Low-density lipoprotein concentration in the normal left coronary artery tree

Background

The blood flow and transportation of molecules in the cardiovascular system plays a crucial role in the genesis and progression of atherosclerosis. This computational study elucidates the Low Density Lipoprotein (LDL) site concentration in the entire normal human 3D tree of the LCA.

Methods

A 3D geometry model of the normal human LCA tree is constructed. Angiographic data used for geometry construction correspond to end-diastole. The resulted model includes the LMCA, LAD, LCxA and their main branches. The numerical simulation couples the flow equations with the transport equation applying realistic boundary conditions at the wall.

Results

High concentration of LDL values appears at bifurcation opposite to the flow dividers in the proximal regions of the Left Coronary Artery (LCA) tree, where atherosclerosis frequently occurs. The area-averaged normalized luminal surface LDL concentrations over the entire LCA tree are, 1.0348, 1.054 and 1.23, for the low, median and high water infiltration velocities, respectively. For the high, median and low molecular diffusivities, the peak values of the normalized LDL luminal surface concentration at the LMCA bifurcation reach 1.065, 1.080 and 1.205, respectively. LCA tree walls are exposed to a cholesterolemic environment although the applied mass and flow conditions refer to normal human geometry and normal mass-flow conditions.

Conclusion

The relationship between WSS and luminal surface concentration of LDL indicates that LDL is elevated at locations where WSS is low. Concave sides of the LCA tree exhibit higher concentration of LDL than the convex sides. Decreased molecular diffusivity increases the LDL concentration. Increased water infiltration velocity increases the LDL concentration. The regional area of high luminal surface concentration is increased with increasing water infiltration velocity. Regions of high LDL luminal surface concentration do not necessarily co-locate to the sites of lowest WSS. The degree of elevation in luminal surface LDL concentration is mostly affected from the water infiltration velocity at the vessel wall. The paths of the velocities in proximity to the endothelium might be the most important factor for the elevated LDL concentration.     

Flow patterns in three-dimensional porcine epicardial coronary arterial tree

The branching pattern of epicardial coronary arteries is clearly three-dimensional, with correspondingly complex flow patterns. The objective of the present study was to perform a detailed hemodynamic analysis using a three-dimensional finite element method in a left anterior descending (LAD) epicardial arterial tree, including main trunk and primary branches, based on computed tomography scans. The inlet LAD flow velocity was measured in an anesthetized pig, and the outlet pressure boundary condition was estimated based on scaling laws. The spatial and temporal wall shear stress (WSS), gradient of WSS (WSSG), and oscillatory shear index (OSI) were calculated and used to identify regions of flow disturbances in the vicinity of primary bifurcations. We found that low WSS and high OSI coincide with disturbed flows (stagnated, secondary, and reversed flows) opposite to the flow divider and lateral to the junction orifice of the main trunk and primary branches. High time-averaged WSSG occurs in regions of bifurcations, with the flow divider having maximum values. Low WSS and high OSI were found to be related through a power law relationship. Furthermore, zones of low time-averaged WSS and high OSI amplified for larger diameter ratio and high inlet flow rate. Hence, different focal atherosclerotic-prone regions may be explained by different physical mechanism associated with certain critical levels of low WSS, high OSI, and high WSSG, which are strongly affected by the diameter ratio. The implications of the flow patterns for atherogenesis are enumerated.     

Hemodynamic impacts of various types of stenosis in the left coronary artery bifurcation: A patient-specific analysis

This study investigates the hemodynamic changes to various types of coronary stenosis in the left coronary artery bifurcation, based on a patient-specific analysis. Twenty two patients with left coronary artery disease were included in this study. All stenoses involving the left coronary artery bifurcation were classified into four types, according to their locations: A) left circumflex (LCx) and left anterior descending (LAD), B) LCx only, C) left main stem only, and D) LAD only. Computational fluid dynamics (CFD) was performed to analyze the flow and wall shear stress (WSS) changes in all reconstructed left coronary geometries. Our results showed that the flow velocity and WSS were significantly increased at stenotic locations. High WSS was found at >70% lumen stenosis, which ranged from 2.5 Pa to 3.5 Pa. This study demonstrates that in patients with more than 50% stenosis in the left coronary artery bifurcation, WSS plays an important role in providing information about the extent of coronary atherosclerosis in the left coronary artery branch.     

