Antonios P. Antoniadis

Role of endothelial shear stress in stent restenosis and thrombosis: pathophysiologic mechanisms and implications for clinical translation.

Restenosis and thrombosis are potentially fatal complications of coronary stenting with a recognized multifactorial etiology. The effect of documented risk factors, however, cannot explain the preponderance of certain lesion types, stent designs, and implantation configurations for the development of these complications. Local hemodynamic factors, low endothelial shear stress (ESS) in particular, are long known to critically affect the natural history of atherosclerosis. Increasing evidence now suggests that ESS may also contribute to the development of restenosis and thrombosis upon stenting of atherosclerotic plaques, in conjunction with well-appreciated risk factors. In this review, we present in vivo and mechanistic evidence associating ESS with the localization and progression of neointimal hyperplasia and in-stent clotting. Clinical studies have associated stent design features with the risk of restenosis. Importantly, computational simulations extend these observations by directly linking specific stent geometry and positioning characteristics with the post-stenting hemodynamic milieu and with the stents thrombogenicity and pro-restenotic potential, thereby indicating ways to clinical translation. An enhanced understanding of the pathophysiologic role of ESS in restenosis and thrombosis might dictate hemodynamically favorable stent designs and deployment configurations to reduce the potential for late lumen loss and thrombotic obstruction. Recent methodologies for in vivo ESS profiling at a clinical level might allow for early identification of patients at high risk for the development of restenosis or thrombosis and might thereby guide individualized, risk-tailored treatment strategies to prevent devastating complications of endovascular interventions.

Pathogenetic mechanisms of coronary ectasia

Coronary ectasia is defined as local or generalized aneurysmal dilatation of the coronary arteries. The present review summarizes the molecular, cellular and vascular mechanisms which are involved in the pathobiology of coronary ectasia. Coronary ectasia likely represents an exaggerated form of expansive vascular remodeling (i.e. excessive expansive remodeling) in response to atherosclerotic plaque growth. Enzymatic degradation of the extracellular matrix of the media is the major pathophysiologic process that leads to ectasia. Atherosclerotic lesions within ectatic regions of the coronary arteries appear to be highly inflamed high-risk plaques with proclivity to rupture. Better understanding of the pathogenetic processes involved in coronary ectasia is anticipated that will provide a further insight into the clinical significance and natural history of this entity, and may also have direct clinical implications in the management and follow-up strategy of this condition.

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.

Flow and atherosclerosis in coronary bifurcations

Coronary bifurcations are among the most frequent sites affected by atherosclerosis. In these regions, complex haemodynamic conditions prevail and local flow disturbances dictate the localisation and progression of atheroma. Endothelial shear stress (ESS) is the main flow-related factor affecting the distribution of atherosclerosis in a bifurcation. Plaques are more prevalent in low ESS areas, such as the lateral walls of the main vessel and side branches, while they are less common in the flow divider or carina, which is characterised by high ESS. However, the carina is not free of atheroma and is affected in up to one third of cases, but never in isolation. Lesions in the carina are likely to develop at a later stage of atherosclerosis, as result of circumferential expansion of plaques from the lateral wall. Pulsatile flow augments the local atherogenic environment by inducing low and oscillatory ESS. The geometrical configuration is also important as increased curvature and wide angles between the side branches of the bifurcation intensify flow perturbations, and highly curved segments show low ESS in the inner aspect of curvatures. Further research on the flow conditions which determine the initiation and progression of atherosclerosis in bifurcations will allow for more efficient prevention and management strategies.

Crimean-Congo hemorrhagic fever in Greece: a public health perspective.

In June 2008 the first non-imported fatal case of Crimean-Congo hemorrhagic fever (CCHF) was recorded in northern Greece. We present herein the public health interventions and the case definitions we developed for the epidemiological investigation. The possibility of CCHF establishing endemicity in this area is discussed.

Biomechanical Modeling to Improve Coronary Artery Bifurcation Stenting: Expert Review Document on Techniques and Clinical Implementation

Treatment of coronary bifurcation lesions remains an ongoing challenge for interventional cardiologists. Stenting of coronary bifurcations carries higher risk for in-stent restenosis, stent thrombosis, and recurrent clinical events. This review summarizes the current evidence regarding application and use of biomechanical modeling in the study of stent properties, local flow dynamics, and outcomes after percutaneous coronary interventions in bifurcation lesions. Biomechanical modeling of bifurcation stenting involves computational simulations and in vitro bench testing using subject-specific arterial geometries obtained from in vivo imaging. Biomechanical modeling has the potential to optimize stenting strategies and stent design, thereby reducing adverse outcomes. Large-scale clinical studies are needed to establish the translation of pre-clinical findings to the clinical arena.

