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Background: After myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth, but counterproductive leaflet thickening and fibrosis augment mitral regurgitation (MR), doubling heart failure and mortality. MV fibrosis post-MI is associated with excessive endothelial-to-mesenchymal transition (EMT), driven by transforming growth factor (TGF)-β overexpression. In vitro, losartan-mediated TGF-β inhibition reduces EMT of MV endothelial cells.Objectives: This study tested the hypothesis that profibrotic MV changes post-MI are therapeutically accessible, specifically by losartan-mediated TGF-β inhibition.Methods: The study assessed 17 sheep, including 6 sham-operated control animals and 11 with apical MI and papillary muscle retraction short of producing MR; 6 of the 11 were treated with daily losartan, and 5 were untreated, with flexible epicardial mesh comparably limiting left ventricular (LV) remodeling. LV volumes, tethering, and MV area were quantified by using three-dimensional echocardiography at baseline and at 60 ± 6 days, and excised leaflets were analyzed by histopathology and flow cytometry.Results: Post-MI LV dilation and tethering were comparable in the losartan-treated and untreated LV constraint sheep. Telemetered sensors (n = 6) showed no significant losartan-induced changes in arterial pressure. Losartan strongly reduced leaflet thickness (0.9 ± 0.2 mm vs. 1.6 ± 0.2 mm; p < 0.05; 0.4 ± 0.1 mm sham animals), TGF-β, and downstream phosphorylated extracellular-signal-regulated kinase and EMT (27.2 ± 12.0% vs. 51.6 ± 11.7% α-smooth muscle actin-positive endothelial cells, p < 0.05; 7.2 ± 3.5% sham animals), cellular proliferation, collagen deposition, endothelial cell activation (vascular cell adhesion molecule-1 expression), neovascularization, and cells positive for cluster of differentiation (CD) 45, a hematopoietic marker associated with post-MI valve fibrosis. Leaflet area increased comparably (17%) in constrained and losartan-treated sheep.Conclusions: Profibrotic changes of tethered MV leaflets post-MI can be modulated by losartan without eliminating adaptive growth. Understanding the cellular and molecular mechanisms could provide new opportunities to reduce ischemic MR. [ABSTRACT FROM AUTHOR]

Background: In patients with myocardial infarction (MI), leaflet tethering by displaced papillary muscles induces mitral regurgitation (MR), which doubles mortality. Mitral valves (MVs) are larger in such patients but fibrosis sets in counterproductively. The investigators previously reported that experimental tethering alone increases mitral valve area in association with endothelial-to-mesenchymal transition.Objectives: The aim of this study was to explore the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies mitral valve adaptation.Methods: Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the papillary muscle tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered alone). Papillary muscle retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered plus MI), and left ventricular remodeling was limited by external constraint in 5 additional sheep (left ventricular constraint). Six sham-operated sheep were control subjects. Diastolic mitral valve surface area was quantified by 3-dimensional echocardiography at baseline and after 58 ± 5 days, followed by histopathology and flow cytometry of excised leaflets.Results: Tethered plus MI leaflets were markedly thicker than tethered-alone valves and sham control subjects. Leaflet area also increased significantly. Endothelial-to-mesenchymal transition, detected as α-smooth muscle actin-positive endothelial cells, significantly exceeded that in tethered-alone and control valves. Transforming growth factor-β, matrix metalloproteinase expression, and cellular proliferation were markedly increased. Uniquely, tethering plus MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered plus MI findings were comparable with external ventricular constraint.Conclusions: MI altered leaflet adaptation, including a profibrotic increase in valvular cell activation, CD45-positive cells, and matrix turnover. Understanding cellular and molecular mechanisms underlying leaflet adaptation and fibrosis could yield new therapeutic opportunities for reducing ischemic MR. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background-Undersized ring annuloplasty for ischemic mitral regurgitation (MR) is associated with variable results and >30% MR recurrence. We tested whether subvalvular repair by severing second-order mitral chordae can improve annuloplasty by reducing papillary muscle tethering. Methods and Results-Posterolateral myocardial infarction known to produce chronic remodeling and MR was created in 28 sheep. At 3 months, sheep were randomized to sham surgery versus isolated undersized annuloplasty versus isolated bileaflet chordal cutting versus the combined therapy (n = 7 each). At baseline, chronic myocardial infarction (3 months), and euthanasia (6.6 months), we measured left ventricular (LV) volumes and ejection fraction, wall motion score index, MR regurgitation fraction and vena contracta, mitral annulus area, and posterior leaflet restriction angle (posterior leaflet to mitral annulus area) by 2-dimensional and 3-dimensional echocardiography. All groups were comparable at baseline and chronic myocardial infarction, with mild to moderate MR (MR vena contracta, 4.6±0.1 mm; MR regurgitation fraction, 24.2±2.9%) and mitral annulus dilatation (P<0.01). At euthanasia, MR progressed to moderate to severe in controls but decreased to trace with ring plus chordal cutting versus trace to mild with chordal cutting alone versus mild to moderate with ring alone (MR vena contracta, 5.9±1.1 mm in controls, 0.5±0.08 with both, 1.0±0.3 with chordal cutting alone, 2.0±0.4 with ring alone; P<0.01). In addition, LV end-systolic volume increased by 108% in controls versus 28% with ring plus chordal cutting, less than with each intervention alone (P<0.01). In multivariate analysis, LV end-systolic volume and mitral annulus area most strongly predicted MR (r2=0.82, P<0.01). Conclusions-Comprehensive annular and subvalvular repair improves long-term reduction of both chronic ischemic MR and LV remodeling without decreasing global or segmental LV function at follow-up [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Little is known regarding the mechanisms, the feasibility and the long-term results of re-repair in ‘posterior failure’ of a previous mitral valve repair performed for severe degenerative mitral regurgitation. We report our 16-year experience in redo surgery for late posterior failure of mitral valve repair in degenerative disease. Methods: From 1991 to 2004, 13 consecutive patients (10 males; median age: 65 years) were reoperated for late posterior failure of mitral valve repair. All patients had grade ≥3+ mitral regurgitation. Repair was mainly performed using Carpentier''s techniques. Results: Repair failure was due to posterior leaflet prolapse, leaflet retraction or leaflet dehiscence in eight (62%), three (23%) and two (15%) patients, respectively. Repair was performed in nine patients (69%). There was no perioperative death. During follow-up (median: 105 months; range: 40–170 months) one late death occurred in the mitral valve replacement group. One (11%) patient underwent mechanical mitral valve replacement 125 months after re-repair. Congestive heart failure occurred in one patient in each group. At the latest follow-up, all but one patient in the mitral valve repair group were in NYHA functional class I or II and all were in sinus rhythm. Doppler echocardiographic studies of the re-repaired valves (n =8) showed no or trivial, grade 1+ and grade 2+ residual mitral regurgitation in 6 (75%), 1 and 1 patients, respectively. Mean transmitral gradient was 3mmHg (2–8mmHg) and left ventricular ejection fraction was 59% (43–77%). Conclusion: In case of late posterior failure of mitral valve repair for severe degenerative, re-repair is feasible in about 70% of the patients with encouraging results at 10 years. [Copyright &y& Elsevier]