Which diameter and angle rule provides optimal flow patterns in a coronary bifurcation?

The branching angle and diameter ratio in epicardial coronary artery bifurcations are two important determinants of atherogenesis. Murray's cubed diameter law and bifurcation angle have been assumed to yield optimal flows through a bifurcation. In contrast, we have recently shown a 7/3 diameter law (HK diameter model), based on minimum energy hypothesis in an entire tree structure. Here, we derive a bifurcation angle rule corresponding to the HK diameter model and critically evaluate the streamline flow through HK and Murray-type bifurcations. The bifurcations from coronary casts were found to obey the HK diameter model and angle rule much more than Murray's model. A finite element model was used to investigate flow patterns for coronary artery bifurcations of various types. The inlet velocity and pressure boundary conditions were measured by ComboWire. Y-bifurcation of Murray type decreased wall shear stress-WSS (10%-40%) and created an increased oscillatory shear index-OSI in atherosclerosis-prone regions as compared with HK-type bifurcations. The HK-type bifurcations were found to have more optimal flow patterns (i.e., higher WSS and lower OSI) than Murray-type bifurcations which have been traditionally believed to be optimized. This study has implications for changes in bifurcation angles and diameters in percutaneous coronary intervention.     

Cellular distribution of immunoreactive urotensin-II in human tissues with evidence of increased expression in atherosclerosis and a greater constrictor response of small compared to large coronary arteries

We detected urotensin-II-like immunoreactivity in the endothelium of normal human blood vessels from heart, kidney, placenta, adrenal, thyroid and umbilical cord. Immunoreactivity was also detected in endocardial endothelial and kidney epithelial cells. In atherosclerotic coronary artery, immunoreactivity localized to regions of macrophage infiltration. Urotensin-II constricted human atherosclerotic epicardial coronary arteries with pD2=10.58 +/- 0.46 (mean +/- S.E.M.) and Emax=11.4 +/- 4.2% KCl and small coronary arteries with pD2=9.25 +/- 0.38 and Emax=77 +/- 16% KCl. Small coronary arteries clearly exhibited a greater maximum response to urotensin-II than epicardial vessels. This enhanced responsiveness may be of importance in heart failure, where circulating concentrations of U-II are increased, or in atherosclerosis where focally up-regulated urotensin-II production may act down stream to produce significant vasospasm, compromising blood flow to the myocardium. We conclude that urotensin-II is a locally released vasoactive mediator that may be an important regulator of blood flow particularly to the myocardium and may have a specific role in human atherosclerosis.     

Non-Newtonian Blood Flow in Left Coronary Arteries with Varying Stenosis: A Comparative Study

This paper presents Computational fluid dynamic (CFD) analysis of blood flow in three different 3-D models of left coronary artery (LCA). A comparative study of flow parameters (pressure distribution, velocity distribution and wall shear stress) in each of the models is done for a non-Newtonian (Carreau) as well as the Newtonian nature of blood viscosity over a complete cardiac cycle. The difference between these two types of behavior of blood is studied for both transient and steady states of flow. Additionally, flow parameters are compared for steady and transient boundary conditions considering blood as non-Newtonian fluid. The study shows that the highest wall shear stress (WSS), velocity and pressure are found in artery having stenosis in all the three branches of LCA. The use of Newtonian blood model is a good approximation for steady as well as transient blood flow boundary conditions if shear rate is above 100 s-1. However, the assumption of steady blood flow results in underestimating the values of flow parameters such as wall shear stress, pressure and velocity.     

Effects of thromboxane analog U46619 on endothelial damaged canine coronary arteries in vivo

We studied the effects of the thromboxane analog, U46619, infused into the left anterior descending (LAD) artery of intact dogs before and after producing endothelial denudation of the mid portion of the LAD. Proximal artery cross-sectional area (CSA) decreased by 47% with 0.1 microgram/min infusion of U46619 with intact and denuded endothelium, while resting CSA reduced spontaneously following denudation. Coronary resistance vessels demonstrated a marked constrictor response to U46619 with a rise in resistance and a fall in flow and myocardial O2 consumption. U46619 produces significant narrowing of proximal epicardial coronary arteries as well as resistance coronary vessels. This effect could cause ischemia in patients with moderate coronary atherosclerosis.     

