Michail I. Papafaklis

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.

Recanalisation of chronic total coronary occlusions: 2012 consensus document from the EuroCTO club.

Georgios Sianos1*, MD, PhD, FESC; Gerald S. Werner2, MD, PhD, FESC, FACC, FSCI; Alfredo R. Galassi3, MD, FESC, FACC, FSCAI; Michail I. Papafaklis4, MD, PhD; Javier Escaned5, MD, PhD, FESC; David Hildick-Smith6, MD, FESC; Evald Hoj Christiansen7, MD, PhD; Anthony Gershlick8, MD, FRCP, FESC; Mauro Carlino9, MD, FESC; Angelos Karlas1, MD; Nikolaos V. Konstantinidis1, MD; Salvatore D. Tomasello3, MD; Carlo Di Mario10, MD, PhD, FRCP, FESC; Nicolaus Reifart11, MD, PhD, FESC for the EuroCTO Club

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.

The Effect of Shear Stress on Neointimal Response Following Sirolimus- and Paclitaxel-Eluting Stent Implantation Compared With Bare-Metal Stents in Humans

OBJECTIVES We aimed to explore the relationship of neointimal thickness (NT) to shear stress (SS) after implantation of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) compared with bare-metal stents (BMS). We then tested the hypothesis that drug elution attenuates the SS effect. BACKGROUND Neointimal thickness after BMS implantation has been associated with SS; pertinent data for drug-eluting stents (DES) are limited. METHODS Three-dimensional coronary artery and stent reconstruction was performed in 30 patients at 6-month follow-up after SES (n = 10), PES (n = 10), or BMS (n = 10) implantation. Baseline SS at the stent surface was calculated using computational fluid dynamics and NT at follow-up was computed in 3-dimensional space. RESULTS Neointimal thickness was lower in DES versus BMS (0.03 ± 0.07 mm vs. 0.16 ± 0.08 mm, p < 0.001) and maximum NT was reduced in SES versus PES (0.33 ± 0.13 mm vs. 0.46 ± 0.13 mm, p = 0.025). In the total population, both SS (slope: -0.05 mm/Pa, p < 0.001) and DES (coefficient for DES vs. BMS: -0.17 mm, p = 0.003) were independent predictors of NT. Subgroup analysis demonstrated a significant negative relationship of NT to SS in PES (slope: -0.05 mm/Pa, p = 0.016) and BMS (slope: -0.05 mm/Pa, p = 0.001). Sirolimus elution significantly attenuated the effect of SS on NT (interaction coefficient for SES vs. BMS: 0.04 mm/Pa, p = 0.023), whereas the SS effect remained unchanged in PES (interaction coefficient for PES vs. BMS: 0.01 mm/Pa, p = 0.71). CONCLUSIONS Neointimal thickness is significantly correlated (inversely) to SS in PES as in BMS. Sirolimus elution abrogates the SS effect on the neointimal response following stent implantation, whereas the SS effect is unchanged in PES.

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.

Endothelial Shear Stress and Coronary Plaque Characteristics in Humans Combined Frequency-Domain Optical Coherence Tomography and Computational Fluid Dynamics Study

