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Background: An estimated two-thirds of heart failure (HF) patients with reduced ejection fraction (HFrEF) hospitalized in the United States have a severely reduced left ventricular ejection fraction (LVEF < 30%). Few studies have categorized patients according to their severity of left ventricular dysfunction beyond an LVEF of < 30%., Methods: Intermountain Health patients (≥18 years), with a primary HF diagnosis, ≥1 inpatient hospitalization with a primary discharge diagnosis of HF, a documented LVEF of < 30%, and a BNP > 100 pg/mL within one year of hospitalization were studied. Patients were stratified by LVEF levels (≤15%, 16-25%, and 26-29%) and evaluated for death, HF hospitalization, healthcare resource utilization, and medical costs., Results: Overall, 2 184 patients (mean age 64.2 ± 15.5 years, 72.5% male) were stratified by LVEF (≤15%, n = 468 [21.4%]; 16-25%, n = 1399 [64.1%]; and 26-29%, n = 317 [14.5%]). Lower LVEF was associated with younger age, male sex, and fewer comorbidities. Although one-year mortality differed significantly between LVEF stratifications, which remained after adjustment by risk factors (vs. LVEF 26-29% [referent]): ≤15%, hazard ratio (HR)=1.92, p < 0.0001; and 16-25%, HR = 1.42, p = 0.01), mortality was similar by 3-years. HF hospitalizations at 1- and 3-years were similar among LVEF groups. Total HF costs-driven by increased HF outpatient costs-were significantly higher among LVEF of ≤ 15%., Conclusions: Patients with an LVEF of ≤ 15% had a modestly increased risk of 1-year mortality, as well as significantly higher total HF costs. Patients with HFrEF and a severely reduced LVEF continue to face an increased clinicoeconomic burden, and novel therapies to treat this unmet medical need are warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background : Patient outcomes after percutaneous coronary intervention (PCI) have improved over the last 30 years due to better techniques, therapies, and care processes. This study evaluated contemporary predictors of post-PCI major adverse cardiovascular events (MACE) and summarized risk in a parsimonious risk prediction model. Methods : The Cardiovascular Patient-Level Analytical Platform (CLiPPeR) is an observational dataset of baseline variables and longitudinal outcomes from the American College of Cardiology's CathPCI Registry ® and national claims data. Cox regression was used to evaluate 2-6 years of patient follow-up (mean: 2.56 years), ending in December 2017, after index PCI between 2012 and 2015 (N = 1,450,787), to examine clinical and procedural predictors of MACE (first myocardial infarction, stroke, repeat PCI, coronary artery bypass grafting, and mortality). Cox analyses of post-PCI MACE were landmarked 28 days after index PCI. Results : Overall, 12.4% (n = 179,849) experienced MACE. All variables predicted MACE, with cardiogenic shock, cardiac arrest, four diseased coronary vessels, and chronic kidney disease having hazard ratios (HRs) ≥ 1.50. Other major predictors of MACE were in-hospital stroke, three-vessel disease, anemia, heart failure, and STEMI presentation. The index revascularization and discharge prescription of aspirin, P2Y 12 inhibitor, and lipid-lowering medication had HR ≤ 0.67. The primary Cox model had c-statistic c = 0.761 for MACE versus c = 0.701 for the parsimonious model and c = 0.752 for the parsimonious model plus treatment variables. Conclusions : In a nationally representative US sample of post-PCI patients, predictors of longitudinal MACE risk were identified, and a parsimonious model efficiently encapsulated them. These findings may aid in assessing care processes to further improve care post-PCI outcomes.

Background: Statins can improve outcomes in high-risk primary prevention populations. However, application in clinical practice has lagged., Objectives: The objective of this study was to compare an active vs a passive strategy (ie, usual care) to statin prescription for primary prevention of atherosclerotic cardiovascular disease (ASCVD)., Methods: A total of 3,770 patients ≥50 years of age without a history of ASCVD or statin use were invited to enroll in CorCal, with 601 consenting to participate. These patients were randomized 1:1 to statin initiation guided by the pooled cohort equation or by coronary artery calcium scoring (CACS). Outcomes (2.8-year follow-up) compared patients managed actively vs passively (randomly invited but declined or did not respond)., Results: Patient demographics were well matched. Statin recommendation was common among enrolled patients (41.7%). During follow-up, 25.3% of active patients were taking a statin vs 9.8% managed passively ( P  < 0.0001). Active patients had more lipid panels (median 2.0 vs 1.0), lower low-density lipoprotein cholesterol (109 vs 117 mg/dL) (both P  < 0.0001), and a low rate of major adverse cardiovascular events during follow-up (0.6% vs 1.0%, P  = 0.47). Statistical comparisons included t -tests, chi-squared tests, nonparametric tests, and time-to-event tests as appropriate., Conclusions: An active approach to statin selection for primary ASCVD prevention identified a large treatment opportunity and led to over twice as many patients on statins compared to passive (usual care) management. A large CorCal Outcomes Trial is underway to more definitively assess the impact on outcomes of active management of statins for primary prevention., Competing Interests: This study was supported by departmental funds. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Intermittent fasting may increase longevity and lower cardiometabolic risk. This study evaluated whether fasting modifies clinical risk scores for mortality [i.e., Intermountain Mortality Risk Score (IMRS)] or chronic diseases [e.g., Pooled Cohort Risk Equations (PCRE), Intermountain Chronic Disease score (ICHRON)]., Methods and Results: Subjects (N = 71) completing the WONDERFUL trial were aged 21-70 years, had ≥1 metabolic syndrome criteria, elevated cholesterol, and no anti-diabetes medications, statins, or chronic diseases. The intermittent fasting arm underwent 24-h water-only fasting twice-per-week for 4 weeks and once-per-week for 22 weeks (26 weeks total). Analyses examined the IMRS change score at 26 weeks vs. baseline between intermittent fasting (n = 38) and ad libitum controls (n = 33), and change scores for PCRE, ICHRON, HOMA-IR, and a metabolic syndrome score (MSS). Age averaged 49 years; 65% were female. Intermittent fasting increased IMRS (0.78 ± 2.14 vs. controls: -0.61 ± 2.56; p = 0.010) but interacted with baseline IMRS (p-interaction = 0.010) to reduce HOMA-IR (but not MSS) more in subjects with higher baseline IMRS (median HOMA-IR change: fasters, -0.95; controls, +0.05) vs. lower baseline IMRS (-0.29 vs. -0.32, respectively). Intermittent fasting reduced ICHRON (-0.92 ± 2.96 vs. 0.58 ± 3.07; p = 0.035) and tended to reduce PCRE (-0.20 ± 0.22 vs. -0.14 ± 0.21; p = 0.054)., Conclusions: Intermittent fasting increased 1-year IMRS mortality risk, but decreased 10-year chronic disease risk (PCRE and ICHRON). It also reduced HOMA-IR more in subjects with higher baseline IMRS. Increased IMRS suggests fasting may elevate short-term mortality risk as a central trigger for myriad physiological responses that elicit long-term health improvements. Increased IMRS may also reveal short-term fasting-induced safety concerns., Competing Interests: BDH, HTM, and JLA are inventors of risk scores (including IMRS; not ICHRON) licensed by Intermountain to Alluceo and CareCentra. BDH is a member of the advisory boards of Opsis Health and Lab Me Analytics, a consultant to Pfizer regarding risk scores (funds paid to Intermountain), PI of a risk prediction grant from 10.13039/100004325AstraZeneca, and site PI of a grant funded by the Task Force for Global Health. KUK and BDH are site PIs of grants from the Patient-Centered Outcomes Research Institute and the NIH RECOVER initiative. The authors declare no other potential conflicts of interest., (© 2023 The Authors.)

Introduction: Long-chain omega-3 polyunsaturated fatty acids (OM3 PUFA) are commonly used for cardiovascular disease prevention. High-dose eicosapentaenoic acid (EPA) is reported to reduce major adverse cardiovascular events (MACE); however, a combined EPA and docosahexaenoic acid (DHA) supplementation has not been proven to do so. This study aimed to evaluate the potential interaction between EPA and DHA levels on long-term MACE., Methods: We studied a cohort of 987 randomly selected subjects enrolled in the INSPIRE biobank registry who underwent coronary angiography. We used rapid throughput liquid chromatography-mass spectrometry to quantify the EPA and DHA plasma levels and examined their impact unadjusted, adjusted for one another, and fully adjusted for comorbidities, EPA + DHA, and the EPA/DHA ratio on long-term (10-year) MACE (all-cause death, myocardial infarction, stroke, heart failure hospitalization)., Results: The average subject age was 61.5 ± 12.2 years, 57% were male, 41% were obese, 42% had severe coronary artery disease (CAD), and 311 (31.5%) had a MACE. The 10-year MACE unadjusted hazard ratio (HR) for the highest (fourth) vs. lowest (first) quartile (Q) of EPA was HR = 0.48 (95% CI: 0.35, 0.67). The adjustment for DHA changed the HR to 0.30 (CI: 0.19, 0.49), and an additional adjustment for baseline differences changed the HR to 0.36 (CI: 0.22, 0.58). Conversely, unadjusted DHA did not significantly predict MACE, but adjustment for EPA resulted in a 1.81-fold higher risk of MACE (CI: 1.14, 2.90) for Q4 vs. Q1. However, after the adjustment for baseline differences, the risk of MACE was not significant for DHA (HR = 1.37; CI: 0.85, 2.20). An EPA/DHA ratio ≥1 resulted in a lower rate of 10-year MACE outcomes (27% vs. 37%, adjusted p -value = 0.013)., Conclusions: Higher levels of EPA, but not DHA, are associated with a lower risk of MACE. When combined with EPA, higher DHA blunts the benefit of EPA and is associated with a higher risk of MACE in the presence of low EPA. These findings can help explain the discrepant results of EPA-only and EPA/DHA mixed clinical supplementation trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor (MB) declared a past coauthorship with the authors (JN and VL)., (© 2023 Le, Knight, Watrous, Najhawan, Dao, Mccubrey, Bair, Horne, May, Muhlestein, Nelson, Carlquist, Knowlton, Jain and Anderson.)

