이 작업은 QREN 프로젝트 2013/30196, "la Caixa" Banking Foundation, Fundação para a Ciência e Tecnologia (FCT) 프로젝트, LCF/PR/HP17/52190002에 따라 지원 및 자금 지원을 받았습니다. JS와 EB는 Marie Sklodowska-Curie 보조금 계약 번호 813716에 따라 유럽 연합의 Horizon 2020 연구 및 혁신 프로그램의 지원을 받았습니다. PdCM은 Stichting Life Sciences Health(LSH)-TKI 프로젝트 MEDIATOR(LSHM 21016)의 지원을 받았습니다.

압력 과부하 유발 심부전을 연구하기 위한 상행 대동맥 밴딩

<ol>
	<li>Savarese, G., 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+burden+of+heart+failure:+a+comprehensive+and+updated+review+of+epidemiology.">Global burden of heart failure: a comprehensive and updated review of epidemiology.</a> Cardiovascular Research. 118 (17), 3272-3287 (2023).</li><li>Hartley, 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=Trends+in+mortality+from+aortic+stenosis+in+Europe:+2000-2017.">Trends in mortality from aortic stenosis in Europe: 2000-2017.</a> Frontiers in Cardiovascular Medicine. 8, 748137 (2021).</li><li>Silva, K. A. S., Emter, C. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Large+Animal+models+of+heart+failure:+a+translational+bridge+to+clinical+success.">Large Animal models of heart failure: a translational bridge to clinical success.</a> Journal of the American College of Cardiology: Basic to Translational Science. 5 (8), 840-856 (2020).</li><li>Brink, C. B., Lewis, D. I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+12+Rs+framework+as+a+comprehensive,+unifying+construct+for+principles+guiding+animal+research+ethics.">The 12 Rs framework as a comprehensive, unifying construct for principles guiding animal research ethics.</a> Animals (Basel). 13 (7), 1128 (2023).</li><li>Choy, J. S., Zhang, Z. D., Pitsillides, K., Sosa, M., Kassab, G. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Longitudinal+hemodynamic+measurements+in+swine+heart+failure+using+a+fully+implantable+telemetry+system.">Longitudinal hemodynamic measurements in swine heart failure using a fully implantable telemetry system.</a> PLoS One. 9 (8), 103331 (2014).</li><li>Ishikawa, K., 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=Increased+stiffness+is+the+major+early+abnormality+in+a+pig+model+of+severe+aortic+stenosis+and+predisposes+to+congestive+heart+failure+in+the+absence+of+systolic+dysfunction.">Increased stiffness is the major early abnormality in a pig model of severe aortic stenosis and predisposes to congestive heart failure in the absence of systolic dysfunction.</a> Journal of the American Heart Association. 4 (5), 001925 (2015).</li><li>Emter, C. A., Baines, C. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Low-intensity+aerobic+interval+training+attenuates+pathological+left+ventricular+remodeling+and+mitochondrial+dysfunction+in+aortic-banded+miniature+swine.">Low-intensity aerobic interval training attenuates pathological left ventricular remodeling and mitochondrial dysfunction in aortic-banded miniature swine.</a> American Journal of Physiology-Heart and Circulatory Physiology. 299 (5), H1348-H1356 (2010).</li><li>Brito, J., Raposo, L., Teles, R. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Invasive+assessment+of+aortic+stenosis+in+contemporary+practice.">Invasive assessment of aortic stenosis in contemporary practice.</a> Frontiers in Cardiovascular Medicine. 9, 1007139 (2022).</li><li>Tan, W., 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=A+Porcine+model+of+heart+failure+with+preserved+ejection+fraction+induced+by+chronic+pressure+overload+characterized+by+cardiac+fibrosis+and+remodeling.">A Porcine model of heart failure with preserved ejection fraction induced by chronic pressure overload characterized by cardiac fibrosis and remodeling.</a> Frontiers in Cardiovascular Medicine. 8, 677727 (2021).</li><li>Bikou, O., Miyashita, S., Ishikawa, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pig+model+of+increased+cardiac+afterload+induced+by+ascending+aortic+banding.">Pig model of increased cardiac afterload induced by ascending aortic banding.</a> Methods in Molecular Biology. 1816, 337-342 (2018).</li><li>Lelovas, P. P., Kostomitsopoulos, N. G., Xanthos, T. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+comparative+anatomic+and+physiologic+overview+of+the+porcine+heart.">A comparative anatomic and physiologic overview of the porcine heart.</a> Journal of the American Association for Laboratory Animal Science. 53 (5), 432-438 (2014).</li><li>Tian, L., 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=Supra-coronary+aortic+banding+improves+right+ventricular+function+in+experimental+pulmonary+arterial+hypertension+in+rats+by+increasing+systolic+right+coronary+artery+perfusion.">Supra-coronary aortic banding improves right ventricular function in experimental pulmonary arterial hypertension in rats by increasing systolic right coronary artery perfusion.</a> Acta Physiologica (Oxf). 229 (4), 13483 (2020).</li><li>Sorensen, M., Hasenkam, J. M., Jensen, H., Sloth, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Subcoronary+versus+supracoronary+aortic+stenosis.+An+experimental+evaluation.">Subcoronary versus supracoronary aortic stenosis. An experimental evaluation.</a> Journal of Cardiothoracic Surgery. 6, 100 (2011).</li><li>Lygate, C. 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=Serial+high+resolution+3D-MRI+after+aortic+banding+in+mice:+band+internalization+is+a+source+of+variability+in+the+hypertrophic+response.">Serial high resolution 3D-MRI after aortic banding in mice: band internalization is a source of variability in the hypertrophic response.</a> Basic Research in Cardiology. 101 (1), 8-16 (2006).</li><li>Jalal, Z., 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=Unexpected+Internalization+of+a+Pulmonary+Artery+Band+in+a+Porcine+Model+of+Tetralogy+of+Fallot.">Unexpected Internalization of a Pulmonary Artery Band in a Porcine Model of Tetralogy of Fallot.</a> World Journal for Pediatric and Congenital Heart Surgery. 8 (1), 48-54 (2017).</li></ol>

