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Interactions between flow and biological cells and tissues are intrinsic to the circulatory, respiratory, digestive and genitourinary systems. In the circulatory system, an understanding of the complex interaction between the arterial wall (a living multi-component organ with anisotropic, nonlinear material properties) and blood (a shear-thinning fluid with 45% by volume consisting of red blood cells, platelets, and white blood cells) is vital to our understanding of the physiology of the human circulation and the etiology and development of arterial diseases, and to the design and development of prosthetic implants and tissue-engineered substitutes. Similarly, an understanding of the complex dynamics of flow past native human heart valves and the effect of that flow on the valvular tissue is necessary to elucidate the etiology of valvular diseases and in the design and development of valve replacements. In this paper we address the influence of biomechanical factors on the arterial circulation. The first part presents our current understanding of the impact of blood flow on the arterial wall at the cellular level and the relationship between flow-induced stresses and the etiology of atherosclerosis. The second part describes recent advances in the application of fluid-structure interaction analysis to arterial flows and the dynamics of heart valves.

Purpose: To assess pulmonary artery (PA) size, flow variables, and wall shear stress (WSS) in patients after Fontan operation at a young age., Materials and Methods: Flow in the branch PA was obtained with phase contrast velocity-encoded cardiovascular magnetic resonance imaging in 14 patients before and after low-dose dobutamine stress (7.5 microg/kg/min) and in 17 healthy controls at rest., Results: At rest, stroke index, total flow, average, and peak flow rate were all statistically significantly lower in patients than in controls (P<0.001). With stress-testing, all variables increased in patients (P<0.001), apart from stroke index, which did not change. At rest, branch PA area did not differ between patients and controls. Distensibility was lower in patients than in controls (P<0.001). With stress-testing, area and distensibility did not change. At rest, WSS was lower in patients than in controls (P<0.001). WSS increased with stress-testing (P<0.001), but not to the same levels as during resting conditions of the control group., Conclusion: PA size is normal long-term after Fontan operation at a young age. Flow variables, distensibility, and WSS are significantly lower compared to healthy controls, and do not show adequate reactions with stress-testing, which is suggestive of pulmonary artery endothelial and/or vascular dysfunction., (Copyright (c) 2008 Wiley-Liss, Inc.)

Atherosclerosis is a chronic lipid-driven inflammatory disease of the arteries. Early lesions (fatty streaks) contain monocytes and T lymphocytes which are recruited from the circulation by adhesion to activated vascular endothelial cells (EC). This process is described as the leukocyte adhesion cascade. Atherogenesis occurs predominantly at branches and bends of the arterial tree that are exposed to relatively low or re-circulating blood flow. Here we briefly review the effects of blood flow and shear stress on the leukocyte adhesion cascade and endothelial cell function.

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.

Tissue harmonic imaging (THI) has been shown to increase image quality of medical ultrasound in the frequency range from 2 to 10 MHz and might, therefore, also be used to improve image quality in intravascular ultrasound (IVUS). In this study we constructed a prototype IVUS system that could operate in both fundamental frequency and second harmonic imaging modes. This system uses a conventional, continuously rotating, single-element IVUS catheter and was operated in fundamental 20 MHz, fundamental 40 MHz, and harmonic 40 MHz modes (transmit 20 MHz, receive 40 MHz). Hydrophone beam characterization measurements demonstrated the build-up of a second harmonic signal as a function of increasing pressure. Imaging experiments were conducted in both a tissue-mimicking phantom and in an atherosclerotic animal model in vivo. Acquisitions of fundamental 20 and 40 MHz and second harmonic acquisitions resulted in cross sections of the phantom and a rabbit aorta. The harmonic results of the imaging experiments showed the feasibility of intravascular THI with a conventional IVUS catheter both in a phantom and in vivo. The harmonic acquisitions also showed the potential of THI to reduce image artifacts compared to fundamental imaging.

Background: Hypotension during haemodialysis results from an inadequate cardiovascular response to ultrafiltration-induced hypovolaemia. It has been suggested that plasma volume could be increased as a result of systemic vasoconstriction., Methods: We studied the effect of a norepinephrine (NOR) infusion (30 min), compared with no infusion, on relative blood volume (RBV) in six haemodialysis patients. During infusion we measured RBV, systolic blood pressure (SAP), heart rate (HR), stroke volume index (SI), total peripheral resistance (TPRI), ejection fraction (EF), inferior vena cava diameter (VCD) and core temperature., Results: At the end of the NOR infusion, we observed a significant increase in TPRI (47+/-47% vs 4+/-17%; P<0.01) and SAP (27+/-12% vs 0+/-8%; P<0.01). Norepinephrine-induced vasoconstriction resulted in a significant decrease in RBV (-9+/-3% vs 0+/-1%; P<0.01). No significant changes were seen in SI (-4+/-21% vs 0+/-8%), HR (-5+/-19% vs -4+/-5%), EF (7+/-14% vs -2+/-10%), VCD or temperature., Conclusions: We conclude that norepinephrine-induced vasoconstriction results in a decrease in RBV. This indicates that improved haemodynamic stability during haemodialysis through vasoconstriction can be accompanied by a decrease in RBV and that part of the variability in blood volume may be due to changes in arterial tone. Such changes must be taken into account if RBV measurements are used to improve the haemodynamic tolerance of dialysis.

