Role of Platelets in the Pathogenicity of Atherosclerosis and Thrombosis in Coronary Heart Diseases

Atherosclerosis is a chronic inflammatory process that results in coronary artery disease, peripheral artery disease and in many cases of stroke. It is a disease that involves multiple inflammatory cytokine which is regarded as the primary underlying cause of cardiovascular diseases (CVD). CVD is the leading cause of death in the developed and developing countries like Nigeria. From pathological perspective, the chronic inflammatory condition of atherosclerosis occurs due to interplay between platelets, monocytes, macrophages. Physiologically platelets play a significant role in coagulation and repair of endothelial injury. Pathologically, studies have shown that activated platelets release multiple inflammatory cytokines and chemokines that serve as positive mediators of atherosclerosis. This chemokine is (RANTES, P-selectin and PF-4). Activated platelet release p-selectin that mediate platelet adhesion and rolling to injured endothelial cell, RANTES trigger the recruitment of monocytes into the sub- endothelium and PF4 promote the differentiation of monocytes into macrophages in the intimal layer of the endothelium which engulf ox-LDL to form FOAM cells. Thus, the aim of this review is to understand and describe the role of activated platelets in atherosclerosis as well as therapeutic target of these platelet inflammatory chemokines which is the major mediator of atherosclerosis in human.

B- mode ultrasound- guided balloon angioplasty of occluded artery accompanied by combined focused ultrasound sonodynamic therapy and catheter- based 192Ir- mediated brachytherapy

Background and aims Three mechanisms are responsible for the development of restenosis: elastic recoil, intimal hyperplasia and late vascular constriction, all grouped under the catch phrase “negative remodeling”. Neointimal hyperplasia is usually defined in an artery as thickening of the intimal layer after an injury such as balloon angioplasty methods. The aim of this study was to evaluate the effect of combined ultrasound sonodynamic therapy and catheter- based 192Ir-mediated β-brachytherapy on restenosis reduction after balloon angioplasty. Methods Briefly, golden Syrian hamsters were submitted to common carotid artery advanced atherosclerotic occlusion by primary perivascular Co2 laser-mediated far-infrared injury followed by a 2% cholesterol-rich diet for six weeks. Histopathology results showed the formation of a thick-cap fibroatheromatic plaque, resulted to occlusion in all of the hamsters' arteries. Then treatment group (n=10) underwent B-mode ultrasound-guided balloon angioplasty followed by combined pulsed low level focused ultrasound (F=750 KHz, I=1.5 W/cm2, PD=120 ms)-mediated sonosensitizer protoporphyrin-IX-loaded PESDA (Perfluorocarbon Exposed Sonicated Dextrose Albumin) microbubbles (100ml/kg, 2–5×105 bubbles/ml) sonodynamic therapy and catheter- based β-brachytherapy (125I−, 18 Gy). Results Results from ultrasonography and histopathology showed a significant reduction in the mean value for macrophages and smooth muscle hyperplasia cells density after balloon angioplasty in the treated group compared with the other groups (p<0.05). Conclusions Enhanced anti-inflammatory effect of sonodynamic therapy, induced by collapsed microbubbles accompanied by apoptotic effect of β-brachytherapy, can cause to reduce the inflammation and smooth muscle hyperplasia cells in the intimal layer. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab

Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study

A physiologically based model describing the dissolution, diffusion, and transfer of drug from the intra-articular (IA) space to the plasma, was developed for GastroPlus® v9.8. The model is subdivided into compartments representing the synovial fluid, synovium, and cartilage. The synovium is broken up into two sublayers. The intimal layer acts as a diffusion barrier between the synovial fluid and the subintimal layer. The subintimal layer of the synovium has fenestrated capillaries that allow the free drug to be transported into systemic circulation. The articular cartilage is broken up into 10 diffusion sublayers as it is much thicker than the synovium. The cartilage acts as a depot tissue for the drug to diffuse into from synovial fluid. At later times, the drug will diffuse from the cartilage back into synovial fluid once a portion of the dose enters systemic circulation. In this study, a listing of all relevant details and equations for the model is presented. Methotrexate was chosen as a case study to show the application and utility of the model, based on the availability of intravenous (IV), oral (PO) and IA administration data in patients presenting rheumatoid arthritis (RA) symptoms. Systemic disposition of methotrexate in RA patients was described by compartmental pharmacokinetic (PK) model with PK parameters extracted using the PKPlus™ module in GastroPlus®. The systemic PK parameters were validated by simulating PO administration of methotrexate before being used for simulation of IA administration. For methotrexate, the concentrations of drug in the synovial fluid and plasma were well described after adjustments of physiological parameters to account for RA disease state, and with certain assumptions about binding and diffusion. The results indicate that the model can correctly describe PK profiles resulting from administration in the IA space, however, additional cases studies will be required to evaluate ability of the model to scale between species and/or doses.

Endovascular therapies for Type B Aortic Dissection

: Aortic dissection is a life-threatening condition resulting from a tear in the intimal layer of the aorta, requiring emergent diagnosis and prompt multi-disciplinary management strategy for best patient outcomes. While type A dissection involving ascending aorta is best managed surgically due to high early mortality, type B aortic dissection (TBAD) involving descending aorta generally has better outcomes with conservative management and medical therapy as primary strategy is favored. However, there has been a recent paradigm shift in management of TBAD due to late aneurysmal degeneration of TBAD increasing morbidity and mortality at longer-term. Late surgical intervention can be prevented by early endovascular intervention when combined with optimal medical therapy. In this narrative review, we explore available literature on different endovascular therapies for TBAD in different populations of patients.

