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© 2014 Graham et al.We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and

Chronic heart failure continues to impose a substantial health-care burden, despite recent treatment advances. The key pathophysiological process that ultimately leads to chronic heart failure is cardiac remodelling in response to chronic disease stresses. Here, we review recent advances in our understanding of molecular and cellular mechanisms that play a part in the complex remodelling process, with a focus on key molecules and pathways that might be suitable targets for therapeutic manipulation. Such pathways include those that regulate cardiac myocyte hypertrophy, calcium homoeostasis, energetics, and cell survival, and processes that take place outside the cardiac myocyte--eg, in the myocardial vasculature and extracellular matrix. We also discuss major gaps in our current understanding, take a critical look at conventional approaches to target discovery that have been used to date, and consider new investigational avenues that might accelerate clinically relevant discovery. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cardiac fibrosis is a major determinant of myocardial stiffness, diastolic dysfunction, and heart failure (HF). By reducing cardiac fibrosis, aldosterone antagonists have the potential to be beneficial in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial of 44 patients with HFpEF, we examined the effects of eplerenone, an aldosterone antagonist, on changes in 6-minute walk distance (primary end point), diastolic function, and biomarkers of collagen turnover (secondary end points). All patients had a history of hypertension, 61% were diabetic, and 52% had prior HF hospitalization. After 6 months of treatment, similar improvements in 6 minute walk distance were noted in the eplerenone and placebo groups (P = .91). However, compared with placebo, eplerenone was associated with a significant reduction in serum markers of collagen turnover (procollagen type I aminoterminal peptide, P = .009 and carboxy-terminal telopeptide of collagen type I, P = .026) and improvement in echocardiographic measures of diastolic function (E/E', P = .01). CONCLUSIONS: Although eplerenone was not associated with an improvement in exercise capacity compared to placebo, it was associated with significant reduction in markers of collagen turnover and improvement in diastolic function. Whether these favorable effects will translate into morbidity and mortality benefit in HFpEF remains to be determined. [ABSTRACT FROM AUTHOR]

Background: Ventricular assist devices (VADs) are used to bridge heart failure patients to transplantation, to allow their own hearts to recover, or as permanent ("destination") therapy. To date, the use of VADs has been limited to late-stage heart failure patients because of the associated device risks. In 2008, a National Heart, Lung, and Blood Institute (NHLBI) working group met to evaluate the treatment of heart failure using VADs and to advise the institute on how therapy for heart failure may be best advanced by clinical trials involving the devices.Methods and Results: Recognizing the improvements in VAD technology and in patient care and selection over the past decade, the working group recommended that a trial be performed to assess the use of chronic VAD therapy in patients who are less ill than those currently eligible for destination therapy. The hypothesis proposed for the trial is that VAD therapy may improve both survival and quality of life in moderately advanced heart failure patients who are neither inotrope-dependent nor exercise-intolerant and have not yet developed serious consequences such as malnourishment, end-organ damage, and immobility.Conclusion: Based on the group's recommendations, NHLBI issued an RFP in 2009 for the REVIVE-IT Pilot Trail, which will serve to test the hypothesis and inform the pivotal trial. [ABSTRACT FROM AUTHOR]

BACKGROUND: In the general population, 27% of adults have the metabolic syndrome (MetS) and is associated with increased mortality. Similar data are not available for a heart failure (HF) population. This study sought to determine the prevalence of the MetS and its effect on mortality in a HF population. METHODS AND RESULTS: Patients (n = 886) discharged from the hospital with a primary diagnosis of HF were retrospectively identified. Demographic, clinical, and laboratory data were extracted by chart review. The MetS was defined according to National Cholesterol Education Program Expert Panel criteria with a body mass index >or=30 kg/m(2) substituted for increased waist circumference. Mortality data were acquired by query of the National Death Index, with a median follow-up of 856 days. Data were available to evaluate for the presence or absence of MetS in 71% (n = 625). The prevalence of MetS in this cohort was 68%. MetS was most common in Hispanics (79%) compared with whites (70%) and blacks (61%, P = .003). Mortality was lower in those with MetS (44%) compared with those without (58%, unadjusted HR 0.67 [95% CI, 0.53-0.85]). In a fully adjusted model, there was still a significantly lower risk of mortality in those with MetS (adjusted HR 0.73 [95% CI, 0.56-0.94]). CONCLUSIONS: In a cohort hospitalized with HF, the prevalence of MetS exceeds that of the general population, and unlike the general population, MetS is associated with a lower mortality. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF) beta plays an important role in normal pulmonary morphogenesis and function and in the pathogenesis of lung disease. The effect of TGFbeta is regulated via a selective pathway of TGFbeta synthesis and signaling that involves activation of latent TGFbeta, specific TGFbeta receptors, and intracellular signaling via Smad molecules. All three isoforms of TGFbeta are expressed at high levels during normal lung development, being particularly important for branching morphogenesis and epithelial cell differentiation with maturation of surfactant synthesis. Small amounts of TGFbeta are still present in the adult lung, and TGFbeta is involved in normal tissue repair following lung injury. However, in a variety of forms of pulmonary pathology, the expression of TGFbeta is increased. These include chronic lung disease of prematurity as well as several forms of acute and chronic adult lung disease. While TGFbeta1 appears to be the predominant isoform involved, elevated levels of all three isoforms have been demonstrated. The increase in TGFbeta precedes abnormalities in lung function and detectable lung pathology, but correlates with the severity of the disease. TGFbeta plays a key role in mediating fibrotic tissue remodeling by increasing the production and decreasing the degradation of connective tissue via several mechanisms. [ABSTRACT FROM AUTHOR]

