1,721,541 research outputs found
A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging
Full text link: The population of cancer survivors is rapidly increasing due to improving healthcare. However, cancer therapies often have long-term side effects. One example is cancer therapy-related cardiac dysfunction (CTRCD) caused by doxorubicin: up to 9% of the cancer patients treated with this drug develop heart failure at a later stage. In recent years, doxorubicin-induced cardiotoxicity has been associated with an accelerated aging phenotype and cellular senescence in the heart. In this review we explain the evidence of an accelerated aging phenotype in the doxorubicin-treated heart by comparing it to healthy aged hearts, and shed light on treatment strategies that are proposed in pre-clinical settings. We will discuss the accelerated aging phenotype and the impact it could have in the clinic and future research
Studying cardiac diseases using human stem cell-derived cardiomyocytes
Full text linkHeart failure is a complex syndrome characterized by the inability of the heart to pump enough blood to meet the needs of the body and can be caused by various cardiac diseases. Representative models are essential to understand the nature of these diseases. To that end, recapitulating cardiac diseases in vitro provides an accessible platform to study cell autonomous molecular mechanisms. We have employed human pluripotent stem cells to generate (patient-specific) cardiomyocytes. Consequently, we have demonstrated that cellular iron deficiency impairs both mitochondrial respiration and contractile function in human cardiomyocytes. Also, a specific signaling pathway in cardiac hypertrophy was identified, and inhibition of this pathway prevented hypertrophy altogether. In addition, we studied aspects of peripartum cardiomyopathy, a severe pregnancy-related cardiac disease. This intricate disease is believed to be the result of a complex interplay between genetic factors, cathepsin D, prolactin, multiple cell types and a specific microRNA. We established that increased levels of circulating cathepsin D are not only associated with peripartum cardiomyopathy, but also correlated with heart failure severity in large European population of heart failure patients. Moreover, we provide evidence that cathepsin D is protective for the heart during stress. Finally, through induced pluripotent stem cells, we generated peripartum cardiomyopathy patient-specific cardiomyocytes. Transcriptome sequencing revealed aberrant metabolic regulation in patient-specific cells. These studies signify in vitro cardiac disease models as a valuable tool to study afflictions of the heart in great detail to accelerate the progress of future treatment development
Hematinics in heart failure
Full text linkOur research focused on iron deficiency in heart failure. Heart failure is a clinical syndrome which is characterized by a reduced pumping function of the heart. Many heart failure patients also have other diseases (comorbidity), of which iron deficiency is very common. Iron is an important part of the molecule hemoglobin, which is involved in oxygen transport in the human body. Moreover, iron has a role in the energy metabolism. Compared to heart failure patients without iron deficiency, patients with iron deficiency have more complaints, a reduced exercise tolerance and a worse prognosis. Treatment of iron deficiency with iron infusion leads to less complaint and less hospital admissions for heart failure. To date, little is known about the causes of iron deficiency in heart failure patients. My thesis focused on the causes of iron deficiency in heart failure patients. Our studies showed that iron deficiency can have multiple causes, for example the use of blood thinners or drugs that reduce the amount of acid that the stomach produces, reduced protein intake from the diet, symptoms of heart failure (breathlessness, swollen legs), inflammation and kidney failure. We also showed that there are several forms of iron deficiency, which should probably be treated differently. Each heart failure patient should be frequently screened for the presence of iron deficiency. Besides iron, vitamin B12 and folic acid are also important for the production of hemoglobin. Therefore, we also studied these vitamins. Compared to iron deficiency, vitamin B12 and folic acid deficiency are quite rare in heart failure patients
Novel therapies in heart failure
