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Purpose: We compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT)., Patients and Methods: In 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ 2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores., Results: Patient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years ( P  = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years ( P  = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance ( P  = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up ( P  < 0.001 for all). Higher magnitudes of recovery from absenteeism (at 1 year, P  = 0.05; and at 2 years, P  = 0.04) and composite work impairment scores (at 1 year, P  = 0.04; and at 2 years, P  = 0.04) were seen in patients treated with IMPT versus those treated with IMRT., Conclusion: In patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank reports grants and personal fees from Hitachi. Outside the submitted work, Dr Frank is a cofounder of C4 Imaging, LLC, for which he reports grants and personal fees, and he reports grants from Eli Lilly and Elekta, other remuneration from Breakthrough Chronic Care, and personal fees from Varian, Augmenix, and the National Comprehensive Cancer Center (NCCN). The other authors have no conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: To characterize our experience and the disease control and toxicity of proton therapy (PT) for patients with head and neck cancer (HNC)., Patients and Methods: Clinical outcomes for patients with HNC treated with PT at our institution were prospectively collected in 2 institutional review board-approved prospective studies. Descriptive statistics were used to summarize patient characteristics and outcomes. Overall survival, local-regional control, and disease-free survival were estimated by the Kaplan-Meier method. Treatment-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events (version 4.03) scale., Results: The cohort consisted of 573 patients treated from February 2006 to June 2018. Median patient age was 61 years. Oropharynx (33.3%; n = 191), paranasal sinus (11%; n = 63), and periorbital tissues (11%; n = 62) were the most common primary sites. Patients with T3/T4 or recurrent disease comprised 46% (n = 262) of the cohort. The intent of PT was definitive in 53% (n = 303), postoperative in 37% (n = 211), and reirradiation in 10% (n = 59). Median dose was 66 Gy (radiobiological equivalent). Regarding systemic therapy, 43% had received concurrent (n = 244), 3% induction (n = 19), and 15% (n = 86) had both. At a median follow-up of 2.4 years, 88 patients (15%) had died and 127 (22%) developed disease recurrence. The overall survival, local-regional control, and disease-free survival at 2 and 5 years were, respectively, 87% and 75%, 87% and 78%, and 74% and 63%. Maximum toxicity (acute or late) was grade 3 in 293 patients (51%), grade 2 in 234 patients (41%), and grade 1 in 31 patients (5%). There were 381 acute grade 3 and 190 late grade 3 unique toxicities across 212 (37%) and 150 (26%) patients, respectively. There were 3 late-grade 4 events across 2 patients (0.3%), 2 (0.3%) acute-grade 5, and no (0%) late-grade 5 events., Conclusions: The overall results from this prospective study of our initial decade of experience with PT for HNC show favorable disease control and toxicity outcomes in a multidisease-site cohort and provide a reference benchmark for future comparison and study., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank is a scientific advisory board member of Breakthrough Chronic Care; he has received research grants from C4 Imaging, Eli Lilly, Elekta, and Hitachi, and he has reported personal fees from Varian Medical Systems, Inc (consultant/advisory board), C4 Imaging (founder and director), Hitachi (honoraria/advisory board), Augmenix (honoraria), and National Comprehensive Cancer Center (board member). Stephen G. Chun, MD, is a consultant for AstraZeneca, PLC. The authors report no other conflicts of interest., (©Copyright 2021 The Author(s).)

The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as a broader recognition of extrapulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and focus on the early initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PAH today is an early diagnosis for prompt initiation of treatment to achieve a minimal symptom burden; optimize the patient's biochemical, hemodynamic, and functional profile; and limit adverse events. To accomplish this end, clinicians must be familiar with novel risk factors and the revised hemodynamic definition for PAH. Fresh insights into the role of developmental biology (i.e., perinatal health) may also be useful for predicting incident PAH in early adulthood. Emergent or underused approaches to PAH management include a novel TGF-β ligand trap pharmacotherapy, remote pulmonary arterial pressure monitoring, next-generation imaging using inert gas-based magnetic resonance and other technologies, right atrial pacing, and pulmonary arterial denervation. These and other PAH state of the art advances are summarized here for the wider pulmonary medicine community.

Opinion Statement: The rise in the incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC), the relatively young age at which it is diagnosed, and its favorable prognosis necessitate the use of treatment techniques that reduce the likelihood of side effects during and after curative treatment. Intensity-modulated proton therapy (IMPT) is a form of radiotherapy that de-intensifies treatment through dose de-escalation to normal tissues without compromising dose to the primary tumor and involved, regional lymph nodes. Preclinical studies have demonstrated that HPV-positive squamous cell carcinoma is more sensitive to proton radiation than is HPV-negative squamous cell carcinoma. Retrospective studies comparing intensity-modulated photon (X-ray) radiotherapy to IMPT for OPC suggest comparable rates of disease control and lower rates of pain, xerostomia, dysphagia, dysgeusia, gastrostomy tube dependence, and osteoradionecrosis with IMPT-all of which meaningfully affect the quality of life of patients treated for HPV-associated OPC. Two phase III trials currently underway-the "Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck" and the "TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)" trial-are expected to provide prospective, level I evidence regarding the effectiveness of IMPT for such patients.

Aims: We sought to compare the generalizability and prognostic implications of heart failure with preserved ejection fraction (HFpEF) scores (HFA-PEFF and H 2 FPEF score) in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial participants and matched controls from the Atherosclerosis Risk in Community (ARIC) study., Methods and Results: Based on the respective scores, the study participants from the TOPCAT (N = 356), RELAX (N = 216), and ARIC (N = 379) studies were categorized as having a low, intermediate, or high likelihood of HFpEF. Age, sex, and race matched controls free of cardiovascular disease who had unexplained dyspnoea were used to evaluate the diagnostic performance. The prognostic value of scores was assessed using multivariable-adjusted Cox regression analyses. The median HFA-PEFF scores in the TOPCAT, RELAX, and ARIC studies were 5.0 [interquartile range (IQR): 5.0-6.0], 4.0 (IQR: 2.0-4.0), and 3.0 (IQR: 2.0-4.0), respectively. The median H 2 FPEF scores in the three studies were 5.5 (IQR: 4.0-7.0), 6.0 (IQR: 4.0-7.0), and 3.0 (IQR: 2.0-5.0), respectively. A low HFA-PEFF and H 2 FPEF score can rule out HFpEF with high sensitivity (99.5% and 99.6%, respectively) and negative predictive value (95.7% and 98.3%, respectively). A high HFA-PEFF and H 2 FPEF score can rule-in HFpEF with good specificity (82.8% and 95.6%, respectively) and positive predictive value (79.9% and 90.4%, respectively). Among TOPCAT participants, the hazard for adverse cardiovascular events per point increase in HFA-PEFF and H 2 FPEF score was 1.26 (95% confidence interval: 0.98-1.63) and 1.01 (95% confidence interval: 0.88-1.15), respectively. A higher H 2 FPEF score was associated with lower peak oxygen intake in RELAX trial participants (adjusted P = 0.01)., Conclusions: The HFA-PEFF and the H 2 FPEF scores are reliable diagnostic tools for HFpEF. The prognostic utility of HFpEF scores requires further validation in larger rigorously phenotyped populations., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest.

