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Background: Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone., Objectives: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death)., Methods: N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint., Results: At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates., Conclusions: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The authors investigated the relationship between past or incident myocardial infarction (MI) and cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF)., Background: MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain., Methods: The authors pooled data from 3 trials-CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N = 8,916)-and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization., Results: At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p < 0.001). Excess sudden death drove this difference (1.9 vs. 1.2 events/100 py, adjusted HR: 1.55 [95% CI: 1.23 to 1.97]; p < 0.001). There was no difference in HF hospitalization (5.9 vs. 5.5 events/100 py, adjusted HR: 1.05, 95% CI: 0.92 to 1.19) or HF death by prior MI. During follow-up, MI occurred in 336 patients (3.8%). Risk of CV death increased 31-fold in the first 30 days after first post-enrollment MI, and remained 58% higher beyond 1 year after MI. Risk of first or recurrent HF hospitalization increased 2.4-fold after MI., Conclusions: Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF., Methods: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker)., Findings: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy., Interpretation: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial., Background: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide ≥200 ng/l or N-terminal pro-B-type natriuretic peptide ≥800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria., Methods: We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death., Results: A total of 5,022 patients with left ventricular ejection fraction ≤40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints., Conclusions: In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The authors sought to evaluate the prognostic significance of baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups., Background: Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF)., Methods: In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization., Results: Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p < 0.001). This relationship was stronger in patients with atrial fibrillation (adjusted RR: 2.33 [95% CI: 1.89 to 2.87] vs. 1.58 [95% CI: 1.42 to 1.75] in patients without atrial fibrillation; p interaction <0.001) and weaker in obese patients (adjusted RR: 1.50 [95% CI: 1.31 to 1.71] vs. 1.92 [95% CI: 1.70 to 2.17] in nonobese patients; p interaction <0.001). Screening NT-proBNP did not modify the treatment effect of sacubitril/valsartan compared with valsartan (p interaction = 0.96). Sacubitril/valsartan reduced NT-proBNP by 19% (95% CI: 14% to 23%; p < 0.001) compared with valsartan 16 weeks post-randomization, with similar reductions in men (20%) and women (18%), and in patients with left ventricular EF ≤57% (20%) and >57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint., Conclusions: Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In patients hospitalized with acute heart failure (AHF), low urine sodium concentration (U Na ) after diuretic treatment may identify patients at risk for longer length of stay (LOS) and adverse events. We investigated the prognostic significance of 24-hour cumulative postdiuretic urine sodium concentration in a multicenter clinical trial population., Methods: The Renal Optimization Strategies Evaluation AHF (ROSE AHF) trial randomized 360 patients with AHF and renal dysfunction receiving intravenous diuretic to dopamine, nesiritide, or placebo. Sodium concentration was measured in cumulative urine sample collected during the first 24 hours after randomization in 298 patients. Based on prior studies, lower U Na was defined as ≤60 mmol/L., Results: Lower U Na was present in 142 (48%) patients, who had longer LOS (7 days vs 5 days, P < .001) and less 72-hour weight loss (5.7 lb vs 9.0 lb, P < .001). These associations persisted after controlling for baseline estimated glomerular filtration rate and outpatient furosemide dose. Lower U Na did not modify the null effects of dopamine or nesiritide on clinical outcomes. Results were similar for spot rather than cumulative 24-hour U Na concentration., Conclusion: In patients hospitalized for AHF and renal dysfunction, U Na  ≤ 60 mmol/L during the first 24 hours of diuresis identifies patients at risk for prolonged hospitalization but does not provide an indication for adjunctive dopamine or nesiritide., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Peak oxygen consumption (pVO 2 ) measured by cardiopulmonary exercise test (CPET) predicts mortality in adults with a Fontan circulation. The purpose of this study was to assess the additive prognostic value of change in pVO 2 over time., Methods: We analyzed a cohort of adults (≥18 years old) with a Fontan circulation who underwent at least 2 maximal CPETs separated by 6-30 months at Boston Children's Hospital between 2000 and 2015. Survival analysis was performed to determine whether changes in CPET variables, including pVO 2 between consecutive tests, were associated with subsequent clinical events. The primary outcome was transplant-free survival., Results: The study included 130 patients with 287 CPET test pairs. Average age was 26.6±9.5 years. Baseline pVO 2 averaged 22.0±5.7 mL/kg/min or 60.9%±13.7% predicted. In the cohort overall, there was no change in mean pVO 2 between sequential CPETs. Eleven patients died and 2 underwent transplant. On average, pVO 2 declined for patients who subsequently died or underwent transplant but remained stable among those who did not (-9.8%±14.6% vs 0.0±13.0%, P<.01). Those with a decline in pVO 2 between CPETs were at greater risk of death or transplantation (per 10% decrease in pVO 2 : HR=2.0, 95% CI 1.2-3.1, P=.004). Change in pVO 2 remained a significant predictor of death or transplant after adjusting for pVO 2 at first CPET (per 10% decline in pVO 2 : HR=2.5, 95% CI 1.5-4.2, P<.001)., Conclusions: A decline in pVO 2 between consecutive CPETs predicts increased risk for death or transplant in adults with a Fontan circulation independent of baseline pVO 2 . These results support the additive clinical value of serial CPET in this population., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Obesity is a major correlate of cardiovascular disease. Weight loss improves cardiovascular risk factors and has the potential to improve outcomes. Two drugs, phentermine plus topiramate and lorcaserin, have recently been approved by the US Food and Drug Administration for the indication of obesity; a third, bupropion plus naltrexone, is under consideration for approval. In clinical trials, these drugs cause weight loss and improve glucose tolerance, lipid profile, and, with the exception of bupropion plus naltrexone, blood pressure. However, their effect on cardiovascular outcomes is unknown. In defining appropriate roles for these drugs in preventive cardiology, it is important to remember the checkered history of drugs for obesity. New weight-loss drugs share the serotonergic and sympathomimetic mechanisms that proved harmful in the cases of Fen-Phen and sibutramine, respectively, albeit with significant differences. Given these risks, randomized cardiovascular outcomes trials are needed to establish the safety, and potential benefit, of these drugs. This review will discuss the history of pharmacotherapy for obesity, existing efficacy and safety data for the novel weight-loss drugs, and issues in the design of postapproval clinical trials., (© 2014 Wiley Periodicals, Inc.)

