Arrhythmia/Electrophysiology:
1、Direct Intramyocardial But Not Intracoronary Injection of Bone Marrow Cells Induces Ventricular Arrhythmias in a Rat Chronic Ischemic Heart Failure Model
Background— Therapeutic efficacy of bone marrow (BM) cell injection for treating ischemic chronic heart failure has not been established. In addition, experimental data are lacking on arrhythmia occurrence after BM cell injection. We hypothesized that therapeutic efficacy and arrhythmia occurrence induced by BM cell injection may be affected by the cell delivery route.
Methods and Results— Three weeks after left coronary artery ligation, wild-type female rats were injected with 1x107 mononuclear BM cells derived from green fluorescent protein–transgenic male rats through either a direct intramyocardial or a retrograde intracoronary route. Both intramyocardial and intracoronary injection of BM cells demonstrated similar improvement in left ventricular ejection fraction measured by echocardiography and a similar graft size analyzed by real-time polymerase chain reaction for the Y chromosome–specific Sry gene. Noticeably, intramyocardial injection of BM cells induced frequent ventricular premature contractions (108±73 per hour at 7 days after BM cell injection), including multiform, consecutive ventricular premature contractions and ventricular tachycardia for the initial 14 days; intracoronary injection of BM cells and intramyocardial injection of phosphate-buffered saline rarely induced arrhythmias. Immunohistochemistry demonstrated that intramyocardial BM cell injection formed distinct cell clusters containing donor-derived cells and accumulated host-derived inflammatory cells in the infarct border zone, whereas intracoronary BM cell injection provided more homogeneous donor cell dissemination with less inflammation and without disrupting the native myocardial structure.
Conclusions— BM cell injection is able to improve cardiac function in ischemic chronic heart failure but has a risk of arrhythmia occurrence when the intramyocardial route is used. Such arrhythmias may be prevented by using the intracoronary route.
Coronary Heart Disease
2、Global Improvement of Vascular Function and Redox State With Low-Dose Folic Acid
Implications for Folate Therapy in Patients With Coronary Artery Disease
Background— Although dietary folate fortification lowers plasma homocysteine and may reduce cardiovascular risk, high-dose folic acid therapy appears to not alter clinical outcome. Folic acid and its principal circulating metabolite, 5-methyltetrahydrofolate, improve vascular function, but mechanisms relating folate dose to vascular function remain unclear. We compared the effects of folic acid on human vessels using pharmacological high-dose versus low-dose treatment, equivalent to dietary folate fortification.
Methods and Results— Fifty-six non–folate-fortified patients with coronary artery disease were randomized to receive low-dose (400 µg/d) or high-dose (5 mg/d) folic acid or placebo for 7 weeks before coronary artery bypass grafting. Vascular function was quantified by magnetic resonance imaging before and after treatment. Vascular superoxide and nitric oxide bioavailability were determined in segments of saphenous vein and internal mammary artery. Low-dose folic acid increased nitric oxide–mediated endothelium-dependent vasomotor responses, reduced vascular superoxide production, and improved enzymatic coupling of endothelial nitric oxide synthase through availability of the cofactor tetrahydrobiopterin. No further improvement in these parameters occurred with high-dose compared with low-dose treatment. Whereas plasma 5-methyltetrahydrofolate increased proportionately with treatment dose of folic acid, vascular tissue 5-methyltetrahydrofolate showed no further increment with high-dose compared with low-dose folic acid.
Conclusions— Low-dose folic acid treatment, comparable to daily intake and dietary fortification, improves vascular function through effects on endothelial nitric oxide synthase and vascular oxidative stress. High-dose folic acid treatment provides no additional benefit. These direct vascular effects are related to vascular tissue levels of 5-methyltetrahydrofolate rather than plasma levels. High-dose folic acid treatment likely confers no further benefit in subjects already receiving folate supplementation.
Genetics
3、Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A352–372)
Naturally Occurring Amino Acid Variant Gly364Ser Causes Profound Changes in Human Autonomic Activity and Alters Risk for Hypertension
Background— Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release–inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure.
Methods and Results— Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by 47%) and downward deflections (by 44%), increased cardiac parasympathetic index (by 2.4-fold), and decreased cardiac sympathetic index (by 26%). Renal norepinephrine excretion was diminished by 26% and epinephrine excretion by 34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to 70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by 5 to 6 mm Hg, and the polymorphism accounted for 1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men.
Conclusions— The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.
4、Heredity of Endothelin Secretion
Human Twin Studies Reveal the Influence of Polymorphism at the Chromogranin A Locus, a Novel Determinant of Endothelial Function
Background— Endothelial dysfunction predisposes to vascular injury in association with hypertension. Endothelin (ET-1) is a potent vasoactive peptide that is synthesized and released by the vascular endothelium and is a marker of endothelial function. Chromogranin A (CHGA) regulates the storage and release of catecholamines and may have direct actions on the microvasculature. CHGA, a candidate gene for intermediate phenotypes that contribute to hypertension, shows a pattern of single nucleotide polymorphism variations that alter the expression and function of this gene both in vivo and in vitro.
Methods and Results— In a study of twins (n=238 pairs), plasma ET-1 was 58±5% (P<0.0001) heritable. Plasma ET-1 was both correlated and associated with chromogranin fragment levels, and the 2 were influenced by shared genetic determination (pleiotropy [G]; for the CHGA precursor, G=0.318±0.105; P=0.0032). We therefore hypothesized that variation in the CHGA gene may influence ET-1 secretion. Carriers of the CHGA promoter –988G, –462A, and –89A minor alleles showed significantly higher mean plasma ET-1 than their major allele homozygote counterparts (P=0.02, P=0.006, P=0.03, respectively). Analysis of a linkage disequilibrium block that spans these 3 single nucleotide polymorphisms showed a significant association between the GATACA haplotype and plasma ET-1 (P=0.0075). In cultured human umbilical vein endothelial cells, CHGA caused dose-dependent secretion of ET-1 over a brief (<1 hour) time course at relatively low concentrations of CHGA (10 to 100 nmol/L) with a threshold concentration (10 nmol/L) in the range found circulating in humans in vivo.
Conclusions— These results suggest that common, heritable variation in expression of the human CHGA gene influences endothelial ET-1 secretion in vivo, explained by a CHGA stimulus/ET-1 secretion coupling in endothelial cells in vitro. The findings document a previously unsuspected interaction between the sympathochromaffin system and the endothelium and suggest novel genetic and cell biological approaches to the prediction, diagnosis, and mechanism of endothelial dysfunction in human disease.
Imaging
5、Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor
Background— Cathepsin K (CatK), a potent elastinolytic and collagenolytic cysteine protease, likely participates in the evolution and destabilization of atherosclerotic plaques. To assess better the biology of CatK activity in vivo, we developed a novel near-infrared fluorescence (NIRF) probe for imaging of CatK and evaluated it in mouse and human atherosclerosis.
Methods and Results— The NIRF imaging agent consists of the CatK peptide substrate GHPGGPQGKC-NH2 linked to an activatable fluorogenic polymer. In vitro, CatK produced a 2- to 14-fold activation of the agent over other cysteine and matrix metalloproteinases (P<0.0001), as well as a >8-fold activation over a control imaging agent (P<0.001). Optical imaging of atheroma revealed >100% NIRF signal increases in apolipoprotein E–/– mice in vivo (n=13; P<0.05, CatK imaging agent versus control agent) and in human carotid endarterectomy specimens ex vivo (n=14; P<0.05). Fluorescence microscopy of plaque sections demonstrated that enzymatically active CatK (positive NIRF signal) localized primarily in the vicinity of CatK-positive macrophages. Augmented NIRF signal (reflecting CatK activity) colocalized with disrupted elastin fibers within the media underlying plaques.
Conclusions— Use of this novel protease-activatable NIRF agent for optical imaging in vivo demonstrated preferential localization of enzymatically active CatK to macrophages, consistent with their known greater elastinolytic capabilities compared with smooth muscle cells. Augmented CatK proteolysis in atheromata further links CatK to vascular remodeling and plaque vulnerability.
