A numerical study on the influence of vulnerable plaque composition on intravascular thermography measurements.

Intracoronary thermography is a technique that measures lumen wall temperatures for vulnerable plaque detection. In this paper the influence of vulnerable plaque composition on lumen wall temperatures was studied numerically. Concerning the vulnerable plaque heat generation, the location of the heat source and its heat production were varied. Concerning the heat transfer, the thermal properties of the lipid core and the location of the vasa vasorum were studied. The heat source location was the main determinant of the lumen wall temperature distribution. The strongest effect was noted when the heat producing macrophages were located in the shoulder region leading to focal spots of higher temperature. The maximal lumen wall temperature was mainly determined by the heat production of the macrophages and the cooling effect of blood. The insulating properties of the lipid core increased lumen wall temperatures when the heat source was located in the cap and the presence of vasa vasorum lowered the temperatures. These results show that the lumen wall temperature distribution is influenced by vulnerable plaque composition and that intracoronary thermography techniques require a high spatial resolution. To be able to couple temperature measurements to plaque vulnerability, intracoronary thermography needs to be combined with an imaging modality.

The role of shear stress in the destabilization of vulnerable plaques and related therapeutic implications.

American Heart Association type IV plaques consist of a lipid core covered by a fibrous cap, and develop at locations of eccentric low shear stress. Vascular remodeling initially preserves the lumen diameter while maintaining the low shear stress conditions that encourage plaque growth. When these plaques eventually start to intrude into the lumen, the shear stress in the area surrounding the plaque changes substantially, increasing tensile stress at the plaque shoulders and exacerbating fissuring and thrombosis. Local biologic effects induced by high shear stress can destabilize the cap, particularly on its upstream side, and turn it into a rupture-prone, vulnerable plaque. Tensile stress is the ultimate mechanical factor that precipitates rupture and atherothrombotic complications. The shear-stress-oriented view of plaque rupture has important therapeutic implications. In this review, we discuss the varying mechanobiologic mechanisms in the areas surrounding the plaque that might explain the otherwise paradoxical observations and unexpected outcomes of experimental therapies.

The role of shear stress in the generation of rupture-prone vulnerable plaques.

Blood-flow-induced shear stress acting on the arterial wall is of paramount importance in vascular biology. Endothelial cells sense shear stress and largely control its value in a feedback-control loop by adapting the arterial dimensions to blood flow. Nevertheless, to allow for variations in arterial geometry, such as bifurcations, shear stress control is modified at certain eccentrically located sites to let it remain at near-zero levels. In the presence of risk factors for atherosclerosis, low shear stress contributes to local endothelial dysfunction and eccentric plaque build up, but normal-to-high shear stress is atheroprotective. Initially, lumen narrowing is prevented by outward vessel remodeling. Maintenance of a normal lumen and, by consequence, a normal shear stress distribution, however, prolongs local unfavorable low shear stress conditions and aggravates eccentric plaque growth. While undergoing such growth, eccentric plaques at preserved lumen locations experience increased tensile stress at their shoulders making them prone to fissuring and thrombosis. Consequent loss of the plaque-free wall by coverage with thrombus and new tissue may bring shear-stress-controlled lumen preservation to an end. This change causes shear stress to increase, which as a new condition may transform the lesion into a rupture-prone vulnerable plaque. We present a discussion of the role of shear stress, in setting the stage for the generation of rupture-prone, vulnerable plaques, and how this may be prevented.

Temperature distribution in atherosclerotic coronary arteries: influence of plaque geometry and flow (a numerical study).