Objectives: Patients with heart failure have increased circulating levels of tumor necrosis factor (TNF) and TNF receptors. It is not known whether TNF, which is known to blunt beta-adrenergic responsiveness in experimental models, contributes to the loss of heart rate variability in patients with heart failure. Therefore, we examined heart rate variability in relation to circulating levels of TNF, TNF receptors, and norepinephrine in patients with heart failure and in control subjects.Methods: Heart rate variability was obtained from 24-h ambulatory ECG recordings in age-matched control subjects (n = 10) and patients with mild (n = 15) to moderate (n = 14) heart failure. Plasma levels of TNF and soluble type 1 and 2 TNF receptors were measured by enzyme-linked immunoassay; plasma norepinephrine levels were measured by high-performance liquid chromatography.Results: There was a significant inverse linear correlation between increased circulating levels of TNF, TNF receptors, and norepinephrine for time-domain and frequency-domain indexes of heart rate variability among patients with heart failure and control subjects. Multiple stepwise linear regression analysis showed that TNF was a stronger independent predictor of frequency-domain indexes of heart rate variability than norepinephrine.Conclusions: TNF is an independent predictor of depressed heart rate variability in patients with heart failure. Insofar as TNF blunts beta-adrenergic signaling, this study suggests the possibility that overexpression of TNF and subsequent loss of beta-adrenergic responsiveness contributes to the decrease in heart rate variability observed in heart failure. [ABSTRACT FROM AUTHOR]

Study Objectives: Proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there is interest in developing therapeutic agents with anticytokine properties that might be used as adjunctive therapy to modulate proinflammatory cytokine levels in patients with heart failure. Previous experimental studies suggested that vesnarinone has potent anticytokine properties in vitro. Therefore, we examined the effects of vesnarinone on circulating levels of cytokines and cytokine receptors in a large-scale, multicenter, clinical trial of patients with moderate-to-advanced heart failure: the Vesnarinone Trial (VEST).Methods: Circulating levels of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type 1, soluble TNF-receptor type 2, as well as interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) were measured on plasma samples by enzyme-linked immunosorbent assay at baseline and at 24 weeks in patients who were receiving placebo (n = 352), 30 mg of vesnarinone (n = 367), and 60 mg of vesnarinone (n = 327).Results: Treatment with 30 mg and 60 mg of vesnarinone had no effect on circulating levels of cytokines or cytokine receptors in patients with advanced heart failure over a 24-week period.Conclusions: In contrast to the potent anticytokine effects observed with vesnarinone in experimental studies in vitro, the results of this clinical study suggest that vesnarinone does not have any measurable anticytokine effects in vivo in patients with moderate-to-advanced heart failure. [ABSTRACT FROM AUTHOR]

Background: Acquired immunodeficiency syndrome (AIDS) is associated with the occurrence of tumors such as Kaposi's sarcoma (KS) and B-cell lymphoma. However, no evidence exists yet that human immunodeficiency virus type 1, the causative agent of AIDS, is directly responsible for cell transformation. It is also not clear whether KS lesions, which are of complex cellularity, contain tumor cells derived from a true monoclonal malignancy (originating from a single malignant cell) or whether the lesions are just polyclonally hyperplastic in nature (containing increased numbers of normal cells). In fact, the presence of malignant KS cells has never been unequivocally shown in AIDS-associated KS, and previously isolated KS cell cultures were not immortal or malignant.Purpose: Our purpose was to (a) utilize technology that could facilitate isolation and enrichment of tumor cells from AIDS-associated KS lesions, (b) establish and characterize an immortalized KS cell line, and (c) test the malignant potential of such a cell line in animal models.Methods: Mononuclear cells were isolated from 2.5 L of pleural effusion from an AIDS-associated KS patient. T-lymphocytes, B-lymphocytes, monocytes/macrophages, and fibroblasts were removed by a cytotoxicity method, using monoclonal antibodies specific for cell surface markers and baby rabbit complement. KS cells were cultured in the absence of exogenous growth factors in an effort to select for transformed cells capable of self-sustained growth. The karyotype abnormalities were detected by G-banded marker studies, and phenotypic markers were determined by indirect immunofluorescence and immunocytochemical methods. Beige nude XID and severe combined immunodeficient mice were used to evaluate the tumorigenic, angiogenic, and metastatic potentials of cells.Results: An immortalized cell line, named KS Y-1, was isolated. Its phenotype is similar to that of endothelial cells with positive CD34 and CD31 markers. Tetraploid chromosomal abnormalities were found in primary fresh KS tissue and in vitro passages of KS Y-1 cells. These cells promoted tumorigenesis, angiogenesis, and metastasis in immunodeficient mice. Tumors produced at the site of injection as well as metastases in the lung, spleen, pancreas, gastrointestinal tract, and skin showed a human tetraploid karyotype. KS Y-1 cells show high plating efficiency.Conclusion: The KS Y-1 cell line could be the first evidence of AIDS-associated KS cells that may develop clones with an indisputable malignant cell phenotype.Implications: KS Y-1 cells in the in vivo mouse model can be used to study the effects of therapeutic compounds in advanced KS. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated whether a xanthine oxidase (XO) inhibitor, oxypurinol, produces clinical benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy.Background: Increased XO activity may contribute to heart failure pathophysiology.Methods: Patients (n = 405) were randomized to oxypurinol (600 mg/day) or placebo. Efficacy at 24 weeks was assessed using a composite end point comprising heart failure morbidity, mortality, and quality of life.Results: The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving oxypurinol or placebo. Oxypurinol reduced serum uric acid (SUA) by approximately 2 mg/dl (p < 0.001). In a subgroup analysis, patients with elevated SUA (>9.5 mg/dl, n = 108) responded favorably to oxypurinol (p = 0.02 for interaction term), whereas oxypurinol patients with SUA <9.5 mg/dl exhibited a trend towards worsening. In addition, SUA reduction to oxypurinol correlated with favorable clinical response. Within the entire oxypurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who worsened (-2.3 +/- 2.1 mg/dl vs. -1.0 +/- 1.9 mg/dl, p = 0.0006). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome.Conclusions: Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Serum uric acid may serve as a valuable biomarker to target XO inhibition in heart failure. (Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure; NCT00063687). [ABSTRACT FROM AUTHOR]