Interventional Cardiology
6、Randomized Trial Comparing Same-Day Discharge With Overnight Hospital Stay After Percutaneous Coronary Intervention
Results of the Elective PCI in Outpatient Study (EPOS)
Background— Percutaneous coronary intervention (PCI) in a day-case setting might reduce logistic constraints on hospital resources, but data on safety are limited. We evaluated the safety and feasibility of same-day discharge after PCI.
Methods and Results— Eight hundred consecutive patients scheduled for elective PCI by femoral approach were randomized to same-day discharge or overnight hospital stay. Four hours after PCI, patients were triaged as suitable for early discharge or not. Suitable patients were discharged immediately or kept overnight, according to randomization. Patients with an indication for extended hospital stay were not discharged regardless of randomization. Primary end points were death, myocardial infarction, coronary artery bypass graft surgery, repeat PCI, or puncture-related complications occurring within 24 hours after PCI. A total of 403 patients were assigned to same-day discharge, of whom 77 (19%) were identified for extended observation; 397 patients were assigned to overnight stay, of whom 85 (21%) were identified for extended observation. Among all patients, the composite primary end point occurred in 9 (2.2%) same-day discharge patients and in 17 (4.2%) overnight stay patients (risk difference, –0.020; 95% CI, –0.045 to –0.004; P for noninferiority <0.0001). Among patients deemed suitable for early discharge, the composite end point occurred in 1 of 326 (0.3%) same-day discharge patients and 2 of 312 (0.6%) overnight-stay patients (risk difference, –0.003; 95% CI, –0.014 to 0.007; P for noninferiority <0.0001). The last 3 events were related to puncture site.
Conclusions— Same-day discharge after elective PCI is feasible and safe in the majority (80%) of patients selected for day-case PCI. Same-day discharge does not lead to additional complications compared with overnight stay.
Molecular Cardiology
7、A1 Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction
Background— It is well known that adenosine levels are increased during ischemia and protect the heart during ischemia/reperfusion. However, less is known about the role of adenosine–adenosine receptor (AR) pathways in hearts with left ventricular dilation and dysfunction. Therefore, we assessed adenosine levels and selective AR expression in transgenic mice with left ventricular systolic dysfunction secondary to overexpression of tumor necrosis factor- (TNF 1.6).
Methods and Results— Cardiac adenosine levels were reduced by 70% at 3 and 6 weeks of age in TNF 1.6 mice. This change was accompanied by a 4-fold increase in the levels of A1-AR and a 50% reduction in the levels of A2A-AR. That the increase in A1-AR density was of physiological significance was shown by the fact that chronotropic responsiveness to the A1-AR selective agonist 2-chloro-N6-cyclopentanyladenosine was enhanced in the TNF 1.6 mice. Similar changes in adenosine levels were found in 2 other models of heart failure, mice overexpressing calsequestrin and mice after chronic pressure overload, suggesting that the changes in adenosine-AR signaling were secondary to myocardial dysfunction rather than to TNF overexpression.
Conclusions— Cardiac dysfunction secondary to the overexpression of TNF is associated with marked alterations in myocardial levels of adenosine and ARs. Modulation of the myocardial adenosine system and its signaling pathways may be a novel therapeutic target in patients with heart failure.
Pediatric Cardiology
8、Instability in the Diagnosis of Metabolic Syndrome in Adolescents
Background— Factor analyses suggest that the structure underlying metabolic syndrome is similar in adolescents and adults. However, adolescence is a period of intense physiological change, and therefore stability of the underlying metabolic structure and clinical categorization based on metabolic risk is uncertain.
Methods and Results— We analyzed data from 1098 participants in the Princeton School District Study, a school-based study begun in 2001–2002, who were followed up for 3 years. We performed factor analyses of 8 metabolic risks at baseline and follow-up to assess stability of factor patterns and clinical categorization of metabolic syndrome. Metabolic syndrome was defined using the current American Heart Association/National Heart, Lung, and Blood Institute definition for adults (AHA), a modified AHA definition used in prior pediatric metabolic syndrome studies (pediatric AHA), and the International Diabetes Federation (IDF) guidelines. We found that factor structures were essentially identical at both time points. However, clinical categorization was not stable. Approximately half of adolescents with baseline metabolic syndrome lost the diagnosis at follow-up regardless of the definitions used: pediatric AHA=56% (95% confidence interval [CI], 42% to 69%), AHA=49% (95% CI, 32% to 66%), IDF=53% (95% CI, 38% to 68%). In addition to loss of the diagnosis, new cases were identified. Cumulative incidence rates were as follows: pediatric AHA=3.8% (95% CI, 2.8% to 5.2%); AHA=4.4% (95% CI, 3.3% to 5.9%); IDF=5.2% (95% CI, 4.0% to 6.8%).
Conclusions— During adolescence, metabolic risk factor clustering is consistent. However, marked instability exists in the categorical diagnosis of metabolic syndrome. This instability, which includes both gain and loss of the diagnosis, suggests that the syndrome has reduced clinical utility in adolescence and that metabolic syndrome–specific pharmacotherapy for youth may be premature.
Stroke
9、Targeting Platelets in Acute Experimental Stroke
Impact of Glycoprotein Ib, VI, and IIb/IIIa Blockade on Infarct Size, Functional Outcome, and Intracranial Bleeding
Background— Ischemic stroke is a frequent and serious disease with limited treatment options. Platelets can adhere to hypoxic cerebral endothelial cells by binding of their glycoprotein (GP) Ib receptor to von Willebrand factor. Exposure of subendothelial matrix proteins further facilitates firm attachment of platelets to the vessel wall by binding of collagen to their GPVI receptor. In the present study, we addressed the pathogenic role of GPIb, GPVI, and the aggregation receptor GPIIb/IIIa in experimental stroke in mice.
Methods and Results— Complete blockade of GPIb was achieved by intravenous injection of 100 µg Fab fragments of the monoclonal antibody p0p/B to mice undergoing 1 hour of transient middle cerebral artery occlusion. At 24 hours after transient middle cerebral artery occlusion, cerebral infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining. In mice treated with anti-GPIb Fab 1 hour before middle cerebral artery occlusion, ischemic lesions were reduced to 40% compared with controls (28.5±12.7 versus 73.9±17.4 mm3, respectively; P<0.001). Application of anti-GPIb Fab 1 hour after middle cerebral artery occlusion likewise reduced brain infarct volumes (24.5±7.7 mm3; P<0.001) and improved the neurological status. Similarly, depletion of GPVI significantly diminished the infarct volume but to a lesser extent (49.4±19.1 mm3; P<0.05). Importantly, the disruption of early steps of platelet activation was not accompanied by an increase in bleeding complications as revealed by serial magnetic resonance imaging. In contrast, blockade of the final common pathway of platelet aggregation with anti-GPIIb/IIIa F(ab)2 fragments had no positive effect on stroke size and functional outcome but increased the incidence of intracerebral hemorrhage and mortality after transient middle cerebral artery occlusion in a dose-dependent manner.
Conclusions— Our data indicate that the selective blockade of key signaling pathways of platelet adhesion and aggregation has a different impact on stroke outcome and bleeding complications. Inhibition of early steps of platelet adhesion to the ischemic endothelium and the subendothelial matrix may offer a novel and safe treatment strategy in acute stroke.
Vascular Medicine
10、Phosphodiesterase 1 Upregulation in Pulmonary Arterial Hypertension
Target for Reverse-Remodeling Therapy
Background— Pulmonary arterial hypertension (PAH) is a life-threatening disease, characterized by vascular smooth muscle cell hyperproliferation. The calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) may play a major role in vascular smooth muscle cell proliferation.
