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      Myocardial Strain and Cardiac Output are Preferable Measurements for Cardiac Dysfunction and Can Predict Mortality in Septic Mice

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          Abstract

          Background

          Sepsis is the overwhelming host response to infection leading to shock and multiple organ dysfunction. Cardiovascular complications greatly increase sepsis‐associated mortality. Although murine models are routinely used for preclinical studies, the benefit of using genetically engineered mice in sepsis is countered by discrepancies between human and mouse sepsis pathophysiology. Therefore, recent guidelines have called for standardization of preclinical methods to document organ dysfunction. We investigated the course of cardiac dysfunction and myocardial load in different mouse models of sepsis to identify the optimal measurements for early systolic and diastolic dysfunction.

          Methods and Results

          We performed speckle‐tracking echocardiography and assessed blood pressure, plasma inflammatory cytokines, lactate, B‐type natriuretic peptide, and survival in mouse models of endotoxemia or polymicrobial infection (cecal ligation and puncture, [ CLP]) of moderate and high severity. We observed that myocardial strain and cardiac output were consistently impaired early in both sepsis models. Suppression of cardiac output was associated with systolic dysfunction in endotoxemia or combined systolic dysfunction and reduced preload in the CLP model. We found that cardiac output at 2 hours post‐ CLP is a negative prognostic indicator with high sensitivity and specificity that predicts mortality at 48 hours. Using a known antibiotic (ertapenem) treatment, we confirmed that this approach can document recovery.

          Conclusions

          We propose a non‐invasive approach for assessment of cardiac function in sepsis and myocardial strain and strain rate as preferable measures for monitoring cardiovascular function in sepsis mouse models. We further show that the magnitude of cardiac output suppression 2 hours post‐ CLP can be used to predict mortality.

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          Most cited references 68

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            Why have clinical trials in sepsis failed?

            The systemic inflammatory response is biologically complex, redundant, and activated by both infectious and noninfectious triggers. Its manipulation can cause both benefit and harm. More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments. The current challenge for sepsis research lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate large studies of clinical and biochemical epidemiology to understand the course of illness, better integration of basic and clinical science, and the creation of stratification systems to target treatment towards those who are most likely to benefit.
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              The Surviving Sepsis Campaign Bundle: 2018 update

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                Author and article information

                Contributors
                drosatos@temple.edu
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                21 May 2019
                21 May 2019
                : 8
                : 10 ( doiID: 10.1002/jah3.2019.8.issue-10 )
                Affiliations
                [ 1 ] Center for Translational Medicine and Department of Pharmacology Lewis Katz School of Medicine Temple University Philadelphia PA
                [ 2 ] Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences University of Campania “Luigi Vanvitelli” Naples Italy
                [ 3 ] Department for Anesthesiology and Intensive Care Medicine Friedrich‐Schiller‐University Jena Germany
                [ 4 ] Division of Cardiology, Angiology, Intensive Medical Care and Pneumology Department of Internal Medicine I University Hospital Jena Germany
                [ 5 ] Heart Failure and Transplant Unit Onassis Cardiac Surgery Center Athens Greece
                Author notes
                [* ] Correspondence to: Konstantinos Drosatos, MSc, PhD, Metabolic Biology Laboratory, Lewis Katz School of Medicine at Temple University 3500 N. Broad Street, Philadelphia 19140. E‐mail: drosatos@ 123456temple.edu
                [†]

                Mr Hoffman and Dr Kyriazis contributed equally to this work.

                Article
                JAH34139
                10.1161/JAHA.119.012260
                6585345
                31112430
                © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 10, Tables: 1, Pages: 20, Words: 11566
                Product
                Funding
                Funded by: National Institutes of Health
                Award ID: HL130218
                Award ID: P01HL091799
                Funded by: W.W. Smith Charitable Trust
                Funded by: American Heart Association
                Award ID: 18PRE34060115
                Award ID: 17POST33660942
                Funded by: Kahn Family Post‐Doctoral Fellowship in Cardiovascular Research
                Award ID: 18POST34060150
                Categories
                Original Research
                Original Research
                Imaging
                Custom metadata
                2.0
                jah34139
                21 May 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.3 mode:remove_FC converted:23.05.2019

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