Journal of Veterinary Cardiology (2012) 14, 3e5
Mitral valve degeneration: Still more questions than answers The importance of degenerative (myxomatous) mitral valve disease (DMVD) as a canine health problem can hardly be overstated. Data regarding the overall prevalence of DMVD in dogs are reviewed in this issue by Borgarelli and Buchanan and range from 3% to 7% depending on study type and population.1 In the U.S.A., with a total estimated canine population of 77.7 million (highest in the world), that translates to between 2.3 and 5.3 million dogs affected with DMVD. Estimates for European countries, Japan, and Brazil are equally dramatic since all fall within the top 10 countries with the highest populations of dogs. Studies overwhelming support strong associations of the prevalence of canine DMVD with age, breed, and body size.1 The incidence of DMVD in some breeds of dog approaches 100% over a lifetime.1 In discussing the significance of mitral valve disease in humans, it is important to distinguish between mitral valve prolapse (MVP) and DMVD. MVP is a functional disorder of the mitral valve and its diagnosis is based on echocardiographic criteria. The overall prevalence of MVP based on echocardiographic criteria in the human population is 2.4% based on the Framingham Heart Study.2 However only 7% of patients with MVP go on to develop severe mitral regurgitation (MR) compared to 0.5% of patients without MVP.2 Thus MVP is a risk factor, not a synonym, for DMVD. The overall age-adjusted prevalence of moderate to severe mitral regurgitation (MR) in the human population is 1.7%.3 The prevalence of moderate to severe MR in humans <44 years is only 0.5%, but increases to 6.4% in humans 65e74 years and 9.3% in humans >75 years.3 The most important causes of MR in humans in industrialized countries are primary degenerative MR and functional MR secondary to ventricular remodeling or
dysfunction.4 According to the Euro Heart Survey on Valvular Heart Disease, 61.3% of moderate to severe MR has a degenerative etiology.5 Much of the research emphasis on canine DMVD to date has justifiably been focused on improving diagnostic methods and developing effective therapies for the long-term medical management of heart failure. Without question this research has translated to improved quality of life and survival for dogs with DMVD. In this issue, Atkins and Ha ¨ggstro ¨m critically review the evidence behind the recently published ACVIM consensus statement that now guides medical therapy in dogs.6 New therapeutic strategies aimed at slowing progression during the pre-congestion phase (stage B) promise to yield new benefits and controversies. These cardioprotective strategies target the secondary consequences of chronic low-pressure volume overload on the left ventricle. Much of our understanding of the pathogenesis of volume overload ventricular remodeling derives from the work of Dillon and colleagues; and this impressive body of work is comprehensively reviewed in this issue.7 This work is a testament to the biologic complexity of pathogenic processes and illustrates the challenges of targeting therapies to alter them. An important issue that the consensus statement and other clinical studies have been relatively silent on is the potential role that hypertension plays in the initiation and progression of canine DMVD. Given the growing body of experimental evidence that high tensile loading on mitral valves can initiate myxomatous gene expression, the possible role of hypertension in canine DMVD deserves future attention. In this issue, Uechi describes his methods for surgical mitral valve repair in dogs, which have long been the standard-of-care therapy for severe
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4 degenerative MR in humans.8 His impressive results in small- and toy-breed dogs demonstrate the feasibility of surgical repair in small dogs; and yet the significant challenges of more expanded application of surgery in dogs remain. Despite considerable progress in the treatment of degenerative MR, no current therapy in dogs or humans is directed at its underlying pathology. Attention is now appropriately turning to understanding the causes and pathogenesis of valve degeneration, with the goal of identifying strategies to slow or prevent mitral valve degeneration. Most accept the original conclusion of Pomerance and Whitney that canine DMVD shares pathologic features with human DMVD.9 These features include exuberant deposition of glycosaminoglycan (formally mucopolysaccharide) and disorganization and net destruction of the fibular (collagen and elastin) extracellular matrix (ECM). In this issue Fox reviews the pathology DMVD and points out differences between humans and dogs, large and small dogs, young and old dogs that will be important as we seek to better understand the pathogenesis of DMVD in both species.10 Nevertheless there is enough similarity in the human and canine disease to ask the question: What do humans and dogs have in common that place them at particular risk for mitral degeneration compared to other species? Interestingly dogs are not afflicted with degenerative (calcific) aortic valve disease, which the most prevalent valvular heart disease in humans. Other than their association with aging, the pathology and pathogenic mechanisms of degenerative mitral and