Aims: Residual cardiovascular risk persists despite statin therapy. In REDUCE-IT, icosapent ethyl (IPE) reduced total events, but the mechanisms of benefit are not fully understood. EVAPORATE evaluated the effects of IPE on plaque characteristics by coronary computed tomography angiography (CCTA). Given the conclusion that the IPE-treated patients demonstrate that plaque burden decreases has already been published in the primary study analysis, we aimed to demonstrate whether the use of an analytic technique defined and validated in histological terms could extend the primary study in terms of whether such changes could be reliably seen in less time on drug, at the individual (rather than only at the cohort) level, or both, as neither of these were established by the primary study result., Methods and Results: EVAPORATE randomized the patients to IPE 4 g/day or placebo. Plaque morphology, including lipid-rich necrotic core (LRNC), fibrous cap thickness, and intraplaque hemorrhage (IPH), was assessed using the ElucidVivo® (Elucid Bioimaging Inc.) on CCTA. The changes in plaque morphology between the treatment groups were analyzed. A neural network to predict treatment assignment was used to infer patient representation that encodes significant morphological changes. Fifty-five patients completed the 18-month visit in EVAPORATE with interpretable images at each of the three time points. The decrease of LRNC between the patients on IPE vs. placebo at 9 months (reduction of 2 mm 3 vs. an increase of 41 mm 3 , p  = 0.008), widening at 18 months (6 mm 3 vs. 58 mm 3 increase, p  = 0.015) were observed. While not statistically significant on a univariable basis, reductions in wall thickness and increases in cap thickness motivated multivariable modeling on an individual patient basis. The per-patient response assessment was possible using a multivariable model of lipid-rich phenotype at the 9-month follow-up, p  < 0.01 (sustained at 18 months), generalizing well to a validation cohort., Conclusion: Plaques in the IPE-treated patients acquired more characteristics of stability. Reliable assessment using histologically validated analysis of individual response is possible at 9 months, with sustained stabilization at 18 months, providing a quantitative basis to elucidate drug mechanism and assess individual patient response., Competing Interests: MB receives grant support from Amarin, participates in its speaker's bureau, and receives grant support from General Electric. AB is the founder and shareholder of Elucid Bioimaging, Inc. PL is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, MedImmune, Merck, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. PL is a member of the scientific advisory board for Amgen, Caristo, Cartesian, CSL Behring, DalCor Pharmaceuticals, Dewpoint, Kowa Pharmaceuticals, Olatec Therapeutics, MedImmune, Novartis, PlaqueTec, and XBiotech, Inc. PL's laboratory has received research funding from Novartis, Genentech, and Novo Nordisk in the last 2 years. PL is on the Board of Directors of XBiotech, Inc. PL has a financial interest in Xbiotech, a company developing therapeutic human antibodies. DB discloses the following relationships—Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: Angiowave (stock options), Boston VA Research Institute, Bristol-Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures, Hims; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. JN discloses the following: Amarin, Amgen, Boehringer Ingelheim, and Boston Heart Diagnostic speaker bureaus. Consultant and advisor to and stock shareholder of Amarin Pharma and Amgen. AN was employed by Elucid Bioimaging Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Buckler, Doros, Kinninger, Lakshmanan, Le, Libby, May, Muhlestein, Nelson, Nicolaou, Roy, Shaikh, Shekar, Tayek, Zheng, Bhatt and Budoff.)

Background: The use of statins in patients with heart failure (HF) is controversial. In patients without HF, statins reduce atherosclerotic cardiovascular disease (ASCVD) risk, including HF-related events. However, in some large studies, no benefit was seen in statin-treated HF patients., Objectives: The purpose of this study was to determine the impact of statin therapy in HF with reduced ejection fraction (HFrEF)., Methods: Intermountain Healthcare medical records identified patients with a HF diagnosis and an ejection fraction of ≤40%. Patients prescribed and not prescribed a statin were compared for major adverse cardiovascular events (MACE) (death, myocardial infarction, stroke) (median of 4.5 years follow-up). Statin use was defined as use at or after a HF diagnosis but at least 60 days before MACE or end of follow-up. Cox proportional hazards regression was used to determine the relationship between statin use and outcomes., Results: A total of 15,010 patients (n = 9,641 [64%] on statins) were studied. Statin use was associated with more frequent ASCVD risk factors yet a lower risk of MACE risk (adjusted HR: 0.53; 95% CI: 0.51-0.56; P  < 0.0001). Benefit was similar for primary and secondary prevention patients and for prior and new statin prescriptions. Using time-varying hazard ratio analysis, the longer the patient was on a statin, the greater the reduction in risk of MACE ( P  < 0.0001)., Conclusions: These results suggest a potential benefit of selective statin use in the real-world management of HFrEF patients with ASCVD or at high ASCVD risk., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE: Statin treatment in patients with HFrEF is associated with a lower risk of MACE during follow-up. This benefit is observed both in the primary and for the secondary risk cohorts. Furthermore, the longer the patient was on a statin, the greater the reduction in risk of a cardiovascular event. COMPETENCY IN PATIENT CARE: The use of statins in patients with HF is controversial. Discussions with the patient about the potential benefit of statin therapy should be made. TRANSLATIONAL OUTLOOK: Although this is an observational study, it provides additional evidence of statin benefit in HF patients and the need for future pragmatic, clinical trials., (© 2023 The Authors.)

Patients with ST-elevation myocardial infarction (STEMI), but without standard modifiable risk factors (SMuRF-less), are surprisingly common and appear to have a worse, or at best similar, short-term prognosis. However, relatively little attention has been paid to the prevalence and prognosis of SMuRF-less patients with non-STEMI (NSTEMI). The aim of our study was to identify the proportion and outcomes of SMuRF-less NSTEMI patients in a large US healthcare population. Patients with NSTEMI between 2001-2021 presenting to Intermountain Healthcare hospitals and catheterization laboratories were included. SMuRF-less status was defined as no clinical diagnosis of, or treatment for, hypertension, hyperlipidemia, diabetes, and smoking. Outcomes were assessed at 60 days and long-term for major adverse cardiovascular events (MACE: death, myocardial infarction, and heart failure hospitalization). Multivariable Cox proportional hazard regression was used to determine MACE hazard ratios (HR) for SMuRF-less versus patients with SMuRF. NSTEMI patients totaled 8196, of which 1458 (17.8%) were SMuRF-less. SMuRF-less patients were younger, more frequently male, had fewer comorbidities, and were slightly less likely to have revascularization. For SMuRF-less patients, 60-day MACE outcomes were lower (adj HR = 0.55, p < 0.0001), and this persisted for long-term MACE outcomes (adj HR = 0.64, p < 0.0001) and for each of its components. In this large US healthcare population, SMuRF-less NSTEMI presentation, as with STEMI presentation, was found to be common (17.8%). However, unlike STEMI reports, short- and long-term outcomes were better for SMuRF-less patients. Further studies to increase understanding of risk factors and preventive measures for NSTEMI in SMuRF-less patients are indicated.