저자는 공개할 것이 없습니다.

최근 몇 년 동안 여러 연구에서 외과적 대동맥 밴딩을 좌심실 압력 과부하 및 심부전(하행9 에서상행 대동맥 10)에 대한 모델로 활용하여 연구자들이 특정 요구에 맞는 다양한 표현형을 얻을 수 있도록 했습니다. 이러한 모델을 사용하려면 값비싼 장비와 전문 지식이 필요하지만 이러한 모델이 제공하는 정보는 매우 중요합니다. 돼지는 크기와 인간의 심장과 유...

심부전(HF)은 전 세계 수백만 명의 사람들에게 영향을 미치는 생명을 위협하는 질병으로, 사회적, 경제적으로 큰 영향을 미칩니다1. 중요한 병인 중 하나는 대동맥 판막 질환 또는 대동맥 협착증(AS)입니다. 대동맥 협착증은 고령기에 더 많이 발생하며 미국에서 두 번째로 흔한 판막 병변으로 꼽힙니다. AS 관련 사망률은 유럽에서도 증가했으며, 특히 최근 중재적 시술을 받을 수 없는 국가에서 증가했다2. 심방세공의 복잡성과 치료 혁신의 부족을 감안할 때, 인간의 상태를 재현하고 새로운 중재의 테스트를 용이하게 할 수 있는 신뢰할 수 있는 동물 모델이 절실히 필요하다3. 설치류 모델이 대형 동물 모델보다 많지만 후자는 크기와 생리적 유사성으로 인해 몇 가지 이점을 제공하여 인간이 사용할 수 있는 약물 용량 및 의료 기기를 테스트할 수 있습니다.
이 방법의 목적은 생물의학 연구에 사용되는 대부분의 대형 동물 종에 적용할 수 있는 상행 대동맥 밴딩(AAB)의 재현 가능한 모델을 확립하는 것입니다. 이 연구에서 절차는 3R 원칙(교체, 감소 및 정제4)을 준수하는 최소 침습적 접근 방식을 사용하여 돼지에서 입증되었습니다. 이 접근 방식은 정확한 압력 구배를 생성하여 높은 재현성을 제공합니다(잠재적으로 필요한 동물의 수를 줄일 수 있음). 또한, 작은 수술 절개(2-3cm)는 수술적 모욕을 최소화하여 흉골 절개술 및 더 큰 개흉술5 (정제)과 같은 보다 공격적인 접근법에 비해 동물의 웰빙을 개선한다. 또한, 문헌의 자세한 설명과 함께 방법의 비디오 데모를 제공하면 잠재적으로 훈련 목적으로만 사용되는 동물의 필요성을 줄여 동물 사용을 더욱 줄일 수 있습니다. 이 모델은 뚜렷한 성장률을 가진 다양한 돼지 균주/품종에 적용할 수 있으며 지속적인 압력 과부하를 유도하여 1개월 또는 2개월의 추적 관찰 후 상당한 비대를 유발합니다.
현재의 방법은 동물의 크기 변동성을 무시하고 고정 협착증6을 사용하거나, 고충실도 압력 센서보다 신뢰성이 떨어지고 신호 감쇠8에 취약한 유체 충전 압력 판독값7을 사용하여 기울기를 계산한다. 또 다른 접근법은 협착증 원위부(stenosis 5)에 대한 단일 압력 측정을 사용한다. 그러나 경피적으로 전달된 고충실도 압력 센서를 사용하여 동시 근위 및 원위 압력 신호를 통해 협착을 교정하면 프로토콜이 크게 최적화되어 그룹 균질성이 향상됩니다. 이 방법을 시각적으로 시연함으로써 다른 연구자들은 큰 장애물 없이 이를 복제할 수 있어야 하며, 3R 원칙의 적용을 촉진하는 동시에 이 모델의 가용성을 높일 수 있습니다.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>3-0 PDS II suture</td>
			<td>Ethicon</td>
			<td>Z683G</td>
			<td>Aorta banding</td>
		</tr>
		<tr>
			<td>5-0 prolene</td>
			<td>Ethicon</td>
			<td>7472H</td>
			<td>Aorta banding</td>
		</tr>
		<tr>
			<td>ACUSON NX2 Ultrasound System</td>
			<td>Siemens</td>
			<td>(240)11284381</td>
			<td>Vascular Access and Echocardiography</td>
		</tr>
		<tr>
			<td>Arterial Extension 200 cm</td>
			<td>PMH</td>
			<td>303.0666</td>
			<td>Anesthesia Maintenance</td>
		</tr>
		<tr>
			<td>Atlan A300 Ventilator</td>
			<td>Draeger</td>
			<td>8621300</td>
			<td>Ventilation</td>
		</tr>
		<tr>
			<td>Bone cutters</td>
			<td>Fehling</td>
			<td>AMP 367.00</td>
			<td>Aorta banding</td>
		</tr>
		<tr>
			<td>Cefazolin 1000 mg</td>
			<td>Labesfal</td>
			<td>100063</td>
			<td>Antibiotic</td>
		</tr>
		<tr>
			<td>Chlorhexidine 4% Wash Solution</td>
			<td>AGA</td>
			<td>19110008</td>
			<td>Cleaning</td>
		</tr>
		<tr>
			<td>Doyen Intestinal Forceps</td>
			<td>Aesculap</td>
			<td>EA121R</td>
			<td>Intubation</td>
		</tr>
		<tr>
			<td>Echogenic Introducer Needle</td>
