Cells and gene expression programs in the adult human heart

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and strategies to improve therapeutic opportunities require deeper understanding of the molecular processes of the normal heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavor. Here, using large-scale single cell and nuclei transcriptomic profiling together with state-of-the-art analytical techniques, we characterise the adult human heart cellular landscape covering six anatomical cardiac regions (left and right atria and ventricles, apex and interventricular septum). Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, revealing distinct subsets in the atria and ventricles indicative of diverse developmental origins and specialized properties. Further we define the complexity of the cardiac vascular network which includes clusters of arterial, capillary, venous, lymphatic endothelial cells and an atrial-enriched population. By comparing cardiac cells to skeletal muscle and kidney, we identify cardiac tissue resident macrophage subsets with transcriptional signatures indicative of both inflammatory and reparative phenotypes. Further, inference of cell-cell interactions highlight a macrophage-fibroblast-cardiomyocyte network that differs between atria and ventricles, and compared to skeletal muscle. We expect this reference human cardiac cell atlas to advance mechanistic studies of heart homeostasis and disease

Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model.

Myocardial fibrosis is a key pathologic feature of hypertrophic cardiomyopathy (HCM). However, the fibrotic pathways activated by HCM-causing sarcomere protein gene mutations are poorly defined. Because lysophosphatidic acid is a mediator of fibrosis in multiple organs and diseases, we tested the role of the lysophosphatidic acid pathway in HCM. Lysphosphatidic acid receptor 1 (LPAR1), a cell surface receptor, is required for lysophosphatidic acid mediation of fibrosis. We bred HCM mice carrying a pathogenic myosin heavy-chain variant (403(+/-)) with Lpar1-ablated mice to create mice carrying both genetic changes (403(+/-) LPAR1(-/-)) and assessed development of cardiac hypertrophy and fibrosis. Compared with 403(+/-) LPAR1(WT), 403(+/-) LPAR1(-/-) mice developed significantly less hypertrophy and fibrosis. Single-nucleus RNA sequencing of left ventricular tissue demonstrated that Lpar1 was predominantly expressed by lymphatic endothelial cells (LECs) and cardiac fibroblasts. Lpar1 ablation reduced the population of LECs, confirmed by immunofluorescence staining of the LEC markers Lyve1 and Ccl21a and, by in situ hybridization, for Reln and Ccl21a. Lpar1 ablation also altered the distribution of fibroblast cell states. FB1 and FB2 fibroblasts decreased while FB0 and FB3 fibroblasts increased. Our findings indicate that Lpar1 is expressed predominantly by LECs and fibroblasts in the heart and is required for development of hypertrophy and fibrosis in an HCM mouse model. LPAR1 antagonism, including agents in clinical trials for other fibrotic diseases, may be beneficial for HCM

Court Review: Volume 41, Issue 3-4 - Balancing Act: Can Judicial Independence Coexist with Court Accountability?

The fifth panel discussion at the National Forum on Judicial Independence explored the intersection between judicial independence and public accountability. The discussion was led by Michael W. Manners, a circuit judge on the Jackson County Circuit Court in Independence, Missouri. Panelists were Michael L. Buenger, Missouri state court administrator, Kevin S. Burke, a district judge in Hennepin County District Court in Minneapolis, Minnesota, Bobby B. DeLaughter, a circuit judge on the Hinds County Circuit Court in Jackson, Mississippi, Malcolm Feeley, professor of law at the University of California-Berkeley, Michael R. McAdam, judge on the Kansas City (Mo.) Municipal Court, Mary Campbell McQueen, president of the National Center for State Courts, Jeffrey Rosinek, a circuit judge on the Miami-Dade County Circuit Court in Miami, Florida, John Russonello, a pollster and consultant, Roy A. Schotland, professor of law at Georgetown University, and RobertWessels, court manager for the county criminal courts at law in Harris County (Houston), Texas. The National Forum on Judicial Independence was supported by a generous grant from the Joyce Foundation of Chicago, Illinois

Are cells from a snowman realistic? Cryopreserved tissues as a source for single-cell RNA-sequencing experiments

A recently published study in Genome Biology shows that cells isolated from cryopreserved tissues are a reliable source of genetic material for single-cell RNA-sequencing experiments.Please see related Method article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1171-9

Can stories influence African-American patients’ intentions to change hypertension management behaviors? A randomized control trial.

Objectives Information-only interventions for hypertension management have limited effectiveness, particularly among disadvantaged populations. We assessed the impact of viewing African-American patients’ stories of successfully controlling hypertension on intention to change hypertension management behaviors and engagement with educational materials. Methods In a three-site randomized trial, 618 African-American Veterans with uncontrolled hypertension viewed an information-only DVD about hypertension (control) or a DVD adding videos of African-American Veterans telling stories about successful hypertension management (intervention). After viewing, patients were asked about their engagement with the DVD, and their intentions to change behavior. Mean scores were compared with two-sided t-tests. Results Results favored the Stories intervention, with significantly higher emotional engagement versus control (4.3 vs. 2.2 p < 0.0001). Intervention patients reported significantly greater intentions to become more physically active (4.6 vs. 4.4, p = 0.018), use salt substitutes (3.9 vs. 3.4, p = 0.006), talk openly with their doctor about hypertension (4.6 vs. 4.5, p = 0.049), and remember to take hypertension medication (4.8 vs. 4.6, p = 0.04). Conclusion Patients were more emotionally engaged and reported intentions to change behavior when watching real patient hypertension management success stories. Practice implications Stories may be more influential than information alone, and represent a scalable approach to modifying behavioral intention