Methods and Results— We investigated the expression of PDE1 in explanted lungs from idiopathic PAH patients and animal models of PAH and undertook therapeutic intervention studies in the animal models. Strong upregulation of PDE1C in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was noted on the mRNA level by laser-assisted vessel microdissection and on the protein level by immunohistochemistry. In chronically hypoxic mouse lungs and lungs from monocrotaline-injected rats, PDE1A upregulation was detected in the structurally remodeled arterial muscular layer. Long-term infusion of the PDE1 inhibitor 8-methoxymethyl 3-isobutyl-1-methylxanthine in hypoxic mice and monocrotaline-injected rats with fully established pulmonary hypertension reversed the pulmonary artery pressure elevation, structural remodeling of the lung vasculature (nonmuscularized versus partially muscularized versus fully muscularized small pulmonary arteries), and right heart hypertrophy.
Conclusions— Strong upregulation of the PDE1 family in pulmonary artery smooth muscle cells is noted in human idiopathic PAH lungs and lungs from animal models of PAH. Inhibition of PDE1 reverses structural lung vascular remodeling and right heart hypertrophy in 2 animal models. The PDE1 family may thus offer a new target for therapeutic intervention in pulmonary hypertension.
Special Reports
11、Clinical End Points in Coronary Stent Trials
A Case for Standardized Definitions
Background— Although most clinical trials of coronary stents have measured nominally identical safety and effectiveness end points, differences in definitions and timing of assessment have created confusion in interpretation.
Methods and Results— The Academic Research Consortium is an informal collaboration between academic research organizations in the United States and Europe. Two meetings, in Washington, DC, in January 2006 and in Dublin, Ireland, in June 2006, sponsored by the Academic Research Consortium and including representatives of the US Food and Drug Administration and all device manufacturers who were working with the Food and Drug Administration on drug-eluting stent clinical trial programs, were focused on consensus end point definitions for drug-eluting stent evaluations. The effort was pursued with the objective to establish consistency among end point definitions and provide consensus recommendations. On the basis of considerations from historical legacy to key pathophysiological mechanisms and relevance to clinical interpretability, criteria for assessment of death, myocardial infarction, repeat revascularization, and stent thrombosis were developed. The broadly based consensus end point definitions in this document may be usefully applied or recognized for regulatory and clinical trial purposes.
Conclusion— Although consensus criteria will inevitably include certain arbitrary features, consensus criteria for clinical end points provide consistency across studies that can facilitate the evaluation of safety and effectiveness of these devices.
AHA Scientific Statement
12、Exercise and Acute Cardiovascular Events
Placing the Risks Into Perspective: A Scientific Statement From the American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology
In Collaboration With the American College of Sports Medicine; Paul D. Thompson, MD, FAHA, Co-Chair; Barry A. Franklin, PhD, FAHA, Co-Chair; Gary J. Balady, MD, FAHA; Steven N. Blair, PED, FAHA; Domenico Corrado, MD, PhD; N.A. Mark Estes, III, MD, FAHA; Janet E. Fulton, PhD; Neil F. Gordon, MD, PhD, MPH; William L. Haskell, PhD, FAHA; Mark S. Link, MD; Barry J. Maron, MD; Murray A. Mittleman, MD, FAHA; Antonio Pelliccia, MD; Nanette K. Wenger, MD, FAHA; Stefan N. Willich, MD, FAHA; Fernando Costa, MD, FAHA
Habitual physical activity reduces coronary heart disease events, but vigorous activity can also acutely and transiently increase the risk of sudden cardiac death and acute myocardial infarction in susceptible persons. This scientific statement discusses the potential cardiovascular complications of exercise, their pathological substrate, and their incidence and suggests strategies to reduce these complications. Exercise-associated acute cardiac events generally occur in individuals with structural cardiac disease. Hereditary or congenital cardiovascular abnormalities are predominantly responsible for cardiac events among young individuals, whereas atherosclerotic disease is primarily responsible for these events in adults. The absolute rate of exercise-related sudden cardiac death varies with the prevalence of disease in the study population. The incidence of both acute myocardial infarction and sudden death is greatest in the habitually least physically active individuals. No strategies have been adequately studied to evaluate their ability to reduce exercise-related acute cardiovascular events. Maintaining physical fitness through regular physical activity may help to reduce events because a disproportionate number of events occur in least physically active subjects performing unaccustomed physical activity. Other strategies, such as screening patients before participation in exercise, excluding high-risk patients from certain activities, promptly evaluating possible prodromal symptoms, training fitness personnel for emergencies, and encouraging patients to avoid high-risk activities, appear prudent but have not been systematically evaluated.
认领第一篇
认领第十篇和第十一篇
第12篇
12、Exercise and Acute Cardiovascular Events
Placing the Risks Into Perspective: A Scientific Statement From the American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology
Habitual physical activity reduces coronary heart disease events, but vigorous activity can also acutely and transiently increase the risk of sudden cardiac death and acute myocardial infarction in susceptible persons. This scientific statement discusses the potential cardiovascular complications of exercise, their pathological substrate, and their incidence and suggests strategies to reduce these complications. Exercise-associated acute cardiac events generally occur in individuals with structural cardiac disease. Hereditary or congenital cardiovascular abnormalities are predominantly responsible for cardiac events among young individuals, whereas atherosclerotic disease is primarily responsible for these events in adults. The absolute rate of exercise-related sudden cardiac death varies with the prevalence of disease in the study population. The incidence of both acute myocardial infarction and sudden death is greatest in the habitually least physically active individuals. No strategies have been adequately studied to evaluate their ability to reduce exercise-related acute cardiovascular events. Maintaining physical fitness through regular physical activity may help to reduce events because a disproportionate number of events occur in least physically active subjects performing unaccustomed physical activity. Other strategies, such as screening patients before participation in exercise, excluding high-risk patients from certain activities, promptly evaluating possible prodromal symptoms, training fitness personnel for emergencies, and encouraging patients to avoid high-risk activities, appear prudent but have not been systematically evaluated.
运动与急性心血管事件
把危险因素纳入的前瞻性研究：美国心脏协会营养、运动及代谢委员会和临床心脏病学委员会的一份科学声明
平常的体育运动减少心血管事件的发生，但是激烈的运动也能急速增加易感患者心脏猝死及急性心梗的危险性。这份科学声明讨论了运动时潜在的心血管并发症、其病理机制、发生率以及减少并发症建议的措施。运动相关的急性心血管事件在器质性心脏病患者常见。遗传性及先天性心血管异常是年轻人心血管事件的主要原因，然而，在成年人中主要是动脉粥样硬化。运动相关的心脏猝死的绝对发生率在不同的疾病发生率的人群研究中结果不一。急性心梗和心脏猝死发生率最高的都是最活跃的人群。能减少运动相关的急性心血管事件的措施还未有得到充分的研究。通过规则的运动保持身材能减少事件的发生，因为活跃人群在进行激烈运动时有个不对称的心血管事件的发生率。比如进行运动前筛查患者，包括杜绝高危患者从事一定量的运动，快速评价可能的前区症状，训练适宜人群学习急救，以及鼓励患者避免高危运动等等其他措施似乎审慎，但尚未有系统的评价。
1、Direct Intramyocardial But Not Intracoronary Injection of Bone Marrow Cells Induces Ventricular Arrhythmias in a Rat Chronic Ischemic Heart Failure Model
对鼠慢性缺血性心衰模型直接心肌内注射而非经冠脉注射骨髓细胞可引起室性心律失常
Background— Therapeutic efficacy of bone marrow (BM) cell injection for treating ischemic chronic heart failure has not been established.研究背景——注射骨髓细胞对于慢性缺血性心衰的治疗效果还未得到证实。 In addition, experimental data are lacking on arrhythmia occurrence after BM cell injection.此外，关于骨髓细胞注射治疗后心律失常发生率的实验数据还很缺乏。 We hypothesized that therapeutic efficacy and arrhythmia occurrence induced by BM cell injection may be affected by the cell delivery route. 我们假设骨髓细胞注射的治疗效果和心律失常的发生率可能和骨髓细胞的注射途径有关。
Methods and Results— Three weeks after left coronary artery ligation, wild-type female rats were injected with 1x107 mononuclear BM cells derived from green fluorescent protein–transgenic male rats through either a direct intramyocardial or a retrograde intracoronary route.方法和结果——将取自绿荧光蛋白-转基因雄性鼠的骨髓细胞或者直接心肌内注射或者经冠脉注射入左冠状动脉结扎三周后的野生型雌性鼠。Both intramyocardial and intracoronary injection of BM cells demonstrated similar improvement in left ventricular ejection fraction measured by echocardiography and a similar graft size analyzed by real-time polymerase chain reaction for the Y chromosome–specific Sry gene.之后经超声心动图显示两种途径注射后的雌鼠左室射血分数均有相似程度的改善，并且用实时PCR检测Y染色体特异的SRY基因在两种途径注射后的雌鼠身上的表达程度也相似。 Noticeably, intramyocardial injection of BM cells induced frequent ventricular premature contractions (108±73 per hour at 7 days after BM cell injection), including multiform, consecutive ventricular premature contractions and ventricular tachycardia for the initial 14 days; intracoronary injection of BM cells and intramyocardial injection of phosphate-buffered saline rarely induced arrhythmias.引人注意的是在起始的14天内，直接心肌内注射骨髓细胞引起了频发的室性期前收缩（在骨髓细胞注射后7天108±73每小时），包括多形，持续的室性期前收缩和室性心律失常；而冠脉内注射和直接心肌注射经磷酸盐缓冲的骨髓细胞则很少引起心律失常。 Immunohistochemistry demonstrated that intramyocardial BM cell injection formed distinct cell clusters containing donor-derived cells and accumulated host-derived inflammatory cells in the infarct border zone, whereas intracoronary BM cell injection provided more homogeneous donor cell dissemination with less inflammation and without disrupting the native myocardial structure. 免疫组化结果显示，直接心肌内注射的雌鼠在心肌梗死的边缘存在一些特异的细胞群，包括起源于供体的细胞和起源于宿主的聚集的炎性细胞，而冠脉注射的雌鼠则有更多的同种的供体细胞而较少炎症反应也没有心肌结构的变化。
Conclusions— BM cell injection is able to improve cardiac function in ischemic chronic heart failure but has a risk of arrhythmia occurrence when the intramyocardial route is used. Such arrhythmias may be prevented by using the intracoronary route.
