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The transplantation of hearts from donors who suffered intracranial bleeding (ICB) has been associated with inferior long-term survival in both single-center analyses and, more recently, with the UNOS registry. The purpose of this study was to further explore this relationship through propensity matching in recipients receiving donor hearts from ICB and non-ICB donors in a large national registry. We performed a retrospective cohort analysis of the UNOS Registry OPTN from 2006-2018 for adult candidates wait-listed for isolated heart transplantation. Recipients were stratified by ICB and non-ICB donors. Propensity score matching was performed to estimate causal effects and Kaplan-Meier analysis was used to estimate survival posttransplant. Cox proportional hazards modeling evaluated the independent effect of ICB as a COD. A total of 25315 candidates met inclusion criteria. Head trauma was the leading COD in the non-ICB group, while cerebrovascular was the leading amongst the ICB group. Recipients of ICB donor hearts (N=5529) were older (median age, 42 vs. 27 years; P<0.001), less likely men (68.9% vs. 75.7%; P<0.001), and more often had a history of smoking (20.1% versus 11.7%; P<0.001), and hypertension (34.2% vs. 9.5%; P<0.001). Prior to matching there was a significant difference in long-term posttransplant survival the non-ICB (60.7% [59.5%,.61.9%] versus 56.8% [54.7%, 59.0%]; P<0.0001). However, when analyzing the propensity-matched groups for outcomes, no difference was found between the cohorts in terms of long-term survival as well as in rates of rejection, yet younger donor age was associated with improved recipient survival. In the largest propensity matching analysis of heart transplants from donors who had experienced ICB, we found similar survival and rejection rates in heart transplant recipients. Future studies should address specific subpopulations within the ICB group to address concerns about posttransplant survival. [ABSTRACT FROM AUTHOR]

Editorial. Comments on the growing awareness of diastolic heart failure in the United States. Account of the literature on diastolic heart failure; Types of diastolic abnormalities; Features of patients with diastolic heart failure; Role of coronary heart disease in systolic heart failure; Implications for the design of optimal therapy.

Although patients with familial dilated cardiomyopathy (DCM) usually present at earlier age, the impact of genetic susceptibility on the DCM severity has remained unclear. Advanced DCM may lead to heart failure requiring ventricular assisted device (VAD) or heart transplantation. This study aims to assess the role of a genetic signature of DCM on severity of DCM presentation. We analyzed clinical and genetic sequencing data from patients enrolled in the multisite DCM Precision Medicine Study, who were a geographically representative, multi-racial/ethnic cohort, between 2016 and 2021. A clinical evaluation included medical history, physical examination, electrocardiography, and echocardiography. Research exome sequencing and array-based genotyping were conducted for all patients. DCM severity was classified into 3 groups: VAD or heart transplant, ICD, or none. Genetic susceptibility was measured by the presence of DCM-related rare variants (LP, P, VUS) and more granular genetic risk groups based on the number of variant alleles or separate analyses for VUS/LP/P and LP/P variants. Confounding factors considered included gender, race/ethnicity, age at diagnosis, comorbidities, medication use, and DCM duration. Crude and adjusted associations between DCM severity and genetic susceptibility were assessed using generalized mixed models. Results :: Of 1,188 patients with DCM, mean (SD) age was 52.0 (13.6) years with 43% African American, 9% Hispanic, and 44% female participants. The analysis will: 1) compare clinical characteristics of DCM patients with VAD or heart transplant (n=342), with ICD alone (n=508), or none (n=338); 2) compare genetic profiles of patients in the 3 DCM severity groups; and 3) examine differences in DCM-related genetic variants (P, LP, VUS) among patients in the 3 severity groups after controlling for confounding factors. Contributions of specific DCM-related genetic variants will also be explored. Data from this study will help assess the risk of DCM outcomes for early patient management and guide genetic counseling regarding genetic and environmental exposure that may worsen DCM. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD 405 ] of 0.93 (SD = 1.21) units, and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD 405  ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody-negative patients. We observed statistical differences between antibody-positive and -negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody-positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including in vitro binding studies and larger observational cohorts., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Concentric remodeling (cRM) can precede heart failure with preserved ejection fraction (HFpEF), a condition prevalent in women., Methods: Patients (n=60 593, 54.2% women) visiting outpatient clinics of Cardiology Centers of the Netherlands were analyzed for cRM, HFpEF development, and mortality risk. We studied risk factors for relative wall thickness both sex-stratified and in women and men combined. Biomarker profiling was performed (4534 plasma proteins) in a substudy involving 557 patients (65.4% women) to identify pathways involved in cRM., Results: cRM was present in 23.5% of women and 27.6% of men and associated with developing HFpEF (HR, 2.15 [95% CI, 1.51-2.99]) and mortality risk (HR, 1.09 [95% CI, 1.00-1.19]) in both sexes. Age, heart rate, and hypertension were statistically significantly stronger risk factors for relative wall thickness in women than men. Higher circulating levels of IFNA5 (interferon alpha-5) were associated with higher relative wall thickness in women only. Pathway analysis revealed differential pathway activation by sex and increased expression of inflammatory pathways in women., Conclusions: cRM is prevalent in approximately 1 in 4 women and men visiting outpatient cardiology clinics and associated with HFpEF development and mortality risk in both sexes. Known risk factors for cRM were more strongly associated in women than men. Proteomic analysis revealed inflammatory pathway activation in women, with a central role for IFNA5. Differential biologic pathway activation by sex in cRM may contribute to the female predominance of HFpEF and holds promise for identification of new therapeutic avenues for prevention and treatment of HFpEF., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT001747., Competing Interests: Disclosures None.

