George D. Giannoglou

Endothelial shear stress in the evolution of coronary atherosclerotic plaque and vascular remodelling: Current understanding and remaining questions

The heterogeneity of plaque formation, the vascular remodelling response to plaque formation, and the consequent phenotype of plaque instability attest to the extraordinarily complex pathobiology of plaque development and progression, culminating in different clinical coronary syndromes. Atherosclerotic plaques predominantly form in regions of low endothelial shear stress (ESS), whereas regions of moderate/physiological and high ESS are generally protected. Low ESS-induced compensatory expansive remodelling plays an important role in preserving lumen dimensions during plaque progression, but when the expansive remodelling becomes excessive promotes continued influx of lipids into the vessel wall, vulnerable plaque formation and potential precipitation of an acute coronary syndrome. Advanced plaques which start to encroach into the lumen experience high ESS at their most stenotic region, which appears to promote plaque destabilization. This review describes the role of ESS from early atherogenesis to early plaque formation, plaque progression to advanced high-risk stenotic or non-stenotic plaque, and plaque destabilization. The critical implication of the vascular remodelling response to plaque growth is also discussed. Current developments in technology to characterize local ESS and vascular remodelling in vivo may provide a rationale for innovative diagnostic and therapeutic strategies for coronary patients that aim to prevent clinical coronary syndromes.

The syndrome of rhabdomyolysis: Complications and treatment

Rhabdomyolysis is a syndrome of skeletal muscle cell damage that leads to the release of toxic intracellular material into the systemic circulation. The pathogenesis of rhabdomyolysis is based on an increase in free ionized calcium in the cytoplasm. Its main complications include (a) acute renal failure, which is triggered by renal vasoconstriction and ischemia, (b) myoglobin cast formation in the distal convoluted tubules, and (c) direct renal toxic effect of myoglobin on the epithelial cells of proximal convoluted tubules. Other major complications include electrolyte disorders, such as hyperkalemia, which may cause cardiac arrhythmias, metabolic acidosis, hyperphosphatemia, early hypocalcemia, and late hypercalcemia. Compartmental syndrome and disseminated intravascular coagulopathy may also emerge. The management of myoglobinuric acute renal failure includes aggressive fluid administration to restore the hypovolemia and urine alkalization. The concomitant electrolyte and metabolic disorders should also be treated appropriately; hemodialysis should be considered when life-threatening hyperkalemia and metabolic acidosis exist. In the case of compartmental syndrome, it is important to monitor the intra-compartmental pressure and to perform fasciotomy, if required. When diagnosed early and if the appropriate treatment is initiated promptly, the complications of rhabdomyolysis are preventable and the syndrome has a good prognosis.

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.

Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment

HMG-CoA reductase inhibitors (‘statins’) represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of statins, the patient population suitable for long-term statin treatment is expected to further expand. An overall positive safety and tolerability profile of statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical.The purpose of this review is to summarize the factors that increase the risk of statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant inter-individual variability in the myopathic risk are presented. Physicochemical properties of statins have been implicated in the differential risk of currently marketed statins. Pharmacokinetic interactions with concomitant medications that interfere with statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of statins with other classes of lipid-lowering agents; current data on the relative safety of available combinations are summarized. Finally, we provide an update of current guidelines for the prevention and management of statin myopathy.The identification of patients with an increased proclivity to statin-induced myopathy could allow more cost-effective approaches of monitoring and screening, facilitate targeted prevention of potential complications, and further improve the already overwhelmingly positive benefit-risk ratio of statins.

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.

Haemodynamic factors and the important role of local low static pressure in coronary wall thickening

UNLABELLED BACKGROUND/STUDY OBJECTIVES: The purpose of our study was to investigate the possible correlation between blood flow physical parameters and the wall thickening in typical human coronary arteries. METHODS Digitized images of seven transparent arterial segments prepared post-mortem were adopted from a previous study in order to extract the geometry for numerical analysis. Using the exterior outline, reconstructed forms of the vessel geometries were used for subsequent computational fluid dynamic analysis. Data was input to a pre-processing code for unstructured mesh generation. The flow was assumed to be two-dimensional, steady, laminar with parabolic inlet velocity profile. The vessel walls were assumed to be smooth, inelastic and impermeable. Non-Newtonian power law was applied to model blood rheology. The arterial wall thickening was measured and correlated to the wall shear stress, static pressure, molecular viscosity, and near wall blood flow velocity. RESULTS Wall shear stress, static pressure and near wall velocity magnitude exhibit negative correlation to wall thickening, while molecular viscosity exhibits positive correlation to wall thickening. CONCLUSION There is a strong correlation between the development of vessel wall thickening and the blood flow physical parameters. Amongst these parameters the role of local low wall static pressure is predominant.

Safety of dental extractions during uninterrupted single or dual antiplatelet treatment.

