肺动脉高压中右心功能研究进展——聚焦第七届世界肺动脉高压研讨会Advacnes in right ventricular function in pulmonary hypertension: focus on the 7th World Symposium on Pulmonary Hypertension
刘少飞,王瑞琦,郭志福,朱霓
摘要(Abstract):
自1973年以来,世界肺动脉高压研讨会(WSPH)一直是推动肺动脉高压研究进展的重要交流平台。在2018年第六届WSPH上,WSPH工作组提出了心肺生理学与右心衰竭的定义,凸显了右心衰竭在肺动脉高压进展中的关键作用。随着研究的深入,肺动脉高压相关的右心衰竭受到越来越多关注,并被认为是影响肺动脉高压预后的重要决定因素。2024年第七届WSPH于西班牙的巴塞罗那召开,会议更新了右心室病理生理学及其与肺血管相互作用的最新研究进展,重点探讨了右心衰竭病理的新认识、不同肺动脉高压分型下的右心室表型及右心衰竭的新药进展。此外,WSPH工作组还提出了右心衰竭研究的未来方向及亟待解决的问题。本文将解读第七届WSPH的右心功能进展的相关内容及近些年关于肺动脉高压中右心功能研究的新发现,系统回顾肺动脉高压中右心功能研究的演进与突破。
关键词(KeyWords): 肺动脉高压;世界肺动脉高压研讨会;右心衰竭;病理生理;异质性
基金项目(Foundation): 国家重点研发计划项目(2020YFC2008100);; 上海创新药械产品应用示范项目(24SF1904800)
作者(Author): 刘少飞,王瑞琦,郭志福,朱霓
参考文献(References):
- [1] Kovacs G,Bartolome S,Denton CP,et al.Definition,classification and diagnosis of pulmonary hypertension[J]. Eur Respir J,2024,64(4):2401324. DOI:10.1183/13993003.01324-2024.
- [2] Humbert M, GalièN, Rubin LJ,et al. The Seventh World Symposium on Pulmonary Hypertension:our journey to Barcelona[J]. Eur Respir J,2024,64(4):2401222.DOI:10.1183/13993003.01222-2024.
- [3] Vonk Noordegraaf A,Chin KM,Haddad F,et al. Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension:an update[J]. Eur Respir J,2019,53(1):1801900. DOI:10.1183/13993003.01900-2018.
- [4] Hemnes AR,Celermajer DS,D’Alto M,et al.Pathophysiology of the right ventricle and its pulmonary vascular interaction[J]. Eur Respir J,2024,64(4):2401321. DOI:10.1183/13993003.01321-2024.
- [5] Edward J, Banchs J, Parker H, et al.Right ventricular function across the spectrum of health and disease[J]. Heart,2023,109(5):349-355. DOI:10.1136/heartjnl-2021-320526.
- [6] Sanz J,Sánchez-Quintana D,Bossone E,et al. Anatomy,function,and dysfunction of the right ventricle:JACC state-of-theart review[J]. J Am Coll Cardiol,2019,73(12):1463-1482.DOI:10.1016/j.jacc.2018.12.076.
- [7] Mendiola EA,da Silva Goncalves Bos D,Leichter DM,et al.Right ventricular architectural remodeling and functional adaptation in pulmonary hypertension[J]. Circ Heart Fail,2023,16(2):e009768. DOI:10.1161/CIRCHEARTFAILURE.122.009768.
- [8] Park JF, Clark VR, Banerjee S, et al.Transcriptomic analysis of right ventricular remodeling in two rat models of pulmonary hypertension:identification and validation of epithelial-tomesenchymal transition in human right ventricular failure[J].Circ Heart Fail,2021,14(2):e007058. DOI:10.1161/CIRCHEARTFAILURE.120.007058.
- [9] Suen CM, Chaudhary KR, Deng Y, et al.Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension:a genetically prone model for right heart failure[J]. Cardiovasc Res,2019,115(4):788-799. DOI:10.1093/cvr/cvy258.
- [10] Prins KW, Archer SL, Pritzker M, et al. Interleukin-6is independently associated with right ventricular function in pulmonary arterial hypertension[J]. J Heart Lung Transplant,2018,37(3):376-384. DOI:10.1016/j.healun.2017.08.011.
- [11] Agrawal V, Kropski JA, Gokey JJ, et al.Myeloid cell derived IL1beta contributes to pulmonary hypertension in HFpEF[J].Circ Res,2023,133(11):885-898. DOI:10.1161/CIRCRESAHA.123.323119.