Background: Complex and incompletely understood metabolic dysfunction associated with inflammation and protein-energy wasting contribute to the increased mortality risk of older patients and those with chronic organ diseases affected by cachexia, sarcopenia, malnutrition, and frailty. However, these wasting syndromes have uncertain relevance for patients with cardiovascular disease or people at lower risk. Studies are hampered by imperfect objective clinical assessment tools for these intertwined metabolic malnutrition and inflammation syndromes. We aimed to assess, in two independent cohorts of patients who underwent cardiac catheterisation, the mortality risk associated with the metabolic vulnerability index (MVX), a multimarker derived from six simultaneously measured serum biomarkers plausibly linked to these dysmetabolic syndromes., Methods: In this prospective, longitudinal, observational study, we included patients aged ≥18 years recruited into the CATHGEN biorepository (Jan 2, 2001, to Dec 30, 2011) and the Intermountain Heart Collaborative Study (Sept 12, 2000, to Sept 21, 2006) who underwent coronary angiography and had clinical nuclear magnetic resonance metabolomic profiling done on frozen plasma obtained at catheterisation. We aggregated six mortality risk biomarkers (GlycA, small HDL, valine, leucine, isoleucine, and citrate concentrations) into sex-specific MVX multimarker scores using coefficients from predictive models for all-cause mortality in the CATHGEN cohort. We assessed associations of biomarkers and MVX with mortality in both cohorts using Cox proportional hazards models adjusted for 15 clinical covariates., Findings: We included 5876 participants from the CATHGEN biorepository and 2888 from the Intermountain Heart study. Median follow-up was 6·2 years (IQR 4·4-8·9) in CATHGEN and 8·2 years (6·9-9·2) in the Intermountain Heart study. The six nuclear magnetic resonance biomarkers and MVX made strong, independent contributions to 5-year mortality risk prediction in both cohorts (hazard ratio 2·18 [95% CI 2·03-2·34] in the CATHGEN cohort and 1·67 [1·50-1·87] in the Intermountain Heart cohort). CATHGEN subgroup analyses showed similar MVX associations in men and women, older and younger individuals, for death from cardiovascular or non-cardiovascular causes, and in patients with or without multiple comorbidities., Interpretation: MVX made a dominant contribution to mortality prediction in patients with cardiovascular disease and in low-risk subgroups without pre-existing disease, suggesting that metabolic malnutrition-inflammation syndromes might have a more universal role in survival than previously thought., Funding: Labcorp., Competing Interests: Declaration of interests JDO is a consultant, stockholder, and former employee of Labcorp. IS is an employee and stockholder of Labcorp. JDO and IS are co-inventors on a patent (US11156621B2) owned by Labcorp relating to multi-variable metabolic vulnerability index evaluations. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Studies primarily outside the United States have reported that SMuRF-less STEMI patients are surprisingly common (14-27%) and have a worse in-hospital/short-term prognosis. Given potential demographic and management differences over time and in the US, we aimed to identify the proportion and outcomes of SMuRF-less STEMI patients in a large US healthcare population. Patients with a first STEMI presenting to Intermountain Healthcare catheterization laboratories between 2001-2021 were included. SMuRF included a clinical diagnosis of, or treatment for, hypertension, hyperlipidemia, diabetes, and smoking. Follow-up MACE were defined as death, MI, and heart failure hospitalization (HFH) by 60 days and long-term. Qualifying STEMI patients totaled 3510, 26.2% (919) with no SMuRF. SMuRF-less patients were younger, more frequently male, and had fewer comorbidities. Neither total MACE (adj HR 0.95, p = 0.72) nor death (adj HR 1.06, p = 0.69) differed by SMuRF status at 60 days. Long-term outcomes were more frequent in SMuRF patients, which remained significant for total MACE (adj HR 0.83, p = 0.02) and HFH (HR 0.36, p = 0.0005) after adjustment for baseline differences other than SMuRF. Results were consistent through subgroup and sensitivity analyses. In this moderately large US healthcare population, SMuRF-less STEMI presentation was confirmed to be common (26.2%). However, unlike earlier, mostly non-US reports, adjusted short-term outcomes were similar, and long-term outcomes were more favorable. Further studies to increase understanding, recognition, and treatment of risk factors in SMuRF-less subjects and to optimize STEMI management are indicated.

Background: New-onset atrial fibrillation (AF) during COVID-19 infection is associated with worse cardiovascular outcomes and mortality, with new-onset AF being associated with worse clinical outcomes than recurrent AF. However, it is not known whether a prior history of AF is an independent cardiovascular risk factor predicting worse outcomes in COVID-19 patients. The present investigation sought to determine whether AF should be considered a risk factor for worse outcomes in COVID-19 illness., Methods: From March 2020-September 2021 patients testing positive for SARS-CoV-2 with a prior AF diagnosis (n = 3623) were propensity matched to non-AF SARS-CoV-2 positive patients (n = 3610). Multivariable Cox hazard regression was used to determine subsequent MACE (all-cause death, myocardial infarction, HF and stroke) risk among patients with and without AF., Results: COVID-19 patients with a prior history of AF were more likely to be hospitalized, require ICU care, supplemental oxygen, and ventilator support compared COVID-19 patients without a history of AF. There was a 1.40 times higher rate of MACE in the COVID-19 patients with prior AF compared to patients without prior AF ( p  < 0.0001). The increased rate of MACE in patients with a prior AF was primarily secondary to increases in heart failure hospitalization and death. This finding was confirmed even after controlling for acute AF during COVID-19 illness (HR 1.22, p  = 0.0009)., Conclusion: AF history was shown to be an independent risk factor for MACE during a COVID-19 illness. Both recurrent and principally new-onset AF were associated with an increased risk of poor clinical outcomes during COVID-19 illness., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V.)

Background: Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Anticoagulation use and efficacy impact long-term risk of dementia in AF patients in observational trials., Methods: The cognitive decline and dementia in patients with non-valvular atrial fibrillation (CAF) Trial was a randomized, prospective, open-label vanguard clinical study with blinded endpoint assessment involving patients with moderate- to high-risk (CHADS2 or CHA2DS2-Vasc scores of ≥2) non-valvular AF assigned to dabigatran etexilate or warfarin. The primary endpoint was incident dementia or moderate cognitive decline at 24 months., Results: A total of 101 patients were enrolled [mean age:73.7 ± 6.0 years, male: 54(53.5%)]. Prior stroke and stroke risk factors were similar between groups. Average INR over the study was 2.41 ± 0.68 in the warfarin group. No patient experienced a stroke or developed dementia. Mini-Mental Status Evaluation, Hachinski Ischemic scale, cognitive subscale of the Alzheimer's Disease Assessment Scale, Disability Assessment for Dementia, Quality of Life Improvement as assessed by Minnesota Living with Heart Failure Scale and the Anti-Clot Treatment Scale Quality of Life Survey scores did not vary at baseline or change over 2 years. Biomarker analysis indicated a similar efficacy of anticoagulation strategies., Conclusion: Use of dabigatran and well-managed warfarin therapy were associated with similar risks of stroke, cognitive decline, and dementia at 2 years, suggestive that either strategy is acceptable. The results of this Vanguard study did not support the pursuit of a larger formally powered study., Competing Interests: TJB: Research grants: Altathera, Boehinger Ingelheim, Boston Scientific, Heartline Study Steering Committee for Janssen Scientific Affairs/Johnson & Johnson, HM: None, MJC: Heartline Study Steering Committee for Janssen Scientific Affairs/Johnson & Johnson, SCW: None, VJ: None, SMS: None, JC: None, KUK: none, JBM: None, BAS: National Heart, Lung, And Blood Institute of the National Institutes of Health (#K23HL143156), and reports research support from Abbott, Boston Scientific, and Janssen; and consulting to Janssen, AltaThera, Merit Medical, and Bayer; and speaking for NACCME (funded by Sanofi), JLA: None., (© 2022 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Alcohol consumption has long been associated with cardiovascular (CV) benefit, but it also has adverse potential. Statins are currently widely used for CV prevention. We evaluated whether alcohol use is associated with lower CV risk in patients on statins. We searched Intermountain Medical Center cardiac catheterization laboratory medical records for patients with a prescription history of statin use or non-use and a self-report of alcohol use or non-use. Alcohol and statin prescription data were available together with long-term (mean [SD], 4.4 [2.4] years) major adverse CV events (MACE, including death, myocardial infarction, stroke, and heart failure hospitalizations) in 1701 patients at primary and 3266 patients at secondary CV risk. MACE rates were lower for primary prevention alcohol users than non-users not on statins (adjusted hazard ratio [adj-HR] 0.50 (95% CI 0.33, 0.78, p = 0.002), but not for those on statins (adj-HR 0.84, CI 0.54, 1.32, p = 0.45). MACE rates for secondary prevention were not reduced by alcohol consumption either in statin non-users or users (adj HR 1.18, CI 0.85, 1.64, p = 0.33; adj HR 1.08, CI 0.87, 1.35, p = 0.45, respectively). These findings, together with other recent supportive studies, can help inform personal choices in alcohol consumption and professional society recommendations for CV prevention.

Objectives: Intermittent fasting boosts some host defence mechanisms while modulating the inflammatory response. Lower-frequency fasting is associated with greater survival and lower risk from COVID-19-related comorbidities. This study evaluated associations of periodic fasting with COVID-19 severity and, secondarily, initial infection by SARS-CoV-2., Design: Prospective longitudinal observational cohort study., Setting: Single-centre secondary care facility in Salt Lake City, Utah, USA with follow-up across a 24-hospital integrated healthcare system., Participants: Patients enrolled in the INSPIRE registry in 2013-2020 were studied for the primary outcome if they tested positive for SARS-CoV-2 during March 2020 to February 2021 (n=205) or, for the secondary outcome, if they had any SARS-CoV-2 test result (n=1524)., Interventions: No treatment assignments were made; individuals reported their personal history of routine periodic fasting across their life span., Main Outcome Measures: A composite of mortality or hospitalisation was the primary outcome and evaluated by Cox regression through February 2021 with multivariable analyses considering 36 covariables. The secondary outcome was whether a patient tested positive for SARS-CoV-2., Results: Subjects engaging in periodic fasting (n=73, 35.6%) did so for 40.4±20.6 years (max: 81.9 years) prior to COVID-19 diagnosis. The composite outcome occurred in 11.0% of periodic fasters and 28.8% of non-fasters (p=0.013), with HR=0.61 (95% CI 0.42 to 0.90) favouring fasting. Multivariable analyses confirmed this association. Other predictors of hospitalisation/mortality were age, Hispanic ethnicity, prior MI, prior TIA and renal failure, with trends for race, smoking, hyperlipidaemia, coronary disease, diabetes, heart failure and anxiety, but not alcohol use. In secondary analysis, COVID-19 was diagnosed in 14.3% of fasters and 13.0% of non-fasters (p=0.51)., Conclusions: Routine periodic fasting was associated with a lower risk of hospitalisation or mortality in patients with COVID-19. Fasting may be a complementary therapy to vaccination that could provide immune support and hyperinflammation control during and beyond the pandemic., Trial Registration: Clinicaltrials.gov, NCT02450006 (the INSPIRE registry)., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: funding from the Intermountain Research and Medical Foundation through the philanthropy of the Dell Loy Hansen Heart Foundation for the submitted work; BDH has also received other research grants from the Intermountain Research and Medical Foundation for other fasting-related studies, but the authors have no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; BDH is a member of the scientific advisory boards of Opsis Health and Lab Me Analytics outside of the submitted work; BDH received a grant from AstraZeneca for prepandemic clinical risk prediction in percutaneous coronary intervention outside the submitted work, and BDH, HTM and JLA are inventors of clinical decision tools that are licensed to CareCentra and Alluceo., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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)., Competing Interests: Declaration of competing interest BDH is PI of other intermittent fasting-related grants from the Intermountain Research and Medical Foundation and a member of the scientific advisory boards of Opsis Health and Lab Me Analytics. The authors declare no other potential conflicts of interest., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2021. Published by Elsevier Inc.)

