A large, multi-center survey assessing health, social support, literacy, and self-management resources in patients with heart failure.

BACKGROUND: Most patients with heart failure (HF) have multimorbidity which may cause difficulties with self-management. Understanding the resources patients draw upon to effectively manage their health is fundamental to designing new practice models to improve outcomes in HF. We describe the rationale, conceptual framework, and implementation of a multi-center survey of HF patients, characterize differences between responders and non-responders, and summarize patient characteristics and responses to the survey constructs among responders. METHODS: This was a multi-center cross-sectional survey study with linked electronic health record (EHR) data. Our survey was guided by the Chronic Care Model to understand the distribution of patient-centric factors, including health literacy, social support, self-management, and functional and mental status in patients with HF. Most questions were from existing validated questionnaires. The survey was administered to HF patients aged ≥ 30 years from 4 health systems in PCORnet® (the National Patient-Centered Clinical Research Network): Essentia Health, Intermountain Health, Mayo Clinic, and The Ohio State University. Each health system mapped their EHR data to a standardized PCORnet Common Data Model, which was used to extract demographic and clinical data on survey responders and non-responders. RESULTS: Across the 4 sites, 10,662 patients with HF were invited to participate, and 3330 completed the survey (response rate: 31%). Responders were older (74 vs. 71 years; standardized difference (95% CI): 0.18 (0.13, 0.22)), less racially diverse (3% vs. 12% non-White; standardized difference (95% CI): -0.32 (-0.36, -0.28)), and had higher prevalence of many chronic conditions than non-responders, and thus may not be representative of all HF patients. The internal reliability of the validated questionnaires in our survey was good (range of Cronbach's alpha: 0.50-0.96). Responders reported their health was generally good or fair, they frequently had cardiovascular comorbidities, > 50% had difficulty climbing stairs, and > 10% reported difficulties with bathing, preparing meals, and using transportation. Nearly 80% of patients had family or friends sit with them during a doctor visit, and 54% managed their health by themselves. Patients reported generally low perceived support for self-management related to exercise and diet. CONCLUSIONS: More than half of patients with HF managed their health by themselves. Increased understanding of self-management resources may guide the development of interventions to improve HF outcomes.

A highly predictive cardiac positron emission tomography (PET) risk score for 90-day and one-year major adverse cardiac events and revascularization.

BACKGROUND: With the increase in cardiac PET/CT availability and utilization, the development of a PET/CT-based major adverse cardiovascular events, including death, myocardial infarction (MI), and revascularization (MACE-Revasc) risk assessment score is needed. Here we develop a highly predictive PET/CT-based risk score for 90-day and one-year MACE-Revasc. METHODS AND RESULTS: 11,552 patients had a PET/CT from 2015 to 2017 and were studied for the training and development set. PET/CT from 2018 was used to validate the derived scores (n = 5049). Patients were on average 65 years old, half were male, and a quarter had a prior MI or revascularization. Baseline characteristics and PET/CT results were used to derive the MACE-Revasc risk models, resulting in models with 5 and 8 weighted factors. The PET/CT 90-day MACE-Revasc risk score trended toward outperforming ischemic burden alone [P = .07 with an area under the curve (AUC) 0.85 vs 0.83]. The PET/CT one-year MACE-Revasc score was better than the use of ischemic burden alone (P < .0001, AUC 0.80 vs 0.76). Both PET/CT MACE-Revasc risk scores outperformed risk prediction by cardiologists. CONCLUSION: The derived PET/CT 90-day and one-year MACE-Revasc risk scores were highly predictive and outperformed ischemic burden and cardiologist assessment. These scores are easy to calculate, lending to straightforward clinical implementation and should be further tested for clinical usefulness.

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Behavioral Nudges as Patient Decision Support for Medication Adherence: The ENCOURAGE Randomized Controlled Trial.

