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Background: U.S. nationwide estimates of the proportion of patients newly diagnosed with heart failure with reduced ejection fraction (HFrEF) eligible for quadruple medical therapy, and the associated benefits of rapid implementation, are not well characterized., Objectives: This study sought to characterize the degree to which patients newly diagnosed with HFrEF are eligible for quadruple medical therapy, and the projected benefits of in-hospital initiation., Methods: Among patients hospitalized for newly diagnosed HFrEF in the Get With The Guidelines-Heart Failure registry from 2016 to 2023, eligibility criteria based on regulatory labeling, guidelines, and expert consensus documents were applied for angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor therapies. Of those eligible, the projected effect of quadruple therapy on 12-month mortality was modeled using treatment effects from pivotal clinical trials utilized by the AHA/ACC/HFSA Guideline for the Management of Heart Failure, and compared with observed outcomes among patients treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blockers., Results: Of 33,036 patients newly diagnosed with HFrEF, 27,158 (82%) were eligible for quadruple therapy, and 30,613 (93%) were eligible for ≥3 components. From 2021 to 2023, of patients eligible for quadruple therapy, 15.3% were prescribed quadruple therapy and 41.5% were prescribed triple therapy. Among Medicare beneficiaries eligible for quadruple therapy, 12-month incidence of mortality was 24.7% and HF hospitalization was 22.2%. Applying the relative risk reductions in clinical trials, complete implementation of quadruple therapy by time of discharge was projected to yield absolute risk reductions in 12-month mortality of 10.4% (number needed to treat = 10) compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker, and 24.8% (number needed to treat = 4) compared with no GDMT., Conclusions: In this nationwide U.S. cohort of patients hospitalized for newly diagnosed HFrEF, >4 of 5 patients were projected as eligible for quadruple therapy at discharge; yet, <1 in 6 were prescribed it. If clinical trial benefits can be fully realized, in-hospital initiation of quadruple medical therapy for newly diagnosed HFrEF would yield large absolute reductions in mortality., Competing Interests: Funding Support and Author Disclosures The Get With The Guidelines–Heart Failure (GWTG-HF) program is provided by the American Heart Association and sponsored, in part, by Novartis, Boehringer Ingelheim, and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards or as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Cytokinetics, Eli Lilly, Lexicon, Merck, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Bayer, Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. Dr Fonarow has consulted for Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson and Johnson, Medtronic, Merck, Novartis, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Emulation of the "target trial" (TT), a hypothetical pragmatic randomized controlled trial (RCT), using observational data can be used to mitigate issues commonly encountered in comparative effectiveness research (CER) when randomized trials are not logistically, ethically, or financially feasible. However, cardiovascular (CV) health research has been slow to adopt TT emulation. Here, we demonstrate the design and analysis of a TT emulation using electronic health records to study the comparative effectiveness of the addition of a disease-modifying anti-rheumatic drug (DMARD) to a regimen of methotrexate on CV events among rheumatoid arthritis (RA) patients., Methods: We used data from an electronic medical records-based cohort of RA patients from Northwestern Medicine to emulate the TT. Follow-up began 3 months after initial prescription of MTX (2000-2020) and included all available follow-up through June 30, 2020. Weighted pooled logistic regression was used to estimate differences in CVD risk and survival. Cloning was used to handle immortal time bias and weights to improve baseline and time-varying covariate imbalance., Results: We identified 659 eligible people with RA with average follow-up of 46 months and 31 MACE events. The month 24 adjusted risk difference for MACE comparing initiation vs non-initiation of a DMARD was -1.47% (95% confidence interval [CI]: -4.74, 1.95%), and the marginal hazard ratio (HR) was 0.72 (95% CI: 0.71, 1.23). In analyses subject to immortal time bias, the HR was 0.62 (95% CI: 0.29-1.44)., Conclusion: In this sample, we did not observe evidence of differences in risk of MACE, a finding that is compatible with previously published meta-analyses of RCTs. Thoughtful application of the TT framework provides opportunities to conduct CER in observational data. Benchmarking results of observational analyses to previously published RCTs can lend credibility to interpretation., Competing Interests: ASR was supported by the American Heart Association Predoctoral Fellowship (825793) for unrelated research. LCP receives funds for unrelated research from Omron Healthcare Co., Ltd. Other authors have no other conflicts to declare. The mentioned organizations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Rivera et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Clinical practice in the contemporary cardiac intensive care unit (CICU) has evolved significantly over the last several decades. With more frequent multisystem organ failure, increasing use of advanced respiratory support, and the advent of new mechanical circulatory support platforms, clinicians in the CICU are increasingly managing patients with complex comorbid disease in addition to their high-acuity cardiovascular illnesses. Here, the authors discuss challenges associated with traditional trial design in the CICU setting and