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., (© 2020. American Society of Nuclear Cardiology.)

Objectives: To support development of a robust postmarket device evaluation system using real-world data (RWD) from electronic health records (EHRs) and other sources, employing unique device identifiers (UDIs) to link to device information., Methods: To create consistent device-related EHR RWD across 3 institutions, we established a distributed data network and created UDI-enriched research databases (UDIRs) employing a common data model comprised of 24 tables and 472 fields. To test the system, patients receiving coronary stents between 2010 and 2019 were loaded into each institution's UDIR to support distributed queries without sharing identifiable patient information. The ability of the system to execute queries was tested with 3 quality assurance checks. To demonstrate face validity of the data, a retrospective survival study of patients receiving zotarolimus or everolimus stents from 2012 to 2017 was performed using distributed analysis. Propensity score matching was used to compare risk of 6 cardiovascular outcomes within 12 months postimplantation., Results: The test queries established network functionality. In the analysis, we identified 9141 patients (Mercy = 4905, Geisinger = 4109, Intermountain = 127); mean age 65 ± 12 years, 69% males, 23% zotarolimus. Separate matched analyses at the 3 institutions showed hazard ratio estimates (zotarolimus vs everolimus) of 0.85-1.59 for subsequent percutaneous coronary intervention ( P  = .14-.52), 1.06-2.03 for death ( P  = .16-.78) and 0.94-1.40 for the composite endpoint ( P  = .16-.62)., Discussion: The analysis results are consistent with clinical studies comparing these devices., Conclusion: This project shows that multi-institutional data networks can provide clinically relevant real-world evidence via distributed analysis while maintaining data privacy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Aims: Despite proven benefits of LDL-C lowering among those with atherosclerotic cardiovascular disease (ASCVD), statin adherence remains low. Very little real-world data exist on the effect of long-term statin adherence on cardiovascular outcomes., Methods and Results: A total of 7339 patients ≥18 years first diagnosed with ASCVD with a statin prescription within 12 months of diagnosis who had 5 years of continuous Select Health insurance or died during Years 2-5, while a member was studied. The proportion of days covered (PDC) was calculated using pharmacy claims for statin use by year, and patients were stratified into pre-defined categories: fully adherent [PDC ≥ 80% for Years 1-5 or until death, n = 353 (4.8%)], short-term-adherent [PDC ≥ 80% for Years 1-3, n = 330 (4.5%)], early-adherent only [PDC ≥ 80% for Year 1, n = 890 (12.1%)], complex-adherent (PDC ≥ 80% in any of Years 2-5, but not Year 1, n = 1292 [17.6%]), and non-adherent [PDC < 80% for Years 1-5 or until death, n = 3942 (72.1%)]. Patients were followed for major adverse clinical events (MACE = death, myocardial infarction, and stroke). Patients averaged 56.4 ± 9.6 years and 76.5% were male. During Year 1, statin adherence was poor, with PDC < 20% in 4007 (54.6%) patients and PDC ≥80% in 1573 (21.4%) patients, which dropped to 16.9% by Year 5. Increased adherence was associated with significantly fewer MACE (11.6%, 17.9%, 21.9%, 21.1%, and 26.4% for those fully adherent, short-term adherent, early-adherent only, complex-adherent, and non-adherent, respectively, P-trend < 0.0001). After adjustment, fully adherent was associated with a significant decrease in MACE (hazard ratio = 0.51, 0.37-0.71)., Conclusion: Among ASCVD patients with at least 5 years of continuous pharmacy benefits, long-term adherence to statins was associated with decreased long-term MACE in a linear-fashion., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

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-β signalling molecules and spectrin β. 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: This study sought to determine the feasibility of performing an extensive randomized outcomes trial comparing a coronary artery calcium (CAC)- versus a pooled cohort equations (PCE) risk score-based strategy for initiating statin therapy for primary atherosclerotic cardiovascular disease (ASCVD) prevention., Background: Statin therapy is standard for the primary prevention of ASCVD in subjects at increased risk. National guidelines recommend using the American College of Cardiology/American Heart Association PCE risk score to guide a statin recommendation. Whether guidance by a CAC score is equivalent or superior is unknown., Methods: CorCal (Effectiveness of a Proactive Cardiovascular Primary Prevention Strategy, With or Without the Use of Coronary Calcium Screening, in Preventing Future Major Adverse Cardiac Events) was a randomized trial consenting 601 patients without known ASCVD, diabetes, or prior statin therapy recruited from primary care clinics and randomized to CAC- (n = 302) or PCE guidance (n = 299) of statin initiation for primary prevention. Enrolled subjects and their physicians made final treatment decisions. Primary outcomes compared the proportion of statin recommendations received and subject adherence over 1 year between CAC- and PCE-arm subjects. Modeled medical costs, adverse effects, and low-density lipoprotein-cholesterol (LDL-C) were additional measures of interest., Results: Subjects were well matched, and 540 (89.9%) completed entry testing and received a protocol-based recommendation. A statin was recommended in 101 (35.9%) CAC-arm and 124 (47.9%) PCE-arm subjects (P = 0.005). Compared to PCE-based recommendations, CAC-arm subjects were reclassified from statin to no statin in 36.0% and from no statin to statin in 5.6% of cases, resulting in a total reclassification of 20.6%. Physicians accepted the study-dictated recommendation to start a statin in 88.1% of CAC-arm vs 75.0% of PCE-arm subjects (P = 0.01). Patient-reported adherence to this recommendation at 3 months was 62.2% vs 42.2%, respectively (P = 0.009). At 1 year, statin adherence remained superior, LDL-C levels were lower, estimated costs were similar or reduced in CAC subjects, and few events occurred., Conclusions: CAC guidance may be a more efficient, personalized, cost-effective, and motivating approach to statin initiation and maintenance in primary prevention. This feasibility phase of CorCal should be regarded as hypothesis-generating with respect to cardiovascular outcomes, which is being addressed in a large, longer-term outcomes trial. (Effectiveness of a Proactive Cardiovascular Primary Prevention Strategy, With or Without the Use of Coronary Calcium Screening, in Preventing Future Major Adverse Cardiac Events [CorCal]; NCT03439267)., Competing Interests: Funding Support and Author Disclosures All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hyperkalaemia (HK) is a serious and potentially life-threatening condition. Both acute and chronic conditions may alter potassium homeostasis. Our aim is to describe HK incidence, clinical outcomes, and associated resource use within a large, integrated healthcare system., Methods: Adult patients seen at Intermountain Healthcare facilities with a serum potassium (sK) result between January 1, 2003 and December 31, 2018 were retrospectively studied. Descriptive assessment of a population with detected HK, defined by any sK > 5.0 mmol/L and HK frequency and severity to associated resource use and characteristics of HK predictors were made. Multivariable Cox hazard regression was used to evaluate HK to outcomes., Results: Of 1,208,815 patients included, 13% had HK. Compared to no-HK, HK patients were older (60 ± 18 vs 43 ± 18 years, P < 0.001), male (51% vs 41%, P < 0.001), and had greater disease burden (Charlson Comorbidity Index 3.5 ± 2.8 vs 1.7 ± 1.4, P < 0.001). At 3 years, more HK patients experienced major adverse cardiovascular events (MACEs) (19 vs 3%, P < 0.001), persisting post-adjustment (multivariable hazard ratio = 1.60, P < 0.001). They incurred higher costs for emergency department services ($552 ± 7,574 vs $207 ± 1,930, P < 0.001) and inpatient stays ($10,956 ± 93,026 vs $1,477 ± 21,423, P < 0.001). HyperK Risk Scores for the derivation and validation cohorts were: 44% low-risk, 45% moderate-risk, 11% high-risk. Strongest HK predictors were renal failure, dialysis, aldosterone blockers, diabetes, and smoking., Conclusion: Within this large system, HK was associated with a large clinical burden, affecting over 1 in 10 patients; HK was also associated with increased 3-year MACE risk and higher medical costs. Although risk worsened with more severe or persistently recurring HK, even mild or intermittent HK episodes were associated with significantly greater adverse clinical outcomes and medical costs. The HyperK Score predicted patients who may benefit from closer management to reduce HK risk and associated costs. It should be remembered that our assumptions are valid only for detected HK and not HK per se., (© 2022. The Author(s).)

