Cause Of Arteriosclerosis Research Articles

The Development of the Structure of Atherosclerosis and Aspects of Coronary Heart Disease

The genesis of arteriosclerosis and, as a consequence, coronary heart disease is put up for discussion. On the basis of morphological considerations, it appears to be absurd to define the cause of arteriosclerosis exclusively on the molecular level. Cholesterol is a functionally important building block in the body. It is regulated by the body. Long-term observations of statin therapy indicate consequential damage, which makes it necessary to rethink this form of therapy. The cause of arteriosclerosis is the result of a chronic ischemic disorder of the arterial vessel wall

The impact of hyperuricemia on all patients and low-BMI patients after endovascular treatments: from I-PAD registry

Abstract Background Hyperuricemia (≥7.0 mg / dl) is known to be one of the risks of arteriosclerosis. For a long time, it has been said that metabolic syndrome and high-BMI has been implicated to hyperuricemia and also that it's a consequence of those patient background, not a cause of arteriosclerosis. Now, the accumulation of data about hyperurisemia is still not enough. Also the importance of secondary prevention for patients after endovascular treatment (EVT) is still unclear too. Purpose To investigate the impact of hyperuricemia on prognosis of all patients and low-BMI patients after EVT. Methods From July 2015 to July 2016, 335 consecutive PAD patients who performed EVT were enrolled in I-PAD registry. And we divided them into 2 groups; with hyperuricemia or not, and analyzed them. In addition to that, among them, we selected 245 low-BMI patients (<25) and divided them into 2 groups; with hyperuricemia or not, and analyzed them. The primary end point was all-cause-death and the secondary endpoint was MACLE (Major Adverse Cardiovascular and limbs Events) at 3-years. Result At 3 years in the patients group with hyperuricemia, overall survival and freedom from MACLE were significantly lower (57.7% vs 83.4% P=0.0012; 30.3% vs 68.6% P=0.0095) than the group without hyperuricemia. Even among the low-BMI patients, in the patients with hyperuricemia, overall survival and freedom from MACLE were significantly lower (55.2% vs 77.1% P=0.003; 48.2% vs 69.9% P=0.002) than the patients without hyperuricemia at 3 years. Conclusion In this study, the prognosis of patients after EVT with hyperuricemia was worse than the patient without. And even among the low-BMI patients, The prognosis after EVT with hyperuricemia was worse than the patient without. Funding Acknowledgement Type of funding source: None

Carotid artery blood velocity decreases in patients with coronary slow flow: A manifestation of systemic arteriosclerosis.

Coronary slow flow phenomenon (CSFP) could be a manifestation of systemic arteriosclerosis, as coronary and carotid arteries have similar intimal thickening. However, as an initial cause of arteriosclerosis, hemodynamic changes in carotid arteries have rarely been studied. Twenty patients with angiography-proven CSFP and 39 patients with normal coronary flow (NCF) were enrolled. TIMI frame counts (CTFC) were investigated. Carotid intima-media thickness (CIMT), peak systolic velocity (PSV), and end-diastolic velocity (EDV) were measured by ultrasonography, and shear rate (SR) and resistance index (RI) were calculated. The results showed that PSV, EDV, SR, and RI were significantly lower in patients with CSFP (p＜0.01), but CIMT was significantly increased (P＜0.01). PSV, EDV, SR, and RI were negatively correlated with CTFC, while CIMT was positively correlated with CTFC. Logistic regression analysis revealed that PSV (OR=0.95, P<0.01) could be an independent protective factor against CSFP, but CIMT (OR=1.10, P＜0.05) and male gender (OR=9.89, P＜0.01) could be risk factors for CSFP. The slow flow phenomenon was observed in both coronary and carotid arteries, which could be a characteristic manifestation of systemic arteriosclerosis in CSFP; the lower wall shear stress may be the underlying mechanism. Carotid ultrasound could be applied in the noninvasive diagnosis of CSFP in the future.

