Despite successful therapeutic strategies in the prevention and treatment of arteriosclerosis, the cardiovascular complications remain a major clinical and societal issue worldwide. Increased ...vascular calcification promotes arterial stiffness and accelerates cardiovascular morbidity and mortality. Upregulation of the Runx2 (Runt-related transcription factor 2), an essential osteogenic transcription factor for bone formation, in the cardiovascular system has emerged as an important regulator for adverse cellular events that drive cardiovascular pathology. This review discusses the regulatory mechanisms that are critical for Runx2 expression and function and highlights the dynamic and complex cross talks of a wide variety of posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and O-linked β-N-acetylglucosamine modification, in regulating Runx2 stability, cellular localization, and osteogenic transcriptional activity. How the activation of an array of signaling cascades by circulating and local microenvironmental factors upregulates Runx2 in vascular cells and promotes Runx2-mediated osteogenic transdifferentiation of vascular smooth muscle cells and expression of inflammatory cytokines that accelerate macrophage infiltration and vascular osteoclast formation is summarized. Furthermore, the increasing appreciation of a new role of Runx2 upregulation in promoting vascular smooth muscle cell phenotypic switch, and Runx2 modulated by
-linked β-N-acetylglucosamine modification and Runx2-dependent repression of smooth muscle cell-specific gene expression are discussed. Further exploring the regulation of this key osteogenic transcription factor and its new perspectives in the vasculature will provide novel insights into the transcriptional regulation of vascular smooth muscle cell phenotype switch, reprograming, and vascular inflammation that promote the pathogenesis of arteriosclerosis.
Elevated plasma homocysteine (Hcy) is suggested as an independent risk factor for stroke. We aimed to investigate the association of Hcy concentration with intracranial atherosclerosis (ICAS) and ...extracranial AS (ECAS) in hypertensive patients without stroke in Chinese population and to explore modified effect of methylenetetrahydrofolate reductase (MTHFR) C677T on their relationship. The stenosis of intracranial and extracranial arteries were evaluated in a total of 929 subjects through computerized tomographic angiography (CTA) from aortic arch to the skull base. Hcy concentration showed significantly association with both ICAS (OR: 1.105; 95% CI: 1.057-1.155) and ECAS (OR: 1.096; 95% CI: 1.047-1.146) for 1 µmol/L increment in Hcy. Meanwhile, hyperhomocysteinemia (≥15 µmol/L) was also displayed association with ICAS (OR: 1.587; 95% CI: 1.029-2.446) and ECAS (OR: 2.164; 95% CI: 1.392-3.364) after fully adjustment. Furthermore, in the subgroup analysis, such association remained significant only in the subjects that were younger, with normal renal function and with MTHFR 677 C allele. Our study showed the significant association of Hcy with ECAS and ICAS in asymptomatic hypertension patients. Hcy played a universal effect on the cervico-cerebral atherosclerosis. Such association was modified by the MTHFR C677T genotype.
Renal fibrosis is the final pathological process common to any ongoing, chronic kidney injury or maladaptive repair. It is considered as the underlying pathological process of chronic kidney disease ...(CKD), which affects more than 10% of world population and for which treatment options are limited. Renal fibrosis is defined by excessive deposition of extracellular matrix, which disrupts and replaces the functional parenchyma that leads to organ failure. Kidney's histological structure can be divided into three main compartments, all of which can be affected by fibrosis, specifically termed glomerulosclerosis in glomeruli, interstitial fibrosis in tubulointerstitium and arteriosclerosis and perivascular fibrosis in vasculature. In this review, we summarized the different appearance, cellular origin and major emerging processes and mediators of fibrosis in each compartment. We also depicted and discussed the challenges in translation of anti-fibrotic treatment to clinical practice and discuss possible solutions and future directions.
Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. In westernized societies, it is the underlying cause of about 50% of all deaths. Epidemiological ...studies have revealed several important environmental and genetic risk factors associated with atherosclerosis. Progress in defining the cellular and molecular interactions involved, however, has been hindered by the disease's aetiological complexity. Over the past decade, the availability of new investigative tools, including genetically modified mouse models of disease, has resulted in a clearer understanding of the molecular mechanisms that connect altered cholesterol metabolism and other risk factors to the development of atherosclerotic plaque. It is now clear that atherosclerosis is not simply an inevitable degenerative consequence of ageing, but rather a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis.
Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and confers a high risk of stroke recurrence, despite aggressive management of risk factors.
This ...study identified the role of risk factors and risk of vascular events in subjects with asymptomatic ICAS for improved risk stratification.
Stroke-free participants in the NOMAS (Northern Manhattan Study), prospectively followed since 1993, underwent a brain magnetic resonance angiogram from 2003 to 2008. The study rated stenosis in 11 brain arteries as: 0: no stenosis; 1: <50% or luminal irregularities; 2: 50%-69%; and 3: ≥70% stenosis or flow gap. The study ascertained vascular events during the post-magnetic resonance imaging (MRI) period. Proportional odds regression quantified the association of pre-MRI exposures, and proportional hazard adjusted models were built to identify the risk of events in the post-MRI period.
The included sample included 1,211 participants from NOMAS (mean age: 71 ± 9 years; 59% women; 65% Hispanic; 45% had any stenosis). Older age (OR: 1.02 per year; 95% CI: 1.01 to 1.04), hypertension duration (OR: 1.01 per year; 95% CI: 1.00 to 1.02), higher number of glucose-lowering drugs (OR: 1.64 per each medication; 95% CI: 1.24 to 2.15), and high-density lipoprotein (OR: 0.96 per mg/dL; 95% CI: 0.92 to 0.99) were associated with ICAS. The highest event risk was noted among participants with ICAS ≥70% (5.5% annual risk of vascular events; HR: 2.1; 95% CI:1.4 to 3.2; compared with those with no ICAS).
