JACC: CARDIOVASCULAR IMAGING © 2008 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
VOL. 1, NO. 3, 2008 ISSN 1936-878X/08/$34.00 DOI:10.1016/j.jcmg.2008.04.003
Mitral Valve Prolapse A Deeper Look* Robert A. Levine, MD, FACC, Ronen Durst, MD Boston, Massachusetts
Two myths have been prevalent regarding heart valve disease: that the valves are simply mechanical flaps, and that the importance to the patient of regurgitation in particular relates almost entirely to ventricular function only. The paper in this issue of JACC: Cardiovascular Imaging by Han et al. (1) provides a more comprehensive picture that counterbalances these concepts. See page 294
The investigators set out to characterize mitral valve prolapse (MVP) by cardiovascular magnetic resonance (CMR) imaging, and found it could match the diagnostic sensitivity and specificity of transthoracic echocardiography. The 3-dimensional (3D) CMR image can be sectioned in a parallel series of long-axis views to analyze segmental anatomy and provide a “road map” for repair (2). There are several messages from this study pertinent to cardiovascular imaging: 1) Understanding the basic principles of image acquisition affects interpretation of results—CMR provides a blunted measure of leaflet thickness and, to a lesser extent, leaflet length, likely caused by a partial volume effect from surrounding blood pool. 2) Three-dimensional acquisitions achieve their maximum value by providing not only 3D images but also spatially registered 2D views to explore segmental anatomy, as displayed admirably by O’Gara et al. (3) for 3D transesophageal echocardiography in the March
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Cardiac Ultrasound Laboratory, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts. Supported in part by the Leducq Foundation Transatlantic Network of Excellence in Mitral Valve Disease, and by National Institutes of Health grants K24 HL67434 and R01 HL38176.
issue of JACC: Cardiovascular Imaging. The 3D acquisition has therefore contributed in many ways to our understanding of mitral valve disease, including improved diagnostic specificity, inspiration for annuloplasty ring design, and analysis of valve mechanics based on showing the 3D saddle shape of the valve (4 –10). A caveat is that the most useful segmental anatomy may be best derived from nonparallel views transecting the mitral coaptation line to intersect opposing central, medial, and lateral segments of both leaflets derived from a 3D scout view (3,11). The greatest novelty comes from the deeper and more profound look that CMR provides into the biology of the valve and its linked myocardium, made possible in part by a technological advance, the improved spatial resolution provided by 3D acquisition of images with delayed gadolinium (Gd) enhancement. Such enhancement occurs when the kinetics of Gd excretion is different in 2 adjacent compartments, so that over time, one compartment enhances more than the other. This has been a powerful tool for delineating infarcted and scarred myocardium, which excrete Gd slower than viable tissue (12–15). Han et al. (1) report frequently delayed Gd enhancement in both the mitral leaflets themselves and the papillary muscle (PM) tips in patients with MVP and not in control subjects. This complementary and unique tissue characterization requires further exploration, but indicates biological differences in both the valve tissue and the myocardium directly linked to it. Delayed Gd enhancement reinforces understanding of the myxomatous valve as one in which the processes of altered cell and extracellular matrix biology, normally quiescent in adult life, are reactivated (16,17). Noninvasive imaging may therefore be of value in confirming such intrinsic changes, with potential for strengthening phenotypic characterization in genetic studies of familial MVP
Levine and Durst Editorial Comment