Administration of hydrogen-rich water prevents vascular aging of the aorta in LDL receptor-deficient mice

The main cause of arteriosclerosis is atherosclerosis in the aorta. Atherosclerosis is recognized as a chronic inflammatory condition that begins with the dysfunction or activation of arterial endothelium. Low-density lipoprotein (LDL) and especially its oxidized form play a key role in endothelial dysfunction and atherogenesis. Recent studies showed that senescent cells are involved in the development and progression of atherosclerosis, and eliminating senescent cells suppresses the senescence-associated secretory phenotype. We previously reported that molecular hydrogen-rich water (HW) has antioxidant and anti-inflammatory effects in numerous diseases. Here, we used LDL receptor-deficient mice fed a high-fat diet (HFD) for 13 weeks as a model for atherosclerosis and evaluated the effects of continuous administration of HW. The numbers of endothelial cells in the atheroma expressing the senescence factors p16INK4a and p21 decreased in HFD-fed mice given HW compared with HFD-fed mice given control water. Furthermore, macrophage infiltration and Tnfα expression in the atheroma were also suppressed. These results suggest that vascular aging can be suppressed by HW.

Localised micro-mechanical stiffening in the ageing aorta

Age-related loss of tissue elasticity is a common cause of human morbidity and arteriosclerosis (vascular stiffening) is associated with the development of both fatal strokes and heart failure. However, in the absence of appropriate micro-mechanical testing methodologies, multiple structural remodelling events have been proposed as the cause of arteriosclerosis. Therefore, using a model of ageing in female sheep aorta (young: <18 months, old: >8 years) we: (i) quantified age-related macro-mechanical stiffness, (ii) localised in situ micro-metre scale changes in acoustic wave speed (a measure of tissue stiffness) and (iii) characterised collagen and elastic fibre remodelling. With age, there was an increase in both macro-mechanical stiffness and mean microscopic wave speed (and hence stiffness; young wave speed: 1701±1ms−1, old wave speed: 1710±1ms−1, p<0.001) which was localized to collagen fibril-rich regions located between large elastic lamellae. These micro-mechanical changes were associated with increases in both collagen and elastic fibre content (collagen tissue area, young: 31±2%, old: 40±4%, p<0.05; elastic fibre tissue area, young: 55±3%, old: 69±4%, p<0.001). Localised collagen fibrosis may therefore play a key role in mediating age-related arteriosclerosis. Furthermore, high frequency scanning acoustic microscopy is capable of co-localising micro-mechanical and micro-structural changes in ageing tissues.

Dual Anti-oxidative Effects of Fraxetin Isolated from Fraxinus rhinchophylla

Atherosclerosis is main cause of arteriosclerosis. The pivotal role of low-density lipoprotein (LDL) oxidation in atherogenesis suggests antioxidants may help prevent cardiovascular disease. Fraxinus rhynchophylla DENCE (Oleaceae) is a traditional medicinal plant from East Asia. During the course of characterizing potential drug candidates from natural products, we isolated two major coumarins, esculetin and fraxetin and found that fraxetin has dual-antioxidative functions. Low concentrations (1-5 microM) of fraxetin potently inhibited LDL oxidation induced by metal and free radicals. Moreover, treatment of vascular smooth muscle cells (VSMCs) with higher concentrations (above 30 microM) of fraxetin significantly increased the protein level of heme oxygenase-1 (HO-1), a key enzyme that inhibits vascular proliferation and atherosclerosis. Subcellular fractionation and reporter gene analysis using an antioxidant response element (ARE) construct revealed that fraxetin increased the level of nuclear factor (NF)-E2-related factor 2 (Nrf2) and reporter activity, and these were associated with the induction of antioxidant enzymes, such as HO-1 and glutathione S-transferase-alpha. In conclusion, fraxetin has direct protective properties against LDL oxidation at lower concentrations, and higher concentrations of fraxetin induce antioxidant enzymes via Nrf2/ARE activation. These effects suggest potential anti-atherosclerosis effects of Fraxinus rhynchophylla D.

1607 粒子法を用いた微小血管の内部流動と変形解析(OS16-2 生物・生体工学に関する流れ,オーガナイズドセッション)

In order to investigate the cause of arteriosclerosis or thrombosis, research of the flow characteristic of blood attracts attention. In this research, a flow and modification in the micro blood vessel of a fingertip are analyzed using the blood-flow analysis technique by the particle method. Furthermore, the relation between blood fluid and blood vessel modification is studied.