Background: Angioplasty and stent implantation have become accepted therapies for isolated peripheral pulmonary stenosis, and have been shown to increase vessel diameter and reduce right ventricular (RV) pressure acutely in patients with pulmonary artery (PA) stenosis. The purpose of this study was to assess long-term outcomes after primary transcatheter therapy for peripheral pulmonary stenosis., Methods and Results: We studied 69 patients who underwent primary transcatheter intervention for severe isolated peripheral pulmonary stenosis at ≤ 5 years of age. Genetic/syndromic diagnoses included Williams syndrome (n=23), non-Williams familial arteriopathy (n=12), and Alagille syndrome (n=3). At the initial PA intervention, median RV:aortic pressure ratio decreased from 1.00 to 0.88 (median decrease, 0.18; P<0.001). Patients with a higher preintervention RV:aortic pressure ratio had a greater reduction (P<0.001). During follow-up (median, 8.5 years), 10 patients died, 5 from complications of PA catheterization (all before 1998). Thirteen patients underwent surgical PA intervention, most within 1 year and along with repair of supravalvar aortic stenosis. Freedom from any PA reintervention was 38 ± 6% at 1 year and 22 ± 6% at 5 years. The median RV:aortic pressure ratio decreased from 1.0 at baseline to 0.53 at the most recent catheterization (P<0.001), and 82% of patients with available clinical follow-up were asymptomatic., Conclusions: Transcatheter therapy for infants with severe peripheral pulmonary stenosis has become safer, regardless of genetic condition. Coupled with reintervention and surgical relief in selected cases, RV:aortic pressure ratios decrease substantially and most patients are asymptomatic at late follow-up.

In the current study, the validity of a task designed to assess the automatic word recognition skills of persons with complex communication needs was investigated. A total of 78 students without communication impairments in kindergarten through second grade completed a standard automatic word recognition task requiring oral reading of words presented for less than 0.25 s. The same students completed an experimental word recognition task that did not require a spoken response. Results support the validity of the experimental task. For example, the mean performance scores on both tasks decreased in the expected direction, and there was a significant correlation between the standard and experimental tasks. Other results suggest that the same trait was being measured by both tasks. The data highlight directions for future research and development of the experimental task, while leaving us enthusiastic about the future of the experimental task as a valid means of assessing automatic word recognition for persons with complex communication needs.

School-age students who use AAC need access to communication, reading, and writing tools that can support them to actively engage in literacy learning. They also require access to core literacy learning opportunities across grade levels that foster development of conventional literacy skills. The importance of the acquisition of conventional literacy skills for students who use AAC cannot be overemphasized. And yet, one of the critical challenges in supporting the literacy learning of students who use AAC has been a lack of knowledge about literacy curricula and supports to literacy learning for these students. Most students who use AAC do not become conventionally literate and few of those who do achieve literacy skills beyond the second grade level. This article will provide an overview of the most frequent reading instructional activities in first and third grade classrooms. To better understand the foundational experiences important to literacy learning, the results of a survey project that examined the reading activities of general education students and teachers during primary grade instruction are presented, and critical shifts in instruction that occurred between first and third grade are highlighted. The primary instructional focus of core reading activities is also examined, along with adaptations for students who use AAC.

A limited number of studies have been completed on the factors contributing to accident-related injuries sustained by occupants of pickup trucks. The increasing number and changing pattern of use of light trucks necessitates the need to critically review this vehicle type with respect to contributing accident factors and associated injuries. This paper investigates the injury mechanisms of occupants of pickup trucks and the surfaces that the occupants contact in roadway accidents. Selection of cases from the Canadian vehicle database was based on the location of the vehicles' most severe impact deformation. The overall occupant injury severity was examined with respect to impact location, impact speed, and magnitude of occupant compartment intrusion. The results of the investigation illustrate the benefits of seat belt restraint use. In addition, identification of frequent injury contact surfaces establishes a reference for improved vehicle design initiatives and standards.