review novel clinical trial designs that may facilitate better evidence generation in the CICU., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sacubitril/valsartan improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with angiotensin-converting enzyme inhibitors (ACEis). However, data on postdischarge outcomes in renin-angiotensin system inhibitor (RASi)-naïve patients are limited. We included Medicare beneficiaries aged ≥65 years who were hospitalized for HFrEF in the Get With The Guidelines-Heart Failure registry between October 2015 and June 2019, had part D prescription coverage, and were not on RASi therapy during the 6 months before hospital admission. We examined the associations between sacubitril/valsartan prescription at hospital discharge and outcomes at 30 days and 1 year after discharge using overlap-weighted median regression and Cox proportional hazards models. The end points included "home time" (defined as days alive and out of any health care institution), mortality, and rehospitalization. Among 3,572 patients with HFrEF and who are naïve to RASi therapy, at discharge, 290 (8.1%) were prescribed sacubitril/valsartan and 1,390 (38.9%) were prescribed ACEis and angiotensin receptor blockers. After adjusting for baseline characteristics, patients prescribed sacubitril/valsartan had a longer median home time (parameter estimate 27.0 days, 95% confidence interval [CI] 12.40 to 41.6, p <0.001) and lower all-cause mortality (hazard ratio [HR] 0.74, 95% CI 0.61 to 0.91, p = 0.004) at 1 year than patients not prescribed sacubitril/valsartan. The prescription of sacubitril/valsartan was not significantly associated with all-cause rehospitalization (HR 0.87, 95% CI 0.74 to 1.03, p = 0.10) or heart failure rehospitalization (HR 0.87, 95% CI 0.70 to 1.07, p = 0.19). In a restricted comparison of patients discharged on sacubitril/valsartan versus ACEis and angiotensin receptor blockers, there were no significant differences in the outcomes. In conclusion, in this contemporary population of RASi-naïve patients with HFrEF from routine clinical practice, compared with not initiating, the initiation of sacubitril/valsartan at discharge was associated with longer home time and improvements in overall survival., Competing Interests: Declaration of Competing Interest GCF reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. LAA receives grant funding from the American Heart Association, the National Institutes of Health, and the Patient-Centered Outcomes Research Institute, and consulting fees from Boston Scientific, Cytokinetics, Novartis, UpToDate, and WCG ACI Clinical. PNP receives grant funding from the National Institutes of Health. RJM receives research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. SJG has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association (#929502), Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/ Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, Sanofi, and scPharmaceuticals; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim/ Lilly, Corteria Pharmaceuticals, CSL Vifor, Lexicon, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Clinical guidelines for patients with heart failure with reduced ejection fraction (HFrEF) strongly recommend treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) to reduce cardiovascular mortality or HF hospitalization. Nationwide adoption of SGLT2i for HFrEF in the US is unknown., Objective: To characterize patterns of SGLT2i use among eligible US patients hospitalized for HFrEF., Design, Setting, and Participants: This retrospective cohort study analyzed 49 399 patients hospitalized for HFrEF across 489 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry between July 1, 2021, and June 30, 2022. Patients with an estimated glomerular filtration rate less than 20 mL/min/1.73 m2, type 1 diabetes, and previous intolerance to SGLT2i were excluded., Main Outcomes and Measures: Patient-level and hospital-level prescription of SGLT2i at hospital discharge., Results: Of 49 399 included patients, 16 548 (33.5%) were female, and the median (IQR) age was 67 (56-78) years. Overall, 9988 patients (20.2%) were prescribed an SGLT2i. SGLT2i prescription was less likely among patients with chronic kidney disease (CKD; 4550 of 24 437 [18.6%] vs 5438 of 24 962 [21.8%]; P < .001) but more likely among patients with type 2 diabetes (T2D; 5721 of 21 830 [26.2%] vs 4262 of 27 545 [15.5%]; P < .001) and those with both T2D and CKD (2905 of 12 236 [23.7%] vs 7078 vs 37 139 [19.1%]; P < .001). Patients prescribed SGLT2i therapy were more likely to be prescribed background triple therapy with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, β-blocker, and mineralocorticoid receptor antagonist (4624 of 9988 [46.3%] vs 10 880 of 39 411 [27.6%]; P < .001), and 4624 of 49 399 total study patients (9.4%) were discharged with prescriptions for quadruple medical therapy including SGLT2i. Among 461 hospitals with 10 or more eligible discharges, 19 hospitals (4.1%) discharged 50% or more of patients with prescriptions for SGLT2i, whereas 344 hospitals (74.6%) discharged less than 25% of patients with prescriptions for SGLT2i (including 29 [6.3%] that discharged zero patients with SGLT2i prescriptions). There was high between-hospital variance in the rate of SGLT2i prescription in unadjusted models (median odds ratio, 2.53; 95% CI, 2.36-2.74) and after adjustment for patient and hospital characteristics (median odds ratio, 2.51; 95% CI, 2.34-2.71)., Conclusions and Relevance: In this study, prescription of SGLT2i at hospital discharge among eligible patients with HFrEF was low, including among patients with comorbid CKD and T2D who have multiple indications for therapy, with substantial variation among US hospitals. Further efforts are needed to overcome implementation barriers and improve use of SGLT2i among patients with HFrEF.

