Morton H. Friedman

Effects of cardiac motion on right coronary artery hemodynamics.

AbstractThe purpose of this work was to investigate the effects of physiologically realistic cardiac-induced motion on hemodynamics in human right coronary arteries. The blood flow patterns were numerically simulated in a modeled right coronary artery (RCA) having a uniform circular cross section of 2.48 mm diam. Arterial motion was specified based on biplane cineangiograms, and incorporated physiologically realistic bending and torsion. Simulations were carried out with steady and pulsatile inflow conditions (mean ReD=233, α =1.82) in both fixed and moving RCA models, to evaluate the relative importance of RCA motion, flow pulsation, and the interaction between motion and flow pulsation. RCA motion with a steady inlet flow rate caused variations in wall shear stress (WSS) magnitude up to 150% of the inlet Poiseuille value. There was significant spatial variability in the magnitude of this motion-induced WSS variation. However, the time-averaged WSS distribution was similar to that predicted in a static model representing the time-averaged geometry. Furthermore, the effects of flow pulsatility dominated RCA motion-induced effects; specifically, there were only modest differences in the WSS history between simulations conducted in fixed and moving RCA models with pulsatile inflow. RCA motion has little effect on time-averaged WSS patterns. It has a larger effect on the temporal variation of WSS, but even this effect is overshadowed by the variations in WSS due to flow pulsation. The hemodynamic effects of RCA motion can, therefore, be ignored as a first approximation in modeling studies.

Coronary Artery Dynamics In Vivo

AbstractThere is considerable evidence that the localization and evolution of vascular disease are mediated, at least in part, by mechanical factors. The mechanical environment of the coronary arteries, which are tethered to the beating heart, is influenced by cardiac motion; the motion of the vessels must be described quantitatively to characterize fully the mechanical forces acting on and in the vessel wall. Several techniques that have been used to characterize coronary artery dynamics from biplane cineangiograms are described and illustrated. There is considerable variability in dynamic geometric parameters from site to site along a vessel, between the right and left anterior descending arteries, and among individuals, consistent with the hypotheses that variations in stresses mediated by geometry and dynamics affect the localization of atherosclerosis and individual risk of coronary heart disease. The few frankly atherosclerotic vessels that have been examined exhibit high torsions in the neighborhood of lesions, an observation which may have etiologic or diagnostic implications.

Relationship Between the Dynamic Geometry and Wall Thickness of a Human Coronary Artery

Objective—It is widely recognized that hemodynamic and wall mechanical forces are involved in the initiation and development of atherosclerosis. In the coronary vasculature, these forces are likely mediated by arterial dynamics and geometry. This research examines the hypothesis that coronary artery motion and geometry affect the local predisposition to disease, presumably through their influence on the stresses at and in the artery wall. Methods and Results—The dynamics of a human right coronary artery and the variation of wall thickness along its length were characterized from biplane cineangiograms and intravascular ultrasound records, respectively. The dynamic geometry parameters were distance along the vessel, cyclic displacement, axial strain, curvature, and torsion. Multiple regression analyses using principal components show that (1) no single dynamic geometry parameter has a dominant influence on wall thickness, (2) linear combinations of such parameters predict wall thickness measures with high confidence (P <0.001; R2 between 0.17 and 0.44), and (3) both the time-average values of curvature and torsion and their excursion during the cardiac cycle are positively correlated with maximum wall thickness and cross-sectional asymmetry. Conclusions—The relationships seen here support the hypothesis that dynamic geometry plays a role in the localization of early coronary artery thickening.

In vivo differences between endothelial transcriptional profiles of coronary and iliac arteries revealed by microarray analysis.

Endothelial cells (ECs) from different vascular beds display a remarkable heterogeneity in both structure and function. Phenotypic heterogeneity among arterial ECs is particularly relevant to atherosclerosis since the disease occurs predominantly in major arteries, which vary in their atherosusceptibility. To explore EC heterogeneity between typical atheroprone and atheroresistant arteries, we used DNA microarrays to compare gene expression profiles of freshly harvested porcine coronary (CECs) and iliac artery (IECs) ECs. Statistical analysis revealed 51 genes that were differentially expressed in CECs relative to IECs at a false discovery rate of 5%. Seventeen of these genes are known to be involved in atherogenesis. Consistent with coronary arteries being more atherosusceptible, almost all putative atherogenic genes were overexpressed in CECs, whereas all atheroprotective genes were downregulated, relative to IECs. A subset of the identified genes was validated by quantitative polymerase chain reaction (PCR). PCR results suggest that the differences in expression levels between CECs and IECs for the HOXA10 and HOXA9 genes were >100-fold. Gene ontology (GO) and biological pathway analysis revealed a global expression difference between CECs and IECs. Genes in twelve GO categories, including complement immune activation, immunoglobulin-mediated response, and system development, were significantly upregulated in CECs. CECs also overexpressed genes involved in several inflammatory pathways, including the classical pathway of complement activation and the IGF-1-mediated pathway. The in vivo transcriptional differences between CECs and IECs found in this study may provide new insights into the factors responsible for coronary artery atherosusceptibility.