Importance: The variant V122I is commonly enriched in the transthyretin (TTR) gene in individuals of African ancestry and associated with greater risk of heart failure (HF) in older adulthood, after age 65 years. Prevention of HF may be most effective earlier in life, but whether screening with echocardiography can identify subclinical cardiac abnormalities during middle age to risk-stratify individuals appears to be unknown., Objective: To examine the association between the V122I TTR variant and cardiac structure and function during middle age in those without prevalent HF., Design, Setting, and Participants: This serial cross-sectional study of 875 Black participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort was conducted at 4 urban sites across the US. Recruiting was completed in 1985-1986, and follow-up examinations occurred 25 and 30 years later. A subset of Black adults from the CARDIA cohort who underwent TTR genotyping was included. Data analysis was completed from January 2020 to October 2020., Exposures: The V122I TTR genotype., Main Outcomes and Measures: Echocardiographic left ventricular (LV) circumferential and longitudinal systolic strain and LV structure, measured at years 25 and 30 of follow-up. The analyses were adjusted for age, sex, echocardiography quality, genetic ancestry, and field center., Results: Among the 875 Black adults (mean [SD] age, 49.4 [3.8] years at year 25; 543 women [62.1%]), there were 31 individuals who were heterozygous and 1 who was homozygous for the V122I TTR variant. Of the adults who had an echocardiogram at year 25, rates of hypertension (312 [46%]), diabetes (102 [15%]), and current smoking (128 [19%]) were not significantly different between those who did and did not carry V122I TTR. At year 25, there was no difference in LV circumferential strain, longitudinal strain, or LV structure between those who did vs did not carry V122I TTR. At year 30, those who carried V122I TTR had significantly lower absolute LV circumferential strain (mean [SD], 12.4 [4.2] percentage units) compared with those who did not carry the variant (mean [SD], 14.5 [3.7] percentage units). Those who carried V122I TTR also had significantly higher LV mass index values (mean [SD], 97.5 [34.1] g/m2) compared with those who did not (mean [SD], 83.7 [22.6] g/m2) at year 30., Conclusions and Relevance: Carrier status for the V122I TTR variant is associated with subclinical cardiac abnormalities in middle age (worse LV systolic function and higher LV mass) that have been associated with increased risk of incident HF. Midlife screening of individuals who carry V122I TTR with echocardiography may prognosticate risk of symptomatic HF and inform prevention strategies.

Purpose: Cyclic guanosine monophosphate (cGMP) is a second messenger for natriuretic peptide (NP) and nitric oxide pathways; its enhancement a target for heart failure and cardiovascular disease (CVD). We evaluated whether plasma cGMP was associated with change in left ventricular mass (LVM) among individuals free of CVD and if this differed by sex. Methods and Results: In 611 men and 612 women aged 45-84 years with plasma cGMP measured at baseline and cardiac MRI performed at baseline and 10 years later, we tested associations of cGMP [log-transformed, per 1 SD increment] with LVM, adjusting for CVD risk factors and N-terminal pro-B-type-NP (NT-proBNP). Participants had mean (SD) age of 63.1(8.5) years and cGMP 4.8(2.6) pmol/mL. Cross-sectionally, higher cGMP was associated with lesser LVM, non-lin- early. In contrast, longitudinally, higher cGMP was associated with increase in LVM [1.70g (0.61, 2.78)] over 10 years. Higher cGMP was associated with greater LVM change in men [2.68g (1.57, 3.79)] but not women [0.24g ((-0.92, 1.39); p-interaction < 0.001]. Conclusion: In conclusion, in a community-based cohort, higher cGMP levels were associated with increase in LVM over 10 years independent of CVD risk factors and NT-proBNP in men, perhaps reflecting compensatory changes. Further studies are needed to understand mechanistic roles of cGMP in LV remodelling and associated sex differences.

[Figure: see text].

Background: Older adults with atrial fibrillation (AF) have multiple risk factors for disablement. Long-term function and the contribution of strokes to disability have not been previously characterized. Our objective was to determine long-term function among older adults with AF and the relative contribution of stroke., Methods: We used data from the nationally representative Health and Retirement Study (1992-2014) with participants ≥65 years with incident AF. We examined the association of incident stroke with three outcomes: independence with activities of daily living (ADL), instrumental activities of daily living (IADL), and residence outside a nursing home (community-dwelling). We fit logistic regression models with repeated measures adjusting for comorbidities and demographics to estimate the effect of stroke on function. We estimated the contribution of strokes to the overall population burden of disability using the method of recycled predictions., Results: Among 3530 participants (median age 79 years, 53% women), 262 had a stroke over 17,396 person-years. Independent of stroke and accounting for comorbidities, annually, ADL independence decreased by 4.4%, IADL independence decreased by 3.9%, and community dwelling decreased by 1.2% (p < 0.05 for all). Accounting for comorbidities, of those who experienced a stroke, 31.9% developed new ADL dependence, 26.5% developed new IADL dependence, and 8.6% newly moved to a nursing home (p < 0.05 for all). Considering all causes of function loss, 1.7% of ADL disability-years, 1.2% of IADL disability-years, and 7.3% of nursing home years could be attributed to stroke over 7.4 years., Conclusion: Older adults lose substantial function over time following AF diagnosis, independent of stroke. Stroke was associated with a significant functional decline and increase in the likelihood of nursing home move, but stroke did not accelerate subsequent disability accrual. Because of the high background rate of disability, stroke was not the dominant determinant of population-level disability in older adults with AF., (© 2021 The American Geriatrics Society.)

Purpose of Review: This review discusses the mechanisms, clinical implications, and treatments of left atrial (LA) myopathy in comorbid atrial fibrillation (AF) and heart failure (HF) across the spectrum of ejection fraction., Recent Findings: AF and HF are highly comorbid conditions. Left atrial (LA) myopathy, characterized by impairments in LA structure, function, or electrical conduction, plays a fundamental role in the development of both AF and HF with preserved ejection fraction (AF-HFpEF) along with AF and HF with reduced ejection fraction (AF-HFrEF). While the nature of LA myopathy in AF-HFpEF is unique from that of AF-HFrEF, LA myopathy also leads to progression of both of these conditions. There may be a vulnerable cohort of AF-HF patients who have a disproportionate degree of LA myopathy compared with left ventricular (LV) dysfunction. Further investigations are required to identify therapies to improve LA function in this cohort.

Transthyretin amyloid cardiomyopathy, an often unrecognized cause of heart failure, is now treatable with a transthyretin stabilizer. It is therefore important to identify at-risk patients who can undergo targeted testing for earlier diagnosis and treatment, prior to the development of irreversible heart failure. Here we show that a random forest machine learning model can identify potential wild-type transthyretin amyloid cardiomyopathy using medical claims data. We derive a machine learning model in 1071 cases and 1071 non-amyloid heart failure controls and validate the model in three nationally representative cohorts (9412 cases, 9412 matched controls), and a large, single-center electronic health record-based cohort (261 cases, 39393 controls). We show that the machine learning model performs well in identifying patients with cardiac amyloidosis in the derivation cohort and all four validation cohorts, thereby providing a systematic framework to increase the suspicion of transthyretin cardiac amyloidosis in patients with heart failure.