3548: Functional tests performed under color Doppler ultrasound monitoring in the evaluation of arterial vessels reactivity. A new method for testing endothelium-dependent function-effort test

Objectives: Evaluation of the arterial vessel function is conducted in order to determine early the individual predisposition to arteriosclerosis. It is hypothesized that one of the predisposing causes of arteriosclerosis is a defect in NO secretion by the endothelium. This endothelial dysfunction can be observed during functional tests (US-CD monitoring). Aim of the study was to investigate arterial reaction in age groups during the most commonly used tests: nitrate stimulation and ischemic test.

An analytical model for the investigation of axial wall forces generated by an arterial stenosis

The causes of arteriosclerosis are intensively investigated since many decades. While circumferential wall stress has received a lot of attention, axial stress (also called "longitudinal" stress) has been largely neglected, and practically never incriminated. However, it has been suggested in 2003 that moderate and severe arterial stenoses may induce non negligible axial forces cyclically in the vessel segment just proximal to the constriction cone. In the present contribution, we describe a simple analytical model that allows to study the distribution of these forces along the vessel in dependence of the respective axial elasticities of vessel and surrounding tissues, and of the stenosis length.

The role of autonomic cardiovascular neuropathy in pathogenesis of ischemic heart disease in patients with diabetes mellitus

Diabetes is strongly associated with macrovascular complications, among which ischemic heart disease is the major cause of mortality. Autonomic neuropathy increases the risk of complications, which calls for an early diagnosis. The aim of this study was to determine both presence and extent of cardiac autonomic neuropathy, in regard to the type of diabetes mellitus, as well as its correlation with coronary disease and major cardiovascular risk factors. We have examined 90 subjects, classified into three groups, with 30 patients each: those with type 1 diabetes, type 2 diabetes and control group of healthy subjects. All patients underwent cardiovascular tests (Valsalva maneuver, deep breathing test, response to standing, blood pressure response to standing sustained, handgrip test), electrocardiogram, treadmill exercise test and filled out a questionnaire referring to major cardiovascular risk factors: smoking, obesity, hypertension, and dyslipidemia. Our results showed that cardiovascular autonomic neuropathy was more frequent in type 2 diabetes, manifesting as autonomic neuropathy. In patients with autonomic neuropathy, regardless of the type of diabetes, the treadmill test was positive, i.e. strongly correlating with coronary disease. In regard to coronary disease risk factors, the most frequent correlation was found for obesity and hypertension. Cardiovascular autonomic neuropathy is considered to be the principal cause of arteriosclerosis and coronary disease. Our results showed that the occurrence of cardiovascular autonomic neuropathy increases the risk of coronary disease due to dysfunction of autonomic nervous system. Cardiovascular autonomic neuropathy is a common complication of diabetes that significantly correlates with coronary disease. Early diagnosis of cardiovascular autonomic neuropathy points to increased cardiovascular risk, providing a basis for preventive and therapeutic measures.

Near-field infrared imaging of molecular changes in cholesteryl oleate by free electron laser infrared ablation

We have applied infrared near-field scanning optical microscopy (IR–NSOM) to enable evaluation of detailed molecular changes in cholesteryl oleate, a primary cause of arteriosclerosis. In our IR–NSOM, a wide wavelength range of 2.9–6.7 μm is achieved by use of an optical parametric amplifier and an apertured cantilever. IR irradiation from a free-electron laser (FEL) tuned to a 5.75 μm wavelength induced molecular structural changes and caused cholesteryl oleate to decompose to cholesterol and fatty acids in the FEL irradiated areas. The IR–NSOM images at two different wavelengths, 5.75 and 5.3 μm, with a 2 μm apertured cantilever probe successfully identified areas of molecular change in cholesteryl oleate beyond the diffraction limit of IR microspectroscopy. In-depth molecular structure changes were also evaluated by the IR–NSOM and we demonstrated that the FEL irradiation induced subsurface molecular structure changes throughout cholesteryl oleate in the irradiated areas.

John Gibbon and the heart-lung machine: a personal encounter and his import for cardiovascular surgery

John Gibbon and the heart-lung machine: a personal encounter and his import for cardiovascular surgery

VE-statin, an endothelial repressor of smooth muscle cell migration.

