Translational Strategies for Developing and Evaluating Transcatheter Devices in Swine Heart Failure Models.

Translational Strategies for Developing and Evaluating Transcatheter Devices in Swine Heart Failure Models - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Ann Biomed Eng . 2026 Jan 6;54(5):1237–1257. doi: 10.1007/s10439-025-03960-3 Search in PMC Search in PubMed View in NLM Catalog Add to search Translational Strategies for Developing and Evaluating Transcatheter Devices in Swine Heart Failure Models Chihiro Miyagi Chihiro Miyagi 1 The Research Institute at Nationwide Children’s Hospital, Columbus, OH USA Find articles by Chihiro Miyagi 1 , Kirthana S Suresh Kirthana S Suresh 2 Structural Heart Research and Innovation Laboratory, Atlanta, GA USA Find articles by Kirthana S Suresh 2 , Marissa Guo Marissa Guo 3 The Ohio State University College of Medicine, Columbus, OH USA Find articles by Marissa Guo 3 , Daisuke Onohara Daisuke Onohara 1 The Research Institute at Nationwide Children’s Hospital, Columbus, OH USA 3 The Ohio State University College of Medicine, Columbus, OH USA Find articles by Daisuke Onohara 1, 3, ✉ Author information Article notes Copyright and License information 1 The Research Institute at Nationwide Children’s Hospital, Columbus, OH USA 2 Structural Heart Research and Innovation Laboratory, Atlanta, GA USA 3 The Ohio State University College of Medicine, Columbus, OH USA Associate Editor Lakshmi Prasad Dasi oversaw the review of this article. ✉ Corresponding author. Received 2025 May 13; Accepted 2025 Dec 22; Issue date 2026. © The Author(s) 2025 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13091859  PMID: 41495353 Abstract Developing a therapeutic transcatheter device for cardiovascular diseases requires precise preclinical large animal models and robust evaluation methods. Three key aspects are essential for evaluating the safety and efficacy of a device: (1) types of swine heart failure models, (2) appropriate echocardiographic methods, and (3) the specific implantation approaches in swine. Common heart failure models include rapid pacing heart failure models, volume overload models, and ischemic models. Among the ischemic models, several approaches are performed to replicate the pathological conditions, such as coronary artery ligation, ameroid constrictor implantation, balloon occlusion, and coronary embolization. The optimal choice of echocardiographic method varies based on the procedure and includes transthoracic, transesophageal, intracardiac, and epicardial techniques. Echocardiographic imaging serves as an invaluable tool in both preclinical and clinical settings, providing structural and functional assessments, procedural guidance during device placement, and comprehensive evaluations of cardiac function and structural changes before and after implantation. Implantation approaches, such as trans-atrial, trans-apical, trans-septal, and trans-right pulmonary methods, each offer unique advantages and challenges. A thorough understanding of these approaches, including the orientation of the catheter tip relative to critical anatomical structures like the mitral annulus or coronary vasculature, is essential for ensuring procedural success. This review explores these aspects to contribute to the development and refinement of catheter-based cardiovascular interventions, ensuring reliability in preclinical data and successful clinical translation. Keywords: Transcatheter device, Echocardiography, Heart failure model, Large animal model Introduction Cardiovascular disease is the leading cause of mortality worldwide, resulting in an enormous number of premature and preventable deaths [ 1 ]. Traditional surgical interventions, such as open-heart surgery, are effective but often associated with significant morbidity, prolonged recovery times, and limited accessibility for high-risk heart failure (HF) patients. Therefore, the introduction of therapeutic strategies using transcatheter devices has significantly reshaped the fields of cardiology and cardiac surgery, providing less invasive alternatives to conventional surgical approaches. Notably, contemporary investigations on the efficacy of percutaneous interventions compared to open-heart surgery remain controversial regarding the superiority of one treatment modality over the other [ 2 , 3 ]. Such outcomes indicate that there is room for potential improvements in current transcatheter techniques. However, the development and validation of novel transcatheter devices require reliable preclinical models, as well as robust methods of evaluation. Porcine models, in particular, are well suited for cardiovascular device testing given their anatomical and physiological similarities to humans. Nevertheless, existing literature on the practical nuances of device delivery in large animal models has been very limited, especially with respect to thoracic orientation, echocardiographic guidance, and access to the heart and vasculature. As summarized in Fig. 1 , this review aims for the following: Examine the key characteristics and considerations of swine models of HF, Highlight the effective use of echocardiography, and Outline the catheter-based access strategies most compatible with porcine anatomy. Fig. 1. Open in a new tab Successful development of therapeutic transcatheter devices for cardiovascular disease relies on an integrated understanding of the following: (1) swine heart failure models, (2) imaging modalities, and (3) device placement approaches By integrating our practical experience with recognized approaches and imaging modalities, we seek to provide a resource that addresses persistent knowledge gaps in the experimental design and procedural execution of transcatheter experiments in large animal models. Developing Heart Failure Models in Swine Swine models are widely used in the evaluation of transcatheter devices due to their highly accurate representation of human anatomy and physiology [ 4 ]. Their heart size, coronary distribution, and myocardial structure closely resemble those of humans, enhancing the translational relevance of findings from porcine studies to clinical settings [ 5 ]. Swine models have been developed to investigate various cardiovascular conditions, the most prominent of which include rapid pacing-induced, volume overload, and ischemia-induced HF. Rapid Pacing Models Rapid pacing-induced HF models in swine are created using high-frequency electrical stimulation [ 6 – 12 ]. Electrodes are typically implanted either in the left atrium (LA) for atrial pacing or in the right ventricular apex for ventricular pacing. Following a postoperative recovery period of 1–2 weeks, the heart is paced at 170 to 240 beats/min until the pigs demonstrate clinical evidence of cardiac dysfunction. This model replicates a form of HF resembling dilated cardiomyopathy, although it primarily recapitulates tachycardia-mediated or arrhythmia-induced cardiomyopathy rather than structural dilated cardiomyopathy, and the reversibility of dysfunction differentiates these. Functionally, left ventricular ejection fraction (LVEF) and fractional shortening (FS) are significantly reduced. Studies over a 3- to 4-week pacing period have