Patients with rare conditions such as cardiac amyloidosis (CA) are difficult to identify, given the similarity of disease manifestations to more prevalent disorders. The deployment of approved therapies for CA has been limited by delayed diagnosis of this disease. Artificial intelligence (AI) could enable detection of rare diseases. Here we present a pipeline for CA detection using AI models with electrocardiograms (ECG) or echocardiograms as inputs. These models, trained and validated on 3 and 5 academic medical centers (AMC) respectively, detect CA with C-statistics of 0.85-0.91 for ECG and 0.89-1.00 for echocardiography. Simulating deployment on 2 AMCs indicated a positive predictive value (PPV) for the ECG model of 3-4% at 52-71% recall. Pre-screening with ECG enhance the echocardiography model performance at 67% recall from PPV of 33% to PPV of 74-77%. In conclusion, we developed an automated strategy to augment CA detection, which should be generalizable to other rare cardiac diseases.

Objectives: The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF)., Background: There are no proven effective treatments for patients with PH-HFpEF., Methods: Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1 ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages., Results: Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (-1.4 mm Hg; 95% confidence interval [CI]: -7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (-3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo., Conclusions: Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603)., Competing Interests: Funding Support and Author Disclosures This study was supported by TENAX Therapeutics. TENAX participated in the execution of the study. Data were collected and analyzed by a clinical research organization. Analysis and interpretation of the data were performed by an independent statistician and the investigators (no role of sponsor). The manuscript was prepared by the investigators. The sponsor was allowed to review the manuscript before submission but had no role in preparing or approval. Dr. Burkhoff has received an institutional research grant from TENAX Therapeutics; and advisory board/consulting from Impulse Dynamics, Corvia Medical, and Axon Therapies. Dr. Borlaug has received research grants from the National Institutes of Health (R01 HL128526, U01 HL125205), AstraZeneca, Corvia, Medtronic, Mesoblast, GlaxoSmithKline, and TENAX Therapeutics; and advisory board/consulting fees for Aria, Actelion, Boehringer-Ingelheim, Imbria, Janssen, Merck, Novartis, Lilly, Novo Nordisk, Pfizer, and VADovations. Dr. Shah has received research grants from the National Institutes of Health (R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), American Heart Association (16SFRN28780016), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapeutics, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GlaxoSmithKline, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Shifamed, TENAX, and United Therapeutics. Dr. Zolty has received research grants from the National Institutes of Health (P01 HL108797, R01 HL134905, R01 LM01), Actelion, TENAX Therapeutics, Gossamer Bio, Lung Biotech, and United Therapeutics; consulting/advisory board for Morphegen-IX, Vivus, Actelion, and Pfizer; and patent holder of FK506 for the treatment of pulmonary hypertension. Dr. Tedford has received institution research funding from TENAX Therapeutics as part of this study; has consulting relationships with Medtronic, Aria CV, Acceleron, Arena Pharmaceuticals, and United Therapeutics; is on the steering committees for Medtronic, Acceleron, and Abbott; on the research advisory board for Abiomed; and does hemodynamic core laboratory work for Actelion and Merck. Dr. Thenappan has received research grants from the Cardiovascular Medical Research and Education Fund, Lillehei Heart Institute High Risk and High Reward Award, United Therapeutics, and TENAX Therapeutics; and consulting/advisory board for United Therapeutics, Actelion, and Altavant Sciences. Dr. Zamanian has consulted for United Therapeutics, Actelion, and Alnylam. Dr. Mazurek has received advisory board honoraria from Actelion Pharmaceuticals and United Therapeutics; has received speaker honoraria from Abbott; and has received research support from Actelion, Complexa, and Corvia. Dr. Rich has consulted for Abbott, Medtronic, Boehringer-Ingelheim, and Novartis. Dr. Simon has received research grants from the National Institutes of Health (R01 AG058659, P01 HL103455), Aadi Biosciences, and Novartis; and has received consulting fees from Actelion, Acceleron, Altavant, United Therapeutics. Dr. Chung has received consulting fees from Abbott, Medtonic, Intershunt, LivaNova, CVRx, and EBR. Dr. Raza has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Majure has received a research grant from TENAX Therapeutics. Dr. Lewis has received research grants from the National Institutes of Health (1R01HL131029, R01HL151841, and AHA GPSGC24800006), Amgen, Applied Therapeutics, AstraZeneca, Corvia, Cytokinetics, and Novartis; and consulting/advisory board for American Reagent, AstraZeneca, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Cytokinetics, Ironwood, Merck, Novartis, and Pfizer. Dr. Preston has received research grants from Acceleron, Actelion, Complexa, PhaseBio, United Therapeutics, and TENAX Therapeutics; steering committee for Acceleron, Actelion, and United Therapeutics; is on the consulting/advisory board for Actelion, Gilead, Liquidia, and United Therapeutics; and data and safety monitoring board for Pfizer. Dr. Rich has received consulting from TENAX Therapeutics., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO - heart rate and stroke volume - and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses., Methods and Results: Data from two prospective trials of HFpEF (n = 108) and a study of healthy participants (n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39-56% of patients with HFpEF and 3-56% of healthy participants depending on the definition used, but some (n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m 2 , healthy participants: +24 ± 12 mL/m 2 , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF., Conclusion: The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response., (© 2021 European Society of Cardiology.)

Background: Myocardial strain, measured by speckle-tracking echocardiography, is a novel measure of subclinical cardiovascular disease and may reflect myocardial aging. We evaluated the association between myocardial strain and frailty-a clinical syndrome of lack of physiological reserve., Methods: Frailty was defined in participants of the CHS (Cardiovascular Health Study) as having ≥3 of the following clinical criteria: weakness, slowness, weight loss, exhaustion, and inactivity. Using speckle-tracking echocardiography data, we examined the cross-sectional (n=3206) and longitudinal (n=1431) associations with frailty among participants who had at least 1 measure of myocardial strain, left ventricular longitudinal strain (LVLS), left ventricular early diastolic strain rate and left atrial reservoir strain, and no history of cardiovascular disease or heart failure at the time of echocardiography., Results: In cross-sectional analyses, lower (worse) LVLS was associated with prevalent frailty; this association was robust to adjustment for left ventricular ejection fraction (adjusted odds ratio, 1.32 [95% CI, 1.07-1.61] per 1-SD lower strain; P =0.007) and left ventricular stroke volume (adjusted OR, 1.32 [95% CI, 1.08-1.61] per 1-SD lower strain; P =0.007). In longitudinal analyses, adjusted associations of LVLS and left ventricular early diastolic strain with incident frailty were 1.35 ([95% CI, 0.96-1.89] P =0.086) and 1.58 ([95% CI, 1.11-2.27] P =0.013, respectively). Participants who were frail and had the worst LVLS had a 2.2-fold increased risk of death (hazard ratio, 2.20 [95% CI, 1.81-2.66]; P <0.0001)., Conclusions: In community-dwelling older adults without prevalent cardiovascular disease, worse LVLS by speckle-tracking echocardiography, reflective of subclinical myocardial dysfunction, was associated with frailty. Frailty and LVLS have an additive effect on mortality risk.

