By Brad Farrell, PhD
Acute feasibility preclinical studies can establish whether a mechanism is technically achievable, expose procedural and device-related failure modes that theoretical or benchtop work may not reveal, and define the questions that should govern the next investment.
These are high value activities, especially when the technology or procedure is in its relative infancy. Our recent work on a new vacuum-assisted catheter-based left atrial appendage inversion with a transseptal approach as published in July in Bioengineering shows the evidence.
In non-valvular atrial fibrillation, the left atrial appendage (LAA) is the predominant site of intracardiac thrombus formation. Current percutaneous LAA occlusion devices address that risk by leaving a permanent implant in place, creating concerns that include device-related thrombus, peri-device leak, and the need for post-procedural antithrombotic therapy. Could a catheter-based procedure exclude the appendage without leaving an implant behind?
Dr. Muhammad Ali, MD, a practicing interventional cardiologist, theorized that using a transseptal aspiration catheter and negative pressure alone might successfully invert the left atrial appendage into the left atrium, “excluding it” by turning it inside out. More specifically, that “A catheter-based, non-implant mechanical inversion strategy may offer an alternative approach to stroke prevention.”
Veranex Preclinical Services in Atlanta developed the protocol, sourced the study animal, and provided the anesthesia, veterinary surgery, imaging, and procedural support that made the study possible.
Editor’s note: Veranex contributors acknowledged in the publication include Jessica Amilcar, DVM, who performed the surgery, and Michael Sweet, who conducted the echocardiography used to guide catheter placement and confirm inversion. Study Director Brad Farrell (this blog’s author) is one of the publication’s three co-authors.
Dr. Ali developed the concept with his brother, Dr. Khaldoun Ali, MD, a cardiothoracic and vascular surgeon who had worked with epicardial atrial appendage exclusion systems. Earlier work had shown that an inverted appendage heals and fibroses predictably, but that work excluded the appendage wall surgically. Dr. M. Ali's question was whether negative pressure, delivered transseptally, could accomplish the same thing.
The technique reads simply: cross the septum into the left atrium, position a large-bore aspiration catheter at the appendage, apply suction, and withdraw the catheter to draw the LAA apex inward. If sustained inversion occurs, imaging will confirm the result.
A first-in-animal study asks a lab to bring everything except the answer. Three requirements narrowed the field here, and each trace back to work we have been doing on this specific anatomy for years.
Surgical proficiency, specifically: Transseptal access with a 22-F catheter. Puncture the septum in the wrong location, and you fight the catheter the rest of the way to the appendage or increase the risk of pushing the subject into atrial or ventricular fibrillation. The correct puncture angles you toward the appendage and spares you the manipulation.
According to my colleague and Veranex Preclinical Study Director Michael Sweet, transseptal access with large steerable sheaths in large-animal models requires specialized experience, particularly when catheter orientation and subsequent device delivery are critical to study success.
Our veterinary surgeons and technicians in Atlanta hold it, as do our colleagues in Paris, because left atrial appendage programs have demanded it across prior preclinical study work on closure clips, interventionally placed occluders, surgical approaches, and ablation work.
Multimodality imaging. Fluoroscopy and intracardiac echocardiography (ICE) guided transseptal puncture at the fossa ovalis. During catheter delivery and positioning, the team used fluoroscopy, ICE, and transesophageal echocardiography (TEE) with multiplane TEE central to confirmation of complete inversion.
Anatomical and model expertise, specifically: Judgment about the appendage itself. Based on prior LAA work, the team considered both canine and porcine models. The porcine model presented a particular feasibility challenge because its shallower LAA anatomy created uncertainty regarding whether sufficient tissue movement could be achieved for complete inversion. The acute study therefore evaluated both the procedure and the practical limits of the selected anatomy.
What our history and capabilities could not tell us is whether the available aspiration catheter could generate sufficient traction to achieve inversion. That stayed unknown right up to the procedure, for Dr. Ali and for us. Method development carries real risk of failure. Adjacent experience is what makes that risk something a team can manage rather than something it absorbs.
Based on prior LAA work, the Veranex team initially recommended a canine model because its appendage has greater depth for an inversion procedure. Dr. Ali preferred a porcine model, who's shallower LAA anatomy left the team uncertain whether there would be enough tissue movement to achieve complete inversion. The acute study therefore tested both the procedure and the practical limits of the selected anatomy.
As the publication states, “All procedures were approved by the Institutional Animal Care and Use Committee (IACUC). The study was conducted in accordance with ARRIVE guidelines and institutional animal care standards.”
The uncertainty proved meaningful. The first three suction attempts produced inward deformation, but the appendage returned to its native configuration when suction was released.
Inversion succeeded on the fourth suction attempt, confirmed on multiplane transesophageal echocardiography as a smooth tissue mound protruding into the left atrium. Hemodynamics stayed stable throughout, with no signs of tamponade or compromise. Contrast injection during the later stages of the procedure revealed a mild pericardial effusion. At necropsy, the appendage showed a discolored ring consistent with localized bruising, and a small perforation at the region of maximal catheter interaction.
The result established technical feasibility in this animal while also clarifying the need for purpose-built catheter geometry and controlled suction in future work. The porcine model is also the more widely accessible of the two, which extends the reach of what this study demonstrated.
The value of a feasibility study is rarely the headline result. It is the list of things you now know that you could not have known before running it.
The result exposed the limitations of the improvised system. The aspiration catheter had not been designed for LAA inversion, and its stiff distal tip likely contributed to bruising and the small perforation. Suction was generated manually with a 60-mL syringe, which limited precise control over the magnitude and rate of negative pressure. These findings point to three engineering priorities: an atraumatic tissue interface, pressure-limited suction control, and catheter geometry tailored to LAA anatomy.
To repeat, an acute feasibility study can establish whether a mechanism is technically achievable, expose procedural and device-related failure modes that theoretical or benchtop work may not reveal, and define the questions that should govern the next investment.
Here, the observed tissue response identified engineering priorities for a purpose-built catheter, while the study’s limitations defined the endpoints for subsequent chronic work: durability of inversion, fibrosis and endothelialization, atrial function, and thrombus risk at the inverted stump.
A single acute study cannot determine whether an inverted appendage stays inverted, and the authors acknowledge this limitation. But it de-risks the next step investment allowing the sponsor, Dr. Ali in this case, to move forward with confidence.
We congratulate Dr. Muhammad Ali, Dr. Khaldoun Ali, and the Atlanta team on this publication. We look forward to advancing the work into prospective studies that extend the procedural knowledge farther into healing response, durability, longer-term stability, clinical translation and the potential clinical value of a custom catheter or purpose-built system designed expressly for the procedure.
Dr. Ali brought a hypothesis and a clinical vision grounded in an unmet need he had encountered in practice. Together, we generated early evidence to inform the concept’s next engineering and study decisions.
If that describes you, the first step may be closer than you think. Acute feasibility is a defined, achievable, bounded piece of work, and it answers the question you cannot answer any other way. It is what turns a hypothesis or conviction into evidence you can build on, raise against, or walk away from.
We are prepared to help.
About the author: Brad Farrell, PhD, is Senior Preclinical Study Manager in Veranex' Atlanta lab. Nicolas Borenstein, DVM, PhD, is Co-President of Preclinical Contract Research Services at Veranex.
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