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Sympathetic activation and outcomes in chronic heart failure: Does the neurohormonal hypothesis apply to mid-range and preserved ejection fraction patients?

  • Santiago Jimenez-Marrero
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Cardio-Oncology Unit, Cardiology Department, Bellvitge University Hospital-Catalan Institute of Oncology (ICO), L'Hospital de Llobregat, Barcelona, Spain
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  • Pedro Moliner
    Correspondence
    Corresponding authors at: 19th Floor, Feixa Llarga s/n, 08907.
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Cardio-Oncology Unit, Cardiology Department, Bellvitge University Hospital-Catalan Institute of Oncology (ICO), L'Hospital de Llobregat, Barcelona, Spain
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  • Iris Rodríguez-Costoya
    Affiliations
    Department of Cardiology, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain

    Heart Diseases Biomedical Research Group, Research Programme in Inflammatory and Cardiovascular Disorders, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
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  • Cristina Enjuanes
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
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  • Lidia Alcoberro
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Cardio-Oncology Unit, Cardiology Department, Bellvitge University Hospital-Catalan Institute of Oncology (ICO), L'Hospital de Llobregat, Barcelona, Spain
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  • Sergi Yun
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Department of Internal Medicine, Bellvitge University Hospital, L’ Hospitalet de Llobregat, Barcelona, Spain
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  • Jose Gonzalez-Costello
    Affiliations
    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Advanced Heart Failure and Heart Transplant Unit, Department ion Cardiology, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain

    Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain
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  • Alberto Garay
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Cardio-Oncology Unit, Cardiology Department, Bellvitge University Hospital-Catalan Institute of Oncology (ICO), L'Hospital de Llobregat, Barcelona, Spain
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  • Marta Tajes
    Affiliations
    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
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  • Esther Calero
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
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  • Encarnación Hidalgo
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
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  • Carmen Guerrero
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain
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  • Elena García-Romero
    Affiliations
    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Advanced Heart Failure and Heart Transplant Unit, Department ion Cardiology, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain
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  • Carles Díez-López
    Affiliations
    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Advanced Heart Failure and Heart Transplant Unit, Department ion Cardiology, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain

    Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain
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  • Miguel Cainzos-Achirica
    Affiliations
    Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore MD, United States

    Division of Cardiovascular Prevention and Wellness, Department of Cardiology, Houston Methodist Hospital, Houston TX, United States
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  • Josep Comin-Colet
    Correspondence
    Corresponding authors at: 19th Floor, Feixa Llarga s/n, 08907.
    Affiliations
    Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain

    Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

    Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain
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      Highlights

      • Information about sympathetic activation (SA) in HFpEF and HFmrEF and its clinical implications is scarce.
      • HFpEF and HFmrEF are associated with lower SA compared to HFrEF in adjusted analyses.
      • SA estimated with NE levels is associated with all-cause and CV mortality across the entire LVEF spectrum.
      • The strongest association between NE and CV mortality is HFmrEF patients, and the weakest in HFpEF.
      • This fact could help to explain why the response to the neurohormonal treatment of patients with HFmrEF is similar to HFrEF, instead of to HFpEF.

      Abstract

      Background

      Sympathetic activity (SA) is increased in patients with heart failure and reduced ejection fraction (HFrEF) and is associated with poor outcomes. However, its clinical implications are less understood in HF with mid-range (HFmrEF) and preserved ejection fraction (HFpEF). We aimed to study SA across left ventricle ejection fraction (LVEF) groups and its association with clinical outcomes.

      Methods and Results

      SA estimated by norepinephrine (NE) levels was determined in 742 consecutive outpatients with chronic HF: 348 (47%) with HFrEF, 116 (16%) HFmrEF, and 278 (37%) HFpEF. After a mean follow-up of 15 months, 17% died. Adjusted analyses showed that patients with HFpEF and HFmrEF had lower estimated marginal means of NE levels compared to HFrEF (278 and 116 pg/mL, respectively, vs. 348 pg/mL; p-value=0.005). Adjusted Cox regression analyses showed that high norepinephrine levels independently predicted all-cause mortality (ACM) in all 3 groups. The strongest associations between high NE levels and cardiovascular mortality (CVM) were observed in HFmrEF (HR: 4.7 [1.33–16.68]), while the weakest association was in HFpEF (HR: 2.62 [1.08–6.35]).

      Conclusions

      Adjusted analyses showed that HFpEF and HFmrEF were associated with lower SA compared to HFrEF. Nevertheless, increasing NE levels were independently associated with ACM and CVM in all three LVEF groups. The strongest association between high NE levels and CVM was present in HFmrEF patients, while the weakest was seen in HFpEF. These findings could explain why the response to neurohormonal therapies in patients with HFmrEF is similar to that of patients with HFrEF rather than with HFpEF.

      Keywords

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