Introduction: An increasing number of patients are voicing their opinions and expectations about the quality of care in online forums and on physician rating websites (PRWs). This paper analyzes patient online reviews (PORs) to identify emerging and fading topics and sentiment trends in PRWs during the early stage of the COVID-19 outbreak., Methods: Text data were collected, including 55,612 PORs of 3430 doctors from three popular PRWs in the United States (RateMDs, HealthGrades, and Vitals) from March 01 to June 27, 2020. An improved latent Dirichlet allocation (LDA)-based topic modeling (topic coherence-based LDA [TCLDA]), manual annotation, and sentiment analysis tool were applied to extract a suitable number of topics, generate corresponding keywords, assign topic names, and determine trends in the extracted topics and specific emotions., Results: According to the coherence value and manual annotation, the identified taxonomy includes 30 topics across high-rank and low-rank disease categories. The emerging topics in PRWs focus mainly on themes such as treatment experience, policy implementation regarding epidemic control measures, individuals' attitudes toward the pandemic, and mental health across high-rank diseases. In contrast, the treatment process and experience during COVID-19, awareness and COVID-19 control measures, and COVID-19 deaths, fear, and stress were the most popular themes for low-rank diseases. Panic buying and daily life impact, treatment processes, and bedside manner were the fading themes across high-rank diseases. In contrast, provider attitude toward patients during the pandemic, detection at public transportation, passenger, travel bans and warnings, and materials supplies and society support during COVID-19 were the most fading themes across low-rank diseases. Regarding sentiment analysis, negative emotions (fear, anger, and sadness) prevail during the early wave of the COVID-19., Conclusion: Mining topic dynamics and sentiment trends in PRWs may provide valuable knowledge of patients' opinions during the COVID-19 crisis. Policymakers should consider these PORs and develop global healthcare policies and surveillance systems through monitoring PRWs. The findings of this study identify research gaps in the areas of e-health and text mining and offer future research directions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: This study investigated the prognostic importance of heart failure (HF) signs and symptoms in patients with heart failure and preserved ejection fraction (HFpEF), and the effect of sacubitril/valsartan on HF signs and symptoms., Background: In patients with HFpEF, worsening of HF symptoms, as a marker of cardiac decompensation, is frequently the reason for hospitalization. In this heterogenous disease entity, the prognostic value of HF signs and symptoms with regard to cardiovascular (CV) outcomes is poorly defined., Methods: The authors examined the association between baseline HF signs and symptoms (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, and third heart sound) as well as burden of these HF signs and symptoms (classified as ≤2 and ≥3 HF signs and symptoms) and the primary composite of total HF hospitalizations and CV death, its components, and all-cause death in 4,725 patients enrolled in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HFpEF) with available signs and symptoms at randomization. Response to sacubitril/valsartan on the basis of the presence of signs and symptoms was evaluated. Effects of sacubitril/valsartan on signs and symptoms over time were assessed using binary repeated-measures logistic regression., Results: Patients with high (≥3) burden of HF signs and symptoms (n = 1,772 [38%]) were more commonly women, had slightly lower left ventricular ejection fractions, higher body mass index, and more advanced New York Heart Association functional class compared with patients with low (≤2) burden (n = 2,953 [62%]) (p < 0.001 for all). Levels of N-terminal pro-B-type natriuretic peptide did not differ significantly between groups (p = 0.14). Greater burden of signs and symptoms was associated with higher risk for total HF hospitalizations and CV death (rate ratio [RR]: 1.50; 95% confidence interval [CI]: 1.30 to 1.74) and all-cause death (RR: 1.41; 95% CI: 1.21 to 1.65). Among individual signs and symptoms, orthopnea (RR: 1.29; 95% CI: 1.04 to 1.61) and rales (RR: 1.52; 95% CI: 1.10 to 2.10) were most predictive of the primary endpoint. Treatment response to sacubitril/valsartan was not significantly modified by burden of HF signs and symptoms (p for interaction = 0.08), though patients with orthopnea appeared to derive greater benefit from sacubitril/valsartan (RR: 0.67; 95% CI: 0.49 to 0.90) than those without orthopnea (RR: 0.97; 95% CI: 0.82 to 1.14; p for interaction = 0.04). Compared with valsartan, sacubitril/valsartan did not significantly decrease overall burden of HF signs and symptoms over time (odds ratio: 0.84; 95% CI: 0.67 to 1.07) but did reduce exertional dyspnea (odds ratio: 0.76; 95% CI: 0.63 to 0.93)., Conclusions: High burden of HF signs and symptoms, particularly the presence of orthopnea and rales, portends a higher risk for adverse CV events in patients with HF with preserved ejection fraction. Sacubitril/valsartan did not significantly decrease the burden of HF signs and symptoms over time but did reduce exertional dyspnea relative to valsartan. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., Competing Interests: Funding Support and Author Disclosures PARAGON-HF was funded by Novartis. Dr. Jering is supported by the National Institutes of Health (training grant 5-T32 HL007604). Dr. Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, and Novartis. Dr. Redfield has served as an unpaid consultant for Novartis. Dr. Shah has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapies, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GlaxoSmithKline, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr. Anand has received fees for serving as U.S. national leader of a trial for AstraZeneca; receives fees for serving on steering committees for ARCA Biopharma, Amgen, LivaNova, and Novartis; has received fees for serving on an endpoint committee for Boehringer Ingelheim; has received fees for serving as chair of a data and safety monitoring board for Boston Scientific; and has received advisory board fees from Zensun. Dr. Martinez has received personal fees from AstraZeneca, Novartis, and Boehringer Ingelheim as honoraria. Drs. Sabarwal and Lefkowitz are salaried employees of Novartis. Dr. Seferović has received honoraria for lectures for Medtronic, Abbott, Servier, AstraZeneca, and Respicardia; has consultancy agreements with and has received honoraria for lectures from Boehringer Ingelheim and Novartis; and has a consultancy agreement with Vifor Pharma. Dr. Saraiva has received lecture fees from Amgen, Merck Sharpe & Dohme, and Pfizer; has received lecture fees, fees for serving on advisory boards, consulting fees, and fees for serving as a national leader of clinical trials from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk; and has received lecture fees and fees for serving on advisory boards from Eli Lilly and Servier. Dr. Katova has received lecture fees, fees for serving on an advisory board, and travel support from Novartis; and receives lecture fees, consulting fees, and fees for serving on an advisory board from AstraZeneca. Dr. Pfeffer has received consulting fees from AstraZeneca, DalCor, GlaxoSmithKline, Novo Nordisk, Sanofi, Jazz, MyoKardia, Servier, Takeda, and Corvidia. Dr. McMurray’s employer, Glasgow University, has received funding for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardurion, Cytokinetics, DalCor, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from Abbott, Hickma Pharmaceuticals, Sun Pharmaceuticals, and Servier. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Respicardia, Sanofi-Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, and Moderna. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

