Abstract:Ferroptosis is a novel type of cell death, which is closely modulated by multiple signaling transduction pathways including iron homeostasis pathway, cystine/glutamate transporter (System XC－) pathway and voltage-dependent anion channel (VDAC) pathway. Although there is evidence that ferroptosis contributes to myocardial ischemia/reperfusion injury, many questions remain to be solved, such as which stage ferroptosis mainly appear following myocardial ischemia/reperfusion? Is it a necessary condition for the involvement of iron in ferroptosis? It is of significance for seeking novel drugs to protect the heart against ischemia/reperfusion injury once the mechanisms for ferroptosis are elucidated.

Abstract:Aim To study the effects of high mobility group box-1 protein (HMGB1) and its receptor on proliferation and migration of human aortic vascular smooth muscle cells (VSMC) in vitro. Methods VSMC was cultured in vitro and treated with 0,0, 200 μg/L HMGB1 for 24 hours. Proliferation of VSMC was analyzed by CCK kit. VSMC migration was detected by scratch assay and Transwell chamber experiment. Real-time PCR and Western blot were used to examine receptor for advanced glycosylation end product(RAGE)expression after transfection with siRNA-RAGE. The expression of nuclear factor-κB (NF-κB) was analyzed by Western blot. Results HMGB1 could obviously promote cell proliferation and migration of VSMC (P＜0.05). Real-time PCR and Western blot assay both displayed that expressions of RAGE mRNA and protein were significantly decreased in VSMC after transfection of siRNA-RAGE (P＜0.05). Compared with HMGB1 group, siRNA-RAGE inhibited HMGB1 induced cell proliferation, migration and NF-κB protein expression (P＜0.05). Conclusions HMGB1 can promote the proliferation and migration of VSMC. The mechanism may be related to the activation of NF-κB expression after the combination of HMGB1 and RAGE.

Abstract:Aim To investigate the role of calcineurin/nuclear factor of activated T cells (CaN/NFAT) signaling pathway in aerobic exercise-induced increased expression of KV2.1 channel in mesenteric artery vascular smooth muscle cell from spontaneously hypertensive rats (SHR). Methods Male SHR and Wistar-Kyoto rats (WKY), 12 weeks age, were randomly divided into control groups (WKY-SED, SHR-SED), and exercise groups (WKY-EX, SHR-EX). Exercise groups were subjected to a 12-week treadmill training protocol:20 m/min, 60 min/day, 5 d/w. After 12 weeks, heart rate (HR) and blood pressure (BP) was acquired in each group. Immunocytochemistry was used to observe the distribution and changing of KV2.1 and CaN in mesenteric artery (MA). Western blot was applied to examine the expression levels of KV2.1, CaN, NFATc3, p-NFATc3, A-kinase anchoring protein (AKAP150) and calmodulin (CaM) protein in MA. Results (1)After 12 weeks of exercise, HR, systolic blood pressure (SBP)and mean blood pressure (MBP) in SHR-EX group was significantly lower than that in SHR-SED group (P＜0.01); SBP in WKY-EX group was lower than that in WKY-SED group (P＜0.05). (2) The distribution and protein expression of KV2.1 in SHR-SED group was significantly lower than that in WKY-SED group (P＜0.01); Exercise training markedly increased the expression of KV2.1 in SHR-EX group (P＜0.01). (3) Compared with the WKY-SED group, the distribution and protein expression of CaN was significantly increased, but the protein expression of p-NFATc3 was significantly lower in SHR-SED group(P＜0.01); Exercise training markedly inhibited the distribution and expression of CaN and increased the expression of p-NFATc3 in SHR-EX group (P＜0.01). (4) The protein expression of AKAP150 in SHR-SED group was significantly higher than that of WKY-SED group (P＜0.01); aerobic exercise obviously decreased the upregulation protein expression of AKAP150 in hypertension(P＜0.01). (5) The protein expression of CaM in SHR-SED group was significantly higher than that of WKY-SED group (P＜0.01); Compared with the SHR-SED group, the protein expression of CaM was significantly decreased in SHR-EX group (P＜0.01); Compared with the WKY-SED group, the protein expression of CaM was significantly increased in WKY-EX group (P＜0.05). Conclusion The increased CaN/NFAT signaling pathway may induce the KV2.1 expression downregulation, however, aerobic exercise can effectively inhibit such effects, which may be the mechanism of exercise restoring cardiovascular function.