Intravascular coronary thermography is a method that may detect vulnerable, atherosclerotic plaques and is currently evaluated in a clinical setting. Active macrophages or enzymatic heat releasing processes in vulnerable plaques may act as heat sources. To better understand the parameters of influence on thermographic measurements, numerical simulations have been performed on a model of a coronary artery segment containing a heat source. Heat source parameters and flow were varied to study their influence on temperatures at the lumen wall. Maximal temperature differences at the lumen wall increased when the source volume increased and they differ with the source geometry. The simulations showed that blood flow acts as a coolant to the lumen wall. Blood flow decreased maximal temperatures depending on the source geometry, source volume and the maximal flow velocity. Influence of flow was highest for circumferentially extended sources, up to a factor 3.7, and lowest for longitudinally extended sources, down to a factor 1.9. When cap thickness increased, maximal temperatures decreased and the influence of flow increased. This study shows that correct interpretation of intravascular thermographic measurements requires data on the flow and on the morphologic characteristics of the atherosclerotic plaque.

On-line electrical impedance measurement for monitoring blood viscosity during on-pump heart surgery.

BACKGROUND: The viscosity of blood (eta) as well as its electrical impedance at 20 kHz at high shear rate depends on hematocrit, temperature, concentration of macromolecules and red cell deformability. The aim of our study was to investigate the relation between viscosity and electrical impedance in a heart-lung machine-like set-up, because during on-pump heart surgery considerable viscosity changes occur. METHODS: Blood of 10 healthy volunteers was examined under temperature variation between 18.5 and 37 degrees C at four different levels of hemodilution. Blood viscosity was examined with a golden-standard technique, i.e. a Contraves LS 30 Couette viscometer, and the results were compared with measurements of the electrical resistivity (R) at 20 kHz by a specially designed device in series with the tubing system of a heart-lung machine. All measurements were performed at a shear rate of 87 s(-1). RESULTS: Using stepwise multiparameter regression analysis (SPSS) a highly significant correlation was found (r(2) = 0.882) between viscosity (eta) and resistivity (R). Adding the variables sodium ([Na(+)]) and fibrinogen ([Fibr]) concentration the coefficient of correlation further improved to r(2) = 0.928 and the relation became: eta = -0.6844 + 0.038 R + 0.038 [Na(+)] + 0.514 [Fibr]. All coefficients showed a statistical significance of p < 0. 001. CONCLUSIONS: Electrical impedance measurement is feasible in a heart-lung machine-like set-up and allows accurate continuous on-line estimation of blood viscosity; it may offer an adequate way to record and control viscosity changes during on-pump heart surgery.

Imaging of coronary atherosclerosis and identification of the vulnerable plaque.

Identification of the vulnerable plaque responsible for the occurrence of acute coronary syndromes and acute coronary death is a prerequisite for the stabilisation of this vulnerable plaque. Comprehensive coronary atherosclerosis imaging in clinical practice should involve visualisation of the entire coronary artery tree and characterisation of the plaque, including the three-dimensional morphology of the plaque, encroachment of the plaque on the vessel lumen, the major tissue components of the plaque, remodelling of the vessel and presence of inflammation. Obviously, no single diagnostic modality is available that provides such comprehensive imaging and unfortunately no diagnostic tool is available that unequivocally identifies the vulnerable plaque. The objective of this article is to discuss experience with currently available diagnostic modalities for coronary atherosclerosis imaging. In addition, a number of evolving techniques will be briefly discussed.

The clinical significance of whole blood viscosity in (cardio)vascular medicine.

Whole blood is a non-Newtonian fluid, which means that its viscosity depends on shear rate. At low shear, blood cells aggregate, which induces a sharp increase in viscosity, whereas at higher shear blood cells disaggregate, deform and align in the direction of flow. Other important determinants of blood viscosity are the haematocrit, the presence of macro-molecules in the medium, temperature and, especially at high shear, the deformability of red blood cells. At the sites of severe atherosclerotic obstructions or at vasospastic locations, when change of vessel diameter is limited, blood viscosity contributes to stenotic resistance thereby jeopardising tissue perfusion. However, blood viscosity plays its most important role in the microcirculation where it contributes significantly to peripheral resistance and may cause sludging in the postcapillary venules. Apart from the direct haemodynamic significance, an increase in blood viscosity at low shear by red blood cell aggregation is also associated with increased thrombotic risk, as has been demonstrated in atrial fibrillation. Furthermore, as increased red blood cell aggregation is a reflection of inflammation, hyperviscosity has been shown to be a marker of inflammatory activity. Thus, because of its potential role in haemodynamics, thrombosis and inflammation, determination of whole blood viscosity could provide useful information for diagnostics and therapy of (cardio)vascular disease.