Importance: Prior studies have suggested patients with heart failure (HF) from rural areas have worse clinical outcomes. Contemporary differences between rural and urban hospitals in quality of care and clinical outcomes for patients hospitalized for HF remain poorly understood., Objective: To assess quality of care and clinical outcomes for US patients hospitalized for HF at rural vs urban hospitals., Design, Setting, and Participants: This retrospective cohort study analyzed 774 419 patients hospitalized for HF across 569 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry between January 1, 2014, and September 30, 2021. Postdischarge outcomes were assessed in a subset of 161 996 patients linked to Medicare claims. Data were analyzed from August 2022 to January 2023., Main Outcomes and Measures: GWTG-HF quality measures, in-hospital mortality, length of stay, and 30-day mortality and readmission outcomes., Results: This study included 19 832 patients (2.6%) and 754 587 patients (97.4%) hospitalized at 49 rural hospitals (8.6%) and 520 urban hospitals (91.4%), respectively. Of 774 419 included patients, 366 161 (47.3%) were female, and the median (IQR) age was 73 (62-83) years. Compared with patients at urban hospitals, patients at rural hospitals were older (median [IQR] age, 74 [64-84] years vs 73 [61-83] years; standardized difference, 10.63) and more likely to be non-Hispanic White (14 572 [73.5%] vs 498 950 [66.1%]; standardized difference, 34.47). In adjusted models, patients at rural hospitals were less likely to be prescribed cardiac resynchronization therapy (adjusted risk difference [aRD], -13.5%; adjusted odds ratio [aOR], 0.44; 95% CI, 0.22-0.92), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (aRD, -3.7%; aOR, 0.71; 95% CI, 0.53-0.96), and an angiotensin receptor-neprilysin inhibitor (aRD, -5.0%; aOR, 0.68; 95% CI, 0.47-0.98) at discharge. In-hospital mortality was similar between rural and urban hospitals (460 of 19 832 [2.3%] vs 20 529 of 754 587 [2.7%]; aOR, 0.86; 95% CI, 0.70-1.07). Patients at rural hospitals were less likely to have a length of stay of 4 or more days (aOR, 0.75; 95% CI, 0.67-0.85). Among Medicare beneficiaries, there were no significant differences between rural and urban hospitals in 30-day HF readmission (adjusted hazard ratio [aHR], 1.03; 95% CI, 0.90-1.19), all-cause readmission (aHR, 0.97; 95% CI, 0.91-1.04), and all-cause mortality (aHR, 1.05; 95% CI, 0.91-1.21)., Conclusions and Relevance: In this large contemporary cohort of US patients hospitalized for HF, care at rural hospitals was independently associated with lower use of some guideline-recommended therapies at discharge and shorter length of stay. In-hospital mortality and 30-day postdischarge outcomes were similar at rural and urban hospitals.

