Fn Frans van de Vosse

Coronary thermodilution to assess flow reserve : validation in humans

Background—Guide wire–based simultaneous measurement of fractional flow reserve (FFR) and coronary flow reserve (CFR) is important to understand microvascular disease of the heart. The aim of this study was to investigate the feasibility of simultaneous measurement of FFR and CFR by one pressure-temperature sensor-tipped guide wire with the use of coronary thermodilution and to compare CFR by thermodilution (CFRthermo) with simultaneously measured Doppler CFR (CFRDoppl). Methods and Results—In 103 coronary arteries in 50 patients, a pressure-temperature sensor-tipped 0.014-inch floppy guide wire and a 0.014-inch Doppler guide wire were introduced. Both normal vessels and a wide range of stenotic vessels were included. With 3 mL of saline at room temperature used as an indicator, by hand-injection, thermodilution curves in the coronary artery were obtained in triplicate, both at baseline and at intravenous adenosine-induced maximum hyperemia. After adequate curve-fitting, CFRthermo was calculated from the ratio of inverse mean transit times and compared with CFRDoppl calculated by velocities at hyperemia and baseline. Adequate sets of thermodilution curves and corresponding CFRthermo could be obtained in 87% of the arteries versus 91% for Doppler CFR and 100% for FFR. CFRthermo correlated fairly well to CFRDoppl (CFRthermo=0.84 CFRDoppl+0.17;r =0.80;P <0.001), although individual differences of >20% between both indexes were seen in a quarter of all arteries. Conclusions—This study shows the feasibility of simultaneous measurement of FFR (by coronary pressure) and CFR (by coronary thermodilution) in humans by one single guide wire in a practical and straightforward way and will facilitate assessment of microvascular disease.

Epicardial stenosis severity does not affect minimal microcirculatory resistance

Background—Whether minimal microvascular resistance of the myocardium is affected by the presence of an epicardial stenosis is controversial. Recently, an index of microcirculatory resistance (IMR) was developed that is based on combined measurements of distal coronary pressure and thermodilution-derived mean transit time. In normal coronary arteries, IMR correlates well with true microvascular resistance. However, to be applicable in the case of an epicardial stenosis, IMR should account for collateral flow. We investigated the feasibility of determining IMR in humans and tested the hypothesis that microvascular resistance is independent of epicardial stenosis. Methods and Results—Thirty patients scheduled for percutaneous coronary intervention were studied. The stenosis was stented with a pressure guidewire, and coronary wedge pressure (Pw) was measured during balloon occlusion. After successful stenting, a short compliant balloon with a diameter 1.0 mm smaller than the stent was placed in the stented segment and inflated with increasing pressures, creating a 10%, 50%, and 75% area stenosis. At each of the 3 degrees of stenosis, fractional flow reserve (FFR) and IMR were measured at steady-state maximum hyperemia induced by intravenous adenosine. A total of 90 measurements were performed in 30 patients. When uncorrected for Pw, an apparent increase in microvascular resistance was observed with increasing stenosis severity (IMR=24, 27, and 37 U for the 3 different degrees of stenosis; P<0.001). In contrast, when Pwis appropriately accounted for, microvascular resistance did not change with stenosis severity (IMR=22, 23, and 23 U, respectively; P=0.28). Conclusions—Minimal microvascular resistance does not change with epicardial stenosis severity, and IMR is a specific index of microvascular resistance when collateral flow is properly taken into account.

Effects of wall calcifications in patient-specific wall stress analyses of abdominal aortic aneurysms.

It is generally acknowledged that rupture of an abdominal aortic aneurysm (AAA) occurs when the stress acting on the wall over the cardiac cycle exceeds the strength of the wall. Peak wall stress computations appear to give a more accurate rupture risk assessment than AAA diameter, which is currently used for a diagnosis. Despite the numerous studies utilizing patient-specific wall stress modeling of AAAs, none investigated the effect of wall calcifications on wall stress. The objective of this study was to evaluate the influence of calcifications on patient-specific finite element stress computations. In addition, we assessed whether the effect of calcifications could be predicted directly from the CT-scans by relating the effect to the amount of calcification present in the AAA wall. For 6 AAAs, the location and extent of calcification was identified from CT-scans. A finite element model was created for each AAA and the areas of calcification were defined node-wise in the mesh of the model. Comparisons are made between maximum principal stress distributions, computed without calcifications and with calcifications with varying material properties. Peak stresses are determined from the stress results and related to a calcification index (CI), a quantification of the amount of calcification in the AAA wall. At calcification sites, local stresses increased, leading to a peak stress increase of 22% in the most severe case. Our results displayed a weak correlation between the CI and the increase in peak stress. Additionally, the results showed a marked influence of the calcification elastic modulus on computed stresses. Inclusion of calcifications in finite element analysis of AAAs resulted in a marked alteration of the stress distributions and should therefore be included in rupture risk assessment. The results also suggest that the location and shape of the calcified regions--not only the relative amount--are considerations that influence the effect on AAA wall stress. The dependency of the effect of the wall stress on the calcification elastic modulus points out the importance of determination of the material properties of calcified AAA wall.

