DOUBLE DOSE

2021

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.

 

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Collaborators

Contact person:

Dr. J. van der Velden (Jolanda)

Principal investigators

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ADMINISTER II

2024
Heart failure is an escalating global health challenge, affecting over 64 million people worldwide. Despite advancements in guideline-directed medical therapy (GDMT) that significantly reduce mortality and hospitalizations, many patients still do not receive optimal medication regimens or dosages. This gap in care highlights the need for innovative, collaborative approaches to improve treatment delivery and outcomes. The research The ADMINISTER I study demonstrated the potential of digital care solutions to enhance medication prescription accuracy and accelerate the time required to achieve GDMT. In real-world clinical practice, optimizing medications to meet GDMT standards is a complex and time-intensive process. It requires frequent monitoring, adjustments, and multiple visits to healthcare providers, posing a significant burden on both patients and clinicians. Building on this foundation, the ADMINISTER II consortium is a collaborative effort uniting multiple stakeholders, including healthcare providers, researchers, and (biomedical) engineers. This consortium aims to evaluate the impact of a cutting-edge digital care intervention designed to streamline medication optimization. By leveraging a robust remote monitoring infrastructure, this approach seeks to make the process more efficient, scalable, and accessible, while focusing on improving critical clinical outcomes. This collaborative digital intervention represents a transformative step toward patient care and offers hope for better heart failure management. Insights from ADMINISTER II could pave the way for the widespread adoption of innovative, integrated solutions, benefiting patients, caregivers, and healthcare systems worldwide. The ADMINISTER II consortium brings together the expertise of a leading Technical University, major referral hospitals, and a renowned academic center to deliver state-of-the-art digital care across a large nationwide hospital network. This unique synergy is pivotal to achieving the ambitious goals set by the Dutch Cardiovascular Alliance (DCVA): a 25% reduction in the cardiovascular burden by 2030. By integrating cutting-edge digital infrastructure with clinical excellence, the consortium aims to significantly lower hospitalizations and mortality rates. This partnership not only accelerates the adoption of innovative digital solutions but also ensures their effective implementation in diverse healthcare settings, marking a critical step toward transforming cardiovascular care on a national scale. The origin The ADMINISTER II is created after successful completion of the ADMINISTER I trial. The ADMINISTER I was fully funded by Amsterdam UMC and was a collaboration with Netherlands heart institute, UMC Utrecht, Rode Kruis hospital and CCN. The ADMINISTER II consortium will be on a larger scale; with a larger network and multiple funders.
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PREDICT 2

2019
Sudden cardiac arrest (SCA) remains a significant public health challenge, accounting for nearly 20% of all deaths in developed nations and approximately half of all heart disease-related fatalities. A notable subset of SCA cases occurs in individuals without prior heart disease diagnosis, resulting in profound psychosocial impacts on affected families and society. Ventricular fibrillation (VF) is the primary arrhythmia leading to SCA, often occurring outside healthcare settings with survival rates ranging from 5% to 20%. Prevention is crucial, yet gaps in our understanding of SCA causes and mechanisms hinder effective prevention efforts. Various genetic and non-genetic factors, such as gender, age, comorbidities, and lifestyle, likely influence SCA risk, but their specific contributions remain unclear. The Focus The PREDICT2 initiative brings together leading Principal Investigators with expertise in epidemiology, clinical studies, genetics, and functional research to elucidate factors contributing to SCA, uncover underlying mechanisms, and develop strategies for prevention and treatment. The Research Building on foundational work from PREDICT1, which involved extensive patient characterization and preclinical model development, PREDICT2 focuses on inherited arrhythmia syndromes as models to understand the arrhythmogenic substrate in more common cardiac syndromes associated with SCA. Specifically, PREDICT2 aims to: Identify genetic and non-genetic factors that contribute to SCA risk and develop personalized risk prediction algorithms for individual patient assessment. Conduct functional studies to elucidate the mechanisms underlying SCA, enabling the development of novel risk stratification and therapeutic approaches. Implement clinical studies to evaluate risk prediction algorithms and therapeutic interventions, aiming to enhance the treatment and prevention of SCA. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation.
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