David S. Molony

An assessment of intra-patient variability on observed relationships between wall shear stress and plaque progression in coronary arteries.

BackgroundWall shear stress (WSS) has been associated with sites of plaque localization and with changes in plaque composition in human coronary arteries. Different values have been suggested for categorizing WSS as low, physiologic or high; however, uncertainties in flow rates, both across subjects and within a given individual, can affect the classification of WSS and thus influence the observed relationships between local hemodynamics and plaque changes over time. This study examines the effects of uncertainties in flow rate boundary conditions upon WSS values and investigates the influence of this variability on the observed associations of WSS with changes in VH-IVUS derived plaque components.MethodsThree patients with coronary artery disease underwent baseline and 12 month follow-up angiography and virtual histology-intravascular ultrasound (VH-IVUS) measurements. Coronary artery models were reconstructed from the data and models with and without side-branches were created. Patient-specific Doppler ultrasound (DUS) data were employed as inflow boundary conditions and computational fluid dynamics was used to calculate the WSS in each model. Further, the influence of representative coronary artery flow waveforms upon WSS values was investigated and the concept of treating WSS using relative, rather than actual, values was explored.ResultsModels that included side-branch outflows and subject-specific DUS velocities were considered to be the reference cases. Hemodynamic differences were caused by the exclusion of side-branches and by imposing alternative velocity waveforms. One patient with fewer side-branches and a scaled generic waveform had little deviation from the reference case, while another patient with several side-branches excluded showed much larger departures from the reference situation. Differences between models and the respective reference cases were reduced when data were analyzed using relative, rather than actual, WSS.ConclusionsWhen considering individual subjects, large variations in patient-specific flow rates and exclusion of multiple side-branches in computational models can cause significant differences in observed associations between plaque evolution and ranges of computed WSS. These differences may contribute to the large variability typically found among subjects in pooled populations. Relative WSS may be more useful than actual WSS as a correlative variable when there is a large degree of uncertainty in flow rate data.

Oscillatory wall shear stress is a dominant flow characteristic affecting lesion progression patterns and plaque vulnerability in patients with coronary artery disease

Although experimental studies suggest that low and oscillatory wall shear stress (WSS) promotes plaque transformation to a more vulnerable phenotype, this relationship has not been examined in human atherosclerosis progression. Thus, the aim of this investigation was to examine the association between oscillatory WSS, in combination with WSS magnitude, and coronary atherosclerosis progression. We hypothesized that regions of low and oscillatory WSS will demonstrate progression towards more vulnerable lesions, while regions exposed to low and non-oscillatory WSS will exhibit progression towards more stable lesions. Patients (n = 20) with non-flow-limiting coronary artery disease (CAD) underwent baseline and six-month follow-up angiography, Doppler velocity and radiofrequency intravascular ultrasound (VH-IVUS) acquisition. Computational fluid dynamics models were constructed to compute time-averaged WSS magnitude and oscillatory WSS. Changes in VH-IVUS-defined total plaque and constituent areas were quantified in focal regions (i.e. sectors; n = 14 235) and compared across haemodynamic categories. Compared with sectors exposed to low WSS magnitude, high WSS sectors demonstrated regression of total plaque area (p < 0.001) and fibrous tissue (p < 0.001), and similar progression of necrotic core. Sectors subjected to low and oscillatory WSS exhibited total plaque area regression, while low and non-oscillatory WSS sectors demonstrated total plaque progression (p < 0.001). Furthermore, compared with low and non-oscillatory WSS areas, sectors exposed to low and oscillatory WSS demonstrated regression of fibrous (p < 0.001) and fibrofatty (p < 0.001) tissue and similar progression of necrotic core (p = 0.82) and dense calcium (p = 0.40). Herein, we demonstrate that, in patients with non-obstructive CAD, sectors subjected to low and oscillatory WSS demonstrated regression of total plaque, fibrous and fibrofatty tissue, and progression of necrotic core and dense calcium, which suggest a transformation to a more vulnerable phenotype.