Background/objectives: Obesity increases with age, is disproportionately prevalent in black populations, and is associated with heart failure with preserved ejection fraction (HFpEF). An "obesity paradox," or improved survival with obesity, has been reported in patients with HFpEF. The aim of this study was to examine whether racial differences exist in the temporal trends and outcomes associated with obesity among older patients with HFpEF., Design: Community surveillance of acute decompensated heart failure (ADHF) hospitalizations, sampled by stratified design from 2005 to 2014., Setting: Atherosclerosis Risk in Communities Study (NC, MS, MD, MN)., Participants: A total of 10,147 weighted hospitalizations for ADHF (64% female, 74% white, mean age 77 years), with ejection fraction ≥50%., Measurements: ADHF classified by physician review, HFpEF defined by ejection fraction ≥50%. Body mass index (BMI) calculated from weight at hospital discharge. Obesity defined by BMI ≥30 kg/m 2 , class III obesity by BMI ≥40 kg/m 2 ., Results: When aggregated across 2005-2014, the mean BMI was higher for black compared to white patients (34 vs 30 kg/m 2 ; P < .0001), as was prevalence of obesity (56% vs 43%; P < .0001) and class III obesity (24% vs 13%; P < .0001). Over time, the annual mean BMI and prevalence of class III obesity remained stable for black patients, but steadily increased for white patients, with annual rates statistically differing by race (P-interaction = .04 and P = .03, respectively). For both races, a U-shaped adjusted mortality risk was observed across BMI categories, with the highest risk among patients with a BMI ≥40 kg/m 2 ., Conclusion: Black patients were disproportionately burdened by obesity in this decade-long community surveillance of older hospitalized patients with HFpEF. However, temporal increases in mean BMI and class III obesity prevalence among white patients narrowed the racial difference in recent years. For both races, the worst survival was observed with class III obesity. Effective strategies are needed to manage obesity in patients with HFpEF., (© 2021 The American Geriatrics Society.)

Aims: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan., Methods and Results: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up., Conclusions: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Early, noninvasive identification of patients with heart failure with preserved ejection fraction (HFpEF) with congestion may allow timely tailoring of decongestive therapies. The 2016 American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines provide an algorithm to assess for elevated left atrial pressure (LAP); the associations of echocardiographic LAP with clinical status and disease progression in patients with HFpEF are unclear., Methods: Participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF trial were categorized into one of four prespecified guideline-based echocardiographic LAP categories: (1) normal, (2) elevated, (3) atrial fibrillation (AF) at the time of echocardiography, or (4) indeterminate. Associations of echocardiographic LAP categories with baseline exercise capacity, change in exercise capacity, and change in N-terminal pro-B-type natriuretic peptide over 24 weeks were evaluated., Results: Of 216 participants, 199 underwent mitral inflow Doppler echocardiography for LAP categorization. Participants with elevated echocardiographic LAP (n = 81) or AF (n = 57) were older and had a higher prevalence of kidney dysfunction. Compared with the normal echocardiographic LAP group (n = 28), elevated echocardiographic LAP and AF were each independently associated with a greater reduction in peak oxygen consumption over 24 weeks after adjusting for baseline values and clinical covariates (β for elevated echocardiographic LAP = -1.55 [95% CI, -2.59 to -0.51], P = .004; β for AF = -1.33 [95% CI, -2.49 to -0.17], P = .03). Indeterminate echocardiographic LAP (n = 33) was also independently associated with a reduction in exercise capacity at 24 weeks compared with normal echocardiographic LAP (β = -1.35; 95% CI, -2.51 to -0.19; P = .02). Finally, elevated echocardiographic LAP and AF were significantly associated with increases in N-terminal pro-B-type natriuretic peptide over 24 weeks compared with normal echocardiographic LAP., Conclusions: In patients with chronic HFpEF, elevated echocardiographic LAP and indeterminate echocardiographic LAP, as defined by contemporary guidelines, and AF were each independently associated with a reduction in exercise capacity compared with normal echocardiographic LAP. These findings suggest the potential utility of noninvasive LAP assessment in patients with HFpEF for tailoring treatments that decrease congestion., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background Emergency cricothyrotomy is a critical, yet infrequently performed and time-sensitive procedure that requires practice in order to be reliably completed in emergent airway situations. Many physicians never have the opportunity to practice this rarely performed but highly impactful procedure during their training due to a lack of an affordable, high-fidelity training model. In this study, the educational impact and realism of a new synthetic cricothyrotomy training model (high-fidelity emergency cricothyrotomy, HiFEC) were compared with those of a standard porcine explant model. Methodology A total of thirty-one attending physicians from four medical specialties were recruited on a volunteer basis to participate in a cricothyrotomy simulation workshop. Participants were randomly assigned to complete the initial workshop using one of the two models but had the opportunity to practice on both trainers. Pre- and post-workshop comfort level as well as the realism of the models were surveyed using questionnaires and evaluated using a five-point Likert scale. Results Improvements in self-reported comfort levels were seen in both the porcine group (p = 0.0014) and HiFEC group (p = 0.0036) as well as overall (p < 0.001). The realism rating of both training models was similar with a median score of 4 on a five-point Likert scale. When comparing the cost of conducting our workshop using these models, the synthetic model saved over $650. Conclusions Given the similar realism of the models and the improvement in participant comfort level, the synthetic HiFEC trainer is an effective and more affordable alternative training model for emergency cricothyrotomies., Competing Interests: The Principal Investigator (FNJ) consulted on the design and initial iterative testing of the HiFEC model but has no financial interests to disclose; the model was designed and developed by Lazarus 3D, Inc. Other authors (TTJ, SJS, NBD) declare no competing interests., (Copyright © 2021, Jing et al.)

