A G-Rich Motif in the lncRNA Braveheart Interacts with a Zinc-Finger Transcription Factor to Specify the Cardiovascular Lineage.

Long non-coding RNAs (lncRNAs) are an emerging class of transcripts that can modulate gene expression; however, their mechanisms of action remain poorly understood. Here, we experimentally determine the secondary structure of Braveheart (Bvht) using chemical probing methods and show that this âˆ¼590 nt transcript has a modular fold. Using CRISPR/Cas9-mediated editing of mouse embryonic stem cells, we find that deletion of 11 nt in a 5' asymmetric G-rich internal loop (AGIL) of Bvht (bvhtdAGIL) dramatically impairs cardiomyocyte differentiation. We demonstrate a specific interaction between AGIL and cellular nucleic acid binding protein (CNBP/ZNF9), a zinc-finger protein known to bind single-stranded G-rich sequences. We further show that CNBP deletion partially rescues the bvhtdAGIL mutant phenotype by restoring differentiation capacity. Together, our work shows that Bvht functions with CNBP through a well-defined RNA motif to regulate cardiovascular lineage commitment, opening the door for exploring broader roles of RNA structure in development and disease.

Objects and landmarks: hippocampal place cells respond differently to manipulations of visual cues depending on size, perspective, and experience.

Human navigation studies show that landmarks are used for orientation, whereas objects contribute to the contextual representation of an environment. What constitutes a landmark? Classic rodent studies show that hippocampal place fields are controlled by distal, polarizing cues. Place fields, however, are also influenced by local cues. One difficulty in examining mechanisms by which distal and local cues influence the activity of hippocampal cells is that distant cues are necessarily processed visually, whereas local cues are generally multimodal. Here, we compared the effects of 90° rotations under different cue conditions in which cues were restricted to the visual modality. Three two-dimensional visual cue conditions were presented in a square open field: a large vertical cue on one wall, a large floor cue in a corner abutting two walls, and a smaller complex floor cue in a corner adjacent to two walls. We show that rotations of large distal cues, whether on the wall or floor, were equally effective in controlling place fields. Rotations of the smaller floor cues were significantly more likely to result in remapping, whether or not animals were also exposed to the distal polarizing cues. Responses of distal and local cues were affected differently by extended experience. Our data provide evidence that hippocampal place cell responses to visual cues are influenced by perspective, salience of the cue, and prior experience. The hippocampus processes visual cues either as stable landmarks useful for orientation and navigation or as nonstationary objects or features of the local environment available for associative learning or binding items in context.

Characteristics and Predictors of Late Right Heart Failure After Left Ventricular Assist Device Implantation.

Late right heart failure (LRHF) following left ventricular assist device (LVAD) implantation remains poorly characterized and challenging to predict. We performed a multicenter retrospective study of LRHF in 237 consecutive adult LVAD patients, in which LRHF was defined according to the 2020 Mechanical Circulatory Support Academic Research Consortium guidelines. Clinical and hemodynamic variables were assessed pre- and post-implant. Competing-risk regression and Kaplan-Meier survival analysis were used to assess outcomes. LRHF prediction was assessed using multivariable logistic and Cox proportional hazards regression. Among 237 LVAD patients, 45 (19%) developed LRHF at a median of 133 days post-LVAD. LRHF patients had more frequent heart failure hospitalizations ( p < 0.001) alongside other complications. LRHF patients did not experience reduced bridge-to-transplant rates but did suffer increased mortality (hazard ratio 1.95, 95% confidence interval [CI] 1.11-3.42; p = 0.02). Hemodynamically, LRHF patients demonstrated higher right atrial pressure, mean pulmonary arterial pressure, and pulmonary vascular resistance (PVR), but no difference in pulmonary arterial wedge pressure. History of early right heart failure, blood urea nitrogen (BUN) > 35 mg/dl at 1 month post-LVAD, and diuretic requirements at 1 month post-LVAD were each significant, independent predictors of LRHF in multivariable analysis. An LRHF prediction risk score incorporating these variables predicted LRHF with excellent discrimination (log-rank p < 0.0001). Overall, LRHF post-LVAD is more common than generally appreciated, with significant morbidity and mortality. Elevated PVR and precapillary pulmonary pressures may play a role. A risk score using early right heart failure, elevated BUN, and diuretic requirements 1 month post implant predicted the development of LRHF.

Heart Team Approach for Cardiogenic Shock Management in Pregnancy Complicated by Mechanical Mitral Valve Thrombosis.

A 27-year-old pregnant woman at 24 weeks of gestation was admitted with cardiogenic shock due to mechanical mitral valve thrombosis. Following discussion with the heart team, thrombolysis was achieved with tissue plasminogen activator therapy followed by heparin infusion. Ultimately, the patient required mitral valve replacement for persistently elevated gradients.

A Modified Grading System for Early Right Heart Failure Matches Functional Outcomes and Survival After Left Ventricular Assist Devices.

Early right heart failure (ERHF) remains a common complication after continuous-flow left ventricular assist device (cf-LVAD) and has been associated with increased mortality. The specific criteria used to define ERHF remain somewhat arbitrary. Correlating the degree of ERHF with outcomes after LVAD could inform a more clinically relevant definition. We identified 196 patients who underwent first durable cf-LVAD between 2008 and 2015 at a single center. Postimplant ERHF was graded as absent, mild (requiring inotropic support for 14-20 days), moderate (inotropes for ≥ 21 days), or severe (requiring unplanned RVAD at any time during the index hospitalization). ERHF was associated with clinical outcomes including 1 year survival and New York Heart Association (NYHA) class and 6 minute walk distance (6MWD) at 3 and 6 months. Survival was assessed using the Kaplan-Meier method with log-rank testing and multivariate Cox proportional-hazards modeling. Compared to patients without ERHF, those with mild ERHF had similar 1 year survival (hazard ratio [HR] 0.69, 95% confidence interval [CI]: 0.26-1.80, p = 0.45), while mortality was substantially increased in patients with moderate (HR 2.65, 95% CI: 1.27-5.54, p = 0.009) and severe ERHF (HR 8.16, 95% CI: 3.97-16.76, p < 0.0001). The severity of ERHF was associated with 6MWD at both 3 months (p = 0.001) and 6 months (p = 0.013). The relationship between ERHF and postimplant survival and functional status persisted in multivariate modeling. A simple, modified grading system for ERHF severity is strongly associated with 1 year survival and functional capacity after cf-LVAD. These results argue against using a binary definition for ERHF and suggest the need to modify definition of ERHF severity.