Comprehensive Assessment of Coronary Plaque Progression With Advanced Intravascular Imaging, Physiological Measures, and Wall Shear Stress: A Pilot Double‐Blinded Randomized Controlled Clinical Trial of Nebivolol Versus Atenolol in Nonobstructive Coronary Artery Disease

Background We hypothesized that nebivolol, a β‐blocker with nitric oxide–mediated activity, compared with atenolol, a β‐blocker without such activity, would decrease oxidative stress and improve the effects of endothelial dysfunction and wall shear stress (WSS), thereby reducing atherosclerosis progression and vulnerability in patients with nonobstructive coronary artery disease. Methods and Results In this pilot double‐blinded randomized controlled trial, 24 patients treated for 1 year with nebivolol 10 mg versus atenolol 100 mg plus standard medical therapy underwent baseline and follow‐up coronary angiography with assessments of inflammatory and oxidative stress biomarkers, microvascular function, endothelial function, and virtual histology intravascular ultrasound. WSS was calculated from computational fluid dynamics. Virtual histology intravascular ultrasound segments were assessed for vessel volumetrics and remodeling. There was a trend toward more low‐WSS segments in the nebivolol cohort (P=0.06). Low‐WSS regions were associated with greater plaque progression (P<0.0001) and constrictive remodeling (P=0.04); conversely, high‐WSS segments demonstrated plaque regression and excessive expansive remodeling. Nebivolol patients had decreased lumen and vessel areas along with increased plaque area, resulting in more constrictive remodeling (P=0.002). There were no significant differences in biomarker levels, microvascular function, endothelial function, or number of thin‐capped fibroatheromas per vessel. Importantly, after adjusting for β‐blocker, low‐WSS segments remained significantly associated with lumen loss and plaque progression. Conclusion Nebivolol, compared with atenolol, was associated with greater plaque progression and constrictive remodeling, likely driven by more low‐WSS segments in the nebivolol arm. Both β‐blockers had similar effects on oxidative stress, microvascular function, and endothelial function. Clinical Trial Registration URL: https://clinicaltrials.gov/. Unique identifier: NCT01230892.

Comparison of angiographic and IVUS derived coronary geometric reconstructions for evaluation of the association of hemodynamics with coronary artery disease progression.

Wall shear stress (WSS) has been investigated as a prognostic marker for the prospective identification of rapidly progressing coronary artery disease (CAD) and atherosclerotic lesions likely to gain high-risk (vulnerable) characteristics. The goal of this study was to compare biplane angiographic vs. intravascular ultrasound (IVUS) derived reconstructed coronary geometries to evaluate agreement in geometry, computed WSS, and association of WSS and CAD progression. Baseline and 6-month follow-up angiographic and IVUS imaging data were collected in patients with non-obstructive CAD (n = 5). Three-dimensional (3D) reconstructions of the coronary arteries were generated with each technique, and patient-specific computational fluid dynamics models were constructed to compute baseline WSS values. Geometric comparisons were evaluated in arterial segments (n = 9), and hemodynamic data were evaluated in circumferential sections (n = 468). CAD progression was quantified from serial IVUS imaging data (n = 277), and included virtual-histology IVUS (VH-IVUS) derived changes in plaque composition. There was no significant difference in reconstructed coronary segment lengths and cross-sectional areas (CSA), however, IVUS derived geometries exhibited a significantly larger left main CSA than the angiographic reconstructions. Computed absolute time-averaged WSS (TAWSSABS) values were significantly greater in the IVUS derived geometries, however, evaluations of relative TAWSS (TAWSSREL) values revealed improved agreement and differences within defined zones of equivalence. Associations between VH-IVUS defined CAD progression and angiographic or IVUS derived WSS exhibited poor agreement when examining TAWSSABS data, but improved when evaluating the association with TAWSSREL data. We present data from a small cohort of patients highlighting strong agreement between angiographic and IVUS derived coronary geometries, however, limited agreement is observed between computed WSS values and associations of WSS with CAD progression.

Combining IVUS and Optical Coherence Tomography for More Accurate Coronary Cap Thickness Quantification and Stress/Strain Calculations: A Patient-Specific Three-Dimensional Fluid-Structure Interaction Modeling Approach