BACKGROUND: Medication adherence is generally low and challenging to address because patient actions control healthcare delivery outside of medical environments. Behavioral nudging changes clinician behavior, but nudging patient decision-making requires further testing. This trial evaluated whether behavioral nudges can increase statin adherence, measured as the proportion of days covered (PDC). METHODS: In a 12-month parallel-group, unblinded, randomized controlled trial, adult patients in Intermountain Healthcare cardiology clinics were enrolled. Inclusion required an indication for statins and membership in SelectHealth insurance. Subjects were randomized 1:1 to control or nudges. Nudge content, timing, frequency, and delivery route were personalized by CareCentra using machine learning of subject motivations and abilities from psychographic assessment, demographics, social determinants, and the Intermountain Mortality Risk Score. PDC calculation used SelectHealth claims data. RESULTS: Among 182 subjects, age averaged 63.2±8.5 years, 25.8% were female, baseline LDL-C was 82.5±32.7 mg/dL, and 93.4% had coronary disease. Characteristics were balanced between nudge (n = 89) and control arms (n = 93). The statin PDC was greater at 12 months in the nudge group (PDC: 0.742±0.318) compared to controls (PDC: 0.639±0.358, P = 0.042). Adherent subjects (PDC ≥80%) were more concentrated in the nudge group (66.3% vs controls: 50.5%, P = 0.036) while a composite of death, myocardial infarction, stroke, and revascularization was non-significant (nudges: 6.7% vs control: 10.8%, P = 0.44). CONCLUSIONS: Persuasive behavioral nudges driven by artificial intelligence resulted in a clinically important increase in statin adherence in general cardiology patients. This precision patient decision support utilized computerized nudge design and delivery with minimal on-going human input.

Insulin Growth Factor Phenotypes in Heart Failure With Preserved Ejection Fraction, an INSPIRE Registry and CATHGEN Study.

BACKGROUND: The insulin-like growth factor (IGF) axis emerged as an important pathway in heart failure with preserved ejection (HFpEF). We aimed to identify IGF phenotypes associated with HFpEF in the context of high-dimensional proteomic profiling. METHODS: From the INtermountain Healthcare Biological Samples Collection Project and Investigational REgistry for the On-going Study of Disease Origin, Progression and Treatment (Intermountain INSPIRE Registry), we identified 96 patients with HFpEF and matched controls. We performed targeted proteomics, including IGF-1,2, IGF binding proteins (IGFBP) 1-7 and 111 other proteins (EMD Millipore and ELISA). We used partial least square discriminant analysis (PLS-DA) to identify a set of proteins associated with prevalent HFpEF, pulmonary hypertension and 5-year all-cause mortality. K-mean clustering was used to identify IGF phenotypes. RESULTS: Patients with HFpEF had a high prevalence of systemic hypertension (95%) and coronary artery disease (74%). Using PLS-DA, we identified a set of biomarkers, including IGF1,2 and IGFBP 1,2,7, that provided a strong discrimination of HFpEF, pulmonary hypertension and mortality with an area under the curve of 0.91, 0.77 and 0.83, respectively. Using K mean clustering, we identified 3 IGF phenotypes that were independently associated with all-cause 5-year mortality after adjustment for age, NT-proBNP and kidney disease (P = 0.004). Multivariable analysis validated the prognostic value of IGFBP-1 and 2 in the CATHeterization GENetics (CATHGEN) biorepository. CONCLUSION: IGF phenotypes were associated with pulmonary hypertension and mortality in HFpEF.

Spectrum of radionuclide perfusion study abnormalities in takotsubo cardiomyopathy.

