Bisphosphonates and atherosclerosis

Bisphosphonates are used for the treatment of bone resorption, hypercalcemia, osteoporosis and Paget's disease. Etidronate, pamidronate and clodronate also inhibit the development of experimental atherosclerosis without altering serum lipid profile. Bisphosphonates inhibit the arterial calcification, lipid accumulation and fibrosis. They accumulate extensively in arterial walls and suppress macrophages in atheromatous lesions. In macrophage cultures, bisphosphonates inhibit the cellular accumulation and degradation of atherogenic LDL-cholesterol and foam cell formation. Further, they inhibit various enzymes involved in cell signal transduction and cholesterol biosynthesis. Recently, etidronate has been shown to inhibit the thickening of carotid arterial wall even in man.     

Oxidized lipoproteins and macrophages

Macrophages are important participants in the development of atherosclerotic lesions, in cholesterol accumulation, as mediators of the immune response, and as sources of secreted enzymes and growth factors. Besides potentially contributing to local oxidation of lesion lipoproteins, many aspects of macrophage function can be affected by interaction with oxidized lipoproteins. Here we review macrophage responses to oxidized lipoproteins and provide novel data on the effects of a major oxidation product, 7-ketocholesterol, on high-density lipoprotein (HDL) function in cholesterol removal from macrophages.     

Effects of cholesterol and oxysterols on gap junctional communication between human smooth muscle cells.

Intercellular communication is considered to play an essential role in maintaining and controlling cell growth, cell differentiation and homeostasis. Cell-cell communication can be regulated by factors that influence gap junctional function. In this study it was demonstrated that cholesterol and oxidized cholesterol have the potential to modulate gap junctional communication between human smooth muscle cells in an opposite way. Cholesterol supplementation to human smooth muscle cells resulted in an increase of gap junctional communication up to 130% with regard to the control values. However, autooxidized cholesterol inhibited gap junctional communication more than 40%. Testing of several pure cholesterol oxidation derivates on gap junctional communication demonstrated that all of them were capable to inhibit intercellular communication in the order 25-hydroxycholesterol greater than cholestan-3 beta,5 alpha,6 beta-triol greater than 7-ketocholesterol greater than cholesterol 5,6 alpha-epoxide. The cell-cell communication-inhibiting potency of these oxysterols is in accordance with their atherogenic potency. This implies that cholesterol oxidation products, instead of pure cholesterol, can be promoting factors in the atherogenesis by influencing gap junctional communication between arterial smooth muscle cells, the target cells of atherosclerotic lesions.     

Effects of cholesterol and oxysterols on gap junctional communication between human smooth muscle cells

Intercellular communication is considered to play an essential role in maintaining and controlling cell growth, cell differentiation and homeostasis. Cell-cell communication can be regulated by factors that influence gap junctional function. In this study it was demonstrated that cholesterol and oxidized cholesterol have the potential to modulate gap junctional communication between human smooth muscle cells in an opposite way. Cholesterol supplementation to human smooth muscle cells resulted in an increase of gap junctional communication up to 130% with regard to the control values. However, autooxidized cholesterol inhibited gap junctional communication more than 40%. Testing of several pure cholesterol oxidation derivates on gap junctional communication demostrated that all of them were capable to inhibit intercellular communication in the order 25-hydroxycholesterol > cholestan-3β,5α,6β-triol > 7-ketocholesterol > cholesterol 5,6α-epoxide. The cell-cell communication-inhibiting potency of these oxysterols is in accordance with their atherogenic potency. This implies that cholesterol oxidation products, instead of pure cholesterol, can be promoting factors in the atherogenesis by influencing gap junctional communication between arterial smooth muscle cells, the target cells of atherosclerotic lesions.     