Numerical simulation of pulsatile flow in a compliant curved tube model of a coronary artery

The endothelial cells (ECs) lining a blood vessel wall are exposed to both the wall shear stress (WSS) of blood flow and the circumferential strain (CS) of pulsing artery wall motion. These two forces and their interaction are believed to play a role in determining remodeling of the vessel wall and development of arterial disease (atherosclerosis). This study focused on the WSS and CS dynamic behavior in a compliant model of a coronary artery taking into account the curvature of the bending artery and physiological radial wall motion. A three-dimensional finite element model with transient flow and moving boundaries was set up to simulate pulsatile flow with physiological pressure and flow wave forms characteristic of the coronary arteries. The characteristic coronary artery curvature and flow conditions applied to the simulation were: aspect ratio (lambda) = 10, diameter variation (DV) = 6 percent, mean Reynolds number (Re) = 150, and unsteadiness parameter (alpha) = 3. The results show that mean WSS is about 50 percent lower on the inside wall than the outside wall while WSS oscillation is stronger on the inside wall. The stress phase angle (SPA) between CS and WSS, which characterizes the dynamics of the mechanical force pattern applied to the endothelial cell layer, shows that CS and WSS are more out of phase in the coronaries than in any other region of the circulation (-220 deg on the outside wall, -250 deg on the inside wall). This suggests that in addition to WSS, SPA may play a role in localization of coronary atherosclerosis.     

Use and limitations of magnetic resonance phase-contrast assessment of coronary flow reserve in a model of collateral dependence

Phase-contrast magnetic resonance imaging (PC-MRI) is useful for assessing coronary artery flow reserves (CFR) in man and acute animal models with intermediate coronary lesions. The present study examines the use of PC-MRI for assessing CFR in a model with critical stenosis and collateral dependence. PC-MRI quantitative flow measurements from the proximal left anterior descending (LAD) and left circumflex (LCX) coronary arteries were compared with myocardial tissue perfusion reserve measurements (microsphere techniques) after placement of a 2.25-mm ameroid constrictor on the proximal LCX in a porcine model; measurements were obtained at implantation (n = 4) and at 3 to 4 weeks (n = 4) and 6 weeks (n = 5) postimplantation. CFR is defined as the ratio of maximal hyperemic flow to baseline flow. Hyperemia was induced using intravenous adenosine (140 mg/kg/min). Collateral dependence in the LCX distri bution was evidenced by angiographic findings of critical stenosis with minimal myocardial histological changes and normal baseline myocardial perfusion (microsphere techniques). In this setting, PC-MRI CFR was correlated with microsphere measures of perfusion reserve. Collateral dependence was confirmed by Evan's blue dye injection. This study provides angiographic, myocardial perfusion, and histological correlates associated with PC-MRI epicardial CFR changes during chronic, progressive coronary artery constriction. It also demonstrates the disparity between epicardial and myocardial measures of coronary flow reserve with collateral dependence and the caveats for PC-MRI use in models of progressive coronary constriction.     

Effects of vessel compliance on flow pattern in porcine epicardial right coronary arterial tree

The compliance of the vessel wall affects hemodynamic parameters which may alter the permeability of the vessel wall. Based on experimental measurements, the present study established a finite element (FE) model in the proximal elastic vessel segments of epicardial right coronary arterial (RCA) tree obtained from computed tomography. The motion of elastic vessel wall was measured by an impedance catheter and the inlet boundary condition was measured by an ultrasound flow probe. The Galerkin FE method was used to solve the Navier–Stokes and Continuity equations, where the convective term in the Navier–Stokes equation was changed in the arbitrary Lagrangian–Eulerian (ALE) framework to incorporate the motion due to vessel compliance. Various hemodynamic parameters (e.g., wall shear stress—WSS, WSS spatial gradient—WSSG, oscillatory shear index—OSI) were analyzed in the model. The motion due to vessel compliance affects the time-averaged WSSG more strongly than WSS at bifurcations. The decrease of WSSG at flow divider in elastic bifurcations, as compared to rigid bifurcations, implies that the vessel compliance decreases the permeability of vessel wall and may be atheroprotective. The model can be used to predict coronary flow pattern in subject-specific anatomy as determined by noninvasive imaging.     

