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Inflammation, Iron and Vitamin D Metabolism in Different Pteridines 2020; 31: 28–37 Research Article Open Access Lukas Lanser, Nada Nemati, Markus Seifert, Dietmar Fuchs, Günter Weiss, Gerhard Pölzl, Katharina Kurz* Inflammation, iron and vitamin D metabolism in different cardiomyopathy aetiologies https://doi.org/10.1515/pteridines-2020-0004 received June 25, 2019; accepted February 19, 2020. Keywords: cardiomyopathy; immune activation; Abstract: Immune activation coincides with disturbances anaemia; iron deficiency; FGF23. in iron and vitamin D metabolism in patients with cardiomyopathy. In this study, we investigated whether there are differences regarding immune activation, iron and vitamin D metabolism between the different Introduction cardiomyopathy aetiologies. Cardiomyopathies (CMPs) represent a heterogenic Patients and methods: Parameters of iron group of heart muscle disease. The heart muscle metabolism (haemoglobin, iron, transferrin, transferrin can be affected as a primary pathologic process or saturation, ferritin, hepcidin), vitamin D metabolism secondarily in the course of a systemic disorder. (Ct-FGF23, parathormone, phosphate, vitamin D) and CMPs can be classified due to their morphology immune activation (C-reactive protein and neopterin) into dilated CMP (DCM), hypertrophic CMP (HCM), were determined in 149 patients (98 men, 51 women) with restrictive CMP (RCM), arrhythmogenic right ventricular non-ischaemic cardiomyopathy. CMP (ARVC) and undefined CMP [1-3]. DCM is the most Results: Patients with amyloid cardiomyopathy common morphologic form of CMP with rising incidence presented with higher neopterin, ferritin and hepcidin and defined as dilatation of the left ventricle (LV) and levels than other cardiomyopathy aetiologies. later on of both ventricles [4]. HCM is the most common Furthermore, they showed the highest rate of genetic heart disease and the most common cause of cardiovascular events. C-reactive protein levels were sudden cardiac death in young adults [5]. Its morphology significantly higher in patients with inflammatory is characterised by a cardiac hypertrophy especially of cardiomyopathy. Patients with virus positive the LV [6]. RCM is the most uncommon morphologic form cardiomyopathy presented with significantly higher of CMPs in developed countries and characterised by ferritin and Ct-FGF23 levels compared to patients with an increased myocardial stiffness reflected by diastolic virus negative inflammatory cardiomyopathy. dysfunction usually of the LV [7]. ARVC is a relatively Conclusion: This study indicates that there are some uncommon genetic heart disease that typically affects differences regarding the extent of immune activation and men between the second and fourth decade of life and is inflammation as well as alterations in iron metabolism associated with loss of right ventricular myocardium with disorders between different cardiomyopathy aetiologies. following substitution by fibrous and fatty tissue [8]. Further studies with larger patient cohorts are needed to CMPs can also be classified due to the underlying investigate these findings more precisely. aetiology. A widely used classification by the World Health Organisation (WHO) divides CMPs into inflammatory, *Corresponding author: Katharina Kurz, Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, ischaemic, hypertensive, valvular, metabolic, toxic, Austria, E-mail: [email protected] peripartum and tachycardic CMP [1] and can be completed Lukas Lanser, Nada Nemati, Markus Seifert, Günter Weiss, with genetic and idiopathic aetiology. Inflammatory CMP, Department of Internal Medicine II, Medical University of Innsbruck, also described as myocarditis, presents as DCM and can 6020 Innsbruck, Austria be infective-induced or noninfective-induced [9-11]. A Dietmar Fuchs, Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria wide variety of infectious agents including viral (e.g. Gerhard Pölzl, Department of Internal Medicine III, Medical human herpesvirus 6, parvovirus B19, coxsackievirus University of Innsbruck, 6020 Innsbruck, Austria A/B, adenovirus) [10, 12], bacterial (e.g. meningococcus, Open Access. © 2020 Lukas Lanser et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution alone 4.0 License. Inflammation, iron and vitamin D metabolism in different cardiomyopathy aetiologies 29 borreliosis, diphtheria) [13], rickettsial (e.g. typhus) [14], 23 (Ct-FGF23) concentrations) were not available for all fungal (e.g. aspergillosis, candiasis) [9, 15] and parasitic patients. Acute HF, coronary artery disease on coronary pathogens (Chagas diseases, toxoplasmosis) [16, 17] angiography or vitamin D or calcium supplement within can cause an inflammatory process in the myocardium. the