New COST Action ‘EUropean network to tackle METAbolic alterations in HEART failure’ (EU-METAHEART)

Cardiovascular diseases (CVDs) are the main cause of morbidity and mortality in Europe, and heart failure (HF) is the terminal consequence of most CVD, making HF the largest disease burden in Europe. The prevalence of HF increases with age, and so does the prevalence of comorbidities. The most frequent comorbidities are chronic kidney disease, anaemia, and metabolic disorders, such as obesity and diabetes. Such metabolic (and also other) comorbidities adversely affect HF outcome, and vice versa, HF induces metabolic alterations and predisposes to the development of diabetes and other comorbidities.1 Therefore, HF is not a single-organ disease but a systemic disease that requires an interdisciplinary approach towards prevention, diagnostics, and treatment. Major routes of communication between the heart and other organs are neuroendocrine activation, inflammation, and metabolism. Treatment of patients with HF has long been limited to drugs interfering with neuroendocrine activation, such as angiotensin-converting enzyme inhibitors, β-blockers, aldosterone antagonists, and angiotensin receptor/neprilysin inhibition. However, while these treatments are effective in patients with HF with reduced ejection fraction (HFrEF), they are not (or clearly less) effective in patients with HF with preserved ejection fraction (HFpEF). In recent years, major breakthroughs were achieved in targeting metabolism in HF. Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve morbidity and prognosis in HF of any EF,2 and the glucagon-like peptide-1 (GLP-1) agonist semaglutide reduces body weight and improves quality of life in obese patients with HFpEF.3 However, the mechanisms that underlie these benefits are not well understood but likely involve improvements of systemic and cardiac metabolism. In addition, mitochondria-targeted therapies, such as nicotinamide adenine dinucleotide (NAD+) precursors,4 ketones, and compounds that interfere with mitochondria and oxidative stress improve cardiac function in preclinical studies, but their translation to the clinic is not yet accomplished.5 It has been a long-held concept that the failing heart is an engine out of fuel.6 However, it is still difficult to decipher whether the alterations in substrate utilization and the energetic deficit are sufficient to cause contractile dysfunction in their own right or rather the associated alterations in metabolic intermediates through inducing maladaptive cardiac remodeling.5 This latter hypothesis stems from the growing recognition that such metabolic intermediates can induce post-translational modifications of cytosolic and nuclear proteins, modifying their interactome and function in cardiac myocytes (Figure 1).5 Furthermore, coupling of cardiac mechanics to metabolism, mediated by cytosolic and mitochondrial ion handling and adenosine diphosphate, is disrupted in various forms of HF, increasing mitochondrial reactive species that hamper excitation–contraction coupling and activate redox-sensitive, maladaptive signalling pathways (Figure 1).5,7 Pathophysiological concept of EU-METAHEART consortium. Four distinct fields of research covering metabolic aspects in heart failure are integrated towards a comprehensive approach to gain deeper understanding of heart failure pathophysiology and identify novel treatment targets. In all areas, sex- and age-related aspects will be integrated as key influencing factors. PTM, post-translational modifications; NAD, nicotinamide adenine dinucleotide; mPTP, mitochondrial permeability transition pore; CaMKII, Ca2+/calmodulin-dependent protein kinase II; HDAC4, histone deacetylase 4; ERK1/2, extracellular-signal regulated kinases 1/2. From https://www.cost.eu/actions/CA22169/ Metabolic diseases are also important risk factors for vascular dysfunction. While macroangiopathy with myocardial ischaemia and infarction typically leads to HFrEF, microvascular dysfunction is particularly relevant in patients with HFpEF.1 In both scenarios, the relationship between coronary blood flow and the failing heart is bidirectional, as reduced coronary blood flow impairs contractile function, and vice versa, HF impairs coronary blood flow.8 Finally, there is a tight interplay between metabolism and immunity, and inflammation plays an important role in atherosclerosis but also myocardial remodelling during HF development (Figure 1). Hence, it is essential to analyse perturbations of cardiac metabolism in an integrative fashion, taking into account the tight interplay of metabolism with cardiac and vascular functions. Despite the substantial advancements in basic and clinical research in recent years, scientific progress has been hampered by the complexity of metabolism per se and the fact that the interdependence of the mechanisms controlling metabolism (Figure 1) often supersedes the capacity of single-discipline researchers and institutes to address the functional impact of dysregulated metabolic pathways and networks. Therefore, the new COST Action EU-METAHEART (CA22169; https://www.cost.eu/actions/CA22169/) will facilitate interdisciplinary dialogue, knowledge, and technology transfer to improve our understanding of metabolic alterations in HF and identify biomarkers and treatment targets for the benefit of patients with this devastating syndrome. At the same time, the Action will train the next generation of scientists to tackle the challenges imposed by the ever-growing burden of metabolic and cardiovascular disease. COST stands for ‘European Cooperation in Science and Technology’ and is a funding organization for research and innovation networks (https://www.cost.eu/). COST ‘Actions’ help connect research initiatives across Europe and beyond and enable researchers and innovators to grow their ideas in any science and technology field by sharing them with their peers. COST Actions are bottom-up networks with a duration of 4 years that boost research, innovation, and careers. COST Actions are typically made up of researchers from academia, small and medium-sized