BACKGROUND: Takotsubo (stress) cardiomyopathy (TCM) is characterized by transient apical left ventricular dysfunction precipitated by emotional or physical stress. Its presentation makes it difficult to differentiate from an acute coronary syndrome. A suggestive echocardiogram plus normal coronary angiography most often are used for diagnosis. Radionuclide perfusion study (RPS) findings in TCM, including by positron emission tomography (PET), have been poorly characterized. METHODS AND RESULTS: Intermountain Healthcare electronic medical records were searched from 2009 to 2019 for patients with a discharge diagnosis of TCM, stress CM, or takotsubo syndrome. 16 TCM patients with an RPS, including by PET in 8, were identified: 13 (81%) were women; age averaged 72 years (50-89 years); 14 had an identified stressor. TCM diagnosis was definite in 11 and probable/possible in 5. RPS was abnormal in 11, with 9 showing an apical perfusion deficit, whereas angiography in 14 showed normal coronaries in 12 and non-obstructive disease in 2. Echo ejection fraction averaged 41% (29%-60%); an apical wall motion abnormality was present in 14 (88%). Troponin elevations were noted in 14/15. The presenting ECG was abnormal is 14, frequently showing ST-T-wave abnormalities. 13 patients were discharged on a beta-blocker. Follow-up echo (in 12) showed recovered ejection fraction in 9 and recovered apical wall motion in 11. CONCLUSIONS: Despite having normal or non-obstructive epicardial coronary arteries on angiography, TCM patients frequently present with apical wall motion abnormalities and matching RPS perfusion defects. These findings suggest microvascular abnormalities, whose pathophysiology, temporal course, and clinical implications should be the subject of further investigation.

Intermittent fasting and changes in Galectin-3: A secondary analysis of a randomized controlled trial of disease-free subjects.

BACKGROUND AND AIMS: Intermittent fasting reduces risk of interrelated cardiometabolic diseases, including type 2 diabetes and heart failure (HF). Previously, we reported that intermittent fasting reduced homeostasis model assessment of insulin resistance (HOMA-IR) and Metabolic Syndrome Score (MSS) in the WONDERFUL Trial. Galectin-3 may act to reduce insulin resistance. This post hoc evaluation assessed whether intermittent fasting increased galectin-3. METHODS AND RESULTS: The WONDERFUL Trial enrolled adults ages 21-70 years with ≥1 metabolic syndrome features or type 2 diabetes who were not taking anti-diabetic medication, were free of statins, and had elevated LDL-C. Subjects were randomized to water-only 24-h intermittent fasting conducted twice-per-week for 4 weeks and once-per-week for 22 weeks or to a parallel control arm with ad libitum energy intake. The study evaluated 26-week change scores of galectin-3 and other biomarkers. Overall, n = 67 subjects (intermittent fasting: n = 36; control: n = 31) completed the trial and had galectin-3 results. At 26-weeks, the galectin-3 change score was increased by intermittent fasting (median: 0.793 ng/mL, IQR: -0.538, 2.245) versus control (median: -0.332 ng/mL, IQR: -0.992, 0.776; p = 0.021). Galectin-3 changes correlated inversely with 26-week change scores of HOMA-IR (r = -0.288, p = 0.018) and MSS (r = -0.238, p = 0.052). Other HF biomarkers were unchanged by fasting. CONCLUSION: A 24-h water-only intermittent fasting regimen increased galectin-3. The fasting-triggered galectin-3 elevation was inversely correlated with declines in HOMA-IR and MSS. This may be an evolutionary adaptive survival response that protects human health by modifying disease risks, including by reducing inflammation and insulin resistance. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02770313 (registered on May 12, 2016; first subject enrolled: November 30, 2016; final subject's 26-week study visit: February 19, 2020).

Simplifying the ISCHEMIA trial algorithm for clinical practice: Identifying left main coronary artery disease using coronary artery calcium scans.