Myocardial bridging and endothelial dysfunction – Computational fluid dynamics study

Myocardial bridging (MB) is associated with endothelial dysfunction in patients with angina and non-obstructive coronary artery disease. This study aims to determine if there is a link between abnormal blood flow patterns and endothelial dysfunction in patients with MB. Ten patients with MB in their left anterior descending (LAD) artery were selected, 5 of whom had endothelial dysfunction and 5 had no endothelial dysfunction based on their response to acetylcholine. Similarly, 10 patients without MB in their LAD, 5 of whom had endothelial dysfunction and 5 of whom had no endothelial dysfunction, were studied as a control group. Transient computational fluid dynamics simulations were performed to derive wall shear stress (WSS) over the entire vessel including proximal, middle and distal segments. Patients with MB and endothelial dysfunction had lower WSS in the proximal LAD and greater WSS in the mid-LAD than patients with MB but without endothelial dysfunction. When comparing patients with endothelial dysfunction, those with MB had significantly lower shear stress in the proximal LAD (0.32 ± 0.14 Pa (with MB) vs 0.71 ± 0.38 Pa (without MB), p = 0.01) and greater shear stress in the mid-LAD (2.81 ± 1.20 Pa (with MB) vs 1.66 ± 0.31 Pa (without MB), p = 0.014) than patients without MB. Our findings demonstrated that the presence of MB significantly contributes to low WSS and endothelial dysfunction relationship.     

Alterations in wall shear stress predict sites of neointimal hyperplasia after stent implantation in rabbit iliac arteries

Restenosis resulting from neointimal hyperplasia (NH) limits the effectiveness of intravascular stents. Rates of restenosis vary with stent geometry, but whether stents affect spatial and temporal distributions of wall shear stress (WSS) in vivo is unknown. We tested the hypothesis that alterations in spatial WSS after stent implantation predict sites of NH in rabbit iliac arteries. Antegrade iliac artery stent implantation was performed under angiography, and blood flow was measured before casting 14 or 21 days after implantation. Iliac artery blood flow domains were obtained from three-dimensional microfocal X-ray computed tomography imaging and reconstruction of the arterial casts. Indexes of WSS were determined using three-dimensional computational fluid dynamics. Vascular histology was unchanged proximal and distal to the stent. Time-dependent NH was localized within the stented region and was greatest in regions exposed to low WSS and acute elevations in spatial WSS gradients. The lowest values of WSS spatially localized to the stented area of a theoretical artery progressively increased after 14 and 21 days as NH occurred within these regions. This NH abolished spatial disparity in distributions of WSS. The results suggest that stents may introduce spatial alterations in WSS that modulate NH in vivo.     

Adolescent with occluded left main coronary artery

Here we report unexpected findings in a 17-year-old female patient referred for coronary angiography and percutaneous intervention. During the angiography we observed a complete occlusion of the left main coronary artery (LMCA).The occurrence of coronary abnormalities at this age is extremely rare and mostly caused by congenital abnormalities. The diagnosis of premature atherosclerosis at this age is unlikely unless the patient suffers from severe lipoprotein disease. Here we describe a rare case of LMCA occlusion, the most likely cause of the disease and the potential implications for therapy.     

Influence of non-Newtonian properties of blood on the wall shear stress in human atherosclerotic right coronary arteries

The objective of this work is to investigate the effect of non-Newtonian properties of blood on the wall shear stress (WSS) in atherosclerotic coronary arteries using both Newtonian and non-Newtonian models. Numerical simulations were performed to examine how the spatial and temporal WSS distributions are influenced by the stenosis size, blood viscosity, and flow rate. The computational results demonstrated that blood viscosity properties had considerable effect on the magnitude of the WSS, especially where disturbed flow was observed. The WSS distribution is highly non-uniform both temporally and spatially, especially in the stenotic region. The maximum WSS occurred at the proximal side of the stenosis, near the outer wall in the curved artery with no stenosis. The lumen area near the inner wall distal to the stenosis region experienced a lower WSS during the entire cardiac cycle. Among the factors of stenosis size, blood viscosity, and flow rate, the size of the stenosis has the most significant effect on the spatial and temporal WSS distributions qualitatively and quantitatively.     