Shear-stress and wall-stress regulation of vascular remodeling after balloon angioplasty: effect of matrix metalloproteinase inhibition.

BACKGROUND: Constrictive vascular remodeling (VR) is the most significant component of restenosis after balloon angioplasty (PTA). Whereas in physiological conditions VR is associated with normalization of shear stress (SS) and wall stress (WS), after PTA the role of SS and WS in VR is unknown. Furthermore, whereas matrix metalloproteinase inhibition (MMPI) has been shown to modulate VR after PTA, its effect on the SS and WS control mechanisms after PTA is unknown. METHODS AND RESULTS: PTA was performed in external iliac arteries of 12 atherosclerotic Yucatan pigs, of which 6 pigs (7 vessels) received the MMPI batimastat and 6 pigs (10 vessels) served as controls. Before and after the intervention and at 6-week follow-up, intravascular ultrasound pullback was performed, allowing 3D reconstruction of the treated segment and computational fluid dynamics to calculate the media-bounded area and SS. WS was derived from the Laplace formula. Immediately after PTA, media-bounded area, WS, and SS changed by 20%, 16%, and -49%, respectively, in both groups. VR was predicted by SS and WS. In the control group, SS and WS had been normalized at follow-up with respect to the reference segment. In contrast, for the batimastat group, the SS had been normalized, but not the WS. The latter is attributed to an increase in wall area at follow-up. CONCLUSIONS: Vascular remodeling after PTA is controlled by both SS and WS. MMPI inhibited the WS control system.

Oxygen wastage of stunned myocardium in vivo is due to an increased oxygen cost of contractility and a decreased myofibrillar efficiency.

OBJECTIVE: We investigated whether an increased oxygen cost of contractility and/or a decreased myofibrillar efficiency contribute to oxygen wastage of stunned myocardium. Because Ca(2+)-sensitizers may increase myofibrillar Ca(2+)-sensitivity without increasing cross-bridge cycling, we also investigated whether EMD 60263 restores myofibrillar efficiency and/or the oxygen cost of contractility. METHODS: Regional fiber stress and strain were calculated from mesomyocardially implanted ultrasound crystals and left ventricular pressure in anesthetized pigs (n=18). Regional myocardial oxygen consumption (MVO(2)) was measured before contractility (end-systolic elastance, E(es)) and total myofibrillar work (stress-strain area, SSA) were determined from stress-strain relationships. Atrial pacing at three heart rates and two doses of dobutamine were used to vary SSA and E(es), respectively. After stunning (two times 10-min ischemia followed by 30-min reperfusion), measurements were repeated following infusion of saline (n=8) or EMD 60263 (1.5 mg.kg(-1) i.v., n=10). Linear regression was performed using: MVO(2)=alpha.SSA+beta.E(es)+gamma.HR(-1) (alpha(-1), myofibrillar efficiency; beta, oxygen cost of contractility; and gamma, basal metabolism/min). RESULTS: Stunning decreased SSA by 57% and E(es) by 64%, without affecting MVO(2), while increasing alpha by 71% and beta by 134%, without affecting gamma. From the wasted oxygen, 72% was used for myofibrillar work and 18% for excitation-contraction coupling. EMD 60263 restored both alpha and beta. CONCLUSIONS: Oxygen wastage in stunning is predominantly caused by a decreased myofibrillar efficiency and to a lesser extent by an increased oxygen cost of contractility. Considering that EMD 60263 reversed both causes of oxygen wastage, it is most likely that this drug increases myofibrillar Ca(2+)-sensitivity without increasing myofibrillar cross-bridge cycling.

Relationship between neointimal thickness and shear stress after Wallstent implantation in human coronary arteries.

