Right heart failure is a prevalent mechanism of cardiovascular collapse and dis-tinctly different from left heart failure. Conventionally, afterload reduction has beenthe main focus to treat right ventricular (RV) dysfunction, but it cannot be achievedin many cases. A new strategy is to directly target RV remodelling. Pulmonaryartery banding (PAB) in mice is used to induce a chronic pressure overload on theRV, without any changes in the pulmonary vasculature.This work addressed two questions: a) the time-course of effects of PAB onright- and left-ventricular (LV) hypertrophy and function, assessed non-invasivelyvia magnetic resonance imaging (MRI). b) Stimulation of the nitric oxide pathwaywas shown to ameliorate maladaptive changes in murine models of chronic LV pres-sure overload. Therefore, the effects of the sGC stimulator Riociguat and the PDE5inhibitor Sildenafil on RV function and fibrosis were investigated.Chronic RV pressure overload was induced by PAB in male C57Bl/6 wild-typemice. For the time-course study, 1, 3, 7, 14, 28, 56 and 105 days after PAB, thefunctional and morphological consequences of sustained pressure overload on the RVand LV were assessed non-invasively using MRI. Additionally, the time-course of theeffects of PAB on cardiomyocyte size and fibrosis was investigated.For the pharmacological intervention study, drug treatment was started sevendays after surgery for 2 weeks. Animals received either 30 mg/kg/d Riociguat peros, Sildenafil 100 mg/kg/d per drinking water, or placebo. The consequences ofthe sustained pressure overload on RV fibrosis, cardiomyocyte size and functionwere assessed using Picrosirius red staining, WGA-FITC staining and MagneticResonance Imaging.PAB led to RV dilatation, indicated by an increase in end-diastolic volume. RVmass, cardiomyocyte size, as well as the collagen content of the RV increased inbanded animals. The ejection fraction and the stroke volume (SV) of the RV de-creased, as well as the LV SV and the cardiac output (CO).Whilst RV mass increasedcontinually over the time-course of the study, the RV performance declined initially,followed by a weak compensatory phase. In the course of the study, the heart con-tinued to decompensate, which finally resulted in heart failure of the animals.Treatment with both Riociguat and Sildenafil led to significant improvementsin RV ejection fraction (35.4 ± 1.7% vs. 43.7 ± 2.2% vs. 48.2 ± 3.3% [Placebovs. Riociguat vs. Sildenafil]), but only Riociguat significantly reduced the collagencontent of the RV (5.6 ± 0.3% vs. 3.0 ± 0.8% vs. 5.4 ± 0.2%). Neither drug had ef-fects on RV hypertrophy (62.3 ± 3.1 mg vs. 59.6 ± 2.5 mg vs. 57.1 ± 2.2 mg), on theRV/(LV+S) ratio (0.84 ± 0.04 mg/mg vs. 0.91 ± 0.04 mg/mg vs. 0.83 ± 0.03 mg/mg),nor on cardiomyocyte size (20.7 ± 0.6 μm vs. 19.8 ± 0.3 μm vs. 19.7 ± 0.6 μm).It was shown, that chronic pressure overload in C57Bl/6 mice induced RV di-latation, hypertrophy and contractile dysfunction. Furthermore, LV performancewas negatively affected by intraventricular interaction, resulting in decreased LVSV and CO. Riociguat and Sildenafil both led to significant improvements in RVfunction, without any changes in RV mass or cardiomyocyte size. One reason forthe functional improvement of the RV under Riociguat treatment is the decreasein collagen content, making the RV more apt to deal with the pressure overload.Further experiments will be needed to determine the mechanism of the functionalimprovement with Sildenafil treatment, and the reason for the differential effects of the drugs.
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