结论——对于慢性缺血性心衰骨髓细胞注射能改善心脏功能，但是直接心肌注射有引起心律失常的风险，而经冠脉注射则可减少心律失常的发生率。
第10篇
10、Phosphodiesterase 1 Upregulation in Pulmonary Arterial Hypertension
Target for Reverse-Remodeling Therapy
在肺动脉高血压中磷酸二脂酶-1的上调
目标：逆转重构治疗
Background— Pulmonary arterial hypertension (PAH) is a life-threatening disease, characterized by vascular smooth muscle cell hyperproliferation. The calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) may play a major role in vascular smooth muscle cell proliferation.
背景—肺动脉高压(PAH)是一种威及生命的疾病，以血管平滑肌细胞高度增生为特征。钙/钙调节素依赖的磷酸二脂酶1（PDE1）在血管平滑肌细胞增生过程中可能发挥了主要作用
Methods and Results— We investigated the expression of PDE1 in explanted lungs from idiopathic PAH patients and animal models of PAH and undertook therapeutic intervention studies in the animal models. Strong upregulation of PDE1C in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was noted on the mRNA level by laser-assisted vessel microdissection and on the protein level by immunohistochemistry. In chronically hypoxic mouse lungs and lungs from monocrotaline-injected rats, PDE1A upregulation was detected in the structurally remodeled arterial muscular layer. Long-term infusion of the PDE1 inhibitor 8-methoxymethyl 3-isobutyl-1-methylxanthine in hypoxic mice and monocrotaline-injected rats with fully established pulmonary hypertension reversed the pulmonary artery pressure elevation, structural remodeling of the lung vasculature (nonmuscularized versus partially muscularized versus fully muscularized small pulmonary arteries), and right heart hypertrophy.
方法与结果—我们研究了来自原发性PAH病人和PAH动物模型分离的肺脏中PDE1的表达情况，并且在动物模型中进行了治疗性干预研究。与健康供者肺脏相比在原发性PAH肺动脉血管中通过激光辅助血管显微解剖（laser-assisted vessel microdissection ）和免疫组化法分别发现PDE1C在mRNA水平、蛋白水平大大上调。在慢性缺氧小鼠肺和野百合碱（monocrotaline）注射的大鼠肺中，在结构重塑的动脉肌层中观测到PDE1A的上调。在完全确诊肺动脉高压的缺氧小鼠和野百合碱注射的大鼠中长期注射PDE1抑制剂8-甲氧基甲基3-异丁基-1-甲基黄嘌呤能逆转肺动脉压力升高，肺脉管系统的结构重塑（无肌化vs部分肌化vs完全肌化肺小动脉）和右心肥厚。
Conclusions— Strong upregulation of the PDE1 family in pulmonary artery smooth muscle cells is noted in human idiopathic PAH lungs and lungs from animal models of PAH. Inhibition of PDE1 reverses structural lung vascular remodeling and right heart hypertrophy in 2 animal models. The PDE1 family may thus offer a new target for therapeutic intervention in pulmonary hypertension.
Special Reports
结论：在人原发性PAH肺脏和PAH动物模型的肺脏中观测到肺动脉平滑肌细胞中PDE1家族的大大上调。在2种动物模型中抑制PDE1能逆转肺血管结构的重塑和右心肥厚。PDE1家族可能为肺动脉高压治疗性干预提供新的靶点。
特别报道
本人才疏学浅，希望能够得到大家的指导，现翻译第7篇摘要，如下。请不吝赐教！！！！！
7、A1 Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction
左心室功能不全的老鼠心肌腺苷水平降低伴随A1腺苷受体的上调
Background— It is well known that adenosine levels are increased during ischemia and protect the heart during ischemia/reperfusion. However, less is known about the role of adenosine–adenosine receptor (AR) pathways in hearts with left ventricular dilation and dysfunction. Therefore, we assessed adenosine levels and selective AR expression in transgenic mice with left ventricular systolic dysfunction secondary to overexpression of tumor necrosis factor- (TNF 1.6). 背景-众所周知腺苷水平在局部缺血时的升高的，并且在缺血/再灌注时保护心脏。然而，很少有人知道在左心室扩展及功能障碍的心脏中腺苷-腺苷受体（AR）途径的作用。因此，我们检测了左心室收缩功能障碍并继发肿瘤坏死因子（TNF1.6）过表达的转基因老鼠腺苷水平和选择性AR的表达。
Methods and Results— Cardiac adenosine levels were reduced by 70% at 3 and 6 weeks of age in TNF 1.6 mice. This change was accompanied by a 4-fold increase in the levels of A1-AR and a 50% reduction in the levels of A2A-AR. That the increase in A1-AR density was of physiological significance was shown by the fact that chronotropic responsiveness to the A1-AR selective agonist 2-chloro-N6-cyclopentanyl adenosine was enhanced in the TNF 1.6 mice. Similar changes in adenosine levels were found in 2 other models of heart failure, mice overexpressing calsequestrin and mice after chronic pressure overload, suggesting that the changes in adenosine-AR signaling were secondary to myocardial dysfunction rather than to TNF overexpression. 方法与结果-强心剂腺苷水平在3和6周龄的TNF1.6老鼠中下降70%。此变化是伴随于A1-AR水平升高4成和A2A-AR水平降低50%。A1-AR密度增加具有生理学意义，这个事实说明心跳频率性对A1-AR选择性激动剂2-氯-N6-环戊芬腺苷的反应在TNF1.6老鼠中是增强的。在其它2种心衰模型（过表达隐钙素的老鼠和慢性压力符合过大的老鼠）的腺苷水平也发现相似的变化，说明腺苷-AR信号的变化是继发于心肌功能异常的，而不是继发于TNF的过表达 。
Conclusions— Cardiac dysfunction secondary to the overexpression of TNF is associated with marked alterations in myocardial levels of adenosine and ARs. Modulation of the myocardial adenosine system and its signaling pathways may be a novel therapeutic target in patients with heart failure.结论-继发于TNF过表达的心脏功能障碍与心肌腺苷和AR水平的显著改变有关。调节心肌腺苷系统和它的信号途径可能是兴衰病人治疗的新途径。
认领第8篇~~~
8、Instability in the Diagnosis of Metabolic Syndrome in Adolescents
8. 青少年代谢综合症诊断的不稳定性
Background— Factor analyses suggest that the structure underlying metabolic syndrome is similar in adolescents and adults. However, adolescence is a period of intense physiological change, and therefore stability of the underlying metabolic structure and clinical categorization based on metabolic risk is uncertain.
