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      Sex Differences in Heart Failure With Preserved Ejection Fraction

      research-article
      , MD, PhD 1 , , MD, PhD 1 , , , MD, PhD 1 , , MD, PhD 1 , , MD, PhD 1 , , MD, PhD 1 , , MD, MSc, DrPH 2 , , MD 1 , , MAS 1 , , MD 1 , , MD 1 , , PhD 3 , , MD, PhD 4 , , MD, PhD 5 , , MD, PhD 6 , , MD, PhD 7 , 8 , , MD, PhD 9 , , MD, PhD 7 , , MD, PhD 4 , , MD, PhD 1 , the PURSUIT‐HFpEF Investigators
      Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
      John Wiley and Sons Inc.
      diastolic dysfunction, heart failure, preserved left ventricular function, prognosis, sex, Heart Failure

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          Abstract

          Background

          The female preponderance in heart failure with preserved ejection fraction (HFpEF) is a distinguishing feature of this disorder, but the association of sex with degree of diastolic dysfunction and clinical outcomes among individuals with HFpEF remains unclear.

          Methods and Results

          We conducted a prospective, multicenter, observational study of patients with HFpEF (PURSUIT‐HFpEF [Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction]: UMIN000021831). Between 2016 and 2019, 871 patients were enrolled from 26 hospitals (follow‐up: 399±349 days). We investigated sex‐related differences in diastolic dysfunction and postdischarge clinical outcomes in patients with HFpEF. The echocardiographic end point was diastolic dysfunction according to American Society of Echocardiography/European Association of Cardiovascular Imaging criteria. The clinical end point was a composite of all‐cause death and heart failure readmission. Women accounted for 55.2% (481 patients) of the overall cohort. Compared with men, women were older and had lower prevalence rates of hypertension, coronary artery disease, and chronic kidney disease. Women had diastolic dysfunction more frequently than men (52.8% versus 32.0%, P<0.001). The incidence of the clinical end point did not differ between women and men (women 36.1/100 person‐years versus men 30.5/100 person‐years, P=0.336). Female sex was independently associated with the echocardiographic end point (adjusted odds ratio, 2.839; 95% CI, 1.884–4.278; P<0.001) and the clinical end point (adjusted hazard ratio, 1.538; 95% CI, 1.143–2.070; P=0.004).

          Conclusions

          Female sex was independently associated with the presence of diastolic dysfunction and worse clinical outcomes in a cohort of elderly patients with HFpEF. Our results suggest that a sex‐specific approach is key to investigating the pathophysiology of HFpEF.

          Registration

          URL: https://upload.umin.ac.jp; Unique identifier: UMIN000021831.

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          Most cited references35

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          A Proportional Hazards Model for the Subdistribution of a Competing Risk

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            Sex differences in immune responses

            Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.
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              Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure

              We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
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                Author and article information

                Contributors
                hikoso@cardiology.med.osaka-u.ac.jp
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                23 February 2021
                02 March 2021
                : 10
                : 5 ( doiID: 10.1002/jah3.v10.5 )
                : e018574
                Affiliations
                [ 1 ] Department of Cardiovascular Medicine Osaka University Graduate School of Medicine Osaka Japan
                [ 2 ] Department of Social and Environmental Medicine Osaka University Graduate School of Medicine Osaka Japan
                [ 3 ] Division of Biomedical Statistics Department of Integrated Medicine Graduate School of Medicine Osaka University Osaka Japan
                [ 4 ] Division of Cardiology Osaka General Medical Center Osaka Japan
                [ 5 ] Division of Cardiology Osaka Rosai Hospital Osaka Japan
                [ 6 ] Cardiovascular Division Osaka Police Hospital Osaka Japan
                [ 7 ] Division of Cardiology Amagasaki Chuo Hospital Hyogo Japan
                [ 8 ] Department of Medical Informatics Osaka University Graduate School of Medicine Suita Japan
                [ 9 ] Division of Cardiology Kawanishi City Hospital Hyogo Japan
                Author notes
                [*] [* ] Correspondence to: Shungo Hikoso, MD, PhD, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2‐2 Yamadaoka, Suita, Osaka 565‐0871, Japan. E‐mail: hikoso@ 123456cardiology.med.osaka-u.ac.jp

                [*]

                A complete list of the PURSUIT‐HFpEF Investigators can be found in the Supplemental Material.

                Author information
                https://orcid.org/0000-0003-2284-1970
                https://orcid.org/0000-0002-4329-2520
                https://orcid.org/0000-0003-1637-4536
                https://orcid.org/0000-0001-8276-1505
                https://orcid.org/0000-0002-5618-4721
                Article
                JAH35997
                10.1161/JAHA.120.018574
                8174270
                33619973
                4b0191c6-2b01-4f23-bcc8-3c90b01e0531
                © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 August 2020
                : 19 January 2021
                Page count
                Figures: 3, Tables: 4, Pages: 12, Words: 8163
                Funding
                Funded by: Roche Diagnostics K.K.
                Funded by: Fuji Film Toyama Chemical Co. Ltd
                Categories
                Go Red for Women Spotlight
                Go Red for Women Spotlight
                Original Research
                Custom metadata
                2.0
                02 March 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.0 mode:remove_FC converted:22.03.2021

                Cardiovascular Medicine
                diastolic dysfunction,heart failure,preserved left ventricular function,prognosis,sex

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