Background: Iron deficiency (ID) is currently defined as a serum ferritin level <100 or 100 to 299 ng/mL with transferrin saturation (TSAT) <20%. Serum ferritin and TSAT are currently used to define absolute and functional ID. However, individual markers of iron metabolism may be more informative than current arbitrary definitions of ID., Methods: We assessed prognostic associations of ferritin, serum iron, and TSAT among 2050 participants with heart failure (HF) with reduced/mid-range (n=1821) or preserved (n=229) left ventricular ejection fraction enrolled in the PHFS (Penn HF Study), a prospective cohort study. We measured 4928 plasma proteins using an aptamer-based assay (SOMAScanv4) and assessed prognostic and proteomic associations of markers of iron metabolism., Results: Ferritin concentrations were not associated with outcomes, whereas low TSAT and serum iron were associated with the risk of all-cause death (TSAT: standardized hazard ratio, 0.84 [95% CI, 0.76-0.93]; P =0.001; serum iron: standardized hazard ratio, 0.87 [95% CI, 0.79-0.96]; P =0.007). Similarly, TSAT was associated with the risk of death or HF-related admission (standardized hazard ratio, 0.89 [95% CI, 0.83-0.95]; P =0.0006). Significant interactions between TSAT and HF with preserved ejection fraction status were found such that TSAT was more strongly associated with the risk of death and death or HF-related admission in HF with preserved ejection fraction. We identified 359 proteins associated with TSAT, including TFRC (transferrin receptor protein; β, -0.455; P <0.0001) and CRP (C-reactive protein; β, -0.355; P <0.0001). Pathway analyses demonstrated associations with lipid metabolism, complement activation, and inflammation. In contrast to the robust associations between TSAT and outcomes, ID and absolute ID defined by current criteria were not associated with death or death or HF-related admission. TSAT was associated with outcomes regardless of the presence of functional versus absolute ID., Conclusions: Low TSAT, but not ferritin concentrations, is significantly associated with adverse outcomes in HF. Low TSAT is more strongly associated with outcomes in HF with preserved ejection fraction. Pathways related to inflammation and lipid metabolism are associated with low TSAT in HF.

Purpose: Understanding the impact of vision impairment on dynamic tasks requiring visual processing is crucial for developing effective adaptive strategies that support individuals with vision impairment in optimizing their performance in natural tasks. This study aimed to establish the gaze patterns used by individuals with vision impairment when hitting a moving target., Methods: Nineteen tennis players with vision impairment were recruited and their eye and head movements were tracked while they returned tennis serves., Results: Participants used a variety of different strategies to track the ball visually, dictated largely by the nature of their impairment rather than its severity. Cluster analysis showed distinct strategies based on the type of vision impairment: those with peripheral vision loss foveated the ball closely and avoided predictive eye movements; those with poor oculomotor control initially tracked the ball but lagged as it approached; and those with central vision loss used a variety of strategies that did not align with the use of a single preferred retinal locus: some tracked the ball using a single preferred location in their peripheral vision, some switched the area of retina used to track the ball, and another did not move their gaze at all., Conclusions: Tennis players with vision impairment adopt a variety of impairment-specific adaptations to their gaze-tracking strategies, enabling them to successfully hit an approaching tennis ball despite severe vision impairments., Translational Relevance: This study provides insight into the impairment-specific gaze strategies that well-adapted individuals with vision impairment adopt when hitting a moving target.

