Name: a model of reverse vascular remodeling in pulmonary hypertension due to left heart disease by aortic debanding in rats
Uploaded: 2022-03-01T14:45:00
Description: Watch this Scientific Journal Video about A Model of Reverse Vascular Remodeling in Pulmonary Hypertension Due to Left Heart Disease by Aortic Debanding in Rats at JoVE.com

这项研究得到了DZHK（德国心血管研究中心）对CK和WMK的资助，BMBF（德国教育和研究部）在VasBio框架内向CK的赠款，以及WMK在VasBio，SYMPATH和PROVD的框架内的赠款，以及德国研究基金会（DFG）对WMK（SFB-TR84 A2，SFB-TR84 C9， SFB 1449 B1、SFB 1470 A4、KU1218/9-1 和 KU1218/11-1）。

所有程序均按照“实验动物护理和使用指南”（实验动物资源研究所，2011年第8版）进行，并得到德国国家卫生和社会事务办公室（Landesamt für Gesundheit und Soziales，柏林）地方政府动物护理和使用委员会的批准;议定书编号为。G0030/18）。首先，通过在上主动脉（主动脉条带，AoB）上放置内径为0.8mm的钛夹（主动脉条带，AoB）来手术诱导充血性心力衰竭〜100g体重（bw）（见 材料表）。如?...

