TRR 19: Inflammatory Cardiomyopathy - Molecular Pathogenesis and Therapy
Biology
Final Report Abstract
Clinical And Socioeconomic Background: CRC Transregio 19 (CRC/TR 19) was supported 01.07.2004 to 31.12.2013. Goals of this CRC “Inflammatory Cardiomyopathy – Molecular Pathogenesis and Treatment” were elucidation of structural and epidemiological foundations, and improvement of differential diagnosis, treatment, and long-term prognosis of inflammatory cardiomyopathy (DCMi), a subtype of dilated cardiomyopathy. Besides coronary heart disease, DCM is the most frequent cause of heart failure. Among ≈1.5 million heart failure patients in Germany alone, ≈500.000 patients develop heart failure on basis of DCM which has the highest incidence from 3rd-5th decade of life. Despite progress in conventional heart failure therapy, prognosis of this disease remains severe with 5-years mortality of ≈50%. Direct economical burden is estimated at 2-4 billion € per year, enhanced by the fact that patients are usually young at 10-30 years before retirement age. Additional costs arise from heart transplantation or cardiac assist device therapy for patients with terminal heart failure. Important research achievements of CRC/TR 19 over all funding periods encompass the following: Structural Foundations and Epidemiology of the Disease: Structural foundations at the molecular and cellular level, and epidemiology of DCMi including exogenous and genetic contributing factors: Regarding structural foundations, CRC identified multiple new regulators of innate and adaptive immunity, both proteins and ncRNA (e.g. PARs, CCNs, APN, miRs, lncRNAs), and investigated their roles in the pathogenesis of viral and autoimmune DCMi. Molecular and cell structures determining cardiotropic virus infections were investigated in depth, including expression patterns and biological functions of cellular receptors for viruses (e.g. for CVB3, B19V) and cell-specific properties enabling replicative vs. latent virus infections. Knockout and transgenic animal and cell culture models were used to elucidate determinants of the differential cellular and organ tropism, and intracellular behavior, of viruses relevant in the context of DCMi. Regarding epidemiology, the frequency of multiple cardiotropic viruses (e.g. CVB3, ADV, B19V, HHV6) and disease associations were determined in large cohorts. Further, mutations in immune response genes were identified (e.g. TLRs). Novel Molecular Pathomechanisms and Therapeutic Strategies: Virus-host interactions were investigated under the aspects of 1. molecular virology and direct virus effects and 2. immune-system mediated indirect effects. Regarding aspect 1, activation/silencing mechanisms of viruses in different target cells were characterized in models and patients, including the characterization of protein-coding and noncoding virus-derived transcripts. This enabled e.g. the discrimination of B19V-positive patient subgroups distinguished by viral transcriptional activity, and similar studies on other cardiotropic viruses are under way. Regarding aspect 2, overwhelming impact of indirect immunological vs. direct virological damage under certain conditions became evident from work in immunogenetically modified animal models (e.g. TRIF, TLR, PAR, APN, lncRNA knockout mice), and some of these finding were already confirmed in patients. Of note, disturbed immune cell migration emerged as a unifying theme mediating the influence of immunogenetic factors/deficiencies upon cardiac pathogenesis. Accordingly, immune system-heart interactions became a central research and will certainly influence research in the field beyond the CRC. CRC research on aspects 1 and 2 led to important new insights and the identification of novel targets (proteins, miRs, lncRNAs) for treatment of dysregulated pathogenic immune system functions. Regarding direct antiviral therapies, e.g. recombinant protein-based blockade or RNAi-mediated silencing of virus receptors were evaluated, and RNAi to silence pathogenic virus-encoded transcripts. Regarding immunomodulation therapies, e.g. new cell migration-modulating proteins and mimetic peptides were discovered and evaluated, as well as anti-miR oligonucleotides and mesenchymal stem cells to control immune systemheart interactions. Novel delivery systems for in vivo application of molecular therapeutic tools were newly developed by the CRC. Clinical Diagnostic and Therapeutic Translation of New Insights: During the decade of funding, a very large clinical data set and biosamples collection accumulated and enabled diagnostic translational research 1. on long-term natural disease courses associated with DCMi subtypes (different cardiotropic viruses, various forms of pathogenic immune reactions) and 2. to identify novel markers for their prognostic assessment. The CRC network has created the data and biosample basis to enable such studies, and employed it to identify clinical, protein, and ncRNA prognostic markers of disease course. Without the continuous interdisciplinary cooperation between clinical and basic research disciplines within the CRC network over many years, these translational studies would certainly have been impossible. In parallel with these investigations, and supporting them from the clinical side, novel diagnostic procedures and guidelines for clinical practice were written by or with CRC reseachers. In this way, the clinical differential diagnostics, prognostic assessment of DCMi has been greatly improved, which in turn is a prerequisite for more targeted and efficient differential therapies of the various subtypes. Implications of CRC for Future Research: CRC research as outlined above has important implications beyond the primary target disease DCMi, since several research pathways have led to new pathogenic processes and therapeutic strategies of high interest for cardiovascular medicine in general. One of these is the continued exploration of immune system-heart interactions, which play key roles in multiple cardiovascular disease associated with pathogenic immune processes. A second pathway has led, triggered by both clinical and experimental observations, to increasing awareness of the pathogenic and therapeutic implications of the noncoding human genome, including miRs and lncRNAs as pathogenic factors and possible therapeutic targets. Both of these lines of CRC work converge with important research from other research groups worldwide, documenting impact and role of CRC research in the current international context. This includes also international efforts for clinical translation of targeted molecular approaches, e.g. gene and other nucleic acid-based therapies and recombinant immune-modulating proteins, peptides, and small molecule drugs. International cooperation towards these goals will be continued in years to come.
