Frank Helderman

Effect of shear stress on vascular inflammation and plaque development

Purpose of review This review describes evidence that shear stress acts through modulation of inflammation and by that process affects atherogenesis and plaque composition. Recent findings In low shear stress regions antiatherogenic transcription factors are downregulated and pro-atherogenic transcription factors are upregulated. Consequently, inflammatory cells may home low shear stress regions more easily to the plaques because of increased expression of adhesion factors, a decreased rolling speed and an increased expression of chemokines, thereby changing the composition of the plaques into a more vulnerable phenotype. In contrast, in advanced plaque development vascular lumen decreases and shear stress increases, especially upstream of the plaques. The predominant upstream location of lipids induces a prevalent upstream location of inflammatory cells leading to localized plaque rupture. Summary Shear stress has been shown to play a role in plaque induction, plaque progression and plaque rupture. The mechanism for plaque induction seems to differ from the role of shear stress for plaque rupture, whereby the former mechanism is induced by low shear stress and the latter by high shear stress.

The role of shear stress in atherosclerosis: action through gene expression and inflammation?

Atherosclerotic lesions preferentially localize near side branches or curved vessels. During the last few decades, research has been shown that low or low and oscillating shear stress is associated with plaque location. Despite ample evidence, the precise mechanism is unknown. This is mainly because of a lack of appropriate animal models. We describe two novel methods to study the hypothesis that shear stress acts through endothelial gene expression or shear stress acts through localizing of inflammation. Both literature evidence and own findings support a role for both mechanisms in atherosclerosis.

Gelatinolytic Activity in Atherosclerotic Plaques Is Highly Localized and Is Associated With Both Macrophages and Smooth Muscle Cells In Vivo

Background— Atherosclerosis is considered an inflammatory disease. Recent studies provided evidence for a predominant upstream location of plaque inflammation. The present study introduces a novel technique that evaluates the underlying mechanism of this spatial organization. Methods and Results— In hypercholesterolemic rabbits, atherosclerosis of the infrarenal aorta was induced by a combination of endothelial denudation and a high-cholesterol diet (2% cholesterol for 2 months). At the time of death, aortic vessel segments were dissected and reconstructed with a new technique that preserved the original intravascular ultrasound-derived lumen geometry. This enabled us to study the spatial relation of histological markers like macrophages, smooth muscle cells, lipids, gelatinolytic activity, and oxidized low-density lipoprotein. Results showed a predominant upstream localization of macrophages and gelatinase activity. Colocalization studies indicated that gelatinase activity was associated with macrophages and smooth muscle cells. Further analysis revealed that this was caused by subsets of smooth muscle cells and macrophages, which were associated with oxidized low-density lipoprotein accumulation. Conclusions— Upstream localization of a vulnerable plaque phenotype is probably due to an accumulation of oxidized low-density lipoprotein, which activates/induces subsets of smooth muscle cells and macrophages to gelatinase production.

A numerical model to predict abdominal aortic aneurysm expansion based on local wall stress and stiffness

Aneurysms of the abdominal aorta enlarge until rupture occurs. We assume that this is the result of remodelling to restore wall stress. We developed a numerical model to predict aneurysm expansion based on this assumption. In addition, we obtained aneurysm geometry of 11 patients from computed tomography angiographic images to obtain patient specific calculations. The assumption of a wall stress related expansion indeed resulted in a series of local expansions, adjusting global geometry in an exponential fashion similar as in patients. Furthermore, it revealed that location of peak wall stress changed over time. The assumptions of this model are discussed in detail in this manuscript, and the implications are related to literature findings.

Pulmonary artery size and function after Fontan operation at a young age

To assess pulmonary artery (PA) size, flow variables, and wall shear stress (WSS) in patients after Fontan operation at a young age.

Predicting Patient-Specific Expansion of Abdominal Aortic Aneurysms

OBJECTIVE Local anatomy and the patients risk profile independently affect the expansion rate of an abdominal aortic aneurysm. We describe a hybrid method that combines finite element modelling and statistical methods to predict patient-specific aneurysm expansion. METHODS The 3-D geometry of the aneurysm was imaged with computed tomography. We used finite element methods to calculate wall stress and aneurysm expansion. Expansion rate was adjusted by risk factors obtained from a database of 80 patients. Aneurysm diameters predicted with and without the risk profiles were compared with diameters measured with ultrasound for 11 patients. RESULTS For this specific group of patients, local anatomy contributed 62% and the risk profile 38% to the aneurysmal expansion rate. Predictions with risk profiles resulted in smaller root mean square errors than predictions without risk profiles (2.9 vs. 4.0 mm, p < 0.01). CONCLUSIONS This hybrid approach predicted aneurysmal expansion for a period of 30 months with high accuracy.

Visualization of the Vulnerable Plaque

Thrombosis is the main cause of acute coronary syndrome and myocardial infarction (Naghavi et al., 2003). The mechanism underlying thrombus formation is presently under debate, but several pathological conditions have been identified fromhuman postmortem studies that correspondwith the presence of thrombus. Of these conditions plaque rupture is the most common, but erosion of the endothelial layer and existence of calcified nodules without the existence of plaque rupture have also been identified. Plaques that have been ruptured have certain features in common (Falk, 1999; Virmani et al., 2002): (i) size of the lipid core (40% of the entire plaque), (ii) thickness of the fibrous cap (less than 65 μm), (iii) presence of inflammatory cells, (iv) amount of remodeling and extent of plaque-free vessel wall. Several terms have been identified focusing either on the pathological aspects (“thin-cap fibroatheroma”) or on the possibility to rupture (“rupture-prone plaques”) or on the possibility to induce thrombosis (“vulnerable plaque”). As vulnerable plaque is the term encompassing all other terms, therefore this term will be used throughout the chapter.

1057 Pulmonary artery size and function after Fontan operation at young age: assessment with phase contrast magnetic resonance imaging

Methods 14 patients (9 males, aged 13.1 ± 4.0 years, follow-up after Fontan completion 9.7 (5.4–16.8) years) and 17 healthy controls (9 males, aged 13.3 ± 2.3 years) were included. Flow measurements in the branch PA were made during a CMR study, using phase contrast velocity-encoded imaging. In patients, flow measurements were repeated during low-dose dobutamine stress of 7.5 μg/kg/min. Shear stress was determined according to a previously published method [1]. Results CMR scanning and dobutamine administration was well tolerated by all subjects without side effects. Results of the flow studies and shear stress determination are summarized in Table 1 (NS = not significant).