Objectives: Older adults face racism, sexism, and ageism. As the U.S. population ages, it is important to understand how the current population views older adults., Methods: Participants recruited through Amazon's Mechanical Turk provided perceptions of older Black and White models' photographs. Using mixed-effect models, we assessed interactions between race and gender of participants and models., Results: Among Participants of Color and White participants ( n  = 712, 70% non-Hispanic White, 70% women, mean 37.81 years), Black models were perceived as more attractive, less threatening, and sadder than White models, but differences were greater for White participants (race-by-race interaction: attractive p  = 0.003, threatening p  = 0.009, sad p  = 0.016). Each gender perceived their respective gender as more attractive (gender-by-gender interaction p  < 0.0001). Male and female participants perceived male models as happier than female models, but differences were greater for male participants ( p  = 0.026). Irrespective of participant age group, women were perceived as more threatening ( p  = 0.012). Other perceptions were not significant., Discussion: Participants had few biases toward older Black and White models, while gender biases favored men., Competing Interests: Authors declare no conflict of interest., (© Forest Melton et al., 2022; Published by Mary Ann Liebert, Inc.)

Objectives: In this study, the authors sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial., Background: Atrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes., Methods: A total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death., Results: History of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR: 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan., Conclusions: History of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (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 The PARAGON-HF study was sponsored by Novartis; no additional funding was provided for this analysis. Dr Cikes has received institutional grants or contracts from Novartis, Abbott, and Corvia; payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Novartis, GE Healthcare, Pfizer, Bayer, Boehringer Ingelheim, AstraZeneca, Teva Pharmaceutical Industries, Sanofi, and LivaNova; and participation on advisory boards for Pfizer, Boehringer Ingelheim, Bayer, and Novartis. Dr Planinc has received an educational grant from Boehringer Ingelheim; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Sanofi Aventis, Pfizer, Bayer, Teva Pharmaceuticals, Krka-Farma, Servier-Pharma, Sandoz, Mylan, and AstraZeneca; has received support for attending meetings and/or travel from Pfizer, Bayer, and Abbott; and has participated on advisory boards for Novartis and Boehringer Ingelheim. Dr Claggett has received consulting fees from Amgen, Boehringer Ingelheim, Corvia, Myokardia, and Novartis. Dr Cunningham has received grant support from the United States National Heart Lung and Blood Institute (T32HL094301). Dr Sweitzer has received salary support from Novartis for work as PARAGON-HF national leader, Merck for work as national leader, and the American Heart Association for work as journal editorship; and has received research support from the National Institutes of Health. Dr Shah has received institutional grants from Actelion, AstraZeneca, Corvia, Pfizer, and Novartis; has received royalties or licenses from UpToDate; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapies, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eidos, Eisai, GlaxoSmithKline, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr Packer has received consulting fees from Abbvie, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Lilly, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; has received payment for expert testimony from Actavis; and has received support for attending meetings and/or travel from Boehringer Ingelheim. Dr Pfeffer has received institutional research grant support from Novartis for serving on the PARAGON-HF Steering Committee and as Study Chair of PARADISE-MI; has received personal consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, CinCor, Corvidia, DalCor, GlaxoSmithKline, Innovative Science Solutions, Jazz, Lexicon, MyoKardia, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, Pfizer, Pharmascience, Roche, Sanofi, Servier, and