Background: LV systolic dysfunction in dialysis patients has been implicated in the genesis of dialysis hypotension. End-systolic elastance (E(es)), a relatively load-independent parameter of myocardial contractility, was assessed by testing the acute left ventricular (LV) response to nitroglycerine (NTG) in hypotension-prone (HP) and hypotension-resistant (HR) patients., Methods: Routine measurement of ejection fraction (EF) was done before dialysis in 15 patients without significant valvular disease or symptoms of coronary heart disease. Continuous arterial pressure was measured by Finapres, with systolic blood pressure (SBP) as surrogate for LV end-systolic pressure. Simultaneously, LV area was measured using automated border detection. SBP and LV area data were combined online to create pressure-area loops in real time following intravenous NTG bolus. E(es) was determined offline by beat-to-beat analysis of consecutive pressure-area loops., Results: SBP, at baseline 168 mmHg (128-188 mmHg), decreased to 127 mmHg (79-161 mmHg). End-systolic LV area, at baseline 6 cm2 (1-12 cm2), decreased to 4 cm2 (1-10 cm2). E(es) in the HP group (11 mmHg cm(-2); 7-22 mmHg cm(-2)) was not different from E(es) in the HR group (9 mmHg cm(-2); 4-16 mmHg cm(-2)). EF was 61% (45-73%). There was no correlation between E(es) and EF., Conclusions: In this population of dialysis patients without clinically manifest heart disease, the HP and HR groups had a similar E(es). Therefore, these two types of dialysis patients were not distinguished by a difference in myocardial contractility. The results of this study argue against a role for reduced myocardial contractility in the genesis of intradialytic hypotension.

Aims: Plaque rupture has been associated with a high matrix metalloproteinase (MMP) activity. Recently, regional temperature variations have been observed in atherosclerotic plaques in vivo and ascribed to the presence of macrophages. As macrophages are a major source of MMPs, we examined whether regional temperature changes are related to local MMP activity and macrophage accumulation., Methods and Results: Plaques were experimentally induced in rabbit (n=11) aortas, and at the day of sacrifice, a pull-back was performed with a thermography catheter. Hot (n=10), cold (n=10), and reference (n=11) regions were dissected and analysed for smooth muscle cell (SMC), lipids (L), collagen (COL), and macrophage (MPhi) cell densities (%); a vulnerability index (VI) was calculated as VI=MPhi+L/(SMC+COL). In addition, accumulation and activity of MMP-2 and MMP-9 were determined with zymography. Ten hot regions were identified with an average temperature of 0.40+/-0.03 degrees C (P<0.05 vs. reference) and 10 cold regions with 0.07+/-0.03 degrees C (P<0.05 vs. hot). In the hot regions, a higher macrophage density (173%), less SMC density (77%), and a higher VI (100%) were identified. In addition, MMP-9 (673%) activity was increased. A detailed regression analysis revealed that MMP-9 predicted hot regions better than macrophage accumulation alone., Conclusion: In vivo temperature measurements enable to detect plaques that contain more macrophages, less SMCs, and a higher MMP-9 activity.

Background: Rupture of thin-cap fibroatheroma is a major cause of acute myocardial infarction and stroke. Identification of these plaques is one of the major challenges in cardiovascular medicine. At present, techniques with sufficient sensitivity and specificity to identify these unstable plaques are not clinically available. This paper describes a new technique to identify these plaques., Methods and Results: Three-dimensional intravascular ultrasound palpography is a catheter-based technique that visualizes radial strain (deformation) of vascular tissue induced by physiological variations in intraluminal pressure. A three-dimensional palpogram of these cross sections can be constructed by performing a continuous pullback of the catheter. Phantom and animal experiments revealed feasibility and good reproducibility of three-dimensional palpography. Increased strain values were observed in areas with reduced cap thickness and increased macrophage accumulation. In patients (n = 2) three-dimensional palpography is feasible and identifies areas with high and low strain., Conclusion: Three-dimensional palpography allows scanning of coronary arteries in patients to identify and localize highly deformable regions.

