Both types of isolated heart preparations have problems in common that should be considered when attempting to extrapolate results to the in vivo condition. First, the isolation process used for these models requires global myocardial ischemia (a period of no perfusion). Typically, once the organ is reperfused, baseline data (heart rate, left ventricular pressure, coronary blood flow) must be collected after a stabilization period to ensure relative viability of the preparation. Clearly, both the ischemic time and stabilization time may influence research outcomes. Therefore, any results obtained must be carefully analyzed with reference to the preparation’s baseline state as well as to the normal in vivo values, to avoid falsely attributing changes in cardiac function to the experimental protocol.

The composition of the perfusate can greatly impact the function and viability of the preparation in both of the aforementioned models. Early studies utilizing isolated heart models have employed whole blood as a perfusate [20]. However, significant problems with clotting and hemolysis may limit the time that the preparation remains viable. Saline compounds, which lack the potential for clotting and hemolysis, are considered useful alternatives to whole blood. However, such buffers have a lower colloid osmotic pressure and, coupled with the lower coronary vascular resistance, will typically result in progressive and severe edema; this results in interstitial edema formation and nonuniform perfusion. To extend the usefulness of the preparation, one can add osmotically active substances to the medium used for bathing and perfusing the preparation in an attempt to limit edema [21, 22]. Nevertheless, despite the technical difficulties associated with these models, isolated hearts have been used in research ranging from ischemia to transplant studies. For more details on isolated heart experimentation, the reader is also referred to Chap. 41.

The significant morbidity and mortality associated with heart valve disease has produced a highly competitive market for manufactured prosthetic valves. Efforts to develop the ideal replacement heart valve have focused on producing a device that functions like the native valve (Table 27.1). To this end, certain basic principles of physics are fundamental in the design of mechanical valves, as evidenced by the evolution of various designs. 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 (Fig. 27.2).

Guidelines for the design and testing of bio-artificial and/or mechanical heart valves have been established by the Center for Devices and Radiological Health of the Food and Drug Administration (FDA) and the International Organization for Standardization (ISO). The FDA has provided industry assistance in the form of guidance documents, advice, reporting, premarket approval, development of standards, and third-party reviews. Typically, prosthetic valve replacements are classified as either tissue (Fig. 27.3) or mechanical (Figs. 27.2 and 27.4), yet despite their common purpose, specific valve composition and function vary widely. Nevertheless, all valves must undergo performance-based testing to examine hydrodynamic performance (Table 27.2). For example, accelerated cyclic testing provides wear information, allowing for estimates of structural performance by providing data on fatigue, endurance limits, and damage tolerances 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 [23]. To date, all investigational valves undergo a preclinical animal study with valve implantation in the orthotopic or anatomically normal position (with a required 20-week minimum period of evaluation). Specifically, the FDA looks for separate data from mechanical and biological valve studies. For example, mechanical valves generally place extreme shearing forces on the red blood cells and platelets, causing hemolysis and thrombosis that necessitate chronic anticoagulation after valve implantation. On the other hand, biologic valves place very low shear forces on the red blood cells and platelets, and thus there is no need for anticoagulation; however, they are sensitive to formation of calcium deposition, requiring the incorporation of some measures in their manufacturing that will attempt to prevent calcification after implantation. The lack of naturally occurring models of valve disease and the need for standardized models for FDA/ISO approval has led to the use of iatrogenic models of valve disease. To date, the ovine model has been used for producing a graded stenosis in the aortic and mitral valves by banding the aorta in young animals [24]. In contrast, aortic supravalvular stenosis, as well as aortic valvular stenosis, has been commonly induced in the canine model [25, 26]. Additionally, induction of mitral valve regurgitation in the canine is possible by placement of a shunt [27] or by transection of the chordae tendineae. Interestingly, experiments have also been performed to induce stenosis or regurgitation in the tricuspid and pulmonic valves [28]. However, most valve implantation studies approved for human use are completed in normal animals and their primary goals are to strictly examine valve performance (Fig. 27.4). A thorough understanding of the background and natural history of heart valve disease in standard laboratory animal species is needed to ensure that spontaneous valve lesions are not misinterpreted as treatment related [29].

