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      Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction

      1 , 1 , 1 , 2
      Circulation
      Ovid Technologies (Wolters Kluwer Health)

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          Abstract

          Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance is the hallmark of HFpEF and appears to be caused by both cardiac and peripheral abnormalities in the arterial tree and skeletal muscle. Mitochondrial abnormalities can significantly contribute to impaired oxygen utilization and the resulting exercise intolerance in HFpEF. We review key aspects of the complex biology of this organelle, the clinical relevance of mitochondrial function, the methods that are currently available to assess mitochondrial function in humans, and the evidence supporting a role for mitochondrial dysfunction in the pathophysiology of HFpEF. We also discuss the role of mitochondrial function as a therapeutic target, some key considerations for the design of early-phase clinical trials using agents that specifically target mitochondrial function to improve symptoms in patients with HFpEF, and ongoing trials with mitochondrial agents in HFpEF.

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          Most cited references96

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          Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association

          Circulation, 135(10)
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            AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

            Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.
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              Epidemiology of heart failure with preserved ejection fraction

              Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome associated with poor quality of life, substantial health-care resource utilization, and premature mortality. Dunlay and colleagues summarize the epidemiological data on HFpEF, with a focus on the prevalence and incidence of HFpEF in the community as well as associated conditions and risk factors, morbidity and mortality after diagnosis, and quality of life.
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                Author and article information

                Journal
                Circulation
                Circulation
                Ovid Technologies (Wolters Kluwer Health)
                0009-7322
                1524-4539
                March 12 2019
                March 12 2019
                : 139
                : 11
                : 1435-1450
                Affiliations
                [1 ]From the University of Pennsylvania Perelman School of Medicine, Philadelphia (A.K., D.P.K., J.C.)
                [2 ]the Hospital of the University of Pennsylvania, Philadelphia (J.C.).
                Article
                10.1161/CIRCULATIONAHA.118.036259
                6414077
                30856000
                9d7a1e98-79e9-4451-9e19-dfbd814a9d44
                © 2019
                History

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