Background: Clinical guidelines recommend titration of angiotensin converting enzyme inhibitors (ACEi) and beta-blockers among patients with heart failure with reduced ejection fraction (HFrEF) to maximally tolerated doses. Patient characteristics associated with dose titration and clinical outcomes subsequent to dose titration remain poorly characterized., Methods: Among 1999 ambulatory patients with chronic HFrEF in the HF-ACTION trial, use and dosing of ACEi and evidence-based beta-blockers were examined at baseline and 6-month follow-up. Multivariable logistic regression models were used to assess factors associated with dose escalation (medication initation or dosing increase) or dose de-escalation (medication discontinuation or dosing decrease). Cox proportional hazard regression models were used to examine associations between dose trajectory group (stable target, stable sub-target, dose escalation, and dose de-escalation) and subsequent mortality and hospitalization outcomes., Results: For both ACEi and beta-blockers, hospitalization for heart failure in the 6 months prior to enrollment (odds ratio [OR] 2.32 [95% confidence interval 1.58-3.42]) for ACEi; 1.42 [1.05-1.9] for beta-blockers) and higher systolic blood pressure (OR 1.01 [1.00-1.03] per 1 mmHg increase for ACEi; 1.01 [1.00-1.02] for beta-blockers) were associated with dose escalation. Hospitalization 6 months prior to enrollment for any cause (including HF or non-HF causes) was associated with dose de-escalation (OR 1.60 [1.14-2.25] for ACEi; 1.67 [1.20-2.33] for beta-blockers). After adjustment for patient characteristics, compared with stable target dosing, dose de-escalation of either medication was associated with greater all-cause mortality (adjusted hazard ratio [aHR] 1.64 [1.11-2.42] for ACEi; 1.62 [1.04-2.53] for beta-blockers). Compared with stable target dosing, both dose de-escalation (aHR 1.98 [1.36-2.87]) and stable sub-target dosing (aHR 1.49 [1.18-1.87]) of beta-blockers were associated with greater cardiovascular mortality or hospitalization for heart failure., Conclusions: Among outpatients with chronic HFrEF, patient characteristics including recent hospitalization status and blood pressure were associated with odds of subsequent escalation and de-escalation of ACEi and beta-blocker therapy. Compared with patients receiving guildeline-recommended target doses, dose de-escalation of either medication and sub-target dosing of beta-blockers were associated with greater morbidity and mortality over long-term follow-up., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of cellular functions including maintenance of cellular homeostasis as well as the onset and progression of disease. LncRNAs often exhibit cell-, tissue-, and disease-specific expression patterns, making them desirable therapeutic targets. LncRNAs are commonly targeted using oligonucleotide therapeutics, and advances in oligonucleotide chemistry including C2 ribose sugar modifications such as 2'-fluoro, 2'-O-methyl, and 2-O-methoxyethyl modifications; 2'4'-constrained nucleotides such as locked nucleic acids and constrained 2'-O-ethyl (cEt) nucleotides; and phosphorothioate bonds have dramatically improved efficacy of oligonucleotide therapies. Novel delivery platforms such as viral vectors and nanoparticles have also improved pharmacokinetic properties of oligonucleotides targeting lncRNAs. Accumulating pre-clinical studies have utilized these strategies to therapeutically target lncRNAs and alter progression of many different disease states including Snhg12 and Chast in cardiovascular disease, Mirt2 and HOTTIP in sepsis and autoimmune disease, and Malat1 and HOXB-AS3 in cancer. Emerging oligonucleotide conjugation methods including the use of peptide nucleic acids hold promise to facilitate targeting to specific tissue types. Here, we review recent advances in lncRNA therapeutics and provide examples of how lncRNAs have been successfully targeted in pre-clinical models of disease. Finally, we detail remaining challenges facing the lncRNA field and how advances in delivery platforms and oligonucleotide chemistry might help overcome these barriers to catalyze the translation of pre-clinical studies to successful pharmaceutical development., (© 2022. Springer Nature Switzerland AG.)