Abstract:Aim To investigate the intervention effect of total paeony glycoside (TPG) on matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and oxidative stress of vascular remodeling in spontaneously hypertensive rats (SHR). Methods 30 male 8 weeks-old SHR rats were randomly divided into 3 groups:low-dose TPG group (low-dose group, n＝10), high-dose TPG group (high-dose group, n＝10) and control group (n＝10); In addition, Wistar rats were used as a blank group (n＝8). Low-dose group and high-dose group had intragastric administration with 100 and 200 mg/(kg·d) TPG respectively, and control group and blank group had intragastric administration with 2 mL physiological saline. After 8 weeks, serum levels of MMP-9 and TIMP-1 were detected by enzyme-linked immunosorbent assay; Oxidative stress level of thoracic aorta wall cells was determined by reactive oxygen species (ROS) fluorescence probe; Expressions of MMP-9 and TIMP-1 protein in the aorta was detected by immunohistochemical staining. Results Compared with the blank group, the serum levels of MMP-9 and TIMP-1 and the expressions of MMP-9 and TIMP-1 protein in the vascular wall were significantly increased in the control group (P＜0.05). After TPG treatment, MMP-9 was decreased, and the difference between high-dose group and control group was statistically significant (P＜0.05); However, there was no significant difference in TIMP-1 among low-dose group, high-dose group and control group (P＞0.05). The ROS level of thoracic aorta in control group was significantly higher than that in blank group, while the ROS level in low-dose group and high-dose group was lower than that of the control group. Conclusion There are the increases of vascular oxidative stress and MMP-9 level in hypertensive vascular remodeling. TPG can inhibit arterial oxidative stress and MMP-9 level and improve vascular remodeling in hypertension. It can be used as an auxiliary remedy for the treatment of hypertension.

Abstract:Aim To investigate the protective effects of flavonoid crude extracts from Lonicerae Flos on acute myocardial ischemia in rats. Methods The rat model of acute myocardial ischemia (AMI) in oxidative damage was prepared by subcutaneous injection of isoproterenol hydrochloride. After intragastric administration for 7 days, the changes of rat left ventricular pressure and electrocardiogram were detected by dynamic electrocardiogram, the percentage of myocardial ischemia area was observed by nitroblue tetrazol(NBT) staining and the activity of protease or the amount of product in serum were detected by ELISA. Results The acute myocardial ischemia rats fed with honeysuckle flavonoids extract, the ST-segment and T wave in their electrocardiogram elevation by isoproterenol-induced were significantly alleviated, and the time of QT interval was shortened. The percentage of myocardial ischemia area was decreased.The heart rate, the left ventricular systolic pressure, diastolic and mean pressure were rebounded significantly. The serum malondialdehyde(MDA)content was reduced, the activity of protease was back to normal trend with reduction of creatine kinase(CK)and lacate dehydrogenase(LDH) and enhancement of superoxide dismutase(SOD). Conclusion This study shows that improvement effects of flavonoids crude extract from Lonicerae Flos were confirmed on acute myocardial ischemia caused by oxidative damage in rats.