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(18 –21) and monitoring response to therapies targeting hyperactive growth factor stimulation (22,23). The altered PM tip appearance in patients with MVP may provide insight into the intriguing question of ventricular arrhythmias in MVP and the occurrence of sudden death with elongated leaflets alone, even in the absence of important mitral regurgitation or heart failure (24 –27). The pathology literature also includes evidence for localized ventricular changes in patients with MVP (28 –30). We can speculate that the PM is altered by repetitive traction exerted by the prolapsing leaflets (Fig. 1) (31), which has been shown experimentally to lower the threshold for lethal arrhythmias (32). Mitral valve disease is therefore not a bystander but a primary actor in the entire clinical picture. We have recently recognized that mitral regurgitation plays an independent role in altering the biology of the remodeling ventricle after myocardial infarction (33,34), and strongly determines prognosis in the non-ischemic setting as well (35,36). This CMR study suggests a direct impact of the prolapsing valve on a ventricular structure. The PM damage may in turn exacerbate prolapse in a vicious cycle, potentially explaining the frequently observed but as yet unexplained mid to late systolic onset of leaflet displacement, characteristic of the yield stress phenomenon in mechanical engineering in response to a critical threshold overcoming a counteracting force (Ajit P. Yoganathan, PhD, personal communication, 1996). In summary, the study by Han et al. (1) reinforces a new way of thinking of standardizing cardiovascular imaging based on exploring 3D im-
1. Han Y, Peters DC, Salton CJ, et al. Cardiovascular magnetic resonance characterization of mitral valve prolapse. J Am Coll Cardiol Img 2008;1: 294 –303. 2. Foster GP, Isselbacher EM, Rose GA, et al. Accurate localization of mitral regurgitant defects using multiplane transesophageal echocardiography. Ann Thorac Surg 1998;65:1025–31. 3. O’Gara P, Sugeng L, Lang R, et al. The role of imaging in chronic degenerative mitral regurgitation. J Am Coll Cardiol Img 2008;1:221–37. 4. Levine RA, Triulzi MO, Harrigan P, Weyman AE. The relationship of mitral annular shape to the diagnosis of mitral valve prolapse. Circulation 1987;75:756 – 67. 5. Levine RA, Handschumacher MD, Sanfilippo AJ, et al. Three-dimensional
Figure 1. Papillary Muscle Traction in MVP Long-axis schematic of the left ventricle (LV), indicating linked parallel motion of the prolapsing mitral leaﬂets and papillary muscle tips. Figure illustration by Rob Flewell. AO ⫽ aorta; LA ⫽ left atrium.
ages in registered 2D views. It provides a deeper and more profound look into valve biology and the impact of valvular heart disease on the myocardium to which it is inseparably linked, with the potential to monitor, understand, and ultimately treat underlying pathophysiological mechanisms. Acknowledgment
The authors thank Shirley Sims for her expert editorial assistance and Mark Handschumacher for the figure. Reprint requests and correspondence: Dr. Robert A. Le-
vine, Massachusetts General Hospital, Cardiac Ultrasound Laboratory, Yawkey 5-068, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: [email protected]
echocardiographic reconstruction of the mitral valve, with implications for the diagnosis of mitral valve prolapse. Circulation 1989;80:589 –98. 6. Tibayan FA, Rodriguez F, Langer F, et al. Annular remodeling in chronic ischemic mitral regurgitation: ring selection implications. Ann Thorac Surg 2003;76:1549 –54. 7. Gorman JH 3rd, Jackson BM, Enomoto Y, Gorman RC. The effect of regional ischemia on mitral valve annular saddle shape. Ann Thorac Surg 2004;77:544 – 8. 8. Watanabe N, Ogasawara Y, Yamaura Y, et al. Mitral annulus flattens in ischemic mitral regurgitation: geometric differences between inferior and anterior myocardial infarction: a real-time 3-dimensional echocardiographic study. Circulation 2005;112 Suppl:I458 – 62.
9. Jimenez JH, Liou SW, Padala M, et al. A saddle-shaped annulus reduces systolic strain on the central region of the mitral valve anterior leaflet. J Thorac Cardiovasc Surg 2007;134:1562– 8. 10. Salgo IS, Gorman JH 3rd, Gorman RC, et al. Effect of annular shape on leaflet curvature in reducing mitral leaflet stress. Circulation 2002;106: 711–7. 11. Carpentier A. Cardiac valve surgery: the “French correction.” J Thorac Cardiovasc Surg 1983;86:323–37. 12. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999;100:1992–2002. 13. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000;343:1445–53.
