Publications

OBJECTIVES

We examined whether regional improvement in stress myocardial blood flow (sMBF) following angiography-guided coronary revascularization depends on the existence of a perfusion defect on positron emission tomography (PET).

BACKGROUND

Percent stenosis on coronary angiography often is the main factor when deciding whether to perform revascularization, but it does not reliably relate to maximum sMBF. PET is a validated method of assessing sMBF.

METHODS

19 patients (79% M, 65 ± 12 years) underwent PET stress before and after revascularization (17 PCI, 2 CABG). Pre- and post-revascularization sMBF for each left ventricular quadrant (anterior, septal, lateral, and inferior) was stratified by the presence or absence of a baseline perfusion defect on PET and whether that region was revascularized.

RESULTS

Intervention was performed on 40 of 76 quadrants. When a baseline perfusion defect existed in a region that was revascularized (n = 26), post-revascularization flow increased by 0.6 ± 0.7 cc/min/g (1.2 ± 0.4 vs 1.7 ± 0.8, P < 0.001). When no defect existed but revascularization was performed (n = 14), sMBF did not change significantly (1.7 ± 0.3 vs 1.5 ± 0.4 cc/min/g, P = 0.16). In regions without a defect that were not revascularized (n = 29), sMBF did not significantly change (2.0 ± 0.6 vs 1.9 ± 0.7, P = 0.7).

CONCLUSIONS

When a stress-induced perfusion defect exists on PET, revascularization improves sMBF in that region. When there is no such defect, sMBF shows no net change, whether or not intervention is performed in that area. PET stress may be useful for identifying areas of myocardium that could benefit from revascularization, and also areas in which intervention is unlikely to yield improvement in myocardial blood flow.

In epigenome-wide association studies (EWAS), different methylation profiles of distinct cell types may lead to false discoveries. We introduce ReFACTor, a method based on principal component analysis (PCA) and designed for the correction of cell type heterogeneity in EWAS. ReFACTor does not require knowledge of cell counts, and it provides improved estimates of cell type composition, resulting in improved power and control for false positives in EWAS. Corresponding software is available at http://www.cs.tau.ac.il/~heran/cozygene/software/refactor.html.

Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation.

The molecular events leading to the development of the bat wing remain largely unknown, and are thought to be caused, in part, by changes in gene expression during limb development. These expression changes could be instigated by variations in gene regulatory enhancers. Here, we used a comparative genomics approach to identify regions that evolved rapidly in the bat ancestor, but are highly conserved in other vertebrates. We discovered 166 bat accelerated regions (BARs) that overlap H3K27ac and p300 ChIP-seq peaks in developing mouse limbs. Using a mouse enhancer assay, we show that five Myotis lucifugus BARs drive gene expression in the developing mouse limb, with the majority showing differential enhancer activity compared to the mouse orthologous BAR sequences. These include BAR116, which is located telomeric to the HoxD cluster and had robust forelimb expression for the M. lucifugus sequence and no activity for the mouse sequence at embryonic day 12.5. Developing limb expression analysis of Hoxd10-Hoxd13 in Miniopterus natalensis bats showed a high-forelimb weak-hindlimb expression for Hoxd10-Hoxd11, similar to the expression trend observed for M. lucifugus BAR116 in mice, suggesting that it could be involved in the regulation of the bat HoxD complex. Combined, our results highlight novel regulatory regions that could be instrumental for the morphological differences leading to the development of the bat wing.