- [12] Bekedam FT, Goumans MJ, Bogaard HJ, et al. Molecular mechanisms and targets of right ventricular fi brosis in pulmonary hypertension[J]. Pharmacol Ther, 2023,244:108389.DOI:10.1016/j.pharmthera.2023.108389.
- [13] Sun XQ,Abbate A,Bogaard HJ. Role of cardiac infl ammation in right ventricular failure[J]. Cardiovasc Res,2017,113(12):1441-1452. DOI:10.1093/cvr/cvx159.
- [14] Al-Qazazi R, Lima PDA, Prisco SZ, et al. MacrophageNLRP3 activation promotes right ventricle failure in pulmonary arterial hypertension[J]. Am J Respir Crit Care Med,2022,206(5):608-624. DOI:10.1164/rccm.202110-2274OC.
- [15] Agrawal V, Hemnes AR, Shelburne NJ, et al.l-Carnitine therapy improves right heart dysfunction through Cpt1-dependent fatty acid oxidation[J]. Pulm Circ,2022,12(3):e12107.DOI:10.1002/pul2.12107.
- [16] Shimauchi T, Boucherat O, Yokokawa T, et al. PARP1-PKM2 axis mediates right ventricular failure associated with pulmonary arterial hypertension[J]. JACC Basic Transl Sci,2022,7(4):384-403. DOI:10.1016/j.jacbts.2022.01.005.
- [17] Zelt JGE, Cadete V, Deng Y, et al.Right ventricular maladaptation to pressure overload in fischer rats is associated with profound deficiency in adenylate kinase 1 and impaired ventricular energetics[J]. Hypertension,2022,79(12):2774-2786. DOI:10.1161/HYPERTENSIONAHA.122.19300.
- [18] Okninska M, Paterek A, Grzanka M, et al.Myo-inositol trispyrophosphate prevents right ventricular failure and improves survival in monocrotaline-induced pulmonary hypertension in the rat[J]. Br J Pharmacol,2024,181(20):4050-4066.DOI:10.1111/bph.16482.
- [19] Liu K, Zeng Y, Wang H, et al.Global, regional, and national burden of pulmonary arterial hypertension and related heart failure from 1990 to 2021, with predictions to 2050:insights from the global burden of disease study 2021[J].Eur Heart J Qual Care Clin Outcomes,2025:qcaf009. DOI:10.1093/ehjqcco/qcaf009.
- [20] Batton KA, Austin CO, Bruno KA, et al.Sex differences in pulmonary arterial hypertension:role of infection and autoimmunity in the pathogenesis of disease[J]. Biol Sex Diff er,2018,9(1):15. DOI:10.1186/s13293-018-0176-8.
- [21] Hester J,Ventetuolo C,Lahm T. Sex,gender,and s e x hormones in pulmonary hypertension and right ventricular failure[J]. Compr Physiol,2019,10(1):125-170. DOI:10.1002/cphy.c190011.
- [22] Tello K, Richter MJ, Yogeswaran A, et al.Sex diff erences in right ventricular-pulmonary arterial coupling in pulmonary arterial hypertension[J]. Am J Respir Crit Care Med,2020 ,202(7):1042-1046. DOI:10.1164/rccm. 202003-0807LE.
- [23] Lahm T, Frump AL, Albrecht ME, et al. 17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension[J]. Am J Physiol Lung Cell Mol Physiol,2016,311(2):L375-L388. DOI:10.1152/ajplung.00132.2016.
- [24] Frump AL, Albrecht M, Yakubov B, et al.17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin[J]. J Clin Invest,2021,131(6):e129433. DOI:10.1172/JCI129433.
- [25] Harbaum L, Hennigs JK, Pott J, et al. Sex-specifi c genetic determinants of right ventricular structure and function[J]. Am J Respir Crit Care Med,2024,211(1):113-123. DOI:10.1164/rccm.202404-0721OC.
- [26] Wessels JN, Mouratoglou SA, van Wezenbeek J, et al.Right atrial function is associated with right venticular diastolic stiff ness:RA-RV interaction in pulmonary arterial hypertension[J]. Eur Respir J,2022,59(6):2101454. DOI:10.1183/13993003.01454-2021.
