Numerous studies have demonstrated an association between endothelial shear stress (ESS) and neoi... more Numerous studies have demonstrated an association between endothelial shear stress (ESS) and neointimal formation after stent implantation. However, the role of ESS on the composition of neointima and underlying plaque remains unclear. Patients recruited in the Comfortable AMI-IBIS 4 study implanted with bare metal stents (BMS) or biolimus eluting stents (BES) that had biplane coronary angiography at 13month follow-up were included in the analysis. The intravascular ultrasound virtual-histology (IVUS-VH) and the angiographic data were used to reconstruct the luminal surface, and the stent in the stented segments. Blood flow simulation was performed in the stent surface, which was assumed to represent the luminal surface at baseline, to assess the association between ESS and neointima thickness. The predominant ESS was estimated in 3-mm segments and was correlated with the amount of neointima, neointimal tissue composition, and with the changes in the underlying plaque burden and com...
Megakaryocyte maturation and polyploidization are critical for platelet production; abnormalities... more Megakaryocyte maturation and polyploidization are critical for platelet production; abnormalities in these processes are associated with myeloproliferative disorders, including thrombocytopenia. Megakaryocyte maturation signals through cascades that involve p21-activated kinase (Pak) function, however, the specific role for Pak kinases in megakaryocyte biology remains elusive. Here, we identify Pak2 as an essential effector of megakaryocyte maturation, polyploidization and proplatelet formation. Genetic deletion of Pak2 in murine bone marrow is associated with macrothrombocytopenia, altered megakaryocyte ultrastructure, increased bone marrow megakaryocyte precursors and an elevation of mature CD41(+)-megakaryocytes, as well as an increased number of polyploid cells. In Pak2(-/-) mice, platelet clearance rate was increased, as was production of newly synthesized, reticulated platelets. In vitro, Pak2(-/-) megakaryocytes demonstrate increased polyploidization associated with alteratio...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 2011
To analyse the relationship between strut apposition as visualised with optical coherence tomogra... more To analyse the relationship between strut apposition as visualised with optical coherence tomography (OCT) at follow-up and clinical and procedural characteristics at stent implantation, and to examine the relationship between strut apposition and stent healing. Twenty-eight coronary lesions were evaluated. The lesion morphology before stent implantation was described from the baseline angiogram. Strut apposition at follow-up was divided into: (I) apposed struts, (II) struts overlying side branch ostia, (III) malapposed and (IV) protruding struts. Since malapposed and protruding struts often occurred in the same lesions, these were divided into two groups: lesions without (n=20) and lesions with (n=8) the presence of these struts. The thickness of strut coverage was used as a surrogate for stent healing. We analysed 5,159 struts. Sixteen were malapposed and 216 were protruding. Lesions with malapposed and/or protruding struts at OCT follow-up were more frequently associated with acu...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, Jan 20, 2012
To analyse and to compare the changes in the various optical coherence tomography (OCT), echogeni... more To analyse and to compare the changes in the various optical coherence tomography (OCT), echogenicity and intravascular ultrasound virtual histology (VH) of the everolimus-eluting bioresorbable scaffold (ABSORB) degradation parameters during the first 12 months after ABSORB implantation. In the ABSORB study, changes in the appearance of the ABSORB scaffold were monitored over time using various intracoronary imaging modalities. The scaffold struts exhibited a progressive change in their black core area by OCT, in their ultrasound derived grey level intensity quantified by echogenicity, and in their backscattering ultrasound signal, identified as "pseudo dense-calcium" (DC) by VH. From the ABSORB Cohort B trial 35 patients had paired OCT, echogenicity and VH assessment at baseline and at six- (n=18) or 12-months follow-up (n=17). Changes in OCT strut core area, hyperechogenicity and VH-derived DC were analysed and compared at the various time points. At six months, the chan...
This method is based on the intravenous injection of Evans Blue in mice as the test animal model.... more This method is based on the intravenous injection of Evans Blue in mice as the test animal model. Evans blue is a dye that binds albumin. Under physiologic conditions the endothelium is impermeable to albumin, so Evans blue bound albumin remains restricted within blood vessels. In pathologic conditions that promote increased vascular permeability endothelial cells partially lose their close contacts and the endothelium becomes permeable to small proteins such as albumin. This condition allows for extravasation of Evans Blue in tissues. A healthy endothelium prevents extravasation of the dye in the neighboring vascularized tissues. Organs with increased permeability will show significantly increased blue coloration compared to organs with intact endothelium. The level of vascular permeability can be assessed by simple visualization or by quantitative measurement of the dye incorporated per milligram of tissue of control versus experimental animal/tissue. Two powerful aspects of this ...
