The Role of Shear Stress in Coronary Artery Disease.

Coronary artery disease is the leading cause of morbidity and mortality worldwide, especially in developed countries, with an increasing incidence in developing countries. Despite the advances in cardiology, there are yet many unanswered questions about the natural history of coronary atherosclerosis. However, it has not been fully explained why some coronary artery plaques remain quiescent over time, whereas others evolve to a high-risk, "vulnerable" plaque with a predisposition to destabilize and induce a cardiac event. Furthermore, approximately half of the patients with acute coronary syndromes demonstrate no prior symptoms of ischemia or angiographically evident disease. Recent findings have indicated that apart from cardiovascular risk factors, genetics, and other unknown factors, local hemodynamic forces, such as endothelial shear stress, blood flow patterns, and endothelial dysfunction of the epicardial and microvascular coronary arteries, are associated with the progression of coronary plaque and the development of cardiovascular complications with complex interactions. In this review article, we summarize the mechanisms that affect coronary artery plaque progression, indicating the importance of endothelial shear stress, endothelial dysfunction of epicardial and microvascular vessels, inflammation, and their complex associations, underlying in parallel the clinical perspectives of these findings.

Novel Lesional Transcriptional Signature Separates Atherosclerosis With and Without Diabetes in Yorkshire Swine and Humans.

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Reviewing imaging modalities for the assessment of plaque erosion.

Plaque rupture followed by intracoronary thrombus formation is recognized as the most common pathophysiological mechanism in acute coronary syndromes (ACS). The second most common underlying substrate for ACS is plaque erosion whose hallmark is thrombus formation without cap disruption. Invasive and non-invasive methods have emerged as a promising tool for evaluation of plaque features that either predict or detect plaque erosion. Optical coherence tomography (OCT), high-definition intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and near-infrared autofluorescence (NIRF) have been used to study plaque erosion. The detection of plaque erosion in the clinical setting, mainly facilitated by OCT, has shed light upon the complex pathophysiology underlying ACS not related to plaque rupture. Coronary computed tomography angiography (CCTA), which is to date the most commonly used non-invasive technique for coronary plaque evaluation, may also have a role in the evaluation of patients predisposed to erosion. Also, computational models enabling quantification of endothelial shear stress may pave the way to new research in coronary plaque pathophysiology. This review focuses on the recent imaging techniques for the evaluation of plaque erosion including invasive and non-invasive assessment.

Shear Stress Estimated by Quantitative Coronary Angiography Predicts Plaques Prone to Progress and Cause Events.

OBJECTIVES: This study examined the value of endothelial shear stress (ESS) estimated in 3-dimensional quantitative coronary angiography (3D-QCA) models in detecting plaques that are likely to progress and cause events. BACKGROUND: Cumulative evidence has shown that plaque characteristics and ESS derived from intravascular ultrasound (IVUS)-based reconstructions enable prediction of lesions that will cause cardiovascular events. However, the prognostic value of ESS estimated by 3D-QCA in nonflow limiting lesions is yet unclear. METHODS: This study analyzed baseline virtual histology (VH)-IVUS and angiographic data from 28 lipid-rich lesions (i.e., fibroatheromas) that caused major adverse cardiovascular events or required revascularization (MACE-R) at 5-year follow-up and 119 lipid-rich plaques from a control group that remained quiescent. The segments studied by VH-IVUS at baseline were reconstructed using 3D-QCA software. In the obtained geometries, blood flow simulation was performed, and the pressure gradient across the lipid-rich plaque and the mean ESS values in 3-mm segments were estimated. The additive value of these hemodynamic indexes in predicting MACE-R beyond plaque characteristics was examined. RESULTS: MACE-R lesions were longer, had smaller minimum lumen area, increased plaque burden (PB), were exposed to higher ESS, and exhibited a higher pressure gradient. In multivariable analysis, PB (hazard ratio: 1.08; p = 0.004) and the maximum 3-mm ESS value (hazard ratio: 1.11; p = 0.001) were independent predictors of MACE-R. Lesions exposed to high ESS (>4.95 Pa) with a high-risk anatomy (minimal lumen area <4 mm2 and PB >70%) had a higher MACE-R rate (53.8%) than those with a low-risk anatomy exposed to high ESS (31.6%) or those exposed to low ESS who had high- (20.0%) or low-risk anatomy (7.1%; p < 0.001). CONCLUSIONS: In the present study, 3D-QCA-derived local hemodynamic variables provided useful prognostic information, and, in combination with lesion anatomy, enabled more accurate identification of MACE-R lesions.

