Ahmet U. Coskun

Effect of Endothelial Shear Stress on the Progression of Coronary Artery Disease, Vascular Remodeling, and In-Stent Restenosis in Humans In Vivo 6-Month Follow-Up Study

Background—Native atherosclerosis and in-stent restenosis are focal and evolve independently. The endothelium controls local arterial responses by transduction of shear stress. Characterization of endothelial shear stress (ESS) may allow for prediction of progression of atherosclerosis and in-stent restenosis. Methods and Results—By using intracoronary ultrasound, biplane coronary angiography, and measurement of coronary blood flow, we represented the artery in accurate 3D space and determined detailed characteristics of ESS and arterial wall/plaque morphology. Patients who underwent stent implantation and who had another artery with luminal obstruction <50% underwent intravascular profiling initially and after 6-month follow-up. Twelve arteries in 8 patients were studied: 6 native and 6 stented arteries. In native arteries, regions of abnormally low baseline ESS exhibited a significant increase in plaque thickness and enlargement of the outer vessel wall, such that lumen radius remained unchanged (outward remodeling). Regions of physiological ESS showed little change. Regions with increased ESS exhibited outward remodeling with normalization of ESS. In stented arteries, there was an increase in intima-medial thickness, a decrease in lumen radius, and an increase in ESS at all levels of baseline ESS. Conclusions—The present study represents the first experience in humans relating ESS to subsequent outcomes in native and stented arteries. Regions of low ESS develop progressive atherosclerosis and outward remodeling, areas of physiological ESS remain quiescent, and areas of increased ESS exhibit outward remodeling. ESS may have a limited role in in-stent restenosis. This technology can predict areas of minor plaque likely to exhibit progression of atherosclerosis.

Prediction of Progression of Coronary Artery Disease and Clinical Outcomes Using Vascular Profiling of Endothelial Shear Stress and Arterial Plaque Characteristics: The PREDICTION Study

Background— Atherosclerotic plaques progress in a highly individual manner. The purposes of the Prediction of Progression of Coronary Artery Disease and Clinical Outcome Using Vascular Profiling of Shear Stress and Wall Morphology (PREDICTION) Study were to determine the role of local hemodynamic and vascular characteristics in coronary plaque progression and to relate plaque changes to clinical events. Methods and Results— Vascular profiling, using coronary angiography and intravascular ultrasound, was used to reconstruct each artery and calculate endothelial shear stress and plaque/remodeling characteristics in vivo. Three-vessel vascular profiling (2.7 arteries per patient) was performed at baseline in 506 patients with an acute coronary syndrome treated with a percutaneous coronary intervention and in a subset of 374 (74%) consecutive patients 6 to 10 months later to assess plaque natural history. Each reconstructed artery was divided into sequential 3-mm segments for serial analysis. One-year clinical follow-up was completed in 99.2%. Symptomatic clinical events were infrequent: only 1 (0.2%) cardiac death; 4 (0.8%) patients with new acute coronary syndrome in nonstented segments; and 15 (3.0%) patients hospitalized for stable angina. Increase in plaque area (primary end point) was predicted by baseline large plaque burden; decrease in lumen area (secondary end point) was independently predicted by baseline large plaque burden and low endothelial shear stress. Large plaque size and low endothelial shear stress independently predicted the exploratory end points of increased plaque burden and worsening of clinically relevant luminal obstructions treated with a percutaneous coronary intervention at follow-up. The combination of independent baseline predictors had a 41% positive and 92% negative predictive value to predict progression of an obstruction treated with a percutaneous coronary intervention. Conclusions— Large plaque burden and low local endothelial shear stress provide independent and additive prediction to identify plaques that develop progressive enlargement and lumen narrowing. Clinical Trial Registration— URL: http:www.//clinicaltrials.gov. Unique Identifier: NCT01316159.

Prediction of the Localization of High-Risk Coronary Atherosclerotic Plaques on the Basis of Low Endothelial Shear Stress An Intravascular Ultrasound and Histopathology Natural History Study

Background— Low endothelial shear stress (ESS) promotes the development of atherosclerosis; however, its role in the progression of atherosclerotic plaques and evolution to inflamed high-risk plaques has not been studied. Our hypothesis was that the lowest values of ESS are responsible for the development of high-risk coronary atherosclerotic plaques associated with excessive expansive remodeling. Methods and Results— Twenty-four swine, treated with streptozotocin to induce diabetes and fed a high-fat diet, were allocated into early (n=12) and late (n=12) atherosclerosis groups. Intima-media thickness was assessed by intravascular ultrasound in the coronary arteries at weeks 4 and 8 in the early group and weeks 23 and 30 in the late group. Plaques started to develop after week 8, leading to marked heterogeneity in plaque severity at week 30. ESS was calculated in plaque-free subsegments of interest (n=142) in the late group at week 23. Coronary arteries (n=31) of this group were harvested at week 30, and the subsegments of interest were identified and analyzed histopathologically. Low ESS was an independent predictor of the development of high-risk plaques, characterized by intense lipid accumulation, inflammation, thin fibrous cap, severe internal elastic lamina degradation, and excessive expansive remodeling. The severity of high-risk plaque characteristics at week 30 was significantly correlated with the magnitude of low ESS at week 23. Conclusions— The magnitude of low ESS determines the complexity and heterogeneity of atherosclerotic lesions and predicts the development of high-risk plaque.