Background: Adults in rural counties in the United States (US) experience higher rates broadly of cardiovascular disease (CVD) compared with adults in urban counties. Mortality rates specifically due to heart failure (HF) have increased since 2011, but estimates of heterogeneity at the county-level in HF-related mortality have not been produced. The objectives of this study were 1) to quantify nationwide trends by rural-urban designation and 2) examine county-level factors associated with rural-urban differences in HF-related mortality rates., Methods and Findings: We queried CDC WONDER to identify HF deaths between 2011-2018 defined as CVD (I00-78) as the underlying cause of death and HF (I50) as a contributing cause of death. First, we calculated national age-adjusted mortality rates (AAMR) and examined trends stratified by rural-urban status (defined using 2013 NCHS Urban-Rural Classification Scheme), age (35-64 and 65-84 years), and race-sex subgroups per year. Second, we combined all deaths from 2011-2018 and estimated incidence rate ratios (IRR) in HF-related mortality for rural versus urban counties using multivariable negative binomial regression models with adjustment for demographic and socioeconomic characteristics, risk factor prevalence, and physician density. Between 2011-2018, 162,314 and 580,305 HF-related deaths occurred in rural and urban counties, respectively. AAMRs were consistently higher for residents in rural compared with urban counties (73.2 [95% CI: 72.2-74.2] vs. 57.2 [56.8-57.6] in 2018, respectively). The highest AAMR was observed in rural Black men (131.1 [123.3-138.9] in 2018) with greatest increases in HF-related mortality in those 35-64 years (+6.1%/year). The rural-urban IRR persisted among both younger (1.10 [1.04-1.16]) and older adults (1.04 [1.02-1.07]) after adjustment for county-level factors. Main limitations included lack of individual-level data and county dropout due to low event rates (<20)., Conclusions: Differences in county-level factors may account for a significant amount of the observed variation in HF-related mortality between rural and urban counties. Efforts to reduce the rural-urban disparity in HF-related mortality rates will likely require diverse public health and clinical interventions targeting the underlying causes of this disparity., Competing Interests: The authors have declared that no competing interests exist.

Epidemiological studies have highlighted the disparate impact of coronavirus disease 2019 (COVID-19) on racial and ethnic minority and socioeconomically disadvantaged populations, but data at the neighborhood-level is sparse. The objective of this study was to investigate the disparate impact of COVID-19 on disadvantaged neighborhoods and racial/ethnic minorities in Chicago, Illinois. Using data from the Cook County Medical Examiner, we conducted a neighborhood-level analysis of COVID-19 decedents in Chicago and quantified age-standardized years of potential life lost (YPLL) due to COVID-19 among demographic subgroups and neighborhoods with geospatial clustering of high and low rates of COVID-19 mortality. We show that age-standardized YPLL was markedly higher among the non-Hispanic (NH) Black (559 years per 100,000 population) and the Hispanic (811) compared with NH white decedents (312). We demonstrate that geomapping using residential address data at the individual-level identifies hot-spots of COVID-19 mortality in neighborhoods on the Northeast, West, and South areas of Chicago that reflect a legacy of residential segregation and persistence of inequality in education, income, and access to healthcare. Our results may contribute to ongoing public health and community-engaged efforts to prevent the spread of infection and mitigate the disproportionate loss of life among these communities due to COVID-19 as well as highlight the urgent need to broadly target neighborhood disadvantage as a cause of pervasive racial inequalities in life and health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chronic vascular inflammation plays a key role in the pathogenesis of atherosclerosis. Long non-coding RNAs (lncRNAs) have emerged as essential inflammation regulators. We identify a novel lncRNA termed lncRNA-MAP3K4 that is enriched in the vessel wall and regulates vascular inflammation. In the aortic intima, lncRNA-MAP3K4 expression was reduced by 50% during the progression of atherosclerosis (chronic inflammation) and 70% during endotoxemia (acute inflammation). lncRNA-MAP3K4 knockdown reduced the expression of key inflammatory factors (eg, ICAM-1, E-selectin, MCP-1) in endothelial cells or vascular smooth muscle cells and decreased monocytes adhesion to endothelium, as well as reducing TNF-α, IL-1β, COX2 expression in macrophages. Mechanistically, lncRNA-MAP3K4 regulates inflammation through the p38 MAPK signaling pathway. lncRNA-MAP3K4 shares a bidirectional promoter with MAP3K4, an upstream regulator of the MAPK signaling pathway, and regulates its transcription in cis. lncRNA-MAP3K4 and MAP3K4 show coordinated expression in response to inflammation in vivo and in vitro. Similar to lncRNA-MAP3K4, MAP3K4 knockdown reduced the expression of inflammatory factors in several different vascular cells. Furthermore, lncRNA-MAP3K4 and MAP3K4 knockdown showed cooperativity in reducing inflammation in endothelial cells. Collectively, these findings unveil the role of a novel lncRNA in vascular inflammation by cis-regulating MAP3K4 via a p38 MAPK pathway., (© 2020 Federation of American Societies for Experimental Biology.)

Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis. Using RNA-seq profiling of the intima of lesions, here we identify a macrophage-specific lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). Aortic intima expression of MAARS increases by 270-fold with atherosclerotic progression and decreases with regression by 60%. MAARS knockdown reduces atherosclerotic lesion formation by 52% in LDLR -/- mice, largely independent of effects on lipid profile and inflammation, but rather by decreasing macrophage apoptosis and increasing efferocytosis in the vessel wall. MAARS interacts with HuR/ELAVL1, an RNA-binding protein and important regulator of apoptosis. Overexpression and knockdown studies verified MAARS as a critical regulator of macrophage apoptosis and efferocytosis in vitro, in an HuR-dependent manner. Mechanistically, MAARS knockdown alters HuR cytosolic shuttling, regulating HuR targets such as p53, p27, Caspase-9, and BCL2. These findings establish a mechanism by which a macrophage-specific lncRNA interacting with HuR regulates apoptosis, with implications for a broad range of vascular disease states.

Background: Rates of maternal mortality are increasing in the United States with significant rural-urban disparities. Pre-pregnancy hypertension is a well-established risk factor for adverse maternal and offspring outcomes., Objectives: The purpose of this study was to describe trends in maternal pre-pregnancy hypertension among women in rural and urban areas in 2007 to 2018 in order to inform community-engaged prevention and policy strategies., Methods: We performed a nationwide, serial cross-sectional study using maternal data from all live births in women age 15 to 44 years between 2007 and 2018 (CDC Natality Database). Rates of pre-pregnancy hypertension were calculated per 1,000 live births overall and by urbanization status. Subgroup analysis in standard 5-year age categories was performed. We quantified average annual percentage change using Joinpoint Regression and rate ratios (95% confidence intervals [CIs]) to compare yearly rates between rural and urban areas., Results: Among 47,949,381 live births to women between 2007 and 2018, rates of pre-pregnancy hypertension per 1,000 live births increased among both rural (13.7 to 23.7) and urban women (10.5 to 20.0). Two significant inflection points were identified in 2010 and 2016, with highest annual percentage changes between 2016 and 2018 in rural and urban areas. Although absolute rates were lower in younger compared with older women in both rural and urban areas, all age groups experienced similar increases. The rate ratios of pre-pregnancy hypertension in rural compared with urban women ranged from 1.18 (95% CI: 1.04 to 1.35) for ages 15 to 19 years to 1.51 (95% CI: 1.39 to 1.64) for ages 40 to 44 years in 2018., Conclusions: Maternal burden of pre-pregnancy hypertension has nearly doubled in the past decade and the rural-urban gap has persisted., Competing Interests: Author Disclosures This study has been supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (KL2TR001424 to Dr. Khan and K23HL14510102 to Dr. Perak), and the American Heart Association (#19TPA34890060 to Dr. Khan). Research reported in this publication was supported, in part, by the National Institutes of Health's National Center for Advancing Translational Sciences, Grant Number KL2TR001424. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The funding sponsor did not contribute to the design and conduct of the study, collection, management, analysis, or interpretation of the data or preparation, review, or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has led to a global pandemic, failures of local health care systems, and global economic recession. MicroRNAs (miRNAs) have recently emerged as important regulators of viral pathogenesis, particularly among RNA viruses, but the impact of host miRNAs on SARS-CoV-2 infectivity remains unknown. In this study, we utilize the combination of powerful bioinformatic prediction algorithms and miRNA profiling to predict endogenous host miRNAs that may play important roles in regulating SARS-CoV-2 infectivity. We provide a collection of high-probability miRNA binding sites within the SARS-CoV-2 genome as well as within mRNA transcripts of critical viral entry proteins ACE2 and TMPRSS2 and their upstream modulators, the interferons (IFN). By utilizing miRNA profiling datasets of SARS-CoV-2-resistant and -susceptible cell lines, we verify the biological plausibility of the predicted miRNA-target RNA interactions. Finally, we utilize miRNA profiling of SARS-CoV-2-infected cells to identify predicted miRNAs that are differentially regulated in infected cells. In particular, we identify predicted miRNA binders to SARS-CoV-2 ORFs (miR-23a (1ab), miR-29a, -29c (1ab, N), miR-151a, -151b (S), miR-4707-3p (S), miR-298 (5'-UTR), miR-7851-3p (5'-UTR), miR-8075 (5'-UTR)), ACE2 3'-UTR (miR-9-5p, miR-218-5p), TMPRSS2 3'-UTR (let-7d-5p, -7e-5p, miR-494-3p, miR-382-3p, miR-181c-5p), and IFN-α 3'-UTR (miR-361-5p, miR-410-3p). Overall, this study provides insight into potential novel regulatory mechanisms of SARS-CoV-2 by host miRNAs and lays the foundation for future investigation of these miRNAs as potential therapeutic targets or biomarkers.

