Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice

The pathogenic mechanisms by which physical exercise influences atherosclerotic lesion formation remain poorly understood. Because vigorous physical training increases oxidative stress, this study tested the hypothesis that graduated and moderate physical exercise together with metabolic intervention (l-arginine and antioxidants) may contribute to increased vascular protection. Exercise training in mice was induced by graduated swimming. In hypercholesterolemic male mice on an atherogenic high-cholesterol diet, graduated and moderate exercise lowered plasma cholesterol and decreased atherosclerotic lesions compared with sedentary control mice. Antioxidants (1.0% vitamin E added to the chow and 0.05% vitamin C added to the drinking water) and l-arginine (6% in drinking water) supplementation to exercising hypercholesterolemic mice further and synergistically reduced atherosclerosis compared with untreated exercised mice. Arterial oxidation-specific epitopes and systemic oxidative stress were reduced by metabolic intervention. Graduated chronic exercise elicited an increase in production of nitric oxide through increased endothelial nitric oxide synthase expression and ameliorated scavenger activities. Thus, metabolic intervention with l-arginine and antioxidants together with graduated and moderate exercise training reduce atherosclerotic lesion formation.     

Melatonin stabilizes rupture‐prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα‐dependent manner

Rupture of vulnerable plaques is the main trigger of acute cardio‐cerebral vascular events, but mechanisms responsible for transforming a stable atherosclerotic into a vulnerable plaque remain largely unknown. Melatonin, an indoleamine hormone secreted by the pineal gland, plays pleiotropic roles in the cardiovascular system; however, the effect of melatonin on vulnerable plaque rupture and its underlying mechanisms remains unknown. Here, we generated a rupture‐prone vulnerable carotid plaque model induced by endogenous renovascular hypertension combined with low shear stress in hypercholesterolemic ApoE^?/? mice. Melatonin (10 mg/kg/d by oral administration for 9 weeks) significantly prevented vulnerable plaque rupture, with lower incidence of intraplaque hemorrhage (42.9% vs. 9.5%, P = 0.014) and of spontaneous plaque rupture with intraluminal thrombus formation (38.1% vs. 9.5%, P = 0.029). Mechanistic studies indicated that melatonin ameliorated intraplaque inflammation by suppressing the differentiation of intraplaque macrophages toward the proinflammatory M1 phenotype, and circadian nuclear receptor retinoid acid receptor‐related orphan receptor‐α (RORα) mediated melatonin‐exerted vasoprotection against vulnerable plaque instability and intraplaque macrophage polarization. Further analysis in human monocyte‐derived macrophages confirmed the role of melatonin in regulating macrophage polarization by regulating the AMPKα‐STATs pathway in a RORα‐dependent manner. In summary, our data provided the first evidence that melatonin‐RORα axis acts as a novel endogenous protective signaling pathway in the vasculature, regulates intraplaque inflammation, and stabilizes rupture‐prone vulnerable plaques.     

Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse

The rupture of an atherosclerotic plaque is the main underlying cause of coronary artery thrombotic occlusion and subsequent myocardial infarction, but research into the causes and treatment of plaque rupture is hampered by the lack of a suitable animal model. Although complex atherosclerotic plaques can be induced in a number of experimental animal systems, in none of these is plaque rupture an established feature. We have surveyed branch points in the carotid arteries and aortas of apolipoprotein E knockout mice fed a diet supplemented with 21% lard and 0.15% cholesterol for up to 14 months. Six male and five female mice were used. Four of the male mice and four of the female mice died, after 46+/-3 weeks of feeding (range 37-59 weeks). Lumenal thrombus associated with atherosclerotic plaque rupture was observed in three male and all four female mice. In six of these seven mice, an atherosclerotic plaque rupture was found where the brachiocephalic artery branches into the right common carotid and right subclavian arteries. The ruptures were characterised by fragmentation and loss of elastin in the fibrous caps of relatively small and lipid-rich plaques overlying large complex lesions, with intraplaque haemorrhage. Immunocytochemical analysis revealed loss of smooth muscle cells from ruptured caps. These data suggest that long-term fat-feeding of apolipoprotein E knockout mice is a useful and reproducible model of atherosclerotic plaque rupture, and that these ruptures occur predominantly in the brachiocephalic artery.     

