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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. 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). 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.

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. Long non coding RNA molecules have been implicated in the immunopathology of a range of inflammatory pathologies. Here the authors show lncRNA MAARS regulates apoptosis via interaction with HuR in the context of atherosclerosis.

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. 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. 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). 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.

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.

For the last forty years in the United States, there has been a progressively widening disparity in cardiovascular disease (CVD) morbidity and mortality between rural and urban areas known as the “rural mortality penalty.” Drivers of rural-urban disparities in CVD are multifactorial, including differences in demographics, education, economic opportunity, access to care, and healthcare quality. Because of the complex and heterogenous nature of rural areas in the United States, definitions of rural vary significantly, leading to challenges in quantifying disparities and targeting interventions. Potential solutions to increase access to cardiovascular care in rural areas include initiatives to expand the primary care and cardiology workforces, build partnerships between rural healthcare providers and academic medical centers (AMC), establish more outreach clinics in underserved or poorly resourced rural communities, develop rural provider training programs, expand and improve telemedicine offerings, develop community wide CVD prevention programs, expand health insurance coverage in rural areas, continue government support of rural hospitals and address social determinants of health as rural populations often face higher rates of poverty, food insecurity, unemployment, housing instability, and limited access to education, all of which exacerbate health disparities.

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.

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. 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. 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. 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.

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.

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.