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      Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

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          Abstract

          The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.

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          Most cited references 127

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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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            Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation.

             Andrew Leask (2010)
            Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, "activated" fibroblasts migrate into the wound area, where they synthesize and remodel newly created extracellular matrix. The specialized type of fibroblast responsible for this action is the alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblast. Abnormal persistence of the myofibroblast is a hallmark of fibrotic diseases. Proteins such as transforming growth factor (TGF)beta, endothelin-1, angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to myofibroblast differentiation and persistence. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGFbeta, endothelin-1, Ang II, CCN2, and PDGF and to fibroblast activation in tissue repair and fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of cardiac fibrosis.
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              Cardiac interstitium in health and disease: the fibrillar collagen network.

               Karl T Weber (1989)
              Composed of type I and III collagens, the valve leaflets, chordae tendineae and collagen matrix of the myocardium form a structural continuum. Synthesized by cardiac fibroblasts, these fibrillar collagens support and tether myocytes to maintain their alignment, whereas their respective tensile strength and resilience resist the deformation, maintain the shape and thickness, prevent the rupture and contribute to the passive and active stiffness of the myocardium. An acquired or congenital defect in this collagen network can lead to abnormalities in myocardial architecture, mechanics or valve function. In the hypertrophic process that accompanies a pressure overload, for example, increased collagen synthesis, fibroblast proliferation and a structural and biochemical remodeling of the matrix are seen. This includes distinctive patterns of reparative and reactive myocardial fibrosis, each of which alters diastolic and systolic myocardial stiffness and may lead to pathologic hypertrophy. Alternatively, a loss of collagen tethers or decline in matrix tensile strength can be responsible for regional or global transformations in myocardial architecture and function seen in the reperfused ("stunned") myocardium and in dilated (idiopathic) cardiopathy. Inherited disorders in the transcriptional and posttranslational processing of collagen can also alter the biophysical properties of the network. Future studies into collagen gene regulation, gene switching events and the control of collagen synthesis and degradation are needed to develop a more complete understanding of the relation between the collagen network and acquired and inherited forms of heart disease and to utilize therapeutics that will prevent, retard or regress abnormal collagen matrix remodeling.
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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
                2014
                15 October 2014
                : 9
                : 10
                Affiliations
                [1 ]Laboratoire de Recherche en Physiologie et Physiopathologie, Faculté de Médecine, Pôle Technologie Santé, Université Saint Joseph, Beirut, Lebanon
                [2 ]Institut National de Pathologie, Baabda, Lebanon
                Texas A& M University Health Science Center, United States of America
                Author notes

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

                Conceived and designed the experiments: GH YS NF. Performed the experiments: GH YS TI MM. Analyzed the data: GH YS MM GA NF. Wrote the paper: GH YS MM NF.

                GH and YS should be considered co-first authors on this work.

                Article
                PONE-D-14-27624
                10.1371/journal.pone.0109753
                4198123

                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: 13
                Funding
                This work was funded and supported by the Research Council of the Saint Joseph University - Faculty of Medicine. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Endocrine System
                Thyroid
                Biochemistry
                Hormones
                Peptide Hormones
                Thyroid-Stimulating Hormone
                Thyroid Hormones
                Physiology
                Cardiovascular Physiology
                Endocrine Physiology
                Medicine and Health Sciences
                Endocrinology
                Hypothyroidism
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Uncategorized

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