Anemia, erythropoietin and iron in heart failure

In this thesis, two comorbidities have been studied that are very prevalent in patients with heart failure. Both comorbidities exacerbate the already low oxygen transport in these patients: anemia and iron deficiency. It is known that both anemia and iron deficiency have profound effects on the quality of life and prognosis of patients with heart failure. Because of that, both are considered interesting targets of treatment. Anemia is often treated using erythropoietin (EPO) injections. The benefits hereof are limited while it bears the risk of severe side effects. I show that one fourth of patients with heart failure does not respond well to EPO, and that it is difficult to predict which patients this will be. Additionally, I show that subjects from the general population, who produce high EPO levels, have more cardiovascular risk factors and are at increased risk of developing heart failure. In part two, I constructed a reliable definition for iron deficiency using the gold standard of bone marrow iron staining as a reference. Using these bone marrow iron stainings, I studied different causes of iron deficiency. I showed that these distinct forms have diverse consequences for patients with regard to symptoms and prognosis. In human cardiac muscle cells, I induced iron deficiency which caused cells to have an impaired contraction and relaxation. This could be almost fully restored after the supplementation of iron. Finally, I used genetic data to provide evidence that a higher iron storage protects from the development of coronary artery disease

Precision Medicine Approaches for Genetic Cardiomyopathy:Targeting Phospholamban R14del

PURPOSE OF REVIEW: Heart failure is a syndrome with poor prognosis and no curative options for the majority of patients. The standard one-size-fits-all-treatment approach, targeting neurohormonal dysregulations, helps to modulate symptoms of heart failure, but fails to address the cause of the problem. Precision medicine aims to go beyond symptom modulation and targets pathophysiological mechanisms that underlie disease. In this review, an overview of how precision medicine can be approached as a treatment strategy for genetic heart disease will be discussed. PLN R14del, a genetic mutation known to cause cardiomyopathy, will be used as an example to describe the potential and pitfalls of precision medicine. RECENT FINDINGS: PLN R14del is characterized by several disease hallmarks including calcium dysregulation, metabolic dysfunction, and protein aggregation. The identification of disease-related biological pathways and the effective targeting using several modalities, including gene silencing and signal transduction modulation, may eventually provide novel treatments for genetic heart disease. We propose a workflow on how to approach precision medicine in heart disease. This workflow focuses on deep phenotyping of patient derived material, including in vitro disease modeling. This will allow identification of therapeutic targets and disease modifiers, to be used for the identification of novel biomarkers and the development of precision medicine approaches for genetic cardiomyopathies

Cardiac progenitors and paracrine mediators in cardiogenesis and heart regeneration

The mammalian hearts have the least regenerative capabilities among tissues and organs. As such, heart regeneration has been and continues to be the ultimate goal in the treatment against acquired and congenital heart diseases. Uncovering such a long-awaited therapy is still extremely challenging in the current settings. On the other hand, this desperate need for effective heart regeneration has developed various forms of modern biotechnologies in recent years. These involve the transplantation of pluripotent stem cell-derived cardiac progenitors or cardiomyocytes generated in vitro and novel biochemical molecules along with tissue engineering platforms. Such newly generated technologies and approaches have been shown to effectively proliferate cardiomyocytes and promote heart repair in the diseased settings, albeit mainly preclinically. These novel tools and medicines give somehow credence to breaking down the barriers associated with re-building heart muscle. However, in order to maximize efficacy and achieve better clinical outcomes through these cell-based and/or cell-free therapies, it is crucial to understand more deeply the developmental cellular hierarchies/paths and molecular mechanisms in normal or pathological cardiogenesis. Indeed, the morphogenetic process of mammalian cardiac development is highly complex and spatiotemporally regulated by various types of cardiac progenitors and their paracrine mediators. Here we discuss the most recent knowledge and findings in cardiac progenitor cell biology and the major cardiogenic paracrine mediators in the settings of cardiogenesis, congenital heart disease, and heart regeneration.</p