			<td>Teleflex</td>
			<td>AN-04318</td>
			<td>Vascular Access</td>
		</tr>
		<tr>
			<td>Endotracheal tube</td>
			<td>Intersurgical</td>
			<td>8040070</td>
			<td>Intubation</td>
		</tr>
		<tr>
			<td>ePTFE vascular graft (5 mm x 40 cm)</td>
			<td>GORE-TEX</td>
			<td>S0504</td>
			<td>Aorta banding</td>
		</tr>
		<tr>
			<td>Extension line 100 cm</td>
			<td>PMH</td>
			<td>303.0394</td>
			<td>Anesthesia Induction</td>
		</tr>
		<tr>
			<td>F.O. Laryngoscope</td>
			<td>Luxamed</td>
			<td>E1.317.012</td>
			<td>Intubation</td>
		</tr>
		<tr>
			<td>F.O. Miller Blade 4 204 x 17 mm</td>
			<td>Luxamed</td>
			<td>3</td>
			<td>Intubation</td>
		</tr>
		<tr>
			<td>Fenestrated Sterile Drape</td>
			<td>Bastos Viegas</td>
			<td>4882-256</td>
			<td>Aseptic Technique</td>
		</tr>
		<tr>
			<td>Fentanyl 0.5 mg/10 mL</td>
			<td>B.Braun</td>
			<td>5758883</td>
			<td>Anesthesia / Analgesia</td>
		</tr>
		<tr>
			<td>Guidewire 260 cm J-tip</td>
			<td>B.Braun</td>
			<td>J3 FC-FS 260-035</td>
			<td>Left Ventricle catheterization</td>
		</tr>
		<tr>
			<td>Infusomat Space Infusion Pump</td>
			<td>B.Braun</td>
			<td>24101800</td>
			<td>Fluids / Drug administration</td>
		</tr>
		<tr>
			<td>Intercostal retractor</td>
			<td>Fehling Surgical</td>
			<td>MRP-1</td>
			<td>Thoracotomy</td>
		</tr>
		<tr>
			<td>Introcan Certo IV Catheter 20G</td>
			<td>B.Braun</td>
			<td>4251326</td>
			<td>Fluids / Drug administration</td>
		</tr>
		<tr>
			<td>Isotonic Saline Solution 0.9%</td>
			<td>B.Braun</td>
			<td>5/44929/1/0918</td>
			<td>Fluids / Drug administration</td>
		</tr>
		<tr>
			<td>Ketamidor 100 mg/mL</td>
			<td>Richter pharma</td>
			<td>1121908AB</td>
			<td>Anesthesia Induction</td>
		</tr>
		<tr>
			<td>L10-5v Linear Transducer</td>
			<td>Siemens</td>
			<td>11284481</td>
			<td>Vascular Access</td>
		</tr>
		<tr>
			<td>Midazolam 15 mg/3 mL</td>
			<td>Labesfal</td>
			<td>PLB762-POR/2</td>
			<td>Anesthesia Induction</td>
		</tr>
		<tr>
			<td>Mikro-cath</td>
			<td>Millar</td>
			<td>63405(1)</td>
			<td>Pressure recording</td>
		</tr>
		<tr>
			<td>MP1 guide catheter 6 Fr</td>
			<td>Cordis</td>
			<td>67027000</td>
			<td>Left Ventricle catheterization</td>
		</tr>
		<tr>
			<td>Needle Holder</td>
			<td>Fehling Surgical</td>
			<td>ZYY-5</td>
			<td>Aorta banding</td>
		</tr>
		<tr>
			<td>Non-woven adhesive</td>
			<td>Bastos Viegas</td>
			<td>442-002</td>
			<td>Fluids / Drug administration</td>
		</tr>
		<tr>
			<td>P4-2 Phased Array Transducer</td>
			<td>Siemens</td>
			<td>11284467</td>
			<td>Echocardiography</td>
		</tr>
		<tr>