Abstract:Aim To study the efficacy and safety of extra-corporeal membrane oxygenation (ECMO) combined with intra-aortic balloon pump (IABP) in the treatment of refractory cardiogenic shock (RCS). Methods 96 patients with RCS were divided into 3 groups:IABP group (n＝34), ECMO group (n＝32) and IABP＋ECMO combination group (n＝30). On the basis of conventional antishock drugs, IABP, ECMO and IABP＋ECMO were used respectively to support the treatment. Changes of heart rate, mean arterial pressure (MAP), central venous pressure (CVP), oxygen saturation (SO₂), arterial lactate, cardiac troponin I (cTnI), brain natriuretic peptide (BNP), left ventricular end-diastolic diameter (LVED), left ventricular ejection fraction (LVEF), and vasoactive drugs (dobutamine, norepinephrine) dosage, complications and clinical outcomes (weaning success rate and in-hospital mortality) were compared among three groups before treatment and 6 hours, 1 day, 2 days, 3 days after treatment. Results After 3 days of treatment, the above indexes were improved gradually in all the three groups, and the above indexes in the combination group were significantly better than those in the IABP group and the ECMO group (P＜0.05 or P＜0.01). The improvements of heart rate, MAP, CVP, SO₂, arterial lactate, cTnI, LVEF, dobutamine and norepinephrine dosage in ECMO group were better than those in IABP group (all P＜0.01). The improvements of BNP and LVED in IABP group were better than those in ECMO group (P＜0.05, P＜0.01). The incidence of complications in combination group was higher than that in IABP group and ECMO group (χ²＝15.875, P＜0.001; χ²＝4.504, P＝0.034); The incidence of complications in ECMO group was higher than that in IABP group (χ²＝3.957, P＝0.047). The weaning success rate in combination group was higher than that in IABP group and ECMO group (χ²＝16.063, P＜0.001; χ²＝5.792, P＝0.016). There was no significant difference in the in-hospital mortality among the three groups (P＞0.05). Conclusion IABP＋ECMO combined therapy is superior to IABP and ECMO in improving hemodynamics in patients with RCS, but combined therapy increases the incidence of complications, decreases the improvement of clinical prognosis; Reducing complications is the key to improve the efficacy of combined therapy.

Abstract:Aim To investigate the mechanism of Sortilin in diabetic vascular calcification. Methods Thirty patients with diabetic foot amputation were enrolled from June 2015 to June 2017. The calcification of anterior tibial artery was measured by calcium quantification and divided into control group (calcium concentration＜2 μmol/mg, n＝15) and calcification group (calcium volume≥2 μmol/mg, n＝15). Western blot was used to determine the expression of Sortilin in the two groups. And the serological and clinical indexes were also analyzed. The model of diabetic vascular calcification was established based on human aortic smooth muscle cell line (HA-VSMC). The degree of calcification was detected by alizarin red staining. The expression level of Sortilin in the model was detected by Western blot. The calcification model was then treated with Sortilin and Sortilin antibody, and the effect of Sortilin on the calcification model was shown by von Kossa staining, calcium quantification and calcium nodule diameter measurement. Results Calcification of the anterior tibial artery in the calcification group was 4.9 times that of the control group, and the expression level of Sortilin increased by 3.92 times. After treatment with calcified culture medium containing Nε-carboxymethyl-lysine (CML) and oxidized low density lipoprotein (ox-LDL), HA-VSMC calcification increased significantly. The calcification of HA-VSMC was obviously increased under the stimulation of Sortilin recombinant protein, and the diameter of calcium nodules was also significantly increased. Meanwhile, tissue non-specific alkaline phosphatase (TNAP) expression levels were also significantly increased. Conclusion Sortilin promotes the formation of diabetic vascular calcification and develops it into macrocalcification.

Abstract:Aim To explore the influence factors of high on-treatment platelet reactivity after coronary artery bypass grafting. Methods From May 2015 to May 2016, ninety patients accordance with the inclusion criteria were enrolled in this study, and were treated with aspirin enteric-coated tablets and clopidogrel tablets double antiplatelet in combination with thrombelastogram (TEG) detection. Archives were established by consulting the case system and followed-up for 1 year. The status of ischemic events and bleeding events had been recorded by telephone during the follow-up period.The patients were divided into high on-treatment platelet reactivity (HTPR) group and normal on-treatment platelet reactivity (NTPR) group. The collected data were analyzed to evaluate the correlation between TEG detected high on-treatment platelet reactivity and some factors in patients with coronary artery bypass grafting. Results Age, uric acid, alanine aminotransferase, aspartate aminotransferase, intraoperative blood transfusion, 24 h drainage, duration of operation, postoperative TEG (blood clotting K, blood clot strength MA_thrombin, coagulation syndrome CI, blood clot strength MAADP) were statistically different (P＜0.05). Multivariate Logistic regression analysis showed that uric acid elevation was positively correlated with occurrence of HTPR (OR＝1.1,5%CI was 1.003～1.019, P＜0.05). Conclusion Serum uric acid level may be a causal risk factor for a low response to anti-platelet drugs.