Section Review—Cardiovascular & Renal: Emerging Therapies in Atherosclerosis

Elevated blood cholesterol is an established risk factor for coronary heart disease (CHD), and the basis for treatment is normalisation of LDL-cholesterol (LDL-C). If dietary measures fail, inhibitors of HMG-CoA reductase (HMGR) potently lower LDL-C, and have been shown to reduce morbidity and mortality for CHD. New investigational drugs, reviewed herein, will address other medical needs, such as inhibiting cholesterol synthesis without affecting the synthesis of other essential molecules (e.g., ubiquinone, dolichol, etc.), inhibiting biliary and dietary cholesterol absorption, lowering Lp(a), elevating HDL and/or stimulating reverse cholesterol transport, and directly interacting with numerous arterial wall proteins involved in atherogenesis. Potent and specific drugs can best answer important questions about whether elevating HDL-C (or other apoAl-containing particles) or lowering Lp(a) is beneficial, much in the same way that HMGR inhibitors have answered questions about the merits of LDL lowering. Arterial wall targets (e.g., ACAT, VCAM, 15-LO), aimed primarily at CHD patients with normal lipoprotein profiles, will likely be more challenging with regard to drug development. Theoretically, such drugs must achieve sufficient concentrations in the bloodstream so as to result in appreciable uptake/accumulation in arterial lesions, but yet possess an acceptable margin of safety. Moreover, surrogate markers for determining clinical effectiveness, which at present are limited to expensive, specialised techniques, must be identified. Whom and when to treat remain to be established, and drugs affecting targets at the arterial wall will likely have to demonstrate an additive or unique activity compared to HMGR inhibitors. Thus, refined methods of lesion assessment will become essential for all approaches, both lipoprotein and nonlipoprotein-based, to obtain a clinical indication for CHD in man.     

Therapeutic potential of ACAT inhibitors as lipid lowering and anti-atherosclerotic agents

Hypercholesterolemia is one of the few independent risk factors definitively linked to increased morbidity and mortality due to myocardial infarction. One possible therapy of current interest is the prevention of the absorption of dietary cholesterol by inhibiting the enzyme, acyl-CoA: cholesterol acyltransferase (ACAT), which catalyses the intracellular formation of cholesterol esters. Evidence is now accumulating that suggests that ACAT inhibition may not only lower plasma cholesterol levels, but may also have a direct effect at the artery wall, where ACAT has been shown to be responsible for the accumulation of cholesterol esters in arterial lesions. Drago Sliskovic and Andrew White discuss the importance of ACAT in the lipid transport system and the consequences of its inhibition in a variety of tissues, with emphasis on both lipid-lowering and anti-atherosclerotic effects.     

The mechanistic relationships between hemorheological characteristics and cardiovascular disease

Historically, the approach to atherogenesis research has been focused on factors that primarily include vessel wall histology, blood and vessel wall biochemistry, clotting factors and platelets. This approach can be referred to as the 'biochemical' approach. We now recognize that atherosclerosis is an ongoing sterile process that starts with functional impairment of the arterial endothelium. However, the cause of the endothelial injury that initiates this process has not yet been identified. This commentary article proposes that the vasculature is a dynamic organ in which the initiating event leading to atherosclerosis is a protective, adaptive response of the endothelium to a mechanical injury related to the work of the heart (WOH). Evidence is presented that this mechanical injury is readily explained by changes in blood rheology. This represents a paradigm shift from a strictly biochemical approach to our understanding of the atherogenic process to a biomechanical one. Elevated whole blood viscosity (WBV) has been independently correlated with increased carotid intima media thickness and major cardiovascular disease risk factors, including hypertension, smoking, diabetes, advanced age, elevated low density lipoprotein cholesterol, and decreased high density lipoprotein cholesterol. These associations have led several authors to propose increased WBV as a unifying factor linking major cardiovascular risk factors and atherosclerosis. Blood rheology has been more difficult to accurately study than other risk factors for cardiovascular disease, explaining why it may be an overlooked factor in our understanding of cardiovascular disease. The science of rheology is now entering a new phase of acceptance with the development of a new scanning capillary rheometer which, unlike conventional rheometers, easily and accurately determines whole blood viscosity as a function of shear rate.     

Atheroprotection with amlodipine: cells to lesions and the PREVENT trial. Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial

Oxidized lipid and calcium regulatory abnormalities appear to play important roles in early atherogenesis secondary to cholesterol enrichment of the cell membrane in endothelial and arterial smooth muscle cells (SMCs). However, the link between the two is poorly understood. The findings reviewed here demonstrate that amlodipine has membrane-modifying and antioxidant actions at the cell membrane level in addition to its classical calcium channel blocking properties. These multiple pharmacologic actions may explain the cellular mechanisms of the atheroprotective effects of amlodipine in spontaneous atherogenesis and in accelerated atherosclerotic syndromes. Recent animal model studies have demonstrated that amlodipine inhibits the progression of atherosclerotic lesions and protects against restenosis after angioplasty. Amlodipine inhibits the cholesterol-induced increase in calcium permeability in SMCs, and has been shown to repair abnormalities in SMC membrane structure. Recent data have also demonstrated that amlodipine has a marked antioxidant action in membrane bilayers enriched with polyunsaturated fatty acids. However, these findings have been in animal models only; the efficacy of amlodipine in atheroprotection in humans cannot be predicted. The PREVENT trial has therefore been launched to examine the atheroprotective potential of amlodipine in spontaneous lesion development in humans with ischemic heart disease and in the prevention of restenosis after angioplasty.     