reported approximately a 35% reduction in FS compared to controls, with roughly a 38.5% increase in left ventricular end-diastolic dimension (Table 1 ). Despite the overall enlargement in heart size, wall thickness tends to decrease, resulting in a thinner and more dilated left ventricle (LV). Myocardial mass increases due to hypertrophic remodeling, a compensatory mechanism that initially helps to maintain cardiac output but ultimately contributes to decompensation and HF. Table 1. Rapid pacing models Author [ref#] Year # of animals used (control/pacing) Animal size (kg) Pacing site Pacing rate (bpm) Pacing duration Survival rate (%) LVEDV (mL) (before/after pacing) LVEF (%) FS (%) Tomita et al. [ 6 ] 1991 10/10 (SVT), 10 (PSVT) 23–25 LA 240 3 Weeks (SVT), 3 weeks and 4 weeks recovery (PSVT) 80 (SVT), 90 (PSVT) 35 ± 4/36 ± 3 (Control), 36 ± 3/49 ± 5 (SVT), 36 ± 2/42 ± 4 (PSVT) 30 ± 4/32 ± 4 (Control), 32 ± 4/13 ± 5 (SVT), 33 ± 5/31 ± 5 (PSVT) Zellner et al. [ 12 ] 1991 8/8 28.0 ± 1.6 LA 240 3 Weeks 75 35 ± 1/– (Control), –/51 ± 1 (pacing) Helmer et al. [ 7 ] 1996 9/9 40 LV 220 ± 9 26 ± 4 Days 100 39 ± 4/– (Control), –/44 ± 5 (7 days), –/49 ± 9 (14 days), –/58 ± 6 (21–28 days) 39 ± 3/– (Control), –/26 ± 5 (7 days), –/18 ± 6 (14 days), –/13 ± 4 (21-28 days) Spinale et al. [ 8 ] 1997 10/9 20 LA 240 3 Weeks 100 34.5 ± 0.7/– (Control), –/56.1 ± 1.1 (pacing) 39.1 ± 1/– (Control), –/13.4 ± 1.4 (pacing) Möllmann et al. [ 9 ] 2009 6/10 (VVI), 10 (DDD) 34 ± 4 RV 220 3 Weeks 100 39 ± 4/– (Control), –/44 ± 5 (VVI), –/49 ± 9 (DDD) 30 ± 1/–- (Control), –/17 ± 1 (VVI), –/15 ± 2 (DDD), Paslawska et al. [ 10 ] 2011 2/6 70–74 RV 170 14–37 Weeks 100 53.0/– (Control), –/64.8 (mild HF, n = 3), –/68.8 (moderate HF, n = 2), –/71.8 (severe HF, n = 1) 63.4/– (Control), –/35.9 (mild HF, n = 3), –/26.8 (moderate HF, n = 2), –/27.6 (severe HF, n = 1) Hála et al. [ 11 ] 2018 0/5 66 ± 20 RV 200–240 3 Weeks 100 189 ± 59 (Pacing) 25 ± 16 (Pacing) Lampela et al. [ 13 ] 2025 0/3 (Protocol 1), 3 (protocol 2), 9 (protocol 3), 4 (protocol 4) 25–35 RV 1: 6 Weeks starting 220 bpm to gradual decrease 2: 4 Weeks starting 170 gradually increase up to 220 3: 4 Weeks starting 170 and gradual increase up to 220, and additional 4 weeks with 150 4: 1 Week of 170, 3 weeks of 200, and 4 weeks of 150 1: 100 (3/3) 2: 75 (3/4) 3: 75 (9/12) 4: 100 (4/4) LVEDVI 29.2 ± 1.04/28.4 ± 1.3 (Protocol 3) 25.4 ± 2.06/38.6 ± 6.6 (Protocol 4, treadmill exercise stress test) 52.3 ± 1.75/44.9 ± 2.49 (Protocol 3) Open in a new tab LVEDV left ventricular end-diastolic volume, LVEF left ventricular ejection fraction, FS fractional shortening, SVT supraventricular tachycardia, LA left atrium, LV left ventricle, RV right ventricle, HR heart failure, LVEDVI left ventricular end-diastolic volume index While this model is highly reproducible, the reversibility of induced HF upon cessation of pacing complicates long-term studies. Additionally, severe arrhythmias pose significant risks, and reported survival rates vary depending on pacing duration and protocol (Table 1 ). Therefore, the pacing protocols vary considerably, and differences in individual tolerance to pacing create challenges, so adjusting the pacing rate individually based on the progression of HF is often recommended [ 11 ]. The latest report in 2025 by Lampela et al. [ 13 ] optimized the pacing protocol by raising the pacing rate stepwise up to 200 bpm and incorporating well-tolerated moderate pacing at 150 bpm during follow-up after testing new therapeutic applications. This approach may help mitigate the reversibility of pacing-induced HF while maintaining high survival rate. Volume Overload Models Aorto-caval Fistula Model The aorto-caval fistula (ACF) model is a well-established experimental method used to induce chronic HF through sustained volume overload [ 14 , 15 ]. This model involves creating a direct connection between the aorta and inferior vena cava (IVC), resulting in chronic volume overload from augmented venous return. ACF produces high-output HF with eccentric LV hypertrophy and ventricular dilation by increased venous return, and neurohormonal activation (including RAAS up regulation) is a prominent contributor to this pathophysiology, which also reflects aspects of human HF progression. ACF models have primarily been used in small animals, but their application in large animals has also provided valuable insights that are more translatable to human patients. In swine ACF models, the aorto-caval connection is created surgically using a vascular graft. Consequently, the right ventricle (RV) undergoes hypertrophy due to the combined pressure and volume overload. This hypertrophy is characterized by elongation and thickening of cardiomyocytes with increased collagen deposition, leading to myocardial stiffness and impaired diastolic function [ 14 ]. The LV also experiences significant dilation in response to increased preload, while the EF often remains stable or even slightly increased initially due to compensatory hypertrophic remodeling. Prolonged overload eventually exceeds the adaptive capacity of the heart, resulting in RV dysfunction, marked by increased end-diastolic pressures and reduced contractility [ 14 , 16 ]. Such large animal ACF models are valuable for the design and evaluation of transcatheter devices aimed at the treatment of right HF or volume overload conditions. Aortic or Mitral Regurgitation Models Research focused on large animal models of aortic (AR) and mitral regurgitation (MR) is relatively limited, with most studies having been performed in rodents. In swine, Angelsen et al. [ 17 ] and Weisskopf et al. [ 18 ] have described transcatheter methods of damaging the aortic valve under image guidance. Porcine models of MR have also been generated using transcatheter techniques to sever the mitral valve chordae tendineae [ 19 , 20 ]. In this procedure, the catheter is inserted into the LV and visualized on echocardiography and fluoroscopy for precise chordae resection. The resulting MR leads to progressive LV dilation and eccentric hypertrophy. Prolonged volume overload ultimately results in LV dysfunction and HF, with an approximately 50% increase in left ventricular end-diastolic volume and 40–60% reduction in LVEF occurring within a few months [ 19 , 20 ]. Another unique porcine model of functional MR has been described by Onohara et al. [ 21 ], in which the mitral valve chordae tendineae are surgically tethered using snares. By tethering the chordae of either both papillary muscles or the posterior papillary muscle only, the severity and morphology of MR can be adjusted. This technique produces acute MR with predominant loading of the LA and lungs rather than the primary LV dilation typical of DCM, although the authors reported that acute volume overload in this setting can lead to secondary LV dilation. Furthermore, this model allows for immediate MR induction intraoperatively, eliminating the need for prolonged development, as seen in ischemic models of functional MR. In addition, because the sutures pass through the myocardium, they may introduce non-physiological constraint that affects hemodynamic measurements, and this limitation should be considered when interpreting data from this