Usefulness in predicting coronary artery disease by ultrasonic evaluation of the carotid arteries in asymptomatic hypercholesterolemic patients with positive exercise stress tests.

A positive exercise electrocardiogram (ECG) is not infrequent occurrence in asymptomatic hypercholesterolemic patients, but the number of false-positive tests may be relatively high (50%). Therefore, the ability of a positive stress ECG to predict coronary artery lesions is low even in populations with > or =1 cardiovascular risk factors. To increase the diagnostic value of exercise tests for screening asymptomatic individuals, we analyzed whether combined clinical parameters with carotid echography would accurately predict coronary atherosclerotic lesions by coronary angiography in asymptomatic hypercholesterolemic patients with a positive exercise ECG. Seventy-six asymptomatic patients (between 35 and 65 years of age) with hypercholesterolemia (total plasma cholesterol >6.5 mmol/L or 250 mg/dl) and a positive stress ECG were referred for carotid B-mode echography and coronary angiography. Carotid echography data were divided into 2 categories: (1) absence of any atherosclerotic plaque, or (2) presence of > or =1 arterial plaques. Coronary stenosis assessed by coronary angiography was considered to correspond to a > or =50% reduction of coronary lumen diameter. Forty-three patients (57%) displayed coronary lesions; most (38; 88%) had carotid plaque. Multivariate analysis showed that the presence of carotid plaque was significantly associated with coronary stenosis (odds ratio 15.2; confidence interval 5.0 to 54.5). In subgroups characterized by high frequency of false-positive exercise electrocardiographic tests (women and patients with a 10-year predicted risk of coronary artery disease [CAD] <15%), none of the patients without carotid plaque exhibited coronary lesions. Echographic evaluation of carotid plaque (plaque vs no plaque) significantly improved the diagnostic specificity of exercise electrocardiography. We conclude that the combination of clinical, electrical, and echographic data facilitates cost-effective noninvasive detection of CAD in asymptomatic hypercholesterolemic patients.     

ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice

ADAMTS13, a metalloprotease, plays a pivotal role in preventing spontaneous microvascular thrombosis by cleaving hyperactive ultra large von Willebrand factor multimers into smaller, less active multimers. Reduced ADAMTS13 activity in plasma has been described in many diseases associated with systemic inflammation. It remains uncertain, however, whether ADAMTS13 contributes to disease pathogenesis or rather simply serves as an inflammation-associated marker. We hypothesized that, by decreasing vascular inflammation, ADAMTS13 reduces the development of early atherosclerotic plaques. Using intravital fluorescence microscopy, we observed excessive leukocyte adhesion and accelerated atherosclerotic plaque formation at the carotid sinus of Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice fed a high-fat Western diet. At 4 months of age, there was a significant increase in atherosclerosis in the aorta and aortic sinus of Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice. Interestingly, we detected a 2-fold increase in macrophage recruitment to the atherosclerotic plaque of the Adamts13(-/-)/ApoE(-/-) mice compared with ApoE(-/-) mice, suggesting that the atherosclerotic lesions in these mice were not only larger but also more inflammatory. These findings reveal a new functional role for the antithrombotic enzyme ADAMTS13 in reducing excessive vascular inflammation and plaque formation during early atherosclerosis.     

Decreased expression of insulin-like growth factor-1 and apoptosis of vascular smooth muscle cells in human atherosclerotic plaque

Insulin-like growth factor-1 (IGF-1) plays an important role in migration, cell cycle progression and survival of vascular smooth muscle cells (VSMC). We investigated the specific localization of IGF-1 and its receptor (IGF-1R) and their association with apoptosis and the expression of apoptosis-related proteins in early and advanced atherosclerotic lesions. Human atherosclerotic plaques (n=23) from patients undergoing aortic, carotid or femoral arterial surgery were studied. Immunohistochemistry and in situ hybridization revealed significantly higher expression of IGF-1 and IGF-1R in the media than in the intima of early atherosclerotic lesions (P<0.01). Medial VSMC positive for BAX, a proapoptotic protein of the B-cell CLL/lymphoma 2 (BCL2) family, showed colocalization of IGF-1. Apoptosis, as detected by DNA in situ terminal deoxynucleotidyl transferase end labeling (TUNEL), was not present in these early lesions. In advanced atherosclerotic plaques, the expression of IGF-1 and IGF-1R was significantly lower in the intimal regions with macrophage infiltration than in those without macrophage infiltration or than in the media (P<0.01). Furthermore, IGF-1 and IGF-1R immunoreactivity was markedly lower in intimal TUNEL-positive VSMC compared with intimal BAX-positive and medial VSMC (P<0.01). We conclude that IGF-1 and IGF-1R expression are reduced in the deep intima of early atherosclerotic lesions and in areas of advanced plaques with macrophage infiltration. Since IGF-1 is a potent survival factor for VSMC, poor expression of IGF-1 and IGF-1R in intimal regions with macrophage infiltration would likely contribute to triggering VSMC apoptosis potentially leading to plaque weakening, plaque rupture and acute coronary events.     