Background—Despite the exposure of the entire vasculature to the atherogenic effects of systemic risk factors, atherosclerotic plaques preferentially develop at sites with disturbed flow. This study aimed at exploring in vivo the relationship between local endothelial shear stress (ESS) and coronary plaque characteristics in humans using computational fluid dynamics and frequency-domain optical coherence tomography. Methods and Results—Three-dimensional coronary artery reconstruction was performed in 21 patients (24 arteries) presenting with acute coronary syndrome using frequency-domain optical coherence tomography and coronary angiography. Each coronary artery was divided into sequential 3-mm segments and analyzed for the assessment of local ESS and plaque characteristics. A total of 146 nonculprit segments were evaluated. Compared with segments with higher ESS [≥1 Pascal (Pa)], those with low ESS (<1 Pa) showed higher prevalence of lipid-rich plaques (37.5% versus 20.0%; P=0.019) and thin-cap fibroatheroma (12.5% versus 2.0%; P=0.037). Overall, lipid plaques in segments with low ESS had thinner fibrous cap (115 &mgr;m [63–166] versus 170 &mgr;m [107–219]; P=0.004) and higher macrophage density (normalized standard deviation: 8.4% [4.8–12.6] versus 6.2% [4.2–8.8]; P=0.017). Segments with low ESS showed more superficial calcifications (minimum calcification depth: 93 &mgr;m [50–140] versus 152 &mgr;m [105–258]; P=0.049) and tended to have higher prevalence of spotty calcifications (26.0% versus 12.0%; P=0.076). Conclusions—Coronary regions exposed to low ESS are associated with larger lipid burden, thinner fibrous cap, and higher prevalence of thin-cap fibroatheroma in humans. Frequency-domain optical coherence tomography–based assessment of ESS and wall characteristics may be useful in identifying vulnerable coronary regions. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01110538.Background— Despite the exposure of the entire vasculature to the atherogenic effects of systemic risk factors, atherosclerotic plaques preferentially develop at sites with disturbed flow. This study aimed at exploring in vivo the relationship between local endothelial shear stress (ESS) and coronary plaque characteristics in humans using computational fluid dynamics and frequency-domain optical coherence tomography. Methods and Results— Three-dimensional coronary artery reconstruction was performed in 21 patients (24 arteries) presenting with acute coronary syndrome using frequency-domain optical coherence tomography and coronary angiography. Each coronary artery was divided into sequential 3-mm segments and analyzed for the assessment of local ESS and plaque characteristics. A total of 146 nonculprit segments were evaluated. Compared with segments with higher ESS [≥1 Pascal (Pa)], those with low ESS (<1 Pa) showed higher prevalence of lipid-rich plaques (37.5% versus 20.0%; P =0.019) and thin-cap fibroatheroma (12.5% versus 2.0%; P =0.037). Overall, lipid plaques in segments with low ESS had thinner fibrous cap (115 μm [63–166] versus 170 μm [107–219]; P =0.004) and higher macrophage density (normalized standard deviation: 8.4% [4.8–12.6] versus 6.2% [4.2–8.8]; P =0.017). Segments with low ESS showed more superficial calcifications (minimum calcification depth: 93 μm [50–140] versus 152 μm [105–258]; P =0.049) and tended to have higher prevalence of spotty calcifications (26.0% versus 12.0%; P =0.076). Conclusions— Coronary regions exposed to low ESS are associated with larger lipid burden, thinner fibrous cap, and higher prevalence of thin-cap fibroatheroma in humans. Frequency-domain optical coherence tomography–based assessment of ESS and wall characteristics may be useful in identifying vulnerable coronary regions. Clinical Trial Registration— URL: . Unique identifier: [NCT01110538][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01110538&atom=%2Fcirccvim%2F7%2F6%2F905.atom

A new methodology for accurate 3-dimensional coronary artery reconstruction using routine intravascular ultrasound and angiographic data: implications for widespread assessment of endothelial shear stress in humans.