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	<li>Rosenkranz, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pulmonary+hypertension+due+to+left+heart+disease:+Updated+recommendations+of+the+cologne+consensus+conference+2011.">Pulmonary hypertension due to left heart disease: Updated recommendations of the cologne consensus conference 2011.</a> International Journal of Cardiology. 154, 34-44 (2011).</li><li>Rosenkranz, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Left+ventricular+heart+failure+and+pulmonary+hypertension.">Left ventricular heart failure and pulmonary hypertension.</a> European Heart Journal. 37 (12), 942-954 (2016).</li><li>Fayyaz, A. U., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Global+Pulmonary+vascular+remodeling+in+pulmonary+hypertension+associated+with+heart+failure+and+preserved+or+reduced+ejection+fraction.">Global Pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction.</a> Circulation. 137 (17), 1796-1810 (2018).</li><li>Hunt, J. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pulmonary+veins+in+the+normal+lung+and+pulmonary+hypertension+due+to+left+heart+disease.">Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease.</a> The American Journal of Physiology - Lung Cellular and Molecular Physiology. 305 (10), 725-736 (2013).</li><li>Bursi, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pulmonary+pressures+and+death+in+heart+failure:+A+community+study.">Pulmonary pressures and death in heart failure: A community study.</a> Journal of the American College of Cardiology. 59 (3), 222-231 (2012).</li><li>Ryan, J. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Right+ventricular+adaptation+and+failure+in+pulmonary+arterial+hypertension.">Right ventricular adaptation and failure in pulmonary arterial hypertension.</a> Canadian Journal of Cardiology. 31 (4), 391-406 (2015).</li><li>Miller, W. L., Mahoney, D. W., Enriquez-Sarano, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+Doppler-echocardiographic+imaging+and+clinical+outcomes+with+left+ventricular+systolic+dysfunction:+Independent+effect+of+pulmonary+hypertension.">Quantitative Doppler-echocardiographic imaging and clinical outcomes with left ventricular systolic dysfunction: Independent effect of pulmonary hypertension.</a> Circulation: Cardiovascular Imaging. 7 (2), 330-336 (2014).</li><li>Kjaergaard, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prognostic+importance+of+pulmonary+hypertension+in+patients+with+heart+failure.">Prognostic importance of pulmonary hypertension in patients with heart failure.</a> The American Journal of Cardiology. 99 (8), 1146-1150 (2007).</li><li>Shah, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pulmonary+hypertension+after+heart+transplantation+in+patients+bridged+with+the+total+artificial+heart.">Pulmonary hypertension after heart transplantation in patients bridged with the total artificial heart.</a> ASAIO Journal. 62 (1), 69-73 (2016).</li><li>Tracy, G. P., Proctor, M. S., Hizny, C. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reversibility+of+pulmonary+artery+hypertension+in+aortic+stenosis+after+aortic+valve+replacement.">Reversibility of pulmonary artery hypertension in aortic stenosis after aortic valve replacement.</a> The Annals of Thoracic Surgery. 50 (1), 89-93 (1990).</li><li>Lindelow, B., Andersson, B., Waagstein, F., Bergh, C. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High+and+low+pulmonary+vascular+resistance+in+heart+transplant+candidates.+A+5-year+follow-up+after+heart+transplantation+shows+continuous+reduction+in+resistance+and+no+difference+in+complication+rate.">High and low pulmonary vascular resistance in heart transplant candidates. A 5-year follow-up after heart transplantation shows continuous reduction in resistance and no difference in complication rate.</a> European Heart Journal. 20 (2), 148-156 (1999).</li><li>Martin, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Implantable+left+ventricular+assist+device+for+treatment+of+pulmonary+hypertension+in+candidates+for+orthotopic+heart+transplantation-a+preliminary+study.">Implantable left ventricular assist device for treatment of pulmonary hypertension in candidates for orthotopic heart transplantation-a preliminary study.</a> European Journal of Cardio-Thoracic Surgery. 25 (6), 971-977 (2004).</li><li>Gallagher, R. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Univentricular+support+results+in+reduction+of+pulmonary+resistance+and+improved+right+ventricular+function.">Univentricular support results in reduction of pulmonary resistance and improved right ventricular function.</a> ASAIO Transactions. 37 (3), 287-288 (1991).</li><li>Beyersdorf, F., Schlensak, C., Berchtold-Herz, M., Trummer, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regression+of+&amp;#34;fixed&amp;#34;+pulmonary+vascular+resistance+in+heart+transplant+candidates+after+unloading+with+ventricular+assist+devices.">Regression of &amp;#34;fixed&amp;#34; pulmonary vascular resistance in heart transplant candidates after unloading with ventricular assist devices.</a> The Journal of Thoracic and Cardiovascular Surgery. 140 (4), 747-749 (2010).</li><li>Hoffmann, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mast+cells+promote+lung+vascular+remodelling+in+pulmonary+hypertension.">Mast cells promote lung vascular remodelling in pulmonary hypertension.</a> European Respiratory Journal. 37 (6), 1400-1410 (2011).</li><li>Litwin, S. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Serial+echocardiographic-Doppler+assessment+of+left+ventricular+geometry+and+function+in+rats+with+pressure-overload+hypertrophy.+Chronic+angiotensin-converting+enzyme+inhibition+attenuates+the+transition+to+heart+failure.">Serial echocardiographic-Doppler assessment of left ventricular geometry and function in rats with pressure-overload hypertrophy. Chronic angiotensin-converting enzyme inhibition attenuates the transition to heart failure.</a> Circulation. 91 (10), 2642-2654 (1995).</li><li>Rockman, H. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Segregation+of+atrial-specific+and+inducible+expression+of+an+atrial+natriuretic+factor+transgene+in+an+in+vivo+murine+model+of+cardiac+hypertrophy.">Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy.</a> Proceedings of the National Academy of Sciences of the United States of America. 88 (18), 8277-8281 (1991).