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14. Lipton MJ, Bogaert J, Boxt LM, Reba RC. Imaging of ischemic heart disease. Eur Radiol 2002;12:1061– 80. 15. Rozenshtein A, Boxt LM. Computed tomography and magnetic resonance imaging of patients with valvular heart disease. J Thorac Imaging 2000;15: 252– 64. 16. Rabkin E, Aikawa M, Stone JR, et al. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 2001;104: 2525–32. 17. Rabkin-Aikawa E, Farber M, Aikawa M, Schoen FJ. Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves. J Heart Valve Dis 2004;13: 841–7. 18. Disse S, Abergel E, Berrebi A, et al. Mapping of a first locus for autosomal dominant myxomatous mitral-valve prolapse to chromosome 16p11.2p12.1. Am J Hum Genet 1999;65: 1242–51. 19. Freed LA, Acierno JS Jr., Dai D, et al. A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4. Am J Hum Genet 2003;72: 1551–9. 20. Nesta F, Leyne M, Yosefy C, et al. New locus for autosomal dominant mitral valve prolapse on chromosome 13: clinical insights from genetic studies. Circulation 2005;112:2022–30. 21. Kyndt F, Gueffet JP, Probst V, et al. Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. Circulation 2007; 115:40 –9.
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22. Ng CM, Cheng A, Myers LA, et al. TGF-␤-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest 2004;114:1586 –92. 23. Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117–21. 24. Kligfield P, Levy D, Devereux RB, Savage DD. Arrhythmias and sudden death in mitral valve prolapse. Am Heart J 1987;113:1298 –307. 25. Duren DR, Becker AE, Dunning AJ. Long-term follow-up of idiopathic mitral valve prolapse in 300 patients: a prospective study. J Am Coll Cardiol 1988;11:42–7. 26. Grigioni F, Enriquez-Sarano M, Ling LH, et al. Sudden death in mitral regurgitation due to flail leaflet. J Am Coll Cardiol 1999;34:2078 – 85. 27. Farb A, Tang AL, Atkinson JB, McCarthy WF, Virmani R. Comparison of cardiac findings in patients with mitral valve prolapse who die suddenly to those who have congestive heart failure from mitral regurgitation and to those with fatal noncardiac conditions. Am J Cardiol 1992;70:234 –9. 28. Morales AR, Romanelli R, Boucek RJ, et al. Myxoid heart disease: an assessment of extravalvular cardiac pathology in severe mitral valve prolapse. Hum Pathol 1992;23:129 –37. 29. Dollar AL, Roberts WC. Morphologic comparison of patients with mitral valve prolapse who died suddenly with patients who died from severe valvular dysfunction or other condi-
tions. J Am Coll Cardiol 1991;17: 921–31. 30. La Vecchia L, Ometto R, Centofante P, et al. Arrhythmic profile, ventricular function, and histomorphometric findings in patients with idiopathic ventricular tachycardia and mitral valve prolapse: clinical and prognostic evaluation. Clin Cardiol 1998;21: 731–5. 31. Sanfilippo AJ, Harrigan P, Popovic AD, Weyman AE, Levine RA. Papillary muscle traction in mitral valve prolapse: quantitation by two-dimensional echocardiography. J Am Coll Cardiol 1992;19:564 –71. 32. Gornick CC, Tobler HG, Pritzker MC, et al. Electrophysiologic effects of papillary muscle traction in the intact heart. Circulation 1986;73: 1013–21. 33. Beeri R, Yosefy C, Guerrero JL, et al. Mitral regurgitation augments postmyocardial infarction remodeling: failure of hypertrophic compensation. J Am Coll Cardiol 2008;51:476 – 86. 34. Beeri R, Yosefy C, Guerrero JL, et al. Early repair of moderate ischemic mitral regurgitation reverses left ventricular remodeling: a functional and molecular study. Circulation 2007;116:I288 –93. 35. Ling LH, Enriquez-Sarano M, Seward JB, et al. Clinical outcome of mitral regurgitation due to flail leaflet. N Engl J Med 1996;335:1417–23. 36. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352:875– 83.