model. Lastly, the open-heart surgical approach may limit its application for long-term survival studies, but it offers a highly controlled platform that is particularly valuable for acute large animal experiments to assess the feasibility and hemodynamic impact of catheter-based therapies in heart failure. Ischemic Models Swine are commonly used as large animal models of ischemic heart disease due to their coronary artery anatomy, which closely resembles that of humans, particularly with their right coronary artery dominance. Additionally, swine, unlike canines, lack significant collateral vessels, making them especially well suited for ischemic studies. Numerous techniques have been developed to induce myocardial ischemia in animal models. Key findings of coronary artery ligation, ameroid constrictor implantation, and temporary balloon occlusion are summarized in Table 2 , and those of coronary microembolization/embolization in Tables 3 and 4 . Table 2. Coronary artery ligation, ameroid constrictor implantation, and temporary balloon occlusion Author [ref#] Year # of animals (control/MI) Animal size (kg) CA occlusion method Targeted artery Duration for ischemia Infarct size (%LV) Survival rate (%) LVEF (%) Findings Mukherjee et al. [ 23 ] 2003 Early: 0/14 Late: 0/17 23–25 CA ligation OM1, OM2 Early: 2 weeks Late: 8 weeks 23 ± 1 Yarbrough et al. [ 24 ] 2003 0/17 23–25 CA ligation OM1, OM2 8 Weeks Yarbrough et al. [ 25 ] 2003 11/32 23–25 CA ligation OM1, OM2 8 Weeks Infarct size relative to “area at risk”: ~ 47 Apple et al. [ 26 ] 2006 /10 30–32 CA ligation OM1 branch 10 Days 19 ± 3 71 (10/14) LVEDV of control: 55 ± 4 mL, MI: 81 ± 3 Munz et al. [ 27 ] 2011 9 30–42 CA ligation LCX ( n = 3) LAD ( n = 12) [Proximal (LADp: n = 2), Mid (LADm: n = 8), Distal (LADd: n = 2)] 5 Days LCX: 17.9 LADm: 14.9 ± 0.8 LADd: 9.95 and 10.09 LCX 33 (1/3) LADp: 0 (0/2) LADm: 88 (7/8) LADd: 100 (2/2) LCX: 60.9 → 36.8 LADm: 65.5 → 53.4 LADd: 69.9 → 65.2 Thorn et al. [ 28 ] 2023 7/19 20–25 CA ligation OM1, OM2 10–14 Days 9 ± 3 Control: 46.98 ± 14.9 MI: 37.41 ± 11.1 LVEDV/BW of control: 2.18 ± 0.26, MI: 2.70 ± 0.4) Shen et al. [ 29 ] 1995 10 26.1 ± 2.5 Ameroid Constrictor LCX (in one pig LAD) Over weeks Sato et al. [ 30 ] 2001 0/42 13.6–15.9 (30–35 lbs) Ameroid Constrictor LCX 3 Weeks 75 (42/56) Fuchs et al. [ 31 ] 2001 0/33 Adult Yorkshire Ameroid Constrictor LCX 7 Weeks Small scar/hibernation 33/42 Global EF mildly reduced Fallavollita et al. [ 32 ] 2005 8/27 Juvenile pigs Ameroid Constrictor Proximal LAD and LCX 3 Months Small infarcts 29 (21/72) 40 Animals had spontaneous sudden death Global EF was significantly reduced Large regions of viable but dysfunctional myocardium Caillaud et al. [ 33 ] 2010 0/24 15–20 Ameroid Constrictor 2 Months 80 (24/30) 55.2 ± 2.39 → 42.8 ± 2.32 LV volume: 54.56 ± 3.83 → 118.16 ± 9.71 Teramoto et al. [ 34 ] 2011 7/20 18–23 (20 ± 1.2) Ameroid Constrictor + distal LAD ligation before ameroid constrictor was used LCX 4 Months Approximately 27 75 (15/20) at 4 months Control: 66.0 ± 16.2 MI: 39.7 ± 16.9 LVEDV of control: 41.7 ± 11.5, MI: 52.7 ± 10.2 Tarkia et al. [ 35 ] 2015 Ameroid Constrictor 3 Months Keeran et al. [ 36 ] 2017 Procedure article 12–15 Ameroid Constrictor (gradual closure) LCX proximal to OM1 3–4 Weeks Hocum Stone et al. [ 37 ] 2018 Technique article Juvenile pigs Ameroid Constrictor LAD (1 cm distal to LAD/LCX junction) Over several weeks Yajima et al. [ 38 ] 2019 5/5 20–25 Ameroid Constrictor LAD 8 Weeks At 8 weeks, Control: 52 ± 2 MI: 33 ± 8 LVEDV (mL)at 8 weeks. Control: 25 ± 5 MI: 54 ± 6 Kapur et al. [ 39 ] 2013 3/8 45 ± 4 Temporal Balloon Mid LAD distal to first diagonal MI: 120 min of LAD occlusion MI + unload: 120 min of LAD occlusion plus 30 min unloading (150 min total) MI: − 49 ± 14 MI + unload: − 28 ± 7 67 (8/12) LVEF was severely impaired in the CMET group compared to the I/R group at 1 week Bikou et al. [ 40 ] 2019 3/16 38–43 Temporal Balloon Mid LAD distal to first diagonal CMET: 60 min plus thrombus injected I/R: 90 min Scar size at 1 week: CMET 28.4 ± 0.7, I/R 22.0 ± 4.1 CMET: 57 (8/14) I/R: 89 (8/9) Thankam et al. [ 41 ] 2022 0/3 ~ 26 Temporal Balloon Distal branches of LCX 10–15 min 100 Acutely reduced but remained > 40% McCall et al. [ 42 ] 2012 Protocol article 25–35 Temporal Balloon LAD distal to first diagonal 90 min (Yorkshire) or 150 min (Gottingen) Open in a new tab CA coronary artery, MI mitral infarction, LVEDV left ventricular end-diastolic volume, LVEF left ventricular ejection fraction, OM obtuse marginal branch, LAD left anterior descending artery, LCX left circumflex artery, BW body weight, CMET coronary microembolization using autologous thrombus injection, I/R ischemia/reperfusion Table 3. Coronary microembolization Author [ref#] Year # of animals used Animal size (kg) Microsphere size (μm) Emb. site Post Emb. Imaging timing Survival rate (%) LVEF (%) Findings Maylar et al. [ 43 ] 2004 48 32.2 ± 0.8 10, 30, 100 LAD D2,3 4 h 75 (36/48) Decrease in stroke volume correlated to the total non-perfused surface area Non-perfused myocardial volume increased from around 12% (10 μm) to 28% (100 μm) Carlsson et al. [ 44 ] 2009 8 34 ± 1 47–2503 LAD 1 h, 1 weeks 75 (6/8) 49 ± 1 (Baseline), 29 ± 1 (at 1 h), 36 ± 1 (at 1 week) No correlation between LVEF and circumferential extent of microinfarction ( r = 0.19) Jin et al. [ 45 ] 2016 12 23.2 ± 1.5 42 LAD 6 h, 1 weeks 92 (11/12) 52 ± 4 (Baseline), 35 ± 4 (at 6 h), 44 ± 3 (at 1 week) LAD territory wall thickening 42.6 ± 2.0 (baseline), 20.3 ± 2.3 (at 6 h), 31.5 ± 2.1 (at 1 week) Suzuki et al. [ 46 ] 2016 13 24–36 45 LAD 1 h, 2 months, 3 months 85 (11/13) EF was depressed to around 30% at 1 h and remained 30–40% until 3 months LVDd and LVDs were slowly increased Wang et al. [ 47 ] 2017 Sham: 5, ME: 5 25–30 42 LAD 12 h 100 68.6 ± 3.3 (Sham), 50.3 ± 2.9 (at 12 hours) FS (%): 42.8 ± 3.1 (sham), 28.6 ± 2.9 (at 12 h). LVDd (mm): 32.7 ± 1.7 (sham), 38.6 ± 1.2 (at 12 h) Open in a new tab LVEF left ventricular ejection fraction, LAD left anterior descending artery, LVDd left ventricular internal dimension in diastole, LVDs left ventricular internal dimension in systole, FS fractional shortening Table 4. Coronary embolization Author [ref#] Year # of animals (control/MI) Animal size (kg) Embolization material Emb. site Post Emb. Imaging timing Survival rate (%) LVEF (%) Findings Sakaguchi et al. [ 48 ] 2003 13/14 19–21 0.5 mL of gelatin sponge mixture LAD 4 Weeks, 8 weeks 86 (12/14) LVDd increased progressively, whereas that in the control group was unchanged over 8 weeks Reffelmann et al. [ 49 ] 2004 –/21 27–37 Foam sponge LCX 1 Week 62 (13/21) A pronounced granulocyte infiltration at the margin of the infarction Dib et al. [ 50 ] 2006 –/44 32.8 ± 7.2 1–3 Complex helical fibered platinum embolization coils (2 × 10 mm) LAD 30 Days, 90 days 80 (35/44) 56.5 ± 9.1 (Baseline), 55.4 ± 10.6 (post-MI), 49.4 ± 9.9 (at 30 days) LVEDV (mL): 52 ± 4 (Baseline), 35 ± 4 (at 6 h), 44 ± 3 (at 1 week) Rissanen et al. [ 51 ] 2013 –/50 30–35 Bottleneck stent: 3–4 × 8 mm bare metal stent covered by PTFE heat shrink tubing LCX and/or LAD 1 Week, 4 weeks 68 (LCX), 63 (LAD), 29 (LCX + mid LAD) Rest/stress 64/78 (Baseline), 39/55 (LCX, 1 week), 41/62 (LCX, 4 weeks), 41/48 (LAD, 1 week), 43/48 (LAD, 4 weeks), 44/38 (LCX + mid LAD) Shi et al. [ 52 ] 2017 5/12 35–40 100–200% Proof ethanol LCX 8–10 Weeks ( n = 9), 16–20 weeks ( n = 3, for MRI) 58 (7/12) 53.4 ± 5.6 (Baseline), 33.2 ± 2.2 (end of study) LVEDV (mL): 63.4 ± 13.6 (Baseline), 96.9 ± 19.5 (at 1 week), 105.5 ± 26.1 (at 10 weeks) Bikou et al. [ 53 ] 2019 3 (Sham)/9 (I/R)/14 (occlusion with thrombus) 38–43 Autologous thrombus injection LAD 1 Week 89 (I/R), 57 (occlusion) In occlusion group, LVEF was severely impaired compared to I/R group at 1 week time point LVEDVI (mL/m 2 ): 91.6 ± 6.3 to 139.7 ± 8 (at 1 week, occlusion), 96.1 ± 7.8 to 118.5 ± 5.3 (at 1 week, I/R) Hamza et al. [ 54 ] 2020 7/8 60 ± 12 1–2 mL pure ethanol LCX (OM) 6 Weeks 88 (7/8) 63 ± 3 (Baseline), 47 ± 3 (at 6 weeks) LVEDV (mL): 84.7 ± 8.5 (Baseline), 209.7 ± 7.7 (at 6 weeks) Pasrija et al. [ 55 ] 2021 –/35 100% Ethanol LCX 58 Days (mean) 66 (23/35) 65 (Baseline), 40 (Post-MI), 45 (mean 58 days) LVDd (mm): 38 (Baseline), 56 (mean 58 days) Open in a new tab MI myocardial infarction, LVEF left ventricular ejection fraction, LAD left anterior descending artery, LVDd left ventricular internal dimension in diastole, LCX left circumflex artery, LVEDV left ventricular end-diastole volume, I/R ischemia followed by reperfusion, LVEDVI left ventricular end-diastolic volume index, OM obtuse marginal branch Coronary Artery Ligation Coronary artery ligation via open-chest surgery has been widely used throughout the twentieth century [ 22 – 28 ] (Table 2 ). This method allows precise control over coronary artery occlusion and enables direct monitoring of heart function and metabolic changes during and after ischemia. Common targets for ligation include the left anterior descending (LAD) artery and the left circumflex (LCX) artery. Proximal LAD or LCX ligation results in high mortality rates. Occlusion of the LAD immediately distal to the first diagonal branch [ 27 ] or the LCX at the obtuse marginal branches (OM1 and OM2) [ 23 , 24 , 28 ] or just distal to the OM1 branch [ 25 , 26 ] offers a balance between maximizing infarct size and survival rates. This model has been associated with a 22–35% incidence of ventricular fibrillation, a mortality rate of 11.5–25.5%, and an infarct size of 14.9–21%. Ameroid Constrictor Implantation The ameroid constrictor is a ring designed to slowly induce coronary artery occlusion, allowing controlled myocardial ischemia [ 29 – 38 ] (Table 2 ). It consists of casein, a hygroscopic material that swells upon exposure to bodily fluids. Once implanted, the casein ring absorbs fluid over time, expanding to constrict the artery incrementally over days to weeks. This gradual occlusion simulates the progressive nature of coronary artery disease, fostering the development of collateral circulation. Typically, the constrictor is positioned around major coronary arteries, such as the LAD [ 34 , 37 , 38 ], LCX [ 33 , 36 ], or both [ 32 ]. In some animal models [ 35 ], distal coronary artery ligation has been used for ischemic preconditioning, allowing for myocardial adaptation to sustained ischemia. Variability in the closure rate of the ameroid constrictor, as well as differences in the number and anatomical locations of the implants, contributes to significant outcome heterogeneity. Infarct size has been reported to range from 10 to 30%, and mortality rates from 0 to 74%, depending on the specific experimental conditions and procedural techniques. Compared to coronary ligation models, ameroid constrictor models are often implanted closer to the proximal segments, causing larger infarct sizes and higher rates of mortality. Temporary Balloon Occlusion The temporary balloon occlusion method is frequently used in swine to induce controlled myocardial ischemia and ischemic–reperfusion injury [ 39 – 41 ] (Table 2 ). This technique uses a balloon catheter that is inserted into the femoral artery and advanced intravascularly to the heart. The balloon is inflated to temporarily block blood flow, typically in the LAD or LCX. The duration of occlusion varies, but longer occlusion times of 90 to 120 min are commonly used to induce significant myocardial damage and achieve consistent, reproducible infarct sizes. Larger infarcts ranging from 15 to 30% of the LV mass are typically observed when proximal LAD segments are occluded [ 39 ]. Mortality rates vary between 10 and 25%, influenced by the duration of ischemia, the target artery, and the management of lethal arrhythmias [ 39 , 41 , 42 ]. Once the occlusion period is complete, reperfusion is initiated following balloon deflation, and ischemia–reperfusion effects can be monitored. This model facilitates the precise study of ischemia–reperfusion injury and has become a standard in evaluating therapeutic strategies aimed at reducing infarct size and improving cardiac outcomes following acute myocardial infarction. Coronary Microembolization and Embolization Coronary microembolization and embolization are well-established techniques in which embolic materials, such as microspheres, stents, coils, gelatin, autologous thrombi, or ethanol-induced thrombi, are introduced into the coronary circulation, resulting in localized ischemia and myocardial injury. Microembolization causes obstruction of the coronary microvasculature using microspheres ranging in size from 10 to 300 μm [ 43 – 47 ]. This method replicates chronic ischemia and microvascular disease. Multiple embolizations are conducted over 1–12 weeks to simulate the gradual progression of HF. Across several studies, LVEF declined by 35–40% after each embolization, with incomplete recovery over time, and typically stabilized around 30–40% during follow-up, reflecting the sustained impact of microvascular obstruction on myocardial function. Survival rates ranged from 75 to 100% (Table 3 ). As a limitation of this model, the microsphere sizes and imaging timepoints vary widely across reports, making direct comparison difficult. Widely accepted methodologies and shared protocols are warranted to support more consistent and reliable research outcomes. Coronary embolization, in contrast, is a minimally invasive method of inducing an acute myocardial infarction [ 48 – 55 ] and serves as an alternative to the coronary artery ligation model. This technique involves occluding larger coronary arteries with embolic agents such as stents [ 51 ], platinum coils [ 50 ], gelatin sponge particles [ 48 , 49 ], autologous thrombi [ 53 ], or ethanol [ 52 , 54 , 55 ]. Compared to microembolization, coronary embolization generally results in more extensive infarcts, with infarction sizes ranging from 12 to 30% of the LV mass, depending on the target vessel and embolizing material (Table 4 ). LVEF is often significantly impacted, with reductions of 15–30%, and recovery is limited. Acute survival rates typically range from 40 to 75%, with early mortality usually occurring because of ventricular fibrillation or cardiogenic shock. Coronary embolization can also be used to selectively target the lateral wall of the LV and cause infarction of the posteromedial papillary muscle. This approach can be used to produce ischemic MR, where LV dilation and leaflet tethering exacerbate the condition [ 54 , 55 ]. Use of Echocardiography in Device Placement and Evaluation Echocardiography plays a pivotal role in preclinical studies dedicated to the development and evaluation of catheter-based interventions. Techniques including transthoracic, transesophageal, intracardiac, and epicardial echocardiography are essential for guiding device placement and assessing cardiac function and structure pre- and post-procedure [ 56 – 58 ]. This section explores the unique advantages and limitations of each echocardiographic modality in the context of large animal studies (Table 5 ). Table 5. Different echocardiographic imaging modalities outlining the probe placement and the corresponding views Transthoracic echocardiography (TTE) Probe placement Echocardiographic views Advantages Diagnostic tool for any procedural planning Guiding tool to percutaneously introduce vascular access sheaths Non-invasive assessment Ideal for qualitative assessment of ventricular and valvular function Disadvantages Often, entire LV/RV are not visible due to the limited acoustic window, making it challenging for quantitative assessment Challenging to obtain Spectral Doppler assessment because of the poor angle alignment with the transvalvular flow direction Apical views are challenging to obtain due to the orientation of the heart and larger body mass Between 3rd and 5th intercostal space with the probe notch directed dorsally Parasternal long axis Between 3rd and 5th intercostal space with the probe notch directed toward left elbow Parasternal short axis Below the sternum Subcostal view Transesophageal echocardiography (TEE) Probe placement/transducer angle Echocardiographic views Advantages Minimally invasive Adequate imaging window is achievable to assess valvular geometry and function Color Doppler across the valves for regurgitation assessment 3D assessment of the valves and cardiac structures Ideal for spectral Doppler assessment of flow across the aortic and pulmonary valves Disadvantages Foreshortened ventricles—may result in inaccurate assessment of ventricular geometry and function Spectral Doppler assessment may not be accurate due to the poor angle alignment with flow across mitral & tricuspid valve 0°–20° or 160°–180° Mid-esophageal placement 0°–10° (For smaller pigs: 49 ± 3 kg) Modified 4-chamber view 40°–60° Deep esophageal placement 30°–40° (For smaller pigs: 49 ± 3 kg) 60°–90° (For 44–57 kg) Modified 2-chamber view 50°–70° or 100°–130° Mid-esophageal placement Long axis of LV and RV outflow tract 0°–60° High esophageal placement (10 cm withdrawal in larger pigs) 40°–70° High esophageal placement (6 cm withdrawal in larger pigs) Long axis of LV and RV outflow tract Intracardiac echocardiography (ICE) ICE catheter tip placement Echocardiographic views Advantages High image quality due to the proximity to the heart and vascular structures Ideal imaging tool for assisting trans-septal puncture, closure of septal defects, patent foramen ovale, LA appendage occlusion, RF ablation, pericardial effusion procedures Adequate imaging to assess valvular geometry, function, and assist in valvular interventions Disadvantages Monoplanar imaging, which requires the probe to be rotated and flexed Probe contact with tissue can induce arrhythmia Limited imaging depth up to 16 cm Foreshortened ventricles Mid RA; posteroflexed and rotated clockwise if needed Further clockwise rotation for imaging LA appendage Modified bicaval view/Interatrial septal view Mid RA; Flex toward the tricuspid valve Foreshortened RV inflow view Clockwise rotation for short axis of aortic valve and RV outflow tract Low in the RA, posteroflexed and rotated counterclockwise by 60° to 100° Short-axis mitral valve level Anteroflex against fossa ovalis of inter-atrial septum or Posteroflexed and rotate clockwise within RA Foreshortened Long-axis view (LV) At the junction of SVC-RA with slight anteroflexion Long axis of left LV tract and aortic valve Low RA at the annulus level with the tip tilted toward aortic annulus or Inside LA, posteroflexed and rotated counterclockwise Short axis of aortic valve Across tricuspid valve into RV Transventricular long axis of LV Across inter-atrial septum Foreshortened Commissural view From right internal jugular vein—across tricuspid valve into RV outflow tract, extreme anteroflexion Modified 4-chamber view Epicardial echocardiography (EE) Probe placement Echocardiographic views Advantages Valve repair/replacement procedures Coronary catheter placement; Surgical ventricular septal defect closure 3D imaging using multiplane reconstruction Unobstructed view of cardiac anatomy Disadvantages Invasive—requires sternotomy or a mini-thoracotomy Adhesion formation limits imaging, especially in longitudinal studies requiring serial echocardiography At the apex, with the probe notch pointing left Apical 4-chamber view From the 4-chamber view, tilt the probe anteriorly Apical 5-chamber view to expose LVOT and aortic valve From the 4-chamber view, rotate the probe counterclockwise or the imaging plane by 60° Apical 2-chamber view From the 3-chamber view, rotate the probe counterclockwise or the imaging plane by 60° Apical long axis At the left atrium/right atrium Long-axis view of left ventricle/right ventricle Rotating the imaging plane show the commissural view At the heart base with the probe notch pointing left shoulder Tilting and sliding the probe caudally shows short-axis views at different levels LV short axis—Aortic level LV short axis—Mitral valve level LV short axis—Papillary muscle level At the aortic level with probe notch toward right shoulder Long axis of aortic valve and ascending aorta Rotating the probe by 90° counterclockwise for epiaortic short-axis view Open in a new tab LV left ventricle, RV right ventricle, LA left atrium, RA right atrium, RF radiofrequency, SVC superior vena cava Transthoracic Echocardiography (TTE) TTE (Fig. 2 A) provides real-time imaging of the heart and major vessels during transcatheter device implantation and is often used for its convenience and non-invasive nature [ 59 , 60 ]. However, performing TTE is challenging due to anatomical differences between swine and human hearts, which can limit its suitability for precise guidance during device placement. For instance, a swine thorax is more oval-shaped, and the heart’s longitudinal axis lies along the anterior–posterior direction. Additionally, as swine are quadrupeds rather than bipeds like humans, their thoracic alignment is horizontal rather than vertical, requiring modified probe placement compared to humans [ 59 , 61 , 62 ]. Using TTE, modified parasternal long-axis and short-axis views can be obtained to assess ventricular and valvular geometry and function (Table 5 ). Closely spaced ribs require a small transducer footprint to navigate effectively, and a low-frequency transducer (~2 to 5 MHz) is often needed to achieve adequate tissue penetration due to the larger body surface area and deeper heart position within the chest cavity [ 61 , 63 ]; such probes, however, compromise image resolution. Even with lower frequency probes, apical view is not easily obtainable, especially in larger animals. Additionally, in large animals, TTE typically requires sedation to