The mechanical role of thrombus on the growth rate of an abdominal aortic aneurysm

OBJECTIVES In the decision for surgical repair of abdominal aortic aneurysms (AAAs), the maximum diameter is the main factor. Several studies have concluded that the diameter may not be reliable as rupture risk criterion for the individual patient and wall stress was found to have a higher sensitivity and specificity. The AAA wall stress may also be an influential factor in growth of the AAA. This study investigates the effect of intraluminal thrombus on the wall stress and growth rate of aneurysms, using both idealized and patient-specific AAA models in wall stress computations. METHODS Idealized AAA models were created for wall stress analysis. Thrombus was modeled as an incompressible linear elastic material and was fixed to the wall. The reduction in wall stress for a range of thrombus volumes and shear moduli was computed. For 30 patient-specific AAA models with varying thrombus volumes, the wall stress was computed with and without thrombus. The diameter growth rate was compared for AAAs with a small and large thrombus volume. The results were compared between the idealized and patient-specific models. RESULTS The thrombus caused a reduction in wall stress, which was stronger for larger thrombi and higher elastic moduli. Any AAAs with a large thrombus were found to have significant stronger growth in diameter than aneurysms with a small thrombus (P < .01). The stress reduction due to the thrombus showed the same trend for the idealized and patient-specific models, although the effect was overestimated by the idealized models and a considerable variation between patients was observed. CONCLUSION A larger thrombus in AAA was associated with a higher AAA growth rate, but also with a lower wall stress. Therefore, weakening of the AAA wall, under the influence of thrombus, may play a more imminent role in the process of AAA growth than the stress acting on the wall.

A wave propagation model of blood flow in large vessels using an approximate velocity profile function

Lumped-parameter models (zero-dimensional) and wave-propagation models (one-dimensional) for pressure and flow in large vessels, as well as fully three-dimensional fluid–structure interaction models for pressure and velocity, can contribute valuably to answering physiological and patho-physiological questions that arise in the diagnostics and treatment of cardiovascular diseases. Lumped-parameter models are of importance mainly for the modelling of the complete cardiovascular system but provide little detail on local pressure and flow wave phenomena. Fully three-dimensional fluid–structure interaction models consume a large amount of computer time and must be provided with suitable boundary conditions that are often not known. One-dimensional wave-propagation models in the frequency and time domain are well suited to obtaining clinically relevant information on local pressure and flow waves travelling through the arterial system. They can also be used to provide boundary conditions for fully three-dimensional models, provided that they are defined in, or transferred to, the time domain. Most of the one-dimensional wave propagation models in the time domain described in the literature assume velocity profiles and therefore frictional forces to be in phase with the flow, whereas from exact solutions in the frequency domain a phase difference between the flow and the wall shear stress is known to exist. In this study an approximate velocity profile function more suitable for one-dimensional wave propagation is introduced and evaluated. It will be shown that this profile function provides first-order approximations for the wall shear stress and the nonlinear term in the momentum equation, as a function of local flow and pressure gradient in the time domain. The convective term as well as the approximate friction term are compared to their counterparts obtained from Womersley profiles and show good agreement in the complete range of the Womersley parameter α. In the limiting cases, for Womersley parameters α → 0 and α → ∞, they completely coincide. It is shown that in one-dimensional wave propagation, the friction term based on the newly introduced approximate profile function is important when considering pressure and flow wave propagation in intermediate-sized vessels.

The influence of boundary conditions on wall shear stress distribution in patients specific coronary trees

Patient specific geometrical data on human coronary arteries can be reliably obtained multislice computer tomography (MSCT) imaging. MSCT cannot provide hemodynamic variables, and the outflow through the side branches must be estimated. The impact of two different models to determine flow through the side branches on the wall shear stress (WSS) distribution in patient specific geometries is evaluated. Murrays law predicts that the flow ratio through the side branches scales with the ratio of the diameter of the side branches to the third power. The empirical model is based on flow measurements performed by Doriot et al. (2000) in angiographically normal coronary arteries. The fit based on these measurements showed that the flow ratio through the side branches can best be described with a power of 2.27. The experimental data imply that Murrays law underestimates the flow through the side branches. We applied the two models to study the WSS distribution in 6 coronary artery trees. Under steady flow conditions, the average WSS between the side branches differed significantly for the two models: the average WSS was 8% higher for Murrays law and the relative difference ranged from -5% to +27%. These differences scale with the difference in flow rate. Near the bifurcations, the differences in WSS were more pronounced: the size of the low WSS regions was significantly larger when applying the empirical model (13%), ranging from -12% to +68%. Predicting outflow based on Murrays law underestimates the flow through the side branches. Especially near side branches, the regions where atherosclerotic plaques preferentially develop, the differences are significant and application of Murrays law underestimates the size of the low WSS region.