Aims: The relationship between body mass index (BMI) and clinical outcomes in patients with cardiovascular disease, including acute heart failure (AHF) and acute myocardial infarction (AMI), remains debated. This study investigates the association between BMI and clinical outcomes within the PARADISE-MI cohort, while also evaluating the impact of angiotensin receptor-neprilysin inhibitor (ARNI) versus angiotensin-converting enzyme inhibitor (ACE-I) treatment on this relationship., Methods and Results: The analysis included 5589 patients from the PARADISE-MI study with available baseline BMI data. The cohort comprised patients with AMI and pulmonary congestion and/or left ventricular ejection fraction ≤40%. Patients were categorized into six World Health Organization BMI subgroups. The primary outcome of interest was the composite endpoint of cardiovascular death, heart failure (HF)-associated hospitalization, and outpatient symptomatic HF episodes. The mean baseline BMI of the cohort was 28.1 ± 5.0 kg/m 2 . The lowest rate of the primary composite endpoint (6.2/100 patient-years) was observed in overweight patients (BMI 25-29.9 kg/m 2 ), while the highest rates were found in the lowest and highest BMI subgroups (8.4/100 patient-years for BMI <18.5 kg/m 2 and 9.7/100 patient-years for BMI >40 kg/m 2 ). There was no significant interaction between BMI and the treatment effect of ARNI versus ACE-I on the primary composite outcome (p = 0.73). Additionally, no significant differences in the incidence of adverse events or serious adverse events were noted across the BMI subgroups., Conclusions: In AMI with AHF patients, the relationship between BMI and the primary composite outcome is non-linear, with the lowest event rates observed in overweight individuals. Outcomes and safety profiles for ARNI and ACE-I treatments were similar across BMI subgroups., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Study Objectives: There is substantial night-to-night variability (NtNV) in obstructive sleep apnea (OSA) severity in some individuals, however predictors for this remain incompletely understood. This study aims to quantify the degree of NtNV in the apnea-hypopnea index (AHI), hypoxic burden, airflow limitation, and OSA endotypes; to determine if a relationship exists between the degree of NtNV in AHI and in endotype expression; to assess whether the degree of flow limited breathing is predictive of the degree of NtNV of the AHI., Methods: 71 patients with OSA underwent two polysomnograms (PSGs). OSA endotypes, hypoxic burden and flow limitation frequency were extracted from PSG data. Intra-individual agreement was assessed and associations with the NtNV of the AHI were calculated. Patients were grouped into High Variability vs Low Variability based on the degree of difference in AHI between each night., Results: Despite wide limits of agreement, at the group level most PSG and endotype variables were not statistically different between first and second night. Flow limitation frequency was 7.7% (2.1 to 13, P<0.01) higher on the second night compared to baseline. There were weak linear associations between NtNV of endotypes and NtNV of the AHI. In sub-group analysis, there was greater difference between nights for Vactive (5%eupnea, P=0.01), Vpassive (3.1%eupnea, P=0.03), Vcomp (3.2%eupnea, P=0.01) and arousal threshold (4.1%eupnea, P=0.04) in the High Variability compared to the Low Variability group., Conclusions: There is high NtNV in AHI, OSA endotypes and flow limitation in some individuals, however no strong linear relationship exists between these changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Rationale: Excessive daytime sleepiness, an important symptom of obstructive sleep apnea (OSA), is commonly quantified using the Epworth Sleepiness Scale score (ESS). Baseline OSA severity measures (ventilatory burden, flow limitation, and hypoxemia) provide insights into OSA pathophysiology and could predict changes in sleepiness (i.e. change-in-ESS) following continuous positive airway pressure (CPAP) treatment., Objectives: We hypothesized that change-in-ESS following CPAP treatment can be predicted from baseline polysomnography., Methods: Associations between OSA severity measures and ESS were evaluated in 2332 participants, adjusting for age, sex, BMI, and total sleep time. Change-in-ESS prediction was evaluated using 213 CPAP treatment studies (HomePAP, BestAIR, and ABC) in three steps: severity measures were compared (adjusted regression, n =64), a prediction model was developed using baseline ventilatory burden and baseline ESS ( n =139), and then evaluated in holdout participants ( n =74)., Measurements and Main Results: In cross-sectional analysis, ESS was associated with ventilatory burden (0.45 points/SD; 95% CI 0.23-0.67), hypoxic burden (0.39; 0.17-0.62), the apnea-hypopnea index (AHI) (0.36; 0.14-0.59), and flow limitation severity (0.22; 0.01-0.43). Comparison analysis revealed that change-in-ESS was most strongly associated with baseline ventilatory burden (-1.08 points/SD; -2.13 to -0.05) and baseline ESS (-2.75; -3.83 to -1.69); the AHI association was weaker (-0.97; -2.01-0.05). Predicted change-in-ESS and actual change-in-ESS were correlated in holdout participants (adjusted R² =0.313); median [IQR] actual change-in-ESS of predicted responders (≥2-point ESS improvement, n =54, 73.0%) was -5.0 [-10.0 to -2.0] and non-responders was 0.0 [-1.0-1.0] ( P <0.001)., Conclusions: Baseline ventilatory burden and baseline ESS were independently associated with change-in-ESS and could be used together to inform clinicians whether CPAP treatment will likely improve a patient's sleepiness.