minimize body movement. Although some facilities have trained swine using positive reinforcement to reduce stress and motion, the overall image quality is generally inferior compared to that obtained from other echocardiographic methods. For high-resolution imaging, other echocardiographic modalities may be preferable, although TTE remains valuable for general assessments and monitoring of cardiac function and structure over time. Fig. 2. Open in a new tab Representative images of A transthoracic, B transesophageal, C intracardiac, and D epicardial echocardiography. LA left atrium, LV left ventricle, Ao aorta Transesophageal Echocardiography (TEE) TEE (Fig. 2 B) provides more comprehensive imaging than TTE due to the proximity of the esophagus to the heart. This improved visualization makes TEE a useful tool for assessing anatomical features and guiding catheter device placement, particularly in scenarios where TTE is insufficient [ 64 , 65 ]. Moreover, advanced imaging techniques such as 2D and 3D imaging, Doppler, tissue Doppler, and speckle-tracking echocardiography can further enhance its utility in the evaluation of new transcatheter devices. This minimally invasive imaging modality can be used during both closed- and open-chest procedures. In either case, TEE enables intraoperative monitoring of cardiac function without interfering with the ongoing intervention. TEE has been used both as a guiding tool for device implantation and a method for assessing cardiac function [ 66 , 67 ]. Depending on the size of the pig, the depth of TEE probe insertion measured from the incisors varied from 40 to 60 cm. High or mid-esophageal views provide modified 4-chamber views for the evaluation of ventricular and valvular function. Adjusting the probe’s rotation enables additional imaging planes, including a 2-chamber view, a modified 3-chamber view, and a short-axis view of the aortic valve (Table 5 ). These planes are valuable when assessing valvular anatomy and hemodynamics [ 66 , 67 ]. Despite these advantages, the anatomical differences between swine and humans make it difficult to obtain clear imaging. Shadowing caused by the main bronchus and lobes of the lung can obscure views of the septal regions and the right heart [ 66 , 68 ]. Additionally, orientation of the heart in the thorax leads to foreshortened ventricular views, potentially underestimating LV volumes. The angle alignment with the transvalvular flow required for spectral Doppler assessment is also challenging. Of note, a blind pouch-like sac near the esophagus necessitates the use of a laryngoscope with a long blade to facilitate probe insertion. In addition, TEE in swine typically requires general anesthesia, potentially affecting hemodynamic parameters. Intracardiac Echocardiography (ICE) ICE (Fig. 2 C) provides high-resolution near-field imaging [ 69 , 70 ] and has been widely used in a variety of applications, including septal defect closure, trans-septal puncture, and mitral valve repair procedures [ 71 , 72 ]. The ICE catheter is typically inserted via the jugular or femoral vein and advanced into the right atrium, allowing detailed visualization of cardiac structures. In its neutral position, the right ventricular inflow view can be obtained with the probe facing the tricuspid valve. With careful manipulation of the probe, modified long-axis, short-axis, and 4-chamber views can be obtained. ICE overcomes several anatomical challenges associated with TTE and TEE and provides stable, unobstructed imaging that is essential for precise device placement and procedural success. Although introducing the ICE catheter is relatively safe, direct contact between the catheter and cardiac tissue can induce arrhythmias, which can rapidly escalate to life-threatening conditions. Therefore, meticulous handling of the catheter is essential when using ICE. Additionally, despite its high-resolution capabilities, the small imaging crystal on the probe limits the field of view, restricting the visualization. Furthermore, motion artifacts from cardiac and respiratory movement can impact image quality. Unlike TEE probes, which allow adjustment of the imaging angle and planes, ICE probes are typically monoplanar, requiring manual rotation to visualize specific structures [ 69 ]. Incorrect positioning can also occasionally lead to probe kinking, potentially compromising the image quality. However, recent advancements with 3D ICE offer the ability to obtain volumetric measurements and enhanced spatial visualization, facilitating precise procedural navigation across complex anatomical structures, such as the mitral valve, left atrial appendage, and tricuspid valve. Epicardial Echocardiography (EE) EE (Fig. 2 D) provides superior image quality for detailed visualization of cardiac structures because of direct probe placement on the heart via thoracotomy or median sternotomy (Fig. 3 A). This enhances precision in device placement, often achieving image clarity beyond the capabilities of TTE and TEE [ 73 , 74 ]. The unobstructed access to the heart allows for a comprehensive evaluation of cardiac function across multiple planes, including apical, ventricular long and short axes, and epiaortic views. Additionally, the proximity to the heart improves visualization of anterior structures compared to other echocardiographic modalities and vascular anatomy, which is beneficial for procedures like coronary catheter placement [ 75 ]. EE can be performed using both TTE and TEE probes, though TEE probes offer greater maneuverability in confined spaces. Furthermore, the integration of 3D TEE enables detailed three-dimensional views of cardiac structures, which is particularly useful in settings where fluoroscopy is unavailable (Fig. 3 B). Fig. 3. Open in a new tab Using a transesophageal echocardiography (TEE) as an Epicardial Echocardiography (EE), A photograph showing epicardial echocardiography performed using a transesophageal echocardiography (TEE) probe inserted through a left mini-thoracotomy approach, and B representative 3D EE images with a TEE probe obtained during a surgical procedure Despite these advantages, the invasive nature of the procedure could potentially cause arrhythmias and limits its applicability for long-term or repeated assessments. There is also a lack of standardized EE protocols tailored specifically for swine models [ 76 ], which impedes comparability and reproducibility across studies. Nevertheless, EE has been preferred in our large animal experiments [ 21 , 77 – 79 ] due to its high-resolution imaging capabilities and ease of probe placement. For baseline imaging of chronic studies, a small thoracotomy is performed to position the TEE probe in a sterile pouch filled with ultrasound gel, and in subsequent procedures, the probe is positioned via median sternotomy as there are fewer adhesions. Of note, these adhesions can affect probe placement and imaging quality, and consideration of such anatomical barriers is needed to ensure reliable results. Optimizing Catheter-Based Device Placement Techniques in Swine Models Evaluation of the efficacy and feasibility of device deployment in large animal models is a critical component of preclinical testing. This section examines