Objective: This study systematically reviews the existing literature on the management of hereditary angioedema (HAE) and provides an update on the clinical presentation and specific therapies., Methods: A literature search of PubMed and Embase databases was conducted from start of the database to February 2021. Inclusion criteria included relevant systematic reviews, randomized control clinical trials, prospective and retrospective cohort studies, and outcomes research published in English and available in full-text. Out of 310 candidate articles, a total of 55 articles were included in our study., Results: The most common genetic form of HAE in up to 85% of cases is caused by low levels of C1 esterase inhibitor (C1-INH) protein, leading to a bradykinin-mediated increase in vascular permeability. During an attack of HAE, abortive treatment with C1-INH replacement is most commonly described, however, icatibant, ecallantide, or fresh frozen plasma are also used. Long-term prophylaxis in the form of C1-INH replacement (subcutaneous or intravenous), monoclonal antibodies targeting plasma kallikrein, attenuated androgens, and transexemic acid should be considered for those who suffer from frequent, severe attacks., Conclusion: Progressively distal involvement of the upper airway, especially the larynx, has been shown to pose an increased risk of asphyxiation and death in the acute presentation of HAE. Evaluation by an otolaryngologist is often sought during the emergent clinical management of HAE; therefore, it is prudent that the consulting physician is well-versed in the prompt recognition, triage of patients, and appropriate treatment modalities., Level of Evidence: 1A., Competing Interests: Dr. Craig does research, consults and speaks for Biocryst, CSL Behring, Grifols, Pharming, Ionis and Takeda., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Objectives: The radial artery pulse waveform is a continuous measure of pressure throughout the cardiac cycle, and thus can provide more information than just systolic and diastolic blood pressures. New indices based on a Windkessel model of the waveform, PTC1 and PTC2, are related to arterial compliance and add information for prediction of incident cardiovascular disease (coronary heart disease, stroke, myocardial infarction) but their association with heart failure is unknown., Methods: Among 6229 adults (mean age 62 years) from four race/ethnic groups who were initially free of clinical cardiovascular disease and heart failure in 2000-2002, we evaluated the associations of baseline PTC1 and PTC2 with incident heart failure., Results: Mean ± standard deviation PTC1 and PTC2 were 394 ± 334 and 94 ± 46 ms, respectively. During a median of 15.7 years follow-up, there were 357 heart failure events (148 with reduced, 150 with preserved, and 59 with unknown ejection fraction). After adjustment for traditional risk factors, the hazard ratio for heart failure per 1 standard deviation higher PTC2 was 0.73 (95% confidence interval: 0.63--0.85). Higher PTC2 was also significantly associated with lower risk of heart failure with reduced ejection fraction (hazard ratio = 0.67; 95% confidence interval: 0.56--0.80). There was no evidence of a significant association between PTC2 and heart failure with preserved ejection fraction or between PTC1 and heart failure., Conclusion: The PTC2 measure of the radial artery pulse waveform may represent a novel phenotype related to heart failure, especially heart failure with reduced ejection fraction., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The goal of this work was to investigate the role of t-tubule (TT) remodeling in abnormal Ca 2+ cycling in ventricular myocytes of failing dog hearts. Heart failure (HF) was induced using rapid right ventricular pacing. Extensive changes in echocardiographic parameters, including left and right ventricular dilation and systolic dysfunction, diastolic dysfunction, elevated left ventricular filling pressures, and abnormal cardiac mechanics, indicated that severe HF developed. TT loss was extensive when measured as the density of total cell volume, derived from three-dimensional confocal image analysis, and significantly increased the distances in the cell interior to closest cell membrane. Changes in Ca 2+ transients indicated increases in heterogeneity of Ca 2+ release along the cell length. When critical properties of Ca 2+ release variability were plotted as a function of TT organization, there was a complex, nonlinear relationship between impaired calcium release and decreasing TT organization below a certain threshold of TT organization leading to increased sensitivity in Ca 2+ release below a TT density threshold of 1.5%. The loss of TTs was also associated with a greater incidence of triggered Ca 2+ waves during rapid pacing. Finally, virtually all of these observations were replicated by acute detubulation by formamide treatment, indicating an important role of TT remodeling in impaired Ca 2+ cycling. We conclude that TT remodeling itself is a major contributor to abnormal Ca 2+ cycling in HF, reducing myocardial performance. The loss of TTs is also responsible for a greater incidence of triggered Ca 2+ waves that may play a role in ventricular arrhythmias arising in HF. NEW & NOTEWORTHY Three-dimensional analysis of t-tubule density showed t-tubule disruption throughout the whole myocyte in failing dog ventricle. A double-linear relationship between Ca 2+ release and t-tubule density displays a steeper slope at t-tubule densities below a threshold value (∼1.5%) above which there is little effect on Ca 2+ release (T-tubule reserve). T-tubule loss increases incidence of triggered Ca 2+ waves. Chemically induced t-tubule disruption suggests that t-tubule loss alone is a critical component of abnormal Ca 2+ cycling in heart failure.

Background: Independent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied., Methods: We pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF., Results: A total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF., Conclusions: Midlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes., Methods and Results: The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age ± standard deviation, 64.3 ± 8.0 vs. 62.5 ± 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all P difference  < 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54-0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93-1.36), P heterogeneity  < 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin-to-creatinine ratio, were similar between groups (all P difference  > 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (-0.52% vs. -0.64%, P heterogeneity  = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all P heterogeneity  > 0.07)., Conclusions: Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood., Objectives: The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF., Methods: In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term., Results: WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF., Conclusions: Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF., Competing Interests: Funding Support and Author Disclosures The TOPCAT study was supported by a contract from the National Heart, Lung, and Blood Institute, National Institutes of Health (HHSN268200425207C). Dr. Beldhuis has received a research grant from the Dutch Heart Foundation. Dr. Myhre has received speaker fees from Novartis. Dr. Lewis has received research grants from Novartis, Amgen, and Sanofi; and has served as a consultant for and serves on the advisory boards of Modest and Novartis. Dr. Pitt has served as a consultant for Pfizer, Bayer, Relypsa, AstraZeneca, and KBP Biosciences; holds a pending patent related to site-specific delivery of eplerenone to the myocardium; and holds stock options in Relypsa and KBP Biosciences. Dr. Shah has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GlaxoSmithKline, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr. Vardeny has received research support from AstraZeneca. Dr. Voors has received consultancy fees from Amgen, Bayer, Boehringer Ingelheim, Merck/Merck Sharp & Dohme, Novartis, Roche Diagnostics, Sanofi, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, and Vifor; has received research grants from Boehringer Ingelheim and Roche Diagnostics; and has received research support from Singulex, Sphingotec, and Vifor. Dr. Pfeffer has received research support from Novartis; has served as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, DalCor, Genzyme, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Novo Nordisk, Sanofi, Teva, and Thrasos; and has stock options in DalCor. Dr. Solomon has received research support from the National Heart, Lung, and Blood Institute; and has served as a consultant for Novartis and Bayer. Dr. Desai has received consulting fees from Abbott, Amgen, AstraZeneca, Alnylam, Biofourmis, Boston Scientific, Boehringer Ingelheim, Cytokinetics, Dalcor Pharma, Merck, Novartis, Relypsa, and Regeneron; and has received research grants from Novartis, Bayer, AstraZeneca, and Alnylam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The content of this paper is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

Patients with chronic cardiovascular or metabolic diseases, including diabetes, hypertension, obesity, and heart failure, often have comorbid kidney disease. Long-term outcomes are worse in the setting of both cardiac and kidney disease compared with either disease in isolation. In addition, the clinical presentations of certain acute cardiovascular events (such as heart failure) and worsening kidney function overlap and may be challenging to distinguish. Recently, certain novel treatments have demonstrated beneficial effects on both cardiac and kidney outcomes. Sodium-glucose cotransporter-2 inhibitors have exhibited concordant risk reduction and clinically important benefits in chronic kidney disease with and without diabetes, diabetes and established cardiovascular disease or multiple atherosclerotic vascular disease risk factors, and heart failure with reduced ejection fraction with and without diabetes. Primary trial results have revealed that sacubitril-valsartan therapy improves cardiovascular outcomes in patients with chronic heart failure with reduced ejection fraction and post hoc analyses suggest favorable kidney effects. A concordant pattern of kidney benefit with sacubitril-valsartan has also been observed in chronic heart failure with preserved ejection fraction. Given the complex interplay between cardiac and kidney disease and the possibility that treatments may show concordant cardio-kidney benefits, there has been recent interest in formally acknowledging, defining, and using composite cardio-kidney outcomes in future cardiovascular trials. This review describes potential challenges in use of such outcomes that should be considered and addressed before their incorporation into such trials.