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, 2014
We investigated the relationship between coagulation assessed by thromboelastography (TEG) and my... more We investigated the relationship between coagulation assessed by thromboelastography (TEG) and myocardial damage in ST-segment elevation myocardial infarction (STEMI). We measured platelet activity with TEG-maximum amplitude (TEG-MA) in 233 patients undergoing urgent percutaneous coronary intervention (PCI). Infarct size and myocardial salvage index were evaluated using cardiac magnetic resonance, and the relation of these parameters to posttreatment coagulation was examined retrospectively. Adverse events were adjudicated and related to the coagulation status during the index event. Hypercoagulation was found in 82 (35.2%) patients and was neither correlated to infarct size nor correlated to myocardial salvage index (P = .28 and .65, respectively) or clinical adverse events. Patients who experienced an adverse event during follow-up had a slightly higher TEG-MA value than patients with an event-free follow-up, but this was not statistically significant (68.1 vs 67.3, P = .44). The ...
Signaling from small GTPases is a tightly regulated process. In this work we used a protein micro... more Signaling from small GTPases is a tightly regulated process. In this work we used a protein microarray screen to identify the Rac-specific GAP, ArhGAP15, as a substrate of the Rac effectors Pak1 and Pak2. In addition to serving as a substrate of Pak1/2, we found that ArhGAP15, via its PH domain, bound to these kinases. The association of ArhGAP15 to Pak1/2 resulted in mutual inhibition of GAP and kinase catalytic activity, respectively. Knock-down of ArhGAP15 resulted in activation of Pak1/2, both indirectly, as a result of Rac activation, and directly, as a result of disruption of the ArhGAP15/Pak complex. Our data suggest that ArhGAP15 plays a dual negative role in regulating small GTPase signaling, by acting at the level of the GTPase itself, as well interacting with its effector, Pak kinase.
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, Jan 22, 2014
Angiographic evidence of edge dissections has been associated with a risk of early stent thrombos... more Angiographic evidence of edge dissections has been associated with a risk of early stent thrombosis. Optical coherence tomography (OCT) is a high-resolution technology detecting a greater number of edge dissections--particularly non-flow-limiting--compared to angiography. Their natural history and clinical implications remain unclear. The objectives of the present study were to assess the morphology, healing response, and clinical outcomes of OCT-detected edge dissections using serial OCT imaging at baseline and at one year following drug-eluting stent (DES) implantation. Edge dissections were defined as disruptions of the luminal surface in the 5 mm segments proximal and distal to the stent, and categorised as flaps, cavities, double-lumen dissections or fissures. Qualitative and quantitative OCT analyses were performed every 0.5 mm at baseline and one year, and clinical outcomes were assessed. Sixty-three lesions (57 patients) were studied with OCT at baseline and one-year follow-...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 2014
Angiographic ectasias and aneurysms in stented segments have been associated with late stent thro... more Angiographic ectasias and aneurysms in stented segments have been associated with late stent thrombosis. Using optical coherence tomography (OCT), some stented segments show coronary evaginations reminiscent of ectasias. The purpose of this study was to explore, using computational fluid-dynamic (CFD) simulations, whether OCT-detected coronary evaginations can induce local changes in blood flow. OCT-detected evaginations are defined as outward bulges in the luminal vessel contour between struts, with the depth of the bulge exceeding the actual strut thickness. Evaginations can be characterised cross-sectionally by depth and along the stented segment by total length. Assuming an ellipsoid shape, we modelled 3-D evaginations with different sizes by varying the depth from 0.2-1.0 mm, and the length from 1-9 mm. For the flow simulation we used average flow velocity data from non-diseased coronary arteries. The change in flow with varying evagination sizes was assessed using a particle t...
The investigation of asymptomatic but potentially vulnerable atherosclerosis is not yet a major f... more The investigation of asymptomatic but potentially vulnerable atherosclerosis is not yet a major focus for clinical Cardiologists. We have illustrated the contemporary investigation and treatment of such disease using a clinical case that involved monozygotic twins. One twin (T1) had unfortunately suffered a cardiac arrest whilst jogging and survived only due to bystander CPR and prompt defibrillation. His identical twin brother (T2), on subsequent investigation, harbours a compositionally identical lesion in a proximal coronary vessel that has not yet ruptured or provoked a clinical event. Following the presentation of both non-invasive and invasive images, we discuss the need for active suspicion and intensive treatment for those people with a 'genetic' risk of future myocardial infarction.