			<td>Perfusor Compact Syringe Perfusion Pump</td>
			<td>B.Braun</td>
			<td>8717030</td>
			<td>Fluids / Drug administration</td>
		</tr>
		<tr>
			<td>Pressure Signal Conditioner</td>
			<td>ADinstruments</td>
			<td>PCU-2000</td>
			<td>Pressure recording</td>
		</tr>
		<tr>
			<td>Propofol Lipuro 2%</td>
			<td>B.Braun</td>
			<td>357410&#160;</td>
			<td>Anesthesia Maintenance</td>
		</tr>
		<tr>
			<td>Radifocus Introducer II Standard Kit B - Introducer Sheath</td>
			<td>Terumo</td>
			<td>RS+B60K10MQ</td>
			<td>Vascular Access</td>
		</tr>
		<tr>
			<td>Radiopaque marker</td>
			<td>Scanlan</td>
			<td>1001-83</td>
			<td>Aorta banding</td>
		</tr>
		<tr>
			<td>Scissors</td>
			<td>Fehling Surgical</td>
			<td></td>
			<td>Thoracotomy</td>
		</tr>
		<tr>
			<td>Skinprep (Chlorhexidine 2% / 70% Isopropyl alcohol)</td>
			<td>Vygon</td>
			<td>SKPC015ES</td>
			<td>Disinfection</td>
		</tr>
		<tr>
			<td>Stopcock manifold (3 ports)</td>
			<td>PMH</td>
			<td>310.0489</td>
			<td>Fluids / Drug administration</td>
		</tr>
		<tr>
			<td>Straight forceps</td>
			<td>Fehling Surgical</td>
			<td>ZYY-1</td>
			<td>Thoracotomy</td>
		</tr>
		<tr>
			<td>Stresnil 40 mg/mL</td>
			<td>ecuphar</td>
			<td>572184.2</td>
			<td>Anesthesia Induction</td>
		</tr>
		<tr>
			<td>Syringe Luer Lock 20 cc</td>
			<td>Omnifix B.Braun</td>
			<td>4617207V</td>
			<td>Anesthesia Induction</td>
		</tr>
		<tr>
			<td>Syringe Luer Lock 50 cc</td>
			<td>Omnifix B.Braun</td>
			<td>4617509F</td>
			<td>Anesthesia Maintenance</td>
		</tr>
		<tr>
			<td>Transdermal fentanyl Patch 50 mcg/h</td>
			<td>Mylan</td>
			<td>5022153</td>
			<td>Analgesia</td>
		</tr>
		<tr>
			<td>Ultravist</td>
			<td>Bayer</td>
			<td>KT0B019</td>
			<td>Angiography</td>
		</tr>
		<tr>
			<td>Universal Hemostasis Valve Adapter</td>
			<td>Merit Medical</td>
			<td>UHVA08</td>
			<td>Left Ventricle catheterization</td>
		</tr>
		<tr>
			<td>Velcro Limb Immobilizer</td>
			<td>PMH</td>
			<td>SU-211</td>
			<td>Animal stabilization</td>
		</tr>
		<tr>
			<td>Venofix A, 21 G</td>
			<td>B.Braun</td>
			<td>4056337</td>
			<td>Anesthesia Induction</td>
		</tr>
		<tr>
			<td>Vista 120S Patient Monitor</td>
			<td>Draeger</td>
			<td>MS32997</td>
			<td>Monitoring</td>
		</tr>
		<tr>
			<td>Weck titanium clip</td>
			<td>Teleflex</td>
			<td>523760</td>
			<td>Aorta banding</td>
		</tr>
		<tr>
			<td>Weck titanium clip applier</td>
			<td>Teleflex</td>
			<td>523166</td>
			<td>Aorta banding</td>
		</tr>
		<tr>
			<td>Zhiem Vision</td>
			<td>Iberdata</td>
			<td>N/A</td>
			<td>Fluoroscopy</td>
		</tr>
	</tbody>
</table>