Influence of the Accuracy of Angiography-Based Reconstructions on Velocity and Wall Shear Stress Computations in Coronary Bifurcations: A Phantom Study

Introduction

Wall shear stress (WSS) plays a key role in the onset and progression of atherosclerosis in human coronary arteries. Especially sites with low and oscillating WSS near bifurcations have a higher propensity to develop atherosclerosis. WSS computations in coronary bifurcations can be performed in angiography-based 3D reconstructions. It is essential to evaluate how reconstruction errors influence WSS computations in mildly-diseased coronary bifurcations. In mildly-diseased lesions WSS could potentially provide more insight in plaque progression.

Materials Methods

Four Plexiglas phantom models of coronary bifurcations were imaged with bi-plane angiography. The lumens were segmented by two clinically experienced readers. Based on the segmentations 3D models were generated. This resulted in three models per phantom: one gold-standard from the phantom model itself, and one from each reader. Steady-state and transient simulations were performed with computational fluid dynamics to compute the WSS. A similarity index and a noninferiority test were used to compare the WSS in the phantoms and their reconstructions. The margin for this test was based on the resolution constraints of angiography.

Results

The reconstruction errors were similar to previously reported data; in seven out of eight reconstructions less than 0.10 mm. WSS in the regions proximal and far distal of the stenosis showed a good agreement. However, the low WSS areas directly distal of the stenosis showed some disagreement between the phantoms and the readers. This was due to small deviations in the reconstruction of the stenosis that caused differences in the resulting jet, and consequently the size and location of the low WSS area.

Discussion

This study showed that WSS can accurately be computed within angiography-based 3D reconstructions of coronary arteries with early stage atherosclerosis. Qualitatively, there was a good agreement between the phantoms and the readers. Quantitatively, the low WSS regions directly distal to the stenosis were sensitive to small reconstruction errors.     

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. Murray's 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 Murray's 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 Murray's 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 Murray's 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 Murray's law underestimates the size of the low WSS region.     

Analysis of blood flow in an out-of-plane CABG model

Coronary artery bypass graft (CABG) is a routine surgical treatment for ischemic and infarcted myocardium. A large number of CABG fail postoperatively because of intimal hyperplasia within months or years. The cause of this failure is thought to be partly related to the flow patterns and shear stresses acting on the endothelial cells. An accurate representation of the flow field and associated wall shear stress (WSS) requires a detailed three-dimensional (3D) model of the CABG. The purpose of this study is to present a detailed analysis of blood flow in a 3D aorto/left CABG, bypassing the occluded left anterior descending coronary (LAD) artery. The analysis takes into account the influence of the out-of-plane geometry of the graft. The finite volume technique was employed to model the 3D blood flow pattern to determine the velocity and WSS distributions. This study presents the flow field distributions of the velocity and WSS at four instances of the cardiac cycle, two in systole and two in diastole. Our results reveal that the CABG geometry has a significant effect on the velocity distribution. The axial velocity profiles at different instances of the cardiac cycle exhibit strong skewing; significant secondary flow and vortex structures are seen in the in-plane velocity patterns. The maximum WSS on the bed of the occluded LAD artery opposite to the graft junction is 14 Pa in middiastole, whereas there is a significantly lower and more uniform distribution of WSS on the bed of the anastomosis. The present results indicate that nonplanarity of the blood vessel along with the inflow conditions has a substantial effect on the fluid mechanics of CABG that contribute to the patency of graft.     