The recruitment and proliferation of smooth muscle cells and pericytes are two key events for the stabilization of newly formed capillaries during angiogenesis and, when out of control in the adult, are the main causes of arteriosclerosis. We have identified a novel gene, named VE-statin for vascular endothelial-statin, which is expressed specifically by endothelial cells of the developing mouse embryo and in the adult, and in early endothelial progenitors. The mouse and human VE-statin genes have been located on chromosome 2 and 9, respectively, they span >10 kbp and are transcribed in two major variants arising from independent initiation sites. The VE-statin transcripts code for a unique protein of 30 kDa that contains a signal peptide and two epidermal growth factor (EGF)-like modules. VE-statin is found in the cellular endoplasmic reticulum and secreted in the cell supernatant. Secreted VE-statin inhibits platelet-derived growth factor (PDGF)-BB-induced smooth muscle cell migration, but has no effects on endothelial cell migration. VE-statin is the first identified inhibitor of mural cell migration specifically produced by endothelial cells.

Modification of elastin by pentosidine is associated with the calcification of aortic media in patients with end-stage renal disease.

Calcification of the media of arteries is common in patients with end-stage renal disease (ESRD) undergoing haemodialysis and is a major cause of arteriosclerosis. The aim of this study was to clarify the role of glycoxidative modification of elastin in the calcification of aortic media in this group of patients. Samples of tunica media were obtained from non-atherosclerotic areas of the aortas of cadavers of seven non-diabetic patients with ESRD (age 65.5 +/- 10.6 years) and 10 age-matched controls (age 61.1 +/- 10.3 years). The localization of pentosidine, a major glycoxidation product, and calcium deposits in the media were examined using immunohistochemical and von Kossa staining, followed by orcein staining for elastin fibres. Tissue levels of pentosidine and calcium were measured in elastase-digested media using reversed high-performance liquid chromatography and atomic absorption spectrophotometry, respectively. In aortic media, but not intima, immunostained pentosidine was observed along elastin fibres or in the extracellular spaces between them. Early calcification was manifest as small punctate calcified deposits along elastin fibres in the media. Advanced calcification was found as large, confluent calcified deposits in extracellular spaces between elastin fibres. Double staining showed co-localization of pentosidine and calcified deposits in the media. Both the staining density of pentosidine and calcification were more prominent in ESRD patients than in controls. The mean medial contents of both elastin-associated pentosidine and calcium were significantly higher in ESRD patients than in controls. In ESRD patients, the level of calcium in elastase-digested media correlated significantly with pentosidine levels, which increased in parallel with the duration of haemodialysis. Our results indicate that glycoxidative modification of elastin in aortic media may be involved in the enhancement of medial calcification in ESRD patients on haemodialysis.

Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease

It is unresolved whether elevated homocysteine in coronary artery disease (CAD) is the cause of arteriosclerosis or its consequence. In contrast, genetic variants of enzymes that metabolize homocysteine cannot be altered by arteriosclerosis. Consequently, their association with CAD would permit to imply causality. We modeled by regression analysis the effect of 11 variants in the methionine cycle upon CAD manifestation in 591 controls and 278 CAD patients. Among the examined variants only the carriership for the c.844ins68 in the cystathionine β-synthase (CBS) gene was associated with a significantly lowered risk of CAD (OR=0.56; 95% CI=0.35–0.90 in the univariable, and OR=0.41, 95% CI=0.19–0.89 for obese people in the multivariable analysis, respectively). Healthy carriers of the c.844ins68 variant exhibited, compared to the wild type controls, significantly higher postload ratios of blood S-adenosylmethionine to S-adenosylhomocysteine (61.4 vs. 54.9, p=0.001) and of plasma total cysteine to homocysteine (8.6 vs. 7.3, p=0.004). The changes in these metabolites are compatible with an improved methylation status and with enhanced activity of homocysteine transsulfuration. In conclusion, the coincidence of clinical and biochemical effects of a common c.844ins68 CBS variant supports the hypothesis that compounds relating to homocysteine metabolism may play role in the development and/or progression of CAD.