- [27] Wessels JN, van Wezenbeek J, de Rover J, et al. Right atrial adaptation to precapillary pulmonary hypertension:pressurevolume, cardiomyocyte, and histological analysis[J]. J Am Coll Cardiol,2023,82(8):704-717. DOI:10.1016/j.jacc.2023.05.063.
- [28] Marcus JT, Westerhof BE, Groeneveldt JA, et al.Vena cava backflow and right ventricular stiffness in pulmonary arterial hypertension[J]. Eur Respir J,2019,54(4):1900625.DOI:10.1183/13993003.00625-2019.
- [29]尚小珂,卢蓉,柳梅,等.压力-容积环评估肺动脉高压小鼠右心室功能的研究[J].中国介入心脏病学杂志,2017,25(5):271-275. DOI:10.3969/j.issn.1004-8812.2017.05.006.
- [30] Boucherat O, Agrawal V, Lawrie A, et al.The latest in animal models of pulmonary hypertension and right ventricular failure[J]. Circ Res,2022,130(9):1466-1486. DOI:10.1161/CIRCRESAHA.121.319971.
- [31] Ukita R, Tumen A, Stokes JW, et al. Progression toward decompensated right ventricular failure in the ovine pulmonary hypertension model[J]. ASAIO J,2022,68(2):e29-e33.DOI:10.1097/MAT.0000000000001417.
- [32] Guihaire J, Haddad F, Noly PE,et al.Right ventricular reserve in a piglet model of chronic pulmonary hypertension[J]. Eur Respir J,2015,45(3):709-717. DOI:10.1183/09031936.00081314.
- [33] Johnson CA Jr,Cortelli M Jr,Glomp G,et al. A dynamic sheep model to induce pulmonary hypertension and right ventricular failure[J]. Methods Mol Biol,2024,2803:239-258. DOI:10.1007/978-1-0716-3846-0_18.
- [34] Brown RD, Hunter KS, Li M,et al. Functional and molecular determinants of right ventricular response to severe pulmonary hypertension in a large animal model[J]. Am J Physiol Heart Circ Physiol,2023,324(6):H804-H820. DOI:10.1152/ajpheart.00614.2022.
- [35] Ukita R, Stokes JW, Wu WK,et al. Large animal preclinical investigation into the optimal extracorporeal life support configuration for pulmonary hypertension and right ventricular failure[J]. J Heart Lung Transplant,2023,42(7):859-867. DOI:10.1016/j.healun.2022.10.023.
- [36] García-Lunar I, Jorge I, Sáiz J,et al. Metabolic c h a n g e s contribute to maladaptive right ventricular hypertrophy in pulmonary hypertension beyond pressure overload:an integrative imaging and omics investigation[J]. Basic Res Cardiol,2024,119(3):419-433. DOI:10.1007/s00395-024-01041-5.
- [37] Mendelson JB,Sternbach JD,Doyle MJ,et al. Multi-omic and multispecies analysis of right ventricular dysfunction[J].J Heart Lung Transplant,2024 ,43(2):303-313. DOI:10.1016/j.healun.2023.09.020.
- [38] Jone PN, Ivy DD, Hauck A,et al. Pulmonary hypertension in congenital heart disease:a scientific statement from the American Heart Association[J]. Circ Heart Fail,2023,16(7):e00080. DOI:10.1161/HHF.0000000000000080.
- [39] Hsu S,Houston BA,Tampakakis E,et al. Right ventricular functional reserve in pulmonary arterial hypertension[J].Circulation,2016,133(24):2413-2422. DOI:10.1161/CIRCULATIONAHA.116.022082.
- [40] Hsu S, Kokkonen-Simon KM, Kirk JA,et al. Right ventricular myofilament functional differences in humans with systemic sclerosis-associated versus idiopathic pulmonary arterial hypertension[J]. Circulation,2018,137(22):2360-2370.DOI:10.1161/CIRCULATIONAHA.117.033147.
- [41] Lechuga CG, Raza F, Colebank MJ,et al. Role of characteristic pulmonary impedance with exercise for detection of abnormal pulmonary vascular response and uncoupling in pulmonary hypertension resulting from heart failure with preserved ejection fraction[J]. Chest,2025:S0012-3692(25)00268-5. DOI:10.1016/j.chest.2025.02.019.
- [42] Hilde JM, Skj?rten I, Gr?tta OJ,et al. Right ventricular dysfunction and remodeling in chronic obstructive pulmonary disease without pulmonary hypertension[J]. J Am Coll Cardiol,2013,62(12):1103-1111. DOI:10.1016/j.jacc.2013.04.091.