BACKGROUND: In-stent restenosis by excessive intimal hyperplasia reduces the long-term clinical efficacy of coronary stents. Because shear stress (SS) is related to plaque growth in atherosclerosis, we investigated whether variations in SS distribution are related to variations in neointima formation. METHODS AND RESULTS: In 14 patients, at 6-month follow-up after coronary Wallstent implantation, 3D stent and vessel reconstruction was performed with a combined angiographic and intravascular ultrasound technique (ANGUS). The bare stent reconstruction was used to calculate in-stent SS at implantation, applying computational fluid dynamics. The flow was selected to deliver an average SS of 1.5 N/m(2). SS and neointimal thickness (Th) values were obtained with a resolution of 90 degrees in the circumferential and 2.5 mm in the longitudinal direction. For each vessel, the relationship between Th and SS was obtained by linear regression analysis. Averaging the individual slopes and intercepts of the regression lines summarized the overall relationship. Average Th was 0.44+/-0.20 mm. Th was inversely related to SS: Th=(0.59+/-0.24)-(0.08+/-0.10)xSS (mm) (P<0.05). CONCLUSIONS: These data show for the first time in vivo that the Th variations in Wallstents at 6-month follow-up are inversely related to the relative SS distribution. These findings support a hemodynamic mechanism underlying in-stent neointimal hyperplasia formation.

Comparison of different methods to define a target volume for external beam radiation therapy of restenotic coronary arteries.

PURPOSE: Different methods have been described to define a target volume for the treatment of restenotic (stented) coronary arteries by external beam radiation therapy (EBRT). The purpose of this study was to explore two methods to define a target for such therapy, and to compare these with previously investigated methods. MATERIALS AND METHODS: The 3-D position of a stent throughout the cardiac cycle in the three major epicardial coronary arteries was measured in three patients by single-breathhold multislice spiral CT and breathhold biplane conventional X-ray angiography, both indexed in time with the ECG. The volume through which the stent traversed (STV) during the cardiac cycle was determined by use of displacement measurements. RESULTS: For multislice CT and biplane angiography, respectively, the mean STV was 1.23 cm(3) (range 0.65-2.22 cm(3)) and 2.81 cm(3) (range 1.60-4.99 cm(3)). The STV represented only a fraction of the whole heart volume in all patients, that is, equal to or less than 0.4%. CONCLUSIONS: Multislice CT and biplane angiography allowed the measurement of a relatively small potential target, that is the STV, for EBRT of restenotic stented coronary arteries. Both studied imaging modalities are instrumental for targeting the STV by highly conformal radiation therapy in case of restenotic stented coronary arteries.

Relationship between tensile stress and plaque growth after balloon angioplasty treated with and without intracoronary beta-brachytherapy.

AIMS: We investigated the influence of tensile stress on plaque growth after balloon angioplasty with and without beta-radiation therapy. METHODS AND RESULTS: Thirty-one consecutive patients successfully treated with balloon angioplasty were analysed qualitatively and quantitatively by means of an ECG-gated three-dimensional intravascular ultrasound post-procedure and at follow-up. Eighteen patients were irradiated with catheter-based beta-radiation ((90)Sr/(90)Y source) and 13 were not (control). Studied segments were divided into 2 mm subsegments. Thus 184 irradiated and 111 non-irradiated subsegments were included. Tensile stress was calculated according to Laplace's law. The radiation dose was calculated by means of dose-volume histograms. Plaque growth was positively correlated to tensile stress in both the radiation and control groups (r=0.374, P=0.0001 and r=0.305, P=0.001). Low-dose subsegments (<6 Gy) had a significant correlation (r=0.410, P=0.0001) whereas no correlation was observed in the effective-dose subsegments (> or = 6 Gy). Multivariate analysis identified tensile stress as the only independent predictor of plaque increase in non-irradiated subsegments, whereas actual dose and plaque morphology were stronger predictors in irradiated subsegments. CONCLUSION: The results of this study suggest that plaque growth is related to tensile stress after balloon angioplasty. Intracoronary brachytherapy may alter the biophysical process on plaque growth when the prescribed dose is effectively delivered.