Accurate cap thickness and stress/strain quantifications are of fundamental importance for vulnerable plaque research. Virtual histology intravascular ultrasound (VH-IVUS) sets cap thickness to zero when cap is under resolution limit and IVUS does not see it. An innovative modeling approach combining IVUS and optical coherence tomography (OCT) is introduced for cap thickness quantification and more accurate cap stress/strain calculations. In vivo IVUS and OCT coronary plaque data were acquired with informed consent obtained. IVUS and OCT images were merged to form the IVUS + OCT data set, with biplane angiography providing three-dimensional (3D) vessel curvature. For components where VH-IVUS set zero cap thickness (i.e., no cap), a cap was added with minimum cap thickness set as 50 and 180 μm to generate IVUS50 and IVUS180 data sets for model construction, respectively. 3D fluid-structure interaction (FSI) models based on IVUS + OCT, IVUS50, and IVUS180 data sets were constructed to investigate cap thickness impact on stress/strain calculations. Compared to IVUS + OCT, IVUS50 underestimated mean cap thickness (27 slices) by 34.5%, overestimated mean cap stress by 45.8%, (96.4 versus 66.1 kPa). IVUS50 maximum cap stress was 59.2% higher than that from IVUS + OCT model (564.2 versus 354.5 kPa). Differences between IVUS and IVUS + OCT models for cap strain and flow shear stress (FSS) were modest (cap strain <12%; FSS <6%). IVUS + OCT data and models could provide more accurate cap thickness and stress/strain calculations which will serve as basis for further plaque investigations.

The Ongoing Quest to Predict Plaque Rupture

Many plant ion channels have been identified, but little is known about how these transporters are regulated. We have investigated the regulation of a slow vacuolar (SV) ion channel in the tonoplast of barley aleurone storage protein vacuoles (SPV) using the patch-clamp technique. SPV were isolated from barley aleurone protoplasts incubated with CaCl2 in the presence or absence of gibberellic acid (GA) or abscisic acid (ABA). A slowly activating, voltage-dependent ion channel was identified in the SPV membrane. Mean channel conductance was 26 pS when 100 mM KCl was on both sides of the membrane, and reversal potential measurements indicated that most of the current was carried by K+. Treatment of protoplasts with GA3 increased whole-vacuole current density compared to SPV isolated from ABA- or CaCl2-treated cells. The opening of the SV channel was sensitive to cytosolic free Ca2+ concentration ([Ca2+]i) between 600 nM and 100 [mu]M, with higher [Ca2+]i resulting in a greater probability of channel opening. SV channel activity was reduced greater than 90% by the calmodulin (CaM) inhibitors W7 and trifluoperazine, suggesting that Ca2+ activates endogenous CaM tightly associated with the membrane. Exogenous CaM partially reversed the inhibitory effects of W7 on SV channel opening. CaM also sensitized the SV channel to Ca2+. In the presence of ~3.5 [mu]M CaM, specific current increased by approximately threefold at 2.5 [mu]M Ca2+ and by more than 13-fold at 10 [mu]M Ca2+. Since [Ca2+]i and the level of CaM increase in barley aleurone cells following exposure to GA, we suggest that Ca2+ and CaM act as signal transduction elements mediating hormone-induced changes in ion channel activity.

Evaluation of a framework for the co-registration of intravascular ultrasound and optical coherence tomography coronary artery pullbacks

A growing number of studies have used a combination of intravascular ultrasound (IVUS) and optical coherence tomography (OCT) for the assessment of atherosclerotic plaques. Given their respective strengths these imaging modalities highly complement each other. Correlations of hemodynamics and coronary artery disease (CAD) have been extensively investigated with both modalities separately, though not concurrently due to challenges in image registration. Manual co-registration of these modalities is a time expensive task subject to human error, and the development of an automatic method has not been previously addressed. We developed a framework that uses dynamic time warping for the longitudinal co-registration and dynamic programming for the circumferential co-registration of images and evaluated the methodology in a cohort (n = 12) of patients with moderate CAD. Excellent correlation was seen between the algorithm and two expert readers for longitudinal co-registration (CCC = 0.9964, CCC = 0.9959) and circumferential co-registration (CCC = 0.9688, CCC = 0.9598). The mean error of the circumferential co-registration angle was found to be within 10%. A framework for the co-registration of IVUS and OCT pullbacks has been developed which provides a foundation for comprehensive studies of CAD biomechanics.