Takeda; has received support for attending meetings and/or travel from Novartis, Novo Nordisk, and A+ (third party to AstraZeneca); and has received stock options from DalCor and Peerbridge. Dr Zile has received grants, consulting fees and participation on a data safety monitoring board or advisory board as part of the committees for the PARAGON-HF and PARADIGM trials. Dr Anand has received consulting fees from Novartis, Amgen, ARCA, Boehringer Ingelheim, AstraZeneca, and LivaNova; and has participated on a data safety monitoring board or advisory board for Boston Scientific. Dr Chiang is a Novartis employee receiving wages and stocks from Novartis as part of an annual wage package. Dr Lam has received research grants from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has received consulting fees from Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Janssen R & D, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi, St Luke, and Us2.ai; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Medscape/WebMD Global, Novartis, Radcliffe, and Roche Diagnostics; has a patent pending PCT/SG2016/050217; has a patent application number 16/216,929; has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bayer, Boston Scientific, Novartis, Novo Nordisk, and Roche Diagnostics; and has nonexecutive director role and stock or stock options for Us2.ai. Dr Redfield has received steering committee membership for PARAGON-HF without personal compensation. Dr Desai has received institutional research grant support from Abbott, AstraZeneca, Alnylam, Bayer, and Novartis; and has received personal consulting fees from Abbott, Alnylam, Amgen, AstraZeneca, Biofourmis, Boehringer Ingelheim, Boston Scientific, Cytokinetics, DalCor Pharma, Lupin Pharma, Lexicon, Merck, Novartis, Relypsa, Regeneron, and Sun Pharma. Dr McMurray has received institutional support from Novartis; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and The Corpus; and has received other institutional funding from Cytokinetics, KBP Biosciences, AstraZeneca, Amgen, Bayer, AstraZeneca, Theracos, Ionis Pharmaceuticals, DalCor, Glaxo Smith Kline, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion, and Alnylam. Dr Solomon has received an institutional grant from Novartis for conduct of the PARAGON trial; has received institutional grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, and Theracos; and has received consulting fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous research showed association between frailty and an impaired autonomic nervous system; however, the direct effect of frailty on heart rate (HR) behavior during physical activity is unclear. The purpose of the current study was to determine the association between HR increase and decrease with frailty during a localized upper-extremity function (UEF) task to establish a multimodal frailty test., Methods: Older adults aged 65 or older were recruited and performed the UEF task of rapid elbow flexion for 20 s with the right arm. Wearable gyroscopes were used to measure forearm and upper-arm motion, and electrocardiography were recorded using leads on the left chest. Using this setup, HR dynamics were measured, including time to peak HR, recovery time, percentage increase in HR during UEF, and percentage decrease in HR during recovery after UEF., Results: Fifty-six eligible participants were recruited, including 12 non-frail (age = 76.92 ± 7.32 years), and 40 pre-frail (age = 80.53 ± 8.12 years), and four frail individuals (age = 88.25 ± 4.43 years). Analysis of variance models showed that the percentage increase in HR during UEF and percentage decrease in HR during recovery were both 47% smaller in pre-frail/frail older adults compared to non-frails (p < 0.01, effect size = 0.70 and 0.62 for increase and decrease percentages). Using logistic models with both UEF kinematics and HR parameters as independent variables, frailty was predicted with a sensitivity of 0.82 and specificity of 0.83., Conclusion: Current findings showed evidence of strong association between HR dynamics and frailty. It is suggested that combining kinematics and HR data in a multimodal model may provide a promising objective tool for frailty assessment., (© 2022. The Author(s).)