背景----因子分析提示在青少年和成人中代谢综合症的潜在构成是相似的。然而，青少年时期其生理状况会出现显著的改变，因此，潜在的代谢构成的稳定性和基于代谢风险因子的临床确诊也是不肯定的。
Methods and Results— We analyzed data from 1098 participants in the Princeton School District Study, a school-based study begun in 2001–2002, who were followed up for 3 years. We performed factor analyses of 8 metabolic risks at baseline and follow-up to assess stability of factor patterns and clinical categorization of metabolic syndrome. Metabolic syndrome was defined using the current American Heart Association/National Heart, Lung, and Blood Institute definition for adults (AHA), a modified AHA definition used in prior pediatric metabolic syndrome studies (pediatric AHA), and the International Diabetes Federation (IDF) guidelines. We found that factor structures were essentially identical at both time points. However, clinical categorization was not stable. Approximately half of adolescents with baseline metabolic syndrome lost the diagnosis at follow-up regardless of the definitions used: pediatric AHA=56% (95% confidence interval [CI], 42% to 69%), AHA=49% (95% CI, 32% to 66%), IDF=53% (95% CI, 38% to 68%). In addition to loss of the diagnosis, new cases were identified. Cumulative incidence rates were as follows: pediatric AHA=3.8% (95% CI, 2.8% to 5.2%); AHA=4.4% (95% CI, 3.3% to 5.9%); IDF=5.2% (95% CI, 4.0% to 6.8%).
方法与结论----在一个开始于2001-2002年的以学校为基础的普林斯顿学校地段研究中，我们分析了1098位青少年的数据，并随访3年。我们对8种代谢危险因子的基线水平和随访水平进行因子分析，来评估代谢综合症的因子模式和临床确诊的稳定性。使用目前的美国心脏协会/国立心脏、肺、血液研究院的成人诊断标准(AHA)，适用于学前期代谢综合症的修改的AHA标准，和国际糖尿病协会(IDF)指南来诊断代谢综合症。我们发现在两个时间点上的因子构成本质上是一致的。然而，临床的确诊却不稳定。无论用的是哪一条标准，大约一半的青少年在基线水平时诊断为代谢综合症而在随访当中诊断不成立：儿童AHA标准为56%(95%可信区间[CI], 42% to 69%)，AHA标准为49%(95%CI, 32% to 66%)，IDF标准为53%(95%CI, 38% to 68%)。除了旧的诊断的丢失，新的个案被确定。累积发病率如下：儿童AHA标准为3.8% (95% CI, 2.8% to 5.2%); AHA标准为4.4% (95% CI, 3.3% to 5.9%); IDF标准为5.2% (95% CI, 4.0% to 6.8%).
Conclusions— During adolescence, metabolic risk factor clustering is consistent. However, marked instability exists in the categorical diagnosis of metabolic syndrome. This instability, which includes both gain and loss of the diagnosis, suggests that the syndrome has reduced clinical utility in adolescence and that metabolic syndrome–specific pharmacotherapy for youth may be premature.
结论----在青少年时期，代谢危险因子的聚类是一致的。但在代谢综合症的确诊中的确存在着显著的不稳定性。这种不稳定性，包括诊断的获得与丢失，提示在青少年中此病临床诊断效用的减少，以及针对青少年代谢综合症的药物治疗可能不成熟。
自我感觉有些地方翻译得很勉强，请大家指教(蓝色字体)。
我领第2篇，望批评指正
2、Global Improvement of Vascular Function and Redox State With Low-Dose Folic Acid
Implications for Folate Therapy in Patients With Coronary Artery Disease
小剂量叶酸治疗对冠心病病人血管功能和氧化还原状态的根本改善
Background— Although dietary folate fortification lowers plasma homocysteine and may reduce cardiovascular risk, high-dose folic acid therapy appears to not alter clinical outcome. Folic acid and its principal circulating metabolite, 5-methyltetrahydrofolate, improve vascular function, but mechanisms relating folate dose to vascular function remain unclear. We compared the effects of folic acid on human vessels using pharmacological high-dose versus low-dose treatment, equivalent to dietary folate fortification.
研究背景：虽然预防性的食用叶酸可以降低血浆同型半胱氨酸水平可能会降低心血管事件，大剂量的叶酸治疗并没有改变临床终点。叶酸和其主要代谢产物N5-甲基四氢叶酸，改善血管功能，但是起作用的叶酸剂量多少仍然不清楚。我们比较药理性高剂量与等同于日常饮食预防的低剂量的叶酸对血管的效果。
Methods and Results— Fifty-six non–folate-fortified patients with coronary artery disease were randomized to receive low-dose (400 µg/d) or high-dose (5 mg/d) folic acid or placebo for 7 weeks before coronary artery bypass grafting. Vascular function was quantified by magnetic resonance imaging before and after treatment. Vascular superoxide and nitric oxide bioavailability were determined in segments of saphenous vein and internal mammary artery. Low-dose folic acid increased nitric oxide–mediated endothelium-dependent vasomotor responses, reduced vascular superoxide production, and improved enzymatic coupling of endothelial nitric oxide synthase through availability of the cofactor tetrahydrobiopterin. No further improvement in these parameters occurred with high-dose compared with low-dose treatment. Whereas plasma 5-methyltetrahydrofolate increased proportionately with treatment dose of folic acid, vascular tissue 5-methyltetrahydrofolate showed no further increment with high-dose compared with low-dose folic acid.
方法与结论：56位非叶酸强化治疗的冠心病病人择接受冠状动脉旁路移植术前随机分成服用低剂量(400 µg/d)叶酸、高剂量(5 mg/d) 叶酸、安慰剂7周。治疗前后用MRI评价血管功能。用大阴静脉及乳内动脉测定血管超氧化物及NO生物利用度。低剂量的叶酸增加NO介导的内皮细胞收缩反应，减少血管超氧化物的产生，通过辅因子四氢生物蝶呤改善内皮NO合酶活性。与低剂量相比，高剂量组对上述参数并没有进一步的改善。而血浆N5-甲基四氢叶酸随着治疗剂量的增加而成比例的增加，而血管组织中的N5-甲基四氢叶酸在高剂量组没有比低剂量组进一步的增加。
Conclusions— Low-dose folic acid treatment, comparable to daily intake and dietary fortification, improves vascular function through effects on endothelial nitric oxide synthase and vascular oxidative stress. High-dose folic acid treatment provides no additional benefit. These direct vascular effects are related to vascular tissue levels of 5-methyltetrahydrofolate rather than plasma levels. High-dose folic acid treatment likely confers no further benefit in subjects already receiving folate supplementation.
结论：低剂量叶酸治疗，等同于日常摄入量加预防量，通过内皮NO合酶及氧化应激改善血管功能。高剂量的叶酸没有额外的获益。这些效果与组织中的N5-甲基四氢叶酸水平有关，与血浆的的N5-甲基四氢叶酸水平无关。高剂量叶酸治疗在已经接受补充叶酸的患者中不可能有额外的获益。
11、Clinical End Points in Coronary Stent Trials
A Case for Standardized Definitions
题目：冠脉支架实验的临床（评价）终点
——（终点事件）标准化定义会议
Background— Although most clinical trials of coronary stents have measured nominally identical safety and effectiveness end
points, differences in definitions and timing of assessment have created confusion in interpretation.
背景：尽管大多数关于冠脉支架的临床实验名义上具有同样的基于标准的安全和有效的实验终点，但是（终点事件的）定义和评价时间的不同会产生（对实验）理解上的混乱。
Methods and Results— The Academic Research Consortium is an informal collaboration between academic research organizations
in the United States and Europe. Two meetings, in Washington, DC, in January 2006 and in Dublin, Ireland, in June 2006,
sponsored by the Academic Research Consortium and including representatives of the US Food and Drug Administration and all
device manufacturers who were working with the Food and Drug Administration on drug-eluting stent clinical trial programs,
were focused on consensus end point definitions for drug-eluting stent evaluations. The effort was pursued with the
objective to establish consistency among end point definitions and provide consensus recommendations. On the basis of
considerations from historical legacy to key pathophysiological mechanisms and relevance to clinical interpretability,
criteria for assessment of death, myocardial infarction, repeat revascularization, and stent thrombosis were developed. The
broadly based consensus end point definitions in this document may be usefully applied or recognized for regulatory and
clinical trial purposes.
方法和结果：学术研究协会是美国和欧洲的研究机构之间的非正式的联合组织。由学术研究协会发起的，包括美国食品与药品管理局和所有参与其药物洗脱支架临床实验的（支架）制造厂商的代表参加的两个会议，一个于2006年1月在美国华盛顿（举行），另一个于2006年6月于爱尔兰首都都柏林（举行）。这两个会议就药物洗脱支架终点事件的定义达成一致。会议力争建立起相同的重点事件定议（标准）和一致给予的推荐。基于从病理生理学重要机制的历史研究到与此有关的临床应用的考虑，制定出了关于界定死亡，心肌梗死，反复血管再通和支架内血栓形成的（终点事件）评价标准。（会议文件中）制定出的基于广泛意见的，（临床）终点事件的标准将可能为不同的临床实验目的所应用和验证。
Conclusion— Although consensus criteria will inevitably include certain arbitrary features, consensus criteria for clinical end points provide consistency across studies that can facilitate the evaluation of safety and effectiveness of these devices.
结论：尽管一致的标准不可避免的具有特定的主观的特征，但是其提供了不同研究中一致的 （评价）终点事件的标准，从而使的评价支架的安全有效性变的容易。
AHA Scientific Statement
美国心脏病协会科学声明
有些地方感觉翻译的很差,请高手指教
领第九篇
9、Targeting Platelets in Acute Experimental Stroke
Impact of Glycoprotein Ib, VI, and IIb/IIIa Blockade on Infarct Size, Functional Outcome, and Intracranial Bleeding
在急性实验性卒中血小板糖蛋白Ib, VI, 及 IIb/IIIa对阻止梗死范围、功能区结果及颅内出血的作用
Background— Ischemic stroke is a frequent and serious disease with limited treatment options. Platelets can adhere to hypoxic cerebral endothelial cells by binding of their glycoprotein (GP) Ib receptor to von Willebrand factor. Exposure of subendothelial matrix proteins further facilitates firm attachment of platelets to the vessel wall by binding of collagen to their GPVI receptor. In the present study, we addressed the pathogenic role of GPIb, GPVI, and the aggregation receptor GPIIb/IIIa in experimental stroke in mice.
研究背景：缺血性卒中是一种常见的严重而治疗方案少的疾病。血小板通过VW因子与血小板糖蛋白Ib受体结合后黏附在大脑缺血区内皮细胞上。内皮下基层的暴露进一步促使血小板通过糖蛋白VI受体与胶原结合使得血小板紧密的黏附在血管壁上。在实验性卒中鼠模型研究中，我们阐述了糖蛋白Ib, VI,及糖蛋白聚集受体IIb/IIIa的致病作用。
Methods and Results— Complete blockade of GPIb was achieved by intravenous injection of 100 µg Fab fragments of the monoclonal antibody p0p/B to mice undergoing 1 hour of transient middle cerebral artery occlusion. At 24 hours after transient middle cerebral artery occlusion, cerebral infarct volumes were assessed by 2,3,5-triphenyl tetrazolium chloride staining. In mice treated with anti-GPIb Fab 1 hour before middle cerebral artery occlusion, ischemic lesions were reduced to 40% compared with controls (28.5±12.7 versus 73.9±17.4 mm3, respectively; P<0.001). Application of anti-GPIb Fab 1 hour after middle cerebral artery occlusion likewise reduced brain infarct volumes (24.5±7.7 mm3; P<0.001) and improved the neurological status. Similarly, depletion of GPVI significantly diminished the infarct volume but to a lesser extent (49.4±19.1 mm3; P<0.05). Importantly, the disruption of early steps of platelet activation was not accompanied by an increase in bleeding complications as revealed by serial magnetic resonance imaging. In contrast, blockade of the final common pathway of platelet aggregation with anti-GPIIb/IIIa F(ab)2 fragments had no positive effect on stroke size and functional outcome but increased the incidence of intracerebral hemorrhage and mortality after transient middle cerebral artery occlusion in a dose-dependent manner.
方法与结论：在经历1小时短暂阻断大脑中动脉后，通过静脉注射单克隆抗体p0p/B碎片Fab 100ug使鼠糖蛋白Ib完全阻断。在大脑中动脉短暂阻断后24小时，通过2,3,5三苯基四唑盐染色评价梗死范围大小。在大脑中动脉阻塞前1小时就给予糖蛋白Ib拮抗剂Fab治疗的小鼠中，梗死面积与对照组相比减少40％(28.5±12.7 对 73.9±17.4 mm3, ; P<0.001)，在大脑中动脉阻塞后1小时给予糖蛋白Ib拮抗剂Fab治疗的小鼠中，梗死面积同样减少(24.5±7.7 mm3; P<0.001)并且改善精神状态。同样地，糖蛋白VI的消耗明显的减少梗死面积(49.4±19.1 mm3; P<0.05).重要的是，血小板激活的早期步骤的阻断并没有使得MRI显示出来的出血并发症增加。比较而言，通过使用糖蛋白IIb/IIIa最终共同途径集聚的阻滞剂F(ab)2，在梗死面积及功能上没有积极的作用，而且增加大脑中动脉阻塞后鼠剂量依赖性颅内出血事件及死亡率。
Conclusions— Our data indicate that the selective blockade of key signaling pathways of platelet adhesion and aggregation has a different impact on stroke outcome and bleeding complications. Inhibition of early steps of platelet adhesion to the ischemic endothelium and the subendothelial matrix may offer a novel and safe treatment strategy in acute stroke.
结论：我们研究表明：血小板黏附集聚关键途径的选择性阻断对卒中及出血并发症有不同的作用。在血小板黏附在血管内皮细胞及内皮下基层的早期进行抑制可能提供一种新的安全的治疗缺血性卒中的治疗方法。
闲着没事，再领3，4 篇
请相关专业人士指正，谢谢
3、Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A352–372)
Naturally Occurring Amino Acid Variant Gly364Ser Causes Profound Changes in Human Autonomic Activity and Alters Risk for Hypertension
儿茶酚胺释放-抑制性肽Catestatin（嗜铬粒蛋白A 352–372)
自然变异的氨基酸变异体Gly364Ser引起复杂的人体自律性的变化改变患高血压病的风险
Background— Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release–inhibitory fragment catestatin. We identified a natural non synonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure.
研究背景：嗜铬粒蛋白A，由细胞外分泌，与儿茶酚胺有关，伴随儿茶酚胺释放-抑制性片断catestatin，我们证实，天然的非同义的catestatin变异体Gly364Ser，改变了人类自律性及血压。
Methods and Results— Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by 47%) and downward deflections (by 44%), increased cardiac parasympathetic index (by 2.4-fold), and decreased cardiac sympathetic index (by 26%). Renal norepinephrine excretion was diminished by 26% and epinephrine excretion by 34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to 70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by 5 to 6 mm Hg, and the polymorphism accounted for 1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men.