BACKGROUND: Several recent trials have evaluated invasive versus medical therapy for stable ischemic heart disease. Importantly, patients with significant left main coronary stenosis (LMCS) were excluded from these trials. In the ISCHEMIA trial, these patients were identified by a coronary CT angiogram (CCTA), which adds time, expense, and contrast exposure. We tested whether a coronary artery calcium scan (CACS), a simpler, less expensive test, could replace CCTA to exclude significant LMCS. METHODS: We hypothesized that patients with ≥50% LMCS would have a LM CACS score > 0. As a corollary, we postulated that a LM CACS = 0 would exclude patients with LMCS. To test this, we searched Intermountain Healthcare's electronic medical records database for all adult patients who had undergone non-contrast cardiac CT for quantitative CACS scoring prior to invasive coronary angiography (ICA). Patients aged <50 and those with a heart transplant were excluded. Cases with incomplete (qualitative) angiographic reports for LMCS and those with incomplete or discrepant LM CACS results were reviewed and reassessed blinded to CACS or ICA findings, respectively. RESULTS: Among 669 candidate patients with CACS followed by ICA, 36 qualifying patients were identified who had a quantitative CACS score and LMCS ≥ 50%. Their age averaged 71.8 years, and 81% were men. Angiographic LMCS averaged 72% (range 50%-99%). Median time between CACS and ICA was 6 days. Total CACS score averaged 2,383 Agatston Units (AU), range 571-6,636. LM CACS score averaged 197 AU, range 31-610. Importantly, no LMCS patient had a LM CACS score of 0 vs 57% (362/633) of non-LMCS controls (P < .00001). CONCLUSIONS: Our results support the hypothesis that an easily administered, inexpensive, low radiation CACS can identify a large subset of patients with a very low risk of LMCS who would not have the need for routine CCTA. Using CACS to exclude LMCS may efficiently allow for safe implementation of an initial medical therapy strategy of patients with stable ischemic heart disease in clinical practice. These promising results deserve validation in larger data sets.

Long-Term Implications of Abnormal Left Ventricular Strain During Sepsis.

OBJECTIVES: Septic cardiomyopathy develops frequently in patients with sepsis and likely increases short-term mortality. However, whether septic cardiomyopathy is associated with long-term outcomes after sepsis is unknown. We investigated whether septic patients with septic cardiomyopathy have worse long-term outcomes than septic patients without septic cardiomyopathy. DESIGN: Retrospective cohort study. SETTING: Adult ICU. PATIENTS: Adult ICU patients with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Left ventricular global longitudinal systolic strain was our primary measure of septic cardiomyopathy. We employed a suite of multivariable survival analyses to explore linear and nonlinear associations between left ventricular global longitudinal systolic strain and major adverse cardiovascular events, which included death, stroke, and myocardial infarction. Our primary outcome was major adverse cardiovascular event through 24 months after ICU discharge. Among 290 study patients, median left ventricular global longitudinal systolic strain was -16.8% (interquartile range, -20.4% to -12.6%), and 38.3% of patients (n = 111) experienced a major adverse cardiovascular event within 24 months after discharge. On our primary, linear analysis, there was a trend (p = 0.08) toward association between left ventricular global longitudinal systolic strain and major adverse cardiovascular event (odds ratio, 1.03; CI, < 1 to 1.07). On our nonlinear analysis, the association was highly significant (p < 0.001) with both high and low left ventricular global longitudinal systolic strain associated with major adverse cardiovascular event among patients with pre-existing cardiac disease. This association was pronounced among patients who were younger (age < 65 yr) and had Charlson Comorbidity Index greater than 5. CONCLUSIONS: Among patients with sepsis and pre-existing cardiac disease who survived to ICU discharge, left ventricular global longitudinal systolic strain demonstrated a U-shaped association with cardiovascular outcomes through 24 months. The relationship was especially strong among younger patients with more comorbidities. These observations are likely of use to design of future trials.

Transcatheter mitral valve in ring, hazards of long anterior mitral leaflet and 3-dimensional rings.

