Divulgação do autor: Os autores desse artigo não relataram nenhum conflito de interesse atual ou potencial em relação a essa atividade. Os autores e revisores RVT, FASE; Farooq A. Chaudhry, MD, FASE; Robert T. Eberhardt, MD; Benjamin W. Eidem, MD, FASE; Gregory J.Ensing, MD, FASE; Tal Geva, MD, FASE; Kathryn E. Glas, MD, FASE; Sandra Hagen-Ansert, RDCS, RDMS,MS, FASE; Rebecca T. Hahn, MD, FASE; Jeannie Heirs, RDCS; Shunichi Homma, MD; Sanjiv Kaul, MD,FASE; Smadar Kort, MD, FASE; Peg Knoll, RDCS, FASE; Wyman Lai, MD, MPH, FASE; Roberto M. Lang,MD, FASE; Steven Lavine, MD; Steven J. Lester, MD, FASE; Renee Margossian, MD; Victor Mor-Avi,PhD, FASE; Sherif Nagueh, MD, FASE; Alan S. Pearlman, MD, FASE; Patricia A. Pellikka, MD, FASE; MiguelQuinones, MD, FASE; Brad Roberts, RCS, RDCS; Beverly Smulevitz, BS, RDCS, RVS; Kirk T. Spencer,MD, FASE; J. Geoffrey Stevenson, MD, FASE; Wadea Tarhuni, MD, FASE; James D. Thomas, MD; Neil J.Weissman, MD, FASE; Timothy Woods, MD; and William A. Zoghbi, MD, FASE. Os
Background: In patients with myocardial infarction (MI) or left ventricular (LV) dilatation, mitral regurgitation (MR) is frequently induced by leaflet tethering imposed by displaced papillary muscles (PMs), and doubles mortality. Despite this, little is known about mitral valve (MV) tissue biology and its potential to compensate for LV remodeling, which has not yet been studied prospectively. We tested the hypothesis that MV area increases over time with mechanical stretch induced by PM displacement, and as a consequence of cell activation and matrix production as opposed to passive stretching. Methods: Under cardiopulmonary bypass, the PM tips in 6 adult sheep were retracted apically short of producing MR to replicate tethering without confounding MI or turbulence. Diastolic MV leaflet area (without systolic stretch) was quantified by a new validated 3D echo algorithm at baseline and after 61±6 days, and MV tissue collected for histology (H&E, Masson) and fluorescent cell sorting at sacrifice. Data were compared with 6 unstretched sheep MVs. Results: Total diastolic MV leaflet area increased by 2.4±1.3cm2 (17±10%) from 14.3±1.9cm2 to 16.7±1.9cm2 (p<0.01) with maintained stretch, without significant change in unstretched valves despite sham open-heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18±0.43 vs 0.42±0.14mm, p<0.01) due to increased spongiosa layer. Endothelial cells (CD31+) also expressing alpha-smooth muscle actin (α-SMA) were significantly more common by cell sorting in tethered versus normal leaflets (41±19% vs 9±5%, p=0.02), indicating endothelial-mesenchymal transdifferentiation (EMT); α-SMA+ positive cells indicating activation/EMT appeared in the high-stress atrial layer, penetrating into the valve interstitium, with increased collagen deposition, all absent normally. Conclusion: Mechanical stresses imposed by PM tethering increase MV leaflet area and matrix thickness, with cellular changes suggestive of reactivated embryonic valve development pathways. These findings support the concept of an actively adapting MV; understanding adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic MR.
Background-Mitral regurgitation (MR) doubles mortality after myocardial infarction (MI). We have demonstrated thatMR worsens remodeling after MI and that early correction reverses remodeling. Sarcoplasmic reticulum Ca ϩ2 -ATPase (SERCA2a) is downregulated in this process. We hypothesized that upregulating SERCA2a might inhibit remodeling in a surgical model of apical MI (no intrinsic MR) with independent MR-type flow. Methods and Results-In 12 sheep, percutaneous gene delivery was performed by using a validated protocol to perfuse both the left anterior descending and circumflex coronary arteries with occlusion of venous drainage. We administered adeno-associated virus 6 (AAV6) carrying SERCA2a under a Cytomegalovirus promoter control in 6 sheep and a reporter gene in 6 controls. After 2 weeks, a standardized apical MI was created, and a shunt was implanted between the left ventricle and left atrium, producing regurgitant fractions of Ϸ30%. Animals were compared at baseline and 1 and 3 months by 3D echocardiography, Millar hemodynamics, and biopsies. The SERCA2a group had a wellmaintained preload-recruitable stroke work at 3 months (decrease by 8Ϯ10% vs 42Ϯ12% with reporter gene controls; PϽ0.001). Left ventricular dP/dt followed the same pattern (no change vs 55% decrease; PϽ0.001). Left ventricular end-systolic volume was lower with SERCA2a (82.6Ϯ9.6 vs 99.4Ϯ9.7 mL; Pϭ0.03); left ventricular end-diastolic volume, reflecting volume overload, was not significantly different (127.8Ϯ6.2 vs 134.3Ϯ9.4 mL). SERCA2a sheep showed a 15% rise in antiapoptotic pAkt versus a 30% reduction with the reporter gene (PϽ0.001). Prohypertrophic activated STAT3 was also 41% higher with SERCA2a than in controls (PϽ0.001). Proapoptotic activated caspase-3 rose Ͼ5-fold during 1 month in both SERCA2a and control animals (PϭNS) and decreased by 19% at 3 months, remaining elevated in both groups. Conclusions-In this controlled model, upregulating SERCA2a induced better function and lesser remodeling, with improved contractility, smaller volume, and activation of prohypertrophic/antiapoptotic pathways. Although caspase-3 remained activated in both groups, SERCA2a sheep had increased molecular antiremodeling "tone." We therefore conclude that upregulating SERCA2a inhibits MR-induced post-MI remodeling in this model and thus may constitute a useful approach to reduce the vicious circle of remodeling in ischemic MR. (Circ Heart Fail. 2010;3:627-634.)
Functional mitral regurgitation (FMR) is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about how chronic tethering affects leaflet area, in part because of inability to reconstruct leaflet area in situ. Our aim was to do so in order to explore whether adaptive increases occur that meet the needs of tethered geometry in FMR, and to test the hypothesis that leaflet area influences MR. Methods and Results. A new method for 3D echo measurement of mitral leaflet area was developed and validated in vivo against sheep valves, later excised. This method was used to study 80 consecutive patients in 3 groups: patients with normal hearts (n=20); with FMR (n=29) from inferior wall motion abnormality (IWMA) or dilated cardiomyopathy (DCM); and with IWMA or DCM but no MR (n=31). Patients with FMR had 23±5% increased leaflet area compared with normal subjects. The ratio of leaflet to annular area was 1.95±0.40, not different among groups (figure ), indicating a surplus leaflet area that adapts to left heart changes. In contrast, the ratio of total leaflet area to that required to close the orifice in mid-systole was decreased in patients with FMR versus normal (1.29±0.15 vs 1.78±0.39, p=0.001) and versus patients with IWMA or DCM but no MR (1.81±0.38, p=0.001). After adjusting for measures of LV remodeling and tethering, a leaflet-to-closure area ratio <1.7 was associated with significant MR (OR=23.2, p=0.02). Conclusion. Mitral leaflet area increases in response to chronic tethering in patients with IWMA and DCM. However, the adequacy of leaflet adaptation to tethering geometry varies, and may partly explain the heterogeneity of FMR among patients.
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