Mast cells are pluripotent leukocytes that reside in the mucosa and connective tissue. Recent studies show an increased prevalence of cardiovascular disease among patients with mastocytosis, which... Show moreMast cells are pluripotent leukocytes that reside in the mucosa and connective tissue. Recent studies show an increased prevalence of cardiovascular disease among patients with mastocytosis, which is a hematological disease that is characterized by the accumulation of mast cells due to clonal proliferation. This association suggests an important role for mast cells in cardiovascular disease. Indeed, the evidence establishing the contribution of mast cells to the development and progression of atherosclerosis is continually increasing. Mast cells may contribute to plaque formation by stimulating the formation of foam cells and causing a pro-inflammatory micro-environment. In addition, these cells are able to promote plaque instability by neo-vessel formation and also by inducing intraplaque hemorrhage. Furthermore, mast cells appear to stimulate the formation of fibrosis after a cardiac infarction. In this review, the available data on the role of mast cells in cardiovascular disease are summarized, containing both in vitro research and animal studies, followed by a discussion of human data on the association between cardiovascular morbidity and diseases in which mast cells are important: Kounis syndrome, mastocytosis and allergy. Show less
Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease, is a rare genetic disorder, known for its endothelial dysplasia causing vessel malformations, severe nose bleeds and... Show moreHereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease, is a rare genetic disorder, known for its endothelial dysplasia causing vessel malformations, severe nose bleeds and internal bleedings. In the majority of patients mutations are found in genes belonging to the TGFβ superfamily, causing a disbalance in the TGFβ signaling pathway by haploinsufficiency of the remaining functional protein. In this thesis we studied different aims and approaches to influence HHT1-MNC homing and differentiation to restore their contribution to tissue repair. In various experimental methods inducing ischemic and/or direct tissue damage, we aimed to improve tissue repair in the Eng+/- mice. Using DPP4 inhibition, we increased the SDF1-CXCR4 homing mechanism, to restore the impaired homing capacity of the HHT1-MNCs. Furthermore, we focused on correcting the M1/M2 differentiation in Eng+/- mice. Via use of the BMP receptor inhibitor LDN we aimed to restore the skewed BMP/TGFβ signaling; stimulating the TGFβ pathway signaling to induce M2 differentiation. We concluded that DPP4 inhibition can be used to improve the HHT1 immune system and tissue repair, and is best used in concert with other drugs or therapies that stimulate cardiac or tissue repair, like anti-coagulants or cell therapy. Show less
Cell transplantation studies have shown that injection of progenitor cells can improve cardiac function after myocardial infarction (MI). Transplantation of human cardiac progenitor cells (hCPCs)... Show moreCell transplantation studies have shown that injection of progenitor cells can improve cardiac function after myocardial infarction (MI). Transplantation of human cardiac progenitor cells (hCPCs) results in an increased ejection fraction, but survival and integration are low. Therefore, paracrine factors including extracellular vesicles (EVs) are likely to contribute to the beneficial effects. We investigated the contribution of EVs by transplanting hCPCs with reduced EV secretion. Interestingly, these hCPCs were unable to reduce infarct size post-MI. Moreover, injection of hCPC-EVs did significantly reduce infarct size. Analysis of EV uptake showed cardiomyocytes and endothelial cells primarily positive and a higher Ki67 expression in these cell types. Yes-associated protein (YAP), a proliferation marker associated with Ki67, was also increased in the entire infarcted area. In summary, our data suggest that EV secretion is the driving force behind the short-term beneficial effect of hCPC transplantation on cardiac recovery after MI. Show less
Cardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to... Show moreCardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to investigate the role of inflammation in CVD related cardiac and vascular remodelling, which may lead to potential therapeutic agents. We investigated the therapeutic potential of antibodies directed against phosphorylcholine (PC), an endogenous ligand capable of triggering the innate immune system, which is expressed by apoptotic cells and oxidized LDL, in mouse models for myocardial infarction (MI). We found that treatment with anti-PC antibodies reduces adverse cardiac remodelling after both permanent MI as myocardial ischemia reperfusion (MI-R) injury. Furthermore, we found that treatment with annexin A5 also reduces adverse cardiac remodelling after MI-R injury. Interestingly, both anti-PC as annexin A5 treatment reduced the post MI inflammatory response. Next, we investigated the role of PCAF, an inflammatory related epigenetic factor, in vascular remodelling. We found that PCAF deficiency and treatment with a PCAF inhibitor reduces adverse vascular remodelling. Finally, we investigated the role of microRNAs, small RNA molecules that can affect expression of many different gene simultaneously, in vascular remodelling. We show that inhibition of microRNA-495 reduces adverse vascular remodelling. Show less