</li><li>de Montgolfier, O., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High+Systolic+blood+pressure+induces+cerebral+microvascular+endothelial+dysfunction,+neurovascular+unit+damage,+and+cognitive+decline+in+mice.">High Systolic blood pressure induces cerebral microvascular endothelial dysfunction, neurovascular unit damage, and cognitive decline in mice.</a> Hypertension. 73 (1), 217-228 (2019).</li><li>Breitling, S., Ravindran, K., Goldenberg, N. M., Kuebler, W. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+pathophysiology+of+pulmonary+hypertension+in+left+heart+disease.">The pathophysiology of pulmonary hypertension in left heart disease.</a> American Journal of Physiology - Lung Cellular and Molecular Physiology. 309 (9), 924-941 (2015).</li><li>Ranchoux, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metabolic+syndrome+exacerbates+pulmonary+hypertension+due+to+left+heart+disease.">Metabolic syndrome exacerbates pulmonary hypertension due to left heart disease.</a> Circulation Research. 125 (4), 449-466 (2019).</li><li>Zhang, H., Huang, W., Liu, H., Zheng, Y., Liao, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanical+stretching+of+pulmonary+vein+stimulates+matrix+metalloproteinase-9+and+transforming+growth+factor-beta1+through+stretch-activated+channel/MAPK+pathways+in+pulmonary+hypertension+due+to+left+heart+disease+model+rats.">Mechanical stretching of pulmonary vein stimulates matrix metalloproteinase-9 and transforming growth factor-beta1 through stretch-activated channel/MAPK pathways in pulmonary hypertension due to left heart disease model rats.</a> PLoS One. 15, 0235824 (2020).</li><li>Yin, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sildenafil+preserves+lung+endothelial+function+and+prevents+pulmonary+vascular+remodeling+in+a+rat+model+of+diastolic+heart+failure.">Sildenafil preserves lung endothelial function and prevents pulmonary vascular remodeling in a rat model of diastolic heart failure.</a> Circulation: Heart Failure. 4 (2), 198-206 (2011).</li><li>Yin, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaled+nitric+oxide+versus+aerosolized+iloprost+for+the+treatment+of+pulmonary+hypertension+with+left+heart+disease.">Inhaled nitric oxide versus aerosolized iloprost for the treatment of pulmonary hypertension with left heart disease.</a> Critical Care Medicine. 37 (3), 980-986 (2009).</li><li>Breitling, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+mast+cell-B+cell+axis+in+lung+vascular+remodeling+and+pulmonary+hypertension.">The mast cell-B cell axis in lung vascular remodeling and pulmonary hypertension.</a> American Journal of Physiology - Lung Cellular and Molecular Physiology. 312 (5), 710-721 (2017).</li><li>Kerem, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lung+endothelial+dysfunction+in+congestive+heart+failure:+Role+of+impaired+Ca2++signaling+and+cytoskeletal+reorganization.">Lung endothelial dysfunction in congestive heart failure: Role of impaired Ca2+ signaling and cytoskeletal reorganization.</a> Circulation Research. 106 (6), 1103-1116 (2010).</li><li>Goncalves-Rodrigues, P., Miranda-Silva, D., Leite-Moreira, A. F., Falcao-Pires, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Studying+left+ventricular+reverse+remodeling+by+aortic+debanding+in+rodents.">Studying left ventricular reverse remodeling by aortic debanding in rodents.</a> Journal of Visualized Experiments. (173), e60036 (2021).</li><li>Miranda-Silva, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterization+of+biventricular+alterations+in+myocardial+(reverse)+remodelling+in+aortic+banding-induced+chronic+pressure+overload.">Characterization of biventricular alterations in myocardial (reverse) remodelling in aortic banding-induced chronic pressure overload.</a> Scientific Reports. 9, 2956 (2019).</li><li>Chou, S. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+effects+of+debanding+on+the+lung+expression+of+ET-1,+eNOS,+and+cGMP+in+rats+with+left+ventricular+pressure+overload.">The effects of debanding on the lung expression of ET-1, eNOS, and cGMP in rats with left ventricular pressure overload.</a> Experimental Biology and Medicine. 231 (6), 954-959 (2006).</li><li>Hentschel, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhalation+of+the+phosphodiesterase-3+inhibitor+milrinone+attenuates+pulmonary+hypertension+in+a+rat+model+of+congestive+heart+failure.">Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure.</a> Anesthesiology. 106 (1), 124-131 (2007).</li><li>Gs, A. K., Raj, B., Santhosh, K. S., Sanjay, G., Kartha, C. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ascending+aortic+constriction+in+rats+for+creation+of+pressure+overload+cardiac+hypertrophy+model.">Ascending aortic constriction in rats for creation of pressure overload cardiac hypertrophy model.</a> Journal of Visualized Experiments. (88), e50983 (2014).</li><li>Angermann, C. E., Ertl, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Natriuretic+peptides--new+diagnostic+markers+in+heart+disease.">Natriuretic peptides--new diagnostic markers in heart disease.</a> Herz. 29 (6), 609-617 (2004).</li><li>Ordodi, V. L., Paunescu, V., Mic, F. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optimal+access+to+the+rat+heart+by+transverse+bilateral+thoracotomy+with+double+ligature+of+the+internal+thoracic+arteries.">Optimal access to the rat heart by transverse bilateral thoracotomy with double ligature of the internal thoracic arteries.</a> American Association for Laboratory Animal Science. 47 (5), 44-46 (2008).</li><li>Fay, D. S., Gerow, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+biologist's+guide+to+statistical+thinking+and+analysis.">A biologist's guide to statistical thinking and analysis.</a> WormBook. , 1-54 (2013).</li><li>Etz, C. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Medically+refractory+pulmonary+hypertension:+treatment+with+nonpulsatile+left+ventricular+assist+devices.">Medically refractory pulmonary hypertension: treatment with nonpulsatile left ventricular assist devices.</a> The Annals of Thoracic Surgery. 83 (5), 1697-1705 (2007).</li><li>Mikus, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reversibility+of+fixed+pulmonary+hypertension+in+left+ventricular+assist+device+support+recipients.">Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients.</a> European Journal of Cardio-Thoracic Surgery. 40 (4), 971-977 (2011).</li><li>Zelt, J. G. E., Chaudhary, K. R., Cadete, V. J., Mielniczuk, L. M., Stewart, D. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Medical+therapy+for+heart+failure+associated+with+pulmonary+hypertension.">Medical therapy for heart failure associated with pulmonary hypertension.</a> Circulation Research. 124 (11), 1551-1567 (2019).</li></ol>