Cardiac memory is a common cause of deep T-wave inversions (TWI) in the anterior precordial leads and can be difficult to distinguish from alternative causes of TWI such as myocardial ischemia. Cardiac memory is generally a benign condition except in the setting of prolonged QT when it can contribute to the precipitation of torsades de pointes. Herein, we describe the presentation and clinical course of a case of cardiac memory due to intermittent left bundle branch block (LBBB) that presented asymptomatically to our outpatient cardiology clinic with deep anterior TWI. We discuss common causes of and mechanisms underlying cardiac memory and how to distinguish it from alternative causes of TWI based on 12-lead electrocardiogram. In conclusion, intermittent LBBB is an under-recognized cause of cardiac memory that can present as deep anterior TWI mimicking cardiac ischemia, and awareness of this clinical entity may help prevent unnecessary invasive and expensive testing on otherwise healthy patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Long noncoding RNAs (lncRNAs) play important roles in regulating diverse cellular processes in the vessel wall, including atherosclerosis. RNA-Seq profiling of intimal lesions revealed a lncRNA, VINAS (Vascular INflammation and Atherosclerosis lncRNA Sequence), that is enriched in the aortic intima and regulates vascular inflammation. Aortic intimal expression of VINAS fell with atherosclerotic progression and rose with regression. VINAS knockdown reduced atherosclerotic lesion formation by 55% in LDL receptor-deficient (LDLR-/-) mice, independent of effects on circulating lipids, by decreasing inflammation in the vessel wall. Loss- and gain-of-function studies in vitro demonstrated that VINAS serves as a critical regulator of inflammation by modulating NF-κB and MAPK signaling pathways. VINAS knockdown decreased the expression of key inflammatory markers, such as MCP-1, TNF-α, IL-1β, and COX-2, in endothelial cells (ECs), vascular smooth muscle cells, and bone marrow-derived macrophages. Moreover, VINAS silencing decreased expression of leukocyte adhesion molecules VCAM-1, E-selectin, and ICAM-1 and reduced monocyte adhesion to ECs. DEP domain containing 4 (DEPDC4), an evolutionary conserved human ortholog of VINAS with approximately 74% homology, showed similar regulation in human and pig atherosclerotic specimens. DEPDC4 knockdown replicated antiinflammatory effects of VINAS in human ECs. These findings reveal a potentially novel lncRNA that regulates vascular inflammation, with broad implications for vascular diseases.

Despite major advances in the primary and secondary prevention of atherosclerosis and its risk factors, atherosclerotic cardiovascular disease remains a major clinical and financial burden on individuals and health systems worldwide. In addition, neointima formation and proliferation due to mechanical trauma to the vessel wall during percutaneous coronary interventions can lead to vascular restenosis and limit the longevity and effectiveness of coronary revascularization. Long noncoding RNAs (lncRNAs) have emerged as a novel class of epigenetic regulators with critical roles in the pathogenesis of atherosclerosis and restenosis following vascular injury. Here, we provide an in-depth review of lncRNAs that regulate the development of atherosclerosis or contribute to the pathogenesis of restenosis following mechanical vascular injury. We describe the diverse array of intracellular mechanisms by which lncRNAs exert their regulatory effects. We highlight the utility and challenges of lncRNAs as biomarkers. Finally, we discuss the immense translational potential of lncRNAs and strategies for targeting them therapeutically using oligonucleotide-based therapeutics and novel gene therapy platforms.

Future physicians will be key stakeholders in the formation, implementation, and success of health care policies enacted during their careers, though little is known of their opinions of enacted and proposed policies since the 2016 U.S. presidential election. This study aimed to understand the opinions of medical students related to policies including, but not limited to, protections for people with pre-existing conditions, a public option on the private exchange, and single-payer health care. Online surveys were completed by 1,660 medical students at 7 U.S. medical schools between October 2017 and November 2017. The authors used multiple logistic regression to examine associations between student characteristics and support of policies. In total, 1,660 of 4,503 (36.9%) eligible medical students completed the survey. A majority of respondents identified 4 extant Affordable Care Act policies as important, including its protections for patients with pre-existing conditions (95.3%) and Medicaid expansion (77.8%). With respect to prospective reforms, 82.6% supported a public insurance option, and 70.5% supported a single-payer health care system. Only 2.2% supported reducing funding for Medicaid. Although views varied by sex, anticipated specialty, and political affiliation, medical students largely supported prospective policies that would expand insurance coverage and access to health care.