ICAS is an imaging marker of established atherosclerotic disease in stroke-free subjects, and incidental diagnosis of ICAS should trigger a thorough assessment of vascular health.
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Objective
To investigate whether hemodynamic features of symptomatic intracranial atherosclerotic stenosis (sICAS) might correlate with the risk of stroke relapse, using a computational fluid ...dynamics (CFD) model.
Methods
In a cohort study, we recruited patients with acute ischemic stroke attributed to 50 to 99% ICAS confirmed by computed tomographic angiography (CTA). With CTA‐based CFD models, translesional pressure ratio (PR = pressurepoststenotic/pressureprestenotic) and translesional wall shear stress ratio (WSSR = WSSstenotic − throat/WSSprestenotic) were obtained in each sICAS lesion. Translesional PR ≤ median was defined as low PR and WSSR ≥4th quartile as high WSSR. All patients received standard medical treatment. The primary outcome was recurrent ischemic stroke in the same territory (SIT) within 1 year.
Results
Overall, 245 patients (median age = 61 years, 63.7% males) were analyzed. Median translesional PR was 0.94 (interquartile range IQR = 0.87–0.97); median translesional WSSR was 13.3 (IQR = 7.0–26.7). SIT occurred in 20 (8.2%) patients, mostly with multiple infarcts in the border zone and/or cortical regions. In multivariate Cox regression, low PR (adjusted hazard ratio HR = 3.16, p = 0.026) and high WSSR (adjusted HR = 3.05, p = 0.014) were independently associated with SIT. Patients with both low PR and high WSSR had significantly higher risk of SIT than those with normal PR and WSSR (risk = 17.5% vs 3.0%, adjusted HR = 7.52, p = 0.004).
Interpretation
This work represents a step forward in utilizing computational flow simulation techniques in studying intracranial atherosclerotic disease. It reveals a hemodynamic pattern of sICAS that is more prone to stroke relapse, and supports hypoperfusion and artery‐to‐artery embolism as common mechanisms of ischemic stroke in such patients. Ann Neurol 2019;85:752–764
Late-onset sporadic Alzheimer's disease is a heterogeneous disorder. In elderly patients, increasing evidence suggests a link between this neurodegenerative disease, and vascular risk factors and ...atherosclerosis. The nature of this link remains speculative. Some investigators have suggested that the disease arises as a secondary event related to atherosclerosis of extracranial or intracranial vessels. A toxic effect of vascular factors on the microvasculature of susceptible brain regions has also been argued. An alternative explanation is that atherosclerosis and Alzheimer's disease are independent but convergent disease processes. This hypothesis is lent support by observations of shared epidemiology, pathophysiological elements, and response to treatment in both disorders. It provides a potential framework for an improved understanding of the pathogenesis of Alzheimer's disease, especially in elderly patients with vascular risk factors, and offers some promise toward the search for preventive and therapeutic treatments.
The most relevant ideas discussed in this article are described here. Intracranial atherosclerotic disease (ICAD) represents the most common cause of ischemic stroke worldwide. Its importance in ...whites may have been underestimated. New technical developments, such as high-resolution MRI, allow direct assessment of the intracranial atherosclerotic plaque, which may have a profound impact on ICAD diagnosis and therapy in the near future. Early detection of ICAD may allow therapeutic intervention while the disease is still asymptomatic. The Barcelonès Nord and Maresme Asymptomatic Intracranial Atherosclerosis Study is presented here. The main prognostic factors that characterize the patients who are at a higher risk for ICAD recurrence are classified and discussed. The best treatment for ICAD remains to be established. The Stenting Versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Study is currently ongoing to address this crucial issue. These and other topics will be discussed at the Fifth International Intracranial Atherosclerosis Conference (Valladolid, Spain, autumn 2011).
Objectives: Liposome-encapsulated hemoglobin (LEH), a cellular artificial oxygen carrier, has been reported to ameliorate vascular ischemia and reperfusion Injury in various organs. In the current ...study, LEH with low O sub(2) affinity (I-LEH, P sub(50)O sub(2)=45 mmHg) was tested in acute disruption of limb perfusion as a simulation of thrombotlc and/or atherosclerotic occlusion of the limbs, involving skeletal muscular ischemia and reperfusion. Methods: Physiological parameters, such as blood pressure, heart rate, respiratory rate, tissue perfusion by Laser-Doppler flow meter as well as intramuscular PO sub(2), were serially monitored using dual PO sub(2) electrodes in the bilateral hind limbs in the SD rat. After baseline measurements, the left hind limb underwent ischemia by tightening a tourniquet for 70min, followed 10min later by intravenous administration of I-LEH (10mL/kg, n=4) or saline (n=4) to the tail vein. Reperfusion was effected by relaxing the tourniquet and the rat was followed for an additional SOmin. Animals were sacrificed 7 days after ischemia/reperfusion for morphological analyses. Results: While PO sub(2) decreased precipitously after the onset of Ischemia in the ischemlc limb regardless of treatment, the PO sub(2) value in the contralateral intact limb showed a different pattern; decreased in the LEH-treated rats and Increased In the saline-treated control animals. As the result, PO sub(2) ratio in the left Ischemlc limb to the right non-ischemic limb (Lt/Rt ratio) tended to be higher during Ischemia and became significantly higher in the LEH-treated rats than in the saline-treated control animals Immediately after reperfusion to the end of observation. While plasma lactate, blood gases or electrolytes showed no difference after reperfusion, pathological studies 7 days later showed better muscular preservation In LEH-treated animals. Conclusions: The results suggest that early LEH-treatment may be protective of the skeletal muscle after Ischemia and reperfusion In the rat.
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