Objectives: The Intermountain Risk Score (IMRS), composed using published sex-specific weightings of parameters in the complete blood count (CBC) and basic metabolic profile (BMP), is a validated predictor of mortality. We hypothesised that IMRS calculated from prepandemic CBC and BMP predicts COVID-19 outcomes and that IMRS using laboratory results tested at COVID-19 diagnosis is also predictive., Design: Prospective observational cohort study., Setting: Primary, secondary, urgent and emergent care, and drive-through testing locations across Utah and in sections of adjacent US states. Viral RNA testing for SARS-CoV-2 was conducted from 3 March to 2 November 2020., Participants: Patients aged ≥18 years were evaluated if they had CBC and BMP measured in 2019 and tested positive for COVID-19 in 2020., Primary and Secondary Outcome Measures: The primary outcome was a composite of hospitalisation or mortality, with secondary outcomes being hospitalisation and mortality separately., Results: Among 3883 patients, 8.2% were hospitalised and 1.6% died. Subjects with low, mild, moderate and high-risk IMRS had the composite endpoint in 3.5% (52/1502), 8.6% (108/1256), 15.5% (152/979) and 28.1% (41/146) of patients, respectively. Compared with low-risk, subjects in mild-risk, moderate-risk and high-risk groups had HR=2.33 (95% CI 1.67 to 3.24), HR=4.01 (95% CI 2.93 to 5.50) and HR=8.34 (95% CI 5.54 to 12.57), respectively. Subjects aged <60 years had HR=3.06 (95% CI 2.01 to 4.65) and HR=7.38 (95% CI 3.14 to 17.34) for moderate and high risks versus low risk, respectively; those ≥60 years had HR=1.95 (95% CI 0.99 to 3.86) and HR=3.40 (95% CI 1.63 to 7.07). In multivariable analyses, IMRS was independently predictive and was shown to capture substantial risk variation of comorbidities., Conclusions: IMRS, a simple risk score using very basic laboratory results, predicted COVID-19 hospitalisation and mortality. This included important abilities to identify risk in younger adults with few diagnosed comorbidities and to predict risk prior to SARS-CoV-2 infection., Competing Interests: Competing interests: BDH, HTM, BSR and JLA are inventors of clinical decision tools that are licensed to CareCentra and Alluceo. BDH is the principal investigator (PI) of grants related to clinical decision tools that were funded by Intermountain Healthcare’s Foundry innovation programme, the Intermountain Research and Medical Foundation, CareCentra, GlaxoSmithKline and AstraZeneca. BDH is a member of the scientific advisory board of Labme.ai. KUK is PI and BDH is a coinvestigator of a grant funded by the Patient-Centered Outcomes Research Institute. IDP was supported by a grant from the National Institute of General Medical Sciences (K23GM129661). Outside the current work, IDP has received grant support from the National Institutes of Health, Centers for Disease Control and Prevention, Janssen Pharmaceuticals and Immunexpress Inc, and funding to his institution from Regeneron Pharmaceuticals. The authors have no other potential conflicts of interest to report., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Animal models repeatedly show fasting increases longevity. Human data, though, are limited to anecdotal claims. This study evaluated the association of routine fasting with survival and, secondarily, with incident major adverse cardiovascular events., Methods and Results: Cardiac catheterization patients enrolled in the Intermountain INSPIRE longitudinal cohort (n = 2785) during 2013-2015 were followed through March 2019. A fasting survey was completed in n = 2025 (73%) of this cohort and 1957 were included in the final data analysis after 68 participants were removed (24 for data issues and 44 for fasting less than 5 years). Self-reported routine fasting behaviour, years of participation in fasting, and other fasting characteristics were surveyed. Mortality was the primary outcome and incident myocardial infarction (MI), stroke, and heart failure (HF) were secondary. Routine fasters (n = 389, mean age 64 ± 14 years, 34% female) averaged 42 ± 18 years of routine fasting (minimum 5 years). Non-fasters (n = 1568, aged 63 ± 14 years, 36% female) included never fasters (n = 1120 with 0 years of fasting) and previous fasters (n = 448 who averaged 32 ± 21 years of prior fasting but had stopped prior to enrolment). Routine fasters had greater survival vs. non-fasters [adjusted hazard ratio (HR) = 0.54, 95% confidence interval (CI) = 0.36-0.80; P = 0.002] and lower incidence of HF (adjusted HR = 0.31, CI = 0.12-0.78; P = 0.013), but not MI or stroke after adjustment., Conclusions: Routine fasting followed during two-thirds of the lifespan was associated with higher survival after cardiac catheterization. This may in part be explained by an association of routine fasting with a lower incidence of HF., Clinical Study Registration: The Intermountain INSPIRE registry https://clinicaltrials.gov/, NCT02450006., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Class 1C antiarrhythmic drugs (AAD) have been associated with harm in patients treated for ventricular arrhythmias with a prior myocardial infarction. Consensus guidelines have advocated that these drugs not be used in patients with stable coronary artery disease (CAD). However, long-term data are lacking to know if unique risks exist when these drugs are used for atrial fibrillation (AF) in patients with CAD without a prior myocardial infarction., Methods: In 24,315 patients treated with the initiation of AADs, two populations were evaluated: (1) propensity-matched AF patients with CAD were created based upon AAD class (flecainide, n = 1,114, vs class-3 AAD, n = 1,114) and (2) AF patients who had undergone a percutaneous coronary intervention or coronary artery bypass graft (flecainide, n = 150, and class-3 AAD, n = 1,453). Outcomes at 3 years for mortality, heart failure (HF) hospitalization, ventricular tachycardia (VT), and MACE were compared between the groups., Results: At 3 years, mortality (9.1% vs 19.3%, P < .0001), HF hospitalization (12.5% vs 18.3%, P < .0001), MACE (22.9% vs 36.6%, P < .0001), and VT (5.8% vs 8.5%, P = .02) rates were significantly lower in the flecainide group for population 1. In population 2, adverse event rates were also lower, although not significantly, in the flecainide compared to the class-3 AAD group for mortality (20.9% vs 25.8%, P = .26), HF hospitalization (24.5% vs 26.1%, P = .73), VT (10.9% vs 14.7%, P = .28) and MACE (44.5% vs 49.5%, P = .32)., Conclusions: Flecainide in select patients with stable CAD for AF has a favorable safety profile compared to class-3 AADs. These data suggest the need for prospective trials of flecainide in AF patients with CAD to determine if the current guideline-recommended exclusion is warranted., Competing Interests: Declaration of Competing Interest Benjamin Steinberg receives support from the National Heart, Lung, And Blood Institute of the National Institutes of Health (#K23HL143156), and reports research support from Abbott, Boston Scientific, and Janssen; and consulting to Janssen, AltaThera, Merit Medical, and Bayer; and speaking for NACCME (funded by Sanofi). Ravi Ranjan is supported by NIH R01 HL142913. Ravi Fanjan also has or has had recent research grants from Biosense Webster and Abbott and is a consultant to Abbott and Biosense Webster. John Day has consulted with Abbott Medical and Boston Scientific. T. Jared Bunch MD has received research grants: Boehringer Ingelheim, Boston Scientific, Altathera. All others report no conflicts of interest relevant to this study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being administered on an unprecedented scale. Assessing the risks of side effects is needed to aid clinicians in early detection and treatment. This study examined the risk of inflammatory heart disease, including pericarditis and myocarditis, after SARS-CoV-2 vaccination., Methods: Intermountain Healthcare patients with inflammatory heart disease from December 15, 2020 to June 15, 2021, and with or without preceding SARS-CoV-2 vaccinations, were studied. Relative rates of inflammatory heart disease were examined for vaccinated patients compared to unvaccinated patients., Results: Of 67 patients identified with inflammatory heart disease, 21 (31.3%) had a SARS-Cov-2 vaccination within the previous 60 days. Overall, 914 611 Intermountain Healthcare patients received a SARS-CoV-2 vaccine, resulting in an inflammatory heart disease rate of 2.30 per 100 000 vaccinated patients. The relative risk of inflammatory heart disease for the vaccinated patients compared to the unvaccinated patients was 2.05 times higher rate within the 30-day window ( P  = .01) and had a trend toward increase in the 60-day window (relative rate = 1.63; P  = .07). All vaccinated patients with inflammatory heart disease were treated successfully with 1 death related to a pre-existing condition., Conclusions: Although rare, the rate of inflammatory heart disease was greater in a SARS-CoV-2-vaccinated population than the unvaccinated population. This risk is eclipsed by the risk of contracting coronavirus disease 2019 and its associated, commonly severe outcomes. Nevertheless, clinicians and patients should be informed of this risk to facilitate earlier recognition and treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Red cell distribution width (RDW) predicts cardiovascular outcomes, but it is unstudied with regard to intermittent fasting. In WONDERFUL trial subjects, the effect of the interaction between baseline RDW and intermittent fasting on changes in insulin and other cardiometabolic endpoints and the effect of fasting on changes in RDW were evaluated. The subjects enrolled were aged 21-70 years and were free of statins, anti-diabetes medications, and chronic diseases, and had ≥1 metabolic syndrome feature, as well as elevated low-density lipoprotein cholesterol. Subjects were randomized to 24-h, water-only fasting (twice per week for 4 weeks, once per week for 22 weeks) or 26 weeks of ad libitum eating. Subjects (N = 71; n = 38 intermittent fasting, n = 33 controls) had more substantial changes in insulin in intermittent fasting vs. controls (-3.45 ± 2.27 vs. 0.48 ± 3.55 mIU/L) when baseline RDW size distribution (RDW-SD) was ≥median (42.6 fL) than

