Model limitations & comparative anatomy for a TAVI/TAVR preclinical study

By Dale Groth, Surpass, Inc. (from Surpass’ preclinical blog)

Aortic stenosis is the most common valvular heart disease in the elderly population, with an incidence of 4.6% in adults over 75 years of age (1). Surgical replacement of a diseased aortic valve is the recommended treatment for a symptomatic patient experiencing congestive heart failure, syncope, or chest pain (2). Many symptomatic patients also experience significant co-morbidities that make them inoperable for surgical valve replacement. Transcatheter Aortic Valve Replacement (TAVR), or Transcatheter Aortic Valve Implantation (TAVI) as more commonly referenced in Europe, has provided a treatment option for these high-risk symptomatic patients (3).

The first preclinical report of implanting an expandable aortic valve in a swine by catheter delivery technique was published by Andersen in 1992 (4). Transseptal catheter delivery of an aortic valve replacement in humans was first reported by Cribier in 2002 (5) and transfemoral implantation was reported by Webb in 2006 (6).

Throughout recent history surgical prosthetic heart valve researchers and manufacturers have acquired an understanding of the limitations with existing preclinical models. With the evolution of catheter based technologies, new challenges have presented themselves in preclinical studies for TAVR. Being aware of TAVR preclinical model limitations and planning for them upfront can make the difference between a successful or challenging translational study. Surpass has compiled a list of common model challenges to keep in mind while planning for your next TAVR preclinical study.

Aortic valve sizing in preclinical studies requires a different strategy than typically used in human clinical cases. In the clinic, valves being replaced are diseased and typically have a ridged/calcified annulus; while in the animal model, they are healthy. A healthy annulus is malleable and tends to dilate upon waking from anesthesia; so valves in the animal model need to be appropriately oversized to avoid migration and stability issues. However, too much oversizing can cause an increase in other complications such as fatal arrhythmias, which have been seen preclinically and reported in human clinical studies (7). In addition to the initial annulus size, it is important to keep in mind the growth of the animal (and annulus) over the timeframe of the study. If the growth of the annulus exceeds the dimensions of the prosthetic valve, large paravalvular leaks can occur, causing complications in the later stages of the study. For all of these reasons, having a surgeon or interventionalist with experience performing TAVR preclinical studies is critical to the ultimate success of your translational study.

Transcatheter delivery of prosthetic valves has introduced new challenges in the animal model. Not only does the size of the annulus and proper valve oversizing need to be considered, but the diameter of the peripheral vessel used for vascular access and delivery has to be of suitable size. If the animal’s annulus is within the target dimensions but the catheter profile is too large to fit through the peripheral vascular, vessel complications may result or the valve may not be able to be delivered. Working with historical data to compare the annulus size and peripheral artery diameters and knowing how much to oversize without introducing additional unnecessary risks is of key importance. If an acceptable tradeoff between these two parameters cannot be achieved, alternative points of delivery may be considered depending on the endpoints of the TAVR preclinical study.

In addition to annulus size and peripheral artery diameters, the dimensions of the ascending aorta and location of other vascular structures also impact the success of the TAVR implant and study. In the animal model, the length of the ascending aorta has a direct impact on the success of higher-profile implants. Sheep tend to have the brachiocephalic artery that originates off the ascending aorta, which shortens the actual length of the ascending aorta. Depending on the design, higher-profile valves may not sit correctly in the annulus due to the anatomical constraints, causing the valve to ultimately migrate or paravavular leaks to occur. In contrast, the pig’s brachiocephalic artery originates at the arch of the aorta, yielding a longer ascending aorta, which permits higher-profile implants to sit correctly in the annulus.

Occlusion of the left main coronary artery, and ultimately heart bloc, can be a common complication in TAVR preclinical studies within pig and sheep models (8). Both species have coronary ostia originating closer to the aortic valve. This differs from humans where the coronary arteries originate further away from aortic annulus (9). With the shorter distance between the aortic annulus and the coronary ostia in the animal model, there is a higher tendency to occlude the coronary ostia, especially with higher profile valves. So rates of heart bloc can be higher in the animal model for TAVR.

Planning your TAVR preclinical study with these model limitations in mind, working with an experienced surgeon or interventionalist, and prescreening to ensure the optimum anatomy can help you minimize challenges as a result of model limitations and ensure a successful TAVR preclinical study.

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About the Author: Dale Groth, SRS, is Director of Surgical/Interventional Services (Greater Twin Cities) at Surpass, Inc., a preclinical contract research organization with labs in the Silicon Valley and Greater Twin Cities. Dale has more than 20 years of experience performing surgical and interventional translational research procedures including hundreds in the transcatheter aortic and mitral valve space. Dale’s Bio| Surpass’Cardiac Experience

References:

1. Lindroos M, et al.  Prevalence of Aortic Valve Abnormalities in the Elderly: An Echocardiographic Study of a Rando Population Sample.  J Am Coll Cardiol 1993;21:1220-1225.
2. Vahanian A, et al.  Guidelines on the Management of Valvular Heart Disease: The Task Force on the Management of Valvular Heart Disease on the European Society of Cardiology.  Eur Heart J 2007;28:230-268.
3. Lee M.  Transcatheter Aortic Valve Implantation (TAVI) – The Time Has Come.  Hong Kong Medical Diary 2011;16:19-22.
4. Andersen H, et al.  Transluminal Implantation of Artificial Heart Valves.  Description of a New Expandable Aortic Valve and Initial Results with Implantation by Catheter Technique in Closed Chest Pigs.  Eur Heart J 1992;13:704-709.
5. Cribier A, et al.  Percutaneous Transcatheter Implantation of an Aortic Valve Prosthesis for Calcific Aortic Stenosis – First Human Case Description.  Circulation 2002;106:3006-3008.
6. Webb J, et al.  Percutaneous Aortic Valve Implantation Retrograde From the Femoral Artery.  Circulation 2006;113:842-850.
7. Piazza N, et al.  Early and Persistent Intraventricular Conduction Abnormalities and Requirements for Pacemaking After Percutaneous Replacement of the Aortic Valve.  J Am Coll Cardiol Interv 2008;1:310-316.
8. Flecher E, et al.  Coronary Flow Obstruction in Percutaneous Aortic Valve Replacement.  An In Vitro Study.  Eur J Cardiothorac Surg  207;32:291-294.
9. Sahni, D, et al.  Anatomy & Distribution of Coronary Arteries in Pig in Comparison with Man.  Indian J Med Res 2008;127:564-570.

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