Role of local coronary blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and coronary plaque.

PURPOSE OF REVIEW: The natural history of coronary atherosclerosis is complex and atherosclerotic plaques exhibit large morphologic and functional variability within the same individual as well as over time. The purpose of this article is to review the role of blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and atherosclerosis progression. RECENT FINDINGS: Recent breakthroughs in cardiovascular imaging have facilitated in-vivo characterization of the anatomic and functional characteristics of atherosclerotic plaques and have highlighted the role of endothelial shear stress and epicardial and microvascular endothelial dysfunction in the natural history of coronary atherosclerosis. SUMMARY: There is an important need to identify individual lesions which may progress to vulnerable plaque in order to provide early therapeutic management. Evaluation of endothelial shear stress, local blood flow patterns, epicardial and microvascular endothelial dysfunction, as well as their complex associations might indicate those patients who have microvascular endothelial dysfunction and increased risk for upstream epicardial endothelial dysfunction and plaque progression. Such high-risk patients could potentially be targeted for more intensive therapeutic strategies to prevent the progression of both microvascular and epicardial atherosclerotic manifestations.

Local Low Shear Stress and Endothelial Dysfunction in Patients With Nonobstructive Coronary Atherosclerosis.

BACKGROUND: Local hemodynamic factors are important determinants of atherosclerotic plaque development and progression. OBJECTIVES: The goal of this study was to determine the association between low endothelial shear stress (ESS) and microvascular and epicardial endothelial dysfunction in patients with early atherosclerosis. METHODS: Sixty-five patients (mean age 52 ± 11 years) with nonobstructive coronary atherosclerosis (luminal diameter stenosis <30%) were included. Microvascular and epicardial coronary endothelial function was assessed by using intracoronary acetylcholine infusion. Vascular profiling, using 2-plane coronary angiography and intravascular ultrasound, was used to reconstruct the three-dimensional anatomy of the left anterior descending artery. Each reconstructed artery was divided into sequential 3-mm segments and analyzed for local ESS with computational fluid dynamics; that is, lower ESS levels at both a 3-mm regional level (average ESS and low ESS) and at a vessel level (lowest ESS per artery) and for plaque characteristics (plaque area, plaque thickness, and plaque burden). RESULTS: Coronary segments in arteries with abnormal microvascular function exhibited lower ESS compared with segments in arteries with normal microvascular function (average ESS: 1.67 ± 1.04 Pa vs. 2.03 ± 1.72 Pa [p = 0.050]; lowest ESS: 0.54 ± 0.25 Pa vs. 0.72 ± 0.32 Pa [p = 0.014]). Coronary segments in arteries with abnormal epicardial endothelial function also exhibited significantly lower ESS compared with segments in arteries with normal epicardial function (average ESS: 1.49 ± 0.89 Pa vs. 1.93 ± 1.50 Pa [p < 0.0001]; low ESS: 1.26 ± 0.81 Pa vs. 1.56 ± 1.30 Pa [p = 0.001]; lowest ESS: 0.51 ± 0.27 Pa vs. 0.65 ± 0.29 Pa [p = 0.080]). Patients with abnormal microvascular endothelial function exhibited a progressive decrease in average and low ESS, starting from patients with normal epicardial endothelial function to those with both microvascular and epicardial endothelial dysfunction (p < 0.0001 and p = 0.004, respectively). CONCLUSIONS: These data indicate an association between dysfunction of the microvascular and epicardial endothelium and local ESS at the early stages of coronary atherosclerosis in humans.