Full text linkHeart failure is a clinical condition that is characterized by the inability of the heart to meet the oxygen requirements of peripheral tissues and organs, despite normal filling pressures. Despite recent developments in the treatment of heart failure, the prognosis of heart failure patients remains unacceptably poor. This observation stimulates further research on novel targets, novel therapies and novel approaches to study treatment effects. For her thesis, drs. Liu investigated precision medicine in heart failure. Also, she investigated novel drugs for the treatment of patients with heart failure with preserved ejection fraction (HFpEF), and heart failure with reduced ejection fraction (HFrEF). In part I of her thesis, drs. Liu showed that a treatment effect may be heterogeneous across a patient population. In addition, she demonstrated that biomarkers may be useful tools to distinguish responders from non-responders to treatment. In part II of her thesis, Liu demonstrated that, in HFpEF, treatment with LCZ696 was associated with preservation of renal function, while an increase in albumin creatinine ratio was observed, compared with valsartan. Further, Liu showed that treatment with sildenafil was not beneficial in HFpEF patients with pulmonary hypertension. Finally, Liu provides 2 drug evaluations of Finerenone and Omecamtiv Mecarbil in part III of her thesis. Tailoring treatment will result in the greatest treatment benefit while reducing the risk of adverse effects. Liu therefore states that further research is needed to investigate a more personalized approach in order to match the right drug to the right patient
Circulating microRNAs in heart failure
Full text linkHartfalen is een ernstige aandoening waarbij de pompfunctie van het hart tekort schiet en kent helaas een slechte prognose. De ontwikkeling van nieuwe medicamenten is daarom zeer gewenst en meer informatie over onderliggende epigenetische processen zou kunnen leiden tot nieuwe aangrijpingspunten voor therapie. MicroRNAs (miRNAs) zijn kleine stukjes RNA welke niet coderen voor eiwitten maar in staat zijn de genexpressie te beïnvloeden. In verschillende aandoeningen, waaronder hartfalen, blijken miRNAs een grote rol te spelen. MiRNAs oefenen hun functie intracellulair uit, maar zijn ook aanwezig in circulerend bloed en andere lichaamsvloeistoffen, waardoor ze mogelijk als potentiele biomarkers zouden kunnen fungeren. Echter, hun rol en functie in de circulatie van hartfalen patiënten is nog niet bekend. In dit proefschrift hebben we een profiel van consistent verlaagde miRNA waarden geïdentificeerd in de circulatie van patiënten met acuut hartfalen. Een daling tijdens de eerste dagen van opname was geassocieerd met een verhoogde kans op sterfte. Tevens laten we zien dat deze miRNAs geassocieerd zijn aan andere, aan hartfalen gerelateerde biomarkers en onderliggende cardiovasculaire mechanismen. Hierbij bleek dat deze relaties afhankelijk zijn van de ziektestatus van de patiënt en het tijdspunt van meten. Ook vonden we associaties tussen lage miRNA waarden en de aanwezigheid van atherosclerose en gerelateerde ziekteprocessen zoals inflammatie, angiogenese en endotheel dysfunctie, en laten we zien dat deze miRNA waarden gerelateerd zijn aan de volume status van hartfalen patiënten. Daarnaast constateren we dat de eerder gevonden resultaten in hartfalen patiënten niet rechtstreeks te vertalen zijn naar diermodellen met hartfalen
Mimicking heart disease in a dish: Cardiac disease modelling through functional analysis of human stem cell derived cardiomyocytes
Full text linkHeart failure renders the heart unable to pump enough blood through the body. Despite advances in its treatment the quality of life with heart failure remains poor and half of the patients passes away within five years of the diagnosis. Additionally, heart failure affects one out of fifty adults, therefore the need for new treatments is critical. However, it is very challenging to develop new treatments for heart failure because we do not yet fully understand how heart failure develops. In this thesis we have performed research with human stem cells that were cultured to become heart cells after which they start beating in a lab dish. We then simulated several causes of heart failure in the lab to study the responses of these heart cells. In order to perform this research, we first developed a new method that allowed us to more precisely measure the force and speed of the contractions of heart cells. Because iron deficiency results in worse outcomes for patients with heart failure, we then induced iron deficiency in these heart cells and analyzed the effect. Next, we researched the effect of chemotherapy on the heart cells to determine why chemotherapy reduces the contractile function of the heart. The research described in this thesis has provided us with new insights into the effects of iron deficiency and chemotherapy on the human heart. We hope that our methods and the resulting research will contribute to a better treatment for patients with heart failure in the future
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