Chronic cardiac structural damage, diastolic and systolic dysfunction following acute myocardial injury due to bromine e
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ORGAN TOXICITY AND MECHANISMS
Chronic cardiac structural damage, diastolic and systolic dysfunction following acute myocardial injury due to bromine exposure in rats Juan Xavier Masjoan Juncos1 · Shazia Shakil1 · Wayne E. Bradley2,3 · Chih‑Chang Wei2,3 · Iram Zafar1 · Pamela Powell2,3 · Nithya Mariappan1 · William E. Louch4,5 · David A. Ford6 · Aftab Ahmad1 · Louis J. Dell’Italia2,3 · Shama Ahmad1 Received: 11 May 2020 / Accepted: 17 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Accidental bromine spills are common and its large industrial stores risk potential terrorist attacks. The mechanisms of bromine toxicity and effective therapeutic strategies are unknown. Our studies demonstrate that inhaled bromine causes deleterious cardiac manifestations. In this manuscript we describe mechanisms of delayed cardiac effects in the survivors of a single bromine exposure. Rats were exposed to bromine (600 ppm for 45 min) and the survivors were sacrificed at 14 or 28 days. Echocardiography, hemodynamic analysis, histology, transmission electron microscopy (TEM) and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Increases in right ventricular (RV) and left ventricular (LV) end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis were observed. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. Increases in cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) reflected myofibrillar damage and increased LV wall stress. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased sarcoendoplasmic reticulum calcium ATPase (SERCA) inactivation and a striking dephosphorylation of phospholamban. NADPH oxidase 2 and protein phosphatase 1 were also increased. Increased circulating eosinophils and myocardial 4-hydroxynonenal content suggested increased oxidative stress as a key contributing factor to these effects. Thus, a continuous oxidative stress-induced chronic myocardial damage along with phospholamban dephosphorylation are critical for bromine-induced chronic cardiac dysfunction. These findings in our preclinical model will educate clinicians and public health personnel and provide important endpoints to evaluate therapies. Keywords Delayed · Injury · Remodeling · Physiology · Echocardiography · Mechanisms · Animal models of human disease · Translational studies
Introduction Exposure to toxic gases such as bromine (Br2) can result in significant morbidity and mortality (Mackie et al. 2014). Our limited understanding of the pathophysiology stems from Louis J. Dell’Italia and Shama Ahmad are equally contributing senior authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02919-8) contains supplementary material, which is available to authorized users. * Shama Ahmad [email protected] Extended
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