OBJECTIVES: The purpose of this study was to define anterior mitral leaflet (AML) length and mitral ring characteristics associated with LVOT obstruction and PVL following MViR. BACKGROUND: Transcatheter Mitral Valve in Ring (MViR) procedural complications including parvalvular leak (PVL) and left ventricular outflow tract (LVOT) obstruction are frequent. METHODS: Clinical records, computer tomographic scans (CTs) and echocardiograms of consecutive MViR patients were retrospectively reviewed for anterior mitral leaflet length, CT-simulated neoLVOT, and aortomitral angle among patients with and without MViR-induced LVOT obstruction. Acute and 1-year outcomes are described. RESULTS: Twenty-two patients underwent MViR. Technical success was achieved in 13/22 (57.1%) patients, limited by paravalvular regurgitation requiring second transcatheter heart valves (THVs) in seven patients. Second valves were needed in 6/11 (54.5%) patients with 3-dimensional rings but 1/11 (9.1%, p = .06) of patients with planar rings. Procedure success at 30 days was achieved in 20/22 (90.9%) patients. There were no procedural, in-hospital, or 30-day deaths. Two patients developed significant LVOT obstruction, one managed with urgent surgery and one with elective alcohol septal ablation. Anterior mitral leaflets were longer among the two patients with LVOT obstruction than the 20 patients who did not develop LVOT obstruction when measured by TEE (30 mm vs. 21 mm, p = .009) or by CT (29 mm vs. 22 mm, p = .026). CONCLUSIONS: AML >25 mm increases the risk of MViR induced LVOT obstruction. PVL is common, particularly in 3-dimensional rings which can be managed with a second THV.

Cost-effectiveness of managing low-risk pulmonary embolism patients without hospitalization. The low-risk pulmonary embolism prospective management study.

OBJECTIVE: Evaluate the cost-effectiveness and difference in length-of-stay when patients in the ED diagnosed with low-risk pulmonary embolism (PE) are managed with early discharge or observation. METHODS: Single cohort prospective management study from January 2013 to October 2016 of patients with PE diagnosed in the ED and evaluated for a primary composite endpoint of mortality, recurrent venous thromboembolism, and/or major bleeding event at 90 days. Low-risk patients had a PE Severity Index score < 86, no evidence of proximal deep vein thrombosis on venous compression ultrasonography of both lower extremities, and no evidence of right heart strain on echocardiography. Patients were managed either in the ED or in the hospital on observation status. Primary outcomes were total length of stay, total encounter costs, and 30-day costs. RESULTS: 213 patients were enrolled. 13 were excluded per the study protocol. Of the remaining 200, 122 were managed with emergency department observation (EDO) and 78 with hospital observation (HO). One patient managed with EDO met the composite outcome due to a major bleeding event on day 61. The mean length of stay for EDO was 793.4 min (SD -169.7, 95% CI:762-823) and for HO was 1170 (SD -211.4, 95% CI:1122-1218) with a difference of 376.8 (95% CI: 430-323, p < 0.0001). Total encounter mean costs for EDO were $1982.95 and $2759.59 for HO, with a difference of $776.64 (95% CI: 972-480, p > 0.0001). 30-day total mean costs for EDO were $2864.14 and $3441.52 for HO, with a difference of $577.38 (95% CI: -1372-217, p = 0.15). CONCLUSIONS: Patients with low-risk PE managed with ED-based observation have a shorter length of stay and lower total encounter costs than patients managed with Hospital-based observation.

Risk score-guided multidisciplinary team-based Care for Heart Failure Inpatients is associated with lower 30-day readmission and lower 30-day mortality.