four key approaches to catheter-based device placement: trans-atrial, trans-apical, trans-septal, and trans-right pulmonary vein approaches. The summary of this section is presented in Table 6 , as a selection guidance. Table 6. Selection guidance for the four approaches Approach Trans-atrial Trans-apical Trans-septal Trans-right PV Incision/puncture site Left thoracotomy (4th intercostal space) Median sternotomy or subxiphoid approach Right femoral vein Median sternotomy or right thoracotomy Grafting/sutures for catheter insertion Vascular graft anastomosis to LA Purse-string suture at LV apex Not required Vascular graft anastomosis to right PV Route LA to Mitral valve LV to Mitral valve Femoral vein - IVC - RA - Foramen Ovale - LA to Mitral valve Right PV—LA to Mitral valve Additional catheter angle needed to approach mitral plane + < 90″ (From parallel to the mitral valve toward the posterior commissure) Straight from LV side + 90° (IVC–RA) and + > 90° (FO to Mitral valve) + < 90° (Right PV to mitral valve) Distance from catheter entry to mitral plane Short (LA is flatter than human) Length of LV Long (> 1 m) Short (slightly longer than trans-atrial approach) Device target Mitral annulus, mitral leaflet, mitral apparatus, and LV Aortic/mitral valve repair/replacement LA, mitral valve, and LV Mitral valve Suitable device Early-stage devices with short delivery systems Devices that requires precise control with large delivery system (>30 Fr) Devices with small delivery system (24–26 Fr) Disadvantage Rarely used approach in clinical practice Highly invasive (more time for recovery, bleeding, infection, arrhythmia, and myocardial damage) Risks for aortic injury, cardiac tamponade (LA perforation), and arrhythmias. Anatomical difference between porcine and human may affect Technical challenge to suture a graft to right PV Open in a new tab PV pulmonary vein, LA left atrium, RA right atrium, LV left ventricle, IVC inferior vena cava Trans-atrial Approach The trans-atrial approach is typically performed via left thoracotomy through the fourth intercostal space, with anastomosis of a vascular graft to the roof of the LA for device deployment (Fig. 4 ). This method offers a clear anatomical view of the upper heart structures, including the aorta, pulmonary artery, and LA [ 68 ]. EE can be performed by positioning the probe directly on the heart to provide real-time imaging guidance. The accessibility of this approach makes it an ideal option for evaluating transcatheter devices targeting the mitral annulus, mitral leaflet, mitral valve apparatus, and LV. Fig. 4. Open in a new tab Trans-atrial approach via a left thoracotomy at the fourth intercostal space. The vascular graft is anastomosed to the roof of the left atrium (LA). PA pulmonary artery A straight trajectory to the mitral valve requires approaching at an angle parallel to the long axis of the LV. However, porcine hearts have a flatter LA, which shortens the distance from the LA roof to the mitral annulus. Due to the heart’s deep thoracic positioning, achieving a direct trajectory to the mitral valve is challenging. When the delivery system is introduced through the graft site, it often runs parallel to the mitral valve, directing the device toward the posterior commissure (Fig. 5 ). To achieve perpendicularity relative to the mitral valve, steerability of the system becomes essential. As this approach is rarely used in clinical practice, with the exception of a few reports [ 80 , 81 ], it is more suitable for early-stage device development, particularly for the evaluation of devices with short delivery systems. Fig. 5. Open in a new tab Schematic diagram shows the three-dimensional positioning of the transcatheter delivery system when inserted through the vascular graft via the trans-atrial approach. The catheter moves nearly parallel to the mitral annulus, guiding the tip toward the posterior commissure of the mitral valve. LV left ventricle, AL anterior leaflet, PL posterior leaflet, AC anterior commissure, PC posterior commissure Trans-apical Approach The trans-apical approach provides a direct route to the LV, aortic, and mitral valves, allowing for precise device deployment, as demonstrated in several swine studies [ 82 – 84 ]. This approach is typically accessed via a median sternotomy or through a subxiphoid approach, with placement of a purse-string suture on the LV apex to prevent bleeding (Fig. 6 ). The trans-apical method offers improved control over catheters and devices, particularly for valvular repair or replacement procedures, where stability and precision are crucial. Moreover, this approach can accommodate large delivery systems exceeding 30 Fr. It is commonly used in clinical settings [ 85 , 86 ], making it highly relevant in translational research. Fig. 6. Open in a new tab Apical approach through a median sternotomy. A purse-string suture is placed at the cardiac apex for catheter device insertion Despite these advantages, the trans-apical approach is highly invasive, involving complete or partial sternotomy and apical puncture, which increases recovery time and risk of bleeding or infection. There is also an elevated risk for myocardial damage and ventricular arrhythmias, making it less suitable for chronic large animal experiments. Trans-septal Approach The trans-septal approach is a relatively less invasive technique involving introduction of the catheter-based device through the right femoral vein and advancement into the IVC to ultimately cross the inter-atrial septum via the fossa ovalis. With contemporary advancements in steerable catheters, this approach provides reliable access to the LA, mitral valve, and LV. In addition to several porcine experiences [ 87 ], this technique is widely used in human catheter-based interventions, making it the most clinically relevant route of access. Its extensive use in clinical practice provides procedural familiarity and adaptability for various left-sided heart interventions, including those for atrial defects and mitral valve diseases. The trans-septal approach carries some inherent risks, including aortic injury, cardiac tamponade from LA damage, atrial perforation, and life-threatening arrhythmias. Additionally, navigating the catheter from the right atrium through the septum into the LA can be technically challenging. ICE is typically required to visualize the fossa ovalis and guide the septal puncture, adding further complexity to the procedure. Anatomical differences between porcine and human hearts also make trans-septal procedures difficult to perform. Specifically, the IVC and superior vena cava in porcine models are oriented at a right angle to the RA, compared to the more vertical alignment seen in humans [ 61 ]. This difference in angulation, as well as a shorter LA corresponding to a shorter distance between the fossa ovalis and mitral annulus, impedes the process of gaining perpendicularity to the mitral valve when using catheters designed for humans [ 88 ]. Furthermore, porcine femoral veins usually only accommodate delivery systems up to 24–26 Fr, and larger systems exceeding 30 Fr may require a laparotomy for direct access to the iliac vein or IVC. Trans-right Pulmonary Vein Approach