Intestinal Microbial Metabolism of Phosphatidylcholine
and Cardiovascular Risk
W.H. Wilson Tang, M.D., Zeneng Wang, Ph.D., Bruce S. Levison, Ph.D., Robert A. Koeth, B.S., Earl B. Britt, M.D.,
Xiaoming Fu, M.S., Yuping Wu, Ph.D., and Stanley L. Hazen, M.D., Ph.D.
ABSTR ACT
From the Department of Cellular and Molecular Medicine, Lerner Research In-stitute, Cleveland Clinic, Cleveland. Ad-dress reprint requests to Dr. Hazen at the Cleveland Clinic, 9500 Euclid Ave. NC-10, Cleveland, OH 44195, or at hazens@ https://www.doczj.com/doc/0a14765930.html,.
N Engl J Med 2013;368:1575-84.DOI: 10.1056/NEJMoa1109400
Copyright ? 2013 Massachusetts Medical Society.
Background
Recent studies in animals have shown a mechanistic link between intestinal micro-bial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N -oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans.
Methods
We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deu-terium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and in-cident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiog-raphy.
Results
Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of anti-biotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence in-terval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups.
Conclusions
The production of TMAO from dietary phosphatidylcholine is dependent on me-tabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.)
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T he phospholipid phosphatidylcho-line (lecithin) is the major dietary source
of choline, a semiessential nutrient that is part of the B-complex vitamin family.1,2 Choline has various metabolic roles, ranging from its es-sential involvement in lipid metabolism and cell-membrane structure to its role as a precursor for the synthesis of the neurotransmitter acetylcho-line. Choline and some of its metabolites, such as betaine, can also serve as a source of methyl groups that are required for proper metabolism of certain amino acids, such as homocysteine and methionine.3
There is a growing awareness that intestinal microbial organisms, collectively termed micro-biota, participate in the global metabolism of their host.4-6 We recently described the potential role of a complex phosphatidylcholine–choline metabolic pathway involving gut microbiota in contributing to the pathogenesis of atheroscle-rotic coronary artery disease in animal models.7 We also reported an association between a history of cardiovascular disease and elevated fasting plasma levels of trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite of the choline head group of phosphatidylcholine that is excreted in the urine.7-12
Here, we examine the relationship between oral intake of phosphatidylcholine and the involve-ment of the intestinal microbiota in the forma-tion of TMAO in humans. We also examine the relationship between fasting plasma levels of TMAO and the long-term risk of incident major adverse cardiovascular events.
Methods
Study Designs
We designed and performed two prospective clin-ical studies, which were funded by the National Institutes of Health and approved by the institu-tional review board at the Cleveland Clinic. All par-ticipants provided written informed consent. In the first study (phosphatidylcholine challenge), we enrolled 40 healthy adults who had no chronic illnesses (including a known history of heart, re-nal, pulmonary, or hematologic disease), had no active infections, and had not taken antibiotics or probiotics within the past month. Participants un-derwent a dietary phosphatidylcholine challenge during visit 1 (as described below). Six of these study participants were then given metronidazole (500 mg twice daily) plus ciprofloxacin (500 mg once daily) for 1 week. After receipt of the antibi-otics, a repeat phosphatidylcholine challenge was performed at visit 2. A third and final phosphati-dylcholine challenge was performed 1 month or more after the withdrawal of antibiotics (and sub-sequent reacquisition of gut flora), at visit 3. After each challenge, choline metabolites were mea-sured in plasma and urine, as described below. In the second study (clinical outcomes), we enrolled 4007 adults who were undergoing elec-tive diagnostic cardiac catheterization; the par-ticipants had no evidence of an acute coronary syndrome (cardiac troponin T level, <0.1 μg per liter, if available). A history of cardiovascular disease was defined as a documented history of coronary artery disease, peripheral artery disease, coronary or peripheral revascularization, stenosis of 50% or more in one or more vessels observed during coronary angiography, or a remote history of either myocardial infarction or stroke. Fasting blood samples were obtained from all participants at the time of cardiac catheterization.
Laboratory Testing
Routine laboratory tests were performed, and samples were measured on the Abbott Architect platform (Abbott Laboratories), except for testing of myeloperoxidase, which was measured with the use of the CardioMPO test (Cleveland Heart Laboratories). Creatinine clearance was estimat-ed with the use of the Cockcroft–Gault equation. TMAO was measured in plasma, as described be-low. Major adverse cardiovascular events (defined as death from any cause, nonfatal myocardial in-farction, and nonfatal stroke) were ascertained and adjudicated for all participants during 3 years of follow-up.
Phosphatidylcholine Challenge
A simple dietary phosphatidylcholine–choline chal-lenge was administered to all participants in the first study. For each participant, baseline blood and spot urine samples were obtained after an overnight fast (≥12 hours). At baseline, partici-pants were given two large hard-boiled eggs in-cluding yolk (containing approximately 250 mg of total choline each) to be eaten within a 10-minute period together with 250 mg of deuterium-labeled phosphatidylcholine (d9-phosphatidylcholine), as
phosphatidylcholine metabolism and Cardiovascular Risk
a tracer, contained in a gelatin capsule, which was administered under an investigational new drug exemption (IND number, 107940). Serial venous blood sampling was performed at 1, 2, 3, 4, 6, and 8 hours after baseline, along with a 24-hour urine collection.