Background Childhood adversity and trauma have been shown to be associated with poorer cardiovascular disease (CVD) outcomes in adulthood. However, longitudinal studies of this association are rare. Methods and Results Our study used the CARDIA (Coronary Artery Risk Development in Young Adults) Study, a longitudinal cohort that has followed participants from recruitment in 1985-1986 through 2018, to determine how childhood psychosocial environment relates to CVD incidence and all-cause mortality in middle age. Participants (n=3646) completed the Childhood Family Environment (CFE) questionnaire at the year 15 (2000-2001) CARDIA examination and were grouped by high, moderate, or low relative CFE adversity scores. We used sequential multivariable regression models to estimate hazard ratios of incident (CVD) and all-cause mortality. Participants were 25.1±3.6 years old, 47% black, and 56% female at baseline and 198 participants developed CVD (17.9 per 10 000 person-years) during follow-up. CVD incidence was >50% higher for those in the high CFE adversity group compared with those in the low CFE adversity group. In fully adjusted models, CVD hazard ratios (95% CI) for participants who reported high and moderate CFE adversity versus those reporting low CFE adversity were 1.40 (0.98-2.11) and 1.25 (0.89-1.75), respectively. The adjusted hazard ratios for all-cause mortality was 1.68 (1.17-2.41) for those with high CFE adversity scores and 1.55 (1.11-2.17) for those with moderate CFE adversity scores. Conclusions Adverse CFE was associated with CVD incidence and all-cause mortality later in life, even after controlling for CVD risk factors in young adulthood.

Purpose: Although medical students will influence the future U.S. health care system, their opinions on the Patient Protection and Affordable Care Act (ACA) have not been assessed since the 2016 presidential election and elimination of key ACA provisions. Understanding medical students' views on health care policy and professional obligations can provide insight into issues that will be shaped by the next generation of physicians., Method: From October 2017 to November 2017, the authors conducted an electronic survey of medical students from seven U.S. institutions to elicit opinions regarding the ACA and their professional responsibility to address health policy. Participant demographics and responses were tabulated, and multiple logistic regression models were used to assess the associations of demographic characteristics with student opinions., Results: Completed surveys were returned by 1,660/4,503 (36.9%) eligible medical students. Respondent demographics were similar to national estimates. In total, 89.1% (1,475/1,660) supported the ACA, and 82.0% (1,362/1,660) reported that they understood the health care law. Knowledge of the law's provisions was positively associated with support for the ACA (P < .001). Most students (85.8%; 1,423/1,660) reported addressing health policy to be a professional responsibility. Political affiliation was consistently associated with student opinions., Conclusions: Most medical students support the ACA, with greater levels of support among medical students who demonstrated higher levels of objective knowledge about the law. Furthermore, students indicated a professional responsibility to engage in health policy, suggesting that tomorrow's physicians are likely to participate in future health care reform efforts.

Previous studies assessing healthcare provider compliance to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines indicate a significant underuse of statin therapy at appropriate intensity. However, data are limited in primary prevention patients. Our study aimed to evaluate the impact of the 2013 ACC/AHA guidelines through a retrospective analysis of primary prevention patients presenting with first time acute coronary syndrome (ACS). We retrospectively calculated the 10-year predicted Atherosclerotic Cardiovascular Disease (10yASCVD) risk in 1,265 patients ages 40 to 75 who presented with ACS and no previous ASCVD. In patients without known ambulatory systolic blood pressure, a multivariable linear regression model was used to predict outpatient systolic blood pressure. Outcomes analyzed in each 10yASCVD category included statin status and statin intensity (high/medium/low) with further categorization by type of ACS event and date of left heart catheterization. In both primary analysis and sensitivity analysis (patients with predicted systolic blood pressure), statistical significance was shown with respect to overall statin status, ST Elevation Myocardial Infarction, and date of left heart catheterization. In summary, retrospective calculation of 10yASCVD in patients with a first ACS event showed a significant number of ACS patients would have qualified for statin therapy per 2013 ACC/AHA guidelines before their event but had not been initiated on one., (Copyright © 2018. Published by Elsevier Inc.)