AIMS To develop and validate a new methodology that allows accurate 3-dimensional (3-D) coronary artery reconstruction using standard, simple angiographic and intravascular ultrasound (IVUS) data acquired during routine catheterisation enabling reliable assessment of the endothelial shear stress (ESS) distribution. METHODS AND RESULTS Twenty-two patients (22 arteries: 7 LAD; 7 LCx; 8 RCA) who underwent angiography and IVUS examination were included. The acquired data were used for 3-D reconstruction using a conventional method and a new methodology that utilised the luminal 3-D centreline to place the detected IVUS borders and anatomical landmarks to estimate their orientation. The local ESS distribution was assessed by computational fluid dynamics. In corresponding consecutive 3 mm segments, lumen, plaque and ESS measurements in the 3-D models derived by the centreline approach were highly correlated to those derived from the conventional method (r>0.98 for all). The centreline methodology had a 99.5% diagnostic accuracy for identifying segments exposed to low ESS and provided similar estimations to the conventional method for the association between the change in plaque burden and ESS (centreline method: slope= -1.65%/Pa, p=0.078; conventional method: slope= -1.64%/Pa, p=0.084; p =0.69 for difference between the two methodologies). CONCLUSIONS The centreline methodology provides geometrically correct models and permits reliable ESS computation. The ability to utilise data acquired during routine coronary angiography and IVUS examination will facilitate clinical investigation of the role of local ESS patterns in the natural history of coronary atherosclerosis.

ANGIOCARE: An automated system for fast three-dimensional coronary reconstruction by integrating angiographic and intracoronary ultrasound data

The development of an automated, user‐friendly system (ANGIOCARE), for rapid three‐dimensional (3D) coronary reconstruction, integrating angiographic and, intracoronary ultrasound (ICUS) data.

Relationship of shear stress with in-stent restenosis: Bare metal stenting and the effect of brachytherapy

BACKGROUND The association of shear stress (SS) with in-stent restenosis after bare metal stenting is not clear. We investigated the significance of SS on predicting areas with neointima thickness (NT) in humans and the effect of vascular brachytherapy (VBT) following coronary artery stenting on the relationship of SS with NT. METHODS By using coronary angiography and intravascular ultrasound, we performed three-dimensional (3D) artery and stent reconstruction in 14 patients at 8-month follow-up after bare metal stenting with (stent&VBT group; 7 patients) or without (stent group; 7 patients) adjunctive beta-VBT. In-stent SS was calculated by applying computational fluid dynamics to the stent reconstruction and NT was determined in 3D space. RESULTS NT was significantly increased in the stent group (0.2+/-0.16 mm vs. 0.07+/-0.18 mm, p<0.001). The estimated intercepts and slopes regarding the relationship of NT with SS were 0.28 mm [95% confidence interval (CI): 0.20 to 0.36 mm, p<0.001] and -0.057 mm/Pa (95% CI: -0.062 to -0.052 mm/Pa, p<0.001) respectively for the stent group, and 0.15 mm (95% CI: -0.02 to 0.31 mm, p=0.082) and -0.017 mm/Pa (95% CI: -0.023 to -0.010 mm/Pa, p<0.001) respectively for the stent&VBT group. After pooling all data together, a significant effect of VBT on the relationship between NT and SS was found [estimate of interaction term (groupxSS) for stent&VBT vs. stent group: 0.04 mm/Pa; 95% CI: 0.032 to 0.049 mm/Pa, p<0.001]. CONCLUSIONS In-stent restenosis is inversely related to SS after coronary artery stenting and VBT diminishes the inverse relationship between NT and SS.

Drug-eluting stent restenosis: Effect of drug type, release kinetics, hemodynamics and coating strategy

Restenosis following stent implantation diminishes the procedures efficacy influencing long-term clinical outcomes. Stent-based drug delivery emerged a decade ago as an effective means of reducing neointimal hyperplasia by providing localized pharmacotherapy during the acute phase of the stent-induced injury and the ensuing pathobiological mechanisms. However, drug-eluting stent (DES) restenosis may still occur especially when stents are used in complex anatomical and clinical scenarios. A DES consists of an intravascular metallic frame and carriers which allow controlled release of active pharmaceutical agents; all these components are critical in determining drug distribution locally and thus anti-restenotic efficacy. Furthermore, dynamic flow phenomena characterizing the vascular environment, and shear stress distribution, are greatly influenced by stent implantation and play a significant role in drug deposition and bioavailability within local vascular tissue. In this review, we discuss the performance of DES and the interaction of the different DES components with the hemodynamic milieu emphasizing on the inhibition of clinical restenosis.