Analysis of blood flow in the entire coronary arterial tree

A hemodynamic analysis of coronary blood flow must be based on the measured branching pattern and vascular geometry of the coronary vasculature. We recently developed a computer reconstruction of the entire coronary arterial tree of the porcine heart based on previously measured morphometric data. In the present study, we carried out an analysis of blood flow distribution through a network of millions of vessels that includes the entire coronary arterial tree down to the first capillary branch. The pressure and flow are computed throughout the coronary arterial tree based on conservation of mass and momentum and appropriate pressure boundary conditions. We found a power law relationship between the diameter and flow of each vessel branch. The exponent is approximately 2.2, which deviates from Murray's prediction of 3.0. Furthermore, we found the total arterial equivalent resistance to be 0.93, 0.77, and 1.28 mmHg.ml(-1).s(-1).g(-1) for the right coronary artery, left anterior descending coronary artery, and left circumflex artery, respectively. The significance of the present study is that it yields a predictive model that incorporates some of the factors controlling coronary blood flow. The model of normal hearts will serve as a physiological reference state. Pathological states can then be studied in relation to changes in model parameters that alter coronary perfusion.     

Progressive epicardial coronary blood flow reduction fails to produce ST-segment depression at normal heart rates

ST-segment depression is commonly seen in patients with acute coronary syndromes. Most authors have attributed it to transient reductions in coronary blood flow due to nonocclusive thrombus formation on a disrupted atherosclerotic plaque and dynamic focal vasospasm at the site of coronary artery stenosis. However, ST-segment depression was never reproduced in classic animal models of coronary stenosis without the presence of tachycardia. We hypothesized that ST-segment depression occurring during acute coronary syndromes is not entirely explained by changes in epicardial coronary artery resistance and thus evaluated the effect of a slow, progressive epicardial coronary artery occlusion on the ECG and regional myocardial blood flow in anesthetized pigs. Slow, progressive occlusion over 72 min (SD 27) of the left anterior descending coronary artery in 20 anesthetized pigs led to a 90% decrease in coronary blood flow and the development of ST-segment elevation associated with homogeneous and transmural myocardial blood flow reductions, confirmed by microspheres and myocardial contrast echocardiography. ST-segment depression was not observed in any ECG lead before the development of ST-segment elevation. At normal heart rates, progressive epicardial stenosis of a coronary artery results in myocardial ischemia associated with homogeneous, transmural reduction in regional myocardial blood flow and ST-segment elevation, without preceding ST-segment depression. Thus, in coronary syndromes with ST-segment depression and predominant subendocardial ischemia, factors other than mere increases in epicardial coronary resistance must be invoked to explain the heterogeneous parietal distribution of flow and associated ECG changes.     

Scanning electron microscopy substantiates histology in showing the inadequacy of the existing theories on the development of the proximal coronary arteries and their connections with the arterial trunks

Development of proximal coronary arterial segments and coronary arterial orifices was studied by scanning electron microscopy in 20 rat embryos and by light microscopy in serial sections of 20 human and another 18 rat embryos. Neither by scanning electron microscopy nor by light microscopy did we observe more than two coronary arterial orifices. These coronary orifices were always situated in the sinuses of the aorta that faced the pulmonary artery. In the human embryos the coronary orifices emerged between 37-39 days of gestation (16-19 mm crown-rump length, Streeter horizon XVIII-XIX) and were invariably present beyond 39 days (19 mm crown-rump length, Streeter horizon XIX). In rat embryos, the coronary orifices emerged in both scanning electron microscopy and light microscopy at 15-17 days of gestation (13-17 mm crown-rump length) and were invariably present beyond 17 days (17 mm crown-rump length). In both human and rat embryos, either by scanning electron microscopy and light microscopy, the left coronary orifice was observed significantly earlier. In all the investigated embryos, human as well as rat, septation at arterial orifice level was complete, including the earliest stages studied. Light microscopy showed that at the emerging stages of the coronary orifices, the proximal epicardial segments of the left and right coronary arteries could already be identified in a peritruncal ring of epicardial vasculature, before the coronary orifice was observed. This was the case in human as well as in rat embryos. Thus, a coronary orifice was never seen in the absence of a proximal coronary artery. The present theories on development of the proximal coronary arteries and coronary orifices do not offer an adequate explanation for either these data or the known possible congenital abnormalities of the coronary arteries. Our study supports dual proximal coronary arterial development. These two proximal coronary arteries develop out of a peritruncal ring of vascular structures on to the aorta. The process by which the coronary orifices actually develop remains to be explained.