Everyday human interactions require observers to anticipate the actions of others (e.g., when walking past another in a corridor or choosing where to hit a ground stroke in tennis). Yet, experimental paradigms that aim to examine anticipation continue to use simplistic designs that are not interactive and therefore fail to account for the real-life, social nature of these interactions. Here we propose a fundamental, paradigmatic shift toward a "dynamic interactive anticipation" paradigm that models real-life interactions. We propose that it will change the way behavioral experimentalists study anticipation and spark theory development by unravelling the mechanisms underlying anticipation in real-time interactions., (© 2024. The Author(s).)

The most common causes of morbidity and mortality in the myeloproliferative neoplasms (MPNs), with the exception of myelofibrosis, are venous and arterial thrombosis, as well as more recently discovered cardiovascular disease (CVD). Clonal hematopoiesis of indeterminate potential (CHIP) is the subclinical finding in an individual of somatic mutations that are also found in clinically overt MPNs and other myeloid malignancies. The prevalence of "silent" CHIP increases with age. CHIP can transform into a clinically overt MPN at an estimated rate of 0.5 to 1% per year. It is likely, therefore, but not proven, that many, if not all, MPN patients had antecedent CHIP, possibly for many years. Moreover, both individuals with asymptomatic CHIP, as well as clinically diagnosed patients with MPN, can develop thrombotic complications. An unexpected and remarkable discovery during the last few years is that even CHIP (as well as MPNs) are significant, independent risk factors for CVD. This review discusses up-to-date information on the types of thrombotic and cardiovascular complications that are found in CHIP and MPN patients. A systemic inflammatory state (that is often subclinical) is most likely to be a major mediator of adverse reciprocal bone marrow-cardiovascular interplay that may fuel the development of progression of MPNs, including its thrombotic and vascular complications, as well as the worsening of cardiovascular disease, possibly in a "vicious cycle". Translating this to clinical practice for hematologists and oncologists who treat MPN patients, attention should now be paid to ensuring that cardiovascular risk factors are controlled and minimized, either by the patient's cardiologist or primary care physician or by the hematologist/oncologist herself or himself. This review is intended to cover the clinical aspects of thrombosis and cardiovascular complications in the MPN, accompanied by pathobiological comments.

Para athletes present a broad range of sports-related injuries and illnesses, frequently encountering barriers when accessing healthcare services. The periodic health evaluation (PHE) is a valuable tool for continuously monitoring athletes' health, screening for health conditions, assisting in the surveillance of health problems by establishing baseline information and identifying barriers to athlete's performance. This position statement aims to guide sports healthcare providers in the PHE for Para athletes across key impairment categories: intellectual, musculoskeletal, neurological and vision. A panel of 15 international experts, including epidemiologists, physiotherapists, optometrists and physicians with expertise in Para athlete health, convened via videoconferences to discuss the position statement's purpose, methods and themes. They formed working groups to address clinical, cardiorespiratory, neuromusculoskeletal, nutritional status, mental and sleep health, concussion and female Para athlete health assessment considerations. The PHE's effectiveness lies in its comprehensive approach. Health history review can provide insights into factors impacting Para athlete health, inform physical assessments and help healthcare providers understand each athlete's needs. During the PHE, considerations should encompass the specific requirements of the sport modality and the impairment itself. These evaluations can help mitigate the common tendency of Para athletes to under-report health issues. They also enable early interventions tailored to the athlete's health history. Moreover, the PHE serves as an opportunity to educate Para athletes on preventive strategies that can be integrated into their training routines, enhancing their performance and overall health. This position statement can potentially enhance clinical translation into practice and improve the healthcare quality for Para athletes., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Sudden death is a leading cause of death after acute myocardial infarction (AMI). The Prospective ARNi vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) and Valsartan in Acute Myocardial Infarction (VALIANT) trials enrolled patients with pulmonary congestion and/or left ventricular dysfunction after AMI. Whether the prognosis in such patients has changed over time has not been examined., Objective: To compare the rate of sudden death/resuscitated cardiac arrest (RCA) after AMI in the PARADISE-MI and VALIANT trials., Design, Setting, and Participants: This was a secondary analysis of multicenter randomized clinical trials enrolling patients after AMI. In the primary analysis, the VALIANT cohort was restricted to patients with "PARADISE-MI-like" characteristics (eg, at least 1 augmenting risk factor and no history of heart failure). The baseline characteristics of people in both trials were compared. The VALIANT trial enrolled from December 1998 to June 2001, and the PARADISE-MI trial enrolled between December 2016, and March 2020. The median follow-up in the VALIANT and PARADISE-MI trials was 24.7 and 22 months, respectively. People with AMI, complicated by pulmonary congestion and/or left ventricular dysfunction, were included in the analysis., Exposure: Sudden death after AMI., Results: A total of 5661 patients were included in the PARADISE-MI cohort (mean [SD] age, 63.7 [11.5] years; 4298 male [75.9%]), 9617 were included in the VALIANT (PARADISE-MI-like) cohort (mean [SD] age, 66.1 [11.5] years; 6504 male [67.6%]), and 14 703 patients were included in the VALIANT (total) cohort (mean [SD] age, 64.8 [11.8] years; 10 133 male [68.9%]). In the PARADISE-MI-like cohort of the VALIANT trial, 707 of 9617 participants (7.4%) experienced sudden death/RCA. A total of 148 of 5661 people (2.6%) in the PARADISE-MI trial experienced sudden death/RCA. Sudden death rates were highest in the first month after infarction in both trials: 19.3 (95% CI, 16.4-22.6) per 100 person-years in the VALIANT trial and 9.5 (95% CI, 7.0-12.7) per 100 person-years in the PARADISE-MI trial, and these rates declined steadily thereafter. Compared with the VALIANT cohort, people in the PARADISE-MI trial were more often treated with percutaneous coronary intervention for their qualifying AMI and received a β-blocker, statin, and mineralocorticoid receptor antagonist more frequently., Conclusions and Relevance: After AMI, the risk of sudden death/RCA was highest in the first month, declining rapidly thereafter. Results revealed that compared with counterparts from 20 years ago, the rate of sudden death/RCA in patients with a reduced left ventricular ejection fraction and/or pulmonary congestion was 2- to 3-fold lower in people receiving contemporary management. Interventions to further protect people in the highest risk first month after infarction are needed., Trial Registration: ClinicalTrials.gov Identifier: NCT02924727.