Background: Older individuals encounter the greatest racial/gender biases. It is unknown whether younger generations, who often lead culture shifts, have racial and gender biases against older populations., Methods: Using Amazon's Mechanical Turk's crowdsourcing, we identified how an individual's race and gender are associated with perceptions of individuals aged mid-60s. Participants were asked to rate photograph appearances on Likert Scale (1-10). Interactions between participant and photograph race and gender were assessed with mixed effects models. Delta represents rating differences (positive value higher rating for Whites or women, negative value higher rating for African-Americans or men)., Results: Among 1563 participants (mean 35 years ± 12), both non-Hispanic White (WP) and all Other race/ethnicity (OP) participants perceived African-American photos as more trustworthy [Delta WP -0.60(95%CI-0.83, - 0.37); Delta OP - 0.51(- 0.74,-0.28), interaction p = 0.06], more attractive [Delta non-Hispanic White participants - 0.63(- 0.97, - 0.29); Delta Other race/ethnicity participants - 0.40 (- 0.74, - 0.28), interaction p < 0.001], healthier [Delta WP -0.31(- 0.53, - 0.08); Delta OP -0.24(- 0.45, -0.03), interaction p = 1.00], and less threatening than White photos [Delta WP 0.79(0.36,1.22); Delta OP 0.60(0.17,1.03), interaction p < 0.001]. Compared with OP, WP perceived African-American photos more favorably for intelligence (interaction p < 0.001). Both genders perceived photos of women as more trustworthy [Delta Women Participants (WmP) 0.50(0.27,0.73); Delta Men Participants(MnP) 0.31(0.08,0.54); interaction p < 0.001] and men as more threatening [Delta WmP -0.84(-1.27, -0.41), Delta MnP - 0.77(- 1.20, - 0.34), interaction p = 0.93]. Compared with MnP, WmP perceived photos of women as happier and more attractive than men (interaction p < 0.001). Compared with WmP, MnP perceived men as healthier than women (interaction p < 0.001)., Conclusions: Among a young generation, older African-Americans were perceived more favorably than Whites. Gender perceptions followed gender norms. This suggests a decline in implicit bias against older minorities, but gender biases persist. Future work should investigate whether similar patterns are observed in healthcare., (© 2020. W. Montague Cobb-NMA Health Institute.)

Background: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19., Methods: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009., Findings: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m 2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; β-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ 2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups., Interpretation: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19., Funding: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

ACE2 (angiotensin-converting enzyme 2) is a key component of the renin-angiotensin-aldosterone system. Yet, little is known about the clinical and biologic correlates of circulating ACE2 levels in humans. We assessed the clinical and proteomic correlates of plasma (soluble) ACE2 protein levels in human heart failure. We measured plasma ACE2 using a modified aptamer assay among PHFS (Penn Heart Failure Study) participants (n=2248). We performed an association study of ACE2 against ≈5000 other plasma proteins measured with the SomaScan platform. Plasma ACE2 was not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 was associated with older age, male sex, diabetes mellitus, a lower estimated glomerular filtration rate, worse New York Heart Association class, a history of coronary artery bypass surgery, and higher pro-BNP (pro-B-type natriuretic peptide) levels. Plasma ACE2 exhibited associations with 1011 other plasma proteins. In pathway overrepresentation analyses, top canonical pathways associated with plasma ACE2 included clathrin-mediated endocytosis signaling, actin cytoskeleton signaling, mechanisms of viral exit from host cells, EIF2 (eukaryotic initiation factor 2) signaling, and the protein ubiquitination pathway. In conclusion, in humans with heart failure, plasma ACE2 is associated with various clinical factors known to be associated with severe coronavirus disease 2019 (COVID-19), including older age, male sex, and diabetes mellitus, but is not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 protein levels are prominently associated with multiple cellular pathways involved in cellular endocytosis, exocytosis, and intracellular protein trafficking. Whether these have a causal relationship with ACE2 or are relevant to novel coronavirus-2 infection remains to be assessed in future studies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin-converting enzyme 2 (ACE2), which facilitates SARS-CoV-2 host cell entry, may be impacted by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long-term outpatient ACEI or ARB upon hospitalization with COVID-19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project., (© 2020 Wiley Periodicals LLC.)