The high-purity d9-phosphatidylcholine (>98% isotope enrichment) that was provided was syn-thesized from 1-palmitoyl-2-palmitoyl-sn-glycero-3-phosphoethanolamine after exhaustive methyl-ation with d3-methyliodide (Cambridge Isotopes Laboratories). The d9-phosphatidylcholine was isolated by means of sequential preparative thin-layer chromatography and high-performance liq-uid chromatography and was crystallized and dried under vacuum. Its purity (>99%) was con-firmed by both multinuclear nuclear magnetic resonance spectroscopy and mass spectrometry.
Measurements of Choline Metabolites Plasma aliquots were isolated from whole blood collected in EDTA tubes, maintained at 0 to 4°C until processing within 4 hours and stored at ?80°C. An aliquot from each 24-hour urine collec-tion was spun to precipitate any potential cellular debris, and supernatants were stored at ?80°C until analysis. TMAO, trimethylamine, choline, betaine, and their d9-isotopologues were quanti-fied with the use of a stable-isotope-dilution as-say and high-performance liquid chromatography with on l ine electrospray ionization tandem mass spectrometry on an AB SCIEX QTRAP 5500 mass spectrometer; d4(1,1,2,2)-choline, d3(methyl)-tri-methylamine-N-oxide, and d3(methyl)-trimethyl-amine were used as internal standards.7 For mea-surement of trimethylamine in plasma, a sample aliquot was acidified to a final concentration of 60 mM of hydrochloric acid before storage at ?80°C. Levels of TMAO in urine were adjusted for urinary dilution by analysis of the urine creatinine level.
Statistical Analysis
In the clinical-outcomes study, we used Student’s t-test and the Wilcoxon rank-sum test for continu-ous variables and the chi-square test for categor-ical variables to analyze the differences between participants who had major adverse cardiovascu-lar events during follow-up and those who did not. For most analyses of outcomes, we divided plasma TMAO levels into quartiles. Where indi-cated, TMAO was also analyzed as a continuous variable, with the hazard ratio determined per standard-deviation change in the TMAO level. We used Kaplan–Meier analysis with Cox proportional-hazards regression for the time-to-event analysis to determine hazard ratios and 95% confidence intervals for major adverse cardiovascular events. We performed Cox proportional-hazards re-gression analysis with adjustment for traditional cardiovascular risk factors (age, sex, systolic blood pressure, presence or absence of diabetes mellitus, low-density and high-density lipoprotein choles-terol levels, triglyceride levels, and smoking status) and for log-transformed high-sensitivity C-reac-tive protein levels (both alone and with myeloper-oxidase), the log-transformed estimated glo-merular filtration rate, total leukocyte count, body-mass index, medication history, and angio-graphic extent of coronary artery disease. For subgroup analyses, Cox proportional-hazards re-gression analysis was performed with adjustment for traditional cardiovascular risk factors and log-transformed high-sensitivity C-reactive protein levels. Improvement in model performance that was introduced by the inclusion of TMAO levels was evaluated with the use of net reclassification improvement. We calculated the C statistic using the area under the receiver-operating-characteris-tic (ROC) curve. Three-year predicted probabili-ties of a major adverse cardiovascular event were estimated from the Cox model. All analyses were performed with the use of R software, versions 2.8.0 and 2.15.1. A two-sided P value of less than 0.05 was considered to indicate statistical sig-nificance.
R esults Phosphatidylcholine Challenge
For the 40 participants in the phosphatidylcho-line challenge, plasma levels of TMAO are shown in Figure 1, and plasma levels of choline and be-taine in Figure S1 in the Supplementary Appendix (available with the full text of this article at NEJM .org). Endogenous (unlabeled) TMAO (Fig. 1C) and choline and betaine (Fig. S1 in the Supple-mentary Appendix) were present in fasting plasma samples at baseline. Both TMAO and d9-TMAO were readily detected in plasma after the dietary phosphatidylcholine challenge at visit 1 (Fig. 1A and 1B). Time-dependent increases in the levels of both TMAO (Fig. 1C) and d9-TMAO (Fig. 1D)
T h e ne w engl a nd jour na l o f medicine
were also observed postprandially. Examination of 24-hour urine specimens after the phosphati-dylcholine challenge also showed the presence of both TMAO and d9-TMAO (Fig. S2 in the Supple-mentary Appendix). A strong correlation was ob-served between plasma levels of TMAO and the
phosphatidylcholine metabolism and Cardiovascular Risk
absolute urine TMAO level (Spearman’s r = 0.58, P<0.001) and the urinary ratio of TMAO to creati-nine (Spearman’s r = 0.91, P<0.001). Time-depen-dent increases in the plasma levels of both the natural isotopes and d9-tracer forms of choline and betaine also increased after the phosphati-dylcholine challenge (Fig. S1A and S1B in the Supplementary Appendix).