Objectives: The present study introduces a modification of the diastolic coronary conductance concept that maintains its sensitive properties to detect changes in the coronary microcirculation in human hypertrophy., Background: Decrements of coronary flow in hypertrophy have been explained by changes in the coronary microcirculation. No measure is available to detect these changes., Methods: Doppler velocity catheters were introduced into the left anterior descending artery (LAD) and left circumflex coronary artery (LCx) of patients with obstructive hypertrophic cardiomyopathy (HCM) (n = 11) and into the LAD of cardiac transplant recipients (n = 9). The diastolic coronary conductance was measured at rest and after maximal hyperemia induced by a bolus injection of adenosine. Diastolic coronary vasodilator reserve (DCVR) was calculated as the hyperemic diastolic coronary conductance, divided by the coronary conductance during resting conditions., Results: Left ventricular outflow tract gradient in the HCM group (83 +/- 31 mm Hg) was significantly higher (p < 0.05). Septal wall thickness was significantly increased (p < 0.05), while wall thickness was unchanged in the posterior wall of the HCM group. The coronary flow reserve was significantly decreased in the HCM-LCx region (to 64 +/- 7% of control) and in the HCM-LAD regions (to 57 +/- 7% of control). The DCVR was only decreased in the HCM-LAD (to 46 +/- 3% of control) and not in the HCM-LCx group (86 +/- 6%, p > 0.05). Esmolol did affect the pressure gradient and systolic shortening, but did not affect the maximal diastolic conductance., Conclusions: The DCVR, in contrast with the coronary flow reserve, is decreased in those regions that display a disturbance in the microcirculation and may, therefore, offer a new way to study coronary adaptations in patients with hypertrophy.

Aims: To investigate safety, feasibility, and injurious effect on endothelial cells of a thermography catheter as well as effect of flow on measured temperature in non-obstructive arteries., Methods and Results: Safety and feasibility were tested in both rabbit aortas and pig coronary arteries. Evaluation of endothelial damage by the catheter (acute, 7 and 14 days) was performed in pig coronaries using Evans Blue, scanning electron microscopy (SEM) and Factor-VIII antibody and compared with normal arteries and arteries that underwent intravascular ultrasound (IVUS). The effect of flow on temperature heterogeneity was analysed both in vitro and in vivo conditions. All procedures were successful without any adverse events; intra- and inter-operator variability was low. Intracoronary use of the catheter was associated with acute but reversible de-endothelialization, paralleling the findings associated with IVUS use. Changes in flow velocities under physiologic flow conditions did not significantly influence the temperature differences measured both in vitro and in vivo; temperature heterogeneity was more pronounced in absence of flow., Conclusions: Intracoronary thermography using a dedicated catheter is safe and feasible with a similar degree of de-endothelialization as IVUS. Temperature heterogeneity remained unchanged under normal physiologic flow conditions allowing clinical use of thermography.

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.

Background: Vascular wall shear stress (WSS) has been implied in the pathogenesis of atherosclerosis and vascular remodeling. Our aim was to calculate WSS after balloon angioplasty and evaluate its predictive value for long-term outcome., Methods: WSS was calculated proximal to, in, and distal to the lesion after angiographically successful balloon dilatation and at follow-up with the Hagen-Poiseuille formula (WSS = 4 microQ/piR3) in 202 patients. Volumetric blood flow (Q) and lumen radius (R) were derived from Doppler scanning velocities and videodensitometric cross-sectional areas., Results: Postprocedural proximal and in-lesion values were higher in vessels that developed restenosis (n = 72; 1.22 +/- 0.61 N/m2 and 3.61 +/- 2.38 N/m2, respectively) than in those without restenosis (n = 130, 1.05 +/- 0.51 N/m2 and 2.46 +/- 1.39 N/m2, respectively; P <.05). In-lesion WSS was revealed to be predictive of restenosis by means of logistic regression analysis (odds ratio [OR] = 1.42, P <.05), whereas WSS of the proximal segment was associated with an increased rate of target lesion revascularization (OR = 2.33, P <.005). In the multivariate regression model, WSS of the proximal segment was the only independent predictor when entered with known predictors such as diameter stenosis and coronary flow reserve (OR = 2.15, P <.05)., Conclusions: WSS in the lesion after balloon angioplasty is predictive of angiographic restenosis. Moreover, the proximal value is an independent predictor of target lesion revascularization. This study opens perspectives for the on-line use of WSS as a combined parameter of anatomy and physiology to assess the necessity of adjunctive therapy after successful balloon dilatation.

External work, efficiency of energy transfer (EET), and mechanical efficiency (defined as the ratio of external work over myocardial oxygen consumption (MVO2) are reduced in stunned myocardium. We therefore evaluated how inotropic stimulation by dobutamine and the calcium sensitizer EMD 57033 affected the regional stress-strain relationship as, from which contractility (E(es)), external work at the working point (EWwp), maximal external work (EWmax), EETwp (%), and EETmax are determined. Thirty minutes after regional stunning in 11 open chest pigs by two 10-min coronary occlusions separated by 10 min of reperfusion, dobutamine (0.5, 1, and 2 microg x kg(-1) x min(-1)) was infused, after an ample washout period followed by infusion of EMD 57033 (0.05, 0.1, 0.2 mg x kg(-1) x min(-1)). Stunning decreased E(es) (30%), EWwp (56%), EWmax (63%), EETwp (34%), EETmax (33%) and mechanical efficiency (55%), but MVO2 was unaffected. EWwp, EWmax, EETwp, and EETmax increased similarly with the two drugs, whereas MVO2 increased only after dobutamine. Consequently, mechanical efficiency increased linearly with contractility during EMD 57033 infusion but remained constant during infusion of dobutamine.