International Journal of Cardiovascular Imaging, 2011
To quantify with in vivo OCT and histology, the device/vessel interaction after implantation of t... more To quantify with in vivo OCT and histology, the device/vessel interaction after implantation of the bioresorbable vascular scaffold (BVS). We evaluated the area and thickness of the strut voids previously occupied by the polymeric struts, and the neointimal hyperplasia (NIH) area covering the endoluminal surface of the strut voids (NIHEV), as well as the NIH area occupying the space between
To determine the relationship between optical coherence tomography (OCT) images of the retina and... more To determine the relationship between optical coherence tomography (OCT) images of the retina and retinal substructure in vitro and in vivo. In vitro, OCT images of human and bovine retina were acquired after sequential excimer laser ablation of the inner retinal layers. Measurements of bands in the OCT images were compared with measurements of retinal layers on histology of the ablated specimens. In vivo, OCT images were acquired of retinal lesions in which there was a displacement of pigmented retinal pigment epithelial (RPE) cells: retinitis pigmentosa and laser photocoagulation (eight eyes each). The mean thickness of human inner OCT bands (131 microm; 95% confidence interval [CI], 122-140 microm) was 7.3 times that of the retinal nerve fiber layer (RNFL). This band persisted despite ablation greater than 140 microm. The inner aspect of the outer OCT band corresponded to the apical RPE, but the mean thickness of this band in human tissue (55 microm; 95% CI, 48-62 microm) was 2.6 times the thickness of the RPE-choriocapillaris complex. OCT measurement of total retinal thickness was accurate (coefficient of variance, 0.05) and precise (coefficient of correlation with light microscopy, 0.98). Hyperpigmented lesions gave rise to high signal, attenuating deeper signal; hypopigmented lesions had the opposite effect on deeper signal. The inner band is not RNFL specific, partly consisting of a surface-related signal. The location, not thickness, of the outer band corresponds to RPE melanin. Given the additional effect of polarization settings, precise OCT measurement of specific retinal layers is currently precluded.
Numerous studies have demonstrated an association between endothelial shear stress (ESS) and neoi... more Numerous studies have demonstrated an association between endothelial shear stress (ESS) and neointimal formation after stent implantation. However, the role of ESS on the composition of neointima and underlying plaque remains unclear. Patients recruited in the Comfortable AMI-IBIS 4 study implanted with bare metal stents (BMS) or biolimus eluting stents (BES) that had biplane coronary angiography at 13month follow-up were included in the analysis. The intravascular ultrasound virtual-histology (IVUS-VH) and the angiographic data were used to reconstruct the luminal surface, and the stent in the stented segments. Blood flow simulation was performed in the stent surface, which was assumed to represent the luminal surface at baseline, to assess the association between ESS and neointima thickness. The predominant ESS was estimated in 3-mm segments and was correlated with the amount of neointima, neointimal tissue composition, and with the changes in the underlying plaque burden and com...