Background: Left ventricular assist device (LVAD) use remains uncommon in advanced heart failure (HF) patients not dependent on inotropes., Objectives: Before considering a randomized trial comparing a strategy of earlier use of LVAD to continued medical therapy, a better understanding is needed of the clinical trajectory of ambulatory patients with advanced systolic HF on optimal guideline-directed medical therapy (GDMT)., Methods: REVIVAL enrolled 400 patients with advanced ambulatory systolic HF, ≥1 HF mortality risk marker (≥2 HF hospitalizations past year; or HF hospitalization and high natriuretic peptide; or no HF hospitalizations but low peak oxygen consumption, 6-minute walk, serum sodium, HF survival score or Seattle HF model predicted survival), and no LVAD contraindication at 21 LVAD centers from July 2015 to June 2016. Patients were followed for 2 years or until a primary outcome (death, durable ventricular assist device, or urgent transplant). Clinical outcomes and health-related quality of life were evaluated., Results: Mean baseline left ventricular ejection fraction was 21%, median 6-minute walk was 341 m, and 92% were Interagency Registry for Mechanically Assisted Circulatory Support profiles 5 to 7. Adherence to GDMT and electrical device therapies was robust. Composite primary outcome occurred in 22% and 37% at 1 and 2 years, with death alone in 8% and 16%, respectively. Patients surviving for 2 years maintained GDMT intensity and had no decline in health-related quality of life., Conclusions: Structured, serial follow-up at programs with expertise in caring for advanced ambulatory systolic HF patients facilitates triage for advanced therapies. Better strategies are still needed to avoid deaths in a small but significant group of patients who die without advanced therapies. REVIVAL patients not selected for VAD or transplant have robust survival and patient-reported outcomes, which challenges advocacy for earlier VAD implantation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407)., Competing Interests: Funding Support and Author Disclosures Supported by funding from the National Institutes of Health, National Heart, Lung, and Blood Institute (contract number HHSN268201100026C) for REVIVAL and the National Center for Advancing Translational Sciences (grant numbers UL1TR002240 and UM1TR004404) for the Michigan Institute for Clinical and Health Research. The views expressed in this manuscript are those of the authors and do not necessarily represent 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. Dr Aaronson has received research support from Medtronic, Abbott, Bioventrix, Amgen; has held ownership interest in Procyrion; and has served as a consultant/on the Advisory Board for Medtronic and Procyrion; at the time of submission of this manuscript, he does not have industry research funding, ownership interests, or ongoing consulting relationships. Dr Stewart has served as a consultant for Abbott and Procyrion. Dr Cascino has received research support from Johnson & Johnson and has served as a consultant for Merck & Co. Dr Stehlik has received honoraria from Medtronic; has served as a consultant for Medtronic, TransMedics, and Natera; and has received research support from Natera and Merck. Dr Lala has received honoraria from Zoll. Dr Pagani has served as a scientific advisor (without compensation) for Abbott, CH Biomedical, FineHeart, and Medtronic; has served as a medical monitor (without compensation) for Abiomed; and has received salary support from Blue Shield of Michigan. Dr Mann has served as a consultant/on the Advisory Board for Novartis and Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Currently, all eligible goalball players compete together irrespective of their level of vision impairment, yet it remains unclear whether those with more impairment are disadvantaged during competition. Following the International Paralympic Committee's requirement for evidence-based, sport-specific classification, this study assessed whether individual goalball performance relates to the level of visual impairment. Using results from the 2016 and 2020 Paralympic Games, players' sport classes and in-competition key performance statistics (minutes played, throws per minute, goals per minute, penalties conceded per minute, blocks per minute, and goals per throw) were extracted. Players' visual acuity and visual field results were obtained through the IBSA Sport Administration System. Results showed no statistically significant differences in performance between classes. Further, there were no significant relationships between vision and performance for all six variables for female players. A small but significant positive correlation was found between visual acuity and the number of penalties conceded for male players. Collectively, the results suggest that currently eligible players compete fairly against one another during competitive goalball matches. Results provide support for the existing system of classification whereby all eligible athletes compete against each other irrespective of their level of impairment.

