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      Thyroid Hormone Reverses Aging-Induced Myocardial Fatty Acid Oxidation Defects and Improves the Response to Acutely Increased Afterload

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          Abstract

          Background

          Subclinical hypothyroidism occurs during aging in humans and mice and may contribute to the development of heart failure. Aging also impairs myocardial fatty acid oxidation, causing increased reliance on flux through pyruvate dehydrogenase (PDH) to maintain function. We hypothesize that the metabolic changes in aged hearts make them less tolerant to acutely increased work and that thyroid hormone supplementation reverses these defects.

          Methods

          Studies were performed on young (Young, 4–6 months) and aged (Old, 22–24 months) C57/BL6 mice at standard (50 mmHg) and high afterload (80 mmHg). Another aged group received thyroid hormone for 3 weeks (Old-TH, high afterload only). Function was measured in isolated working hearts along with substrate fractional contributions (Fc) to the citric acid cycle (CAC) using perfusate with 13C labeled lactate, pyruvate, glucose and unlabeled palmitate and insulin.

          Results

          Old mice maintained cardiac function under standard workload conditions, despite a marked decrease in unlabeled (presumably palmitate) Fc and relatively similar individual carbohydrate contributions. However, old mice exhibited reduced palmitate oxidation with diastolic dysfunction exemplified by lower -dP/dT. Thyroid hormone abrogated the functional and substrate flux abnormalities in aged mice.

          Conclusion

          The aged heart shows diminished ability to increase cardiac work due to substrate limitations, primarily impaired fatty acid oxidation. The heart accommodates slightly by increasing efficiency through oxidation of carbohydrate substrates. Thyroid hormone supplementation in aged mice significantly improves cardiac function potentially through restoration of fatty acid oxidation.

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          Most cited references 23

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          Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease.

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            The clinical significance of subclinical thyroid dysfunction.

            Subclinical thyroid disease (SCTD) is defined as serum free T(4) and free T(3) levels within their respective reference ranges in the presence of abnormal serum TSH levels. SCTD is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms, signs, and cardiovascular risk. Here, we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine the mechanisms underlying tissue alterations in SCTD and the effects of replacement therapy on progression and tissue parameters. Lastly, we address the issue of the need to treat slight thyroid hormone deficiency or excess in relation to the patient's age.
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              Thyroid disease and the heart.

              The cardiovascular signs and symptoms of thyroid disease are some of the most profound and clinically relevant findings that accompany both hyperthyroidism and hypothyroidism. On the basis of the understanding of the cellular mechanisms of thyroid hormone action on the heart and cardiovascular system, it is possible to explain the changes in cardiac output, cardiac contractility, blood pressure, vascular resistance, and rhythm disturbances that result from thyroid dysfunction. The importance of the recognition of the effects of thyroid disease on the heart also derives from the observation that restoration of normal thyroid function most often reverses the abnormal cardiovascular hemodynamics. In the present review, we discuss the appropriate thyroid function tests to establish a suspected diagnosis as well as the treatment modalities necessary to restore patients to a euthyroid state. We also review the alterations in thyroid hormone metabolism that accompany chronic congestive heart failure and the approach to the management of patients with amiodarone-induced alterations in thyroid function tests.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                7 June 2013
                : 8
                : 6
                Affiliations
                [1 ]Seattle Children's Research Institute, Seattle, Washington, United States of America
                [2 ]Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, Washington, United States of America
                [3 ]Environmental Molecular Sciences Laboratory (EMSL), Pacific Northwest National Laboratory, Richland, Washington, United States of America
                Max Delbrueck Center for Molecular Medicine, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DL MP AO. Performed the experiments: DL MP MK NI AO. Analyzed the data: DL MP NI AO. Contributed reagents/materials/analysis tools: DL MP MK NI AO. Wrote the paper: DL MP AO.

                Article
                PONE-D-13-06815
                10.1371/journal.pone.0065532
                3676337
                23762386

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 8
                Funding
                This work was supported by the National Heart, Lung, and Blood Institute Grant K08-HL-092333 to A.K.O. and National Institute of Aging R21-AG-033815 to M.A.P. A portion of the research was performed using EMSL, a national scientific user facility sponsored by the Department of Energy's Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Physiological Processes
                Aging
                Biochemistry
                Lipids
                Fatty Acids
                Model Organisms
                Animal Models
                Mouse
                Medicine
                Anatomy and Physiology
                Endocrine System
                Endocrine Physiology
                Thyroid
                Cardiovascular
                Cardiomyopathies
                Geriatric Cardiology
                Endocrinology
                Thyroid
                Hypothyroidism

                Uncategorized

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