Quantification of the focal progression of coronary atherosclerosis through automated co-registration of virtual histology-intravascular ultrasound imaging data.

The goal of this study was to evaluate the accuracy of a novel algorithm that circumferentially co-registers serial virtual histology-intravascular ultrasound (VH-IVUS) data for the focal assessment of coronary atherosclerosis progression. Thirty-three patients with an abnormal non-invasive cardiac stress test or stable angina underwent baseline and follow-up (6 or 12 months) invasive evaluation that included acquisition of VH-IVUS image data. Baseline and follow-up image pairs (n = 4194) were automatically co-registered in the circumferential direction via a multi-variate cross-correlation algorithm. Algorithm stability and accuracy were assessed by comparing results from multiple iterations of the algorithm (iteration 1 vs. iteration 2) and against values determined manually by two expert VH-IVUS readers (algorithm vs. two expert readers). Furthermore, focal plaque progression values were compared between the algorithm and expert readers following co-registration by the independently determined angles. Strong agreement in circumferential co-registration angles were observed across multiple iterations of the algorithm (stability) and between the algorithm and expert readers (accuracy; all concordance correlation coefficients >0.98). Furthermore, circumferential co-registration angles determined by the algorithm were not statistically when compared to values determined by two expert readers (p = 0. 99). Bland-Altman analysis indicated minimal bias when comparing focal VH-IVUS defined plaque progression in corresponding sectors following circumferential co-registration between the algorithm and expert readers. Finally, average differences in changes in total plaque and constituent areas between the algorithm and readers were within the average range of difference between readers (interobserver variability). We present a stable and validated algorithm to automatically circumferentially co-register serial VH-IVUS imaging data for the focal quantification of coronary atherosclerosis progression.

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.

Elevated Levels of Serum Fibrin and Fibrinogen Degradation Products Are Independent Predictors of Larger Coronary Plaques and Greater Plaque Necrotic Core.

BACKGROUND: Co-existence of vulnerable plaque and pro-thrombotic state may provoke acute coronary events. It was hypothesized that elevated serum levels of fibrin and fibrinogen degradation products (FDP) are associated with larger total plaque and necrotic core (NC) areas. METHODS AND RESULTS: Seventy-five patients presenting with stable anginal symptoms (69%) or stabilized acute coronary syndrome (ACS; 31%), and found to have non-obstructive coronary artery disease (CAD) with a fractional flow reserve >0.8, were studied. Invasive virtual histology intravascular ultrasound (VH-IVUS) was performed in 68 LAD arteries, 6 circumflex arteries, and 1 right coronary artery. Serum FDP levels were measured using ELISA technique. Plaque volumetrics and composition were assessed in each VH-IVUS frame and averaged. The median age of patients was 56 (47-63) years; 52% were men and 23% had diabetes. The average length of coronary artery studied was 62 mm. After adjustment for systemic risk factors, medications, CRP levels and ACS, male gender (P<0.001) and serum FDP levels (P=0.02) were independent predictors of a larger NC area. Older age (P<0.001), male gender (P<0.0001) and increased serum FDP level (P=0.03) were associated with a larger plaque area. CONCLUSIONS: In patients with CAD, a higher serum level of FDP is independently associated with larger plaques and greater plaque NC.

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 ß-blocker with nitric oxide-mediated activity, compared with atenolol, a ß-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 ß-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 ß-blockers had similar effects on oxidative stress, microvascular function, and endothelial function. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/. Unique identifier: NCT01230892.

Plasma soluble urokinase-type plasminogen activator receptor level is independently associated with coronary microvascular function in patients with non-obstructive coronary artery disease.