Aims: Burst steroid therapy, effective in acute respiratory diseases, may benefit patients with acute heart failure (AHF) in whom inflammatory activation is associated with adverse outcomes., Methods and Results: CORTAHF assessed whether burst steroid therapy reduces inflammation and results in better quality of life and clinical outcomes in AHF. Patients with AHF, N-terminal pro-B-type natriuretic peptide >1500 pg/ml, and high-sensitivity C-reactive protein (hsCRP) >20 mg/L were randomized 1:1 to oral, once daily 40 mg prednisone for 7 days or usual care, without blinding. Patients were followed for 90 days. A total of 101 patients were randomized. At day 7 the primary endpoint, hsCRP decreased in both arms - adjusted geometric mean ratios (GMRs) were 0.30 and 0.40 in the prednisone and usual care arms (ratio of GMRs 0.75, 95% confidence interval [CI] 0.56-1.00, p = 0.0498). The 90-day risk of worsening heart failure (HF), HF readmission or death as reported by the unblinded investigators was significantly lower in the prednisone group (10.4%) than in usual care (30.8%) (hazard ratio 0.31, 95% CI 0.11-0.86, p = 0.016). The EQ-5D visual analogue scale score as reported by the unblinded patients increased more in the prednisone group on day 7 (least squares mean difference 2.57, 95% CI 0.12-5.01 points, p = 0.040). All effects were statistically significant in the pre-specified subgroup with centrally-measured interleukin-6 >13 pg/ml. Adverse events, particularly hyperglycaemia, occurred more in the prednisone group with no difference in infection rate., Conclusion: In this small open-label study of patients with AHF, burst steroid therapy was associated with reduced inflammation as measured by hsCRP levels at day 7 (primary endpoint). Secondary endpoints showed improved quality of life at day 7 and reduced 90-day risk of death or worsening HF. Large prospective studies are needed to evaluate these findings., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Inflammation has emerged as a potential key pathophysiological mechanism in heart failure (HF) in general and acute HF (AHF) specifically, with inflammatory biomarkers shown to be highly predictive of adverse outcomes in these patients. The CORTAHF study builds on both these data and the fact that steroid burst therapy has been shown to be effective in the treatment of respiratory diseases and COVID-19. Our hypothesis is that in patients with AHF and elevated C-reactive protein (CRP) levels without symptoms or signs of infection, a 7-day course of steroid therapy will lead to reduced inflammation and short-term improvement in quality of life and a reduced risk of worsening HF (WHF) events., Methods and Results: The study, which is currently ongoing, will include 100 patients with AHF ages 18-85, regardless of ejection fraction, screened within 12 h of presentation. Patients will be included who have NT-proBNP > 1500 pg/mL and CRP > 20 mg/L at screening. Exclusion criteria include haemodynamic instability and symptoms and signs of infection. After signed consent, eligible patients will be randomized according to a central randomization scheme stratified by centre 1:1 to either treatment once daily for 7 days with 40 mg prednisone orally or to standard care. Patients will be assessed at study day 2, day 4 or at discharge if earlier, and at days 7 and 31 at the hospital; and at day 91 through a telephone follow-up. The primary endpoint is the change in CRP level from baseline to day 7, estimated from a mixed model for repeated measures (MMRM) including all measured timepoints, in patients without a major protocol violation. Secondary endpoints include the time to the first event of WHF adverse event, readmission for HF, or death through day 91; and changes to day 7 in EQ-5D visual analogue scale score and utility index. Additional clinical and laboratory measures will be assessed., Conclusions: The results of the study will add to the knowledge of the role of inflammation in AHF and potentially inform the design of larger studies with possibly longer duration of anti-inflammatory therapies in AHF., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The effect of steroids on congestion in patients with acute heart failure (AHF) is not known., Methods and Results: Patients with AHF, NT-proBNP levels > 1500 pg/mL and high-sensitivity C-reactive protein (hsCRP) levels > 20 mg/L were randomized to once-daily oral 40 mg prednisone for 7 days or usual care. In this post hoc analysis, congestion score was calculated on the basis of orthopnea, edema and rales (0 reflecting lack of congestion, and 9 maximal congestion) at each time point. Among 100 eligible patients randomized, those assigned to prednisone had a greater improvement in congestion score at day 31 (win odds for the prednisone group compared to usual care at day 31 was 1.77 (95% CI 1.17-2.84; P = 0.0066) in all patients and 2.41 (95% CI 1.37-5.05; P = 0.0016) in patients with IL-6 > 13 pg/mL at baseline. In patients with congestion scores ≥ 7 at baseline, the effects of prednisone therapy on the EQ-5D visual analog scale score were 4.30 (95% CI 0.77-7.83) points at day 7 and 5.40 (0.51-10.29) points at day 31, accompanied by lower heart rate and respiratory rate and higher oxygen saturation compared to usual care., Conclusions: In patients with AHF and inflammatory activation, 7-day steroid therapy was associated with reduction in signs of congestion up to day 31. These results need confirmation in larger studies examining potential effects of steroids on congestion, diuresis, fluid redistribution and vascular permeability as well as clinical effects in AHF., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Although the ability of the heart to adapt to environmental stress has been studied extensively, the molecular and cellular mechanisms responsible for cardioprotection are not yet fully understood., Methods: We administered Toll-like receptor (TLR) agonists or a diluent to wild-type mice and assessed their potential to induce cardiac protection against injury from a high intraperitoneal dose of isoproterenol (ISO) administered 7 days later. Cardioprotective effects were analyzed through serum cardiac troponin I levels, immune cell profiling via flow cytometry, echocardiography, and multiomic single-nuclei RNA and ATAC sequencing., Results: Pretreatment with the TLR4 agonist lipopolysaccharide (LPS), but not TLR1/2 or TLR3 agonists, conferred cardioprotection against ISO, as demonstrated by reduced cardiac troponin I leakage, decreased inflammation, preservation of cardiac structure and function, and improved survival. Remarkably, LPS-induced tolerance was reversed by β-glucan treatment. Multiomic analysis showed that LPS-tolerized hearts had greater chromatin accessibility and upregulated gene expression compared to hearts treated with LPS and β-glucan (reverse-tolerized). The LPS tolerance was associated with upregulation of interferon response pathways across various cell types, including cardiac myocytes and stromal cells. Blocking both type 1 and type 2 interferon signaling eliminated LPS-induced tolerance against ISO, while pretreatment with recombinant type 1 and 2 interferons conferred cardiac protection. Multiomic sequencing further revealed enhanced cytoprotective signaling in interferon-treated hearts. Analysis of cell-cell communication networks indicated increased autocrine signaling by cardiac myocytes, as well as greater paracrine signaling between stromal cells and myeloid cells, in LPS-tolerized versus reverse-tolerized hearts., Conclusions: LPS pretreatment confers cardiac protection against ISO-induced injury through TLR4 mediated type 1 and 2 interferon signaling, consistent with trained innate immune tolerance. The observation that LPS-induced protection in cardiac myocytes involves both cell-autonomous and non-cell-autonomous mechanisms underscores the complexity of innate immune tolerance in the heart, warranting further investigation into this cardioprotective phenotype., Clinical Perspective: What is new?: The Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) confers cardiac protection against isoproterenol-mediated injury in a manner consistent with trained innate immune tolerance, which is reversed by β-glucan treatment.Activation of type 1 and 2 interferon signaling, which is downstream of Toll-like receptor 4, is necessary and sufficient for LPS-induced cardiac protection.LPS-tolerized hearts show heightened autocrine signaling by cardiac myocytes and, to a greater degree, increased cell-cell communication between cardiac myocytes and stromal and myeloid cells compared to reverse-tolerized hearts. What are the clinical implications?: TLR4 and interferon signaling play key roles in the establishment of cardiac protection and LPS-induced trained innate immune tolerance.The protective effects of LPS are mediated by cell-autonomous and non-cell-autonomous mechanisms, suggesting that a deeper understanding of the molecular and cellular signatures of innate immune tolerance is required for the development of targeted approaches to modulate trained innate immunity, and consequently cytoprotection, in the heart.