在这里，报道了在大鼠AoB模型中用于主动脉切除的详细手术技术，该技术可用于研究PH-LHD的可逆性以及驱动肺血管系统和RV反向重塑的细胞和分子机制。幼年大鼠主动脉收缩三周导致PH-LHD明显表现为左心室压力增加，左心室肥大，伴随RV压力增加和RV肥大。AoB后第3周的主动脉瓣解除能够在Deb后两周内卸载左心室并完全逆转左心室肥大。同时，主动脉拆解也导致右心室压力完全正常化和右心室肥大部...

心力衰竭是发达国家的主要死因，预计未来十年将增加25%。肺动脉高压（PH） - 肺循环中血压的病理性升高 - 影响约70%的终末期心力衰竭患者;世界卫生组织将PH归类为左心病引起的肺动脉高压（PH-LHD）1。PH-LHD 是由收缩压和/或舒张性左心室 （LV） 功能受损引起的，该功能导致充盈压升高和血液被动充血进入肺循环2。尽管最初是可逆的，但由于肺循环所有区室（即动脉、毛细血管和静脉）的肺血管重塑，PH-LHD 逐渐变得固定3，4。可逆和固定 PH 均增加心房室后负荷，最初导致适应性心肌肥大，但最终导致心房扩张、运动功能减退、纤维化和失代偿，从而逐渐导致心房室衰竭1，2，5，6。因此，PH加速心力衰竭患者的疾病进展并增加死亡率，特别是在通过植入左心室辅助装置（LVAD）和/或心脏移植进行手术治疗的患者中7，8，9。目前，没有治愈性疗法可以逆转肺血管重塑的过程，因此需要在适当的模型系统中进行基本的机制研究。
重要的是，临床研究表明，PH-LHD作为主动脉瓣狭窄患者的常见并发症，在主动脉瓣置换术后的早期可以迅速改善10。类似地，在一项为期 5 年的随访研究中，高（>3 Wood 单位）的术前肺血管阻力 （PVR） 在硝普钠上是可逆的，但在心脏移植后可持续地正常化11。同样，通过使用植入式脉动和非脉动性心室辅助装置12，13，14，可以在几个月内完成LHD患者可逆和固定PVR的充分降低以及RV功能的改善。目前，驱动肺循环和RV心肌逆转重塑的细胞和分子机制尚不清楚。然而，他们的理解可能为生理途径提供重要的见解，这些途径可能在治疗上被利用来逆转PH-LHD和其他形式的PH中的肺血管和RV重塑。
充分复制PH-LHD病理生理学和分子特征的合适临床前模型可用于大鼠手术主动脉束带（AoB）引起的压力超负荷诱导的充血性心力衰竭的转化研究4，15，16。与横主动脉收缩（TAC）17小鼠模型中由于压力超负荷引起的类似心力衰竭相比，AoB大鼠升主动脉高于主动脉根部的束带不会在左颈动脉中产生高血压，因为束带部位是左颈动脉从主动脉流出的近端。因此，AoB不会像TAC18的特征那样在皮层中引起左侧神经元损伤，并且可能会影响研究结果。与其他手术诱导的PH-LHD的啮齿动物模型相比，一般的大鼠模型，特别是AoB，被证明更健壮，可重复，并复制PH-LHD患者肺循环特征的重塑。同时，围手术期致死率低19。AoB大鼠左心室压力升高和左心室功能障碍诱导PH-LHD发展，导致RV压力升高和RV重塑。因此，AoB大鼠模型在包括我们自己在内的独立小组之前的一系列研究中被证明是非常有用的，以确定肺血管重塑的病理机制并测试PH-LHD4，15，20，21，22，23，24，25的潜在治疗策略。
本研究利用AoB大鼠模型建立了主动脉拆解外科手术，研究了肺血管系统和RV中反向重塑的机制。此前，已经开发了小鼠26 和大鼠27 的主动脉剥离等心肌反向重塑模型，以研究调节左心室肥厚消退的细胞和分子机制，并测试潜在的治疗方案以促进心肌 恢复。此外，数量有限的早期研究探索了主动脉拆带对大鼠PH-LHD的影响，并表明主动脉解除可以逆转肺小动脉内侧肥大，使前内皮素1的表达正常化并改善肺血流动力学27，28，为心力衰竭大鼠PH的可逆性提供了证据。在这里，拆带手术的技术程序得到优化和标准化，例如，通过应用气管切开术代替气管插管，或者通过使用定义内径的钛夹进行主动脉束带而不是用钝针26，27的聚丙烯缝合线，从而提供更好的手术程序控制，增加模型的可重复性和提高存活率。
从科学的角度来看，PH-LHD解除结合模型的意义不仅在于证明心力衰竭中心血管和肺部表型的可逆性，更重要的是，在识别触发和/或维持肺动脉反向重塑的分子驱动因素，作为未来治疗靶向的有希望的候选者。