Role of Low Endothelial Shear Stress and Plaque Characteristics in the Prediction of Nonculprit Major Adverse Cardiac Events: The PROSPECT Study.

OBJECTIVES: This study sought to determine whether low endothelial shear stress (ESS) adds independent prognostication for future major adverse cardiac events (MACE) in coronary lesions in patients with high-risk acute coronary syndrome (ACS) from the United States and Europe. BACKGROUND: Low ESS is a proinflammatory, proatherogenic stimulus associated with coronary plaque development, progression, and destabilization in human-like animal models and in humans. Previous natural history studies including baseline ESS characterization investigated low-risk patients. METHODS: In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, 697 patients with ACS underwent 3-vessel intracoronary imaging. Independent predictors of MACE attributable to untreated nonculprit (nc) coronary lesions during 3.4-year follow-up were large plaque burden (PB), small minimum lumen area (MLA), and thin-cap fibroatheroma (TCFA) morphology. In this analysis, baseline ESS of nc lesions leading to new MACE (nc-MACE lesions) and randomly selected control nc lesions without MACE (nc-non-MACE lesions) were calculated. A propensity score for ESS was constructed for each lesion, and the relationship between ESS and subsequent nc-MACE was examined. RESULTS: A total of 145 lesions were analyzed in 97 patients: 23 nc-MACE lesions (13 TCFAs, 10 thick-cap fibroatheromas [ThCFAs]), and 122 nc-non-MACE lesions (63 TCFAs, 59 ThCFAs). Low local ESS (<1.3 Pa) was strongly associated with subsequent nc-MACE compared with physiological/high ESS (≥1.3 Pa) (23 of 101 [22.8%]) versus (0 of 44 [0%]). In propensity-adjusted Cox regression, low ESS was strongly associated with MACE (hazard ratio: 4.34; 95% confidence interval: 1.89 to 10.00; p < 0.001). Categorizing plaques by anatomic risk (high risk: ≥2 high-risk characteristics PB ≥70%, MLA ≤4 mm2, or TCFA), high anatomic risk, and low ESS were prognostically synergistic: 3-year nc-MACE rates were 52.1% versus 14.4% versus 0.0% in high-anatomic risk/low-ESS, low-anatomic risk/low-ESS, and physiological/high-ESS lesions, respectively (p < 0.0001). No lesion without low ESS led to nc-MACE during follow-up, regardless of PB, MLA, or lesion phenotype at baseline. CONCLUSIONS: Local low ESS provides incremental risk stratification of untreated coronary lesions in high-risk patients, beyond measures of PB, MLA, and morphology.

Heterogeneity of Coronary Plaque Morphology and Natural History: Current Understanding and Clinical Significance.

PURPOSE OF REVIEW: Despite the important progress in identifying high-risk atherosclerotic plaques, many key elements are elusive. Advanced imaging modalities provide valuable information about the anatomic and functional plaque characteristics and underscore the presence of multiple plaque morphologies. However, how the heterogeneity of atherosclerotic plaque can alter our current understanding of coronary artery disease is not fully understood. RECENT FINDINGS: Along the length of an individual plaque, the morphology patterns display marked heterogeneity. Contrary to previous beliefs, plaque morphology is also highly dynamic over time, with the vast majority of high-risk plaques becoming quiescent and mild plaques becoming severely obstructive in a short period of time. Endothelial shear stress, a local hemodynamic factor known for its critical effects in plaque initiation and progression, also displays longitudinal heterogeneity contributing to the arterial wall response in all time points. Risk stratification of plaques based on the morphological characteristics at one region of the plaque, usually the minimal lumen diameter, and at one point in time may be misleading. The evaluation of both morphological and hemodynamic characteristics along the length of a plaque will improve the risk assessment of individual plaques.

Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior.

