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LV dysfunction without dilatation fails to produce important MR. Functional MR relates strongly to changes in the 3D geometry of the mitral valve attachments at the PM and annular levels, with practical implications for approaches that would restore a more favorable configuration.

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

Mitral valve prolapse has been diagnosed by two-dimensional echocardiographic criteria with surprising frequency in the general population, even when preselected normal subjects are examined. In most of these individuals, however, prolapse appears in the apical four-chamber view and is absent in roughly orthogonal long-axis views. Previous studies of in vitro models with nonplanar rings have shown that systolic mitral annular nonplanarity can potentially produce this discrepancy. However, to prove directly that apparent leaflet displacement in a two-dimensional view does not constitute true displacement above the three-dimensional annulus requires reconstruction of the entire mitral valve, including leaflets and annulus. Such reconstruction would also be necessary to explore the complex geometry of the valve and to derive volumetric measures of superior leaflet displacement. A technique was therefore developed and validated in vitro for three-dimensional reconstruction of the entire mitral valve. In this technique, simultaneous real-time acquisition of images and their spatial locations permits reconstruction of a localized structure by minimizing the effects of patient motion and respiration. By applying this method to 15 normal subjects, a coherent mitral valve surface could be reconstructed from intersecting scans. The results confirm mitral annular nonplanarity in systole, with a maximum deviation of 1.490.3 cm from planarity. They directly show that leaflets can appear to ascend above the mitral annulus in the apical four-chamber view, as they did in at least one view in all subjects, without actual leaflet displacement above the entire mitral valve in three dimensions, thereby challenging the diagnosis of prolapse by isolated fourchamber view displacement in otherwise normal individuals. This technique allows us to address a uniquely three-dimensional problem with high resolution and provide new information previously unavailable from the two-dimensional images. This new appreciation should enhance our ability to ask appropriate clinical questions relating mitral valve shape and leaflet displacement to clinical and pathologic consequences. (Circulation 1989;80:589-598) irat valve prolapse, initially believed to be uncommon,' has evolved into a pervasive clinical problem.2'3 Based on a variety of criteria, it can be diagnosed in a disturbingly high proportion of individuals from the general population, many of whom are otherwise normal2-8 but who are nevertheless given an uncertain prognosis that includes endocarditis, stroke, and sudden death.1,9-11To resolve this confusion requires a return to basic definitions. Prolapse is the displacement of a bodily part from its normal position or relations.12

Segmental ischemic LV contractile dysfunction without dilation, even in the PM territory, fails to produce important MR. The development of MR relates strongly to changes in the 3D geometry of the mitral apparatus, with implications for approaches to restore a more favorable configuration.

Background-Tricuspid regurgitation (TR) is an important predictor of morbidity and mortality in heart failure. We aimed to examine the 3D geometry of the tricuspid valve annulus (TVA) in patients with functional TR, comparing them with patients with normal tricuspid valve function and relating annular geometric changes to functional TR. Methods and Results-TVA shape was examined by real-time 3D echocardiography in 75 patients: 35 with functional TR and 40 with normal tricuspid valve function (referent group). The 3D shape of the TVA was reconstructed from rotated 2D planes, and the annular plane was computed by least-squares fitting. Annular area and mediolateral, anteroposterior, and high (superior)-low (inferior) distances were calculated. TR was assessed by vena contracta width. The normal TVA has a bimodal pattern (high-low distanceϭ7.23Ϯ1.05 mm). High points were located anteroposteriorly, and low points were located mediolaterally. With moderate or greater TR (vena contracta width 5.80Ϯ2.62 mm), the TVA became dilated (17.24Ϯ4.75 versus 9.83Ϯ2.18 cm 2 , PϽ0.0001, TR versus referent), more planar with decreased high-low distance (4.14Ϯ1.05 mm), and more circular with decreased ratio of mediolateral/anteroposterior (1.11Ϯ0.09 versus 1.32Ϯ0.09, PϽ0.0001, TR versus referent). Conclusions-The normal TVA has a bimodal shape with distinct high points located anteroposteriorly and low points located mediolaterally. With functional TR, the annulus becomes larger, more planar, and circular. These changes in annular shape with TR have potentially important mechanistic and therapeutic implications for tricuspid valve repair.