a minimally invasive model of aortic stenosis in swine

심부전의 대형 동물 모델은 크기와 인간과의 생리학적 유사성으로 인해 새로운 치료 중재 개발에 필수적인 역할을 합니다. 압력 과부하로 인한 심부전, 상향 대동맥 밴딩의 모델을 만들기 위해 노력해 왔으며 여전히 관상 동맥 상부 상태이며 인간의 대동맥 협착증을 완벽하게 모방하지 않고 인간의 상태와 매우 유사합니다.
이 연구의 목적은 경피적으로 도입된 고충실도 압력 센서로 정밀하게 보정된 대동맥 밴드를 배치하여 좌심실 압력 과부하를 유도하는 최소 침습적 접근 방식을 입증하는 것입니다. 이 방법은 수술 절차(3R)를 개선하여 균질한 횡단 협착 구배와 그룹 내 변동성 감소를 나타냅니다. 또한 신속하고 사건 없이 동물을 회복할 수 있어 폐사율을 최소화할 수 있습니다. 연구 기간 동안 동물은 수술 후 최대 2개월 동안 경흉부 심초음파와 압력-부피 루프 분석을 사용하여 추적되었습니다. 그러나 원하는 경우 더 긴 후속 조치를 취할 수 있습니다. 이 대형 동물 모델은 신약, 특히 비대와 좌심실 압력 과부하와 관련된 구조적 및 기능적 변화를 표적으로 하는 약물을 테스트하는 데 유용한 것으로 입증되었습니다.