Objectives: This study was designed to assess whether post-myocardial infarction (MI) in-scar transplantation of skeletal myoblasts (SM) could reduce chronic ischemic mitral regurgitation (MR) by decreasing left ventricular (LV) remodeling. Background: Extensive work has confirmed the relationship between ischemic MR and post-myocardial infarction (MI) remodeling of the LV. Methods: An infero-posterior MI was created in 13 sheep, thereby resulting in increasing MR. Two months post-MI, the animals were randomized and in-scar injected with expanded autologous SM (n = 6, mean: 251 × 106 cells) or culture medium only (n = 7). Three-dimensional echocardiography was performed at baseline, before transplantation, and for two months thereafter (sacrifice), with measurements of LV end-diastolic and end-systolic volumes (ESV), ejection fraction (EF), MR stroke volume, and leaflet tethering distance; wall motion score index (WMSi) was assessed by two-dimensional echo. Results: Measurements were similar between groups at baseline and before transplantation. At sacrifice, transplantation was found to have reduced MR progression (regurgitant volume change: −1.83 ± 0.32 ml vs. 5.9 ± 0.7 ml in control group, p < 0.0001) and tethering distance (−0.41 ± 0.09 cm vs. 0.44 ± 0.12 cm in control group, p < 0.001), with significant improvement of EF (2.01 ± 0.94% vs. −4.86 ± 2.23%, p = 0.02), WMSi (−0.25 ± 0.11 vs. 0.13 ± 0.03 in controls, p < 0.01) and a trend to a lesser increase in ESV (23.3 ± 3.5 ml vs. 35.4 ± 4.2 ml in control group, p = 0.055). Conclusions: Autologous skeletal myoblast transplantation attenuates mild-to-moderate chronic ischemic MR, which otherwise is progressive, by decreasing tethering distance and improving EF and wall motion score, thereby enhancing valve coaptation. These data shed additional light on the mechanism by which skeletal myoblast transplantation may be cardioprotective. [Copyright &y& Elsevier]

This study examines the incidence, predictors, and evolution of postoperative atrioventricular block (AVB) after mitral valve repair (MVR) in 115 consecutive patients using Carpentier’s technique (between November 1996 and April 1997). Postoperative AVB occurred in 27 patients (23%). Third-degree AVB was found in 7 patients (6%) in the immediate postoperative period, but in 4 it was transient, resolving partially or completely before the seventh postoperative day. Second-degree AVB (Mobitz type I) occurred in 4 patients (3%) immediately after operation and resolved in all before hospital discharge. Isolated first-degree AVB occurred in 16 patients (14%) and was permanent in 12. Neither the preoperative variables nor the mitral procedures including anterior versus posterior leaflet repair were related to postoperative AVB. A lesser systemic hypothermia during surgery was the only, modestly independent predictor of postoperative AVB (odds ratio 1.53; 95% confidence interval 1.04 to 2.25; p = 0.031). Three patients (2.6%) had permanent pacemaker implantation, on average 18 days after operation, and all had persistent third-degree AVB. With a mean follow-up of 3 years, no recurrence or worsening of conduction disturbances, no further pacemaker implantation, and no late deaths were observed. [Copyright &y& Elsevier]