Background: Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models., Methods: In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA). We also measured total S1P by liquid chromatography-mass spectrometry and isolated HDL particles to test the association between apo M and HDL-associated S1P. We confirmed the relationship between apo M and outcomes using modified aptamer-based apo M measurements among 2170 adults in the PHFS and 2 independent cohorts: the Washington University Heart Failure Registry (n=173) and a subset of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial; n=218). Last, we examined the relationship between apo M and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure., Results: In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51-0.61]; P <0.0001) and the composite of death/ventricular assist device implantation/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58-0.67]; P <0.0001). This relationship was independent of HDL cholesterol or apo AI levels. Apo M remained associated with death (hazard ratio, 0.78 [95% CI, 0.69-0.88]; P <0.0001) and the composite of death/ventricular assist device/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76-0.94]; P =0.001) in models that adjusted for multiple confounders. This association was present in both heart failure with reduced and preserved ejection fraction and was replicated in the Washington University cohort and a cohort with heart failure with preserved ejection fraction only (TOPCAT). The S1P and apo M content of isolated HDL particles strongly correlated ( R =0.81, P <0.0001). The top canonical pathways associated with apo M were inflammation (negative association), the coagulation system (negative association), and liver X receptor/retinoid X receptor activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays., Conclusions: Reduced circulating apo M is independently associated with adverse outcomes across the spectrum of human heart failure. Further research is needed to assess whether the apo M/S1P axis is a suitable therapeutic target in heart failure.

Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men., Methods: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes., Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men ( P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men., Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding., Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF., Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF., Results: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78-0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76-0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77-0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81-0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions., Conclusions: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men., Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by a preserved ejection fraction but increased diastolic stiffness and abnormalities of filling. Although the prevalence of HFpEF is high and continues to rise, no effective therapies exist; however, the diabetic drug metformin has been associated with improved diastolic function in diabetic patients. Here we determine the therapeutic potential of metformin for improving diastolic function in a mouse model with HFpEF-like symptoms. We combine transverse aortic constriction (TAC) surgery with deoxycorticosterone acetate (DOCA) supplementation to obtain a mouse model with increased diastolic stiffness and exercise intolerance. Echocardiography and pressure-volume analysis reveal that providing metformin to TAC/DOCA mice improves diastolic function in the left ventricular (LV) chamber. Muscle mechanics show that metformin lowers passive stiffness of the LV wall muscle. Concomitant with this improvement in diastolic function, metformin-treated TAC/DOCA mice also demonstrate preserved exercise capacity. No metformin effects are seen in sham operated mice. Extraction experiments on skinned ventricular muscle strips show that the metformin-induced reduction of passive stiffness in TAC/DOCA mice is due to an increase in titin compliance. Using phospho-site-specific antibodies, we assay the phosphorylation of titin's PEVK and N2B spring elements. Metformin-treated mice have unaltered PEVK phosphorylation but increased phosphorylation of PKA sites in the N2B element, a change which has previously been shown to lower titin's stiffness. Consistent with this result, experiments with a mouse model deficient in the N2B element reveal that the beneficial effect of metformin on LV chamber and muscle stiffness requires the presence of the N2B element. We conclude that metformin offers therapeutic benefit during HFpEF by lowering titin-based passive stiffness., (© 2018 Slater et al.)

