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.

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.