Echocardiographic predictors of single versus dual MitraClip device implantation and long-term reduction of mitral regurgitation after percutaneous repair.

OBJECTIVES: To describe predictors of the number of MitraClip devices implanted during percutaneous repair of mitral regurgitation (MR), and the long-term reduction in MR. BACKGROUND: In the EVEREST trials, one or two MitraClip devices were implanted to reduce MR, as needed. METHODS: Preprocedural transthoracic echocardiograms (TTE) and transesophageal echocardiograms (TEE) of 233 subjects who received 1 or 2 MitraClip devices in the EVEREST II Randomized Trial and High-Risk Study were analyzed. TEEs were reviewed for etiology of MR and pathoanatomic features of the valve, valve apparatus, and the regurgitant jet. Follow-up MR was assessed by TTE postprocedure and at 12 months. RESULTS: Ninety-seven subjects (42%) had two MitraClip devices implanted. Subjects with quantitatively more severe MR were more likely to receive two devices [mean regurgitant volume (RV) 45.9 ± 21.9 vs. 36.3 ± 18.5 mL, P <0.001]. On multivariate analysis, increased anterior leaflet thickness (OR 1.7 per mm, P = 0.007) and greater baseline RV (OR 1.21 per 10 mL, P = 0.01) were associated with increased odds of implanting two devices. The frequency of 2+ MR or less at discharge was similar regardless of the number of devices implanted. After propensity matching, patients had quantitatively similar MR at twelve-month follow-up, regardless of whether one or two MitraClip devices were implanted (P = 0.6). CONCLUSIONS: Subjects with thicker anterior mitral leaflets and more severe MR were more likely to receive two MitraClip devices. Immediate and long-term reduction in MR was similar regardless of the number of devices implanted at the time of the procedure.

The organization of the transcriptional network in specific neuronal classes.

Genome-wide expression profiling has aided the understanding of the molecular basis of neuronal diversity, but achieving broad functional insight remains a considerable challenge. Here, we perform the first systems-level analysis of microarray data from single neuronal populations using weighted gene co-expression network analysis to examine how neuronal transcriptome organization relates to neuronal function and diversity. We systematically validate network predictions using published proteomic and genomic data. Several network modules of co-expressed genes correspond to interneuron development programs, in which the hub genes are known to be critical for interneuron specification. Other co-expression modules relate to fundamental cellular functions, such as energy production, firing rate, trafficking, and synapses, suggesting that fundamental aspects of neuronal diversity are produced by quantitative variation in basic metabolic processes. We identify two transcriptionally distinct mitochondrial modules and demonstrate that one corresponds to mitochondria enriched in neuronal processes and synapses, whereas the other represents a population restricted to the soma. Finally, we show that galectin-1 is a new interneuron marker, and we validate network predictions in vivo using Rgs4 and Dlx1/2 knockout mice. These analyses provide a basis for understanding how specific aspects of neuronal phenotypic diversity are organized at the transcriptional level.

Dlx1&2 and Mash1 transcription factors control striatal patterning and differentiation through parallel and overlapping pathways.

Here we define the expression of approximately 100 transcription factors in progenitors and neurons of the developing basal ganglia. We have begun to elucidate the transcriptional hierarchy of these genes with respect to the Dlx homeodomain genes, which are essential for differentiation of most GABAergic projection neurons of the basal ganglia. This analysis identified Dlx-dependent and Dlx-independent pathways. The Dlx-independent pathway depends in part on the function of the Mash1 b-HLH transcription factor. These analyses define core transcriptional components that differentially specify the identity and differentiation of the striatum, nucleus accumbens, and septum.

Developmental regulation of gonadotropin-releasing hormone gene expression by the MSX and DLX homeodomain protein families.

Gonadotropin-releasing hormone (GnRH) is the central regulator of the hypothalamic-pituitary-gonadal axis, controlling sexual maturation and fertility in diverse species from fish to humans. GnRH gene expression is limited to a discrete population of neurons that migrate through the nasal region into the hypothalamus during embryonic development. The GnRH regulatory region contains four conserved homeodomain binding sites (ATTA) that are essential for basal promoter activity and cell-specific expression of the GnRH gene. MSX and DLX are members of the Antennapedia class of non-Hox homeodomain transcription factors that regulate gene expression and influence development of the craniofacial structures and anterior forebrain. Here, we report that expression patterns of the Msx and Dlx families of homeodomain transcription factors largely coincide with the migratory route of GnRH neurons and co-express with GnRH in neurons during embryonic development. In addition, MSX and DLX family members bind directly to the ATTA consensus sequences and regulate transcriptional activity of the GnRH promoter. Finally, mice lacking MSX1 or DLX1 and 2 show altered numbers of GnRH-expressing cells in regions where these factors likely function. These findings strongly support a role for MSX and DLX in contributing to spatiotemporal regulation of GnRH transcription during development.