The suppression of intestinal microbiota by the administration of oral broad-spectrum anti-biotics for 1 week in six of the participants re-sulted in near-complete suppression of detectable TMAO and d9-TMAO after the phosphatidylcho-line challenge during visit 2 in both plasma (Fig. 1) and urine (Fig. S2 in the Supplementary Appen-dix). In parallel analyses, postprandial elevations in plasma trimethlyamine and d9-trimethyl-amine levels were observed after the phosphati-dylcholine challenge, but the levels were unde-tectable after the administration of antibiotics (data not shown). In contrast, the time courses for postprandial changes in free choline and be-taine (natural isotopes and d9-isotopologues) were not altered by suppression of intestinal micro-biota (Fig. S1 in the Supplementary Appendix). After the withdrawal of antibiotics and subse-quent reappearance of intestinal microbiota over a period of 1 month or longer, the phosphatidyl-choline challenge during visit 3 again resulted in readily detectable and time-dependent changes in TMAO and d9-TMAO in plasma (Fig. 1) and urine (Fig. S2 in the Supplementary Appendix). The ex-tent to which TMAO levels in plasma at visit 3 re-turned to preantibiotic levels was variable, a find-ing that is consistent with reports describing variable recovery of intestinal microbiota after antibiotic cessation.13,14
Clinical Outcomes
TMAO Levels and Cardiovascular Events
The baseline characteristics of the 4007 partici-pants in the clinical-outcomes study are shown in Table 1, according to whether they had a major adverse cardiovascular event during the 3-year follow-up. The mean age of the participants was 63 years, and two thirds were men; the preva-lence of cardiovascular risk factors was high, and many of the participants had at least single- vessel coronary disease. Participants who had incident major adverse cardiovascular events dur-ing 3 years of follow-up had higher risk profiles at baseline than those without events, including an older age, higher fasting glucose levels, and higher rates of diabetes, hypertension, and previ-ous myocardial infarction.
Participants who had major adverse cardio-vascular events also had higher baseline levels of TMAO, as compared with those who did not have cardiovascular events (median, 5.0 μM [interquar-tile range, 3.0 to 8.8] vs. 3.5 μM [interquartile range, 2.4 to 5.9]; P<0.001) (Table 1). As com-pared with participants in the lowest quartile of TMAO levels, those in the highest quartile had a significantly increased risk of an event (hazard ratio, 2.54; 95% confidence interval [CI], 1.96 to 3.28; P<0.001) (Table 2).
After adjustment for traditional risk factors and other baseline covariates, elevated plasma levels of TMAO remained a significant predictor of the risk of major adverse cardiovascular events (Ta-ble 2). We observed a graded increase in risk with increasing levels of TMAO, as illustrated in the Kaplan–Meier analysis shown in Figure 2. A simi-lar graded increase in risk was observed when levels of TMAO were analyzed as a continuous variable in increments of 1 SD (unadjusted hazard ratio, 1.40 [95% CI, 1.29 to 1.51; P<0.001]; adjusted hazard ratio, 1.30 [95% CI, 1.20 to 1.41; P<0.001]). When the components of the major adverse cardiovascular events were analyzed separately,
increased levels of TMAO remained significantly
T h e ne w engl a nd jour na l o f medicine
associated with an increased risk of death (haz-ard ratio, 3.37; 95% CI, 2.39 to 4.75; P<0.001) and nonfatal myocardial infarction or stroke (hazard ratio, 2.13; 95% CI, 1.48 to 3.05; P<0.001). The
inclusion of TMAO as a covariate resulted in a significant improvement in risk estimation over traditional risk factors (net reclassification im-
provement, 8.6% [P<0.001]; integrated discrimi-
* Plus–minus values are means ±SD. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the values for glucose to millimoles per liter, multiply by 0.05551. ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, and TMAO trimethylamine-N -oxide.
? The P value is for the comparison between patients who had a major adverse cardiovascular event and those who did not.? The body-mass index is the weight in kilograms divided by the square of the height in meters.
phosphatidylcholine metabolism and Cardiovascular Risk
nation improvement, 9.2% [P<0.001]; C statistic, 68.3% vs. 66.4% [P = 0.01]). In a separate analysis, we excluded all participants who underwent re-vascularization within 30 days after enrollment in the study. In this subcohort of 3475 participants, TMAO remained significantly associated with the risk of major adverse cardiovascular events (unad-
quartile, 2.47 [95% CI, 1.87 to 3.27]; P<0.001).
Cardiovascular Risk in Low-Risk Subgroups
TMAO for cardiovascular risk remained signifi-of age), women, and participants who did or coronary disease risk equivalents, had other known risk markers, such as C-reactive pro-tein, myeloperoxidase, and white-cell count.
Discussion
Studies in germ-free mice and of atherosclerosis in patients with a diet rich in phosphatidylcholine (with major sources includ-ing eggs, liver, beef, and pork) through the for-mation of the metabolite trimethylamine and con-version to TMAO.7,15 In our study, we describe the generation of the proatherogenic metabolite TMAO
* A major adverse cardiovascular event was defined as death, myocardial infarction, or stroke. The quartiles of TMAO levels are as follows: quartile 1, less than 2.43 μM; quartile 2 2.43 to 3.66 μM; quartile 3, 3.67 to 6.18 μM; and quartile 4, more than 6.18 μM. Hazard ratios and P values are for the comparison with quartile 1.
? In model 1, hazard ratios were adjusted for traditional risk factors (age, sex, smoking status, systolic blood pressure, low-density lipoprotein cholesterol level, high-density lipoprotein cholesterol level, and status with respect to diabetes mellitus), plus log-transformed high-sensitivity C-reactive protein level.
? In model 2, hazard ratios were adjusted for all factors in model 1, plus myeloperoxidase level, log-transformed estimated glomerular filtration rate, total white-cell count, body-mass index, and status with respect to receipt of certain medications (aspirin, statin, ACE inhibitor, ARB, or beta-blocker).
§ In model 3, hazard ratios were adjusted for all factors in model 2, plus the extent of disease, as seen on angiography.
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from dietary phosphatidylcholine through the use of stable-isotope-tracer feeding studies. We fur-ther found a role for the intestinal microbiota in the production of TMAO through its suppression by means of oral broad-spectrum antibiotics and then reacquisition of trimethylamine and the
microbiota-dependent metabolite by The intestinal microbiota have previously been 4-6,16-18 However, the involvement of mi-in the inception of atherosclerosis in 7 The from phosphatidylcholine in humans. dietary phosphatidylcholine into trimethyl-which is subsequently converted into by hepatic flavin-containing monooxy-Fig. 3).20-23 The observed delay in the of plasma d9-TMAO levels after the into TMAO,24 since separate analyses trimethylamine and d9-trimethyl-with a precursor-to-product relationship 25 and the inges-theless, the high correlation between urine and plasma levels of TMAO argues for effective uri-nary clearance of TMAO. Hence, an efficient excretion mechanism may provide protection by preventing the accumulation of TMAO and does not undermine the mechanistic link between TMAO and cardiovascular risk.
phosphatidylcholine metabolism and Cardiovascular Risk
Although an association between infectious organisms and atherosclerosis has previously been postulated, studies looking at the role of antimi-crobial therapy in preventing disease progression have been disappointing.26,27 It is important to recognize that the choice of antimicrobial ther-apy in previous intervention trials was based largely on targeting postulated organisms rather than modulating the composition of intestinal microbiota or their metabolites. Furthermore, even if an antibiotic initially suppressed TMAO levels, the durability of that effect with long-term use remains unknown. In unpublished studies, we observed that long-term use of a single antibiotic (6 months of ciprofloxacin), which initially sup-pressed plasma TMAO levels in a rodent model, completely lost its suppressive effect, an obser-vation that is consistent with the expansion of antibiotic-resistant intestinal microbiota. Thus, in-stead of suggesting that intestinal microbes should be eradicated with long-term use of antibiotics, our findings point to the possibility that plasma TMAO levels may identify a pathway within in-testinal microbiota amenable to therapeutic modulation. For example, our data suggest that excessive consumption of dietary phosphatidyl-choline and choline should be avoided; a vege-tarian or high-fiber diet can reduce total choline intake.16 It should also be noted that choline is a semiessential nutrient and should not be com-pletely eliminated from the diet, since this can result in a deficiency state. However, standard dietary recommendations, if adopted, will limit the intake of phosphatidylcholine- and choline-rich foods, since these foods are also typically high in fat and cholesterol content.1 An alternative po-tential therapeutic intervention is targeting the composition of the microbiota or biochemical pathways, with either a functional food such as a probiotic17 or a pharmacologic intervention. The latter hypothetically could take the form of treat-ment with an inhibitor to block specific microbial metabolic pathways or a short course of nonsys-temic antibiotics to reduce the burden of TMAO-producing microbes, two therapies that have been used in the treatment of irritable bowel syn-drome.28 Further studies are warranted to estab-lish whether antimicrobial therapies can signifi-cantly reduce cardiovascular risk.
In conclusion, we have shown that intestinal microbes participate in phosphatidylcholine me-tabolism to form circulating and urinary TMAO. We also established a correlation between high plasma levels of TMAO and an increased risk of incident major adverse cardiovascular events that is independent of traditional risk factors, even in low-risk cohorts.
Supported by grants from the National Institutes of Health and its Office of Dietary Supplements (R01HL103866 and 1P20HL113452). The clinical study GeneBank was supported by grants from the National Institutes of Health (P01HL098055, P01HL076491, R01HL103931, and R01DK080732) and a Cleveland Clinic/Case Western Reserve University Clinical and Translational Science Award (UL1TR000439). Dr. Hazen was supported by a gift from the Leonard Krieger Fund. Mass spectrometry instru-mentation used was housed within the Cleveland Clinic Mass Spectrometry Facility with partial support through a Center of Innovation by AB SCIEX.
Disclosure forms provided by the authors are available with the full text of this article at https://www.doczj.com/doc/0a14765930.html,.
We thank Linda Kerchenski and Cindy Stevenson for their assistance in recruitment of study participants and Amber Gist and Naomi Bongorno for their assistance in the preparation of earlier versions of the figures and the manuscript.
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Copyright ? 2013
Massachusetts Medical Society.