Bizino, M.B.; Tao, Q.; Amersfoort, J.; Siebelink, H.M.J.; Bogaard, P.J. van den; Geest, R.J. van der; Lamb, H.J. 2018
Conclusions: Although Abca1 has a protective role in atherosclerosis, it exerts detrimental effects on cardiac function after MI. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an... Show moreConclusions: Although Abca1 has a protective role in atherosclerosis, it exerts detrimental effects on cardiac function after MI. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
This thesis focuses on the potential of cell-based therapy in ischemic heart disease and the role of the inflammatory response after myocardial infarction (MI). Chapter 2 reviews the specific... Show moreThis thesis focuses on the potential of cell-based therapy in ischemic heart disease and the role of the inflammatory response after myocardial infarction (MI). Chapter 2 reviews the specific myocardial inflammatory events that occur following MI and explores the potential role of cell therapy, in specific of the mesenchymal stromal cell (MSC), to positively influence this process. In chapter 3 we studied the usefulness of a clinically relevant transient ischemia MI model in immunodeficient mice to investigate the potential of human stem cell therapy and compared this to the commonly used animal MI model via permanent ischemia. Next, in chapter 4 we aimed to extend our previous research regarding the positive therapeutic effects of MSC therapy after MI by injecting MSCs stimulated with the pro-inflammatory cytokine interferon-γ, since pro-inflammatory priming has shown additional beneficial effects in several experimental disease models. Chapter 5 evaluates the short-term effect of human cardiomyocyte progenitor cell infusion on cardiac function in an animal MI model. Chapter 6 discusses the effect of diet-induced hypercholesterolemia on both cardiac function and inflammation after myocardial ischemia-reperfusion injury. Finally, chapter 7 provides an overview of the results described in this thesis, and discusses future perspectives. Show less
Patients with structural heart disease - e.g. after myocardial infarction or due to a cardiomyopathy - are at increased risk for sudden cardiac death because of arrhythmia. The department of... Show morePatients with structural heart disease - e.g. after myocardial infarction or due to a cardiomyopathy - are at increased risk for sudden cardiac death because of arrhythmia. The department of Cardiology at the Leiden University Medical Center has a strong interest for the underlying substrate and mechanisms of ventricular arrhythmias. Since 2011, research fellow Sebastiaan Piers and his supervisor prof. dr. Katja Zeppenfeld have performed innovative studies, combining advanced electrophysiological data with detailed imaging data derived from CT and MRI. These studies have led to important insights into the substrate and mechanisms of ventricular arrhythmia in patients after myocardial infarction or with a cardiomyopathy. An improved understanding may be the most important prerequisite for the development of effective, individualized and substrate-based therapies for ventricular arrhythmias in the future. Sebastiaan Piers will defend his thesis "Understanding Ventricular Tachycardia: Towards Individualized Substrate-based Therapy" on Thursday January 28th 2016. Show less
Evaluation of patients with ischemic heart disease using echocardiography is indispensable. Both in the acute setting of STEMI, at follow-up and in the chronic phase during the possible development... Show moreEvaluation of patients with ischemic heart disease using echocardiography is indispensable. Both in the acute setting of STEMI, at follow-up and in the chronic phase during the possible development of heart failure, routine echocardiographic assessment is an essential part of daily clinical practice. Show less
Louwe, M.C.; Lammers, B.; Frias, M.A.; Foks, A.C.; Leeuw, L.R. de; Hildebrand, R.B.; ... ; Eck, M. van 2016
Background and aims We explored the role of ATP-binding cassette transporter A1 (Abca1), in post-myocardial infarction (MI) cardiac injury. Methods In Abca1–/– mice, wild type (WT) mice, and WT... Show moreBackground and aims We explored the role of ATP-binding cassette transporter A1 (Abca1), in post-myocardial infarction (MI) cardiac injury. Methods In Abca1–/– mice, wild type (WT) mice, and WT mice transplanted with Abca1–/– or WT bone marrow, an MI was induced in vivo. Furthermore, an ex vivo MI was induced in isolated Abca1–/– and WT hearts. Results Twenty-four hours and two weeks after in vivo MI induction, MI size was reduced in Abca1–/– (−58%, p = 0.007; −59%, p = 0.03) compared to WT. Ex vivo MI induction showed no effect of Abca1–/– on infarct size. Interestingly, two weeks after MI, Abca1–/– mice showed higher circulating levels of B-cells (+3.0 fold, p = 0.02) and T-cells (+4.2 fold, p = 0.002) compared to WT. Bone marrow-specific Abca1–/– tended to reduce infarct size (−43%, p = 0.12), suggesting a detrimental role for hematopoietic Abca1 after MI. Conclusions Although Abca1 has a protective role in atherosclerosis, it exerts detrimental effects on cardiac function after MI. Keywords * Abca1 deficiency; * Myocardial infarction; * Immune cells; * Mice Show less