Background: Heart failure education programs are not standardized. The best form of education is unclear. We evaluated whether addition of a novel tablet application to nurse practitioner (NP) education was superior to NP education alone in reducing 30-day readmission after heart failure hospitalization., Methods: From February 2015-March 2016, patients admitted to a quaternary academic center with primary diagnosis of heart failure were randomized to 1) treatment - NP education plus tablet application (interactive conditional logic program that flags patient questions to medical staff), or 2) control - NP education. The primary outcome was reduction in 30-day readmission rate. Secondary outcomes included satisfaction and education assessed via survey., Results: Randomization included 60 patients to treatment and 66 to control. A total of 13 patients withdrew prior to intervention (treatment n = 4, control n = 1) or were lost to follow-up (treatment n = 3, control n = 5). The 30-day readmission rate trended lower for treatment compared with control, but results were not statistically significant (13.2% [7/53], 26.7% [16/60], respectively, P = .08). Similarly, satisfaction trended higher with treatment than control (P = .08). Treatment patients rated explanations from their physicians higher than control (Always: 83.7%, 55.8%, respectively, P = .01)., Conclusions: NP education plus tablet use was not associated with significantly lower 30-day readmission rates in comparison with NP alone, but a positive trend was seen. Patient satisfaction trended higher and heart failure explanations were better with NP education plus tablet. A larger study is needed to determine if NP education plus tablet reduces readmission rates following heart failure admission., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to examine the relationship between baseline heart rate (HR), change in HR from a preceding visit, and time-updated HR with subsequent outcomes in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial., Background: Higher resting HR and increase in HR over time in patients with heart failure are associated with adverse outcomes. Whether these relationships between HR and prognosis are also observed in patients with HFpEF requires further assessment., Methods: In 1,767 patients enrolled in the TOPCAT trial from the Americas, the associations between baseline resting HR and change in HR from the preceding visit and clinical outcomes were examined using Cox proportional hazards models, along with the association between HR at each visit and outcome., Results: Both baseline HR (adjusted hazard ratio: 1.08; 95% confidence interval: 1.04 to 1.12) and change in HR from the preceding visit (adjusted hazard ratio: 1.09; 95% confidence interval: 1.05 to 1.14; p < 0.001 per 5 beats/min higher HR), after adjusting for covariates, were associated with a higher risk for the primary endpoint of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Time-updated resting HR at each visit was also associated with risk (adjusted hazard ratio: 1.11; 95% confidence interval: 1.07 to 1.15; p < 0.001 per 5 beats/min higher HR). Furthermore, a rise in resting HR of approximately 10 beats/min, beginning approximately 10 days prior to the primary endpoint, was observed., Conclusions: Baseline resting HR and change in HR over time predict outcomes in patients with HFpEF, as does time-updated HR during follow-up. These data suggest that frequent outpatient monitoring of HR, possibly with remote technologies, may identify patients with HFpEF who may be at increased risk for rehospitalization or death., (Copyright © 2017 American College of Cardiology Foundation. All rights reserved.)

Aims: Left ventricular mechanical dyssynchrony has been described in heart failure with preserved ejection fraction (HFpEF), but its prognostic significance is not known., Methods and Results: Of 3445 patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, dyssynchrony analysis was performed on 424 patients (12%) by multiple speckle tracking echocardiography strain-based criteria. The primary dyssynchrony analysis was the standard deviation of the time to peak longitudinal strain (SD T2P LS). Cox proportional hazards models assessed the association of dyssynchrony with the composite outcome of cardiovascular death or heart failure hospitalization. Mean age was 70 ± 10 years, LVEF was 60 ± 8%, and QRS duration was 101 ± 27 ms. Worse dyssynchrony, reflected in SD T2P LS, was associated with wider QRS, prior myocardial infarction, larger LV volume and mass, and worse systolic (lower LVEF and global longitudinal strain) and diastolic (lower e' and higher E/e') function. During a median follow-up of 2.6 (interquartile range 1.5-3.8) years, 107 patients experienced the composite outcome. Worse dyssynchrony was associated with the composite outcome in unadjusted analysis [hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.01-1.07; P = 0.021, per 10 ms increase], but not after adjusting for clinical characteristics, or after further adjustment for LVEF, AF, NYHA class, stroke, heart rate, creatinine, haematocrit, and QRS duration (HR 1.03, 95% CI 0.99-1.06; P = 0.16, per 10 ms increase)., Conclusion: Worse LV mechanical dyssynchrony, assessed by speckle tracking echocardiography, is not an independent predictor of adverse outcomes in HFpEF, suggesting that mechanical dyssynchrony is unlikely to be an important mechanism underlying this syndrome. These findings warrant validation in an independent study specifically designed to assess the prognostic utility of mechanical dyssynchrony in HFpEF., Trial Registration: NCT00094302., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Measures of interaction between the left ventricle (LV) and arterial system (ventricular-arterial coupling) are important but under-recognised cardiovascular phenotypes in heart failure. Ventriculo-arterial coupling is commonly assessed in the pressure-volume plane, using the ratio of effective arterial elastance (E A ) to LV end-systolic elastance (E ES ) to provide information on ventricular-arterial system mechanical efficiency and performance when LV ejection fraction is abnormal. These analyses have significant limitations, such as neglecting systolic loading sequence, and are less informative in heart failure with preserved ejection fraction (HFpEF). E A is almost entirely dependent on vascular resistance and heart rate. Assessment of pulsatile arterial haemodynamics and time-resolved myocardial wall stress provide critical incremental physiological information and should be more widely utilised. Pulsatile arterial load represents a promising therapeutic target in HFpEF. Here, we review various approaches to assess ventricular-arterial interactions, and their pathophysiological and clinical implications in heart failure., Competing Interests: Disclosure: JAC has received consulting honoraria from Bristol-Myers Squibb, OPKO Healthcare, Fukuda Denshi, Microsoft, Vital Labs and Merck. He has received research grants from the National Institutes of Health, American College of Radiology Network, American Heart Association, Fukuda Denshi, Bristol-Myers Squibb, Microsoft and CVRx Inc., and device loans from AtCor Medical. He is named as inventor in a University of Pennsylvania patent application for the use of inorganic nitrates/nitrites for the treatment of heart failure and preserved ejection fraction. NKS has research grants from the National Institutes of Health, American Heart Association, Novartis, Merck and Corvia Medical. This work was supported by NIH grants R01 HL 121510-01A1 (J.A.C) and R56HL-124073-01A1 (J.A.C).

