Early versus late cardiac remodeling during right ventricular pressure load and impact of preventive versus rescue therapy with endothelin-1 receptor blockers

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.

Relation between right ventricular wall stress, fibrosis, and function in right ventricular pressure loading

“…Animal model. We used previously acquired data in animals that had adequate echo images and complete hemodynamic data (22). Animal experiments complied with the Canadian Council for Animal Care guidelines, and the study was approved by the Animal Care Committee at the SickKids Research Institute.…”

“…One rabbit with inadequate image quality for analysis of wall stress was excluded. Group 4: An additional group received PAB plus treatment with 20 mg•kg Ϫ1 •day Ϫ1 of the endothelin-1 receptor blocker (ERB), macitentan (Actelion Pharmaceuticals, Allschwil, Switzerland), administered by oral gavage starting from one (n ϭ 5) or 3 wk (n ϭ 4) after PAB until the terminal experiment at 6 wk (22).…”

“…Heart rate and oxygen saturation were monitored. An adjustable PAB device (Access Technologies, Norfolk Medical Products) was placed around the pulmonary artery through a left thoracotomy at the third intercostal space (22). The PAB instrument contains an inflation reservoir, connected to a 5-mm C-shaped ring.…”

The role of regenerative therapy in the treatment of right ventricular failure: a literature review

“…Interestingly, myocardial fibrosis does not occur uniformly throughout the RV in pressure overload but is instead emphasized at the septal hinge-points [18]. Inhibition of endothelin-1 ameliorates the pro-fibrotic response and may therefore exert a beneficial effect beyond pulmonary vascular dilation alone [19]. ROS also lead to altered expression of cMyc and forkhead box protein O1 (FOXO1), thereby influencing pyruvate dehydrogenase kinase (PDK) and oxidative metabolism [20].…”

Protective Activity of Resveratrol in Cardio- and Cerebrovascular Diseases

“…Chronic cardiovascular disease, such as hypertension, heart failure, or myocardial infarction, induces remodeling of the heart [50]. The remodeling process is characterized by hypertrophy of myocytes, hyperplasia of fibroblasts and vascular smooth muscle cells, excessive collagen deposition, and conduction abnormalities.…”