DECISION

Heart failure is a severe and chronic condition were the heart is unable to pump blood around the body properly, due to a structural and/or functional abnormality of the heart. It has many different causes, with the most common being hypertension and coronary artery disease. Heart failure is an unpredictable condition with sudden exacerbations of the disease, hospitalization, and will ultimately lead to death. Proper (and early) treatment may improve the symptoms of health failure and may lead to a relatively longer and better quality of life. The origin On the cardiovascular disease research agenda, as drawn up at the initiative of the Dutch Heart Foundation in 2014 and revised in 2020, the themes “Earlier recognition of cardiovascular disease” and “Heart failure” have been placed on the agenda. The DCVA also announced the Delta Plan Heart Failure in the 2022 annual plan. This resulted in the Delta Plan Heart Failure, which is initiated and financed by the Hartstichting, the Netherlands Heart Institute, and the Dutch Cardiovascular Alliance. In this national project, healthcare professionals, researchers, and patients have joined forces and will focus on the entire continuum of the disease from prevention to palliative care. The research We expect that burden of disease can largely be reduced by addressing the following key-points: Increasing public awareness of heart failure Early detection of heart failure Stimulating the collaboration among all (different) disciplines within the field of health failure Initiation of research consortia for innovative treatment and management of heart failure patients Furthermore, this project will not only focus on positively influencing survival but also on optimizing the patient’s quality of life and will pursue a strategic and operational approach.

Cardiomyopathies, caused by genetic mutations affecting cardiac muscle components, pose significant economic and societal burdens due to their hereditary nature and early onset. Despite known genetic defects, predicting disease progression remains challenging due to extreme clinical variability. Recent research indicates that cardiomyopathy mutations induce metabolic stress, exacerbated by factors like obesity, which can accelerate disease progression. The Double Dose hypothesis suggests that targeting metabolic stress may offer preventive or curative strategies for these conditions. The Focus The Double Dose Consortium aims to understand how cardiomyopathy-causing mutations lead to structural changes in cardiomyocytes. This interdisciplinary effort combines experts in preclinical research, clinical genetics, health technology assessment, and clinical care focused on cardiomyopathy in both children and adults. The Research The consortium combines experts in preclinical research, clinical genetics, health technology assessment and clinical researchers with a strong clinical focus on cardiomyopathy in children and adults. These experts investigate how obesity and muscle adiposity contribute to vascular and cardiac muscle dysfunction in mutation carriers through the analysis of clinical data, patient samples, and experimental models. They will also study the mechanisms underlying ultrastructural changes in cardiomyocytes caused by these mutations, leading to impaired metabolism, contraction, relaxation defects, and disrupted cellular communication within the heart. Utilizing extensive patient cohorts and ongoing studies, the consortium aims to optimize care for cardiomyopathy patients by assessing the cost-effectiveness of diagnostics and clinical interventions. They plan to translate findings on metabolic alterations into clinical trials targeting treatments that reduce metabolic stress. The Double Dose program will establish biobanks containing serum, tissue, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to provide mechanistic insights into cardiomyopathy pathophysiology and improve diagnosis and care. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation, together with Stichting Hartedroom. The consortium is a continuation of the Dosis consortium, in which the interaction between mutation and external factors was investigated. They found that cardiomyopathy-mutations induce metabolic stress and that secondary metabolic stress, such as obesity accelerates disease progression.