Tags

Type your tag names separated by a space and hit enter

Early versus late cardiac remodeling during right ventricular pressure load and impact of preventive versus rescue therapy with endothelin-1 receptor blockers.
J Appl Physiol (1985). 2018 05 01; 124(5):1349-1362.JA

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.

Authors+Show Affiliations

The Labatt Family Heart Centre, Hospital for Sick Children and University of Toronto , Toronto, Ontario , Canada. Department of Congenital Cardiovascular Surgery, Hospital Sant Joan de Déu , Barcelona , Spain. Departments of Congenital Cardiac Surgery and Pediatric Cardiology, Bristol Heart Institute and Hospital for Sick Children , Bristol , United Kingdom.The Labatt Family Heart Centre, Hospital for Sick Children and University of Toronto , Toronto, Ontario , Canada. Departments of Congenital Cardiac Surgery and Pediatric Cardiology, Bristol Heart Institute and Hospital for Sick Children , Bristol , United Kingdom.The Labatt Family Heart Centre, Hospital for Sick Children and University of Toronto , Toronto, Ontario , Canada.The Labatt Family Heart Centre, Hospital for Sick Children and University of Toronto , Toronto, Ontario , Canada.The Labatt Family Heart Centre, Hospital for Sick Children and University of Toronto , Toronto, Ontario , Canada.The Labatt Family Heart Centre, Hospital for Sick Children and University of Toronto , Toronto, Ontario , Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29446710

Citation

Ramos, Sara Roldan, et al. "Early Versus Late Cardiac Remodeling During Right Ventricular Pressure Load and Impact of Preventive Versus Rescue Therapy With Endothelin-1 Receptor Blockers." Journal of Applied Physiology (Bethesda, Md. : 1985), vol. 124, no. 5, 2018, pp. 1349-1362.
Ramos SR, Pieles G, Sun M, et al. Early versus late cardiac remodeling during right ventricular pressure load and impact of preventive versus rescue therapy with endothelin-1 receptor blockers. J Appl Physiol. 2018;124(5):1349-1362.
Ramos, S. R., Pieles, G., Sun, M., Slorach, C., Hui, W., & Friedberg, M. K. (2018). Early versus late cardiac remodeling during right ventricular pressure load and impact of preventive versus rescue therapy with endothelin-1 receptor blockers. Journal of Applied Physiology (Bethesda, Md. : 1985), 124(5), 1349-1362. https://doi.org/10.1152/japplphysiol.00975.2017
Ramos SR, et al. Early Versus Late Cardiac Remodeling During Right Ventricular Pressure Load and Impact of Preventive Versus Rescue Therapy With Endothelin-1 Receptor Blockers. J Appl Physiol. 2018 05 1;124(5):1349-1362. PubMed PMID: 29446710.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early versus late cardiac remodeling during right ventricular pressure load and impact of preventive versus rescue therapy with endothelin-1 receptor blockers. AU - Ramos,Sara Roldan, AU - Pieles,Guido, AU - Sun,Mei, AU - Slorach,Cameron, AU - Hui,Wei, AU - Friedberg,Mark K, Y1 - 2018/02/15/ PY - 2018/2/16/pubmed PY - 2019/11/14/medline PY - 2018/2/16/entrez KW - animal models KW - endothelin-1 KW - fibrosis KW - left ventricular remodeling KW - right ventricular pressure overload KW - right ventricular remodeling KW - transforming growth factor-β1 SP - 1349 EP - 1362 JF - Journal of applied physiology (Bethesda, Md. : 1985) JO - J. Appl. Physiol. VL - 124 IS - 5 N2 - 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. SN - 1522-1601 UR - https://www.unboundmedicine.com/medline/citation/29446710/Early_versus_late_cardiac_remodeling_during_right_ventricular_pressure_load_and_impact_of_preventive_versus_rescue_therapy_with_endothelin_1_receptor_blockers_ L2 - http://www.physiology.org/doi/full/10.1152/japplphysiol.00975.2017?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -