Endothelial dysfunction (ED) plays a substantial role in the pathogenesis of atherosclerosis and some other vascular diseases. ED has been demonstrated in patients with hypercholesterolemia, ...diabetes, smoking, hypertension, and in patients with atherosclerotic disease. Besides classical risk factors, ED is affected by chronic inflammatory diseases and acute infections, particularly viral diseases. Causes of ED include oxidative stress, inflammation, and shear stress, which decrease the bioavailability of nitric oxide. Markers of ED have been sought, particularly circulating markers. Using these tests, it is possible to evaluate the response to harmful effects of risk factors and the effects of treatment on vessel wall function. Endothelial dysfunction is significantly and directly correlated with the occurrence of cardiac events and the risk of cardiac events increase as ED worsens. Because endothelial function plays a central role in atherogenesis it became a therapeutic target. Endothelial dysfunction is reversible and its improvement may be achieved by elimination of risk factors, inhibitors of endothelium-derived contracting factors (angiotensin-converting enzyme), smoking cessation, lipid-lowering drugs, diet, and physical exercise. By reversing ED, it is possible to restore vascular function.
Abstract
The inflammatory process is strongly involved in the pathophysiology of venous thromboembolism (VTE) and has a significant role in disease prediction. Inflammation most probably represents a ...common denominator through which classical and nonclassical risk factors stimulate thrombotic process. Inflammation of the venous wall promotes the release of tissue factor, inhibits the release of anticoagulant factors, and hampers endogenous fibrinolysis. Systemic inflammatory response also inhibits restoration of blood flow in the occluded vessel. Recent studies indicate that increased inflammatory response (“cytokine storm”) is related to prothrombotic state and thromboembolic events in patients with coronavirus disease 2019 (COVID-19). The growing evidence of involvement of inflammation in the pathogenesis of VTE indicates the importance of anti-inflammatory treatment and prevention of VTE. While aspirin was shown to be effective in prevention of recurrent venous thrombosis after treatment with anticoagulant drugs, some other anti-inflammatory drugs like nonsteroidal anti-inflammatory agents may have prothrombotic effect, thus potentially increasing the risk of VTE. Recently, new specific anti-inflammatory drug inhibitors of inflammatory markers that have been shown to be involved in the pathogenesis of VTE are being searched. As thrombogenesis is based on activation of coagulation provoked by inflammation, then prevention and treatment of VTE should include both anticoagulant and anti-inflammatory agents. Combined treatment is related to increased risk of bleeding complications, therefore subtherapeutic doses of both drugs should be used to improve the efficacy of management of VTE without increasing the risk of bleeding.
Endothelial dysfunction as an integrating index of the risk factor burden and genetic susceptibility is an early marker of atherothrombotic disease. Therefore, tremendous interest exists in its ...measurement and determination of the clinical utility of the evaluation of endothelial function. Different invasive and non-invasive techniques exist for exploring various aspects of the pathobiology of the endothelium. As endothelial dysfunction is a diffuse-systemic disorder, the peripheral arteries, because of their accessibility, represent the basis for assessment of endothelial dysfunction. Flow-mediated dilation (FMD) of the peripheral conduit arteries is one of the most widely used tests of endothelial function. FMD measures the endothelial vasomotor response during reactive hyperemia, but it does not provide information concerning the control of arterial tone at rest. A new technique, low-flow-mediated constriction (L-FMC), provides complementary information to that by FMD, quantifying the decrease in the forearm conduit artery diameter that occurs in response to the decrease in blood flow during occlusion. This indicated that the L-FMC response is not based on nitric oxide availability but it might be mediated by other substances, providing a coordinated effect of vasodilation and its inhibition; therefore, simultaneous determination of FMD and L-FMC may provide comprehensive information on vascular homeostasis. Peripheral arterial tonometry (PAT) evaluates pulse wave amplitude, which is linked to endothelial function. Like FMD, PAT has also been shown to be reduced in the presence of risk factors, as well as in patients with atherosclerosis; however, FMD of the brachial artery and PAT are very different methods for identification of the vascular reactivity of different arterial territories. FMD directly registers the dilation capability of the large-conduit artery, whereas PAT measures flow response hyperemia, which is related to the endothelial function of small arteries and to the endothelial function of the microcirculation. Therefore, this technique is mostly used for investigation of the functional capability of the microcirculation. Determination of venous endothelial dysfunction is more complicated and invasive and is less reproducible. Micro-invasive techniques such as the dorsal hand vein technique and radionuclide assessment of changes in volume of the legs provide limited information about venous endothelial health; however, as endothelial dysfunction is expected to be a systemic disorder affecting the complete circulatory system, determination of the endothelial function of peripheral arteries also gives insight into venous functional status.
The functional capacity of patients with peripheral arterial disease (PAD) represents an important indicator of patient health and quality of life. The aim of this prospective study was to ...investigate the validity of a walking impairment questionnaire (WIQ) compared with walking tests for the estimation of the therapeutic effect of lower limb revascularization. The study included 36 patients with PAD in whom successful percutaneous revascularization of a lower limb was performed due to disabling intermittent claudication. Before the revascularization procedure and 4–6 weeks after successful revascularization, clinical examination, ankle brachial index (ABI) measurement, 6-min walk test, treadmill test, and WIQ were performed. After revascularization, significant improvement in walking capacity was shown by both 6-min walk test and treadmill exercise test as well as with WIQ. However, the increase in ABI was borderline. Significant correlations between improvement of 6-min walk test and treadmill exercise test results and the sum of WIQ points were found. The ABI was significantly correlated with treadmill maximal walking distance only. According to our results, the WIQ correlates well with walking tests and is a reliable indicator of effective revascularization of lower limb arterial occlusions, even in patients with a nonsignificant improvement of the ABI.
Osteoarthritis (OA) is a chronic condition marked by joint pain, inflammation and loss of articular cartilage, that can be treated with total joint arthroplasty (TJA) at end stages. TJA is marked by ...post-operative inflammation, which directly effects levels of cartilage degradation biomarkers, proteoglycan-4 (PRG4) and matrix metalloproteinase-9 (MMP-9). PRG4 is a protective glycoprotein that is decreased in individuals with OA. MMP-9 is a matrix metalloproteinase that contributes to articular cartilage loss and is elevated in OA patients. It is upregulated by pro-inflammatory markers, such as IL-1, IL-6 and CRP. This study aims to elucidate the immediate post-operative changes in levels of PRG4, MMP-9, IL-6, CRP, and WBC in patients undergoing TJA to clarify the role of inflammation in recovery after surgery and in the overall pathogenesis of OA. Blood was collected at 3 time points (day 0, day 1 post-operatively, and days 5-7 post-operatively), from 63 patients undergoing TJA due to OA, and levels of these biomarkers were quantified. IL-6, CRP, WBC and MMP-9 were lowest at day 0, highest at day 1, and stabilized at an intermediate level at days 5-7. Meanwhile, PRG4 followed the opposite trend. These studies suggest that IL-6, CRP and WBC showed predictable fluctuations, with pro-inflammatory biomarkers upregulating MMP-9 and downregulating PRG4. Measuring these biomarkers may help expose the role of inflammation in the post-surgical recovery of TJA patients and in long-term pathogenesis of OA. These levels may help risk stratify patients pre-operatively and help develop individualized post-surgical plans.
Atherosclerosis is a systemic disease with different faces. Despite similar, or even identical, risk factors and pathogenesis, atherosclerotic lesions and their clinical manifestations vary in ...different parts of the vasculature. Peripheral arterial disease (PAD) in the superficial femoral artery (SFA) represents a frequent clinical manifestation of atherosclerotic disease. The pathohistological characteristics of plaques in PAD differ from lesions in the coronary arteries. Plaques in the SFA have more fibrotic elements with less lipid and degenerative tissue elements; this makes them more stable and less prone to rupture. The density of vasa vasorum, an important determinant of structure and stability of atherosclerotic lesions, is significantly lower in PAD than in coronary arteries. Further, haemodynamic forces and shear stress vary in different segments of the arterial tree and influence the development of atherosclerotic lesions and their stability. It follows that the clinical consequences differ depending on the vascular territory involved. In the coronary arteries, acute thrombotic occlusion with clinical manifestation of myocardial infarction is one of the most frequent manifestations due to unstable atherosclerotic lesions. Atherosclerotic lesions in SFA progress slowly and are more stable; therefore, clinical manifestations develop more gradually.
The atherosclerotic process in SFA is frequently asymptomatic or presents as stable intermittent claudication, and in a relatively low percentage, progresses to critical limb ischaemia. Also, remodelling of the arterial wall in peripheral arteries compensates for the reduction of arterial lumen and provides blood flow in spite of relatively large atherosclerotic lesions. However, arterial restenosis after recanalization procedures in SFA reduces the long-term success of recanalization.
Carotid atherosclerotic lesions are correlated with atherosclerotic deterioration of the arterial wall in other vascular territories and with cardiovascular events. The detection of pre-symptomatic ...carotid lesions like intima-media thickness (IMT) and asymptomatic carotid plaques is possible by non-invasive ultrasound duplex scanning. Current measurement guidelines suggest an average measurement of IMT within 10 mm of the segment of the common carotid artery. The thickening of intima-media appears in a long subclinical period of atherosclerosis. Therefore, the determination of IMT has emerged as one of the methods for determining early structural deterioration of the arterial wall. A close interrelationship was shown between IMT and risk factors of atherosclerosis, their duration, and intensity. Different studies demonstrated that increased IMT is a powerful predictor of coronary, cerebrovascular, and peripheral arterial occlusive disease and their complication. A recent meta-analysis indicated a minimal improvement in the risk estimation of cardiovascular events after adding IMT to the Framingham Risk Score. These findings influenced the latest ACC/AHA guidelines which again recommend the use of carotid IMT measurement for individual risk assessment. The presence of atherosclerotic plaques indicates that the atherosclerotic process is already ongoing. The findings of different studies are equivocal that carotid plaques independently predict cardiovascular events and improve risk predictions for coronary artery disease when added to the Framingham Risk Score. However, besides the size of plaque and grade of stenosis, the structure of plaque calcification, vascularization, lipid core, and the surface of plaques are important indicators of related risks for cardiovascular events.
Our study aimed to investigate the levels and time-course of systemic inflammatory and hemostasis markers in the early postoperative period in patients undergoing total hip replacement (THR). The ...study included 70 patients of both sexes, average age 68.4 ± 10.9 years. Levels of inflammatory and hemostasis markers were measured before surgery (POD 0), a day after the surgery (POD 1) and 5 days after surgery (POD 5). In the postoperative period inflammatory markers increased. The operation provoked a significant increase of CRP on POD 1 in comparison to POD 0 (68.5 ± 5.4 vs 6.8 ± 2.2 μg/mL, p < 0.001) and the additional increase was registered on POD 5 (87.5 ± 8.1 vs 68.5 ± 5.4 μg/mL, p < 0.001). Interleukin-6 significantly increased on POD 1 (251.5 ± 21.6 vs 14.6 ± 7.1 μg/mL, p < 0.001) and after that (POD 5) decreased. After surgery leukocyte count, neutrophil/lymphocyte ratio and platelet/lymphocyte ratio were significantly higher compared to POD 0. Activation of coagulation in the postoperative period was shown by increased peak thrombin on POD 5 in comparison to POD 0 (185 ± 27 vs. 124 ± 31 nM, p < 0.001). D-dimer was increased on POD 1 and an additional rise was observed on POD 5. vWF also progressively increased in the observed period. Results of our study showed that after THR systemic inflammatory markers increased and coagulation function was enhanced. Determination of inflammatory and procoagulant markers could help identify patients at risk for cardiovascular thromboembolic events.
Osteoarthritis (OA) is a degenerative joint disease characterized by loss of articular cartilage, inflammation and pain, which sometimes necessitates total joint arthroplasty (TJA). Profiling ...biomarkers of cartilage degradation and inflammation is a promising area of research to understand the pathogenesis of OA. This study aims to report the post-operative fluctuations of 3 biomarkers of OA, osteopontin (OPN), matrix metalloproteinase-9 (MMP-9), and ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), in patients undergoing TJA to further define the interaction among these biomarkers and delineate their role in OA pathogenesis. OPN is an extracellular matrix (ECM) glycoprotein with increased activity in OA and joint damage and is upregulated by either inflammation or cleavage by MMPs and thrombin. MMP-9 is known to cleave OPN and is upregulated by inflammatory markers, such as IL-1, IL-6 and CRP. ADAMTS4 is an enzyme that degrades aggrecan, a major component of cartilage. These biomarkers were measured in deidentified blood samples collected on the day of surgery, 1 day post-operatively, and day 5-7 post-operatively. MMP-9 and OPN levels were significantly elevated at all times, and ADAMTS4 was significantly decreased at baseline versus controls. OPN and ADAMTS4 inversely fluctuated post-operatively, indicating an interrelation between these 2 biomarkers. This study suggests that the upregulation of MMP-9 and therefore OPN then results in the downregulation of ADAMTS4. The relationship between OPN and thrombin also highlights the importance of monitoring for thrombotic complications. These biomarkers, along with thrombin-mediated cleavage products, may be helpful in the prognostic management of OA patients.
Aim: Inflammation is highlighted in the pathogenesis and destabilization of atherosclerotic lesions. Noninvasive identification of inflammation of atherosclerotic lesions has been challenging. ...18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is a useful technique for detecting inflamed atherosclerotic plaques in vivo. However, it is time consuming, expensive, and accompanied by radiation. Therefore, we investigated the relationship between levels of circulating inflammatory markers and the degree of inflammation of atherosclerotic plaques shown by 18F-FDG uptake. We aimed to identify high-risk patients with inflamed, unstable atherosclerotic plaques on the basis of the determination of inflammatory markers.Methods: The study included 37 patients, 21 with high-grade stenosis of internal carotid artery (ICA group) and 16 with occlusion of common femoral artery (CFA group), who underwent endarterectomy. Mean age of the study population was 69.43±6.2 years. Eight out of 21 patients with ICA stenosis and all patients with CFA occlusion were symptomatic. In all patients before endarterectomy, 18F-FDG-PET imaging was performed and blood samples were obtained for determination of circulating inflammatory markers: high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α), interleukins, and selectins. Both groups were compared with a sex- and age-matched control group composed of 27 healthy volunteers.Results: 18F-FDG uptake, calculated by target-to-background ratio (TBR) was not significantly different between the groups. Levels of inflammatory markers were elevated, and there were no significant differences between ICA and CFA groups, with an exception of interleukin 6 (IL-6) levels, which was higher in the ICA group (3.2±2.5 ng/L vs. 1.8±1.3 ng/L, p＜0.05). There was a positive interrelationship between 18F-FDG-PET and most of the systemic inflammatory markers: hsCRP (r=0.417, p=0.010), IL-6 (r=0.603, p＜0.001), and TNF-α (r=0.374, p=0.023). However, correlation between 18F-FDG-PET and P-selectin, E-selectin, and t-PA was not found.Conclusion: Our study showed that an interrelationship exists between the intensity of inflammatory process of atherosclerotic lesions shown by FDG uptake and circulating inflammatory markers. Therefore, the determination of circulating inflammatory markers can have a potential to identify individuals with unstable, inflamed atherosclerotic plaques.
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