冠状动脉粥样斑块的治疗现状与进展

冠状动脉粥样斑块是冠状动脉粥样硬化性心脏病的基本病理改变，斑块的破裂可以导致急性冠脉综合征。如何干预动脉粥样斑块是目前的研究热点，大量研究已证实，药物治疗、内皮祖细胞移植、生活方式干预等方法可以早期干预动脉粥样斑块。本文将从以上方面介绍冠状动脉粥样斑块的治疗方法研究现状及相关机制。     

Primary peripheral arterial stenoses and restenoses excised by transluminal atherectomy: a histopathologic study

Atherectomy is a new therapeutic intervention for the treatment of peripheral arterial disease, and permits the controlled excision and retrieval of portions of stenosing lesions. The gross and light microscopic features of 218 peripheral arterial stenoses resected from 100 patients by atherectomy were studied. One hundred seventy of these lesions were primary stenoses and 48 were restenoses subsequent to prior angioplasty or atherectomy. Microscopically, primary stenoses were composed of atherosclerotic plaque (150 lesions), fibrous intimal thickening (15 lesions) or thrombus alone (5 lesions). Atherosclerotic plaques had a variable morphology and, in one-third of cases, were accompanied by abundant surface thrombus that probably added to the severity of stenosis. Most patients with fibrous intimal thickening or thrombus alone had typical atherosclerotic plaque removed elsewhere from within the same artery. Intimal hyperplasia, with or without underlying residual plaque, was found at 36 sites of restenosis, the remaining 12 consisting of plaque only. Intimal hyperplasia had a distinctive histologic appearance and was due to smooth muscle cell proliferation within a loosely fibrous stroma. Superimposed thrombus may have contributed to arterial narrowing in 25% of hyperplastic and 8% of atherosclerotic restenoses (p = 0.41). Pathologic examination of tissues recovered by peripheral atherectomy is an important adjunct that may provide insight into the efficacy of vascular interventions and the phenomenon of postintervention restenosis.     

Evolving Concepts in the Triad of Atherosclerosis,Inflammation and Thrombosis

Recent developments into antherothrombosis, the leading cause of morbidity and mortality in Western Society, may help to change our treatment strategy to a more casual approach. The composition of the atherosclerotic plaque, rather than the percent stenosis, appears to be a critical predictor for both risk of plaque rupture and subsequent thrombogenicity. A large lipid core, rich in tissue factor (TF) and inflammatory cells including macrophages, and a thin fibrous cap with compromise of its structural integrity by matrix degrading enzymes, such as metalloproteinases (MMPs), render a lesion susceptible to rupture and subsequent acute thrombosis. Thrombosis may lead to a complete occlusion or, in the case of mural thrombus or intraplaque hemorrhage, to plaque progression. Disruption of a vulnerable or unstable plaque (type IV and Va lesions of the AHA classification) with a subsequent change in plaque geometry and thrombosis may result in an acute coronary syndrome. The high-risk plaque tend to be relatively small, but soft or vulnerable to "passive" disruption because of high lipid content. Inflammatory processes are important components of all stages of atherosclerotic development, including plaque initiation and disruption. As such the early steps in atherosclerotic lesion formation are the over expression of endothelial adhesive protein (i.e. selectins, VCAM and ICAM), chemotactic factors (MCP-1), growth factors (M-CSF), and cytokines (IL-2) that will facilitate the recruitment, internalization and survival of blood-borne inflammatory cells into the vascular wall. Macrophages, following what appears to be a defense mission by protecting the vessel wall from excess lipid accumulation, may eventually undergo apoptosis with release of MMPs and TF. Specific cell recruitment in the vessel wall and build-up of the extracellular matrix are coordinated by a wide variety of stimulators and inhibitors. Active interaction of immune competent cells within the atherosclerotic lesions appears to play a pivotal role in the control of atherosclerotic plaque evolution and, therefore, deserves particular attention from the research community with the ultimate goal of improving preventive and therapeutic medical approaches. Inflammation, thrombosis and atherosclerosis are interdependent and define a triad within the complex pathogenic process of atherothrombosis.     