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危险化学品生产、储存装置个人可接受风险标准和社会可接受风险标准（试行） —、适用范围 《危险化学品生产、储存装置个人可接受风险标准和社会可接受风险标准（试行）》（以下简称《可接受风险标准》）用于确定陆上危险化学品企业新建、改建、扩建和在役生产、储存装置的外部安全防护距离。 二、个人可接受风险标准 我国个人可接受风险标准值表
三、社会可接受风险标准 我国社会可接受风险标准图附录：1 ?相关术语 2?危险化学品生产、储存装置外部安全防护距离推荐方法
附录1 相关术语 定量风险评价：是对某一装置或作业活动中发生事故频率和后果进行定量分析，并与可接受风险标准比较的系统方法。 风险：是指发生特定危害事件的可能性以及发生事件后果严重性的结合。 个人风险：是指因危险化学品生产、储存装置各种潜在的火灾、爆炸、有毒气体泄漏事故造成区域内某一固定位置人员的个体死亡概率，即单位时间内（通常为一年）的个体死亡率。通常用个人风险等值线表示。 社会风险：是对个人风险的补充，指在个人风险确定的基础上，考虑到危险源周边区域的人口密度，以免发生群死群伤事故的概率超过社会公众的可接受范围。通常用累积频率和死亡人数之间的关系曲线（F-N曲线）表示。 防护目标：指在发生危险化学品事故时，易造成群死群伤的危险化学品单位周边的人员密集场所或敏感场所，包括居民区、村镇、商业中心、公园、学校、医院、影剧院、体育场（馆）、养老院、车站等C 不可接受区：指风险不能被接受。 可接受区：指风险可以被接受，无需采取安全改进措施。 尽可能降低区：指需要尽可能采取安全措施，降低风险。 外部安全防护距离：是指危险化学品生产、储存装置危险源在发生火灾、爆炸、有毒气体泄漏时，为避免事故造成防护目标处人员伤亡而设定的安全防护距离C
危险化学品生产、储存装置个人可接受风险标准和社会可接受风险标准（试行） 一、适用范围 《危险化学品生产、储存装置个人可接受风险标准和社会可接受风险标准（试行）》（以下简称《可接受风险标准》）用于确定陆上危险化学品企业新建、改建、扩建和在役生产、储存装置的外部安全防护距离。 二、个人可接受风险标准 我国个人可接受风险标准值表 防护目标 个人可接受风险标准 （概率值） 新建装置 （每年）≤ 在役装置 （每年）≤ 低密度人员场所（人数<30人）：单个或少 量暴露人员。 1×10-53×10-5居住类高密度场所（30人≤人数＜100人）： 居民区、宾馆、度假村等。 公众聚集类高密度场所（30人≤人数＜100 人）：办公场所、商场、饭店、娱乐场所等。 3×10-61×10-5 高敏感场所：学校、医院、幼儿园、养老院、 监狱等。 重要目标：军事禁区、军事管理区、文物保 护单位等。 特殊高密度场所（人数≥100人）：大型体 育场、交通枢纽、露天市场、居住区、宾馆、 度假村、办公场所、商场、饭店、娱乐场所 等。 3×10-73×10-6
三、社会可接受风险标准 1 10100 10001x10 -9 1x10-8 1x10-7 1x10-6 1x10-5 1x10-4 1x10-31x10-2 1x10 -1 我国社会可接受风险标准图 附录：1.相关术语 2.危险化学品生产、储存装置外部安全防护距离推荐方法 死亡人数N （人） 累积频率F （次/年） 不可接受区 尽可能降低区 可接受区
附录1 相关术语 定量风险评价：是对某一装置或作业活动中发生事故频率和后果进行定量分析，并与可接受风险标准比较的系统方法。 风险：是指发生特定危害事件的可能性以及发生事件后果严重性的结合。 个人风险：是指因危险化学品生产、储存装置各种潜在的火灾、爆炸、有毒气体泄漏事故造成区域内某一固定位置人员的个体死亡概率，即单位时间内（通常为一年）的个体死亡率。通常用个人风险等值线表示。 社会风险：是对个人风险的补充，指在个人风险确定的基础上，考虑到危险源周边区域的人口密度，以免发生群死群伤事故的概率超过社会公众的可接受范围。通常用累积频率和死亡人数之间的关系曲线（F-N曲线）表示。 防护目标：指在发生危险化学品事故时，易造成群死群伤的危险化学品单位周边的人员密集场所或敏感场所，包括居民区、村镇、商业中心、公园、学校、医院、影剧院、体育场（馆）、养老院、车站等。 不可接受区：指风险不能被接受。 可接受区：指风险可以被接受，无需采取安全改进措施。 尽可能降低区：指需要尽可能采取安全措施，降低风险。 外部安全防护距离：是指危险化学品生产、储存装置危险源在发生火灾、爆炸、有毒气体泄漏时，为避免事故造成防护目标处人员伤亡而设定的安全防护距离。
危险化学品生产、储存装置个人可接受风险和社会可接受风险基准（征求意见稿） 为落实《危险化学品安全管理条例》（国务院令第591号）有关要求，妥善解决危险化学品新建企业选址、高风险企业搬迁和化工园区规划布局以及现有企业出现的危险化学品生产、储存装置外部安全防护距离不明确的问题。国家安全监管总局在对发达国家和地区土地安全规划、安全距离确定方法进行广泛调研和分析的基础上，结合我国国情，研究提出了我国危险化学品生产、储存装置个人可接受风险和社会可接受风险基准（以下简称可接受风险基准）。 一、我国可接受风险基准制定的必要性 由于危险化学品生产、储存装置自身存在固有风险，会对周边居民、社区和其他公共场所（以下简称防护目标）带来一定的个人风险和社会风险。从风险防范的角度出发，国际上通常采用设定国家可接受风险基准来控制危险源与防护目标的外部安全防护距离，确保防护目标增加的风险在国家设定的可接受风险基准范围内。 为保护人民生命和财产安全，强化风险管理意识，提升我国危险化学品生产、储存企业的本质安全水平，我国急需制定和颁布国家可接受风险基准，以保障人民群众生命安全，合理利用我国有限的土地资源。 二、国际上制定可接受风险基准通行的做法 国外发达国家和地区在确定可接受风险基准时,通常采用个人可