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by left ventricular hypertrophy and decreased exercise capacity. Fibroblast growth factor 23 (FGF23), a hormone involved in phosphate, vitamin D, and iron homeostasis, is linked to left ventricular hypertrophy and HF. We measured c-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels and examined their associations with exercise capacity in patients with HFpEF., Methods and Results: Using multivariable linear regression and linear mixed models, we studied the associations of cFGF23 and iFGF23 with baseline and mean weekly change over 24 weeks in peak oxygen consumption and 6-minute walk distance in individuals enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF trial. Our study population included 172 individuals with available plasma for cFGF23 and iFGF23 measurements. Median (25th-75th percentile) baseline cFGF23 and iFGF23 levels were 208.7 RU/mL (132.1-379.5 RU/mL) and 90.3 pg/mL (68.6-128.5 pg/mL), respectively. After adjustment for cardiovascular disease and hematologic and kidney parameters, higher cFGF23 was independently associated with a lower peak oxygen consumption at baseline. Higher iFGF23 was independently associated with shorter 6-minute walk distance at baseline. No significant associations were appreciated with the longitudinal outcomes., Conclusions: In patients with HFpEF, higher FGF23 levels are independently associated with decreased exercise capacity at baseline., Competing Interests: Declaration of Competing Interest RM has interest in Abbott Laboratories, AbbVie, Inc., and Teva Pharmaceuticals Industries Ltd, and has received honoraria from Akebia/Otsuka. TI has received honoraria from Kyowa Hakko Kirin Co., Ltd and grant support from Shire. MW has received research support, honoraria or consultant fees from Amgen, Ardelyx, DiaSorin, Keryx, Lilly, Pfizer, Shire and Ultragenyx. GDL has received research support from Abbott, Actelion, Amgen, AstraZeneca, Cytokinetics, Corvia, Cyclerion, and Novartis; and has served as a consultant, scientific advisory board member, and/or executive committee/steering committee member for American Regent, Amgen, AstraZeneca, Cytokinetics, Cyclerion, Novartis, Pfizer and Sonivie. SJS has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has served as a consultant, scientific advisory board member, and/or executive committee/steering committee member for Abbott, Actelion, AstraZeneca, Amgen, Axon Therapeutics, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GSK, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Shifamed, Tenax, and United Therapeutics., (Published by Elsevier Inc.)

Purpose: HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) carries a favorable prognosis for patients, yet nearly 30% of patients will experience disease relapse. We sought to detail patterns of failure, associated salvage therapy, and outcomes for patients with recurrent HPV-positive OPSCC., Methods and Materials: This is a single institution retrospective study of patients with recurrent HPV-positive OPSCC irradiated from 2002 to 2014. The primary study outcome was overall survival (OS, calculated using the Kaplan-Meier method). Secondary aims included patterns of first failure with descriptive details of salvage therapy. Solitary recurrences were defined as initial presentation of recurrence in a single site (primary, neck or oligometastatic), and multi-site was defined as local and regional and/or multiple sites of distant recurrence. Survival outcomes were compared using the log-rank test., Results: The cohort consisted of 132 patients. The median follow-up was 59 months for surviving patients. Estimated 2-year and 5-year OS rates were 47% and 32%, respectively. Comparative 2-year and 5-year OS rates were 65% and 46% versus 19% and 9% for the solitary group and multi-site group, respectively (p < .001)., Conclusions: Patients with recurrent HPV-positive OPSCC experience 5-year survival of approximately 32%. However, patients with a "solitary" recurrence including disease at the primary site, neck or oligometastatic site have more favorable long-term outcomes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Targeted prevention of heart failure (HF) remains a critical need given the high prevalence of HF morbidity and mortality. Similar to risk-based prevention of atherosclerotic cardiovascular disease, optimal HF prevention strategies should include quantification of risk in the individual patient. In this review, we discuss incorporation of a quantitative risk-based approach into the existing HF staging landscape and the clinical opportunity that exists to translate available data on risk estimation to help guide personalized decision making. We first summarize the recent development of key HF risk prediction tools that can be applied broadly at a population level to estimate risk of incident HF. Next, we provide an in-depth description of the clinical utility of biomarkers to personalize risk estimation in select patients at the highest risk of developing HF. We also discuss integration of genomics-enhanced approaches (eg, Titin [TTN] ) and other risk-enhancing features to reclassify risk with a precision medicine approach to HF prevention. Although sequential testing is very likely to identify low and high-risk individuals with excellent accuracy, whether or not interventions based on these risk models prevent HF in clinical practice requires prompt attention including randomized placebo-controlled trials of candidate therapies in risk-enriched populations. We conclude with a summary of unanswered questions and gaps in evidence that must be addressed to move the field of HF risk assessment forward.

The Go Red for Women movement was initiated by the American Heart Association (AHA) in the early 2000s to raise awareness concerning cardiovascular disease (CVD) risk in women. In 2016, the AHA funded 5 research centers across the United States to advance our knowledge of the risks and presentation of CVD that are specific to women. This report highlights the findings of the centers, showing how insufficient sleep, sedentariness, and pregnancy-related complications may increase CVD risk in women, as well as presentation and factors associated with myocardial infarction with nonobstructive coronary arteries and heart failure with preserved ejection fraction in women. These projects were augmented by collaborative ancillary studies assessing the relationships between various lifestyle behaviors, including nightly fasting duration, mindfulness, and behavioral and anthropometric risk factors and CVD risk, as well as metabolomic profiling of heart failure with preserved ejection fraction in women. The Go Red for Women Strategically Focused Research Network enhanced the evidence base related to heart disease in women, promoting awareness of the female-specific factors that influence CVD.

Arterial stiffness is increased with increasing age, and pulse pressure (PP), a marker of arterial stiffness, is a predictor of incident cardiovascular disease and mortality. However, the prognostic relevance of PP in heart failure (HF) with preserved ejection fraction has not been fully understood. We studied 4796 patients with HF with preserved ejection fraction from the PARAGON-HF trial. All patients underwent sequential run-in phases of valsartan and sacubitril/valsartan before randomization. We categorized patients by PP quartile and evaluated the influence of baseline PP on the PARAGON-HF primary end point (total HF hospitalizations and cardiovascular death). At screening, the median PP was 58 mm Hg (interquartile range, 50-69 mm Hg). There was a nonlinear, J-shaped association between PP and outcomes. Multivariable Cox proportional hazards models showed that patients in the highest PP quartile had a higher risk of the primary end point (adjusted hazard ratio, 1.39 [95% CI, 1.14-1.69]; P =0.001), total HF hospitalizations (adjusted hazard ratio, 1.43 [95% CI, 1.15-1.79]; P =0.001), and myocardial infarction (adjusted hazard ratio, 1.54 [95% CI, 1.06-2.23]; P =0.022) compared with those in the second (lowest risk) PP quartile. Reductions in PP during sacubitril/valsartan run-in were associated with a decreased risk of the primary end point and total HF hospitalizations. One year after randomization, PP was significantly lower in the sacubitril/valsartan group compared with the valsartan group (3.0 mm Hg decrease [95% CI, 2.4-3.5]; P <0.001). In conclusion, PP was an independent predictor of cardiovascular events in patients with HF with preserved ejection fraction enrolled in PARAGON-HF. Sacubitril/valsartan lowered PP compared with valsartan.