Although the entire coronary tree is exposed to the atherogenic effect of the systemic risk factors, atherosclerotic lesions form at specific arterial regions, where low and oscillatory endothelial shear stress (ESS) occur. Low ESS modulates endothelial gene expression through complex mechanoreception and mechanotransduction processes, inducing an atherogenic endothelial phenotype and formation of an early atherosclerotic plaque. Each early plaque exhibits an individual natural history of progression, regression, or stabilization, which is dependent not only on the formation and progression of atherosclerosis but also on the vascular remodeling response. Although the pathophysiologic mechanisms involved in the remodeling of the atherosclerotic wall are incompletely understood, the dynamic interplay between local hemodynamic milieu, low ESS in particular, and the biology of the wall is likely to be important. In this review, we explore the molecular, cellular, and vascular processes supporting the role of low ESS in the natural history of coronary atherosclerosis and vascular remodeling and indicate likely mechanisms concerning the different natural history trajectories of individual coronary lesions. Atherosclerotic plaques associated with excessive expansive remodeling evolve to high-risk plaques, because low ESS conditions persist, thereby promoting continued local lipid accumulation, inflammation, oxidative stress, matrix breakdown, and eventually further plaque progression and excessive expansive remodeling. An enhanced understanding of the pathobiologic processes responsible for atherosclerosis and vascular remodeling might allow for early identification of a high-risk coronary plaque and thereby provide a rationale for innovative diagnostic and/or therapeutic strategies for the management of coronary patients and prevention of acute coronary syndromes.

Regions of low endothelial shear stress are the sites where coronary plaque progresses and vascular remodelling occurs in humans: an in vivo serial study.

AIM: We performed serial intracoronary studies of patients with stable coronary artery disease (CAD) to investigate the relationships among baseline endothelial shear stress (ESS), CAD progression, and vascular remodelling. Local haemodynamic factors are critical determinants of plaque progression, vascular remodelling, and clinical CAD manifestations. METHODS AND RESULTS: The 3-D anatomy of coronary arteries with lumen obstruction <50% was determined by fusing intracoronary ultrasound and angiographic images in 13 patients at baseline and 8 +/- 2 months later. Cross-sectional area of plaque, lumen, and external elastic membrane (EEM), and coronary flow were measured. Local ESS was calculated. Subsegments with similar ESS were categorized based on low (<12 dynes/cm(2)) and moderate/higher ESS (> or =12 dynes/cm(2)). There were 47 subsegments of similar baseline ESS: nine with low ESS and 38 with moderate/higher ESS. Median subsegment length was 6.9 mm (25th-75th percentiles = 4.2-12.0), and median area of similar ESS of 52.6 mm(2) (25th-75th percentiles = 26.9-88.0). Subsegments with low ESS exhibited plaque progression when compared with subsegments with moderate/higher ESS (33.3% vs. 7.9%, respectively, P = 0.009 adjusted for clustering of lesions within patients) and constrictive remodelling (44.0% vs. 5.3%, respectively, P = 0.16 adjusted for clustering of lesions within patients). Expansive remodelling occurred with similar frequency in subsegments with low vs. moderate/higher baseline ESS. CONCLUSION: Plaque progresses in subsegments with low ESS, associated with either constrictive or expansive remodelling. Different mechanisms are likely responsible for expansive remodelling in different local vascular environments. Early in vivo identification of arterial subsegments likely to develop high-risk plaque characteristics may allow for selective interventions to avoid adverse cardiac outcomes.

Remodeling characteristics of minimally diseased coronary arteries are consistent along the length of the artery.

Using a method that creates anatomically correct, 3-dimensional arterial reconstructions, 55 minimally diseased coronary arteries from 40 patients were studied. Homogenous remodeling characteristics along the entire length of the artery were observed in 48 arteries (87%). In the aggregate, arteries exhibited compensatory expansive remodeling. Individually, the full spectrum of compensatory expansive remodeling (60%), excessive expansive remodeling (21%), and constrictive remodeling (19%) was observed across arteries. Each artery was consistent in its remodeling characteristics from proximal to distal portions of the artery, and the remodeling pattern of each artery was independent within the same patient.

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.