全身型幼年特发性关节炎并发巨噬细胞活化综合征的危险因素分析

目的分析全身型幼年特发性关节炎(systemic juvenile idiopathic arthritis,SJIA)并发巨噬细胞活化综合征(macrophageactivationsyndrome,MAS)的危险因素。方法回顾性分析我院2000年月1月～2009年5月期间诊治的SOJIA和SOJIA-MAS195例患儿的临床及试验室资料,采用Cox模型多因素分析法分析SOJIA发生SOJIA-MAS的危险因素。结果 (1)本组195例SOJIA病例中,MAS的发生率为4.1%(8/195)。(2)SOJIA-MAS组患儿热程,肝脾肿大及淋巴结肿大的程度明显高于SOJIA组,差异有统计学意义。(3)SOJIA-MAS组MAS发生前1周平均血小板(PLT)计数、平均白细胞(WBC)计数、血沉(ESR)、血红蛋白(Hb)、血清白蛋白(ALB)、纤维蛋白原(Fib)明显低于SOJIA组患儿,差异有统计学意义;SOJIA-MAS组平均谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三酯(TG)、血清铁蛋白(SF)高于SOJIA组,差异有统计学意义;SOJIA-MAS组患儿NK细胞计数明显低于SOJIA组患儿,差异有统计学意义。(4)多因素回归分析显示持续高热,WBC<9×109,PLT<250×109,ESR<10mm/h,Fib<1.5g/L,ALT>55u/L,AST>60u/L,LDH>1000μ/L,Fib>500μg/L,TG≥3mmol/L以及NK细胞计数降低是SOJIA患儿发生MAS的临床危险因素。结论通过分析SOJIA患儿发生MAS的临床危险因素,确立可能发生MAS的高危人群,对于早期发现及治疗MAS,改善其预后具有重要意义。     

Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE-/- mice

Exposure to arsenic-contaminated water has been shown to be associated with cardiovascular disease, especially atherosclerosis. We examined the effect of arsenic exposure on atherosclerotic lesion formation, lesion composition and nature in ApoE-/- mice. Early post-natal exposure (3-week-old mice exposed to 49 ppm arsenic as NaAsO₂ in drinking water for 7 weeks) increased the atherosclerotic lesion formation by 3- to 5-fold in the aortic valve and the aortic arch, without affecting plasma cholesterol. Exposure to arsenic for 13 weeks (3-week-old mice exposed to 1, 4.9 and 49 ppm arsenic as NaAsO₂ in drinking water) increased the lesion formation and macrophage accumulation in a dose-dependent manner. Temporal studies showed that continuous arsenic exposure significantly exacerbated the lesion formation throughout the aortic tree at 16 and 36 weeks of age. Withdrawal of arsenic for 12 weeks after an initial exposure for 21 weeks (to 3-week-old mice) significantly decreased lesion formation as compared with mice continuously exposed to arsenic. Similarly, adult exposure to 49 ppm arsenic for 24 weeks, starting at 12 weeks of age increased lesion formation by 2- to 3.6-fold in the aortic valve, the aortic arch and the abdominal aorta. Lesions of arsenic-exposed mice displayed a 1.8-fold increase in macrophage accumulation whereas smooth muscle cell and T-lymphocyte contents were not changed. Expression of pro-inflammatory chemokine MCP-1 and cytokine IL-6 and markers of oxidative stress, protein-HNE and protein-MDA adducts were markedly increased in lesions of arsenic-exposed mice. Plasma concentrations of MCP-1, IL-6 and MDA were also significantly elevated in arsenic-exposed mice. These data suggest that arsenic exposure increases oxidative stress, inflammation and atherosclerotic lesion formation.     

The mechanistic relationships between hemorheological characteristics and cardiovascular disease

SUMMARY

Historically, the approach to atherogenesis research has been focused on factors that primarily include vessel wall histology, blood and vessel wall biochemistry, clotting factors and platelets. This approach can be referred to as the 'biochemical' approach. We now recognize that atherosclerosis is an ongoing sterile process that starts with functional impairment of the arterial endothelium. However, the cause of the endothelial injury that initiates this process has not yet been identified.

This commentary article proposes that the vasculature is a dynamic organ in which the initiating event leading to atherosclerosis is a protective, adaptive response of the endothelium to a mechanical injury related to the work of the heart (WOH). Evidence is presented that this mechanical injury is readily explained by changes in blood rheology. This represents a paradigm shift from a strictly biochemical approach to our understanding of the atherogenic process to a biomechanical one.