Total Cholesterol Content of Erythrocyte Membranes and Coronary Atherosclerosis: An Intravascular Ultrasound Pilot Study

Background: Increasing evidence suggests that erythrocytes may participate in atherogenesis. We sought to investigate the relationship between total cholesterol content in erythrocyte membranes (CEM) and coronary atheroma burden in patients with coronary artery disease (CAD). Methods: We prospectively enrolled 28 participants: 11 patients with angiographically significant CAD and 17 controls. Intravascular ultrasound (IVUS) and 3-dimensional reconstruction of coronary arteries was performed in the patient subgroup. Results: Cholesterol content of erythrocyte membranes was higher in patients compared to controls (P < .01). Cholesterol content of erythrocyte membranes correlated with total atheroma volume (r = .82, P < .01) and with percentage plaque area at the vessel site with minimal lumen area (r = .75, P < .05). On multivariate analysis, CEM was the only variable independently predicting total atheroma volume (P = .05). Conclusions: This pilot study is the first to demonstrate a significant relation between CEM and coronary atherosclerotic burden, suggesting a possible role of erythrocyte membrane—derived lipids in the expansion of atheromata. The results merit validation in larger studies.

Effect of the local hemodynamic environment on the de novo development and progression of eccentric coronary atherosclerosis in humans: Insights from PREDICTION

BACKGROUND Eccentric distribution of atheroma has been associated with plaques likely to rupture and cause an acute coronary syndrome, but the factors responsible for the development of eccentricity remain unknown. Endothelial shear stress (ESS) drives plaque formation. We aimed to investigate the role of the local ESS characteristics in the de novo development and progressive worsening of plaque eccentricity in humans. METHODS Vascular profiling (3-vessel 3D coronary reconstruction by angiography/intravascular ultrasound, and blood flow simulation for ESS computation) was performed in 374 patients at baseline & 6-10 months follow-up. At baseline, we identified (i) disease-free segments (n=2157), and (ii) diseased regions of luminal obstructions (n=408). RESULTS In disease-free regions, baseline low ESS magnitude (p<0.001), marked ESS circumferential heterogeneity (p=0.001), and their interaction (p=0.026) were associated with an increased probability of de novo eccentric plaque formation at follow-up. In diseased regions, baseline low ESS (odds ratio [OR]: 2.33, p=0.003) and large plaque burden (OR: 2.46, p=0.002) were independent predictors of substantially increasing plaque eccentricity index with worsening lumen encroachment. This combined outcome was more frequent in obstructions with both features vs. all others (33 vs. 12%; p<0.001). The incidence of percutaneous coronary intervention in worsening obstructions with increasing plaque eccentricity was higher (13.3 vs. 4.3%, p=0.011). CONCLUSIONS The local hemodynamic environment has a critical effect on the development of eccentric coronary plaques at both an early and advanced stage of atherosclerosis. Local ESS assessment could help in predicting sites prone to plaque disruption and acute coronary syndromes in humans.

Pneumonia caused by Candida krusei and Candida glabrata in a patient with chronic myeloid leukemia receiving imatinib mesylate treatment

In this report we describe a patient suffering from chronic myeloid leukemia (CML), who was treated for 4.5 years with imatinib and developed pneumonia caused by two Candida species, i.e., C. krusei and C. glabrata. The patient was in complete hematologic remission and molecular analyses did not display the presence of TLR2-R752Q, TLR4-D299G and TLR4-T399I polymorphisms that may predispose individuals to fungal infections. This case report indicates that in some patients, as previously observed, the long-term administration of targeted therapy might affect immunity and predispose patients to opportunistic and life-threatening fungal infections.

How do we prevent the vulnerable atherosclerotic plaque from rupturing? Insights from in vivo assessments of plaque, vascular remodeling, and local endothelial shear stress.

Coronary atherosclerosis progresses both as slow, gradual enlargement of focal plaque and also as a more dynamic process with periodic abrupt changes in plaque geometry, size, and morphology. Systemic vasculoprotective therapies such as statins, angiotensin-converting enzyme inhibitors, and antiplatelet agents are the cornerstone of prevention of plaque rupture and new adverse clinical outcomes, but such systemic therapies are insufficient to prevent the majority of new cardiac events. Invasive imaging methods have been able to identify both the anatomic features of high-risk plaque and the ongoing pathobiological stimuli responsible for progressive plaque inflammation and instability and may provide sufficient information to formulate preventive local mechanical strategies (eg, preemptive percutaneous coronary interventions) to avert cardiac events. Local endothelial shear stress (ESS) triggers vascular phenomena that synergistically exacerbate atherosclerosis toward an unstable phenotype. Specifically, low ESS augments lipid uptake and catabolism, induces plaque inflammation and oxidation, downregulates the production, upregulates the degradation of extracellular matrix, and increases cellular apoptosis ultimately leading to thin-cap fibroatheromas and/or endothelial erosions. Increases in blood thrombogenicity that result from either high or low ESS also contribute to plaque destabilization. An understanding of the actively evolving vascular phenomena, as well as the development of in vivo imaging methodologies to identify the presence and severity of the different processes, may enable early identification of a coronary plaque destined to acquire a high-risk state and allow for highly selective, focal preventive interventions to avert the adverse natural history of that particular plaque. In this review, we focus on the role of ESS in the pathobiologic processes responsible for plaque destabilization, leading either to accelerated plaque growth or to acute coronary events, and emphasize the potential to utilize in vivo risk stratification of individual coronary plaques to optimize prevention strategies to preclude new cardiac events.