Megakaryocyte maturation and polyploidization are critical for platelet production; abnormalities... more Megakaryocyte maturation and polyploidization are critical for platelet production; abnormalities in these processes are associated with myeloproliferative disorders, including thrombocytopenia. Megakaryocyte maturation signals through cascades that involve p21-activated kinase (Pak) function, however, the specific role for Pak kinases in megakaryocyte biology remains elusive. Here, we identify Pak2 as an essential effector of megakaryocyte maturation, polyploidization and proplatelet formation. Genetic deletion of Pak2 in murine bone marrow is associated with macrothrombocytopenia, altered megakaryocyte ultrastructure, increased bone marrow megakaryocyte precursors and an elevation of mature CD41(+)-megakaryocytes, as well as an increased number of polyploid cells. In Pak2(-/-) mice, platelet clearance rate was increased, as was production of newly synthesized, reticulated platelets. In vitro, Pak2(-/-) megakaryocytes demonstrate increased polyploidization associated with alteratio...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 2011
To analyse the relationship between strut apposition as visualised with optical coherence tomogra... more To analyse the relationship between strut apposition as visualised with optical coherence tomography (OCT) at follow-up and clinical and procedural characteristics at stent implantation, and to examine the relationship between strut apposition and stent healing. Twenty-eight coronary lesions were evaluated. The lesion morphology before stent implantation was described from the baseline angiogram. Strut apposition at follow-up was divided into: (I) apposed struts, (II) struts overlying side branch ostia, (III) malapposed and (IV) protruding struts. Since malapposed and protruding struts often occurred in the same lesions, these were divided into two groups: lesions without (n=20) and lesions with (n=8) the presence of these struts. The thickness of strut coverage was used as a surrogate for stent healing. We analysed 5,159 struts. Sixteen were malapposed and 216 were protruding. Lesions with malapposed and/or protruding struts at OCT follow-up were more frequently associated with acu...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, Jan 20, 2012
To analyse and to compare the changes in the various optical coherence tomography (OCT), echogeni... more To analyse and to compare the changes in the various optical coherence tomography (OCT), echogenicity and intravascular ultrasound virtual histology (VH) of the everolimus-eluting bioresorbable scaffold (ABSORB) degradation parameters during the first 12 months after ABSORB implantation. In the ABSORB study, changes in the appearance of the ABSORB scaffold were monitored over time using various intracoronary imaging modalities. The scaffold struts exhibited a progressive change in their black core area by OCT, in their ultrasound derived grey level intensity quantified by echogenicity, and in their backscattering ultrasound signal, identified as "pseudo dense-calcium" (DC) by VH. From the ABSORB Cohort B trial 35 patients had paired OCT, echogenicity and VH assessment at baseline and at six- (n=18) or 12-months follow-up (n=17). Changes in OCT strut core area, hyperechogenicity and VH-derived DC were analysed and compared at the various time points. At six months, the chan...
This method is based on the intravenous injection of Evans Blue in mice as the test animal model.... more This method is based on the intravenous injection of Evans Blue in mice as the test animal model. Evans blue is a dye that binds albumin. Under physiologic conditions the endothelium is impermeable to albumin, so Evans blue bound albumin remains restricted within blood vessels. In pathologic conditions that promote increased vascular permeability endothelial cells partially lose their close contacts and the endothelium becomes permeable to small proteins such as albumin. This condition allows for extravasation of Evans Blue in tissues. A healthy endothelium prevents extravasation of the dye in the neighboring vascularized tissues. Organs with increased permeability will show significantly increased blue coloration compared to organs with intact endothelium. The level of vascular permeability can be assessed by simple visualization or by quantitative measurement of the dye incorporated per milligram of tissue of control versus experimental animal/tissue. Two powerful aspects of this ...
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, 2014
We investigated the relationship between coagulation assessed by thromboelastography (TEG) and my... more We investigated the relationship between coagulation assessed by thromboelastography (TEG) and myocardial damage in ST-segment elevation myocardial infarction (STEMI). We measured platelet activity with TEG-maximum amplitude (TEG-MA) in 233 patients undergoing urgent percutaneous coronary intervention (PCI). Infarct size and myocardial salvage index were evaluated using cardiac magnetic resonance, and the relation of these parameters to posttreatment coagulation was examined retrospectively. Adverse events were adjudicated and related to the coagulation status during the index event. Hypercoagulation was found in 82 (35.2%) patients and was neither correlated to infarct size nor correlated to myocardial salvage index (P = .28 and .65, respectively) or clinical adverse events. Patients who experienced an adverse event during follow-up had a slightly higher TEG-MA value than patients with an event-free follow-up, but this was not statistically significant (68.1 vs 67.3, P = .44). The ...
Signaling from small GTPases is a tightly regulated process. In this work we used a protein micro... more Signaling from small GTPases is a tightly regulated process. In this work we used a protein microarray screen to identify the Rac-specific GAP, ArhGAP15, as a substrate of the Rac effectors Pak1 and Pak2. In addition to serving as a substrate of Pak1/2, we found that ArhGAP15, via its PH domain, bound to these kinases. The association of ArhGAP15 to Pak1/2 resulted in mutual inhibition of GAP and kinase catalytic activity, respectively. Knock-down of ArhGAP15 resulted in activation of Pak1/2, both indirectly, as a result of Rac activation, and directly, as a result of disruption of the ArhGAP15/Pak complex. Our data suggest that ArhGAP15 plays a dual negative role in regulating small GTPase signaling, by acting at the level of the GTPase itself, as well interacting with its effector, Pak kinase.