New model of atherosclerosis in insulin resistant sand rats: hypercholesterolemia combined with D2 vitamin

To overcome the sand rats' resistance to cholesterol induced atherosclerosis, animals were given D2 vitamin at 2000 IU/rat per day associated with cholesterol-enriched diet for 45 days, following 45 days of high cholesterol diet alone. At days 0, 45 and 90, plasma parameters, aortic and heart morphology were examined. Other animals receiving a high cholesterol diet alone were used as a control group. Results showed at day 45 severe hypercholesterolemia, elevated plasma LDL and VLDL-cholesterol, oxidized LDL and calcium levels, a rise of lecithin cholesterol acyl transferase activity and moderate hyperinsulinemia. Lesions were characterized by widening of the first interlamellar spaces in the aorta, fibrosis of coronary arterial wall and recent foci of myocardial fibrosis. At day 90, plasma calcium level decreased and oxidized LDL were more enhanced. Insulin resistance development was associated with glucose intolerance and hyperinsulinemia. The D2 vitamin administration induced advanced atherosclerotic lesions in arterial wall, represented by the rupture of elastic lamellae, smooth muscle cell proliferation and lipid-calcic core. The complicated plaque frequently evolved into ulcerations. The ischaemic effects were represented by acute myocardial infarction. D2 vitamin is an atherogenic agent which, when associated with hypercholesterolemia, allows the development of advanced atherosclerotic lesions in sand rat which resembles human plaque.     

Effects of amlodipine,atorvastatin and combination of both on advanced atherosclerotic plaque in APOE*3-Leiden transgenic mice

Combined treatment of statins and calcium channel blockers has been suggested to be superior to statin therapy alone. We quantified the anti-atherosclerotic potential of amlodipine, atorvastatin and their combination on existing atherosclerotic plaques in the aorta of APOE*3-Leiden transgenic mice. Sixty-two mice were fed a high cholesterol containing diet for 18 weeks. A subgroup of 10 mice was then killed. All other mice received the diet for another 18 weeks, alone (late control group), along with 0.01% atorvastatin, 0.002% w/w amlodipine, or their combination (all groups, n = 13). Atherosclerotic lesions, collagen content and monocyte adherence were quantified using standard histology (aortic root). Raman spectroscopy was used to quantify the content of cholesterol and calcification (aortic arch). Compared to the late control group, treatment with amlodipine, atorvastatin or the combination, reduced atherosclerostic lesion area by, respectively, 25%, 39% and 46% in the aortic root (P < 0.01) and by 53%, 55% and 60% in the aortic arch (P < 0.05). Atorvastatin, but not amlodipine reduced the adherence of monocytes in the intima. Lesion severity and plaque contents of collagen, cholesterol and calcification were equal for all treatment groups. Neither treatment resulted in regression of atherosclerotic plaque size. In conclusion, both atorvastatin and amlodipine significantly retard the progression of existing atherosclerotic lesions. No additive effect of the combination of amlodipine and atorvastatin could be observed in this study.     

CD40-CD40L interactions in atherosclerosis.

Increasing evidence supports a central role for CD40-CD40L interactions in the pathogenesis of atherosclerosis. Recently, we have shown that CD40L deficiency as well as pharmacological inhibition of CD40L in ApoE(-/-) mice results in the development of a stable atherosclerotic plaque phenotype. This phenotype is rich in smooth muscle cells and collagen, and contains only a small amount of macrophages and T-lymphocytes. CD40 and CD40L protein are present in almost all cell types in human atherosclerotic lesions. Expression was observed in early plaques, but was more predominant in advanced, rupture-prone, and ruptured plaques. Because most of the acute complications of atherosclerosis are the result of plaque rupture, CD40L inhibition might be a novel therapeutic approach to prevent atherosclerotic plaque destabilization and plaque rupture.     