Heart failure (HF) is a life-threatening disease that affects millions of people worldwide, causing major social and economic impacts1. One of its significant etiologies is aortic valve disease or aortic stenosis (AS). Aortic stenosis is more prevalent in advanced age and ranks as the second most common valvular lesion in the United States. AS-related mortality has also increased in Europe, particularly in countries without access to recent interventional procedures2. Given the complexity of HF and the scarcity of therapeutic innovations, there is a pressing need for reliable animal models that can replicate the human condition and facilitate the testing of new interventions3. While rodent models outnumber large animal models, the latter offers several advantages due to their size and physiological similarities, allowing the testing of drug doses and medical devices intended for human use.
The aim of this method is to establish a reproducible model of ascending aortic banding (AAB) applicable to most large animal species used in biomedical research. In this study, the procedure is demonstrated in swine using a minimally invasive approach, adhering to the 3Rs principles (replacement, reduction, and refinement4). This approach ensures the creation of an accurate pressure gradient, resulting in high reproducibility (potentially reducing the number of required animals). Additionally, the small surgical incision (2-3 cm) minimizes surgical insult, improving animal well-being compared to more aggressive approaches like sternotomy and larger thoracotomies5 (refinement). Furthermore, providing a video demonstration of the method, along with detailed descriptions in the literature, could potentially reduce the need for animals used solely for training purposes (replacement), further decreasing animal usage. This model can be adapted for different swine strains/breeds with distinct growth rates and induces sustained pressure overload, leading to significant hypertrophy after 1 or 2 months of follow-up.
Current methods employ fixed stenosis6, disregarding animal size variability, or calculate gradient using fluid-filled pressure readings7, which are less reliable than high-fidelity pressure sensors and are susceptible to signal damping8. Another approach uses a single pressure measurement distal to the stenosis5. However, calibrating the stenosis through simultaneous proximal and distal pressure signals using percutaneously delivered high-fidelity pressure sensors represents a substantial optimization of the protocol, resulting in improved group homogeneity. By visually demonstrating this method, other researchers should be able to replicate it without significant obstacles, increasing the availability of this model while promoting the application of the 3Rs principles.

저자 스포트라이트: 신뢰할 수 있고 재현성 있는 심혈관 연구를 위한 최소 침습 대동물 모델 개발 

돼지 대동맥 협착증의 최소 침습 모델

Most preclinical cardiovascular research is conducted on rodents and other small animal models. From a logistical, economic, reproducibility, and throughput perspective, it has obvious advantages. However, their phylogenetics, pathophysiological, and pharmacological responses are different from humans, and this may preclude the reliable translation to clinical use.Taking advantage of our highly specialized surgical and endovascular skillset, we have focused on developing surgical and they breed large animal models of common cardiac pathologies. This protocol is one good example of a simple, minimally invasive procedure that provides a good balance between reliability, reproducibility, and animal welfare. By monitoring the gradient in real time using high fidelity pressure sensors, we are able to accurately titrate the pressure gradient across the stenosis, resulting in a very homogeneous degree of severity between animals.Furthermore, the minimally invasive approach results in a much lower complication rate and better animal recovery. The development of large animal models, in this case swine, is promising for human-like pharmacological and device testing. This is particularly true for very sensitive areas where anatomophysiological similarities to humans are key, like anesthesia, cardiopulmonary bypass, ECMO, LVAS, percutaneous interest catheter therapies, and minimally invasive and robotic surgery.

