PAB, rats were randomized to Tranilast (TRN), a dual TGFβ1/ PDGF inhibitor treatment, (300mg/kg/day, p.o.) or vehicle (n=10-12/group) for 5-weeks. Catheter hemodynamics were measured prior to tissue collection. Results: Preliminary hemodynamic measurements (n=8-10/group) showed similar mean RV/LV pressure ratio (PAB Vehicle 0.8±0.22 vs. PAB TRN 0.81±0.23), +dP/dT, and -dP/dT in PAB groups. PAB TRN rats demonstrated improved end-diastolic pressure (7.0±1.7mmHg vs. 8.59±3.0mmHg), tau (24.15±9ms vs. 31.26±16.5ms), and end-systolic elastance (0.084±0.038mmHg/μL vs. 0.1139±0.057mmHg/μL) compared to PAB vehicle. These were associated with reduced RV collagen deposition (6.5±2.3% vs. 10±5.1%, p<0.05), hypertrophy (Fulton ratio 0.46±0.11 vs. 0.61±0.14, p=0.001), and cardiomyocyte area (921.4±131.7μm 2 vs. 1141±168.7μm 2 , p=0.003), when compared to PAB vehicle-treated controls. Immunoblotting (n=5-6/group) demonstrated reduced RV PDGFRβ expression and SMAD2/3 activation (phosphorylation), despite similar TGFβ1 levels in TRN-treated PAB rats vs. controls. Conclusion: Attenuation of TGFβR1 signalling and reduced PDGFRβ expression were associated with reduced fibrosis and hypertrophy and improved RV diastolic function. Combined inhibition of TGFβ1 and PDGF may be a relevant therapeutic target to improve RV diastolic function in RV pressure-loading.
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