OBJECTIVE: Using augmented intelligence clinical decision tools and a risk score-guided multidisciplinary team-based care process (MTCP), this study evaluated the MTCP for heart failure (HF) patients' 30-day readmission and 30-day mortality across 20 Intermountain Healthcare hospitals. BACKGROUND: HF inpatient care and 30-day post-discharge management require quality improvement to impact patient health, optimize utilization, and avoid readmissions. METHODS: HF inpatients (N = 6182) were studied from January 2013 to November 2016. In February 2014, patients began receiving care via the MTCP based on a phased implementation in which the 8 largest Intermountain hospitals (accounting for 89.8% of HF inpatients) were crossed over sequentially in a stepped manner from control to MTCP over 2.5 years. After implementation, patient risk scores were calculated within 24 hours of admission and delivered electronically to clinicians. High-risk patients received MTCP care (n = 1221), while lower-risk patients received standard HF care (n = 1220). Controls had their readmission and mortality scores calculated retrospectively (high risk: n = 1791; lower risk: n = 1950). RESULTS: High-risk MTCP recipients had 21% lower 30-day readmission compared to high-risk controls (adjusted P = .013, HR = 0.79, CI = 0.66, 0.95) and 52% lower 30-day mortality (adjusted P < .001, HR = 0.48, CI = 0.33, 0.69). Lower-risk patients did not experience increased readmission (adjusted HR = 0.88, P = .19) or mortality (adjusted HR = 0.88, P = .61). Some utilization was higher, such as prescription of home health, for MTCP recipients, with no changes in length of stay or overall costs. CONCLUSIONS: A risk score-guided MTCP was associated with lower 30-day readmission and 30-day mortality in high-risk HF inpatients. Further evaluation of this clinical management approach is required.

Failure of vital sign normalization is more strongly associated than single measures with mortality and outcomes.

BACKGROUND: Modified Early Warning Systems (MEWS) scores offer proxies for morbidity and mortality that are easily acquired, but there are limited data on what changing MEWS scores within the ED indicate. We examined the correlation of changing MEWS scores during resuscitation in the ED and in-hospital morbidity and mortality. METHODS: We conducted a retrospective analysis on medical ED patients with simplified MEWS scores (without urine output or mental status) admitted to a single academic tertiary care center over one year. Triage-to-Last delta MEWS score and Triage-to-Max delta MEWS scores were calculated and correlated to in-hospital mortality, ICU admission, length of stay (LOS) and diagnosis of sepsis. RESULTS: Our analysis included 8322 ED patients with an ICU admission rate of 17% and a mortality rate of 2%. Every point of worsened MEWS after triage was more strongly associated with all-cause mortality (OR 2.41, 95% CI 1.96-2.97) than triage MEWS alone (OR 1.33, 95% CI 1.23-1.44; p < 0.001). Likewise, each point of worsened MEWS was associated with increased odds of ICU admission (Triage-to-Last: OR 2.12, 95% CI 1.92-2.33 and Triage-to-Max: OR 1.52, 95% CI 1.45-1.60, respectively). Among patients with suspected infection, similar associations are found. CONCLUSIONS: Dynamic vital signs in the emergency department, as categorized by delta MEWS, and failure to normalize abnormalities, were associated with increased mortality, ICU admission, LOS, and the diagnosis of sepsis. Our results suggest that MEWS scores that do not normalize, from triage onward, are more strongly associated with outcome than any single score.

Augmented intelligence decision tool for stroke prediction combines factors from CHA2 DS2 -VASc and the intermountain risk score for patients with atrial fibrillation.

INTRODUCTION: CHA2 DS2 -VASc and CHADS2 are computationally simple risk prediction tools used to guide anticoagulation decisions for stroke prophylaxis, but they have modest risk discrimination ability and use static dichotomous variables. The Intermountain Mortality Risk Scores (IMRS) are dynamic decision tools using standard clinical laboratory tests. This study derived new stroke prediction scores using variables from both CHA2 DS2 -VASc and IMRS. METHODS AND RESULTS: In outpatients with first atrial fibrillation (AF) diagnosis at the Intermountain Healthcare (females, n = 26 063 males, n = 29 807), sex-specific "IMRS-VASc" scores were derived using variables from CHA2 DS2 -VASc, warfarin use, the complete blood count, and the comprehensive metabolic profile. Validation was performed in an independent Intermountain outpatient AF cohort (females, n = 11 021; males, n = 12 641). Stroke occurred among 3.1% and 3.1% of females and 2.3% and 2.5% of males in derivation and validation groups, respectively. IMRS-VASc stratified stroke with similar ability in derivation (c-statistics, females: c = 0.703, males: c = 0.697) and validation groups (females: c = 0.681, males: c = 0.685). CHA2 DS2 -VASc (females: c = 0.581 and c = 0.605; males: c = 0.616 and c = 0.613 in derivation and validation, respectively) and CHADS2 (females: c = 0.581 and c = 0.608; males: c = 0.620 and c = 0.621 in derivation and validation, respectively) were substantially weaker stroke predictors. IMRS was the strongest mortality predictor (females: c = 0.783 and c = 0.782; males: c = 0.796 and c = 0.794 in derivation and validation, respectively) and all scores were poor at predicting bleeding risk. CONCLUSIONS: A temporally dynamic risk score, IMRS-VASc was derived and validated as a predictor of stroke in outpatients with AF. IMRS-VASc requires further validation and the evaluation of its use in guiding care and treatment decisions for patients with AF.

