W. DAVID MERRYMAN
Heart valve disease is the third leading cause of cardiovascular mortality and morbidity in the United States and, with current aging trends, will increase in prevalence. The historical approach to valve disease treatment is open-chest, surgical replacement. While this tried-and-true approach is very good at treating a large portion of the population, it is not ideal for very young or very old patients. Researchers are exploring a variety of alternatives: tissue engineering, percutaneous methods, and pharmacological intervention.
HEART VALVES: PURE MECHANICS
Heart valves are in many ways like the simple check valves in a household plumbing system or automobile engine; they are controlled by inertial fluid forces and ensure that flow is unidirectional. Unlike toilets or cars, however, the heart is never idle—it never stops pumping blood—meaning the valves must work to near perfection for about 3.5 million cycles per year, or approximately 3 billion cycles over a 75-year lifetime. In the past decade, it has become apparent that heart valve disease is not simply a wearing out of the valve but is more accurately an active biological process that may be understood and treated in various ways.
Heart valve biomechanics has been an active research field for more than 50 years (Sacks et al. 2009). More recently, heart valve mechanobiology has become a field of great interest (Merryman 2010). The distinction between biomechanics and mechanobiology is subtle, but essentially biomechanics is the application of the principles of mechanics to study living organisms and their components, while mechanobiology is the application or analysis of the role of mechanical forces
in eliciting a molecular response, leading to a quantifiable change in form and/or function.
In this article I first explain the two types of heart valve disease (congenital and degenerative) and then review various types of nonsurgical treatments. Each has been the subject of significant research to enhance understanding and application in the past couple of decades, but despite promising indications, challenges remain.
CONGENITAL AND DEGENERATIVE HEART VALVE DISEASE
There are two forms of heart valve disease: congenital and degenerative. Congenital valve disease is a malformation that occurs in utero and may be detected days after birth or not until decades later when the patient becomes symptomatic. Degenerative valve disease is a collective term describing age-related valve disease and occurs later in life, typically beginning around 65 years of age and increasing in prevalence with each passing year. For these two patient populations, different engineering strategies are needed.
Those with congenital valve disease usually need intervention during infancy or adolescence. The ideal solution would be a living tissue–engineered heart valve that could be grown in a laboratory, implanted surgically, and would then grow with the patient. Currently, infants receive size-matched biosprosthetic valves (porcine valves or bovine pericardium) that are chemically fixed and thus not alive. This approach is very limited because as the patient grows (quite rapidly), the implanted valve does not grow and reoperation is necessary. Some patients need up to four open-chest procedures to get to adulthood, and the mortality rate for the fourth procedure is about 50 percent.
Degenerative valve disease has been treated with improved effectiveness over the past 50 years with either bioprosthetic or mechanical valves through open-chest procedures. Although this is an effective solution for many cases of valve disease, it is not a desirable option because the morbidity associated with an open-chest procedure is significant—it is estimated that it takes up to a full year for a patient to return to previous levels of activity. As such, there have been concerted efforts to develop nonsurgical approaches for adult patients.
Realization of a tissue-engineered heart valve that could grow with pediatric patients and would prevent the need for reoperations has been pursued for 20 years (Breuer et al. 1996; Shinoka et al. 1995). In 2000, pulmonary valves were grown in the laboratory (by combining autologous cells and a nonwoven felt scaffold) and implanted in large animals (sheep), which survived for 20 weeks. When evaluated after autopsy, the implanted valve looked very similar to the sheep’s native valve (Hoerstrup et al. 2000). It was expected that this was the breakthrough needed to
translate engineered valves to the clinic, but that has not been the case, and no other studies have been able to replicate the success reported in this seminal study.
There has also been extensive research on novel hydrogels that are much better at controlling the behavior of the valve cells (Kloxin et al. 2009; Sewell-Loftin et al. 2014; Wang et al. 2012) and on off-the-shelf scaffolds that are easy to use/mold and that closely match some of the mechanical properties of native heart valves (Engelmayr et al. 2005, 2006). Although the scaffolding component of engineered heart valve research has made progress, the cellular component to be added to the scaffold has not advanced. The primary reason for this is that it is quite unclear what cell type should be used to populate a tissue-engineered heart valve. The two cell types that make up the heart valves are unique and unlike their similar neighbors that make up blood vessels. The valve interstitial cells that are inside the tissue are essentially fibroblasts, but at the same time they are unlike most fibroblasts and are very specialized (Rabkin-Aikawa et al. 2004; Roy et al. 2000). The valve endothelial cells that cover the valve tissue are quite distinct from vascular endothelial cells (Butcher et al. 2004, 2006; Simmons et al. 2005). In other words, vascular cells from peripheral blood vessels are not sufficiently similar to serve as an appropriate cell source for a tissue-engineered heart valve, and although the field started off fast with early success, it remains a long way from clinical implementation.
As an alternative to an invasive, open-chest procedure, there has been considerable work to develop shorter-term solutions for adult patients, namely transcatheter aortic valve replacement. This strategy was initially created for patients that were deemed nonoperable candidates for open-chest surgery, but the early success has been encouraging and the procedure will likely expand to patients otherwise approved for open-chest surgery.
The mitral valve, unlike the aortic valve, is susceptible to a unique pathology called mitral valve prolapse in which the leaflets lose their ability to close properly and billow back into the atrium, causing regurgitant blood flow. Mitral valve prolapse is often treated with a percutaneous strategy called the Alfieri technique or “edge-to-edge” repair (George et al. 2011), but many more treatment approaches are being developed. Among these are the use of radiofrequency energy to shrink the leaflets and implantation of a “purse string” mechanism around the valve to reduce orifice area (Boronyak and Merryman 2012; Tommaso et al. 2014).
Historically, aortic valve disease, particularly calcification, was thought of as an idiopathic phenomenon likely associated with atherosclerosis. But it is now
believed that calcific aortic valve disease is an active mechanobiological disease process and can therefore be targeted with drugs.
The contractile machinery of the valve interstitial cells that leads to calcification is of particular interest (Hutcheson et al. 2013; Walker et al. 2004; Yip et al. 2009). There are multiple potential targets that may slow or reverse the progression of aortic valve disease (Hutcheson et al. 2014), including the serotonergic pathway that was involved in some drugs that caused heart valve disease in the late 1990s and mid-2000s (Hutcheson et al. 2011).
Heart valve disease will continue to be a significant cause of mortality and morbidity in the coming decades; however, new treatment strategies are currently in development that should reduce the number of open-chest procedures. For pediatric patients, a tissue engineered heart valve that can grow with the child remains the ultimate goal, but this will likely not be realized in the near future unless a significant discovery occurs. For adult patients, there are many percutaneous and pharmacological treatment strategies that are in active development and will likely become available to patients within the next decade.
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