last 6 months were also exclusion criteria. The On the other hand, myocarditis can occur in course of diagnosis of HF was made due to the presence of current a hypersensitivity reaction to drugs (e.g. antibiotics, or previous symptoms or characteristic clinical signs sulphonamides, anticonvulsants, anti-inflammatories) and evidence of LV dysfunction. Patients were treated [18-22] or a radiotherapy of the mediastinum [9] or as an according to CHF guidelines. autoimmunologic process in the course of a rheumatoid Ethical approval: The research related to human arthritis, collagenosis or vasculitis [9, 23, 24]. Metabolic use has been complied with all the relevant national CMP can be caused by endocrine diseases (e.g. diabetes regulations, institutional policies and in accordance with mellitus, storage disease (e.g. lysosomal storage disease, tenets of the Helsinki Declaration, and has been approved glycogen storage disease, haemochromatosis), nutritional by the local ethics committee of Innsbruck Medical related deficiency diseases (vitamin B1 deficiency), University (ID of the Ethical votum: UN4280, session neuromuscular diseases (e.g. neurofibromatosis) or number 298/4.11). amyloidosis [25]. Informed consent: Informed consent has been We know that immune activation plays an important obtained from all individuals included in this study role in different CMP aetiologies (e.g. inflammatory, metabolic or toxic CMP) [26]. Immune activation is also related to alterations of iron metabolism [27]. Actually, Follow-up analysis both iron deficiency and iron overload affect the CMP pathophysiology [28]. Iron deficiency reduces exercise The event-free survival was defined as period of time between tolerance [29] and leads to progressive heart failure the first hospitalisation and the combined endpoint, which and increased mortality [30], while iron overload and was either a heart transplantation (HTx), a ventricular consequently increased oxidative stress induces CMP [31]. assist device (VAD) implantation, a re-hospitalisation for Finally, the recently detected FGF23 also effects the heart cardiac decompensation or patients’ death. Cut-off date for function [32] and interacts with the immune system and the follow-up was May 2017. Information about those events iron metabolism [33]. Since immune activation as well as were received from the clinical information system (KIS), alterations in iron and vitamin D metabolism effect heart the local mortality registry, from the patients’ relatives or function, we were interested, whether these mechanisms from the patients themselves. differ between patients with different CMP morphologies and aetiologies. Measurements Fasting blood samples were drawn in all patients at Methods study entry and stored at - 80°C. All routine laboratory variables were measured at our central laboratory Study population that undergoes regular internal and external quality audits. Neopterin was measured by an enzyme-linked Within this retrospective study, we analysed a data set immunosorbent assay (ELISA; IBL International GmbH, that initially included 475 Caucasian patients with heart Hamburg, Germany) and the C-reactive protein (CRP) failure (HF) due to nonischaemic cardiomyopathy (CMP), by an immunoturbidimetry test (Roche, Mannheim, who underwent right heart catheterization between 2009 Germany). Creatinine and NT-proBNP were determined and 2014 in the Cardiology department of the Innsbruck by standardized automated tests. Hepcidin-25 levels were University Hospital. We only included data of 149 patients determined by ELISA (DRG Instruments GmbH, Marburg, (98 men, 53 women) for further statistical analyses, Germany) in 91 patients. Iron levels were measured since data regarding biomarkers of immune activation with the FerroZineTM method without deproteinization and inflammation (CRP, neopterin), iron metabolism (Merck KGaA, Darmstadt, Germany). Ferritin levels were parameters (haemoglobin, iron, ferritin, transferrin, detected with an immunoturbidimetry test containing transferrin saturation) and vitamin D metabolism anti-ferritin antibodies from rabbits (Roche, Mannheim, parameters (including C-terminal fibroblast growth factor Germany). Transferrin levels were also detected with an 30 Lukas Lanser et al. immunoturbidimetry test containing specific antibodies cardiomyopathy (HCM), 13 patients (8.7 %) had a restrictive from rabbits (Roche, Mannheim, Germany). The cardiomyopathy (RCM) and 16 patients (10.7 %) had an transferrin saturation (TSAT) was calculated as followed: undefined CMP. Demographic and epidemiologic data, iron / transferrin x 70.9. Haemoglobin levels were analysed laboratory measurements and haemodynamics within the photometrically at 555 nm (XE-5000, Sysmex
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