Animal Models In Valve Disease

The significant morbidity and mortality associated with heart valve disease has produced a highly lucrative and competitive market for manufactured prosthetic valves. Efforts to develop the ideal replacement heart valve have focused on producing a product that functions like the native valve (Table 2). The dynamics of blood flow through a tube with its specific viscosity is such that the flow is greatest in the center of the tube. Thus, any structure in the center of the valve (i.e., mechanical valve leaflets) will reduce the velocity through that valve. Such basic principles of physics are important in the fundamental design of mechanical valves, as evidenced by the evolution of mechanical design (Fig. 2).

Guidelines for the design and testing of bioartificial and mechanical valves have been established by the Center for Devices and Radiological Health (part of the Food and Drug Administration, or FDA) and the International Organization for Standardization (ISO). More specifically, the FDA has provided industry assistance in the form of guidance documents, advice, reporting, premarket approval, standard formation, and third-party reviews. Typically, prosthetic valve replacements are classified as either tissue (Fig. 3) or mechanical (Figs. 4 and 5); yet, despite their common purpose, specific valve composition and function vary widely. Nevertheless, all valves must undergo performance-based testing to examine hydrody-namic performance (Table 3). For example, accelerated cyclic testing provides wear information, allowing for estimates of structural performance by providing data on fatigue, endurance limits, and damage tolerance of the valve.

Importantly, the FDA requires the demonstration of both efficacy and safety of prototype heart valve replacements prior to final approval for human implantation. This is based on the principle that additional technical and biological information can be gained by observing the valve in actual use. As a result, animal studies remain a crucial component in the overall evaluation of replacement heart valves. All investigational valves undergo a preclinical animal study, with valve implantation in the orthotopic or anatomically normal position (with a required 20-wk minimum duration).

Specifically, the FDA looks for separate data from mechanical and biological valve studies. For example, mechanical

Table 3

Mechanical Valve Fluid Dynamic Testing valves generally place extreme shearing forces on the red blood cells and thrombocytes, causing hemolysis and thrombosis that necessitate chronic anticoagulation after valve implantation. On the other hand, biological valves place very low shear forces on the red blood cells and thus do not need anticoagulation; however, they are sensitive to calcification formation, requiring some form of anticalcification treatment before implantation.

The lack of naturally occurring models of valve disease and the need for standardized models for FDA/International Organization for Standardization approval has led to the use of iatro-genic models of valve disease. To date, the ovine model has been used for producing graded stenosis in the aortic and mitral valves by banding the aorta in young animals (18). In contrast, aortic supravalvular stenosis, as well as aortic valvular stenosis, have commonly been induced in the canine model (19,20). In addition, mitral valve regurgitation in the canine is possible by placement of a shunt (21) or by incision of the chordae tendinae. Interestingly, experiments have also been performed to induce stenosis or regurgitation in the tricuspid and pulmonic valves (22). However, most valve implantation studies approved for human use are completed in normal animals to strictly examine valve performance (Fig. 6).

A primary advantage of employing the canine model is the large amount of available cardiovascular surgical literature. Historically, the dog was considered the gold standard for acute and chronic models of valve replacement surgery that has been accepted by the FDA. Early success with the canine model in valve replacement identified the need for minimizing the risk of surgical infection at the time of prosthesis implantation. Specifically, the use of preoperative parenteral and postoperative topical antibiotics, strict sterile techniques, minimum numbers of operative arterial and venous lines, and short cardiopulmo-nary bypass times were noted to minimize the risk of bacterial valve implant seeding (23).

As described in Chapter 5, the anatomy of the porcine heart is similar to humans regarding the conduction system, coro-

Table 3

Mechanical Valve Fluid Dynamic Testing

• Forward flow testing

• Backflow leakage testing

• Pulsatile flow pressure drop

• Pulsatile flow regurgitation

• Flow visualization

• Cavitation potential

• Verification of the Bernoulli relationship

Source: Replacement Heart Valve Guidelines, 1994, formulated by the US Department of Health and Human Services, Food and Drug Administration, Center for Devices and Radiological Health.

nary arteries, blood supply to the conduction system, and great vessels. In addition, the coagulation cascade of the swine is quite similar to that of humans. Despite the advantages, several problems have been identified in using this model for valvular research.

First, the porcine heart is extremely sensitive to anesthesia, and surgical manipulation often results in postsurgical complications, arrhythmias, or death. Second, the growth of young swine is rapid, resulting in heart size and physiological flow that is not constant over the required follow-up periods. Specifically, these alterations often result in fibrous sheathing and obstruction of the valve orifice, thrombus formation, or dehis-cence (separation) of the sewing cuff. Finally, significant bleeding complications because of application of anticoagulation therapy and poor survival have limited the use of the pig in studying valve-related thrombosis (24).

The ovine model is now accepted as the gold standard for valve replacement using survival surgeries that meet FDA requirements. Normal cardiovascular physiological parameters of sheep approximate normal human valves in blood pressure, heart rate, cardiac output, and intracardiac pressures (25). In addition, the anatomy of the heart provides a valve orifice diameter that is similar to humans (26). The use of animals of

Fig. 7. Ameroid occluder in the canine model. Photo courtesy of Michael Jerosch-Herold and Cory Swingen.

similar age and weight (8-12 months, 30-40 kg) allows the testing of replacement valves using a single orifice size for comparison of valve performance to an appropriate standard. Despite the fact that the heart and vessels are small in relation to the animal's weight, the sheep's relatively large left and right atria allow for straightforward surgical approaches to either the mitral or tricuspid valve.

Sheep as experimental animals allow easy handling and long-term husbandry (24). Juvenile sheep grow at a rate that does not cause excessive mitral or aortic stenosis during the postimplantation test periods as compared to the porcine model (24). However, specific attention to gastric decompression, perioperative antibiotics, sterile techniques, and minimally invasive interventions in the postoperative period will increase the success of valve implantation studies in the ovine model (27).

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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