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a model of reverse vascular remodeling in pulmonary hypertension due to left heart disease by aortic debanding in rats

左心病引起的肺动脉高压 （PH-LHD） 是最常见的 PH 形式，但其病理生理学特征不如肺动脉高压 （PAH）。因此，用于治疗或预防PH-LHD的批准治疗干预措施缺失。不推荐用于治疗 PAH 患者 PH 的药物治疗 PH-LHD，因为在左侧充盈压升高的情况下，肺血管阻力 （PVR） 降低和肺血流量增加可能导致左心失代偿和肺水肿。需要制定新的策略来逆转LHD患者的PH值。与PAH相反，PH-LHD是由于左心衰竭期间血液充血进入肺循环引起的机械负荷增加而发生的。临床上，主动脉瓣置换术对左心室 （LV） 进行机械卸载，或在终末期心力衰竭患者中植入左心室辅助装置，不仅使肺动脉和右心室 （RV） 压力正常化，也使 PVR 正常化，从而为肺血管系统反向重塑提供间接证据。利用已建立的PH-LHD大鼠模型，该模型由压力过载引发的左心衰竭引发，随后发展为PH，开发了一种模型来研究这种生理逆向重塑过程的分子和细胞机制。具体而言，进行了主动脉切除手术，导致左心室心肌的反向重塑及其卸载。同时，可检测到右心室收缩压完全正常化和右心室肥大的显著但不完全逆转。该模型可能是研究肺循环和RV中生理反向重塑机制的宝贵工具，旨在开发治疗PH-LHD和其他形式的PH的治疗策略。

首先，在AoB动物的拆解手术之前和之后，通过经胸超声心动图确认主动脉切除术的成功（图6）。为此，在胸骨旁长轴（PLAX）B模式视图中评估主动脉弓。可视化AoB动物中升主动脉上夹子的位置及其在Deb手术后不存在的位置（图6A，B）。接下来，通过脉冲波多普勒成像评估主动脉血流（图6C-F）。在剪辑之?...

