Hart- en vaatziekten zijn wereldwijd de belangrijkste doodsoorzaak, waarvan het grootste deel kan worden toegeschreven aan coronairlijden. De belangrijkste veroorzaker hiervan is atherosclerose... Show moreHart- en vaatziekten zijn wereldwijd de belangrijkste doodsoorzaak, waarvan het grootste deel kan worden toegeschreven aan coronairlijden. De belangrijkste veroorzaker hiervan is atherosclerose ofwel aderverkalking, wat een op zichzelf staande complexe lipide-gedreven chronische inflammatoire ontstekingsziekte is. Na een hartinfarct is tijdige reperfusie door een acute dotterbehandeling het belangrijkste doel om verdere schade aan de hartspier te beperken. Echter, het herstel van de coronaire perfusie zelf induceert myocardiale reperfusieschade. Gedurende vele jaren heeft translationeel onderzoek zicht gericht op immunomodulatie van deze post-ischemische inflammatierespons. Dit proefschrift omvat pre-klinisch onderzoek waarin gunstige modulatie van de post-ischemische inflammatierespons door farmacologische interventies met annexine A5 en phosphorylcholine antilichamen wordt aangetoond. Remming van bijvoorbeeld cytokine IL-6 en afweercellen als monocyten, macrofagen en leukocyten, resulteert na een hartinfarct in minder schade aan de hartspier met een verbetering van de resterende hartfunctie. Daarnaast werd onderzocht hoe een pre-klinisch experimenteel onderzoeksmodel kan worden geoptimaliseerd door rekening te houden met zowel ischemie-reperfusie schade als hypercholesterolemie, een belangrijke risicofactor voor hart- en vaatziekten. Door gebruik te maken van klinisch relevantere onderzoeksmodellen kunnen in de toekomst hopelijk meer veelbelovende pre-klinische onderzoeksresultaten succesvol worden vertaald naar de dagelijkse klinische praktijk. Ter introductie worden deze onderzoeksresultaten voorafgegaan door een state-of-the-art review waarin een overzicht wordt gegeven van alle fases die deze post-ischemische inflammatierespons omvat. Hierbij worden de meest toonaangevende onderzoeksresultaten betreffende modulatie van deze inflammatierespons beschreven. Na recente succesvolle grote klinische trials, zal in de toekomst een belangrijke rol zijn weggelegd voor modulatie van deze afweerreactie bij zowel atherosclerose als na een hartinfarct. Show less
BackgroundLiraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with... Show moreBackgroundLiraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease.MethodsPatients with DM2 were randomly assigned to receive liraglutide 1.8mg/day or placebo in this double-blind trial of 26weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported.Results23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (-56mL/s (-91 to -21)), E/A ratio (-0.17 (-0.27 to -0.06)), Edec (-0.9mL/s(2)*10(-3) (-1.3 to -0.2)) and E/Ea (-1.8 (-3.0 to -0.6)), without affecting A (3mL/s (-35 to 41)) and Ea (0.4cm/s (-0.9 to 1.4)). Liraglutide reduced stroke volume (-9mL (-16 to -2)) and ejection fraction (-3% (-6 to -0.1)), but did not change cardiac output (-0.4L/min (-0.9 to 0.2)), cardiac index (-0.1L/min/m(2) (-0.4 to 0.1)) and peak ejection rate (-46mL/s (-95 to 3)).ConclusionsLiraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Show less
With the increase in life expectancy, the prevalence of cognitive disorders is expected to rise the coming years. In this thesis we studied the association between blood pressure, cardiac... Show moreWith the increase in life expectancy, the prevalence of cognitive disorders is expected to rise the coming years. In this thesis we studied the association between blood pressure, cardiac biomarkers and cognitive function in 5800 people with mean age of 75 years. Furthermore, we investigated the feasibility to use smartphone technology to measure home blood pressure in 151 people during a 6 months follow-up period. We show that higher variability in blood pressure is associated with increased microdamage of the brain and worse cognitive function, independent of average blood pressure and use of blood pressure lowering medication. Furthermore, increased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT), both markers of cardiac disease, are associated with worse cognitive function and steeper cognitive decline, independent of cardiovascular diseases or risks. Finally, we show that smartphone-based technology is a reliable and promising method with good adherence to measure blood pressure at home. This provides a possibility for implementation in large-scale studies and can potentially contribute to blood pressure reduction, eventually helping to prevent cognitive impairment. 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
This thesis evaluates the relationship between structural and functional aortic vessel wall alterations and end-organ damage in cross-sectional patient studies with use of MRI. These studies show... Show moreThis thesis evaluates the relationship between structural and functional aortic vessel wall alterations and end-organ damage in cross-sectional patient studies with use of MRI. These studies show that aortic pulse wave velocity (PWV) in DM1 patients is mainly determined by hypertension, whereas the effect of DM1 itself on aortic PWV is marginal. Increased aortic PWV in patients with hypertension is associated with aortic and carotid vessel wall alterations. Also, increased aortic PWV is associated with cardiac as well as cerebral damage both in hypertensive and DM1 patients. Furthermore, this thesis describes and evaluates the ability of more optimized cardiac MRI-techniques for assessment of cardiovascular disease. Right coronary artery flow can be accurately and reproducibly assessed using 3T VE MRI in healthy control subjects. Furthermore, the use of standardized 7T MRI protocols for assessment of LV volumes, function and flow provides similar quantitative results when compared to 1.5T MRI. Finally, 3D three-directional VE MRI better describes LV diastolic function as compared to 2D one-directional VE MRI in patients with ischemic heart failure. Show less