方法与结论：Gly364Ser杂合子组与对照组发生生理的及生化的显型，包括儿茶酚胺的产生，嗜铬粒蛋白A前体，嗜铬粒蛋白A。对照组研究人群中高血压基因的复制效应。Gly364Ser减少来自成熟神经元儿茶酚胺释放的抑制。甘氨酸/色氨酸杂合子增加压力感受器斜率，在上调偏转47%，下调偏转44%，增加心脏副交感神经指数（2~4倍），降低心脏交感神经指数26%。甘氨酸/色氨酸杂合子组肾脏分泌的去甲肾上腺素减少26%肾上腺素减少34%。追溯70000年前的变异体数据，Gly364Ser与嗜铬粒蛋白A启动子单体不均衡连锁，但是启动子单体没有预测自律性表型。364Ser变异体在有确诊高血压及没有高血压的患者中都与较低的舒张压有关。尽管明显的性染色体基因影响作用，尤其是男性增强效应，基因组变化5~6mmHg，基因多态性解释了1.8%人口收缩压变异。
Conclusions— The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.
结论：catestatin Gly364Ser变异体引起复杂的人类自律性变化，副交感神和交感神经，似乎减轻尤其是男性患高血压病的风险。在细胞核压力感受器catestatin模型解释了这些作用。
好多地方非常不满意
4、Heredity of Endothelin Secretion
Human Twin Studies Reveal the Influence of Polymorphism at the Chromogranin A Locus, a Novel Determinant of Endothelial Function
内皮素分泌的遗传
孪生人群研究表明一个新的内皮细胞功能的决定子， 嗜铬粒蛋白A基因组多态性的作用
Background— Endothelial dysfunction predisposes to vascular injury in association with hypertension. Endothelin (ET-1) is a potent vasoactive peptide that is synthesized and released by the vascular endothelium and is a marker of endothelial function. Chromogranin A (CHGA) regulates the storage and release of catecholamines and may have direct actions on the microvasculature. CHGA, a candidate gene for intermediate phenotypes that contribute to hypertension, shows a pattern of single nucleotide polymorphism variations that alter the expression and function of this gene both in vivo and in vitro.
研究背景：内皮细胞功能障碍继发于高血压相关的血管损害。内皮素－1是重要的血管活性肽，由血管内皮细胞合成及释放，是内皮细胞功能的一个标志。嗜铬粒蛋白A调控儿茶酚胺的储存及释放，而且对微血管有直接作用。嗜铬粒蛋白A，一个导致高血压的中介表型的候选基因，单核苷酸多态性变异的模式之一，在体及离体实验中其改变了基因的表达及功能。
Methods and Results— In a study of twins (n=238 pairs), plasma ET-1 was 58±5% (P<0.0001) heritable. Plasma ET-1 was both correlated and associated with chromogranin fragment levels, and the 2 were influenced by shared genetic determination (pleiotropy [G]; for the CHGA precursor, G=0.318±0.105; P=0.0032). We therefore hypothesized that variation in the CHGA gene may influence ET-1 secretion. Carriers of the CHGA promoter –988G, –462A, and –89A minor alleles showed significantly higher mean plasma ET-1 than their major allele homozygote counterparts (P=0.02, P=0.006, P=0.03, respectively). Analysis of a linkage disequilibrium block that spans these 3 single nucleotide polymorphisms showed a significant association between the GATACA haplotype and plasma ET-1 (P=0.0075). In cultured human umbilical vein endothelial cells, CHGA caused dose-dependent secretion of ET-1 over a brief (<1 hour) time course at relatively low concentrations of CHGA (10 to 100 nmol/L) with a threshold concentration (10 nmol/L) in the range found circulating in humans in vivo.
方法和结果：在一个孪生人群的研究中（n=238对），血浆内皮素－1 58±5% (P<0.0001)是可遗传的。血浆内皮素－1与嗜铬粒蛋白碎片水平有关系，每对孪生受共同的基因的影响（基因多效性【G】; 嗜铬粒蛋白前体G=0.318±0.105; P=0.0032)。因此我们假定嗜铬粒蛋白基因变异可能会影响内皮素－1的分泌。嗜铬粒蛋白启动子–988G, –462A, 及 –89A的小等位基因携带者比大的等位基因纯合体的血浆内皮素－1水平更高(P=0.02, P=0.006, P=0.03)。连锁不均衡片断分析，其包含3个核苷酸多态性，与GATACA单体型及血浆内皮素－1有明显的联系(P=0.0075)。在成人脐静脉内皮细胞，在体循环血液中发现阈值浓度(10 nmol/L)，相对低的嗜铬粒蛋白A浓度(10 to 100 nmol/L)引起剂量依赖性的内皮素－1的释放。
Conclusions— These results suggest that common, heritable variation in expression of the human CHGA gene influences endothelial ET-1 secretion in vivo, explained by a CHGA stimulus/ET-1 secretion coupling in endothelial cells in vitro. The findings document a previously unsuspected interaction between the sympathochromaffin system and the endothelium and suggest novel genetic and cell biological approaches to the prediction, diagnosis, and mechanism of endothelial dysfunction in human disease.
结论：研究结果表明，人体嗜铬粒蛋白A基因的常见的可遗传的变异的表达影响内皮素－1的分泌，可以通过嗜铬粒蛋白A刺激物/体外实验内皮细胞伴随内皮素－1的分泌来解释。这一发现证明了以前无庸置疑的交感神经系统与内皮细胞的相互影响，并且提出一种新的遗传学的细胞生物学的方法，可为人类疾病内皮细胞功能障碍作出预测、诊断。
探讨学习
2、Global Improvement of Vascular Function and Redox State With Low-Dose Folic Acid
Implications for Folate Therapy in Patients With Coronary Artery Disease
小剂量叶酸治疗对冠心病病人血管功能和氧化还原状态的根本改善(全面改善)
Background— Although dietary folate fortification lowers plasma homocysteine and may reduce cardiovascular risk, high-dose folic acid therapy appears to not alter clinical outcome. Folic acid and its principal circulating metabolite, 5-methyltetrahydrofolate, improve vascular function, but mechanisms relating folate dose to vascular function remain unclear. We compared the effects of folic acid on human vessels using pharmacological high-dose versus low-dose treatment, equivalent to dietary folate fortification.
研究背景：虽然预防性的食用叶酸（食用叶酸强化）可以降低血浆同型半胱氨酸水平可能会降低心血管事件，大剂量的叶酸治疗并没有改变临床终点。叶酸和其主要代谢产物N5-甲基四氢叶酸，改善血管功能，但是起作用的叶酸剂量多少仍然不清楚（但是对于叶酸发挥作用与剂量有相关性的具体机制尚未明确）。我们比较药理性高剂量与等同于日常饮食预防（强化）的低剂量的叶酸（治疗）对血管的效果。
Methods and Results— Fifty-six non–folate-fortified patients with coronary artery disease were randomized to receive low-dose (400 µg/d) or high-dose (5 mg/d) folic acid or placebo for 7 weeks before coronary artery bypass grafting. Vascular function was quantified by magnetic resonance imaging before and after treatment. Vascular superoxide and nitric oxide bioavailability were determined in segments of saphenous vein and internal mammary artery. Low-dose folic acid increased nitric oxide–mediated endothelium-dependent vasomotor responses, reduced vascular superoxide production, and improved enzymatic coupling of endothelial nitric oxide synthase through availability of the cofactor tetrahydrobiopterin. No further improvement in these parameters occurred with high-dose compared with low-dose treatment. Whereas plasma 5-methyltetrahydrofolate increased proportionately with treatment dose of folic acid, vascular tissue 5-methyltetrahydrofolate showed no further increment with high-dose compared with low-dose folic acid.