이 모델의 초기 개발 당시 사망률은 약 30%였으며, 동물들은 밴드링 후 급성 심부전과 수술 합병증으로 사망했습니다. 그러나 모델이 확립된 후 수술 합병증이 덜 흔해졌고 사망률은 약 15%로 떨어졌습니다. 발생한 2건의 사망은 박리 중 대동맥 파열로 인한 것이었다.
고충실도 압력 센서를 사용하면 고품질 압력 신호를 얻을 수 있으므로(그림 2) 협착을 실...

Watch this Scientific Journal Video about Development of a Minimally Invasive Large-Animal Model for Reliable and Reproducible Cardiovascular Research at JoVE.com

이 프로토콜은 돼지의 상행 대동맥 밴딩에 대한 최소 침습 수술 절차를 설명합니다.

Large animal models of heart failure play an essential role in the development of new therapeutic interventions due to their size and physiological ...

대부분의 전임상 심혈관 연구는 설치류 및 기타 소동물 모델을 대상으로 수행됩니다. 물류, 경제성, 재현성 및 처리량 관점에서 볼 때 분명한 이점이 있습니다. 그러나 계통발생학, 병태생리학적, 약리학적 반응은 인간과 다르기 때문에 임상적 사용으로의 신뢰할 수 있는 번역이 불가능할 수 있습니다.고도로 전문화된 수술 및 혈관 내 기술을 활용하여 외과 수술 개발에 중점을 두었으며 일반적인 심장 병리학의 대형 동물 모델을 육종합니다. 이 프로토콜은 신뢰성, 재현성 및 동물 복지 간의 적절한 균형을 제공하는 간단한 최소 침습 절차의 좋은 예입니다. 고충실도 압력 센서를 사용하여 실시간으로 기울기를 모니터링함으로써 협착 전체의 압력 구배를 정확하게 적정할 수 있어 동물 간에 매우 균일한 정도의 중증도를 얻을 수 있습니다.또한, 최소 침습적 접근법은 합병증 발생률을 훨씬 낮추고 동물의 회복을 향상시킵니다. 대형 동물 모델(이 경우 돼지)의 개발은 인간과 유사한 약리학 및 장치 테스트에 유망합니다. 이는 마취, 심폐 우회술, ECMO, LVAS, 경피적 관심 카테터 요법, 최소 침습 및 로봇 수술과 같이 인간과의 해부생리학적 유사성이 핵심인 매우 민감한 부위에 특히 해당됩니다.

a-minimally-invasive-model-of-aortic-stenosis-in-swine

Research

JoVE Journal

Medicine

A Minimally Invasive Model of Aortic Stenosis in Swine

686 조회수.  University of Porto. 대부분의 전임상 심혈관 연구는 설치류 및 기타 소동물 모델을 대상으로 수행됩니다. 물류, 경제성, 재현성 및 처리량 관점에서 볼 때 분명한 이점이 있습니다. 그러나 계통발생학, 병태생리학적, 약리학적 반응은 인간과 다르기 때문에 임상적 사용으로의 신뢰할 수 있는 번역이 불가능할 수 있습니다.고도로 전문화된 수술 및 혈관 내 기술을 활용하여 외과 수술 개발에...

비디오: 저자 스포트라이트: 신뢰할 수 있고 재현성 있는 심혈관 연구를 위한 최소 침습 대동물 모델 개발 

Large animal models of heart failure play an essential role in the development of new therapeutic interventions due to their size and physiological similarities to humans. Efforts have been dedicated to creating a model of pressure-overload induced heart failure, and ascending aortic banding while still supra-coronary and not a perfect mimic of aortic stenosis in humans, closely resembling the human condition.
The purpose of this study is to demonstrate a minimally invasive approach to induce left ventricular pressure overload by placing an aortic band, precisely calibrated with percutaneously introduced high-fidelity pressure sensors. This method represents a refinement of the surgical procedure (3Rs), resulting in homogenous trans-stenotic gradients and reduced intragroup variability. Additionally, it enables swift and uneventful animal recovery, leading to minimal mortality rates. Throughout the study, animals were followed for up to 2 months after surgery, employing transthoracic echocardiography and pressure-volume loop analysis. However, longer follow-up periods can be achieved if desired. This large animal model proves valuable for testing new drugs, particularly those targeting hypertrophy and the structural and functional alterations associated with left ventricular pressure overload.