Shear-Activated Nanotherapeutics for Drug Targeting to Obstructed Blood Vessels

Bio-Inspired Drug Delivery Noting that platelets naturally migrate to narrowed blood vessels characterized by high fluid shear stress, Korin et al. (p. 738, published online 5 July; see the Perspective by Lavik and Ustin) developed a nanoparticle-based therapeutic that uses a similar targeting mechanism to deliver a drug to vessels obstructed by blood clots. Aggregates of nanoparticles coated with the clot-dissolving drug tPA (tissue plasminogen activator) were designed to fall apart and release the drug only when encountering high fluid shear stress. In preclinical models, the bio-inspired therapeutic dissolved clots and restored normal blood flow at lower doses than free tPA, suggesting that this localized delivery system may help reduce the risk of side effects such as excessive bleeding. Nanoparticles carrying a drug that dissolves blood clots disintegrate at sites of stenosis. Obstruction of critical blood vessels due to thrombosis or embolism is a leading cause of death worldwide. Here, we describe a biomimetic strategy that uses high shear stress caused by vascular narrowing as a targeting mechanism—in the same way platelets do—to deliver drugs to obstructed blood vessels. Microscale aggregates of nanoparticles were fabricated to break up into nanoscale components when exposed to abnormally high fluid shear stress. When coated with tissue plasminogen activator and administered intravenously in mice, these shear-activated nanotherapeutics induce rapid clot dissolution in a mesenteric injury model, restore normal flow dynamics, and increase survival in an otherwise fatal mouse pulmonary embolism model. This biophysical strategy for drug targeting, which lowers required doses and minimizes side effects while maximizing drug efficacy, offers a potential new approach for treatment of life-threatening diseases that result from acute vascular occlusion.

Natural History of Experimental Coronary Atherosclerosis and Vascular Remodeling in Relation to Endothelial Shear Stress. A Serial, In Vivo Intravascular Ultrasound Study

Background— The natural history of heterogeneous atherosclerotic plaques and the role of local hemodynamic factors throughout their development are unknown. We performed a serial study to assess the role of endothelial shear stress (ESS) and vascular remodeling in the natural history of coronary atherosclerosis. Methods and Results— Intravascular ultrasound–based 3-dimensional reconstruction of all major coronary arteries (n=15) was performed serially in vivo in 5 swine 4, 11, 16, 23, and 36 weeks after induction of diabetes mellitus and hyperlipidemia. The reconstructed arteries were divided into 3-mm-long segments (n=304). ESS was calculated in all segments at all time points through the use of computational fluid dynamics. Vascular remodeling was assessed at each time point in all segments containing significant plaque, defined as maximal intima-media thickness ≥0.5 mm, at week 36 (n=220). Plaque started to develop at week 11 and progressively advanced toward heterogeneous, multifocal lesions at all subsequent time points. Low ESS promoted the initiation and subsequent progression of plaques. The local remodeling response changed substantially over time and determined future plaque evolution. Excessive expansive remodeling developed in regions of very low ESS, further exacerbated the low ESS, and was associated with the most marked plaque progression. The combined assessment of ESS, remodeling, and plaque severity enabled the early identification of plaques that evolved to high-risk lesions at week 36. Conclusions— The synergistic effect of local ESS and the remodeling response to plaque formation determine the natural history of individual lesions. Combined in vivo assessment of ESS and remodeling may predict the focal formation of high-risk coronary plaque.

Prediction of sites of coronary atherosclerosis progression: In vivo profiling of endothelial shear stress, lumen, and outer vessel wall characteristics to predict vascular behavior.

PURPOSE OF REVIEW Native atherosclerosis and in-stent restenosis are focal and evolve independently. The endothelium regulates arterial behavior by responding to its local environment of hemodynamic stresses, in particular, shear stress. Identification of endothelial shear stress and arterial wall characteristics may allow for the prediction of the progression of atherosclerosis. Accurate identification of arterial segments at high risk for progression may permit preemptive intervention strategies to avoid adverse coronary events. RECENT FINDINGS In vitro studies indicate that low endothelial shear stress upregulates the genetic and molecular responses leading to the initiation and progression of atherosclerosis, and promotes inflammation and formation of other features characteristic of vulnerable plaque. Physiologic endothelial shear stress is vasculoprotective and fosters quiescence of the endothelium and vascular wall. High endothelial shear stress promotes platelet aggregation. Recent studies have now provided evidence that endothelial shear stress and vascular wall morphology along the course of human coronary arteries can be characterized in vivo, and, in serial studies, may actually predict the focal areas in which atherosclerosis progression occurs. SUMMARY Rapidly evolving methodologies are able to characterize the arterial wall and the local hemodynamic environmental factors likely responsible for progression of coronary disease in humans. These new diagnostic modalities allow for identification of plaque progression. Future studies need to identify the factors responsible for vulnerable plaque formation. The current availability of drug-eluting stents with a low risk of restenosis allows for consideration of preemptive intervention strategies for these high-risk vascular sites such that future adverse coronary events can be averted.

