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Canadian Journal of Cardiology

Heart Failure With Preserved Ejection Fraction in Diabetes: Mechanisms and Management

  • Patrick Meagher
    Affiliations
    Keenan Research Centre for Biomedical Science, St Michael’s Hospital; Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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  • Mohamed Adam
    Affiliations
    Keenan Research Centre for Biomedical Science, St Michael’s Hospital; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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  • Robert Civitarese
    Affiliations
    Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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  • Antoinette Bugyei-Twum
    Affiliations
    Keenan Research Centre for Biomedical Science, St Michael’s Hospital; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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  • Kim A. Connelly
    Correspondence
    Corresponding author: Dr Kim A. Connelly, 30 Bond St, Room 7-052, Toronto, Ontario M5B 1W8, Canada. Tel.: +1-416-864-5201; fax:+1-416-864-5571.
    Affiliations
    Keenan Research Centre for Biomedical Science, St Michael’s Hospital; Department of Physiology, University of Toronto, Toronto, Ontario, Canada

    Keenan Research Centre for Biomedical Science, St Michael’s Hospital; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Division of Cardiology, St Michael’s Hospital, Toronto, Ontario, Canada
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Published:March 01, 2018DOI:https://doi.org/10.1016/j.cjca.2018.02.026

      Abstract

      Diabetes mellitus (DM) is a major cause of heart failure in the Western world, either secondary to coronary artery disease or from a distinct entity known as “diabetic cardiomyopathy.” Furthermore, heart failure with preserved ejection fraction (HFpEF) is emerging as a significant clinical problem for patients with DM. Current clinical data suggest that between 30% and 40% of patients with HFpEF suffer from DM. The typical structural phenotype of the HFpEF heart consists of endothelial dysfunction, increased interstitial and perivascular fibrosis, cardiomyocyte stiffness, and hypertrophy along with advanced glycation end products deposition. There is a myriad of mechanisms that result in the phenotypical HFpEF heart including impaired cardiac metabolism and substrate utilization, altered insulin signalling leading to protein kinase C activation, advanced glycated end products deposition, prosclerotic cytokine activation (eg, transforming growth factor-β activation), along with impaired nitric oxide production from the endothelium. Moreover, recent investigations have focused on the role of endothelial-myocyte interactions. Despite intense research, current therapeutic strategies have had little effect on improving morbidity and mortality in patients with DM and HFpEF. Possible explanations for this include a limited understanding of the role that direct cell-cell communication or indirect cell-cell paracrine signalling plays in the pathogenesis of DM and HFpEF. Additionally, integrins remain another important mediator of signals from the extracellular matrix to cells within the failing heart and might play a significant role in cell-cell cross-talk. In this review we discuss the characteristics and mechanisms of DM and HFpEF to stimulate potential future research for patients with this common, and morbid condition.

      Résumé

      Le diabète est une cause majeure d'insuffisance cardiaque dans les pays occidentaux, qu'il soit consécutif à une coronaropathie ou attribuable à une entité clinique distincte appelée « cardiomyopathie diabétique ». De plus, l'insuffisance cardiaque à fraction d'éjection préservée (ICFEP) est un nouveau problème clinique de plus en plus important chez les patients atteints de diabète. D'après les données cliniques actuelles, de 30 à 40 % des patients atteints d'ICFEP sont diabétiques. La dysfonction endothéliale, l'intensification de la fibrose interstitielle et périvasculaire, la rigidité et l'hypertrophie des cardiomyocytes et le dépôt de produits de la glycation avancée constituent le phénotype structurel caractéristique du cœur dans l'ICFEP. Il existe une multitude de mécanismes qui aboutissent à l'apparition du phénotype du coeur ICFEP, y compris l'altération du métabolisme cardiaque et de l'utilisation des substrats, l'altération de la signalisation insulinique menant à l'activation de la protéine kinase C, le dépôt de produits de la glycation avancée, l'activation de la cytokine prosclérotique (p. ex., activation du facteur de croissance transformant β), et l'altération de la production d'oxyde nitrique dans l'endothélium. De plus, des études récentes ont porté sur le rôle des interactions entre cellules endothéliales et myocytes. Malgré des recherches intensives, les stratégies thérapeutiques actuelles se sont avérées peu efficaces pour améliorer la morbidité et la mortalité chez les patients diabétiques atteints d'ICFEP. Cette situation pourrait notamment s'expliquer par notre compréhension incomplète du rôle joué par la communication directe cellule-cellule et la signalisation paracrine dans la pathogenèse du diabète et de l'ICFEP. De plus, l'intégrine demeure un autre médiateur important des signaux de la matrice extracellulaire vers les cellules dans le cœur insuffisant et pourrait jouer un rôle important dans le dialogue entre les cellules. Dans cette revue, nous présentons les caractéristiques et les mécanismes du diabète et de l'ICFEP afin de stimuler les recherches futures dans l’intérêt des patients atteints de cette affection fréquente et invalidante.
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