Stage B Heart Failure Is Ubiquitous in Emergency Patients with Asymptomatic Hypertension.

Introduction: Hypertension is the leading risk factor for morbidity and mortality throughout the world and is pervasive in United States emergency departments (ED). This study documents the point prevalence of subclinical heart disease in emergency patients with asymptomatic hypertension. Method: This was a prospective observational study of ED patients with asymptomatic hypertension conducted at two urban academic EDs that belong to an eight-hospital healthcare organization in New York. Adult (≥18 years of age) English- or Spanish-speaking patients who had an initial blood pressure (BP) ≥160/100 millimeters of mercury (mmHg) and second BP ≥140/90 mm Hg, and pending discharge, were invited to participate in the study. We excluded patients with congestive heart failure, renal insufficiency, and atrial fibrillation, or who were pregnant, a prisoner, cognitively unable to provide informed consent, or experiencing symptoms of hypertension. We assessed echocardiographic evidence of subclinical heart disease (left ventricular hypertrophy, and diastolic and systolic dysfunction). Results: A total of 53 patients were included in the study; a majority were young (mean 49.5 years old, [SD 14-52]), self-identified as Black or Other (n = 39; 73.5%), and female (n = 30; 56.6%). Mean initial blood pressure was 172/100 mm Hg, and 24 patients (45.3%) self-reported a history of hypertension. Fifty patients completed an echocardiogram. All (100%) had evidence of subclinical heart disease, with 41 (77.4%) displaying left ventricular hypertrophy and 31 (58.5%) diastolic dysfunction. There was a significant relationship between diastolic dysfunction and female gender [x2 (1, n = 53) = 3.98; P = 0.046]; Black or other race [x2 (3, n = 53) = 9.138; P = 0.03] and Hispanic or other ethnicity [x2 (2, n = 53) = 8.03; P = 0.02]. Less than one third of patients demonstrated systolic dysfunction on echocardiogram, and this was more likely to occur in patients with diabetes mellitus [x2 (1, n = 51) = 4.84; P = 0.02]. Conclusion: There is a high probability that Black, Hispanic, and female patients with asymptomatic hypertension are on the continuum for developing overt heart failure. Emergency clinicians should provide individualized care that considers their unique health needs, cultural backgrounds, and social determinants of health.

Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine.

BACKGROUND: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization and the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized ArcCreERT2 × enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact model of TBI. Mice were then administered a contextual fear discrimination paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the dentate gyrus, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination, and this behavioral improvement was reflected in dentate gyrus memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.

( R,S )-ketamine's rapid-acting antidepressant effects are modulated by NR2B-containing NMDA receptors on adult-born hippocampal neurons.

Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. ( R,S )-ketamine, an N -methyl-D-aspartate (NMDA) antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the NR2B subunit of the NMDA receptor (NMDAR) on interneurons in the medial prefrontal cortex (mPFC), no study has investigated the influence of NR2B-expressing adult-born granule cells (abGCs). In this study, we examined whether ( R,S )-ketamine's efficacy depends upon these adult-born hippocampal neurons using a genetic strategy to selectively ablate the NR2B subunit of the NMDAR from Nestin + cells. To validate our findings, we also used several other transgenic lines including one in which NR2B was deleted from an interneuron (Parvalbumin (PV) + ) population. We report that in male mice, NR2B expression on 6-week-old adult-born neurons is necessary for ( R,S )-ketamine's effects on behavioral despair in the forced swim test (FST) and on hyponeophagia in the novelty suppressed feeding (NSF) paradigm, as well on fear behavior following contextual fear conditioning (CFC). In female mice, NR2B expression is necessary for effects on hyponeophagia in the NSF. We also find that ablating neurogenesis increases fear expression in CFC, which is buffered by ( R,S )-ketamine administration. In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing NR2B partially modulate ( R,S )-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of ( R , S )-ketamine's antidepressant actions.

Traumatic brain injury-induced fear generalization in mice involves hippocampal memory trace dysfunction and is alleviated by ( R,S )-ketamine.

INTRODUCTION: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization, the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized the ArcCreER T2 x enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact (CCI) model of TBI. Mice were then administered a contextual fear discrimination (CFD) paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if ( R,S )-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the DG, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, ( R,S )-ketamine facilitated fear discrimination and this behavioral improvement was reflected in DG memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces, and that this deficit can be improved with a single injection of ( R,S )-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.