Giant Pulmonary Artery Thrombotic Material, Due to Chronic Thromboembolic Pulmonary Hypertension, Mimics Pulmonary Artery Sarcoma

In this article, we present the case of a 38-year-old female who suffered from serious respiratory distress. After an extensive pulmonary artery imaging diagnostic work-up (CTPA, MRA and PET), we were unable to differentiate between chronic thromboembolic pulmonary hypertension (CTEPH) vs. pulmonary artery sarcoma (PAS) due to extensive filling defects and extraluminal findings. Although surgery was postponed for nine months due to the COVID-19 pandemic, CTEPH diagnosis, due to a high-thrombus burden, was finally confirmed after pulmonary endarterectomy (PEA). Conclusively, imaging findings of rare cases of CTEPH might mimic PAS and the surgical removal of the lesion are both needed for a final diagnosis. What is Already Known about This Topic? Pulmonary artery sarcoma (PAS) is a rare but aggressive malignancy, which originates from the intimal layer of the pulmonary artery (PA); Chronic thromboembolic pulmonary hypertension (CTEPH) is based on chronic, organized flow-limiting thrombi inside PA circulation and subsequent pulmonary hypertension. What Does This Study Contribute? Since radiological findings of CTEPH cases might rarely mimic PAS, pulmonary artery endarterectomy and subsequent histopathologic study are needed for a final diagnosis.

Cellularized small-caliber tissue-engineered vascular grafts: looking for the ultimate gold standard

Due to the lack of efficacy of synthetic vascular substitutes in the replacement of small-caliber arteries, vascular tissue engineering (VTE) has emerged as a promising solution to produce viable small-caliber tissue-engineered vascular grafts (TEVG). Previous studies have shown the importance of a cellular intimal layer at the luminal surface of TEVG to prevent thrombotic events. However, the cellularization of a TEVG seems to be a critical approach to consider in the development of a TEVG. To date, no standard cellularization method or cell type has been established to create the ideal TEVG by promoting its long-term patency and function. In this review, advances in VTE are described and discussed with a particular focus on the construction approaches of cellularized small-caliber TEVGs, the cell types used, as well as their preclinical and clinical applications.

Association of Cigarette Smoking with Thickness of Intimal Layer of Carotid Arteries on Color Doppler Ultrasound Study and Its Surgical Management

Objectives: Aim of this study is to evaluate the intimal vessel wall thickness in smoker and their co-relation with non-smoker and also surgical management of stenosis. Material and Methods: It is a prospective study of 55 cases. Study span and follow up duration were 4 months. Our patients were presented with the history of CVA (Cerebrovascular accident), hypertension, diabetes, and headache. Results: In all patients, the carotid doppler ultrasound was done and their intimal vessel wall thickness was noted. Our 78% patients were smoker and non-smoker was 22%. In our study, 52% patients had CVA, 41% patients had hypertension, 30% patients had headache and 9% patients were also obese. Forty three smokers used to take 15 – 25 cigarettes daily. Among 43 patients, 5 patients were females. In carotid Doppler study, intimal thickness was increased in 87%, the plaque was observed in 49% and stenosis was observed in 38% cases. In 18 % patients, who had stenosis > 70%, carotid endarterectomy was performed and in rest of the patients medical treatment done.Patients who were chronic smokers and had medical co-morbidities showed greater thickness of intimal layer of vessels on carotid Doppler. In 6 patients, post-operative headache occurred. Conclusion: Smokers had more thickness of intimal layer of carotid vessels. Carotid endarterectomy yields good results in case of stenosis more than 70%. Keywords: Cerebrovascular accident, Intimal layer thickness, Carotid doppler ultrasound, Cigarette smoking

Biology and pathology of atherosclerosis

Atherosclerotic plaques are not randomly distributed, but tend to form at the inner curvatures and branch points of arteries, where laminar flow is either disturbed or insufficient to support the normal, quiescent state of the endothelium (the lining of endothelial cells that separates the circulating blood from the arterial wall). This is an inflammatory process that involves the contribution of endothelial cells, lymphocytes, monocytes, and smooth muscle cells in conjunction with the deposition of atherogenic lipoproteins in the intimal layer of the vascular wall. The initial stage involves activation of the endothelium at regions of non-laminar flow in vessels resulting in increased permeability to Apo B-containing lipoproteins. Inflammatory cells, in particular monocytes, are recruited into the intimal layer of the vessel wall via the action of chemokines and adhesion molecules mobilized by activated endothelium.

The influence of purification of carp collagen used in a novel composite graft with sandwich construction of the wall on its biological properties and graft patency rates

We compared graft outcome between two types of a novel composite three-layer carp-collagen-coated vascular graft in low-flow conditions in a sheep model. Collagen in group A underwent more cycles of purification than in group B in order to increase the ratio between collagen and residual fat. The grafts were implanted end-to-side in both carotid arteries in sheep (14 grafts in 7 sheep in group A, 18 grafts in 9 sheep in group B) and artificially stenosed on the right side. The flow in the grafts in group A decreased from 297±118 ml/min to 158±159 ml/min (p=0.041) after placement of the artificial stenosis in group A, and from 330±164ml/min to 97±29 ml/min (p=0.0052) in group B (p=0.27 between the groups). From the five surviving animals in group A, both grafts occluded in one animal 3 and 14 days after implantation. In group B, from the six surviving animals, only one graft on the left side remained patent (p=0.0017). Histology showed degradation of the intimal layer in the center with endothelization from the periphery in group A and formation of thick fibrous intimal layer in group B. We conclude that the ratio between collagen and lipid content in the novel three-layer graft plays a critical role in its patency and structural changes in vivo.