Publications
- Alterations in myocardial tissue factor expression and cellular localization in dilated cardiomyopathy. J Am Coll Cardiol 2005; 45: 1081-9
Szotowski
(See online at https://doi.org/10.1016/j.jacc.2004.12.061) - High prevalence of viral genomes and multiple viral infections in the myocardium of adults with "idiopathic" left ventricular dysfunction. Circulation 2005; 111:887-93
Kühl
(See online at https://doi.org/10.1161/01.cir.0000155616.07901.35) - Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005; 112:1965-70
Kuhl
(See online at https://doi.org/10.1161/circulationaha.105.548156) - Utility of Doppler echocardiography and tissue Doppler imaging in the estimation of diastolic function in heart failure with normal ejection fraction. Circulation 2007; 116: 637-4
Kasner
(See online at https://doi.org/10.1161/circulationaha.106.661983) - Biglycan is required for adaptive remodeling after myocardial infarction. Circulation 2008; 117: 1269-76
Westermann
(See online at https://doi.org/10.1161/circulationaha.107.714147) - Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period. Circulation 2008; 118: 1722-8
Holzmann
(See online at https://doi.org/10.1161/circulationaha.107.743427) - Description of a local cardiac adiponectin system and its deregulation in dilated cardiomyopathy. Eur Heart J 2008; 29: 1168-80
Skurk
(See online at https://doi.org/10.1093/eurheartj/ehn136) - Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation 2008; 117: 2051-60
Westermann
(See online at https://doi.org/10.1161/circulationaha.107.716886) - Suspected chronic myocarditis at cardiac MR: diagnostic accuracy and association with immunohistologically detected inflammation and viral persistence. Radiology 2008; 246: 401-9
Gutberlet
(See online at https://doi.org/10.1148/radiol.2461062179) - The tight junction protein CAR regulates cardiac conduction and cell-cell communication. J Exp Med 2008; 205: 2369-79
Lisewski
(See online at https://doi.org/10.1084/jem.20080897) - Cardiac deletion of the Coxsackievirus-adenovirus-receptor abolishes CVB3 infection and prevents myocarditis in vivo. J Am Coll Cardiol 2009; 7; 53: 1219- 26
Shi
(See online at https://doi.org/10.1016/j.jacc.2008.10.064) - Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor in human endothelial cells. Circ Res 2009; 104, 589-99
Eisenreich
(See online at https://doi.org/10.1161/circresaha.108.183905) - Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy. Circulation 2009; 119: 1241-52
Suckau
(See online at https://doi.org/10.1161/circulationaha.108.783852) - Osteopontin: a fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host. Circ Res 2009; 104: 851-9
Szalay
(See online at https://doi.org/10.1161/circresaha.109.193805) - Prevention of cardiac dysfunction in acute coxsackievirus B3 cardiomyopathy by inducible expression of a soluble coxsackievirus-adenovirus receptor. Circulation 2009; 120: 2358-66
Pinkert
(See online at https://doi.org/10.1161/circulationaha.108.845339) - Cardiac-targeted delivery of regulatory RNA molecules and genes for the treatment of heart failure (review). Cardiovasc Res 2010; 86:353-64
Poller
(See online at https://doi.org/10.1093/cvr/cvq056) - Human Parvovirus B19-Myocarditis: Quantitative Assessment of Viral Loads. New Engl J Med 2010; 362: 1248-49
Bock
(See online at https://doi.org/10.1056/NEJMc0911362) - Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 2010; 142: 613-24
Seifert
(See online at https://doi.org/10.1016/j.cell.2010.07.036) - Interferon-beta modulates endothelial damage in patients with cardiac persistence of human parvovirus B19 infection. J Infect Dis 2010; 201: 936-45
Schmidt- Lucke
(See online at https://doi.org/10.1086/650700) - Matricellular signaling molecule CCN1 attenuates experimental autoimmune myocarditis by acting as a novel immune cell migration modulator. Circulation 2010; 122: 2688-98
Rother
(See online at https://doi.org/10.1161/circulationaha.110.945261) - Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol 2011; 57:977-85