Background: Although guidelines recommend focusing primarily on stroke risk to recommend anticoagulants in atrial fibrillation (AF), physicians report that geriatric syndromes (e.g., falls and disability) are important when considering anticoagulants. Little is known about the prevalence of geriatric syndromes in older adults with AF or the association with anticoagulant use., Methods: We performed a cross-sectional analysis of the 2014 Health and Retirement Study, a nationally representative study of older Americans. Participants were asked questions to assess domains of aging, including function, cognition, and medical conditions. We included participants 65 years and older with 2 years of continuous Medicare enrollment who met AF diagnosis criteria by claims codes. We examined five geriatric syndromes: one or more falls within the last 2 years, receiving help with activities of daily living (ADLs) or instrumental ADLs (IADL), experienced incontinence, and cognitive impairment. We determined the prevalence of geriatric syndromes and their association with anticoagulant use, adjusting for ischemic stroke risk (i.e., CHA 2 DS 2 -VASc score [congestive heart failure, hypertension, age, diabetes mellitus, stroke, vascular disease, and sex])., Results: In this study of 779 participants with AF (median age = 80 years; median CHA 2 DS 2 -VASc score = 4), 82% had one or more geriatric syndromes. Geriatric syndromes were common: 49% reported falls, 38% had ADL impairments, 42% had IADL impairments, 37% had cognitive impairments, and 43% reported incontinence. Overall, 65% reported anticoagulant use; guidelines recommend anticoagulant use for 97% of participants. Anticoagulant use rate decreased for each additional geriatric syndrome (average marginal effect = -3.7%; 95% confidence interval = -1.4% to -5.9%). Lower rates of anticoagulant use were reported in participants with ADL dependency, IADL dependency, and dementia., Conclusion: Most older adults with AF had at least one geriatric syndrome, and geriatric syndromes were associated with reduced anticoagulant use. The high prevalence of geriatric syndromes may explain the lower than expected anticoagulant use in older adults., (© 2020 The American Geriatrics Society.)

Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. Previous studies have demonstrated that PAI-1 is a mechanistic contributor to several elements of the syndrome, including obesity, hypertension and insulin resistance. Here we show that PAI-1 is also a critical regulator of hepatic lipid metabolism. RNA sequencing revealed that PAI-1 directly regulates the transcriptional expression of numerous genes involved in mammalian lipid homeostasis, including PCSK9 and FGF21. Pharmacologic or genetic reductions in plasma PAI-1 activity ameliorates hyperlipidemia in vivo. These experimental findings are complemented with the observation that genetic deficiency of PAI-1 is associated with reduced plasma PCSK9 levels in humans. Taken together, our findings identify PAI-1 as a novel contributor to mammalian lipid metabolism and provides a fundamental mechanistic insight into the pathogenesis of one of the most pervasive medical problems worldwide.

We compared three fludarabine-based regimens for systemic sclerosis patients with a high-risk cardiac phenotype that according to EBMT criteria would be a contraindication for a high-dose cyclophosphamide (200 mg/kg) transplant regimen. All three regimens included fludarabine, ATG, and cyclophosphamide (60 mg/kg), while two regimens also included rituximab with or without IVIG. Treatment related mortality (TRM) was 2.4%. The mean number of days of neutropenia (ANC < 500) was 5.2, the mean number of platelet and red blood cell transfusions was 0.3 and 1.85, respectively. Skin score, forced vital capacity (FVC), and total lung capacity (TLC) improved with all three regimens. For patients whose regimen did not include rituximab versus those that included rituximab, 1-year overall relapse rate was higher 36% (5/14) versus 3.6% (1 of 28) (p = 0.01), secondary autoimmune diseases were higher 21% (3/14) versus 0% (0/28) (p = 0.03), and upper respiratory tract infections were higher 28% (4/14) versus 3.6% (1/28) (p = 0.04). In this safety study, a fludarabine-based regimen was relatively safe with a TRM of 2.4% and a neutropenic interval of only 5.2 days in systemic sclerosis patients with a high-risk cardiac phenotype. The addition of rituximab decreased 1-year relapse rate, risk of late secondary autoimmune diseases, and upper-respiratory tract infections.

Background: The duration of an opioid prescribed at hospital discharge does not intrinsically account for opioid needs during a hospitalization. This discrepancy may lead to patients receiving much larger supplies of opioids on discharge than they truly require., Objective: Assess a novel discharge opioid supply metric that adjusts for opioid use during hospitalization, compared to the conventional discharge prescription signature., Design, Setting, & Participants: Retrospective study using electronic health record data from June 2012 to November 2018 of adults who received opioids while hospitalized and after discharge from a single academic medical center., Measures & Analysis: We ascertained inpatient opioids received and milligrams of opioids supplied after discharge, then determined days of opioids supplied after discharge by the conventional prescription signature opioid-days ("conventional days") and novel hospital-adjusted opioid-days ("adjusted days") metrics. We calculated descriptive statistics, within-subject difference between measurements, and fold difference between measures. We used multiple linear regression to determine patient-level predictors associated with high difference in days prescribed between measures., Results: The adjusted days metric demonstrates a 2.4 day median increase in prescription duration as compared to the conventional days metric (9.4 vs. 7.0 days; P<0.001). 95% of all adjusted days measurements fall within a 0.19 to 6.90-fold difference as compared to conventional days measurements, with a maximum absolute difference of 640 days. Receiving a liquid opioid prescription accounted for an increased prescription duration of 135.6% by the adjusted days metric (95% CI 39.1-299.0%; P = 0.001). Of patients who were not on opioids prior to admission and required opioids during hospitalization but not in the last 24 hours, 325 (8.6%) were discharged with an opioid prescription., Conclusions: The adjusted days metric, based on inpatient opioid use, demonstrates that patients are often prescribed a supply lasting longer than the prescription signature suggests, though with marked variability for some patients that suggests potential under-prescribing as well. Adjusted days is more patient-centered, reflecting the reality of how patients will take their prescription rather than providers' intended prescription duration., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Author PP receives personal fees from EpiExcellence, LLC as a consulting epidemiologist. The competing interest disclosed does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Psoriasis is associated with elevated risk of heart attack and increased accumulation of subclinical noncalcified coronary burden by coronary computed tomography angiography (CCTA). Machine learning algorithms have been shown to effectively analyze well-characterized data sets., Objective: In this study, we used machine learning algorithms to determine the top predictors of noncalcified coronary burden by CCTA in psoriasis., Methods: The analysis included 263 consecutive patients with 63 available variables from the Psoriasis Atherosclerosis Cardiometabolic Initiative. The random forest algorithm was used to determine the top predictors of noncalcified coronary burden by CCTA. We evaluated our results using linear regression models., Results: Using the random forest algorithm, we found that the top 10 predictors of noncalcified coronary burden were body mass index, visceral adiposity, total adiposity, apolipoprotein A1, high-density lipoprotein, erythrocyte sedimentation rate, subcutaneous adiposity, small low-density lipoprotein particle, cholesterol efflux capacity and the absolute granulocyte count. Linear regression of noncalcified coronary burden yielded results consistent with our machine learning output., Limitation: We were unable to provide external validation and did not study cardiovascular events., Conclusion: Machine learning methods identified the top predictors of noncalcified coronary burden in psoriasis. These factors were related to obesity, dyslipidemia, and inflammation, showing that these are important targets when treating comorbidities in psoriasis., (Published by Elsevier Inc.)