Efficiency of energy transfer, but not external work, is maximized in stunned myocardium.

There is no evidence regarding the effect of stunning on maximization of regional myocardial external work (EW) or efficiency of energy transfer (EET) in relation to regional afterload (end-systolic stress, sigma(es)). To that end, we studied these relationships in both the left anterior descending coronary artery (LADCA) and left circumflex coronary artery regions in anesthetized, open-chest pigs before and after LADCA stunning. In normal myocardium, EET vs. sigma(es) was maximal at 75.4 (69.7-81.0)%, whereas EW vs. sigma(es) was submaximal at 12.0 (6.61-17.3) x 10(2) J/m(3). Increasing sigma(es) increased EW by 18 (10-27)%. Regional myocardial stunning decreased EET (27%) and EW (36%) and caused the myocardium to operate both at maximal EW (EW(max)) and at maximal EET (EET(max)). EET and EW became also more sensitive to changes in sigma(es). In the nonstunned region the situation remained unchanged. Combining the data from before and after stunning, both EW(max) and EET(max) displayed a positive relationship with contractility. In conclusion, the normal regional myocardium operated at maximal EET rather than at maximal EW. Therefore, additional EW could be recruited by increasing regional afterload. After myocardial stunning, the myocardium operated at both maximal EW and maximal EET, at the cost of increased afterload sensitivity. Contractility was a major determinant of this shift.

True 3-dimensional reconstruction of coronary arteries in patients by fusion of angiography and IVUS (ANGUS) and its quantitative validation.

BACKGROUND: True 3D reconstruction of coronary arteries in patients based on intravascular ultrasound (IVUS) may be achieved by fusing angiographic and IVUS information (ANGUS). The clinical applicability of ANGUS was tested, and its accuracy was evaluated quantitatively. METHODS AND REUSLTS: In 16 patients who were investigated 6 months after stent implantation, a sheath-based catheter was used to acquire IVUS images during an R-wave-triggered, motorized stepped pullback. First, a single set of end-diastolic biplane angiographic images documented the 3D location of the catheter at the beginning of pullback. From this set, the 3D pullback trajectory was predicted. Second, contours of the lumen or stent obtained from IVUS were fused with the 3D trajectory. Third, the angular rotation of the reconstruction was optimized by quantitative matching of the silhouettes of the 3D reconstruction with the actual biplane images. Reconstructions were obtained in 12 patients. The number of pullback steps, which determines the pullback length, closely agreed with the reconstructed path length (r=0.99). Geometric measurements in silhouette images of the 3D reconstructions showed high correlation (0.84 to 0.97) with corresponding measurements in the actual biplane angiographic images. CONCLUSIONS: With ANGUS, 3D reconstructions of coronary arteries can be successfully and accurately obtained in the majority of patients.

Coronary stent implantation changes 3-D vessel geometry and 3-D shear stress distribution.

Mechanisms of in-stent restenosis are not fully understood. Shear stress is known to play a role in plaque and thrombus formation and is sensitive to changes in regional vessel geometry. Hence, we evaluated the regional changes in 3-D geometry and shear stress induced by stent placement in coronary arteries of pigs.Methods. 3-D reconstruction was performed, applying a combined angiographic and IVUS technique (ANGUS), from seven Wallstents (diameter 3.5 (n=3) and 5mm (n=4)), which were implanted in seven coronary arteries of five pigs. This 3-D geometry was used to calculate locally the curvature, while the shear stress distribution was obtained by computational fluid dynamics. Local changes in shear stress were obtained at the entrance and exit of the stent for baseline (0. 65+/-0.22 ml/s) and hyperemic flow (2.60+/-0.86 ml/s) conditions. Results. After stent implantation, the curvature increased by 121% at the entrance and by 100% at the exit of the stent, resulting in local changes in shear stress. In general, at the entrance of the stent local maxima in shear stress were generated, while at the exit both local maxima and minima in shear stress were observed (p<0.05). Additionally, the shear stress at the entrance and exit of the stent were correlated with the local curvature (r: 0.30-0.84).Conclusion. Stent implantation changes 3-D vessel geometry in such a way that regions with decreased and increased shear stress occur close to the stent edges. These changes might be related to the asymmetric patterns of in-stent restenosis.

