MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells.

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.

Antidote-mediated control of an anticoagulant aptamer in vivo.

Patient safety and treatment outcome could be improved if physicians could rapidly control the activity of therapeutic agents in their patients. Antidote control is the safest way to regulate drug activity, because unlike rapidly clearing drugs, control of the drug activity is independent of underlying patient physiology and co-morbidities. Until recently, however, there was no general method to discover antidote-controlled drugs. Here we demonstrate that the activity and side effects of a specific class of drugs, called aptamers, can be controlled by matched antidotes in vivo. The drug, an anticoagulant aptamer, systemically induces anticoagulation in pigs and inhibits thrombosis in murine models. The antidote rapidly reverses anticoagulation engendered by the drug, and prevents drug-induced bleeding in surgically challenged animals. These results demonstrate that rationally designed drug-antidote pairs can be generated to provide control over drug activities in animals.

Elongation of chordae tendineae as an adaptive process to reduce mitral regurgitation in functional mitral regurgitation.

AIMS: In functional mitral regurgitation (FMR), increased leaflet area has been described as a remodelling compensatory mechanism. We hypothesized that chordae tendineae elongation would also occur as part of this remodelling. In this study, the lengths of primary chords and measurements of mitral leaflets and annulus were compared with varying degrees of mitral regurgitation (MR). METHODS AND RESULTS: We studied 58 patients who underwent three-dimensional (3D) transoesophageal echocardiography, including 38 with FMR and 20 with normal mitral valves (NL). The FMR group was divided into two subgroups according to two-dimensional vena contracta width (VCW). Three-dimensional datasets from transgastric or mid-oesophageal approach were used to measure primary chordal length, coaptation length, inter-papillary muscle distances, and quantitative 3D measurements of the annulus and leaflets. Leaflet surface area was increased and coaptation length was decreased in FMR compared with NL. While no difference in other 3D measurement of annulus/leaflets was noted between the FMR subgroups, averaged chordal length was shorter in patients with more severe FMR. Chords of the anterior leaflet in FMR with larger VCW were shorter compared with both NL and FMR with smaller VCW. In contrast, the chords of the posterior leaflet were longer in FMR with smaller VCW compared with the other two groups. CONCLUSION: Our results suggest the posterior leaflet chords possibly remodel by elongating and contribute to reduced MR and that in a subgroup of FMR patients, the primary chords may remodel by shortening, resulting in augmented MR. This information could be useful in choosing strategy for FMR correction.

Visualization and measurement of mitral valve chordae tendineae using three-dimensional transesophageal echocardiography from the transgastric approach.

BACKGROUND: The evaluation of the submitral apparatus is challenging from the conventional transesophageal approach. The aim of this study was to test the feasibility of using three-dimensional (3D) transesophageal echocardiographic (TEE) imaging from the transgastric approach to visualize the submitral apparatus and quantify the lengths of the chordae tendineae by using multiplanar reconstruction analysis. METHODS: Twenty-two patients who had transgastric full-volume 3D TEE data sets before mitral valve surgery underwent surgical measurement of chordal length. A short-axis plane at the chordal level was extracted from the 3D data set to identify leaflet segments and the corresponding primary chords. Then, for each chord, the optimal plane was selected to visualize and measure the entire chordal length from its origin at the leaflet margin to the papillary muscle tips. Measurements were performed at the phase of the cardiac cycle when chordal length reached its maximum. Measured values were compared with surgical measurements using linear regression and Bland-Altman analyses. RESULT: One hundred forty-six primary chords were measured intraoperatively. Three-dimensional TEE imaging was able to measure the lengths of all these chords. The surgical and 3D TEE measurements (mean, 1.96 ± 0.56 vs 1.93 ± 0.50 cm, respectively) correlated highly (r = 0.93, P < .0001), with a minimal bias of 0.03 cm and narrow limits of agreement from -0.39 to 0.45 cm. CONCLUSION: Transgastric 3D TEE imaging of the submitral apparatus allows visualization and accurate measurement of chordae tendineae lengths, which may be useful for planning mitral valve repair, including percutaneous transcatheter procedures.

Leaflet-chordal relations in patients with primary and secondary mitral regurgitation.

BACKGROUND: The strategy for mitral valve (MV) repair has recently focused on the restoration of the submitral apparatus. However, the relationship between geometric changes of the submitral apparatus and the mitral leaflets has not been systematically investigated. The aim of this study was to determine the relationships among chordal length (CL) and LV size and leaflet surface area (LSA) in normal subjects, patients with primary (degenerative) mitral regurgitation (PMR), and patients with functional (secondary) mitral regurgitation (FMR). METHODS: A total of 72 patients who underwent three-dimensional transesophageal echocardiography, including: 27 with PMR with isolated P2 flail leaflet, 25 with FMR with greater than mild mitral regurgitation, and 20 with normal mitral valves. LSA was quantified at midsystole from full-volume midesophageal views. CL was calculated by averaging the lengths of eight primary chords from transgastric full-volume data sets using multiplanar reconstruction. RESULTS: Both CL and LSA in the PMR group were significantly longer compared with the FMR and normal control groups. No difference in CL was noted between patients with FMR and normal subjects. In all three groups, CL and LSA did not correlate with LV systolic or diastolic dimensions. Although CL did not correlate with LSA in the FMR group, a moderate correlation (R = 0.62) was observed in the PMR group. CONCLUSIONS: In patients with FMR with greater than mild mitral regurgitation, the chords retain normal length, despite LSA and LV enlargement. In patients with PMR with flail P2 scallops, CL elongation of primary chords is associated with larger LSA but not with LV dimensions. This information may have implications for clinical strategies for mitral valve repair surgery, including the submitral approach and percutaneous procedures.