ABSTRACT
Pulmonary artery banding (PAB) causes right ventricular (RV) dysfunction, biventricular fibrosis, and apoptosis, which are attenuated by endothelin-1 receptor blockade (ERB). Little is known about the time course of remodeling and whether early versus late ERB confers improved outcome. PAB was performed in five groups of rabbits: Shams, 3-wk PAB (3W), 6-wk PAB (6W), 6-wk PAB + ERB administered from day 1 (6WERB1), and 6-wk PAB + ERB administered from day 21 (6WERB21). Biventricular development of profibrotic molecular signaling, fibrosis, apoptosis, and conductance catheter and echocardiography function were studied. Thirty-three rabbits [ n = 6-7 per group; 3.00 (0.23) kg, mean (SD)] developed half to full systemic RV pressures. Biventricular profibrotic signaling and collagen deposition [RV collagen: Shams 3.8 (0.58) vs. 3W 8.69 (2.52) vs. 6W 8.83 (4.02)%, P < 0.005] and apoptosis [RV: Shams 8.32 (3.2) vs. 3W 55.95 (47.55) vs. 6W 38.85 (17.26) apoptotic cells per microfield, P < 0.0005] increased with PAB. Early and late ERB attenuated fibrosis [RV: 6WERB1 5.55 (1.18), 6WERB21 5.63 (0.72)%] and apoptosis [RV: 6WERB1 11.1 (5.25), 6WERB21 20.24 (7.16) apoptotic cells per microfield, P < 0.0001 vs. 6W]. RV dimensions progressively increased at 3W and 6W and decreased with early ERB [end-diastolic dimensions: Shams 0.4 (0.13) vs. 3W 0.55 (0.78) vs. 6W 0.78 (0.25) vs. 6WERB1 0.71 (0.26) vs. 6WERB21 0.49 (0.23) cm, P < 0.05]. Despite increased RV contractility with PAB [RV end-systolic pressure-volume relationship: Shams 3.76 (1.76) vs. 3W 12.21 (3.44) vs. 6W 19.4 (6.88) mmHg/ml], biventricular function and cardiac output [Shams 196.1 (39.73) vs. 3W 149.9 (34.82) vs. 6W 151 (31.69) ml/min] worsened in PAB groups and improved with early and late ERB [6WERB1 202.8 (26.8), 6WERB21 194.8 (36.93) ml/min, P < 0.05 vs. PAB]. In conclusion, RV pressure overload induces early biventricular fibrosis, apoptosis, remodeling, and dysfunction that worsens with persistent RV hypertension. This remodeling is attenuated by early and late ERB. NEW & NOTEWORTHY Our results in a rabbit model of progressive right ventricular (RV) pressure loading indicate that biventricular fibrosis, apoptosis, and dysfunction are already present when RV hypertension is reached at 3 wk of progressive pulmonary artery banding. These findings worsen with persistent RV hypertension to 6 wk and are attenuated with both early and late endothelin-1 receptor blockade, with some advantages to early therapy. These findings highlight the role of endothelin-1 in driving biventricular remodeling secondary to RV hypertension and suggest that early therapy with an endothelin-1 receptor blocker may be beneficial in attenuating biventricular remodeling but that late therapy is also effective.
Subject(s)
Endothelin A Receptor Antagonists/pharmacology , Heart Ventricles/drug effects , Receptor, Endothelin A/metabolism , Ventricular Function, Right/drug effects , Ventricular Pressure/drug effects , Ventricular Remodeling/drug effects , Animals , Apoptosis/drug effects , Apoptosis/physiology , Echocardiography/methods , Endothelin-1/metabolism , Fibrosis/drug therapy , Fibrosis/metabolism , Fibrosis/physiopathology , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Male , Rabbits , Ventricular Dysfunction, Right/drug therapy , Ventricular Dysfunction, Right/metabolism , Ventricular Dysfunction, Right/physiopathology , Ventricular Function, Right/physiology , Ventricular Pressure/physiology , Ventricular Remodeling/physiologyABSTRACT
Quantification of cardiac structure and function is central in cardiovascular research. Rabbits are valuable research models of cardiovascular human disease; however, there is little normal data available. The aim of this study was to investigate feasibility and provide normal values for comprehensive echocardiographic assessment of biventricular function in rabbits. New Zealand white rabbits underwent trans-thoracic echocardiography using a general electric (GE) Vivid 7/E9 system with a 10 MHz transducer, under light sedation, to evaluate biventricular function and dimensions. Images for two-dimensional, M-mode, tissue Doppler imaging (TDI) and speckle-tracking strain echocardiography were acquired and analysed. 55 male rabbits (sized matched with a newborn human baby) were studied, mean weight was 2.9 ± 0.23 kg. Adequate images were obtained in 90% for the left ventricle (LV) and 80% for the right ventricle (RV). Two-dimensional speckle-tracking strain was feasible in 60%. Average heart rate was 248 ± 36 beats per minute; LV ejection faction 72 ± 8.0; RV fractional area change 45.9 ± 9.0%; RV myocardial performance index 0.39 ± 0.35; tricuspid annular planar systolic excursion 0.60 ± 0.24 cm. LV TDI parameters were S' 8.6 ± 3.1 cm/s; E' 12.0 ± 4.46 cm/s. RV TDI parameters were S' 10.49 ± 3.18; E' 14.95 ± 4.64 cm/s. LV and RV global peak systolic longitudinal strain were -17 ± 5 and -22 ± 8%, respectively. Comprehensive investigation of biventricular dimensions and function by echocardiography is feasible in the rabbit. Apical views and strain imaging have lower feasibility. Normal values of LV and RV functional parameters are with comparable values to human children. Animal cardiovascular research is key to develop new goals in clinical practice.