接受风险和社会可接受风险作为确定外部安全防护距离和土地使用规划的依据。 个人可接受风险基准：国际上通常采用国家人口分年龄段死亡率最低值乘以一定的风险可允许增加系数，作为个人可接受风险的基准值。荷兰、英国中国香港等不同国家（地区）具体实例，见表1。 表1 不同国家（地区）所制定的个人可接受风险基准 社会可接受风险基准：国际上通常采用危险化学品生产、储存装置发生火灾、爆炸、中毒事故时，可能造成周边民众和社区群死群伤事故的累积频率来确定，通常由频率（F）/死亡人数（N）曲线体现。荷兰、英国、中国香港等不同国家（地区）具体实例，见图1。 图1 不同国家（地区）制定的社会可接受风险标准
一、相关术语 定量风险评价：是对某一装置或作业活动中发生事故频率和后果进行定量分析，并与可接受风险标准比较的系统方法。 风险：是指发生特定危害事件的可能性以及发生事件后果严重性的结合。 个人风险：是指因危险化学品生产、储存装置各种潜在的火灾、爆炸、有毒气体泄漏事故造成区域内某一固定位置人员的个体死亡概率，即单位时间内（通常为一年）的个体死亡率。通常用个人风险等值线表示。 社会风险：是对个人风险的补充，指在个人风险确定的基础上，考虑到危险源周边区域的人口密度，以免发生群死群伤事故的概率超过社会公众的可接受范围。通常用累积频率和死亡人数之间的关系曲线（F-N曲线）表示。 二、个人可接受风险标准 个人风险是指因危险化学品重大危险源各种潜在的火灾、爆炸、有毒气体泄漏事故造成区域内某一固定位置人员的个体死亡概率，即单位时间内（通常为年）的个体死亡率(AFR——年死亡率)。通常用个人风险等值线表示。 通过定量风险评价，危险化学品单位周边重要目标和敏感场所承受的个人风险应满足表1中可容许风险标准要求 我国个人可接受风险标准值表
三、社会可接受风险标准 社会风险是事故对整个社会的风险总和，指能够引起大于等于N 人死亡的事故累积频率（F），也即单位时间内（通常为年）的死亡人数。通常用社会风险曲线（F-N曲线）表示。
通过定量风险评价，危险化学品重大危险源产生的社会风险应满足图中可容许社会风险标准要求。 F-N 曲线 110100 10001x10 -9 1x10-8 1x10-7 1x10-6 1x10-5 1x10-4 1x10-3 1x10 -2 1x10-1 k N F a =?（K 改变截距、a 改变斜率） F ：社会风险概率 N ：死亡人数 a ：一般取1—2 四、ALARP 准则 死亡人数N （人） 累积频率F （次/年） 不可接受区 尽可能降低区 可接受区
危化品生产、储存个人和社会可接受风险基准值
危险化学品生产、储存装置个人可接受风险和社会可接受风险基准（征求意见稿） 为落实《危险化学品安全管理条例》（国务院令第591号）有关要求，妥善解决危险化学品新建企业选址、高风险企业搬迁和化工园区规划布局以及现有企业出现的危险化学品生产、储存装置外部安全防护距离不明确的问题。国家安全监管总局在对发达国家和地区土地安全规划、安全距离确定方法进行广泛调研和分析的基础上，结合我国国情，研究提出了我国危险化学品生产、储存装置个人可接受风险和社会可接受风险基准（以下简称可接受风险基准）。 一、我国可接受风险基准制定的必要性 由于危险化学品生产、储存装置自身存在固有风险，会对周边居民、社区和其他公共场所（以下简称防护目标）带来一定的个人风险和社会风险。从风险防范的角度出发，国际上通常采用设定国家可接受风险基准来控制危险源与防护目标的外部安全防护距离，确保防护目标增加的风险在国家设定的可接受风险基准范围内。 为保护人民生命和财产安全，强化风险管理意识，提升我国危险化学品生产、储存企业的本质安全水平，我国急需制定和颁布国家可接受风险基准，以保障人民群众生命安全，合理利用我国有限的土地资源。 二、国际上制定可接受风险基准通行的做法 国外发达国家和地区在确定可接受风险基准时,通常采用个人可
接受风险和社会可接受风险作为确定外部安全防护距离和土地使用规划的依据。 个人可接受风险基准：国际上通常采用国家人口分年龄段死亡率最低值乘以一定的风险可允许增加系数，作为个人可接受风险的基准值。荷兰、英国中国香港等不同国家（地区）具体实例，见表1。 表1 不同国家（地区）所制定的个人可接受风险基准 社会可接受风险基准：国际上通常采用危险化学品生产、储存装置发生火灾、爆炸、中毒事故时，可能造成周边民众和社区群死群伤事故的累积频率来确定，通常由频率（F）/死亡人数（N）曲线体现。荷兰、英国、中国香港等不同国家（地区）具体实例，见图1。 图1 不同国家（地区）制定的社会可接受风险标准
一、相关术语 定量风险评价:就是对某一装置或作业活动中发生事故频率与后果进行定量分析,并与可接受风险标准比较的系统方法。 风险:就是指发生特定危害事件的可能性以及发生事件后果严重性的结合。 个人风险:就是指因危险化学品生产、储存装置各种潜在的火灾、爆炸、有毒气体泄漏事故造成区域内某一固定位置人员的个体死亡概率,即单位时间内(通常为一年)的个体死亡率。通常用个人风险等值线表示。 社会风险:就是对个人风险的补充,指在个人风险确定的基础上,考虑到危险源周边区域的人口密度,以免发生群死群伤事故的概率超过社会公众的可接受范围。通常用累积频率与死亡人数之间的关系曲线(F-N曲线)表示。 二、个人可接受风险标准 个人风险就是指因危险化学品重大危险源各种潜在的火灾、爆炸、有毒气体泄漏事故造成区域内某一固定位置人员的个体死亡概率,即单位时间内(通常为年)的个体死亡率(AFR——年死亡率)。通常用个人风险等值线表示。 通过定量风险评价,危险化学品单位周边重要目标与敏感场所承受的个人风险应满足表1中可容许风险标准要求 我国个人可接受风险标准值表