Abstract:Aim To compare the medium-term clinical efficacy and safety of 2-staged hybrid coronary revascularization versus percutaneous coronary intervation (PCI) in treatment of coronary heart disease patients with multivessel disease. Methods A prospective randomized controlled study was adopted from January 2012 to June 2016. 106 patients with coronary artery disease were selected as hybrid coronary revascularization (HCR group):the anterior descending branch was treated with minimally invasive direct coronary artery bypass (MIDCAB), and the other coronary artery branch lesions were treated by simple PCI 7 days after the operation. 106 patients with multiple coronary artery disease were selected as PCI group by using the propensity score methodology and matched with the clinical baseline features, the coronary artery lesions were treated with PCI alone. Follow up was performed at 1,3, 6,9, 12 months and 2 years after operation, and the major adverse cardiovascular and cerebrovascular events (MACCE) and secondary endpoints were recorded. The SYNTAX score and EuroSCORE were used to evaluate the complexity and degree of risk of coronary artery disease 2 years after operation, and to evaluate the 2 year target vascular patency rate; Kaplan-Meier method was used to compare the incidence of MACCE and target vascular smooth survival time in the two groups during the follow-up period, and cardiac function indexes including echocardiography parameters,Bü type natriuretic peptide and 6 min walking distance were evaluated 2 years after operation. Results The follow-up time was 2.3 years, the average was 18.2±8.3 months. The incidence of MACCE in HCR group and PCI group was 9.5% and 25.9% (P＝0.035), and the revascularization rate of HCR group was lower than that of PCI group (4.8% vs. 11.5%, P＝0.038). There was no significant difference in myocardial infarction, cerebrovascular accident, major bleeding events and death (P＞0.05); the all-cause mortality of HCR group was 0.9%, and that of PCI group was 4.8% (P＝0.104). The 2 year survival rate in HCR group was 99.1%, and that in PCI group was 95.2% (P＝0.532). The incidence of acute heart failure and recurrent angina in HCR group was lower than that in PCI group (P＝0.048 or P＝0.011). Kaplan-Meier method was used to compare the survival time of MACCE in the two groups after 2 year follow-up, the incidence of MACCE in HCR group was lower than that in PCI group (P＝0.003). At the end of the 2 year follow-up, the total CAG reexamine rate of the two groups was 90.1%. The target vascular patency rate in HCR group was 94.6% in the medium-term of 2 year follow-up after operation, which was higher than 84.5% of the PCI group (P＝0.037). 2 years after operation, the target vascular patency rate in HCR group was higher than that in PCI group (P＝0.042), SYNTAX score in HCR group was lower than that in PCI group (12.2±3.1 vs. 19.6±4.8, P＜0.001), and EuroSCORE in HCR group was lower than that in PCI group (2.2±1.1 vs. 2.7±1.3, P＝0.031), LVEF in HCR group was higher than that in PCI group (63.3%±9.4% vs. 60.1%±8.5%, P＝0.029), LVEDD and LVESD in HCR group were lower than those in PCI group (P＝0.043 and P＝0.037), and 6 min walking distance in HCR group was higher than that in PCI group (496±57 m vs. 413±413 m, P＝0.042). Conclusion Compared with PCI, the incidence of adverse events was lower during the 2 year follow-up of multiple coronary artery disease patients treated with 2-staged hybrid coronary revascularization, and the target vascular patency rate was higher.

Abstract:Aim To investigate the value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for evaluating the disease condition and prognosis in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods 240 cases of STEMI patients were selected, the average age was 57.28±15.67 years old. Each patient underwent emergency percutaneous coronary intervention. The history of smoking, drinking, hypertension, and diabetes were recorded in each case. Plasma NT-proBNP concentration was measured. Blood biochemical indexes and cardiac troponin I (cTnI), high-sensitivity C-reactive protein (hs-CRP) and blood routine were detected. Color Doppler echocardiography was used to examine the heart. The main adverse cardiovascular events (MACE) occurred within 6 months after discharge were followed up, including cardiac death, nonfatal myocardial infarction, and revascularization of the target vessel blood. Results The plasma NT-proBNP level in patients with STEMI was positively correlated with age and left ventricular end-diastolic diameter (r value was 0.9,0.23, respectively, all P＜0.001), and was negatively correlated with left ventricular ejection fraction (r value was －0.34, P＜0.001). Plasma NT-proBNP concentration increased with the increase of cardiac function Killip grade (P＜0.001), and increased with the increase of Gensini score (P＜0.001). Plasma NT-proBNP concentration was the highest in patients with anterior wall myocardial infarction (P＜0.001). Multiple factor Logistic regression analysis showed that age, Lg[NT-proBNP], cTnI and hs-CRP were all associated with MACE, and Lg[NT-proBNP] was the strongest predictor of MACE (P＜0.001). ROC curve analysis showed that the best cut-off value of NT-proBNP predicting MACE was 4069.5 ng/L. Conclusion The level of plasma NT-proBNP is associated with the severity of the STEMI patient's condition, and NT-proBNP is the strongest predictor of MACE in STEMI patients.