Background: Flecainide is a useful antiarrhythmic for atrial fibrillation (AF). However, because of ventricular proarrhythmia risk, a history of myocardial infarction (MI) or coronary artery disease (CAD) is a flecainide exclusion, and stress testing is used to exclude ischemia. We assessed whether absent/mild coronary artery calcium (CAC) can supplement or avoid the need for stress testing., Methods: We assessed ischemic burden using regadenoson Rb-82 PET/CT in 1372 AF patients ≥50 years old without symptoms or signs of clinical CAD. CAC was determined qualitatively by low dose attenuation computed tomography (CT) (n = 816) or by quantitative CT (n = 556). Ischemic burden and clinical outcomes were compared by CAC burden., Results: Patients with CAC absent or mild (n = 766, 57.2%) were younger, more frequently female, and had higher BMI but lower rates of diabetes, hypertension, and dyslipidemia. Average ischemic burden was lower in CAC-absent/mild patients, and CAC-absent/mild patients showed greater coronary flow reserve, had fewer referrals for coronary angiography, and less often had obstructive CAD. Revascularization at 90 days was lower, and the rate of longer-term major adverse cardiovascular events was favorable., Conclusions: An easily administered, inexpensive, low radiation CAC scan can identify a subset of flecainide candidates with a low ischemic burden on PET stress testing that rarely needs coronary angiography/intervention and has favorable outcomes. Absent or mild CAC-burden combined with other clinical information may avoid or complement routine stress testing. However, additional, ideally randomized and multicenter trials are indicated to confirm these findings before replacing stress testing with CAC screening in selecting patients for flecainide therapy in clinical practice.

Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (N cases  = 48,072, N controls  = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease., (© 2021. The Author(s).)

Aims: Low-density lipoprotein cholesterol (LDL-C) predicts heart disease onset and may be reduced by intermittent fasting. Some studies, though, reported that fasting increased LDL-C; however, no study evaluated LDL-C as the primary endpoint. This randomized controlled trial evaluated the effect of low-frequency intermittent fasting on LDL-C and other biomarkers., Methods and Results: Adults aged 21-70 years were enrolled who were not taking a statin, had modestly elevated LDL-C, had ≥1 metabolic syndrome feature or type 2 diabetes, and were not taking anti-diabetic medication ( N = 103). Water-only 24-h fasting was performed twice weekly for 4 weeks and then once weekly for 22 weeks; controls ate ad libitum . The primary outcome was 26-week LDL-C change score. Secondary outcomes (requiring P ≤ 0.01) were 26-week changes in homeostatic model assessment of insulin resistance (HOMA-IR), Metabolic Syndrome Score (MSS), brain-derived neurotrophic factor (BDNF), and MicroCog general cognitive proficiency index (GCPi). Intermittent fasting ( n = 50) and control ( n = 53) subjects were, respectively, aged 49.3 ± 12.0 and 47.0 ± 9.8 years, predominantly female (66.0% and 67.9%), and overweight (103 ± 24 and 100 ± 21 kg) and had modest LDL-C elevation (124 ± 19 and 128 ± 20 mg/dL). Drop-outs ( n = 12 fasting, n = 20 control) provided an evaluable sample of n = 71 ( n = 38 fasting, n = 33 control). Intermittent fasting did not change LDL-C (0.2 ± 16.7 mg/dL) vs. control (2.5 ± 19.4 mg/dL; P = 0.59), but it improved HOMA-IR (-0.75 ± 0.79 vs. -0.10 ± 1.06; P = 0.004) and MSS (-0.34 ± 4.72 vs. 0.31 ± 1.98, P = 0.006). BDNF ( P = 0.58), GCPi ( P = 0.17), and weight (-1.7 ± 4.7 kg vs. 0.2 ± 3.5 kg, P = 0.06) were unchanged., Conclusions: A low-frequency intermittent fasting regimen did not reduce LDL-C or improve cognitive function but significantly reduced both HOMA-IR and MSS., Trial Registration:  clinicaltrials.gov, NCT02770313., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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., (Copyright © 2021. Published by Elsevier Inc.)