Marked acceleration of atherosclerosis after Lactobacillus casei-induced coronary arteritis in a mouse model of Kawasaki disease

OBJECTIVE: The purpose of this study was to investigate whether Lactobacillus casei cell wall extract-induced Kawasaki disease (KD) accelerates atherosclerosis in hypercholesterolemic mice. Method and Results- Apolipoprotein E knockout or low-density lipoprotein receptor knockout mice were injected with Lactobacillus casei cell wall extract (KD mice) or PBS, fed high-fat diet for 8 weeks, and atherosclerotic lesions in aortic sinuses, arch (AC), and whole aorta were assessed. KD mice had larger, more complex aortic lesions with abundant collagen, and both extracellular and intracellular lipid and foam cells, compared with lesions in control mice despite similar cholesterol levels. Both apolipoprotein E knockout KD and low-density lipoprotein receptor knockout KD mice showed dramatic acceleration in atherosclerosis versus controls, with increases in en face aortic atherosclerosis and plaque size in both the aortic sinuses and AC plaques. Accelerated atherosclerosis was associated with increased circulating interleukin-12p40, interferon-γ, tumor necrosis factor-α, and increased macrophage, dendritic cell, and T-cell recruitment in lesions. Furthermore, daily injections of the interleukin-1Ra, which inhibits Lactobacillus casei cell wall extract-induced KD vasculitis, prevented the acceleration of atherosclerosis. CONCLUSIONS: Our results suggest an important pathophysiologic link between coronary arteritis/vasculitis in the KD mouse model and subsequent atherosclerotic acceleration, supporting the concept that a similar relation may also be present in KD patients. These results also suggest that KD in childhood may predispose to accelerated and early atherosclerosis as adults.     

Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice

Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD.     

Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI

OBJECTIVE: Apolipoprotein E-deficient mice (apoE(-/-)) on a regular diet become hypercholesterolemic and develop atherosclerosis, but endothelium-dependent relaxation remains undisturbed for up to 6 months. We investigated whether vasomotor dysfunction develops in aged apoE(-/-), whether the defect was systemic (hypercholesterolemia-dependent) or focal (plaque-related), and the effect of human apolipoprotein AI transgenesis (apoAI/E(-/-)). METHODS: Arteries of apoE(-/-) (n=5), apoAI/E(-/-) (n=6) and C57Bl/6J (WT, n=4) mice (18 months) were systematically dissected for isometric tension recording and subsequent morphometry. RESULTS: Acetylcholine (ACh)-induced relaxation was impaired (P<0.01) in atherosclerotic segments of apoE(-/-) (26+/-14%) as compared to WT mice (93+/-2%). Similar reduced (P<0.01) responses to adenosine 5'-triphosphate (apoE(-/-) 38+/-14, WT 94+/-3%) and the calcium ionophore A23187 (apoE(-/-) 19+/-6%, WT 97+/-2%) pointed to a post-receptor defect. Indeed, responses to exogenous nitric oxide were impaired in atherosclerotic segments as well (apoE(-/-) 71+/-7%, WT 92+/-1%, P<0.05). Furthermore, relaxations inversely correlated with plaque size (ACh r(s)=-0.74, P<0.01). In adjacent plaque-free segments however, responses to ACh (apoE(-/-) 92+/-3%, WT 97+/-1%) and all other agents were preserved, despite the prolonged hypercholesterolemia. ApoAI improved vasomotor responses in atherosclerotic segments. However, negative correlations between maximal relaxation and plaque area remained in apoAI/E(-/-) mice (ACh r(s)=-0.67, P<0.01). Indeed, covariate analysis of variance did not point to direct protection of vasomotor function by apoAI when the smaller lesions were taken into account. CONCLUSIONS: Endothelial dysfunction in apoE(-/-) mice is not affected by hypercholesterolemia alone, but is strictly associated with plaque formation. Human apoAI transgenesis-known to raise HDL-attenuated atherogenesis, thereby indirectly improving relaxation responses in apoE(-/-) mice.     

ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice

The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)^−/− mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43–48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40–50%). (2) Advanced lesion model. Twenty-four-week-old apoE^−/− mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.     