Environment and vascular bed origin influence differences in endothelial transcriptional profiles of coronary and iliac arteries

Atherosclerotic plaques tend to form in the major arteries at certain predictable locations. As these arteries vary in atherosusceptibility, interarterial differences in endothelial cell biology are of considerable interest. To explore the origin of differences observed between typical atheroprone and atheroresistant arteries, we used DNA microarrays to compare gene expression profiles of harvested porcine coronary (CECs) and iliac artery endothelial cells (IECs) grown in static culture out to passage 4. Fewer differences were observed between the transcriptional profiles of CECs and IECs in culture compared with in vivo, suggesting that most differences observed in vivo were due to distinct environmental cues in the two arteries. One-class significance of microarrays revealed that most in vivo interarterial differences disappeared in culture, as fold differences after passaging were not significant for 85% of genes identified as differentially expressed in vivo at 5% false discovery rate. However, the three homeobox genes, HOXA9, HOXA10, and HOXD3, remained underexpressed in coronary endothelium for all passages by at least nine-, eight-, and twofold, respectively. Continued differential expression, despite removal from the in vivo environment, suggests that primarily heritable or epigenetic mechanism(s) influences transcription of these three genes. Quantitative real-time polymerase chain reaction confirmed expression ratios for seven genes associated with atherogenesis and over- or underexpressed by threefold in CECs relative to IECs. The present study provides evidence that both local environment and vascular bed origin modulate gene expression in arterial endothelium. The transcriptional differences observed here may provide new insights into pathways responsible for coronary artery susceptibility.

Adaptive response of vascular endothelial cells to an acute increase in shear stress frequency

The adaptation of vascular endothelial cells to shear stress alteration induced by global hemodynamic changes, such as those accompanying exercise or digestion, is an essential component of normal endothelial physiology in vivo. An understanding of the transient regulation of endothelial phenotype during adaptation to changes in mural shear will advance our understanding of endothelial biology and may yield new insights into the mechanism of atherogenesis. In this study, we characterized the adaptive response of arterial endothelial cells to an acute increase in shear stress magnitude in well-defined in vitro settings. Porcine endothelial cells were preconditioned by a basal level shear stress of 15 ± 15 dyn/cm(2) at 1 Hz for 24 h, after which an acute increase in shear stress to 30 ± 15 dyn/cm(2) was applied. Endothelial permeability nearly doubled after 40-min exposure to the elevated shear stress and then decreased gradually. Transcriptomics studies using microarray techniques identified 86 genes that were sensitive to the elevated shear. The acute increase in shear stress promoted the expression of a group of anti-inflammatory and antioxidative genes. The adaptive response of the global gene expression profile is triphasic, consisting of an induction period, an early adaptive response (ca. 45 min) and a late remodeling response. Our results suggest that endothelial cells exhibit a specific phenotype during the adaptive response to changes in shear stress; this phenotype is different than that of fully adapted endothelial cells.

Interaction of wall shear stress magnitude and gradient in the prediction of arterial macromolecular permeability.

Large spatial shear stress gradients have anecdotally been associated with early atherosclerotic lesion susceptibility in vivo and have been proposed as promoters of endothelial cell dysfunction in vitro. Here, experiments are presented in which several measures of the fluid dynamic shear stress, including its gradient, at the walls of in vivo porcine iliac arteries, are correlated against the transendothelial macromolecular permeability of the vessels. The fluid dynamic measurements are based on postmortem vascular casts, and permeability is measured from Evans blue dye (EBD) uptake. Time-averaged wall shear stress (WSS), as well as a new parameter termed maximum gradient stress (MGS) that describes the spatial shear stress gradient due to flow acceleration at a given point, are mapped for each artery and compared on a point-by-point basis to the corresponding EBD patterns. While there was no apparent relation between MGS and EBD uptake, a composite parameter, WSS–0.11 MGS0.044, was highly correlated with permeability. Notwithstanding the small exponents, the parameter varied widely within the region of interest. The results suggest that sites exposed to low wall shear stresses are more likely to exhibit elevated permeability, and that this increase is exacerbated in the presence of large spatial shear stress gradients.

Retrieval of cardiac phase from IVUS sequences

Most of the quantitative measures from Intravascular Ultrasound (IVUS) images vary with the cardiac cycle. Although ECG-gated acquisition can prevent the pulsations from influencing the measurements, it may extend the acquisition time, and furthermore, very few IVUS systems currently in clinical use incorporate ECG-gated function. In this paper, we present a practical method to retrieve cardiac phase information directly from in vivo clinical IVUS image sequences. In an IVUS image that contains a cross-section of coronary artery, there are three regions annularly distributed from the center of the image - catheter, lumen, and part of the vessel wall. The catheter region exhibits virtually no change from frame to frame during the catheter pullback. While the lumen is a dark region, the vessel wall region appears bright. The change in lumen size and position that accompanies the pulse causes the image intensity of the IVUS images to exhibit a periodic variation along the pullback path. By extracting this signal attributed to the cardiac cycle, a subsequence of frames during pullback at the same phase of the cardiac cycle can be selected. The method was tested by the IVUS images of both a coronary phantom and a patient.

Correlation Among Shear Rate Measures in Vascular Flows

A variety of shear rate measures have been calculated from hemodynamic data obtained by laser Doppler anemometry in flow-through casts of human aortic bifurcations. Included are measures sensitive to the mean and amplitude of the shear rate, its maximum rate of change, the duration of stasis and flow reversal near the wall, and the unidirectionality of the flow. Many of these measures are highly correlated with one another. This suggests that that it will be difficult to identify from in vivo measurements those aspects of the flow field to which the vessel wall is most sensitive. It may be possible to separate the effects of purely temporal factors (e.g., the duration of flow reversal) from those related to wall shear stress.

Comparison of coronary artery dynamics pre- and post-stenting

Stents have dramatically improved the treatment of coronary artery disease. Since the implantation of stents changes the geometry and dynamics of the coronary artery, it is reasonable to hypothesize that some of these changes may have an important effect on the development of atherosclerosis by modulating the mechanical environment. In this paper, we presented a method to compare the geometric dynamics of the coronary artery before and after stenting using biplane angiography. Two cases are reviewed and a number of parameters are proposed to describe the longitudinal change of the vessel before and after stenting. This analysis technique has the potential to identify some aspects of stent design and procedure that might improve the success rate with this therapeutic approach.