三、社会可接受风险标准 社会风险就是事故对整个社会的风险总与,指能够引起大于等于N人死亡的事故累积频率(F),也即单位时间内(通常为年)的死亡人数。通常用社会风险曲线(F-N曲线)表示。
通过定量风险评价,危险化学品重大危险源产生的社会风险应满足图中可容许社会风险标准要求。 F-N 曲线 110100 10001x10 -9 1x10-8 1x10-7 1x10-6 1x10-5 1x10-4 1x10-3 1x10 -2 1x10-1 k N F a =?(K 改变截距、a 改变斜率) F:社会风险概率 N:死亡人数 a:一般取1—2 四、ALARP 准则 死亡人数N (人) 累积频率F (次/年) 不可接受区 尽可能降低区 可接受区
心血管系统杂志名全称和规范缩写(来源于SCI )(1) 杂志名称 标准缩写 Acta Cardiologica Acta Cardiol American Heart Ho spital Journal Am Heart Ho sp J American Heart Journal Am Heart J American Journal of Cardiovascular Drugs Am J Cardiovasc Drugs American Journal of Geriatric Cardiology Am J Geriatr Cardiol American Journal of Hypertension Am J Hypertens American Journal of Physiology 2Heart and Circulatory Physiology Am J Physiol Heart Circ Physiol Angiology Angiology Annals of Noninvasive Elect rocardiology Ann Noninvasive Elect rocardiol Annals of Vascular Surgery Ann Vasc Surg Arteriosclero sis ,Thrombo sis ,and Vascular Biology Arterioscler Thromb Vasc Biol At hero sclerosis At hero sclero sis At hero sclerosis Supplement s At hero scler Suppl Basic Research in Cardiology Basic Res Cardiol Blood Coagulatio n and Fibrinolysis Blood Coagul Fibrinolysis Blood Pressure Blood Press Blood Pressure Monitoring Blood Press Monit Canadian Jo urnal of Cardiology Can J Cardiol Cardiac Elect rop hysiology Review Card Elect rop hysiol Rev Cardiology Cardiology Cardiology Clinics Cardiol Clin Cardiology in Review Cardiol Rev Cardiology in t he Y oung Cardiol Y oung CardioVascular and Interventional Radiology Cardiovasc Intervent Radiol Cardiovascular drug reviews Cardiovasc Drug Rev Cardiovascular Drugs &Therapy Cardiovasc Drugs Ther Cardiovascular Radiation Medicine Cardiovasc Radiat Med Cardiovascular Research Cardiovasc Res Cardiovascular Revascularization Medicine Cardiovasc Revasc Med Cardiovascular Surgery Cardiovasc Surg Cat heterization and Cardiovascular Interventions Cat heter Cardiovasc Interv Circulatio n Circulation Circulatio n Journal Cir J Circulatio n Research Cir Res Clinical &Applied Thrombo sis/Hemostasis Clin Appl Thromb Hemost Clinical and Experimenual Hypertension Clin Exp Hypertens Clinical Cardiology Clin Cardiol Clinical Research in Cardiology Clin Res Cardiol (待续) ? Ⅳ?