aortic valve disease appear to be very different.11 Thus an equally intriguing question is: What unique risk factors, not shared by dogs, place humans at risk for degenerative calcific aortic valve disease? Implicit in the classification of canine and human myxomatous mitral valve disease as a degenerative condition is that it is associated with aging. Studies of disease prevalence in dogs and humans would seem to support a strong association with age.1,3,4 This basic assumption about DMVD raises questions about what role aging processes might play in the pathogenesis of DMVD. One possibility is that age-associated changes in connective tissue (CT) homeostasis might put heart valves at particular risk given the high cumulative biomechanical load to which they are subjected over a lifetime. The basic assumption that DMVD is a consequence of aging is challenged in the authoritative review in this issue by Cornell et al. on age-related changes in mitral valves.12 They point out that degenerative changes in mitral valves can often be detected in humans and
Editorial dogs at an early age, particularly in high risk groups or breeds. They suggest that it is more the progression of DMVD that is associated with aging. Close examination of the prevalence data in dogs and humans suggest that both likely play a role.1,3 This interesting discussion does emphasize the importance of distinguishing between early mitral valve degeneration and functional risk factors for mitral valve degeneration such as MVP. Two extraordinarily relevant questions related to canine DMVD are: (1) Why does it have such a strong predilection for small dogs, and (2) Why are certain breeds of dog such as Cavalier King Charles Spaniels predisposed? These predilections implicate a heritable basis for canine DMVD. In this issue, Parker and Kilroy-Glynn present an insightful analysis of possible genetic mechanisms that might underlie a heritable basis for canine DMVD.13 Included are direct genetic mutations associated with a historic common ancestor or “hitchhiker” genes associated with growth restriction. An indirect heritable basis might also be possible. This might include morphologic changes associated with diminutive size that are somehow adverse to optimal heart valve function and homeostasis. In humans, a clear risk association between several heritable CT disorders, including Marfan syndrome, and DMVD exists.14 It is possible that the high dynamic load on heart valves make them particularly susceptible to CT disorders. These observations raise the interesting question: Is the breed predilection for DMVD in dogs indirectly related to an unknown heritable CT disorder that crept into the genome during selection for certain breed morphologies? An emerging question receiving considerable research attention is what role does biomechanical loading (or overloading) play in the pathogenesis of DMVD? That mesenchymal cells alter their ECM environment in response to mechanical forces is now a fundamental biologic principle. Given the high cumulative load placed on heart valves over a lifetime, it is reasonable to believe that abnormal loading could lead to dysregulation of ECM hemostasis manifesting as valve degeneration. This biomechanical hypothesis leads to more questions. What are the specific biomechanical forces (e.g. shear, tension, compression, or flexion) that contribute to valve degeneration? What are the specific mechanosensor and signaling mechanisms that mediate degenerative pathology? If pathologic biomechanical loading mediates myxomatous pathology, what are the clinical conditions that contribute to abnormal loading? For example, we know relatively little about the possible role that hypertension might play in the
pathogenesis of canine DMVD. In this special issue, Richards et al. review the complex mechanobiology of normal and abnormal mitral valves.15 From this review it becomes apparent that finding answers will be challenging. Experimental strategies available to unwind these complex questions include in vitro model systems that apply mechanical forces to intact valves or valve cells in culture. In this issue, Lacerda et al. report that static and cyclic tensile strain applied to cultured canine mitral valves increases abundance of myxomatous effector proteins.16 These and similar studies could conceivably identify key signaling mechanisms that reveal new therapeutic strategies for slowing or preventing degenerative processes. In this issue, we review the evidence that various signaling pathways might play in mitral valve degeneration.17 Of particular interest is the growing evidence for a local serotoninergic mechanism in the pathogenesis of DMVD in dogs and humans. In this issue, Lacerda et al. also report the first direct evidence that mitral valves can synthesize serotonin locally.16 If this mechanism is confirmed it could provide the basis for a first ever therapeutic clinical trial aimed directly at slowing the mitral valve degenerative process. While many questions remain, it is apparent that DMVD is receiving ever-increasing and welldeserved attention as a canine and human health problem. Future progress depends on continued collaboration between research scientists and clinician scientists from multiple disciplines. This special issue is testament that the prospect for continued progress looks bright.
3. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005e1011. 4. Iung B, Vahanian A. Epidemiology of valvular heart disease in the adult. Nat Rev Cardiol 2011;8:162e172. 5. Iung B, Baron G, Butchart EG, Delahaye F, GohlkeBarwolf C, Levang OW, Tornos P, Vanoverschelde JL, Vermeer F, Boersma E, Ravaud P, Vahanian A. A prospective survey of patients with valvular heart disease in Europe: the euro heart survey on valvular heart disease. Eur Heart J 2003;24:1231e1243. 6. Atkins CE, Haggstrom J. Pharmacologic management of myxomatous mitral valve disease in dogs. J Vet Cardiol 2012;14:165e184. 7. Dillon AR, Dell’Italia LJ, Tillson M, Killingsworth C, Denney T, Hathcock J, Botzman L. Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs. J Vet Cardiol 2012;14:73e92. 8. Uechi M. Mitral valve repair in dogs. J Vet Cardiol 2012;14: 185e192. 9. Pomerance A, Whitney JC. Heart valve changes common to man and dog: a comparative study. Cardiovasc Res 1970;4:61e66. 10. Fox PR. Pathology of myxomatous mitral valve disease in the dog. J Vet Cardiol 2012;14:103e126. 11. Rajamannan NM. Mechanisms of aortic valve calcification: the LDL-density-radius theory: a translation from cell signaling to physiology. Am J Physiol Heart Circ Physiol 2010;298:H5eH15. 12. Connell PS, Han RI, Grande-Allen KJ. Differentiating the aging of the mitral valve from human and canine myxomatous degeneration. J Vet Cardiol 2012;14:31e45. 13. Parker HG, Kilroy-Glynn P. Mitral valve disease in dogs: does size matter? J Vet Cardiol 2012;14:19e29. 14. Boudoulas H. Etiology of valvular heart disease. Expert Rev Cardiovasc Ther 2003;1:523e532. 15. Richards JM, Farrar EJ, Kornreich BG, Moise NS, Butcher JT. The mechanbiology of mitral valve function, degeneration, and repair. J Vet Cardiol 2012;14:47e58. 16. Lacerda CMR, MacLea HB, Kisiday J, Orton EC. Static and cyclic strain induce myxomatous effector proteins and serotonin in canine mitral valves. J Vet Cardiol 2012;14:223e230. 17. Orton EC, Lacerda CMR, MacLea HB. Signaling pathways in mitral valve degeneration. J Vet Cardiol 2012;14:7e17.
References 1. Borgarelli M, Buchanan JW. Historical review, epidemiology and natural history of degenerative mitral valve disease. J Vet Cardiol 2012;14:93e101. 2. Freed LA, Levy D, Levine RA, Larson MG, Evans JC, Fuller DL, Lehman B, Benjamin EJ. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 1999;341: 1e7.
E. Christopher Orton, DVM, PhD Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1678 Campus Delivery, Fort Collins, CO 80523-1678, United States E-mail address: [email protected]
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