Multimodality ImAging of Cardiovascular Dysfunction : risk factors, diagnostics and treatment options

Cardiovascular diseases are a major cause of mortality worldwide, and includes all diseases of the heart and circulation. Despite improvements in knowledge and treatment options over the last decades, it remains one of the leading causes of disability and death. The underlying mechanisms vary depending on the disease in question. Some of these risk factors can be avoided, controlled, treated or modified such as high cholesterol, high blood pressure and obesity. While others, such as family history and gender, cannot be avoided and their emphasis lies on monitoring and treatment. In this thesis, the role of DNA damage, atherosclerosis and the renin angiotensin system, factors that modulate cardiovascular damage and disease, are investigated and discussed. Additionally, the effect of nutritional and therapeutic interventions is explored

Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3−/− animals. Smad3−/− animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3−/− aortas showed increased nuclear pSmad2 and pErk, indicating TGF-β receptor activation, downstream TGF-β-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3−/− aortas implied that aortic damage and TGF-β receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-β activated transcription resulted in increased Smad3−/− VSMC proliferation. Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibil

Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema

Background: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an

Structure and cell biology of the vessel wall

The purpose of this chapter is to provide a general overview on the structure and composition of blood vessels. Moreover, the cellular constituents of the vessel wall, as well as the different types of blood vessels, are discussed. In addition the effect of ageing on the vascular wall and its role in the pathogenesis of vascular disease is discussed. More detailed insights into the pathogenesis of specific diseases, including atherosclerosis and aneurysms, are provided in other chapters of this book.</p

The renin-angiotensin system and its involvement in vascular disease

The renin-angiotensin system (RAS) plays a critical role in the pathogenesis of many types of cardiovascular diseases including cardiomyopathy, valvular heart disease, aneurysms, stroke, coronary artery disease and vascular injury. Besides the classical regulatory effects on blood pressure and sodium homoeostasis, the RAS is involved in the regulation of contractility and remodelling of the vessel wall. Numerous studies have shown beneficial effect of inhibition of this system in the pathogenesis of cardiovascular diseases. However, dysregulation and overexpression of the RAS, through different molecular mechanisms, also induces, the initiation of vascular damage. The key effector peptide of the RAS, angiotensin II (Ang II) promotes cell proliferation, apoptosis, fibrosis, oxidative stress and inflammation, processes known to contribute to remodelling of the vasculature. In this review, we focus on the components that are under the influence of the RAS and contribute to the development and progression of vascular disease; extracellular matrix defects, atherosclerosis and ageing. Furthermore, the beneficial therapeutic effects of inhibition of the RAS on the vasculature are discussed, as well as the need for additive effects on top of RAS inhibition. (C) 2015 Elsevier B.V. All rights reserved

Folate Receptor–Targeted Single-Photon Emission Computed Tomography/Computed Tomography to Detect Activated Macrophages in Atherosclerosis: Can It Distinguish Vulnerable from Stable Atherosclerotic Plaques?

The need for noninvasive imaging to distinguish stable from vulnerable atherosclerotic plaques is evident. Activated macrophages play a role in atherosclerosis and express folate receptor folate receptor β (FR-β). The feasibility of folate targeting to detect atherosclerosis was demonstrated in human and mouse plaques, and it was suggested that molecular imaging of FR-β through folate conjugates might be a specific marker for plaque vulnerability. However, these studies did not allow differentiation between stable and vulnerable atherosclerotic plaques. We investigated the feasibility of a folate-based radiopharmaceutical (111In-EC0800) with high-resolution animal single-photon emission computed tomography/computed tomography (SPECT/CT) to differentiate between stable and vulnerable atherosclerotic plaques in apolipoprotein E 7 mice in which we can induce plaques with the characteristics of stable and vulnerable plaques by placing a flow-modifying cast around the common carotid artery. Both plaques showed 111In-EC0800 uptake, with higher uptake in the vulnerable plaque. However, the vulnerable plaque was larger than the stable plaque. Therefore, we determined tracer uptake per plaque volume and demonstrated higher accumulation of 111In-EC0800 in the stable plaque normalized to plaque volume. Our data show that 111In-EC0800 is not a clear-cut marker for the detection of vulnerable plaques but detects both stable and vulnerable atherosclerotic plaques in a mouse model of atherosclerosis.ISSN:1535-3508ISSN:1536-012