Human NKX2-5 blocking peptide

Background: The definition of left ventricular (LV) non-compaction is controversial, and discriminating between normal and excessive LV trabeculation remains challenging. Our goal was to quantify LV trabeculation on cardiovascular magnetic resonance (CMR) images in a genetic mouse model of non-compaction using a dedicated semi-automatic software package and to compare our results to the histology used as a gold standard. Methods: Adult mice with ventricular non-compaction were generated by conditional trabecular deletion of Nkx2-5. Thirteen mice (5 controls, 8 Nkx2-5 mutants) were included in the study. Cine CMR series were acquired in the mid LV short axis plane (resolution 0.086 x 0.086x1mm(3)) (11.75 T). In a sub set of 6 mice, 5 to 7 cine CMR were acquired in LV short axis to cover the whole LV with a lower resolution (0.172 x 0.172x1mm(3)). We used semi-automatic software to quantify the compacted mass (M-c), the trabeculated mass (M-t) and the percentage of trabeculation (M-t/M-c) on all cine acquisitions. After CMR all hearts were sliced along the short axis and stained with eosin, and histological LV contouring was performed manually, blinded from the CMR results, and M-t, M-c and M-t/M-c were quantified. Intra and interobserver reproducibility was evaluated by computing the intra class correlation coefficient (ICC). Results: Whole heart acquisition showed no statistical significant difference between trabeculation measured at the basal, midventricular and apical parts of the LV. On the mid-LV cine CMR slice, the median Mt was 0.92 mg (range 0.07-2.56 mg), M-c was 12.24 mg (9.58-17.51 mg), M-t/M-c was 6.74% (0.66-17.33%). There was a strong correlation between CMR and the histology for Mt, Mc and Mt/Mc with respectively: r(2) = 0.94 (p < 0.001), r(2) = 0.91 (p < 0.001), r(2) = 0.83 (p < 0.001). Intra-and interobserver reproducibility was 0.97 and 0.8 for M-t; 0.98 and 0.97 for M-c; 0.96 and 0.72 for M-t/M-c, respectively and significantly more trabeculation was observed in the Mc Mutant mice than the controls. Conclusion: The proposed semi-automatic quantification software is accurate in comparison to the histology and reproducible in evaluating M-c, M-t and M-t/M-c on cine CMR.

The rhythmic contraction of the heart is initiated and controlled by an intrinsic pacemaker system. Cardiac contractions commence at very early embryonic stages and coordination remains crucial for survival. The underlying molecular mechanisms of pacemaker cell development and function are still not fully understood. Heart form and function show high evolutionary conservation. Even in simple contractile cardiac tubes in primitive invertebrates, cardiac function is controlled by intrinsic, autonomous pacemaker cells. Understanding the evolutionary origin and development of cardiac pacemaker cells will help us outline the important pathways and factors involved. Key patterning factors, such as the homeodomain transcription factors Nkx2.5 and Shox2, and the LIM-homeodomain transcription factor Islet-1, components of the T-box (Tbx), and bone morphogenic protein (Bmp) families are well conserved. Here we compare the dominant pacemaking systems in various organisms with respect to the underlying molecular regulation. Comparative analysis of the pathways involved in patterning the pacemaker domain in an evolutionary context might help us outline a common fundamental pacemaker cell gene programme. Special focus is given to pacemaker development in zebrafish, an extensively used model for vertebrate development. Finally, we conclude with a summary of highly conserved key factors in pacemaker cell development and function.