方法与结论：56位非叶酸强化治疗的冠心病病人择接受冠状动脉旁路移植术前随机分成服用低剂量(400 µg/d)叶酸、高剂量(5 mg/d) 叶酸、安慰剂7周。治疗前后用MRI评价血管功能。用大阴静脉及乳内动脉测定血管超氧化物及NO生物利用度。低剂量的叶酸增加NO介导的内皮细胞收缩反应，减少血管超氧化物的产生，通过辅因子四氢生物蝶呤改善内皮NO合酶活性。与低剂量相比，高剂量组对上述参数并没有进一步的改善。而血浆N5-甲基四氢叶酸随着治疗剂量的增加而成比例的增加，而血管组织中的N5-甲基四氢叶酸在高剂量组没有比低剂量组进一步的增加。
Conclusions— Low-dose folic acid treatment, comparable to daily intake and dietary fortification, improves vascular function through effects on endothelial nitric oxide synthase and vascular oxidative stress. High-dose folic acid treatment provides no additional benefit. These direct vascular effects are related to vascular tissue levels of 5-methyltetrahydrofolate rather than plasma levels. High-dose folic acid treatment likely confers no further benefit in subjects already receiving folate supplementation.
结论：低剂量叶酸治疗，等同于日常摄入量加预防量，通过内皮NO合酶及氧化应激改善血管功能。高剂量的叶酸没有额外的获益。这些效果与组织中的N5-甲基四氢叶酸水平有关，与血浆的的N5-甲基四氢叶酸水平无关。高剂量叶酸治疗在已经接受补充叶酸的患者中不可能有额外的获益。
再领5、6两篇
5、Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor
用一种新的蛋白酶可激活的荧光感受器使动脉粥样硬化斑块中组织蛋白酶K活性显影
Background— Cathepsin K (CatK), a potent elastinolytic and collagenolytic cysteine protease, likely participates in the evolution and destabilization of atherosclerotic plaques. To assess better the biology of CatK activity in vivo, we developed a novel near-infrared fluorescence (NIRF) probe for imaging of CatK and evaluated it in mouse and human atherosclerosis.
研究背景：组织蛋白酶K，一种强有力的溶胶原半胱氨酸蛋白酶，可能参与动脉粥样硬化斑块的演化及与斑块不稳定有联系。为了更好的评价机体组织内组织蛋白酶K的生物学活性，我们研发了一种新的使组织蛋白酶K显影的短距红外线荧光探针，利用这种探针可评价鼠及人体动脉粥样硬化斑块中组织蛋白酶K的活性。
Methods and Results— The NIRF imaging agent consists of the CatK peptide substrate GHPGGPQGKC-NH2 linked to an activatable fluorogenic polymer. In vitro, CatK produced a 2- to 14-fold activation of the agent over other cysteine and matrix metallproteinases (P<0.0001), as well as a >8-fold activation over a control imaging agent (P<0.001). Optical imaging of atheroma revealed >100% NIRF signal increases in apolipoprotein E–/– mice in vivo (n=13; P<0.05, CatK imaging agent versus control agent) and in human carotid endarterectomy specimens ex vivo (n=14; P<0.05). Fluorescence microscopy of plaque sections demonstrated that enzymatically active CatK (positive NIRF signal) localized primarily in the vicinity of CatK-positive macrophages. Augmented NIRF signal (reflecting CatK activity) colocalized with disrupted elastin fibers within the media underlying plaques.
方法及结果： 短距红外线荧光显影剂含有组织蛋白酶K缩氨酸感光底物GHPGGPQGKC-NH2，其连结在一个可激活的荧光底物激活体上。在离体实验中，组织蛋白酶K与其他半胱氨酸及金属蛋白酶相比，其产生了2-14倍的显影剂的激活量(P<0.0001),而且是对照组显影剂激活量的8倍以上(P<0.001).动脉粥样硬化斑块中红外线荧光信号显影在鼠体内载脂蛋白E增加(n=13; P<0.05, 组织蛋白酶K 显影剂与 对照组显影剂)及人体颈动脉内膜切除术离体标本(n=14; P<0.05).粥样硬化斑块剖面荧光显微镜下可观察到有酶活性的组织蛋白酶K(阳性红外线信号)主要位于有组织蛋白酶K活性的巨噬细胞附近。增强的红外线荧光信号（反映组织蛋白酶K活性）与粥样硬化斑块内的断裂的弹性纤维蛋白有关。
Conclusions— Use of this novel protease-activatable NIRF agent for optical imaging in vivo demonstrated preferential localization of enzymatically active CatK to macrophages, consistent with their known greater elastinolytic capabilities compared with smooth muscle cells. Augmented CatK proteolysis in atheromata further links CatK to vascular remodeling and plaque vulnerability.
结论：使用这种新的蛋白酶可激活的短距红外线荧光显影剂在体内光学显影揭示了含有酶活性的组织蛋白酶K的巨噬细胞的位置，其与他们的熟知的弹性蛋白与平滑肌细胞相比的性能是一致的。在动脉粥样化斑块中的增强的组织蛋白酶K水解酶进一步使得组织蛋白酶K与血管重构及斑块的稳定性有关。
6、Randomized Trial Comparing Same-Day Discharge With Overnight Hospital Stay After Percutaneous Coronary Intervention Results of the Elective PCI in Outpatient Study (EPOS)
对比门诊病人选择性PCI在PCI术后当天出院与24小时后出院的效果随机实验研究
Background— Percutaneous coronary intervention (PCI) in a day-case setting might reduce logistic constraints on hospital resources, but data on safety are limited. We evaluated the safety and feasibility of same-day discharge after PCI.
研究背景：虽然门诊行PCI术后当天出院可能会降低医疗资源，但是在安全性方面的证据数据是不足的。我们评价PCI术后当天出院的安全性及可行性。
Methods and Results— Eight hundred consecutive patients scheduled for elective PCI by femoral approach were randomized to same-day discharge or overnight hospital stay. Four hours after PCI, patients were triaged as suitable for early discharge or not. Suitable patients were discharged immediately or kept overnight, according to randomization. Patients with an indication for extended hospital stay were not discharged regardless of randomization. Primary end points were death, myocardial infarction, coronary artery bypass graft surgery, repeat PCI, or puncture-related complications occurring within 24 hours after PCI. A total of 403 patients were assigned to same-day discharge, of whom 77 (19%) were identified for extended observation; 397 patients were assigned to overnight stay, of whom 85 (21%) were identified for extended observation. Among all patients, the composite primary end point occurred in 9 (2.2%) same-day discharge patients and in 17 (4.2%) overnight stay patients (risk difference, –0.020; 95% CI, –0.045 to –0.004; P for noninferiority <0.0001). Among patients deemed suitable for early discharge, the composite end point occurred in 1 of 326 (0.3%) same-day discharge patients and 2 of 312 (0.6%) overnight-stay patients (risk difference, –0.003; 95% CI, –0.014 to 0.007; P for noninferiority <0.0001). The last 3 events were related to puncture site.
方法和结果：800个连续的病人预约行股动脉径路选择性PCI后随机分成当天出院组和24小时出院组。PCI术后4小时病人被分类，依其决定是否适合早期出院。按随机化原则，适合早期出院的病人要么立即出院或者24小时后出院。有指针需要延长住院时间的病人不出院。基本终点是死亡、心肌梗死、冠状动脉旁路移植术、再次行PCI、PCI术后24小时内的与穿刺有关的并发症。403位患者分配到当天出院组，其中77(19%)位患者被证实需要延长住院观察，397位患者分配到24小时出院组，其中85(21%)位患者被证实需要延长住院观察。在所有病人中，当天出院组9(2.2%)人及24小时出院组17 (4.2%)人发生复合的基本终点事件(risk difference, –0.020; 95% CI, –0.045 to –0.004; P for noninferiority <0.0001)。在被认为适合早期出院的患者中，当天出院组326人中的1人(0.3%)及24小时出院组312人中的2人(0.6%)发生复合终点事件(risk difference, –0.003; 95% CI, –0.014 to 0.007; P for noninferiority <0.0001).
最末的3个临床事件可能与穿刺位置有关。
Conclusions— Same-day discharge after elective PCI is feasible and safe in the majority (80%) of patients selected for day-case PCI. Same-day discharge does not lead to additional complications compared with overnight stay.
结论：在择期PCI术后评定为适合早期出院的患者中 大多数(80%)术后当天出院是安全可行的。与术后24小时出院相比，当天出院并没有导致更多的并发症的发生。
maomaoxiner，你好
第三第四篇翻译的太差拉，麻烦你在辛苦一下，好人做到底！！谢谢