Short-Term Elevation of Fine Particulate Matter Air Pollution and Acute Lower Respiratory Infection.

RATIONALE: Nearly 60% of U.S. children live in counties with particulate matter less than or equal to 2.5 µm in aerodynamic diameter (PM2.5) concentrations above air quality standards. Understanding the relationship between ambient air pollution exposure and health outcomes informs actions to reduce exposure and disease risk. OBJECTIVES: To evaluate the association between ambient PM2.5 levels and healthcare encounters for acute lower respiratory infection (ALRI). METHODS: Using an observational case-crossover design, subjects (n = 146,397) were studied if they had an ALRI diagnosis and resided on Utah's Wasatch Front. PM2.5 air pollution concentrations were measured using community-based air quality monitors between 1999 and 2016. Odds ratios for ALRI healthcare encounters were calculated after stratification by ages 0-2, 3-17, and 18 or more years. MEASUREMENTS AND MAIN RESULTS: Approximately 77% (n = 112,467) of subjects were 0-2 years of age. The odds of ALRI encounter for these young children increased within 1 week of elevated PM2.5 and peaked after 3 weeks with a cumulative 28-day odds ratio of 1.15 per +10 µg/m3 (95% confidence interval, 1.12-1.19). ALRI encounters with diagnosed and laboratory-confirmed respiratory syncytial virus and influenza increased following elevated ambient PM2.5 levels. Similar elevated odds for ALRI were also observed for older children, although the number of events and precision of estimates were much lower. CONCLUSIONS: In this large sample of urban/suburban patients, short-term exposure to elevated PM2.5 air pollution was associated with greater healthcare use for ALRI in young children, older children, and adults. Further exploration is needed of causal interactions between PM2.5 and ALRI.

Early inpatient calculation of laboratory-based 30-day readmission risk scores empowers clinical risk modification during index hospitalization.

Improving 30-day readmission continues to be problematic for most hospitals. This study reports the creation and validation of sex-specific inpatient (i) heart failure (HF) risk scores using electronic data from the beginning of inpatient care for effective and efficient prediction of 30-day readmission risk. METHODS: HF patients hospitalized at Intermountain Healthcare from 2005 to 2012 (derivation: n=6079; validation: n=2663) and Baylor Scott & White Health (North Region) from 2005 to 2013 (validation: n=5162) were studied. Sex-specific iHF scores were derived to predict post-hospitalization 30-day readmission using common HF laboratory measures and age. Risk scores adding social, morbidity, and treatment factors were also evaluated. RESULTS: The iHF model for females utilized potassium, bicarbonate, blood urea nitrogen, red blood cell count, white blood cell count, and mean corpuscular hemoglobin concentration; for males, components were B-type natriuretic peptide, sodium, creatinine, hematocrit, red cell distribution width, and mean platelet volume. Among females, odds ratios (OR) were OR=1.99 for iHF tertile 3 vs. 1 (95% confidence interval [CI]=1.28, 3.08) for Intermountain validation (P-trend across tertiles=0.002) and OR=1.29 (CI=1.01, 1.66) for Baylor patients (P-trend=0.049). Among males, iHF had OR=1.95 (CI=1.33, 2.85) for tertile 3 vs. 1 in Intermountain (P-trend <0.001) and OR=2.03 (CI=1.52, 2.71) in Baylor (P-trend < 0.001). Expanded models using 182-183 variables had predictive abilities similar to iHF. CONCLUSIONS: Sex-specific laboratory-based electronic health record-delivered iHF risk scores effectively predicted 30-day readmission among HF patients. Efficient to calculate and deliver to clinicians, recent clinical implementation of iHF scores suggest they are useful and useable for more precise clinical HF treatment.