Quantification of plaque volume, shear stress on the endothelium, and mechanical properties of the arterial wall with intravascular ultrasound imaging.

Present intravascular echographic imaging (IVUS) is based on either the mechanically rotated single element catheter or the multi-element phased array catheter principle. In both methods the ultrasonic beam is rotated through 360 degrees and the cross-sectional echo image of plaque and wall structures is visualised. A new development based on intravascular ultrasound is calculation of mechanical properties of the arterial wall. In this so-called elastographic approach, high frequency information obtained at identical positions in the arterial wall is compared under systolic and diastolic pressures. Minute shifts in the echo data indicate local compressibility. It thus becomes possible to indicate areas of high or low strain, which correspond to soft and hard material. Three-dimensional information can be obtained if the position of cross sectional slices is recorded with a pull-back device and slices are united into a 3D image. On the basis of such information it has become possible to view stents in 3D, and with interactive software, to calculate automatically plaque volume. With pull-back information only, the artery is reconstructed as a "straight pipe". Only when the biplane X-ray information is combined with the intravascular pull-back echo information can the true 3D reconstruction of the artery be constructed. Given the true geometric lumen information, it becomes possible, under certain assumptions, to derive the luminal fluid dynamics. From this, shear stress values close to the arterial wall can be calculated. Under the assumption that low values for local shear stress are areas prone to restenosis, predictions of endangered areas can be made.

On the IVUS plaque volume error in coronary arteries when neglecting curvature.

Plaque volume determined by common linear 3-D IVUS analysis systems will show under- or overestimation in curved vessel segments because these systems approximate the true 3-D transducer pull-back trajectory by a straight line. We developed a mathematical model that showed that the error is primarily dependent on the curvature of the pull-back trajectory and not on vessel tortuosity. Furthermore, we measured this error in vivo in the coronary arteries of 15 patients, comparing the plaque volume using a true 3-D reconstruction method with that of the linear approach. The in vivo plaque volume error ranged from 2.3% to -1.2% for 15 coronary segments with lengths ranging from 38.8 to 89.1 mm (62.2 +/- 13 mm). The volume error introduced by linear 3-D IVUS analysis systems is dependent on the curvature of the pull-back trajectory. The error measured in vivo was small and inversely related to segment length.

Effect of catheter placement on 3-D velocity profiles in curved tubes resembling the human coronary system.

Novel measurement techniques based on intravenous ultrasound (IVUS) technology ('IVUS-Flowmetry') require the location of a catheter inside the coronary bed. The present study quantifies disturbances in the 3-D velocity profile induced by catheter placement inside a tube, applying computational fluid dynamics. Two curved, circular meshes (radius K = 0.025 m and K = 0.035 m) with and without a catheter inside the lumen were applied. The catheter was located at the inner curve, the outer curve and at the top position. Boundary conditions were: no slip on the wall, zero stress at the outlet, uniform inflow with entrance velocities of 0.1, 0.2 and 0.4 m/s. Curvature-associated centrifugal forces shifted the maximal velocity to the outer curve and introduced two symmetrical vortices. Additional catheter placement redistributed the 3-D axial velocity field away from the catheter, which was accompanied by the appearance of multiple low-strength vortices. In addition, peak axial velocity increased, peak secondary velocities decreased, axial pressure drop increased and shear stress increased. Flow calculations simulated to resemble IVUS-based flowmetry changed by only 1% after considering secondary velocity. In conclusion, placement of a catheter inside a curved tube resembling the human coronary system changes the velocity field and reduces secondary patterns. The present study supports the usefulness of catheter-based flowmetry during resting flow conditions. During hyperemic flow conditions, flow measurements might be accompanied by large axial pressure drops because the catheter, itself, might act as a significant stenosis.