无锡明慈心血管病医院Wuxi Mingci Cardiovascular Hospital Ein zukünftiges erstklassiges Herzzentrum
1 2 3 4 医院特色 四大特色 Vier Besonderheiten 中德国际合作 Deutsch-Chinesische Zusammenarbeit 一流硬件设施 Hervorragende Ausrüstung 顶尖专家团队 Ein gutes Medizinteam 绿色人文服务 Menschliches Service Besonderheiten
医院特色理念 国际化：与德国北威州心脏和糖尿病中心深度合作，引进国际化管理流程、机制和理念，以优质、高效的医疗水平服务患者Internationalisierung: -Tiefe Kooperation mit Herz- und Diabeteszentrum Nordrhein-Westfalen (NDZ NRW) -übernahme von effizientem Manageentskonzept, Struktur und Prozess, um Patienten mit hocher Qualit?t und Leistungen zu versorgen. 产业化：集预防、诊断、治疗、康复保健、健康管理为一体。 Industrialisierung: Integration von Pr?vention, Diagnostik, Behandlung, Rehabilitation und Gesundheitsmanagement 人性化：我们始终把患者利益置于首位，为患者提供他们真正需要的、有价值的医疗服务。 Menschliche Anliegen: Der Patient steht immer im Mittelpunkt aller Bemühungen Unsere Philosophien
Systematic anatomy-cardiovascular system
Systematic anatomy-cardiovascular system髂总动脉Common iliac artery z第4腰椎水平续自腹主动脉 z沿腰大肌内侧下至骶髂关节 处分为髂内动脉和髂外动脉 腹主动脉 髂总动脉 髂外动脉 髂内动脉
Systematic anatomy -cardiovascular system 髂内动脉internal iliac A. z 壁支–闭孔动脉obturator a. –臀上动脉sup. gluteal a.–臀下动脉inf. gluteal a. –髂腰动脉iliolumbar a. –骶外侧动脉lateral sacral a.右髂外动脉髂内动脉 臀上动脉 臀下动脉膀胱上动脉 骶外侧动脉 髂腰动脉
Systematic anatomy -cardiovascular system 髂内动脉internal iliac A.z 髂内动脉 internal iliac A.–脏支： ?脐动脉umblic a.?子宫动脉uterine a.?阴部内动脉internal pudendal a.?膀胱下动脉Inf. vesical a. ?直肠下动脉Inf. rectal a.右髂总动脉髂外动静脉髂内动脉 阴部内动脉直肠下动脉子宫动脉膀胱上动脉脐动脉膀胱下动脉
Systematic anatomy-cardiovascular system髂内动脉internal iliac A. z子宫动脉uterine a. ：沿盆腔侧壁下行，进入子宫阔韧带底部两层腹膜之间，在子宫颈外侧约2cm处从输尿管ureter前上方跨过，再沿子宫侧缘迂曲上升至子宫底。子宫动脉分支营养子宫uterus 、阴道、输卵管和卵巢，并与卵巢动脉吻合 桥下流水子宫动脉 输尿管
Reference number ISO 8637:2010(E) ? ISO 2010 INTERNATIONAL STANDARD ISO 8637 Third edition 2010-07-01 Cardiovascular implants and extracorporeal systems — Haemodialysers, haemodiafilters, haemofilters and haemoconcentrators Implants cardiovasculaires et systèmes extracorporels — Hémodialyseurs, hémodiafiltres, hémofiltres et hémoconcentrateurs Copyright International Organization for Standardization --`,,```,,,,````-`-`,,`,,`,`,,`---
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《危险化学品生产、储存装置个人可接受风险标 准 和社会可接受风险标准（试行）》解读《危险化学品生产、储存装置个人可接受风险标准和社会可接受风险标准（试行）》（以下简称《可接受风险标准》）已经2014年4月22日国家安全监管总局局长办公会议审议通过，并于5月7日以国家安全监管总局公告2014年第13号公布。 一、颁布《可接受风险标准》的意义 随着我国经济社会快速发展，石化、化工产业布局与工业化、城镇化的矛盾日益突出，城区、居民区与部分危险化学品企业的安全防护距离不足带来的安全风险有不断加剧趋势。从风险防范的角度出发，国际上通常采用可接受风险标准来控制危险源与防护目标间的外部安全防护距离，确保防护目标增加的风险在可接受范围内。 目前我国相关法规、标准中有关危险化学品企业防护距离的概念主要有消防部门牵头组织制定的防火间距和卫生部门牵头组织制定的卫生防护距离。但由于制定的目的不同，实践发现在预防重特大事故时有一定的局限性。如：防火间距主要是针对非爆炸性的火灾事故，以火灾预防和火灾初期扑救为目的来设定，不考虑危险物质泄漏后的毒性危害。其主要标准《建筑设计防火规范》（GB50016-2006）、《石油化工企业设计防火规范》（GB50160-2008）规定的石化企业与居民区等的防火间距一般不超过120米。卫生防护距离是从保障公众健康的角度设定的，指在正常生产条件下，无组织排放的有害气体从车间或生产、储存单元的边界扩散至居住区范围内（对其他公共设施或民用建筑无要求），达到限制浓度的最小距离。其主要标准《石油化工企业卫生防护距离》（SH3093-1999）、《石油加工业卫生防护距离》（GB8195-2011）规定的石化企业与居民区等的卫生防护距离一般不超过1200米。 《可接受风险标准》中明确将危险化学品生产、储存装置（以下简称危化装置）在发生火灾、爆炸、有毒气体泄漏时，为避免事故造成重