- [43] D’Andrea A,Stanziola A,Di Palma E,et al. Right ventricular structure and function in idiopathic pulmonary fibrosis with or without pulmonary hypertension[J]. Echocardiography,2016,33(1):57-65. DOI:10.1111/echo.12992.
- [44] Fukumitsu M, Groeneveldt JA, Braams NJ,et al. When right ventricular pressure meets volume:the impact of arrival time of reflected waves on right ventricle load in pulmonary arterial hypertension[J]. J Physiol,2022,600(10):2327-2344.DOI:10.1113/JP282422.
- [45] Fukumitsu M, Westerhof BE, Ruigrok D,et al.Early return of refl ected waves increases right ventricular wall stress in chronic thromboembolic pulmonary hypertension[J]. Am J Physiol Heart Circ Physiol,2020,319(6):H1438-H1450. DOI:10.1152/ajpheart.00442.2020.
- [46] Yamagata Y, Ikeda S, Kojima S,et al.Right ventricular dyssynchrony in patients with chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension[J]. Circ J,2022,86(6):936-944. DOI:10.1253/circj.CJ-21-0849.
- [47] Braams NJ, Kianzad A, van Wezenbeek J,et al.Long-term eff ects of pulmonary endarterectomy on right ventricular stiff ness and fi brosis in chronic thromboembolic pulmonary hypertension[J]. Circ Heart Fail,2023,16(10):e010336. DOI:10.1161/CIRCHEARTFAILURE.122.010336.
- [48] Lewis RA, Johns CS, Cogliano M,et al. Identification of cardiac magnetic resonance imaging thresholds for risk stratification in pulmonary arterial hypertension[J]. Am J Respir Crit Care Med,2020,201(4):458-468. DOI:10.1164/rccm.201909-1771OC.
- [49] Celant LR,Wessels JN,Kianzad A,et al.Restoration of right ventricular function in the treatment of pulmonary arterial hypertension[J]. Heart,2023,109(24):1844-1850.DOI:10.1136/heartjnl-2023-322742.
- [50] Sommer N,Ghofrani HA,Pak O,et al. Current and f u t u r e treatments of pulmonary arterial hypertension[J]. Br J Pharmacol,2021,178(1):6-30. DOI:10.1111/bph.15016.
- [51] Humbert M,McLaughlin V,Gibbs JSR,et al. Sotatercept for the treatment of pulmonary arterial hypertension[J]. N Engl J Med,2021,384(13):1204-1215. DOI:10.1056/NEJMoa2024277.
- [52] Souza R,Badesch DB,Ghofrani HA,et al. Effects o f sotatercept on haemodynamics and right heart function:analysis of STELLAR trial[J]. Eur Respir J,2023,62(3):2301107.DOI:10.1183/13993003.01107-2023.
- [53] Zhang J, Du L, Qin X,et al.Eff ect of sacubitril/valsartan on the right ventricular function and pulmonary hypertension in patients with heart failure with reduced ejection fraction:a systematic review and meta-analysis of observational studies[J]. J Am Heart Assoc,2022,11(9):e024449. DOI:10.1161/JAHA.121.024449.
- [54] Han Y, Forfia P, Vaidya A,et al.Ranolazine improves right ventricular function in patients with precapillary pulmonary hypertension:results from a double-blind, randomized,placebo-controlled trial[J]. J Card Fail,2021,27(2):253-257. DOI:10.1016/j.cardfail.2020.10.006.
- [55] Han QJ, Forfi a P, Vaidya A,et al. Eff ects of ranolazine on right ventricular function, fluid dynamics, and metabolism in patients with precapillary pulmonary hypertension:insights from a longitudinal, randomized, double-blinded, placebo controlled, multicenter study[J]. Front Cardiovasc Med,2023,10:1118796. DOI:10.3389/fcvm.2023.1118796.
- [56] Brittain EL, Niswender K, Agrawal V,et al. Mechanistic phase II clinical trial of metformin in pulmonary arterial hypertension[J]. J Am Heart Assoc,2020,9(22):e018349. DOI:10.1161/JAHA.120.018349.
- [57] Kresoja KP, Rommel KP, Lücke C, et al. Right ventricular contraction patterns in patients undergoing transcatheter tricuspid valve repair for severe tricuspid regurgitation[J]. JACC Cardiovasc Interv,2021,14(14):1551-1561. DOI:10.1016/j.jcin.2021.05.005.