The trans-right pulmonary vein (PV) approach, which involves attaching a vascular graft to the right PV (Fig. 7 ), is useful for deploying catheter-based devices aimed at the mitral valve [ 88 , 89 ]. In swine models, the IVC and the LV longitudinal axis form a smaller angle than in humans and more in line with each other, which often necessitates increased flexion of the delivery system to access the mitral valve. This PV approach more closely reproduces the human anatomical alignment between the IVC and mitral valve [ 88 , 89 ], allowing for device delivery with minimal flexion adjustments. Fig. 7. Open in a new tab Trans-right pulmonary approach. A right thoracotomy is performed at the fourth intercostal space, and a vascular graft is anastomosed to the right pulmonary vein. LV left ventricle, RV right ventricle However, the need to attach a vascular graft to the right PV is a major limitation to this approach. Suturing in such a deep and confined space poses technical challenges. Nevertheless, despite these technical difficulties, the anatomical accuracy provided by this method makes it a valuable tool in device development. Discussion This review highlights the advantages and limitations of various swine models and echocardiographic techniques employed in the preclinical evaluation of transcatheter therapies for structural heart disease. Though large animal studies are indispensable to medical device development and translational research, literature detailing the important considerations when evaluating catheter-based devices remains scarce. Many swine models have been created to replicate cardiac disorders, such as dilated cardiomyopathy, valvular insufficiencies, and myocardial ischemia. Several open-heart and minimally invasive techniques have been designed to achieve these conditions, including rapid pacing, volume overload, direct surgical manipulation, or coronary artery occlusion. All these procedures carry inherent risks to the animal. Among them, the ischemic swine models have gained traction recently as they can closely replicate the pathophysiology of myocardial infarction and secondary MR, where treatment options remain limited. Although the variability in infarct size and location, and the lack of integration of systemic comorbidities limit their applicability to real-world clinical scenarios, such models are proven valuable for studying mechanisms of ventricular remodeling and valvular dysfunction, as well as assessing the efficacy of novel therapeutic interventions. Echocardiographic imaging is an especially valuable tool in both preclinical and clinical settings, facilitating structural and functional assessment, as well as procedural guidance. There are advantages and disadvantages to each modality when applied to swine models. TTE is non-invasive and well suited for longitudinal studies, but the imaging window and resolution are often restricted. TEE, a clinically preferred imaging modality, is a minimally invasive technique with high-resolution images, but shadowing from the lungs frequently obscures visualization. ICE is often used when spatial resolution is more essential than imaging depth. The high-frequency probes and their proximity to the heart are advantageous, but using ICE often induces arrhythmia. Additionally, it is difficult to obtain long-axis views, which are crucial for guiding devices to the mitral valve and LV structures. EE is another effective technique, and the advantage of EE over ICE is its ability to acquire different imaging planes in real time by direct placement of the probe, although its requirement for open-chest access increases invasiveness. The choice of procedural approach is key to ensuring successful device deployment, and selecting an inappropriate approach can generate misleading results. Beyond the choice of access site, factors such as catheter tip orientation are critical to accurate device placement. For instance, the trans-septal approach, when performed in swine requires the catheter to have increased flexion with sharp angulation to access the mitral annulus, though this does not apply to humans. Meanwhile, the trans-right PV approach enables access to the mitral annulus with only 90° of steerability in the delivery system, significantly reducing the need for extensive manipulation (Fig. 8 ). This distinction underscores the importance of tailoring procedural strategies to the anatomy of different animal models, as well as the specific design and capabilities of the device being tested. Fig. 8. Open in a new tab Difference between the trans-septal approach (yellow) and the trans-right PV approach (blue), A Anatomical comparison of the trans-septal and trans-right PV approaches, B Echocardiographic, and C Fluoroscopic image showing the trans-septal and trans-right PV approaches in relation to the mitral valve annulus. AL anterior leaflet, PL posterior leaflet, FO fossa ovalis Lastly, these components are deeply interdependent, each harboring unique advantages and limitations that become evident through accumulated experimental experience. Standardized practices and collaborative platforms for sharing procedural knowledge can strengthen reproducibility and accelerate device development. Establishing widely accepted methodologies and shared protocols could foster more consistent and reliable research outcomes. Conclusion The successful development of therapeutic transcatheter devices for the treatment of cardiovascular disease relies on an integrated understanding of suitable animal models, imaging modalities, and procedural techniques. Systematic evaluation and refinement of testing protocols can optimize device safety and efficacy, leading to improved translational success and better patient outcomes. Acknowledgments We would like to express our sincere gratitude to Dr. Muralidhar Padala, Former Associate Professor at Emory University, Division of Cardiothoracic Surgery, for his financial support, guidance on experiments, and the supportive research environment he provided. His contributions were instrumental in enabling the large animal experiments discussed in this review paper. Author Contributions Daisuke Onohara developed the concept of this manuscript. The first draft of the manuscript was written by Daisuke Onohara and Chihiro Miyagi. Kirthana Suresh provided additional inputs to the imaging and approach section, and Marissa Guo and all authors contributed to editorial changes in the manuscript. All authors performed the literature search, and read and approved the final manuscript. ChatGPT was used for wording correction. Funding This work was supported by the AHA Career Development Award to Dr. Onohara (23CDA1053806). Data Availability Data availability declaration is not applicable to this review manuscript. Declarations Conflict of interest Daisuke Onohara received the AHA Career Development Award (23CDA1053806). The other authors declare no competing interests relevant to the content of this article. Ethical Approval Not applicable. Informed Consent Not applicable. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Vaduganathan, M., G. A. Mensah, J. V. Turco, V. Fuster, and G. A. Roth. 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