Development of Framework to Examine the Focal Association Between Wall Shear Stress and Coronary Artery Disease Progression in the Clinical Setting

Natural history data on clinical coronary artery disease (CAD) indicates that there is a critical need to prospectively identify rapidly progressing and vulnerable coronary lesions that may cause potentially fatal acute coronary events [1]. Recent prospective clinical investigations have evaluated the value of wall shear stress (WSS) as a prognostic marker for identifying rapidly progressing coronary lesions [2,3]. Data indicate that low WSS is associated with significant plaque progression, while regions of high WSS are associated with plaque regression and phenotypic transformation towards a more vulnerable lesion. While these studies provided unprecedented data on the role of hemodynamic-induced mechanical forces in lesion dynamics, they were limited by a lack of focal understanding of the association between WSS and plaque progression. Specifically, despite the understanding that WSS and plaque progression are heterogeneous around the artery’s circumference, in each image slice WSS values were spatially averaged around the circumference and correlated with average values for changes in virtual histology-intravascular ultrasound (VH-IVUS) defined plaque constituent areas.Copyright

Bulk Flow and Near Wall Hemodynamics of the Rabbit Aortic Arch and Descending Thoracic Aorta: A 4D PC-MRI Derived Computational Fluid Dynamics Study

Animal models offer a flexible experimental environment for studying atherosclerosis. The mouse is the most commonly used animal, however, the underlying hemodynamics in larger animals such as the rabbit are far closer to that of humans. The aortic arch is a vessel with complex helical flow and highly heterogeneous shear stress patterns which may influence where atherosclerotic lesions form. A better understanding of intraspecies flow variation and the impact of geometry on flow may improve our understanding of where disease forms. In this work, we use magnetic resonance angiography (MRA) and 4D phase contrast magnetic resonance imaging (PC-MRI) to image and measure blood velocity in the rabbit aortic arch. Measured flow rates from the PC-MRI were used as boundary conditions in computational fluid dynamics (CFD) models of the arches. Helical flow, cross flow index (CFI), and time-averaged wall shear stress (TAWSS) were determined from the simulated flow field. Both traditional geometric metrics and shape modes derived from statistical shape analysis were analyzed with respect to flow helicity. High CFI and low TAWSS were found to colocalize in the ascending aorta and to a lesser extent on the inner curvature of the aortic arch. The Reynolds number was linearly associated with an increase in helical flow intensity (R = 0.85, p < 0.05). Both traditional and statistical shape analyses correlated with increased helical flow symmetry. However, a stronger correlation was obtained from the statistical shape analysis demonstrating its potential for discerning the role of shape in hemodynamic studies.Animal models offer a flexible experimental environment for studying atherosclerosis. The mouse is the most commonly used animal, however, the underlying hemodynamics in larger animals such as the rabbit are far closer to that of humans. The aortic arch is a vessel with complex helical flow and highly heterogeneous shear stress patterns which may influence where atherosclerotic lesions form. A better understanding of intra-species flow variation and the impact of geometry on flow may improve our understanding of where disease forms. In this work we use Magnetic Resonance Angiography (MRA) and 4D Phase contrast magnetic resonance imaging (PC-MRI) to image and measure blood velocity in the rabbit aortic arch. Measured flow rates from the PC-MRI were used as boundary conditions in computational fluid dynamics models of the arches. Helical flow, cross flow index (CFI) and time-averaged wall shear stress (TAWSS) were determined from the simulated flow field. Both traditional geometric metrics and shape modes derived from statistical shape analysis were analyzed with respect to flow helicity. High CFI and low TAWSS were found to co-localize in the ascending aorta and to a lesser extent on the inner curvature of the aortic arch. The Reynolds number was linearly associated with an increase in helical flow intensity (R=0.85, p<.05). Both traditional and statistical shape analysis correlated with increased helical flow symmetry. However, a stronger correlation was obtained from the statistical shape analysis demonstrating its potential for discerning the role of shape in hemodynamic studies.

A Machine Learning-Based Method for Intracoronary OCT Segmentation and Vulnerable Coronary Plaque Cap Thickness Quantification

Accurate cap thickness quantification is of fundamental importance for vulnerable plaque detection in cardiovascular research. A segmentation method for intracoronary optical coherence tomography (OCT) image based on least squares support vector machine (LS-SVM) was performed to characterize plaque component borders and quantify fibrous cap thickness. Manual segmentation of OCT images were performed by experts based on combination of virtual-histology intravascular ultrasound (VH-IVUS) and OCT images and used as gold standard. The segmentation methods based on LS-SVM provided accurate plaque cap thickness (an 8.6% error by LS-SVM vs. 71% error by IVUS50) serving as solid basis for plaque modeling and assessment.