Reproducibility of coronary lumen, plaque, and vessel wall reconstruction and of endothelial shear stress measurements in vivo in humans

The purpose of this study was to assess the reproducibility of an in vivo methodology to reconstruct the lumen, plaque, and external elastic membrane (EEM) of coronary arteries and estimate endothelial shear stress (ESS). Ten coronary arteries without significant stenoses (five native and five stented arteries) were investigated. The 3D lumen and EEM boundaries of each coronary artery were determined by fusing end‐diastolic intravascular ultrasound images with biplane coronary angiograms. Coronary flow was measured. Computational fluid dynamics was used to calculate local ESS. Complete data acquisition was then repeated. Analysis was performed on each data set in a blinded manner. The intertest correlation coefficients for all arteries for the two measurements of lumen radius, EEM radius, plaque thickness, and ESS were r = 0.96, 0.96, 0.94, 0.91, respectively (all P values < 0.0001). The 3D anatomy and ESS of human coronary arteries can be reproducibly estimated in vivo. This methodology provides a tool to examine the effect of ESS on atherogenesis, remodeling, and restenosis; the contribution of arterial remodeling and plaque growth to changes in the lumen; and the impact of new therapies. Catheter Cardiovasc Interv 2003;60:67–78.

Prediction of coronary artery plaque progression and potential rupture from 320-detector row prospectively ECG-gated single heart beat CT angiography: Lattice Boltzmann evaluation of endothelial shear stress

Advances in MDCT will extend coronary CTA beyond the morphology data provided by systems that use 64 or fewer detector rows. Newer coronary CTA technology such as prospective ECG-gating will also enable lower dose examinations. Since the current standard of care for coronary diagnoses is catheterization, CT will continue to be benchmarked against catheterization reference points, in particular temporal resolution, spatial resolution, radiation dose, and volume coverage. This article focuses on single heart beat cardiac acquisitions enabled by 320-detector row CT. Imaging with this system can now be performed with patient radiation doses comparable to catheterization. The high image quality, excellent contrast opacification, and absence of stair-step artifact provide the potential to evaluate endothelial shear stress (ESS) noninvasively with CT. Low ESS is known to lead to the development and progression of atherosclerotic plaque culminating in high-risk vulnerable plaque likely to rupture and cause an acute coronary event. The magnitude of local low ESS, in combination with the local remodeling response and the severity of systemic risk factors, determines the natural history of each plaque. This paper describes the steps required to derive an ESS map from 320-detector row CT data using the Lattice Boltzmann method to include the complex geometry of the coronary arterial tree. This approach diminishes the limitations of other computational fluid dynamics methods to properly evaluate multiple coronary arteries, including the complex geometry of coronary bifurcations where lesions tend to develop.

Thin-capped atheromata with reduced collagen content in pigs develop in coronary arterial regions exposed to persistently low endothelial shear stress.

Objective—The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques. Approach and Results—Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (<1.2 Pa) exhibited reduced intimal smooth muscle cell content; marked intimal smooth muscle cell phenotypic modulation; attenuated procollagen-I gene expression; increased gene and protein expression of the interstitial collagenases matrix-metalloproteinase-1, -8, -13, and -14; increased collagenolytic activity; reduced collagen content; and marked thinning of the fibrous cap. Conclusions—Eccentric thin-capped atheromata, lesions particularly prone to rupture, form more frequently in coronary regions exposed to low ESS throughout their evolution. By promoting an imbalance of attenuated synthesis and augmented collagen breakdown, low ESS favors the focal evolution of early lesions toward plaques with reduced collagen content and thin fibrous caps—2 critical determinants of coronary plaque vulnerability.

Risk stratification of individual coronary lesions using local endothelial shear stress: a new paradigm for managing coronary artery disease.

Purpose of review The purpose of this review is to summarize the role of endothelial shear stress in the natural history of coronary atherosclerosis, and to propose an individualized risk-stratification strategy of atherosclerotic lesions based on the in-vivo characterization of local endothelial shear stress and wall morphology. Recent findings Low endothelial shear stress promotes the development of early fibroatheromas, which subsequently follow an individualized natural history of progression. This individual natural history is critically dependent on the magnitude of low endothelial shear stress, which subsequently regulates the severity of inflammation within the wall and ultimately the vascular remodeling response. Very low endothelial shear stress enhances plaque inflammation, leading to excessive expansive remodeling. Excessive expansive remodeling leads to perpetuation, or even exacerbation, of the local low endothelial shear stress environment, thereby setting up a self-perpetuating vicious cycle among low local endothelial shear stress, inflammation, and excessive expansive remodeling, which transforms an early fibroatheroma to a high-risk plaque. Summary In-vivo assessment of the local endothelial shear stress environment, severity of inflammation and vascular remodeling response, all responsible for individual plaque behavior and natural history, in combination with systemic biomarkers of vulnerability, may allow for detailed risk stratification of individual early atherosclerotic plaques, thereby guiding both systemic and local, lesion-specific therapeutic strategies.