Watch this Scientific Journal Video about A Model of Reverse Vascular Remodeling in Pulmonary Hypertension Due to Left Heart Disease by Aortic Debanding in Rats at JoVE.com

A Model of Reverse Vascular Remodeling in Pulmonary Hypertension Due to Left Heart Disease by Aortic Debanding in Rats

本方案描述了一种外科手术，用于去除左心病引起的肺动脉高压大鼠模型中的升主动脉束带。该技术研究肺循环和右心中反向重塑的内源性机制，从而为逆转肺动脉高压和/或右心室功能不全的策略提供信息。

大鼠主动脉切除术治疗左心病肺动脉高压反向血管重塑模型

Pulmonary hypertension due to left heart disease (PH-LHD) is the most common form of PH, yet its pathophysiology is poorly characterized than pulmonary ...

我们的方案描述了在左心病引起的肺动脉高压大鼠模型中去除升主动脉瓣带的外科手术，这导致肺动脉高压的逆转。该技术为研究肺循环和右心室中生理反向重塑的机制提供了有价值的工具。它可以帮助制定治疗肺动脉高压的策略。准备好手术器械后，将麻醉的大鼠置于绝育手术台上的仰卧位。然后，用胶带固定动物的腹部和四肢，并用聚维酮碘/碘伏溶液对动物皮肤进行消毒。注意初级手术主动脉带或AoB手术的疤痕和缝合线。在通过捏脚趾确保足够的麻醉深度后，从初级AoB手术中取出缝合线。然后，用细剪刀做一个7至10毫米长的宫颈中线切口，进行气管切开术。在一对钝镊子的帮助下，解剖颈椎软组织以暴露舌骨下肌肉。然后，通过分裂中线的肌肉，可视化气管。完成后，使用倾斜的Noyes弹簧剪刀在两个软骨环之间做一个两毫米的气管切口，将外径两毫米的气管插管插入气管。然后，用4-0丝缝合线固定套管。将气管插管的另一端连接到机械呼吸机，同时保持最小的死区。保持围手术期肺通气，呼吸频率为每分钟90次呼吸，潮气量为每公斤体重8.5毫升。对于主动脉去条带，使用细剪刀在第二肋和第三肋骨之间做一个20毫米长的皮肤切口。在较小的手术剪刀的帮助下，逐层铺开并切割肌肉，然后沿着第二肋和第三肋骨之间的肋间间隙做一个10毫米的侧切口。使用肋骨吊具扩大第二肋和第三肋骨之间的肋间空间，以创建手术窗口。在钝镊子的帮助下，将胸腺与心脏和导管动脉分开，以用夹子可视化主动脉。在镊子的帮助下握住夹子，然后取出夹子周围的结缔组织以暴露主动脉。用针架打开夹子，然后从胸腔中取出夹子。在闭合胸部之前，打开肺肺不张，确保足够的肺募集，机械通气不会过度膨胀，潮气量为每公斤体重9.5毫升，持续10分钟，并恢复到每公斤体重8.5毫升的潮气量。之后，使用4-0丝通过简单的中断缝合来闭合深部肌肉，并用简单的连续缝合连接上部肌肉。然后，用简单的连续缝合线关闭皮肤。断开气管插管与通气机的连接，同时观察大鼠的自主呼吸。如果动物在断开连接后未能自主呼吸，请重新连接呼吸机并继续通气五分钟，然后再重复该过程。重新建立自主呼吸后，从气管中取出套管，并用海绵点清洁气管周围的液体。使用6-0 Prolene用简单的缝合线闭合气管，并使用4-0丝在简单的中断缝合中关闭舌下肌肉。以简单的连续缝合线连接皮肤，然后在此过程中用聚维酮碘/碘伏溶液清洁和消毒肌肉和皮肤。完成外科手术后，将一只动物移动到带有补充氧气和红外灯的恢复笼中，并将氧气面罩放在靠近大鼠鼻子的地方。在这项研究中，AoB动物中上链主动脉夹的位置以及它在去条带或Deb手术后的缺失被可视化。此外，在Deb手术后，通过AoB动物夹子之前和之后的夹子和相应的主动脉段的脉冲波多普勒成像来评估主动脉血流量。结果显示血流梯度明显衰减，与功能性脱条一致。在第五周，Deb大鼠以与假动物相当的水平表达了脑利钠肽或BNP，表明左心室或左心室的逆转，主动脉剥离失败。经胸超声心动图对左心室功能评估显示，与AoB大鼠相比，Deb动物的左心室射血分数和左心室体积增加。与AoB动物相比，在AoB后第三周进行的去条带手术导致左心室收缩压和左心室肥厚显着降低。与第三周和第五周的AoB大鼠相比，Deb动物也显示出右心室收缩压和右心室肥厚的显着降低，表明左心病引起的肺动脉高压的成功逆转。该手术中最关键的步骤是去除夹子并在主动脉剥离后招募肺。如果正确执行这些步骤，可以提高动物的存活率。