動脈硬化の成因に関する研究

Kanazawa et al. and Muraoka et al, reported that cholesterol concentrations of ultra-water-soluble LDLs (UWS-LDL) separated by dialysis from tap-water were higher in cerebral infarction or ischemic heart disease patients than in healthy persons.In this experiment, internalization into macrophages and cell injury caused by UWS-LDLs obtained from patients with arteriosclerotic disease were investigated.1) The internalization rates of UWS-LDLs such as proteins, cholesterol esters (CE), triglycerides (TG), free fatty acids (FFA) and free cholesterol (FC) into macrophages were greater than those of native LDL.2) The internalization rate of UWS-LDLs such as CE and FC into macrophages was enhanced by adding heparin to the medium, although no heparin-related differences were found for protein, TG and FFA.Thus, we concluded that the metabolic pathway as well as the phagocytic pathway might be the mechanism of internalization of UWS-LDLs into macrophages.3) The scanning electron microscope findings of macrophages did not change after incubation with native LDLs and macrophages at 37°C. However, after 2 hours of incubating UWS-LDLs and macrophages, cell swelling and rough change of the cell centrum due to internalization of UWS-LDLs were observed. After 6 hours, cell injury was more advanced and the central part of the cells were destroyed. Finally, floating cells were observed in the medium.Conclusion:The concentration of UWS-LDL-cholesterol was closely related to the incidence of arteriosclerotic disease. We also confirmed that UWS-LDLs were easily internalized into macrophages and that they injured the cells.Thus, we feel that this study on UWS-LDLs was very important to clarify the causes of arteriosclerosis.

Arteriosclerosis in East Asians

Arteriosclerosis is remarkably common in East Asians, both in the greater subcontinent and in their adopted countries after migration. Since arteriosclerosis is an acquired disease, East Asians must possess and preserve a common cultural practice related to the cause of arteriosclerosis and its complications. Therefore, an unusual opportunity is provided to examine East Asian migration and customs, especially diet, searching for a clue to the etiology of this disease. The result of this analysis provides additional support for a new theory proposing arteriosclerosis as an infectious disease caused by Cyanobacteria.

The role of soap and nutrition in producing human diseases I

Direct clinical observation gives insight to the hypothesis of daily soaping by humans as the cause of arteriosclerosis. The constant resupply to sebaceous glands by hepatic synthesis of cholesterol and lipid compounds raises plasma concentrations and accordingly these compounds plaque out of suspension onto arteriolar intimal surfaces.

Prognostic value of initial blood viscosity on vascular surgery and treatment in peripheral disease.

The correlation between extent of arteriosclerosis and blood viscosity, and the reduction in viscosity after successful surgery support the hypothesis that a raised viscosity is a consequence rather than a cause of arteriosclerosis. Measurement of blood viscosity was of little practical help to our team of vascular surgeons when they were faced with the problem of which reconstruction to do and when to do the procedure on a particular patient. The results of our studies show that in patients with arteriosclerosis, in whom only the major arteries are affected, the viscosity of the blood is not grossly abnormal and a knowledge of the blood viscosity does little to influence treatment. Patients with peripheral vascular disease affecting the small arteries and arterioles often have a high blood viscosity. In these circumstances manipulation of blood viscosity by hemodilution or drugs may be of benefit, and there is evidence that isoxsuprine given intravenously can achieve a reduction in viscosity.

The coronary arteries in active viral cardiomyopathies.

Summary These studies reveal that in mice, Coxsackie B4 and EMC viruses produce not only myocardial disease but extensive disease of the myocardial capillaries, coronary arteries, aorta and mesenteric arteries and veins and other arteries and veins. These lesions impair luminal calibre and, in turn, lead to myocardial ischaemia. This ischaemia contributes further to the myocardial damage. It is postulated that viruses initiate arteriosclerosis in man. A 19-year-old man who died of Coxsackie B4 viral cardiomyopathy had changes in the aorta noted on light and electron microscopy which are compatible with atherosclerosis. The relationship of these aortic changes to the viral infection can only be opened to speculation. Nevertheless, all of these studies establish a new concept of the possible initiating cause of arteriosclerosis, a common and extremely important disease of man.