A principal advantage of employing the canine model is the large amount of background information available in the cardiovascular surgical literature. Historically, the dog was considered to be the gold standard for both acute and chronic models of valve replacement that was 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 cardiopulmonary bypass times were all noted parameters to minimize the risk of bacterial valve implant seeding [30].

As described in Chap. 6, the anatomy of the porcine heart is most similar to that of the human heart in regards to the conduction system, coronary 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 these 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, and/or death. Second, the growth of young swine is rapid, resulting in heart size and physiological flow that is not constant over required follow-up periods of several months; yet, if you want to investigate the effects of heart growth on a device, using the swine may be beneficial. Specifically, these alterations often result in fibrous sheathing and obstruction of the valve orifice, thrombus formation, or dehiscence (separation) of the sewing cuff from the native annulus. Finally, significant bleeding complications due to application of anticoagulation therapy and poor survival have limited the use of the pig in studying valve-related thrombosis [31]. A recent porcine model for aortic valve sclerosis was able to mimic early human aortic valve disease by feeding swine a high-fat/high-cholesterol diet. This study showed the efficacy of modifying certain factors in a study, allowing for animal models to mimic changes seen in humans [32].

The ovine model is currently accepted as the gold standard for valve replacement using defined survival surgeries that meet FDA requirements. Normal cardiovascular physiological parameters of sheep approximate those of humans in blood pressure, heart rate, cardiac output, and intracardiac pressure [33]. In addition, the anatomy of the adult heart provides valve orifice diameters that are similar to humans [34]. The use of animals of similar age and weight (8–12 months, 30–40 kg) allows for the testing of replacement valves using a single orifice size for comparison of valve performance to an appropriate standard. Although the heart and vessels are small in animals within this weight range, the sheep’s relatively large left and right atria allow for straightforward surgical approaches to either the mitral or tricuspid valves.

In general, sheep as experimental animals allow for easy handing and long-term husbandry. Furthermore, 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 [31]. However, specific attention to gastric decompression, perioperative antibiotics, sterile techniques, and minimally invasive interventions in the postoperative period will all increase the success of valve implantation studies in the ovine model [35].

Despite great advances in treatment options, atherosclerotic coronary vascular disease remains one of the leading causes of death worldwide. As a result, this disease continues to be an active area of cardiovascular research. Originally defined by the Greeks as a lack of blood flow, the modern definition of ischemia emphasizes both the imbalance between oxygen supply and demand as well as the inadequate removal of waste products. Impaired oxygen delivery causes a reduction in oxidative phosphorylation, resulting in myocardial dependence on anaerobic glycolysis for the production of high-energy phosphates. This shift in metabolism produces excess lactate which then accumulates in the myocardium. As impaired ATP production and local tissue acidosis prevails, there is a resultant decline in cardiac contractility. Ultimately, if ischemia is not reversed, myocardial infarction occurs with permanent cellular loss and impaired cardiac function. Multiple experimental techniques have been developed for the study of cardiac ischemia. Currently, scientists consistently use isolated myocytes to examine single cell responses, while isolated perfused hearts and whole animal models allow for a better understanding of the whole organ responses. Regardless of the model type, experimental animals remain a crucial tool in the area of research.

Alexis Carrel reported the first heterotopic transplantation (Table 27.3) of a canine heart connected to the neck vessels of another dog in 1905, but the transplant succumbed to massive clotting and the animal survived for only 2 h. Many years later, Richard Lower and Norman Shumway perfected an orthotopic transplantation technique in the canine and achieved heart graft survivals of up to 21 days. Translation of this research to clinical practice was first performed by Christiaan Barnard in 1967, but acceptable graft survival required further studies in animal models to overcome rejection by the host immune system.
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