Clinical Decision Support to Efficiently Identify Patients Eligible for Advanced Heart Failure Therapies.

BACKGROUND: Patients who need and receive timely advanced heart failure (HF) therapies have better long-term survival. However, many of these patients are not identified and referred as soon as they should be. METHODS: A clinical decision support (CDS) application sent secure email notifications to HF patients' providers when they transitioned to advanced disease. Patients identified with CDS in 2015 were compared with control patients from 2013 to 2014. Kaplan-Meier methods and Cox regression were used in this intention-to-treat analysis to compare differences between visits to specialized and survival. RESULTS: Intervention patients were referred to specialized heart facilities significantly more often within 30 days (57% vs 34%; P < .001), 60 days (69% vs 44%; P < .0001), 90 days (73% vs 49%; P < .0001), and 180 days (79% vs 58%; P < .0001). Age and sex did not predict heart facility visits, but renal disease did and patients of nonwhite race were less likely to visit specialized heart facilities. Significantly more intervention patients were found to be alive at 30 (95% vs 92%; P = .036), 60 (95% vs 90%; P = .0013), 90 (94% vs 87%; P = .0002), and 180 days (92% vs 84%; P = .0001). Age, sex, and some comorbid diseases were also predictors of mortality, but race was not. CONCLUSIONS: We found that CDS can facilitate the early identification of patients needing advanced HF therapy and that its use was associated with significantly more patients visiting specialized heart facilities and longer survival.

Clinically Feasible Stratification of 3-Year Chronic Disease Risk in Primary Care: The Mental Health Integration Risk Score.

BACKGROUND: Depression is a common illness that imposes a disproportionately large health burden. Depression is generally associated with a higher prevalence of chronic disease risk factors and may contribute to higher chronic disease risk. OBJECTIVE: This study aimed to create and validate sex-specific Mental Health Integration Risk Scores (MHIRS) that predict 3-year chronic disease diagnosis. METHODS: MHIRS was created to predict the first diagnosis of any of the 10 chronic diseases in patients completing a Patient Health Questionnaire-9 Depression Survey who were free at baseline from those 10 chronic disease diagnoses. MHIRS used sex-specific weightings of Patient Health Questionnaire 9 results, age, and components of the complete metabolic profile and complete blood count in randomly chosen derivation (70%) and validation (30%) groups. RESULTS: Among females (N = 10,162, age: 48 ± 16), c-statistics for the composite chronic disease end point were 0.746 (0.725, 0.767) for the derivation group and 0.717 (0.682, 0.753) for the validation group, whereas males (N = 4615, age: 48 ± 15) had 0.755 (0.727, 0.783) and 0.742 (0.702, 0.782). In the validation group, MHIRS strata of low-, moderate-, and high-risk categories had hazard ratios (HR) for any 3-year chronic disease diagnosis among females of HR = 3.42 for moderate vs low and HR = 9.75 for high vs low, whereas males had HR = 4.80 and HR = 10.68, respectively (all p < 0.0001). CONCLUSION: A clinical decision tool comprised by depression severity and common laboratory tests, and MHIRS provides very good stratification of a 3-year chronic disease diagnosis. Designed to be calculated electronically by an electronic health record, MHIRS can be efficiently obtained by clinicians to identify patients at higher chronic disease risk who require further evaluation and more precise clinical management.

Distribution and medical impact of loss-of-function variants in the Finnish founder population.

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹7). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.