Research

JoVE Journal

Medicine

Ascending Aortic Constriction in Rats for Creation of Pressure Overload Cardiac Hypertrophy Model

大鼠建立压力超负荷心肌肥厚模型在升主动脉缩窄

Ascending aortic constriction is the most common and successful surgical model for creating pressure overload induced cardiac hypertrophy and heart ...

科研

医学

Assessment of Vascular Function in Patients With Chronic Kidney Disease

血管功能在慢性肾脏疾病的评估

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this ...

Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure

左冠状动脉前降支的小鼠结扎：对心肌梗死后重塑和心衰模型

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It ...

A Model of Cardiac Remodeling Through Constriction of the Abdominal Aorta in Rats

心脏重构通过大鼠腹主动脉缩窄的模型

Heart failure is one of the leading causes of death worldwide. It is a complex clinical syndromethat includes fatigue, dyspnea, exercise intolerance, and ...

Shunt Surgery, Right Heart Catheterization, and Vascular Morphometry in a Rat Model for Flow-induced Pulmonary Arterial Hypertension

分流手术，右心导管，血管形态计量学在大鼠模型中的流量引起的肺动脉高压

In this protocol, PAH is induced by combining a 60 mg/kg monocrotalin (MCT) injection with increased pulmonary blood flow through an aorto-caval shunt ...

Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension

慢性血栓栓塞性肺动脉高压大型动物模型中急性右心衰竭的诱导和表型分析

The development of acute right heart failure (ARHF) in the context of chronic pulmonary hypertension (PH) is associated with poor short-term outcomes. The ...

Left Atrial Stenosis Induced Pulmonary Venous Arterialization and Group 2 Pulmonary Hypertension in Rat

左心房狭窄致大鼠肺静脉动脉化及第2组肺动脉高压

The mechanism of mitral stenosis-induced pulmonary venous arterialization and group 2 pulmonary hypertension (PH) is unclear. There is no rodent model of ...

The Left Pneumonectomy Combined with Monocrotaline or Sugen as a Model of Pulmonary Hypertension in Rats

左肺切除术联合单氯联氨酸或苏根为大鼠肺动脉高压的模型

In this protocol, we detail the correct procedural steps and necessary precautions to successfully perform a left pneumonectomy and induce PAH in rats ...

Studying Left Ventricular Reverse Remodeling by Aortic Debanding in Rodents

研究左心室反向改造由主动脉脱体在啮齿动物

To better understand the left ventricular (LV) reverse remodeling (RR), we describe a rodent model wherein, after aortic banding-induced LV remodeling, ...

A Rat Model of Pressure Overload Induced Moderate Remodeling and Systolic Dysfunction as Opposed to Overt Systolic Heart Failure

压力过载诱导中度重塑和收缩功能障碍的大鼠模型，而不是过度收缩性心力衰竭

In response to an injury, such as myocardial infarction, prolonged hypertension or a cardiotoxic agent, the heart initially adapts through the activation ...