The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

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Abstract

Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.

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Most cited references 99

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The inflammatory response in myocardial injury, repair, and remodelling.

Nikolaos G Frangogiannis (2014)

Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.

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Inflammation, immunity, and hypertensive end-organ damage.

William G McMaster, Annet Kirabo, Meena S Madhur … (2015)

For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.

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Atlas of the clinical genetics of human dilated cardiomyopathy.

Jan Haas, Karen Frese, Barbara Peil … (2015)

Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

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Author and article information

Contributors

Stefan Frantz: frantz_s@ukw.de

Journal

Journal ID (nlm-ta): Eur J Heart Fail

Journal ID (iso-abbrev): Eur. J. Heart Fail

Journal ID (doi): 10.1002/(ISSN)1879-0844

Journal ID (publisher-id): EJHF

Title: European Journal of Heart Failure

Publisher: John Wiley & Sons, Ltd (Oxford, UK )

ISSN (Print): 1388-9842

ISSN (Electronic): 1879-0844

Publication date (Electronic): 15 January 2018

Publication date (Print): March 2018

Publication date PMC-release: 15 January 2018

Volume: 20

Issue: 3 ( doiID: 10.1002/ejhf.2018.20.issue-3 )

Pages: 445-459

Affiliations

[ ¹ ] Department of Internal Medicine I, University Hospital Würzburg, Germany; Department of Internal Medicine III Martin Luther University Halle‐Wittenberg Halle (Saale) Germany

[ ² ] Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal

[ ³ ] Pole of Pharmacology and Therapeutics, Institut de Recherche Experimentale et Clinique (IREC), and Clinique Universitaire Saint‐Luc Université Catholique de Louvain Brussels Belgium

[ ⁴ ] Department of Cardiology and Angiology Medizinische Hochschule Hannover Germany

[ ⁵ ] Prof. Emer University of Antwerp Antwerp Belgium

[ ⁶ ] Department of Medicine and Surgery University of Salerno Baronissi Italy

[ ⁷ ] School of Medicine and Dentistry University of Aberdeen Aberdeen Scotland

[ ⁸ ] Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health Medicine and Life Sciences, Maastricht University Maastricht The Netherlands

[ ⁹ ] International Centre for Genetic Engineering and Biotechnology (ICGEB) and Department of Medical, Surgical and Health Sciences University of Trieste Trieste Italy

[ ¹⁰ ] Department of Cardiovascular Physiology Ruhr University Bochum Bochum Germany

[ ¹¹ ] Molecular Cardiology, Department of Cardiology and Angiology Medizinische Hochschule Hannover Germany

[ ¹² ] Department of Molecular Biotechnology and Health Sciences University of Torino Torino Italy

[ ¹³ ] Department of Physiology and Cardiothoracic Surgery and Cardiovascular Research Centre, Faculty of Medicine University of Porto Porto Portugal

[ ¹⁴ ] The James Black Centre and King's British Heart Foundation Centre, King's College University of London London UK

[ ¹⁵ ] Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IFB‐Tx, and REBIRTH Excellence Cluster Hannover Medical School Hannover Germany

[ ¹⁶ ] Department of Translational Medical Sciences Federico II University Naples Italy

[ ¹⁷ ] Department of Physiology, VU University Medical Center Amsterdam Cardiovascular Sciences Institute Amsterdam The Netherlands

[ ¹⁸ ] Netherlands Heart Institute Utrecht The Netherlands

[ ¹⁹ ] Center for Basic and Clinical Immunology Research (CISI) Federico II University Naples Italy

[ ²⁰ ] Department of Cardiovascular Sciences Leuven University Leuven Belgium

Author notes

[*] [* ]Corresponding author. Department of Internal Medicine I, University Hospital Würzburg, Comprehensive Heart Failure Center, University of Würzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany. Tel: +49 931 20139001, Fax +49 931 201639001, Email: frantz_s@ 123456ukw.de

Article

Publisher ID: EJHF1138

DOI: 10.1002/ejhf.1138

PMC ID: 5993315

PubMed ID: 29333691

SO-VID: db1436e4-d7f1-4929-9353-05911034bb98

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 01 October 2017

Date revision received : 03 December 2017

Date accepted : 18 December 2017

Page count

Figures: 4, Tables: 1, Pages: 15, Words: 13500

Funding

Funded by: Regione Campania CISI‐Lab

Funded by: European Union Commission's Seventh Framework

Award ID: 305507, 602904

Funded by: FP7‐Health‐2013‐Innovations‐1

Award ID: 602156

Funded by: FWO Flanders, Belgium

Award ID: FWO G080014 N

Funded by: European Union Horizon2020

Award ID: UE LSHM‐CT‐05‐018833, FNRS PDR T.0144.13

Funded by: Bundesministerium für Bildung und Forschung

Award ID: BMBF01 EO1004

Funded by: Deutsche Forschungsgemeinschaft

Award ID: SFB688 TP A10

Custom metadata

source-schema-version-number 2.0

component-id ejhf1138

cover-date March 2018

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:16.04.2018

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: immune system,macrophage,t‐cell,ischaemic cardiomyopathy,hypertensive cardiomyopathy,diabetic cardiomyopathy,toxic cardiomyopathy,viral cardiomyopathy,genetic cardiomyopathy,peripartum cardiomyopathy,autoimmune cardiomyopathy

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: immune system, macrophage, t‐cell, ischaemic cardiomyopathy, hypertensive cardiomyopathy, diabetic cardiomyopathy, toxic cardiomyopathy, viral cardiomyopathy, genetic cardiomyopathy, peripartum cardiomyopathy, autoimmune cardiomyopathy

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

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Abstract

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Cardiovascular Innovations and Applications

Most cited references 99

The inflammatory response in myocardial injury, repair, and remodelling.

Inflammation, immunity, and hypertensive end-organ damage.

Atlas of the clinical genetics of human dilated cardiomyopathy.

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