RESUMEN
BACKGROUND: Right ventricular (RV) hemodynamic performance determines the prognosis of patients with RV pressure overload. Using ultrafast ultrasound, natural wave velocity (NWV) induced by cardiac valve closure was proposed as a new surrogate to quantify myocardial stiffness. OBJECTIVES: This study aimed to assess RV NWV in rodent models and children with RV pressure overload vs control subjects and to correlate NWV with RV hemodynamic parameters. METHODS: Six-week-old rats were randomized to pulmonary artery banding (n = 6), Sugen hypoxia-induced pulmonary arterial hypertension (n = 7), or sham (n = 6) groups. They underwent natural wave imaging, echocardiography, and hemodynamic assessment at baseline and 6 weeks postoperatively. The authors analyzed NWV after tricuspid and after pulmonary valve closure (TVC and PVC, respectively). Conductance catheters were used to generate pressure-volume loops. In parallel, the authors prospectively recruited 14 children (7 RV pressure overload; 7 age-matched control subjects) and compared RV NWV with echocardiographic and invasive hemodynamic parameters. RESULTS: NWV significantly increased in RV pressure overload rat models (4.99 ± 0.27 m/s after TVC and 5.03 ± 0.32 m/s after PVC in pulmonary artery banding at 6 weeks; 4.89 ± 0.26 m/s after TVC and 4.84 ± 0.30 m/s after PVC in Sugen hypoxia at 6 weeks) compared with control subjects (2.83 ± 0.15 m/s after TVC and 2.72 ± 0.34 m/s after PVC). NWV after TVC correlated with both systolic and diastolic parameters including RV dP/dtmax (r = 0.75; P < 0.005) and RV Ees (r = 0.81; P < 0.005). NWV after PVC correlated with both diastolic and systolic parameters and notably with RV end-diastolic pressure (r = 0.65; P < 0.01). In children, NWV after both right valves closure in RV pressure overload were higher than in healthy volunteers (P < 0.01). NWV after PVC correlated with RV E/E' (r = 0.81; P = 0.008) and with RV chamber stiffness (r = 0.97; P = 0.03). CONCLUSIONS: Both RV early-systolic and early-diastolic myocardial stiffness show significant increase in response to pressure overload. Based on physiology and our observations, early-systolic myocardial stiffness may reflect contractility, whereas early-diastolic myocardial stiffness might be indicative of diastolic function.
RESUMEN
Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions where RV mechanical stress is increased, but the underlying mechanisms driving RV fibrosis are incompletely understood. In pulmonary and cardiovascular diseases characterized by elevated mechanical stress and transforming growth factor - beta-1 (TGF-ß1) signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. Here we investigated whether MRTF-A inhibition improves RV pro-fibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure-loading. Rats were assigned into either 1) sham or 2) PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75mg/kg in a subset of PAB animals. Echocardiography and pressure-volume hemodynamics were obtained at a terminal experiment 6-weeks later. RV myocardial samples were analyzed for fibrosis, cardiomyocyte hypertrophy, and pro-fibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, while diastolic function parameters were not significantly improved. RV remodeling was attenuated in PAB rats with MRTF-A inhibition, displaying reduced fibrosis. This was accompanied with a reduction in PAB-induced upregulation of yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ). We also confirmed using a second-generation MRTF-A inhibitor CCG-203971 that MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast transition in response to TGF-ß1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of pro-fibrotic signaling in RV pressure-loading, and as potential targets to improve RV pro-fibrotic remodeling.