Objectives: We sought to determine the relative impact of diabetes mellitus on prognosis in ischemic compared with nonischemic cardiomyopathy., Background: Ischemic myocardium is characterized by increased reliance on aerobic and anaerobic glycolysis. Because glucose utilization by cardiomyocytes is an insulin-mediated process, we hypothesized that diabetes would have a more adverse impact on mortality and progression of heart failure in ischemic compared with nonischemic cardiomyopathy., Methods: We performed a retrospective analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) Prevention and Treatment trials., Results: In adjusted analyses, diabetes mellitus was strongly associated with an increased risk for all-cause mortality in patients with ischemic cardiomyopathy, (relative risk [RR] 1.37, 95% confidence interval [CI] 1.21 to 1.55; p < 0.0001), but not in those with nonischemic cardiomyopathy (RR 0.98, 95% CI 0.76 to 1.32; p = 0.98). The increased mortality in patients with ischemic cardiomyopathy compared with nonischemic cardiomyopathy was limited to those with ischemic cardiomyopathy and diabetes mellitus (RR 1.37, 95% CI 1.21 to 1.56; p < 0.0001). When patients with ischemic cardiomyopathy and diabetes mellitus were excluded, there was no significant difference in mortality risk between the ischemic and nonischemic cardiomyopathy groups after adjusted analysis (RR 0.99, 95% CI 0.86 to 1.15; p = 0.99). Previous surgical revascularization identified patients within the cohort with ischemic cardiomyopathy and diabetes mellitus, with improved prognosis., Conclusions: The differential impact of diabetes on mortality and heart failure progression according to the etiology of heart failure suggests that diabetes and ischemic heart disease interact to accelerate the progression of myocardial dysfunction. Evaluation of the potential for revascularization may be particularly important in patients with ischemic cardiomyopathy and diabetes mellitus.

The presence of multiple medical illnesses often distinguishes elderly patients with heart failure and can make pharmacologic management of symptomatic heart failure challenging in this population. Physiologic changes that occur with normal aging may complicate clinical assessment. Limited data from large clinical trials of heart failure therapy are applicable to aged patients. Available data suggest that elderly patients should be treated with the same regimen as younger patients but that more careful attention should be paid to dosing, especially when initiating a new drug. History and physical examination techniques can be used to uncover evidence of congestion and inadequate perfusion and are critical adjuncts when making therapeutic decisions. The objectives of therapy for elderly patients with heart failure must be individualized within the larger context of patients' goals and stage of life.

People over 65 years account for more than 80% of heart failure hospitalizations, with almost half in patients morer than 75. Heart failure hospitalizations accounted for 21% of the annual health care budget for a representative senior program. Heart failure with preserved ejection fraction accounts for over half of heart failure hospitalizations in the elderly. Current therapy for the elderly is directed to relieve congestion by reducing volume overload and hypertension, while addressing exacerbating factors such as ischemia and anemia. Heart rate reduction is critical when sinus rhythm cannot be maintained but can also improve diastolic filling during sinus rhythm. While cardiac transplantation is rarely indicated, other interventions should be actively considered. Most elderly patients admitted with heart failure wish resuscitation. As heart failure progresses, decisions regarding implantable defibrillators or dialysis require careful consideration, and the risk/benefit balance may shift toward therapies to improve quality of life. (c)1999 by CVRR, Inc.