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) is a novel biomarker released from leukocytes and endothelial cells that has been associated with atherosclerotic cardiovascular disease. We hypothesized that plasma suPAR level is an independent predictor of coronary microvascular function. METHODS: Coronary blood flow velocity and plasma suPAR levels were evaluated in patients with non-obstructive coronary artery disease. Coronary flow reserve (CFR) was calculated as the ratio of hyperemic to basal average peak blood flow velocity and coronary microvascular dysfunction was defined as CFR ≤ 2.0 in the setting of a fractional flow reserve value of ≥0.75. Plasma suPAR levels were measured using ELISA technique. The association between suPAR and CFR was investigated using univariate and multivariate regression analyses. RESULTS: In 66 patients, 47% were men, 26% had diabetes, 68% had hypertension and 76% had dyslipidemia. Mean age was 55 ± 12 years and median suPAR level 2.82 (2.08-3.40) ng/mL. Plasma suPAR levels correlated with age (r = 0.31, p = 0.01), body mass index (r = 0.25, p = 0.04) and high-sensitivity C-reactive protein (hs-CRP) (r = 0.33, p = 0.009). While median suPAR level was not significantly different in patients with different cardiovascular risk factors, patients on statin therapy had significantly higher suPAR level (p = 0.03). SuPAR correlated negatively with CFR and, after multivariate adjustment for established cardiovascular risk factors, medications profiles and hs-CRP, suPAR remained an independent predictor of CFR (B = -0.30, p = 0.04), indicating an independent association between suPAR level and coronary microvascular function. CONCLUSIONS: In this cross-sectional study, plasma suPAR level was an independent predictor of coronary microvascular function. Larger prospective clinical trials are warranted to investigate the prognostic value of this novel biomarker and the role of immune dysregulation in coronary microvascular disease.

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

BACKGROUND: Wall 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. METHODS: Three 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. RESULTS: Models 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. CONCLUSIONS: When 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.

Myocardial bridging: contemporary understanding of pathophysiology with implications for diagnostic and therapeutic strategies.

Patients with myocardial bridging are often asymptomatic, but this anomaly may be associated with exertional angina, acute coronary syndromes, cardiac arrhythmias, syncope, or even sudden cardiac death. This review presents our understanding of the pathophysiology of myocardial bridging and describes prevailing diagnostic modalities and therapeutic options for this challenging clinical entity.

Computational fluid dynamics applied to virtually deployed drug-eluting coronary bioresorbable scaffolds: Clinical translations derived from a proof-of-concept.

BACKGROUND: Three-dimensional design simulations of coronary metallic stents utilizing mathematical and computational algorithms have emerged as important tools for understanding biomechanical stent properties, predicting the interaction of the implanted platform with the adjacent tissue, and informing stent design enhancements. Herein, we demonstrate the hemodynamic implications following virtual implantation of bioresorbable scaffolds using finite element methods and advanced computational fluid dynamics (CFD) simulations to visualize the device-flow interaction immediately after implantation and following scaffold resorption over time. METHODS AND RESULTS: CFD simulations with time averaged wall shear stress (WSS) quantification following virtual bioresorbable scaffold deployment in idealized straight and curved geometries were performed. WSS was calculated at the inflow, endoluminal surface (top surface of the strut), and outflow of each strut surface post-procedure (stage I) and at a time point when 33% of scaffold resorption has occurred (stage II). The average WSS at stage I over the inflow and outflow surfaces was 3.2 and 3.1 dynes/cm(2) respectively and 87.5 dynes/cm(2) over endoluminal strut surface in the straight vessel. From stage I to stage II, WSS increased by 100% and 142% over the inflow and outflow surfaces, respectively, and decreased by 27% over the endoluminal strut surface. In a curved vessel, WSS change became more evident in the inner curvature with an increase of 63% over the inflow and 66% over the outflow strut surfaces. Similar analysis at the proximal and distal edges demonstrated a large increase of 486% at the lateral outflow surface of the proximal scaffold edge. CONCLUSIONS: The implementation of CFD simulations over virtually deployed bioresorbable scaffolds demonstrates the transient nature of device/flow interactions as the bioresorption process progresses over time. Such hemodynamic device modeling is expected to guide future bioresorbable scaffold design.