Dependence of Intramyocardial Pressure and Coronary Flow on Ventricular Loading and Contractility: A Model Study

The phasic coronary arterial inflow during the normal cardiac cycle has been explained with simple (waterfall, intramyocardial pump) models, emphasizing the role of ventricular pressure. To explain changes in isovolumic and low afterload beats, these models were extended with the effect of three-dimensional wall stress, nonlinear characteristics of the coronary bed, and extravascular fluid exchange. With the associated increase in the number of model parameters, a detailed parameter sensitivity analysis has become difficult. Therefore we investigated the primary relations between ventricular pressure and volume, wall stress, intramyocardial pressure and coronary blood flow, with a mathematical model with a limited number of parameters. The model replicates several experimental observations: the phasic character of coronary inflow is virtually independent of maximum ventricular pressure, the amplitude of the coronary flow signal varies about proportionally with cardiac contractility, and intramyocardial pressure in the ventricular wall may exceed ventricular pressure. A parameter sensitivity analysis shows that the normalized amplitude of coronary inflow is mainly determined by contractility, reflected in ventricular pressure and, at low ventricular volumes, radial wall stress. Normalized flow amplitude is less sensitive to myocardial coronary compliance and resistance, and to the relation between active fiber stress, time, and sarcomere shortening velocity.

Plaque and shear stress distribution in human coronary bifurcations: a multislice computed tomography study

AIMS Early atherosclerosis is located in low wall shear-stress (WSS) regions, however plaques are also found in the high WSS sensing flow divider walls of coronary bifurcations. We assessed the plaque distribution and morphology near bifurcations non-invasively with 64-slice computed tomography in relation to the WSS distribution. METHODS AND RESULTS We inspected 65 cross-sections near coronary bifurcations for the presence of plaque. Cross-sections were divided into four equal parts, which we numbered according to expected levels of WSS, with part I the lowest WSS (outer wall) and increasing WSSs in part II (inner bend), III (outer bend) and IV (flow divider). Of the cross-sections 88% had plaque. Of all parts I, 72% contained plaque. This was 62%, 38% and 31% in parts II, III and IV. In cross-sections with only 1 or 2 parts inflicted, plaque was found in part I and/or II in 94%. In 93% of the cross-sections with the flow divider inflicted, parts I and/or II were also inflicted. Plaque was never found exclusively in the flow divider part IV. CONCLUSIONS We demonstrated that plaque is mostly present in low WSS regions, whereas plaque in high WSS regions is accompanied by plaque in adjacent low WSS regions. It is therefore plausible that plaque grows from the outer wall (low WSS) of the bifurcation towards the flow divider (high WSS).

Theoretical models for coronary vascular biomechanics: Progress & challenges

A key aim of the cardiac Physiome Project is to develop theoretical models to simulate the functional behaviour of the heart under physiological and pathophysiological conditions. Heart function is critically dependent on the delivery of an adequate blood supply to the myocardium via the coronary vasculature. Key to this critical function of the coronary vasculature is system dynamics that emerge via the interactions of the numerous constituent components at a range of spatial and temporal scales. Here, we focus on several components for which theoretical approaches can be applied, including vascular structure and mechanics, blood flow and mass transport, flow regulation, angiogenesis and vascular remodelling, and vascular cellular mechanics. For each component, we summarise the current state of the art in model development, and discuss areas requiring further research. We highlight the major challenges associated with integrating the component models to develop a computational tool that can ultimately be used to simulate the responses of the coronary vascular system to changing demands and to diseases and therapies.

A physiologically representative in vitro model of the coronary circulation

With the development of clinical diagnostic techniques to investigate the coronary circulation in conscious humans, the in vitro validation of such newly developed techniques is of major importance. The aim of this study was to develop an in vitro model that is able to mimic the coronary circulation in such a way that coronary pressure and flow signals under baseline as well as hyperaemic conditions are approximated as realistically as possible and are in accordance with recently gained insights into such signals in conscious man. In the present in vitro model the heart, the systemic and coronary circulation are modelled on the basis of the elements of a lumped parameter mathematical model only consisting of elements that can be represented by segments in an experimental set-up. A collapsible tube, collapsed by the ventricular pressure, represents the variable resistance and volume behaviour of the endocardial part of the myocardium. The pressure and flow signals obtained are similar to physiological human coronary pressure and flow, both for baseline and hyperaemic conditions. The model allows for in vitro evaluation of clinical diagnostic techniques.