Optimal dental management in patients on long-term antiplatelet treatment is not clearly defined. Antiplatelet discontinuation increases the risk of thrombotic complications, whereas uninterrupted antiplatelet therapy, which is the currently recommended approach, is assumed to increase the bleeding hazard after dental procedures. We sought to prospectively compare the risk of immediate and late postextraction bleeding in patients receiving uninterrupted single or dual antiplatelet therapy. We recruited 643 consecutive patients referred for dental extractions. In total 111 (17.3%) were on clinically indicated antiplatelet therapy: aspirin (n = 42), clopidogrel (n = 36), and aspirin and clopidogrel (n = 33). Controls (n = 532, 82.7%) were not on antiplatelet treatment. Immediate and late bleeding complications were recorded. Compared to controls the risk of prolonged immediate bleeding was higher in patients on dual antiplatelet therapy (relative risk [RR] 177.3, 95% confidence interval [CI] 43.5 to 722, p <0.001) but not in patients on aspirin alone (RR = 6.3, 95% CI 0.6 to 68.4, p = 0.2) or clopidogrel alone (RR = 7.4, 95% CI 0.7 to 79.5, p = 0.18); however, all immediate bleeding complications in all treatment groups were successfully managed with local hemostatic measures. No patient developed any late hemorrhage. In conclusion, dental extractions may be safely performed in patients receiving single or dual antiplatelet therapy when appropriate local hemostatic measures are taken, thus averting thrombotic risk of temporary antiplatelet discontinuation.

IMAGE ANALYSIS TECHNIQUES FOR AUTOMATED IVUS CONTOUR DETECTION

Intravascular ultrasound (IVUS) constitutes a valuable technique for the diagnosis of coronary atherosclerosis. The detection of lumen and media-adventitia borders in IVUS images represents a necessary step towards the reliable quantitative assessment of atherosclerosis. In this work, a fully automated technique for the detection of lumen and media-adventitia borders in IVUS images is presented. This comprises two different steps for contour initialization: one for each corresponding contour of interest and a procedure for the refinement of the detected contours. Intensity information, as well as the result of texture analysis, generated by means of a multilevel discrete wavelet frames decomposition, are used in two different techniques for contour initialization. For subsequently producing smooth contours, three techniques based on low-pass filtering and radial basis functions are introduced. The different combinations of the proposed methods are experimentally evaluated in large datasets of IVUS images derived from human coronary arteries. It is demonstrated that our proposed segmentation approaches can quickly and reliably perform automated segmentation of IVUS images.

Spatial and phasic oscillation of non-newtonian wall shear stress in human left coronary artery bifurcation : an insight to atherogenesis

ObjectiveTo investigate the wall shear stress oscillation in a normal human left coronary artery bifurcation computational model by applying non-Newtonian blood properties and phasic flow. MethodsThe three-dimensional geometry of the investigated model included the left main coronary artery along with its two main branches, namely the left anterior descending and the left circumflex artery. For the computational analyses a pulsatile non-Newtonian flow was applied. To evaluate the cyclic variations in wall shear stress, six characteristic time-points of the cardiac cycle were selected. The non-Newtonian wall shear stress variation was compared with the Newtonian one. ResultsThe wall shear stress varied remarkably in time and space. The flow divider region encountered higher wall shear stress values than the lateral walls throughout the entire cardiac cycle. The wall shear stress exhibited remarkably lower and oscillatory values in systole as compared with that in diastole in the entire bifurcation region, especially in the lateral walls. Although the Newtonian wall shear stress experienced consistently lower values throughout the entire cardiac cycle than the non-Newtonian wall shear stress, the general pattern of lower wall shear stress values at the lateral walls, particularly during systole, was evident regardless of the blood properties. ConclusionsThe lateral walls of the bifurcation, where low and oscillating wall shear stress is observed, are more susceptible to atherosclerosis. The systolic period, rather than the diastolic one, favors the development and progression of atherosclerosis. The blood viscosity properties do not seem to qualitatively affect the spatial and temporal distribution of the wall shear stress.

Predicting the Risk of Rupture of Abdominal Aortic Aneurysms by Utilizing Various Geometrical Parameters: Revisiting the Diameter Criterion

The authors estimated noninvasively the wall stress distribution for actual abdominal aortic aneurysms (AAAs) in vivo on a patient-to-patient basis and correlated the peak wall stress (PWS) with various geometrical parameters. They studied 39 patients (37 men, mean age 73.7 ± 8.2 years) with an intact AAA (mean diameter 6.3 ± 1.7 cm) undergoing preoperative evaluation with spiral computed tomography (CT). Real 3-dimensional AAA geometry was obtained from image processing. Wall stress was determined by using a finite-element analysis. The aorta was considered isotropic with linear material properties and was loaded with a static pressure of 120.0 mm Hg. Various geometrical parameters were used to characterize the AAAs. PWS and each of the geometrical characteristics were correlated by use of Pearsons rank correlation coefficients. PWS varied from 10.2 to 65.8 N/cm2 (mean value 37.1 ± 9.9 N/cm2). Among the geometrical parameters, the PWS was well correlated with the mean centerline curvature, the maximum centerline curvature, and the maximum centerline torsion of the AAAs. The correlation of PWS with maximum diameter was nonsignificant. Multiple regression analysis revealed that the mean centerline curvature of the AAA was the only significant predictor of PWS and subsequent rupture risk. This noninvasive computational approach showed that geometrical parameters other than the maximum diameter are better indicators of AAA rupture.