Abstract:Aim To explore the risk factors of early neurological deterioration (END) after intravenous thrombolysis and the distribution of cerebral artery stenosis on anterior-posterior circulation. Methods 230 acute ischemic stroke (AIS) patients treated with intravenous alteplase were retrospectively analyzed. The patients were divided into END group and non-END group, which were assessed by National Institute of Health Stroke Scale (NIHSS) with criteria of whether neurological deterioration were≥4 points from baseline or leading to death at 24 hours after therapy. Risk factors of END were analyzed using multivariate Logistic regression model. And the distributions of clinically relevant arteriostenosis were studied on anterior-posterior circulation systems. Results Multivariate Logistic regression analysis showed that END was associated with age, baseline NIHSS score and moderate-severe stenosis of clinically relevant artery. The incidence of intracranial and extracranial artery stenosis in END group was significantly increased than non-END group on anterior circulation AIS (P＜0.05), but no significant distribution difference of cerebral artery stenosis was observed between END group and non-END group on posterior circulation systems AIS. Conclusions Age, baseline NIHSS score, moderate-severe stenosis of relevant artery are risk factors of END in AIS patients treated after intravenous thrombolysis with alteplase. Intracranial or extracranial artery stenosis could help to predict END in AIS patients on anterior circulation system.

Abstract:Aim To analyze the manifestations and outcomes of multi-slice spiral CT angiography (MSCTA) in isolated superior mesenteric artery dissection (ISMAD). Methods The CT data of 14 cases of isolated superior mesenteric artery dissection were retrospectively analyzed by Xiong Jiang's ISMAD image typing method. Results Among the 14 patients, 5 cases were Ⅰ type, 1 case was Ⅱ type, 6 cases were Ⅲ type and Ⅲa, 1 case was Ⅳ type, and 1 case was Ⅴ type. After conservative treatment, 4 cases were followed up, 1 case of Ⅰ type true cavity patency, 1 case of type Ⅰ without change, 1 case of Ⅲa type bag ulcer expansion, 1 case of Ⅲa type false lumen scope expansion, with true cavity further compression narrowed. Conclusion Xiong Jiang's ISMAD image typing method is accurate, rapid and effective for MSCTA diagnosing isolated superior mesenteric artery dissection. It is helpful to evaluate the dynamic changes and outcome of isolated superior mesenteric artery dissection.

Abstract:Aim To evaluate the association between serum uric acid levels with chronic kidney disease (CKD) in middle-aged health checkup population. Methods In this cross-sectional study, 24095 subjects were included in the study. Blood pressure, body height and body mass were measured, blood lipid, blood glucose and renal function were measured. The relationship between the level of blood uric acid and chronic renal disease was observed. CKD was defined as estimated glomerular filtration rate (eGFR)＜60 mL/min/1.73 m². Results The prevalence of hyperuricemia was 16.0%, the prevalence of hyperuricemia in males was significantly higher than in females (21.6% vs. 7.3%), meanwhile its prevalence increased with the age, especial in those postmenopausal female. Compared to the serum uric acid first quartile, the multivariate-adjusted odds for CKD of fourth quartiles were 6.30(95%CI was 4.84～8.19) in male and 9.08(95%CI was 6.27～13.14) in female. Conclusions The serum uric acid was age-related increase, especial in postmenopause female. The hyperuricemia was independent risk factor of CKD, the association of hyperuricemia and CKD in female was significantly robust in female than in male.