This protocol describes a minimally invasive surgical procedure for ascending aortic banding in swine.

연구

의학

Arterial Cannulation for Ascending Aortic Banding in Swine 

To begin, identify the puncture site for arterial cannulation in an anesthetized pig. Using the vascular probe, identify the common femoral artery and confirm the position of the ultrasound marker and correct depth. Before assembling the introducer sheath, flush the introducer and dilator with heparinized saline.Under ultrasound guidance, insert an echogenic arterial needle into the femoral artery. Once the arterial lumen is reached and pulsating arterial blood comes out from the needle hub, advance a J-tip guidewire into the artery. While maintaining pressure on the puncture site, remove the needle, and advance the introducer and dilator assembly into the artery.Next, remove the dilator and aspirate the blood from the side port of the introducer to confirm the correct positioning of the introducer. Sequentially flush the introducer with sterile saline. Finally, connect an arterial pressure line to the side port of the femoral artery introducer to monitor blood pressure.

돼지의 상행 대동맥 밴딩을 위한 동맥 캐뉼레이션 

Ascending Aortic Banding and Left Ventricle/Aorta Catheterization in Swine for Pressure Measurements and Hemodynamic Monitoring 

After performing arterial cannulation in an anesthetized pig, using the cardiac ultrasound transducer, locate the position of the ascending aorta. Then mark the incision site and disinfect the chest of the animal. Using a scalpel, make a two to three centimeter skin incision at the level of the three-fourth intercostal space.Then dissect the underlying fascia and muscle layers until the intercostal space is reached. Stop the ventilation without positive and expiratory pressure. Incise the intercostal muscles to enter the thorax.Then increase the incision to allow the placement of the retractor blades. Retract the ribs and visualize the underlying structures. Using minimally invasive cardiac surgery forceps and scissors, open the pericardium.Then use with sterile gauze to retract the left atria and any lung tissue covering the view of the aorta. Carefully separate the aorta from the pulmonary artery until the transverse pericardial sinus is reached. To facilitate aortic catheterization, place a radiopaque marker in the banding area.Position the ePTFE graft or the nylon band around the ascending aorta. Connect a dual hemostasis valve adapter to a six French MP1 guide catheter, and flush it with heparinized saline. Preload the guide catheter with a 260-centimeter 0.035-inch J-tip guidewire and introduce this assembly through the femoral arterial sheath.Under fluoroscopic guidance, advance the guide wire and guide the catheter into the ascending aorta. When the aortic valve is identified, carefully cross it with a guidewire and introduce the guide catheter into the left ventricle. Check pressure traces to confirm left ventricle positioning.Next, remove the guidewire while leaving the guide catheter in the left ventricle. After aspirating the blood, flush the catheter with sterile saline and ensure no air bubbles are present in the catheter. After advancing two high-fidelity pressure sensors through the dual hemostasis valve adapter, pull the guide catheter back into the ascending aorta distally to the radiopaque marker placed on the banding site.While leaving one of the high-fidelity pressure sensors in the left ventricle, confirm the catheter position using pressure traces. After left ventricle catheterization, close the nylon band one click at a time while closely monitoring pressures. Place sterile plastic tubing on the nylon band end to avoid accidental damage to the surrounding structures.for ePTFE ends, constrict the band using 45-degree forceps. Monitor the pressure to estimate the relative location of the constriction. Finally, place a titanium hemoclip on the forceps position.The use of high fidelity pressure sensors enables obtaining high quality pressure signals, allowing real time and accurate calibration of the stenosis. Transthoracic echocardiography confirm significant aortic stenosis immediately after surgery and during follow-up. Banding surgery resulted in significant aortic stenosis and left ventricular concentric hypertrophy.Post-mortem macroscopic analysis of the heart revealed larger hearts and a thicker left ventricular wall.