enterprises (SMEs), public institutions, and other relevant organizations or interested parties (https://www.cost.eu/cost-actions/what-are-cost-actions/). COST Actions fund the expenses of networking activities rather than specific research projects. The Actions support conferences, short-term scientific missions (STSMs), training schools, communication activities, and virtual networking tools. In this context, COST Actions promote especially young research investigators by involving them in activities, for instance, by giving them the opportunity to visit labs where they can learn new techniques (with STSMs), perform experiments, and gain a broader expertise (https://www.cost.eu/what-do-we-fund/). For our COST Action, we identified four major research areas that are crucial for the investigation of metabolic and mitochondrial dysfunction in HF that will be addressed in four working groups (WGs; 1–4; Figure 1): WG1: Substrate and intermediary metabolism in failing cardiomyocytes WG2: Metabolic impact of coronary vascular dysfunction WG3: Immunometabolism WG4: Mechano-energetic uncoupling and mitochondrial redox alterations EU-METAHEART will bring together excellent European researchers, who share a broad spectrum of scientific expertise and cutting-edge technologies to build a platform to exchange ideas, technologies, and education, fostering breakthroughs in science that move the field forwards and towards improving the treatment of patients with HF. The Action will harness recent advances and breakthroughs in scientific methodologies, such as in: Omics-based technologies In vitro technologies to assess mechano-energetic coupling in isolated cardiac myocytes Small and large animal models for HFpEF and HFrEF but also hereditary cardiomyopathies In vivo functional, metabolic, and immunological imaging Well-characterized and well-phenotyped cohorts of patients with HF and hereditary cardiomyopathies Metabolically and functionally maturated human-induced pluripotent stem cell–derived cardiac myocytes from patients with hereditary cardiomyopathies These complementary resources will develop harmonized integrative approaches that span from bench to bedside, providing fresh insights into metabolic aspects of HF and identifying novel treatment targets and biomarkers. At the same time, EU-METAHEART makes these achievements broadly accessible for laboratories across Europe and its near-neighbouring and less-privileged countries. An important aspect of a COST Action is the transfer of knowledge. To this end, a 5th WG will guide and foster transfer of knowledge via a broad array of channels: Training schools periodically organized to facilitate transfer of skills and technologies Short-term scientific missions to encourage mobility of young scientists among European research institutions Workshops and scientific conferences to enable discussion of the generated knowledge and resources between partners Publications on new results, methodologies, consensus documents, and practical guidelines To increase disease awareness of the general public, communication on the main achievements of the Action will be through a COST Action website, newsletters, press releases, and social media. Finally, the Action will take great care of training young research investigators in all the dimensions of the Action, including scientific publications, conferences, mentoring sessions, workshops, training schools, and mobility programmes (such as STSMs) that can lead to joint projects. EU-METAHEART builds on achievements of previous COST Actions, such as MitoEAGLE (https://www.cost.eu/actions/CA15203/), a mitochondrial data management system that allows to analyse the impact of age, gender, lifestyle, and environment on mitochondrial function,9 and EU-CARDIOPROTECTION (CA16225) that focussed on strategies to protect the myocardium from ischaemia/reperfusion damage.10 On 18 October 2023, EU-METAHEART held its kick-off meeting in Brussels (Figure 2). As of February 2024, the Action has more than 250 members from 36 countries. The list of the members of the management committee can be found in the Supplementary data, and the core group (consisting of working group leaders and officer positions) is listed in the Appendix. It is possible to apply for WG membership anytime at https://www.cost.eu/actions/CA22169/. Members of COST Action EU-METAHEART (CA22169) during the kick-off meeting at the COST office in Brussels, Belgium, on 18 October 2023 Supplementary data are available at European Heart Journal online. C.M. received honoraria for presentations or consultancy from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Edwards, Novo Nordisk, Novartis, Pharmacosmos, and Servier. D.H. has received consultant fees from Faraday Pharmaceuticals Inc. and Boehringer Ingelheim International GmbH, honoraria from Servier, and research funding from AstraZeneca, Merck Sharp Ioanna Andreadou, National and Kapodistrian University of Athens, Greece; Inês Falcao-Pires, Faculdade de Medicina da Universidade do Porto, Portugal; Jeremy Fauconnier, INSERM, France; Alessandra Ghigo, University of Torino, Italy; Derek Hausenloy, University College London, United Kingdom; Lisa Heather, University of Oxford, United Kingdom; Gerd Heusch, University of Essen, Medical School, Germany; Georgios Kararigas, University of Iceland, Iceland; Petra Kleinbongard, University of Essen, Medical School, Germany; Luca Liberale, Universita Degli Studi Di Genova, Italy; Christoph Maack, University Clinic Würzburg, Germany; Mathias Mericskay, Universite Paris Saclay, France; Melanie Paillard, INSERM, Université Claude Bernard Lyon-1, France; Bruno Podesser, Medical University of Vienna, Austria; Marisol Ruiz-Meana, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Spain; Gabriele Schiattarella, Charité Universitätsmedizin Berlin, Germany; Marie Schroeder, Novo-Holdings, Hellerup, Denmark; Simon Sedej, Medizinische Universität Graz, Austria; Katrin Streckfuss-Bömeke, Institute of Pharmacology and Toxicology, University Würzburg, Germany; Gemma Vilahur, Research Institute—Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Spain.