Abstract:Aim Based on coronary artery CT angiography data, to establish the finite element model of coronary artery with different degrees of stenosis and to study the simulative hemodynamics; To analyze the change of wall shear stress (WSS) and its key role in atherosclerosis. Methods Using the data of coronary artery CT angiography in patients with coronary artery stenosis, a three-dimensional model of precise anatomy was established. The finite element software was used to establish the finite element model, and various boundary conditions were set up for simulation analysis. At last the calculation and analysis were performed, and the results were obtained in the form of a graph. Results The WSS of coronary artery was increased significantly at stenosis place, and gradually increased with the increase of the degree of vascular stenosis. The WSS was decreased at the area behind stenosis, and was reverse proportional to the degree of coronary artery stenosis. There was a shear stress gradient between the two, and gradually increased with the increase of vascular stenosis degree. Conclusion The changes of WSS can lead to the development of atherosclerotic plaques and play an important role in the pathogenesis of atherosclerosis.

Abstract:Aim To evaluate systematically the efficacy of ω-3 polyunsaturated fatty acid supplement in the prevention and treatment of arteriosclerosis. Methods Chinese and foreign language databases from their establishment date to August 14th 2017 were systematically searched for adult human clinical trials to investigate the effects of ω-3 polyunsaturated fatty acid supplements on arteriosclerosis. Experimental study of oral ω-3 polyunsaturated fatty acid supplement and placebo were included in the prevention and treatment of arteriosclerosis. No limits were set on dosage sizes or sample characteristics. The research quality and data were evaluated and cross checked by two researchers independently. Meta analysis was carried out using RevMan 5.3 software. Results 12 studies involving 1325 people were included, including 10 parallel tests and 2 cross tests. The Meta analysis showed that the oral ω-3 polyunsaturated fatty acid supplements could reduce the brachial-ankle pulse wave velocity and the C-reactive protein compared with placebo, and the differences were statistically significant (P＜0.05). However, the effects of oral ω-3 polyunsaturated fatty acid supplement on interleukin-6, adiponectin and leptin were not significant, and the differences were not statistically significant (P＞0.05). Conclusion Oral ω-3 polyunsaturated fatty acid supplements may have the efficacy of reducing the degree of arteriosclerosis and improving the inflammatory response in large and middle arteries.

Abstract:Atherosclerosis (As) is a chronic inflammatory disease characterized by dyslipidemia, monocyte-macrophage infiltration, endothelial injury, and thrombosis. Recently, Wnt family plays an important role in the initiation and progression of atherosclerotic plaque. Wnt family is a cysteine-rich secreted glycoprotein which involved in the regulation of various biological processes through both canonical and non-canonical pathways. Previous studies suggest that Wnt family and its signaling pathways regulate the interaction between reverse cholesterol transport (RCT) and inflammatory responses, and play an important role in triggering atherosclerotic lesions. This review summarized the mechanisms of RCT and inflammatory response via Wnt family and its signaling pathway, which might provide novel diagnostic and therapeutic strategies for prevention and treatment of As.

Abstract:Familial hypercholesterolemia (FH) is the most common monogenic disorder of lipid metabolism. The total cholesterol levels begin to rise during fetal stage, which leads to premature coronary heart disease. The diagnosis of FH is based on the serum concentration of low density lipoprotein cholesterol (LDLC), xanthomas, premature coronary heart disease and genetic test. While early detection and intervention are all crucial to the prognosis, the diagnosis rate and LDLC control rates after lipid-lowering drug treatment are extremely low in China.

Abstract:Myocardial infarction and cerebral infarction are the vascular diseases that are currently and seriously endangering human health, and the mortality rate is the first cause of death. The development of thrombosis after atherosclerotic lesions is a common underlying process for a variety of progressive manifestations caused by cardiovascular and cerebrovascular diseases (coronary artery disease and cerebrovascular disease). For the drug treatment to patients with atherosclerosis, the antiplatelet therapy is deemed as the cornerstone. In the past two decades, significant progress has been achieved in antiplatelet drug therapy, especially for coronary artery disease patients. However, it is difficult to definitely determine the risks and benefits of antiplatelet drug combinations for coronary artery disease and cerebrovascular disease patients, since the risk of ischemia and hemorrhage incurred in patients with coronary artery disease is to be increased during the treatment. This article provides the current evidence for the forefront of antiplatelet therapy, and the progress of antiplatelet drugs for thrombosis events in two stage prevention of coronary artery disease and cerebrovascular disease on the basis of atherosclerotic lesions.