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, Jan 22, 2014
Angiographic evidence of edge dissections has been associated with a risk of early stent thrombos... more Angiographic evidence of edge dissections has been associated with a risk of early stent thrombosis. Optical coherence tomography (OCT) is a high-resolution technology detecting a greater number of edge dissections--particularly non-flow-limiting--compared to angiography. Their natural history and clinical implications remain unclear. The objectives of the present study were to assess the morphology, healing response, and clinical outcomes of OCT-detected edge dissections using serial OCT imaging at baseline and at one year following drug-eluting stent (DES) implantation. Edge dissections were defined as disruptions of the luminal surface in the 5 mm segments proximal and distal to the stent, and categorised as flaps, cavities, double-lumen dissections or fissures. Qualitative and quantitative OCT analyses were performed every 0.5 mm at baseline and one year, and clinical outcomes were assessed. Sixty-three lesions (57 patients) were studied with OCT at baseline and one-year follow-...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 2014
Angiographic ectasias and aneurysms in stented segments have been associated with late stent thro... more Angiographic ectasias and aneurysms in stented segments have been associated with late stent thrombosis. Using optical coherence tomography (OCT), some stented segments show coronary evaginations reminiscent of ectasias. The purpose of this study was to explore, using computational fluid-dynamic (CFD) simulations, whether OCT-detected coronary evaginations can induce local changes in blood flow. OCT-detected evaginations are defined as outward bulges in the luminal vessel contour between struts, with the depth of the bulge exceeding the actual strut thickness. Evaginations can be characterised cross-sectionally by depth and along the stented segment by total length. Assuming an ellipsoid shape, we modelled 3-D evaginations with different sizes by varying the depth from 0.2-1.0 mm, and the length from 1-9 mm. For the flow simulation we used average flow velocity data from non-diseased coronary arteries. The change in flow with varying evagination sizes was assessed using a particle t...
The investigation of asymptomatic but potentially vulnerable atherosclerosis is not yet a major f... more The investigation of asymptomatic but potentially vulnerable atherosclerosis is not yet a major focus for clinical Cardiologists. We have illustrated the contemporary investigation and treatment of such disease using a clinical case that involved monozygotic twins. One twin (T1) had unfortunately suffered a cardiac arrest whilst jogging and survived only due to bystander CPR and prompt defibrillation. His identical twin brother (T2), on subsequent investigation, harbours a compositionally identical lesion in a proximal coronary vessel that has not yet ruptured or provoked a clinical event. Following the presentation of both non-invasive and invasive images, we discuss the need for active suspicion and intensive treatment for those people with a 'genetic' risk of future myocardial infarction.
International Journal of Cardiovascular Imaging, 2011
To quantify with in vivo OCT and histology, the device/vessel interaction after implantation of t... more To quantify with in vivo OCT and histology, the device/vessel interaction after implantation of the bioresorbable vascular scaffold (BVS). We evaluated the area and thickness of the strut voids previously occupied by the polymeric struts, and the neointimal hyperplasia (NIH) area covering the endoluminal surface of the strut voids (NIHEV), as well as the NIH area occupying the space between
To determine the relationship between optical coherence tomography (OCT) images of the retina and... more To determine the relationship between optical coherence tomography (OCT) images of the retina and retinal substructure in vitro and in vivo. In vitro, OCT images of human and bovine retina were acquired after sequential excimer laser ablation of the inner retinal layers. Measurements of bands in the OCT images were compared with measurements of retinal layers on histology of the ablated specimens. In vivo, OCT images were acquired of retinal lesions in which there was a displacement of pigmented retinal pigment epithelial (RPE) cells: retinitis pigmentosa and laser photocoagulation (eight eyes each). The mean thickness of human inner OCT bands (131 microm; 95% confidence interval [CI], 122-140 microm) was 7.3 times that of the retinal nerve fiber layer (RNFL). This band persisted despite ablation greater than 140 microm. The inner aspect of the outer OCT band corresponded to the apical RPE, but the mean thickness of this band in human tissue (55 microm; 95% CI, 48-62 microm) was 2.6 times the thickness of the RPE-choriocapillaris complex. OCT measurement of total retinal thickness was accurate (coefficient of variance, 0.05) and precise (coefficient of correlation with light microscopy, 0.98). Hyperpigmented lesions gave rise to high signal, attenuating deeper signal; hypopigmented lesions had the opposite effect on deeper signal. The inner band is not RNFL specific, partly consisting of a surface-related signal. The location, not thickness, of the outer band corresponds to RPE melanin. Given the additional effect of polarization settings, precise OCT measurement of specific retinal layers is currently precluded.
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