Background: The role of cellular senescence in human heart failure (HF) remains unclear. The senescence-associated secretory phenotype (SASP) is composed of proteins released by senescent cells. We assessed the prognostic significance and biologic pathways associated with the SASP in human HF using a plasma proteomics approach., Methods and Results: We measured 25 known SASP proteins among 2248 PHFS (Penn HF Study) participants using the SOMAScan V4 assay. We extracted the common variance in these proteins to generate SASP factor scores and assessed the relationship between these SASP factor scores and (1) all-cause death and (2) the composite of death or HF hospital admission. We also assessed the relationship of each SASP factor to 4746 other proteins, correcting for multiple comparisons, followed by pathway analyses. Two SASP factors were identified. Both factors were associated with older age, lower estimated glomerular filtration rate, and more advanced New York Heart Association class, among other clinical variables. Both SASP factors exhibited a significant positive association with the risk of death independent of the Meta-Analysis of Global-Group in Chronic HF score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. The 2 identified SASP factors were associated with 1201 and 1554 proteins, respectively, belonging to various pathways including the coagulation system, complement system, acute phase response signaling, and retinoid X receptor-related pathways that regulate cell metabolism., Conclusions: Increased SASP components are independently associated with adverse outcomes in HF. Biologic pathways associated with SASP are predominantly related to coagulation, inflammation, and cell metabolism.