Both time in therapeutic range (TTR) for anticoagulation and depression are associated with dementia risk. The purposes of this study were to examine the impact of depression on TTR and to describe the partitioned contribution of depression and TTR on long-term dementia risk. We studied 14,953 patients anticoagulated with warfarin (target INR 2-3) for atrial fibrillation (AF), venous thromboembolism (VTE), or a mechanical heart valve from 2003 to 2015. We excluded patients with a diagnosis of dementia before or within 6 months of warfarin initiation. We examined the association of depression with TTR using finite mixture modeling and logistic regression and utilized multivariable Cox hazard regression to determine the association of TTR and depression with incident dementia at 3 and 13 years. Forty % (n = 6055) of patients were diagnosed with depression before or while on warfarin. Patients with depression had significantly lower TTR and were 1.37 times more likely to have TTR <50% than non-depressed patients (p <0.0001). During follow-up, 4.2% of patients received the diagnosis of dementia within 3 years as compared to 12% during all-time follow up. The 3-year risk of dementia was highest for patients with a ≤50% TTR regardless of depression status. The 3-year dementia risk was associated with TTR (p <0.0001) but not depression. However, for all-time dementia both TTR (p <0.0001) and depression (p <0.0001) as well as their interaction (p = 0.049) were associated with dementia. Depression increased the risk of long-term dementia by 1.69 fold (95% CI: 1.33, 2.15) for patients with the lowest TTR. Depression is prevalent in patients managed with warfarin and is associated with significant decreases in TTR. In conclusion, decreased TTR appears to increase 3-year dementia risk and both low TTR and depression interact to increase risk for all-time dementia in patients taking warfarin., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Though statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular (CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4 g/day will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography than placebo in statin-treated patients., Methods and Results: EVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography (CCTA) (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40-115 mg/dL, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9, and 18 months. Here, we present the protocol-specified interim efficacy results. A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9 months (age = 57 ± 6 years, male = 36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs. 94%, P = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque) (35% vs. 43%, P = 0.010), total plaque (non-calcified + calcified plaque) (15% vs. 26%, P = 0.0004), fibrous plaque (17% vs. 40%, P = 0.011), and calcified plaque (-1% vs. 9%, P = 0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use., Conclusion: EVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high triglyceride levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial., Clinicaltrials. Govidentifier: NCT029226027., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Low vitamin D (serum or plasma 25-hydroxyvitamin D (25(OH)D)) is a global pandemic and associates with a greater prevalence in all-cause and cardiovascular mortality and morbidity. Open-heart surgery is a form of acute stress that decreases circulating 25(OH)D concentrations and exacerbates the preponderance of low vitamin D in a patient population already characterized by low levels. Although supplemental vitamin D increases 25(OH)D, it is unknown if supplemental vitamin D can overcome the decreases in circulating 25(OH)D induced by open-heart surgery. We sought to identify if supplemental vitamin D protects against the acute decrease in plasma 25(OH)D propagated by open-heart surgery during perioperative care. Participants undergoing open-heart surgery were randomly assigned (double-blind) to one of two groups: (a) vitamin D (n = 75; cholecalciferol, 50,000 IU/dose) or (b) placebo (n = 75). Participants received supplements on three separate occasions: orally the evening before surgery and either orally or per nasogastric tube on postoperative days 1 and 2. Plasma 25(OH)D concentrations were measured at baseline (the day before surgery and before the first supplement bolus), after surgery on postoperative days 1, 2, 3, and 4, at hospital discharge (5-8 days after surgery), and at an elective outpatient follow-up visit at 6 months. Supplemental vitamin D abolished the acute decrease in 25(OH)D induced by open-heart surgery during postoperative care. Moreover, plasma 25(OH)D gradually increased from baseline to day 3 and remained significantly increased thereafter but plateaued to discharge with supplemental vitamin D. We conclude that perioperative vitamin D supplementation protects against the immediate decrease in plasma 25(OH)D induced by open-heart surgery. ClinicalTrials.gov Identifier: NCT02460211., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Aims: This analysis qualitatively describes the impact of hyperkalaemia (HK) and renin-angiotensin-aldosterone system inhibitor (RAASi) use on clinical outcomes in patients with heart failure (HF)., Methods and Results: Patients were included if they were ≥18 years old; had a serum potassium result between 1 January 2003 and 3 December 2018; had ≥2 separate, non-urgent care or emergency department encounters; and had an HF diagnosis. Criteria were met by 52 253 patients; 48 333 had sufficient follow-up for analysis. Patients were stratified by the presence/absence of HK (serum potassium >5.0 mmol/L) (n = 31 619 and n = 20 634, respectively) and by baseline left ventricular ejection fraction (LVEF) ≤40% or >40%. Compared with patients without HK (no-HK), those with HK had significantly higher rates of baseline cardiovascular risk factors, prior diagnoses, and greater RAASi use in both baseline and follow-up periods. Assessed outcomes included RAASi use, rate of 3 year major adverse cardiovascular events (MACE), and individual component rates. Between baseline and follow-up analyses, the proportion of patients on RAASi decreased by 5% in patients with HK but increased by 20% in no-HK patients. Overall, MACE and death were consistently highest in the presence of HK without RAASi treatment (63% and 62%, respectively) and lowest in no-HK but on RAASi (25% and 21%, respectively). After complete multivariable adjustment, these trends were consistent regardless of baseline LVEF., Conclusions: In this large, real-world HF population, HK was common and linked to baseline clinical risk factors, declining use of RAASi treatment, and an increase in future MACE, regardless of baseline LVEF. Both HK and reduced RAASi use were independent predictors of future MACE., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Genetic factors play an important role in nonischemic dilated cardiomyopathy (NIDC). However, prime opportunities remain for genetic discovery and prognostic understanding. TITIN gene truncating variant mutations (TTNtv) are of interest because of their frequent appearance in NIDC series. We sought to discover known and novel TTNtv mutations in a NIDC cohort and assess 5-year outcomes. Patients with NIDC entered into the INSPIRE Registry with ≥3 years of follow-up were studied. Whole exome sequencing (WES) was performed using an Illumina Novaseq platform. Genetic analysis used Sentieon software and the GRCh38 human reference genome. Variant calls were annotated with ClinVar. Five-year outcomes were determined by functional assessment and ejection fraction (EF) as recovered (EF ≥50%), persistent (EF 21% to 49%), or progressive (left ventricular assist device, transplant, heart failure [HF] or arrhythmic death, or EF ≤20%). The study comprised 229 NIDC patients (age = 50 ± 15 years, 58% men). TTNtv's were discovered in 27 patients with 22 unique mutations; (7 known, 15 novel). TTNtv+ patients more frequently presented with severe NIDC (EF ≤20%) (p = 0.032). By 5-year, outcomes were worse in TTNtv+ patients (p = 0.027), and patients less often recovered (11% vs. 30%). Prognosis was similar with known and novel mutations. Nongenetic (e.g., environmental) cocausal risk factors for HF were frequently present, and these factors frequently appeared to act in concert with genetic variants to precipitate clinical HF. In conclusion, our study expands the library of likely pathogenic TTN mutations and increases our understanding of their clinical impact in association with other HF risk factors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients., Methods and Results: A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was change in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053)., Conclusions: Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The Intermountain Chronic Disease Risk Score (ICHRON) is a primary prevention risk prediction tool that uses commonly ordered blood tests and is designed to be calculated by the electronic health record. ICHRON was highly predictive of 3-year chronic disease (ChrD) diagnosis in an internal validation; however, external validation is needed., Methods: ICHRON was calculated among patients from a region of Australia using sex-specific weightings of age and components of the comprehensive metabolic panel and the complete blood count. Original ICHRON weightings and risk stratification thresholds from the US-based derivation at Intermountain Healthcare were used. ICHRON was evaluated as a predictor of an incident 3-year ChrD diagnosis (coronary artery disease, myocardial infarction, heart failure, atrial fibrillation, stroke, dementia, diabetes, renal failure, chronic obstructive pulmonary disease, and peripheral vascular disease)., Results: A total 5,512 females (49.6 ± 19.2) and 3,461 males (53.0 ± 18.6) were studied. Among females, 50.3%, 33.7% and 16.0% were low, moderate, and high-risk, respectively; and for males, 39.6%, 35.0%, and 25.4%. Frequency of a 3-year ChrD diagnosis among females was 2.2%, 8.5%, and 15.9% for low, moderate, and high-risk groups, respectively, and 4.7%, 9.7%, and 20.0% among males. C-statistics were 0.726 (0.700, 0.752) for females and 0.694 (0.665, 0.724) for males., Conclusion: ICHRON predicted ChrD diagnosis at 3-years among an external, geographically distant validation cohort. These findings show the value of ICHRON for primary care patients in distinct locales. Additionally, electronic calculation of ICHRON empowers the clinical use of this tool to identify and differentially manage and treat high-risk patients., Competing Interests: Declaration of Competing Interest BDH, JLM, and HTM are inventors of risk scores licensed to CareCentra and Alluceo for integration into their products. BDH is PI of grants funded by Intermountain Healthcare's Foundry innovation program, the Intermountain Research and Medical Foundation, CareCentra, GlaxoSmithKline, and AstraZeneca for the development and/or clinical implementation of risk scores., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Prasugrel is a potent thienopyridine that may be preferentially used in younger patients with lower bleeding risk., Objective: We compared prasugrel use and outcomes by age from the PROMETHEUS study. We also assessed age-related trends in treatment effects with prasugrel versus clopidogrel., Methods: PROMETHEUS was a multicenter acute coronary syndrome (ACS) percutaneous coronary intervention (PCI) registry. We compared patients in age tertiles (T1 < 60 years, T2 60-70 years, T3 > 70 years). Major adverse cardiac events (MACE) were a composite of death, myocardial infarction, stroke or unplanned revascularization. Data were adjusted using multivariable Cox regression for age-related risks and propensity score stratification for thienopyridine effects., Results: The study included 19,914 patients: 7045 (35.0%) in T1, 6489 (33.0%) in T2 and 6380 (32.0%) in T3. Prasugrel use decreased from T1 to T3 (29.2% vs. 23.5% vs. 7.5%, p < 0.001). Crude 1-year MACE rates were highest in T3 (17.4% vs. 16.8% vs. 22.7%, p < 0.001), but adjusted risk was similar between the groups (p-trend 0.52). Conversely, crude incidence (2.8% vs. 3.8% vs. 6.9%, p < 0.001) and adjusted bleeding risk were highest in T3 (HR 1.24, 95% CI 0.99-1.55 in T2; HR 1.83, 95% CI 1.46-2.30 in T3; p-trend < 0.001; reference = T1). Treatment effects with prasugrel versus clopidogrel did not demonstrate age-related trends for MACE (p-trend = 0.91) or bleeding (p-trend = 0.28)., Conclusions: Age is a strong determinant of clinical risk as well as prasugrel prescription in ACS PCI with much lower use among older patients. Prasugrel did not have a differential treatment effect by age for MACE or bleeding. Frequency of prasugrel use and age-related temporal risks of all-cause death and bleeding after ACS PCI.

Statins are among the most prescribed medications because of the well-documented benefits of safely lowering low-density lipoprotein cholesterol. However, many patients are unable or unwilling to continue statin therapy because of real or perceived adverse effects. This study sought to increase understanding about which patients are unlikely to tolerate statin therapy. The Intermountain Healthcare's electronic data repository was queried from January 1, 1999, to December 31, 2013, to identify all adults who survived their first encounter of coronary artery disease (CAD), cerebral vascular disease, or peripheral artery disease and received statin therapy during follow-up. Statin intolerance (SI) was identified by the documentation of clinician-noted intolerance or allergy or by the use of pitavastatin. Patients were followed up for ≥3 years or until death. Of the 48,997 patients evaluated, 3049 (6.2%) were documented with SI. Of those with SI, 9.8% were prescribed a low-intensity, 73.4% a moderate-intensity, and 16.8% a high-intensity statin dose. After adjustment for covariables, significant predictors of SI were female sex [odds ratio (OR) = 1.47, P < 0.0001], age (65-74 vs. <65: OR = 1.15, P = 0.002; ≥75 vs. <65: OR = 0.90, P = 0.03), hypertension (OR = 1.11, P = 0.01), hyperlipidemia (OR = 1.31, P < 0.0001), smoking (OR = 0.88, P = 0.001), renal failure (OR = 1.20, P = 0.009), heart failure (OR = 1.26, P < 0.0001), sleep apnea (OR = 1.22, P < 0.0001), prior malignancy (OR = 1.18, P = 0.007), depression (OR = 1.13, P = 0.04), and index atherosclerotic cardiovascular disease diagnosis (CAD vs. cerebral vascular disease: OR = 1.71, P < 0.0001; CAD vs. peripheral artery disease: OR = 1.23, P = 0.02). In this study, the strongest identified clinical predictor of future SI was female sex. Many standard cardiovascular risk factors were also associated with SI, suggesting that patients with multiple comorbidities are more likely to be vulnerable.

Background: Stroke represents a potentially calamitous complication among patients with acute coronary syndrome (ACS) undergoing percutaneous intervention (PCI). Data on the distribution of stroke occurrence post-PCI and its impact on mortality are scarce., Objectives: We sought to determine the incidence, predictors and impact of stroke on mortality in ACS patients undergoing PCI., Methods: A total of 19,914 ACS patients underwent PCI in the PROMETHEUS multicenter observational study. We calculated the cumulative stroke incidence at 30 days and 1 year using the Kaplan Meier method. We also compared the distribution of stroke, myocardial infarction (MI), and bleeding across time and evaluated their overlap. Predictors of stroke were identified through multivariable Cox-regression. Stroke, MI, and bleeding were assessed as time-updated covariates to estimate how each impacts subsequent mortality., Results: We found that 244 patients had a stroke within 1 year, a cumulative incidence of 1.5%. Previous cerebrovascular disease was the strongest predictor for post-PCI stroke, followed by ST-elevation MI presentation, hypertension, non-ST-elevation MI presentation, smoking, female sex, and age. Mortality risk was significantly higher among those who had a stroke versus those who did not (adjusted HR 4.84, p < .0001). However, the association attenuated over time with a much larger effect in the first 30 days of its occurrence (adjusted HR 17.7; 95% CI: 12.3-25.4, p < .0001) versus beyond 30 days (adjusted HR 1.22; 95% CI: 0.6-2.46, p = .58)., Conclusions: Stroke occurrence within 1 year was not uncommon for ACS patients undergoing PCI. When compared with MI and bleeding, stroke had a substantial impact on mortality that attenuated rapidly over time., (© 2019 Wiley Periodicals, Inc.)