Elevated whole blood viscosity (WBV) has been independently correlated with increased carotid intima media thickness and major cardiovascular disease risk factors, including hypertension, smoking, diabetes, advanced age, elevated low density lipoprotein cholesterol, and decreased high density lipoprotein cholesterol. These associations have led several authors to propose increased WBV as a unifying factor linking major cardiovascular risk factors and atherosclerosis.

Blood rheology has been more difficult to accurately study than other risk factors for cardiovascular disease, explaining why it may be an overlooked factor in our understanding of cardiovascular disease. The science of rheology is now entering a new phase of acceptance with the development of a new scanning capillary rheometer which, unlike conventional rheometers, easily and accurately determines whole blood viscosity as a function of shear rate.     

血脂异常与冠状动脉病变程度的相关性分析

目的：探讨冠状动脉病变与血脂异常的关系。方法：将100例疑似冠心病的患者依据冠状动脉造影结果分为：正常组；1支病变组；2支病变组；3支病变组。同时测定并统计分析血脂各成分与冠状动脉病变之问的关系。结果：各组的总胆同醇（TC）、甘油三酯（TG）差异无显著性。1支病变组，2支病变组在低密度脂蛋白（LDL-C）水平上与正常组比较未见明显增高。但在高密度脂蛋白（HDL-C）水平上，与正常组比较有明显降低且有统计学意义。3支病变组与正常组比较。低密度脂蛋白（LDL-C）明显增高，高密度脂蛋白（HDL-C）明显降低且有统计学意义。结论：血脂各成分与冠状动脉病变相关性分析表明：LDL-C增高和HDL-C降低与冠状动脉病变相关，其中HDL-C指标可能优于LDL-C指标。     

Idiopathic pulmonary arterial hypertension: an avian model for plexogenic arteriopathy and serotonergic vasoconstriction

Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance attributable to vasoconstriction and vascular remodeling of small pulmonary arteries. Vascular remodeling includes hypertrophy and hyperplasia of smooth muscle (medial hypertrophy) accompanied in up to 80% of the cases by the formation of occlusive plexiform lesions (plexogenic arteriopathy). Patients tend to be unresponsive to vasodilator therapy and have a poor prognosis for survival when plexogenic arteriopathy progressively obstructs their pulmonary arteries. Research is needed to understand and treat plexogenic arteriopathy, but advances have been hindered by the absence of spontaneously developing lesions in existing laboratory animal models. Young domestic fowl bred for meat production (broiler chickens, broilers) spontaneously develop IPAH accompanied by semi-occlusive endothelial proliferation that progresses into fully developed plexiform lesions. Plexiform lesions develop in both female and male broilers, and lesion incidences (lung sections with lesions/lung sections examined) averaged approximately 40% in 8 to 52 week old birds. Plexiform lesions formed distal to branch points in muscular interparabronchial pulmonary arteries, and were associated with perivascular mononuclear cell infiltrates. Serotonin (5-hydroxytryptamine, 5-HT) is a potent vasoconstrictor and mitogen known to stimulate vascular endothelial and smooth muscle cell proliferation. Serotonin has been directly linked to the pathogenesis of IPAH in humans, including IPAH linked to serotonergic anorexigens that trigger the formation of plexiform lesions indistinguishable from those observed in primary IPAH triggered by other causes. Serotonin also plays a major role in the susceptibility of broilers to IPAH. This avian model of spontaneous IPAH constitutes a new animal model for biomedical research focused on the pathogenesis of IPAH and plexogenic arteriopathy.     

同型半胱氨酸与冠心病诊断类型的关系

目的　探讨血浆同型半胱氨酸 (Hcy)、血脂浓度与冠状动脉病变严重程度的关系。方法　对 88例行冠状动脉造影的患者检测血浆同型半胱氨酸、血脂 ,冠状动脉病变严重程度以积分计 ,以冠状动脉造影正常作对照并进行 t检验和多因素 L ogistic回归分析。结果　冠状动脉病变组男女 Hcy水平均显著高于对照组 (P<0 .0 1) ;病变组女性 TC、TG高于对照组 (P<0 .0 5 ) ,男性 HDL低于对照组 (P<0 .0 5 )。冠状动脉单支病变 Hcy已显著增高 (P>0 .0 5 ) ;诊断类型中 AMI>AP>OMI>其他 ,提示 Hcy是冠状动脉早期病变及冠状动脉病变活动的预报因子。从单因素相关分析看 ,Hcy与冠状动脉病变严重程度积分 (P<0 .0 1)、年龄、性别 (P<0 .0 5 )呈正相关关系。将 Hcy、TC、TG、HDL、L DL、年龄、性别、吸烟史等 8个冠状动脉病变易患因素引入 L ogistic回归模型进行分析 ,Hcy和年龄、性别是具有统计学意义的冠状动脉病变危险因素。结论　 1Hcy与冠状动脉病变的发生、发展可能有直接关系。 2 Hcy同年龄、性别一样是冠状动脉病变的一个独立危险因素     