Long-term vitamin E supplementation reduces atherosclerosis and mortality in Ldlr mice,but not when fed Western style diet

Objectives

Epidemiological and experimental evidence have indicated potential health benefits of vitamin E supplementation on coronary heart disease (CHD), but several clinical trials have reported no benefit from vitamin E supplementation on CHD. We hypothesized that supplemental intake of vitamin E from an early age may prevent or retard the development and progression of atherosclerosis and CHD mortality.

Methods

To test this hypothesis, 300 Ldlr^−/− mice were divided into groups receiving Western style high fat/cholesterol (HFHC), moderate fat/cholesterol (MFMC), or low fat/cholesterol (LFLC) diets all containing 50 IU of vitamin E. These dietary groups were further subdivided into four sub-groups (n = 25) receiving their respective diets with no vitamin E supplementation or additionally supplemented with vitamin E (500 IU/kg diet) starting at the early age of 5 wks, or 6 mo, or 12 mo. All mice remained on their assigned diets until age 18 mo. Body weight, health status and survival rate of mice were monitored and recorded. After 18 mo of dietary treatments, mice were sacrificed.

Results

Body weight was the highest in HFHC groups and the lowest in LFLC groups. Plasma concentration of cholesterol and triglycerides was high in all dietary groups, and plasma vitamin E was high in vitamin E supplemented groups. Fifty percent of mice fed Western style HFHC diet and 53% of mice fed MFMC diet survived during the 18 mo, whereas 75% of mice fed LFLC diet survived during the 18 mo dietary treatments. At the age of 18 mo, all the Ldlr^−/− mice, regardless of dietary treatments, had several advanced atherosclerotic lesions in both aortic root and aortic tree. Within the LFLC groups, those that received vitamin E supplements from age 5 wks up to 18 mo had a significantly higher survival rate of 88% (p = 0.04) and lower mortality (12%) compared to mice that did not receive vitamin E supplements (64%). This lower mortality rate and higher survival rate coincided with significantly (p = 0.03) fewer aortic lesions in the vitamin E supplemented LFLC group (50%) compared to LFLC mice that did not receive vitamin E supplements in their diets (65%). Subjective immunohistochemical evaluation of aortic valves showed that LFLC mice that received vitamin E supplements for 18 mo had less intima media thickness compared to LFLC mice that did not receive vitamin E supplements in their diet. The LFLC mice that were supplemented with vitamin E for 18 mo had the lowest mRNA expression of inflammatory markers such as VCAM-1, MCP-1 and CD36 in samples obtained from lesion and non-lesionareas.

Conclusion

In conclusion, 500 mg vitamin E/kg diet in Ldlr^−/− mice is not effective at reducing mortality and atherosclerosis when the diet contained high or medium levels of fat and cholesterol. However, a relatively low dose and long-term vitamin E supplementation started from an early age is effective in reducing mortality and atherosclerotic lesions in genetically prone Ldlr^−/− mice fed LFLC diet.     

冠状动脉斑块消退的调脂治疗策略

4项他汀类药物治疗冠心病患者,以血管内超声评价冠状动脉(冠脉)斑块变化的临床试验(RE-VERSAL、ASTEROID、COSMOS和SATURN)结果一致显示,他汀治疗显著降低LDL-C,同时升高Apo-A1和HDL-C,才能观察到冠脉粥样硬化斑块的消退。适度调脂指通过他汀类药物治疗,达到减少胆固醇流入斑块的目标值:降低LDL-C>45%(达到1.81～2.46mmol/L),同时达到增加胆固醇流出斑块的目标值:升高Apo-A1>9%(达到3.50～3.89mmol/L)和HDL-C>8%(达到1.17～1.42mmol/L),实现冠脉斑块的消退。     

The first spontaneous coronary artery perforation due to disruption of atherosclerotic plaque

Spontaneous coronary artery rupture is rarely seen and most of the reorted cases in the world literature are related to rupture of a coronary artery aneurysm or of a saphenous vein graft. There is no report in the literature of a patient with spontaneous coronary artery perforation due to disruption of coronary atherosclerotic plaque. We can confirm that our patient is the first to be successfully treated with intracoronary grafted stent implantation for spontaneous coronary artery perforation as a result of disruption of atherosclerotic plaque.