Background-In patients with left ventricular infarction or dilatation, leaflet tethering by displaced papillary muscles frequently induces mitral regurgitation, which doubles mortality. Little is known about the biological potential of the mitral valve (MV) to compensate for ventricular remodeling. We tested the hypothesis that MV leaflet surface area increases over time with mechanical stretch created by papillary muscle displacement through cell activation, not passive stretching. Methods and Results-Under cardiopulmonary bypass, the papillary muscle tips in 6 adult sheep were retracted apically short of producing mitral regurgitation to replicate tethering without confounding myocardial infarction or turbulence. Diastolic leaflet area was quantified by 3-dimensional echocardiography over 61Ϯ6 days compared with 6 unstretched sheep MVs. Total diastolic leaflet area increased by 2.4Ϯ1.3 cm 2 (17Ϯ10%) from 14.3Ϯ1.9 to 16.7Ϯ1.9 cm 2 (Pϭ0.006) with stretch with no change in the unstretched valves despite sham open heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18Ϯ0.14 versus 0.42Ϯ0.14 mm; PϽ0.0001) at 60 days with an increased spongiosa layer. Endothelial cells (CD31 ϩ ) coexpressing ␣-smooth muscle actin were significantly more common by fluorescent cell sorting in tethered versus normal leaflets (41Ϯ19% versus 9Ϯ5%; Pϭ0.02), indicating endothelial-mesenchymal transdifferentiation. ␣-Smooth muscle actin-positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial ␣-smooth muscle actin. Endothelial-mesenchymal transdifferentiation capacity also was demonstrated in cultured MV endothelial cells. Conclusions-Mechanical stresses imposed by papillary muscle tethering increase MV leaflet area and thickness, with cellular changes suggesting reactivated embryonic developmental pathways. Understanding such actively adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic mitral regurgitation. (Circulation. 2009;120:334-342.)Key Words: echocardiography Ⅲ mitral valve Ⅲ valves I n population studies, valvular heart disease is common, with mitral regurgitation (MR) most prevalent. 1 Although degeneration is the leading cause of MR surgical repair, 2 coronary artery disease with myocardial infarction and left ventricular (LV) dysfunction frequently causes functional MR as a result of global LV remodeling and sphericity 3-5 or localized inferoposterior wall remodeling 6 -12 ; both cause apical, posterior, and outward displacement of the papillary muscles (PMs) 6 -12 and mitral valve (MV) leaflet tethering 13 that prevents effective closure ( Figure 1A and 1B). 12,14 Editorial see p 275 Clinical Perspective on p 342Patients who develop MR after myocardial infarction or with congestive heart failure, even after surgical or catheter revascularization, have doubled mortality and in- To observe leaflet adaptation to tethering over time, we asse...

Background-Mechanistic insights from 3D echocardiography (echo) can guide therapy. In particular, ischemic mitral regurgitation (MR) is difficult to repair, often persisting despite annular reduction. We hypothesized that (1) in a chronic infarct model of progressive MR, regurgitation parallels 3D changes in the geometry of mitral leaflet attachments, causing increased leaflet tethering and restricting closure; therefore, (2) MR can be reduced by restoring tethering geometry toward normal, using a new ventricular remodeling approach based on 3D echo findings. Methods and Results-We studied 10 sheep by 3D echo just after circumflex marginal ligation and 8 weeks later. MR, at first absent, became moderate as the left ventricle (LV) dilated and the papillary muscles shifted posteriorly and mediolaterally, increasing the leaflet tethering distance from papillary muscle tips to the anterior mitral annulus (PϽ0.0001). To counteract these shifts, the LV was remodeled by plication of the infarct region to reduce myocardial bulging, without muscle excision or cardiopulmonary bypass. Immediately and up to 2 months after plication, MR was reduced to trace-to-mild as tethering distance was decreased (PϽ0.0001). LV ejection fraction, global LV end-systolic volume, and mitral annular area were relatively unchanged. By multiple regression, the only independent predictor of MR was tethering distance (r 2 ϭ0.81). Conclusions-Ischemic MR in this model relates strongly to changes in 3D mitral leaflet attachment geometry. These insights from quantitative 3D echo allowed us to design an effective LV remodeling approach to reduce MR by relieving tethering.