Animal models of atherosclerosis and interpretation of drug intervention studies

Atherosclerosis has often been defined as a multifactoral disease; however, a common risk factor associated with accelerated vascular disease in man or animals is an elevated plasma cholesterol level. Even though there is no one perfect animal model that completely replicates the stages of human atherosclerosis, cholesterol feeding and mechanical endothelial injury are two common features shared by most models of atherosclerosis. The models may differ with respect to degree of dietary cholesterol supplementation, length of hypercholesterolemia, dietary regimen and type, duration and degree of mechanical endothelial injury. With the advent of genetic engineering, transgenic mouse models have supplemented the classical dietary cholesterol induced disease models such as the cholesterol-fed hamster, rabbit, pig and monkey. The desire to limit the progression of atherosclerosis has spawned numerous drug intervention studies. Biochemical as well as morphologic and morphometric changes in the extent, structure and composition of atherosclerotic lesions following drug intervention have become major endpoints of in vivo drug intervention studies. Interpretations of alterations in vascular pathology following drug administration are often confounded by associated changes in plasma lipids and lipoproteins, limitation of the animal models and additional properties of compounds unrelated to their primary mode of action. Thus, the current review will summarize the pathology of atherosclerosis, describe various animal models of vascular disease and provide a critical review of the methods utilized and conclusions drawn when evaluating pharmacologic agents in animals.     

Outcomes of lipid-lowering treatment in postmenopausal women

Elevated triglycerides and low high-density lipoprotein (HDL) levels are more important coronary risk factors in women, and elevated low-density lipoprotein (LDL) levels less important in women, than men. There is clear-cut evidence in clinical trials that the benefit of cholesterol lowering in women and men is virtually identical. Modifiers of lipids and lipoproteins in women include diabetes mellitus, bodyweight and its distribution, and menopausal status. Diabetes is a more powerful predictor of risk in women than men. This may relate to the importance of elevated triglycerides as a risk factor in women, and to the effects of lipoprotein glycosylation, which lead to increased susceptibility to arterial deposition of LDL and decreased reverse cholesterol transport with HDL. Therapy for lipoprotein disorders in women and men is identical. For the overwhelming majority of patients, treatment with statin therapy is both highly efficacious and well tolerated.     

Clinical relevance of non-fasting and postprandial hypertriglyceridemia and remnant cholesterol

Non-fasting triglycerides are measured at any time within up to 8 h (14 h) after any normal meal, while postprandial triglycerides are measured at a fixed time point within up to 8 h (14 h) of a standardised fat tolerance test. The simplest possible way of evaluating remnant cholesterol is non-fasting/postprandial total cholesterol minus low-density lipoprotein (LDL) cholesterol minus high-density lipoprotein (HDL) cholesterol. Elevated levels of non-fasting/postprandial triglycerides directly correlate with elevated remnant cholesterol. In the general population, 38% of men have non-fasting/postprandial triglycerides > 2mmol/L (>176 mg/dL) while 45% of men have non-fasting/postprandial triglyceride levels of 1-2 mmol/L (89-176 mg/dL); corresponding fractions in women are 20% and 47%. Also, 31% of men have remnant cholesterol levels > 1mmol/L (>39 mg/dL) while 46% of men have remnant cholesterol levels of 0.5-1 mmol/L (19-39 mg/dL); corresponding fractions in women are 15% and 43%. Non-fasting triglycerides ≥5 mmol/L vs. <1 mmol/L marked a 17 and 5 fold increased risk of myocardial infarction, a 5 and 3 fold increased risk of ischemic stroke, and a 4 and 2 fold increased risk of early death in women and men in the general population. As all cells can degrade triglycerides it is biologically unlikely that it is the triglyceride molecules themselves that cause atherosclerosis and cardiovascular disease. However, elevated remnant cholesterol may lead to cholesterol entrapment in the arterial intima and consequently to accelerated atherosclerosis and cardiovascular disease.