Atherosclerotic cardiovascular disease (ASCVD) is the most important cause of morbidity and mortality nationally and internationally. Improving ASCVD risk prediction is a high clinical priority. We sought to determine which of 3 ASCVD risk scores best predicts the need for revascularization and incident major adverse coronary events (MACE) in symptomatic patients at low-to-intermediate primary ASCVD risk referred for regadenoson-stress positron emission tomography (PET). Risk scores included the standard ASCVD pooled cohort equation (PCE), the multiethnic study of atherosclerosis (MESA) risk equation, and the coronary artery calcium score (CACS), obtained by PET. All qualifying patients in our institution at primary ASCVD risk referred for PET-stress tests in whom PCE, MESA, and CAC scores could be calculated were studied. CACS categories were: 0, 1 to 10, 11 to 299, 300 to 999, and 1000+. MESA and PCE scores were divided into quartiles. Logistic regression modeling was used to predict clinical/PET-driven early revascularization (within 90 days) and 1-year MACE (death, myocardial infarction, or any-time revascularization). A total of 981 patients (54% men, age 67 ± 10 years) qualified and were studied. Scores including CAC (MESA, CACS) performed better than PCE for predicting overall 1-year MACE (MESA p <0.001, CACS p = 0.012 vs PCE), which was driven by early revascularization. In conclusion, in a large population of patients at primary ASCVD risk referred for PET-stress testing, risk scores including CAC (CACS, MESA), which better predicted early revascularization and 1-year MACE, may be particularly useful in primary coronary risk assessment when considering whom to refer for PET-stress testing., (Copyright © 2019. Published by Elsevier Inc.)

Background: Myocardial perfusion imaging, including positron emission tomography/computed tomography (PET/CT), is often used to assess for high-grade coronary artery disease (CAD) requiring revascularization. The use of coronary artery calcium (CAC) to predict risk of major adverse cardiovascular events in asymptomatic patients is accepted. However, little is known regarding the use of CAC in PET/CT patients without known CAD in identifying patients unlikely to need revascularization. Here, we determined whether the absence of CAC, using low-dose attenuation correction CT obtained during the PET/CT, identifies patients unlikely to undergo coronary revascularization within 90 days of a PET/CT., Methods: Patients, without a history of CAD and no elevation in troponin, referred for PET/CT at Intermountain Medical Center were studied (n=5528). The presence of CAC was visually assessed using low-dose attenuation correction CT. The association between CAC and 90-day high-grade CAD and revascularization were assessed. Longer-term (up to 4 years) major adverse cardiovascular events, including all-cause death, myocardial infarction, and late revascularization (>90 days), were examined., Results: There were 2510 (45.4%) patients in CAC-present group and 3018 (54.6%) patients in CAC-absent group. The CAC-absent group, compared with the CAC-present group, was less likely to undergo coronary angiography (3.4% versus 10.2%, P <0.0001), have high-grade CAD (0.5% versus 6.5%, P <0.0001), and receive revascularization (0.4% versus 5.8%, [adjusted odds ratio =0.09; 95% CI, 0.05-0.16]; P <0.0001). In patients with an ischemic burden >10%, the CAC-absent group was associated with reduced revascularization ( P <0.0001). Longer-term major adverse cardiovascular events were lower in the CAC-absent (2.4%) compared with the CAC-present (6.9%) group (adjusted hazard ratio, 0.45 [95% CI, 0.34-0.60]; P <0.0001)., Conclusions: The absence of CAC on low-dose attenuation correction CT identifies PET/CT patients unlikely to have high-grade CAD or require revascularization within 90 days and unlikely to experience longer-term major adverse cardiovascular events. The prognostic value of CAC, beyond ischemic burden, suggests its potential as a first-step screening tool in intermediate-risk patients to identify those who do not need coronary revascularization.

Introduction: Hyperthyroidism is a known precipitating factor for atrial fibrillation (AF). However, recent reports have suggested an increased risk of AF with free thyroxine (fT4) levels even within the upper reference (normal) range. We sought to test whether higher fT4 levels within the reference range are associated with an increased risk of AF., Methods and Results: All patients in the Intermountain Healthcare electronic medical record database with an fT4 level not on thyroid medication were included. The reference range of fT4 was divided into quartiles (Q), and associations with prevalent and incident AF were assessed by multivariable regression. Similar analyses were performed for thyroid stimulating hormone (TSH) and total and free T3. A total of 174 914 patients were included and followed for 7.0 ± 4.9 years. Of these, 7.4%, 88.4%, and 4.2% had fT4 levels below, within, and above the reference range. As expected, prevalent AF was greater with elevated fT4. However, gradients also were noted within the reference range, comparing Q4 to Q1, for prevalent AF (adjusted odds ratio 1.4, P < .0001) and incident AF (adjusted hazard ratio 1.16, P < .0001). In contrast, no relationship with AF prevalence and incidence was noted for total and free T3 within their reference ranges, and the pattern for TSH was uninformative., Conclusion: Higher fT4 levels within the reference range were associated with an increased prevalence and incidence of AF. These findings in a large dataset prospectively validate earlier reports and may have important implications, including a redefinition of the normal range and fT4 targets for replacement therapy., (© 2019 Wiley Periodicals, Inc.)

Objective: To describe the structural sequelae of carbon monoxide (CO) poisoning on the heart assessed using stress cardiac MRI (CMR). CO poisoning is common. While acute cardiac injury is frequent among survivors, the mid- and long-term effects of CO on the myocardium are unclear., Methods: CMR studies performed between the years 2005 and 2014 for a primary diagnosis of CO poisoning at a tertiary care center were reviewed by an experienced cardiologist. Variables of interest were compared between patients with normal and abnormal studies to identify factors associated with cardiac dysfunction., Results: Eighty-eight patients underwent stress CMR, age 34 years (range 11-70); 49% were male, 74 had acute poisoning and 14 had chronic poisoning (CO exposure for longer than 24 hours). Time from CO poisoning to imaging was 24 months (1 day-120 months). Patients were stratified into four categories, which included those with acute poisoning imaged: ≤12 months; 12-60 months; >60 months from the event; and those with chronic poisoning. Overall, 26 studies (30%) were abnormal. The most common findings were: left ventricular systolic dysfunction in 14 patients, right ventricular systolic dysfunction in nine, and LV dilatation in six. Abnormalities were mild in most cases and were equally prevalent in all four patient categories. Dyspnea at the time of follow-up was more frequent among those with abnormal studies., Conclusion: Mild alterations in ventricular structure and function are frequent in survivors of CO poisoning. Myocardial scarring is rare, suggesting that acute hypoxic injury may not fully explain these abnormalities., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Atrial fibrillation (AF) is a source of altered brain perfusion and ischemia, potentially leading to cerebral injury and blood brain barrier (BBB) disruption, which may result in the permeation of neurospecific molecules into the bloodstream. We retrospectively analyzed circulating levels of biomarkers of cerebral injury: Astrocyte-specific glial acidic fibrillary protein (GFAP), calcium-binding protein B (S100 b), stress response marker growth differential factor 15 (GDF15), and microtubule associated Tau protein, in patients with AF and non-AF controls. A total of 196 AF cases and 47 non-AF controls were enrolled in this study all without previous clinical stroke or cerebral injury. Plasma samples were obtained from the Intermountain INSPIRE biobank registry. AF status was determined at the time of the sample draw using clinical diagnosis. Assessment of circulating biomarkers was conducted with EIA. Multivariate linear modeling, using natural log, and square root transformation of the biomarkers, was done adjusting for (1) CHA 2 DS 2 -VASc and anticoagulation, and (2) age, gender, coronary artery disease and anticoagulation. Circulating Tau, GDF15, and GFAP were elevated in AF cases. After multivariate adjustment, GFAP and Tau remained significantly elevated in the AF, whereas the signal for GDF15 was confounded by age. In conclusion, circulating biomarkers of neuronal and glial injury Tau and GFAP are elevated in patients with AF that are consistent with subclinical cerebral injury and disruption of the BBB, which can predispose these patients to the development of cognitive dysfunction and/or dementia later in life., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: MicroRNAs (miRNA)s regulate expression of genes involved in various processes including cardiac automaticity, conduction, excitability, and fibrosis and therefore may provide a diagnostic utility to identify high-risk patients for atrial fibrillation (AF). In this study, we tested the hypothesis that specific profiles of circulating miRNAs can identify patients with AF and can also help to identify patients at high risk of AF recurrence after ablation., Methods: Two patient populations were studied: 140 AF cases (93 paroxysmal and 47 persistent) and 50 healthy controls, and 141 AF ablation cases with (n = 86) and without (n = 55) 1-year recurrence. Assessment of several previously identified AF-associated plasma miRNAs (21, 29a, 133a, 133b, 150, 328) was performed with TaqMan assays, using synthetic miRNAs as standards., Results: The AF cases compared to the healthy controls were older and were more often male and hypertensive. After multivariate adjustment, higher miRNA-21 levels significantly decreased the risk of AF (OR = 0.93 per fmol/μl (95% CI = 0.89-0.98, p = 0.007)). There were no significant differences in circulating miRNAs between the AF subtypes of persistent and paroxysmal. Among the AF ablation cases, miRNA-150 was lower for those with AF recurrences at 1 year (adjusted OR = 0.98 per 500,000 fmol/μl; 95% CI = 0.965, 0.998; p = 0.039)., Conclusions: Decreased circulating miRNA-21 is associated with AF, but not with AF subtypes, suggestive that molecular mechanisms responsible for the onset and progression of the AF may be different. Circulating miRNA-150 was significantly associated with a reduction in 1-year AF recurrence post ablation suggestive of adverse structural and electrical remodeling as recurrence mechanisms.