Kasner
(See online at https://doi.org/10.1016/j.jacc.2010.10.024) - Impairment of immunoproteasome function by beta5i/LMP7 subunit deficiency results in severe enterovirus myocarditis. PLoS Pathogens 2011; 7: e1002233
Opitz
(See online at https://doi.org/10.1371/journal.ppat.1002233) - Mesenchymal stem cells improve murine acute coxsackievirus B3-induced myocarditis. Eur Heart J 2011; 32: 2168-78
Van Linthout
(See online at https://doi.org/10.1093/eurheartj/ehq467) - Reduced degradation of the chemokine MCP-3 by Matrix Metalloproteinase-2 exacerbates myocardial inflammation in experimental viral cardiomyopathy. Circulation 2011; 124: 2082-93
Westermann
(See online at https://doi.org/10.1161/circulationaha.111.035964) - The management of myocarditis (review). Eur Heart J 2011; 32: 2616-25
Schultheiss
(See online at https://doi.org/10.1093/eurheartj/ehr165) - CCN1: A Novel Inflammation Regulated Biphasic Immune Cell Migration Modulator. Cell Mol Life Sci 2012; 69: 3101-13
Löbel
(See online at https://doi.org/10.1007/s00018-012-0981-x) - Interferon-β Improves Survival in Enterovirus-Associated Cardiomyopathy. J Am Coll Cardiol 2012; 60: 1295-6
Kühl
(See online at https://doi.org/10.1016/j.jacc.2012.06.026) - A distinct subgroup of cardiomyopathy patients characterized by transcriptionally active cardiotropic erythrovirus and altered cardiac gene expression. Basic Res Cardiol 2013; 108: 372
Kuhl
(See online at https://doi.org/10.1007/s00395-013-0372-y) - Adiponectin protects against Toll-like receptor 4-mediated cardiac inflammation and injury. Cardiovasc Res 2013; 99: 422-31
Jenke
(See online at https://doi.org/10.1093/cvr/cvt118) - Cardiovascular RNA Interference Therapy: The Broadening Tool and Target Spectrum (review). Circ Res 2013; 113; 588-602
Poller
(See online at https://doi.org/10.1161/circresaha.113.301056) - Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34: 2636-48
Caforio
(See online at https://doi.org/10.1093/eurheartj/eht210) - EMMPRIN and its ligand Cyclophilin A as novel diagnostic markers in inflammatory cardiomyopathy. Int J Cardiol 2013; 163: 299-304
Seizer
(See online at https://doi.org/10.1016/j.ijcard.2011.06.049) - Immunoproteasomes are important for proteostasis in immune responses. Cell 2013; 152: 935-7
Ebstein/ Voigt
(See online at https://doi.org/10.1016/j.cell.2013.02.018) - Innate immune interleukin-1 receptor-associated kinase 4 exacerbates viral myocarditis by reducing CCR5(+) CD11b(+) monocyte migration and impairing interferon production. Circulation 2013; 128: 1542-54
Valaperti
(See online at https://doi.org/10.1161/circulationaha.113.002275) - Myocardial gene expression profiles and cardiodepressant autoantibodies predict response of patients with dilated cardiomyopathy to immunoadsorption therapy. Eur Heart J 2013; 34: 666-675
Ameling
(See online at https://doi.org/10.1093/eurheartj/ehs330) - Protease-activated receptor-2 regulates the innate immune response to viral infection in a Coxsackievirus B3-induced myocarditis. J Am Coll Cardiol 2013; 62: 1737-45
Weithauser
(See online at https://doi.org/10.1016/j.jacc.2013.05.076) - Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses. Basic Res Cardiol 2014; 109: 408
Jenke
(See online at https://doi.org/10.1007/s00395-014-0408-y) - CCR5del32 polymorphism is a protective factor in non-ischemic cardiomyopathy. Int J Cardiol 2014, EPub Mar 21
Lassner
(See online at https://doi.org/10.1016/j.ijcard.2014.03.123) - Improved diagnosis of idiopathic giant cell myocarditis and cardiac sarcoidosis by myocardial gene expression profiling. Eur Heart J 2014, EPub Mar 24
Lassner/ Kühl
(See online at https://doi.org/10.1093/eurheartj/ehu101) - Single-target RNA interference for the blockade of multiple interacting proinflammatory and profibrotic pathways in cardiac fibroblasts J Mol Cell Cardiol 2014; 66: 141-56
Tank/ Lindner
(See online at https://doi.org/10.1016/j.yjmcc.2013.11.004)
