1、1,十章 心血管系统疾病 的生物化学检验 （双语）,2,背景资料,2006年中国城市居民前十位死因 美国前十位死因 1. 恶性肿瘤27.3% 心脏病27.2% 2. 脑血管病17.7% 恶性肿瘤23.1% 3. 心脏病17.1% 脑血管病6.3% 4. 呼吸系病13.1% 慢性呼吸道疾病 5. 损伤及中毒6.1% 意外事件 6. 内分泌营养和代谢疾病3.3% 糖尿病 7. 消化系病2.9% 阿兹海默症 8. 泌尿生殖系病1.4% 流行性感冒和肺炎 9. 神经系病0.9% 肾脏疾病 10. 精神障碍0.7% 败血病 前十位死因占中国死亡总数的90.4， 美国78 。,3,主要内容,第一节 概述
2、第二节 心血管疾病主要生化检测指标 第三节心血管疾病主要生化检测指标的临床应用,4,第一节 概述,一、心脏的解剖和生理 心肌富含的蛋白与酶？有何临床意义？肌钙蛋白 肌红蛋白 CK LD,5,心肌血液供应来自主动脉根部发出的左右冠状动脉，冠状动脉主干行走于心脏表面，沿途发出分支，在心肌和心内膜下层形成丰富的毛细血管网，毛细血管与心肌比例高达1:1。,6,备注： 内膜 内皮细胞 基膜 内弹性膜 中膜 外弹性膜 平滑肌 外膜 内腔 内皮细胞 基膜,7,Heart Disease Heart disease is a general term that refers to a variety of a
3、cute and chronic medical conditions that affect one or more of the components of the heart. The heart is a muscular, fist-sized organ that is located in the left side of the chest cavity胸腔. It continuously pumps blood, beating as many as 100,000 times a day. The blood that the heart moves carries ox
4、ygen and nutrients营养素 throughout the body and transports carbon dioxide二氧化碳 and other wastes to the lungs, kidneys, and liver for removal.,8,The heart ensures its own oxygen supply through a set of coronary arteries冠状动脉 and veins. The heart is also an endocrine内分泌的 organ that produces the hormones a
5、trial natriuretic hormone (ANP) 心房利钠肽,心钠素 and B-type natriuretic peptide (BNP), which coordinate协调 heart function with blood vessels and the kidneys.,9,Diseases affecting the heart may be structural or functional. Anything that damages the heart or decreases the hearts supply of oxygen, makes it les
6、s efficient, reduces its ability to fill and pump, will disrupt the coordinated relationship between the heart, kidneys, and blood vessels and will harm not only the heart but the rest of the body as well.,10,Heart diseases may be due to: Atherosclerosis动脉粥样硬化Common disorder of the arteries in which
7、 deposits沉着物consisting mostly of cholesterol胆固醇and lipids form on the inner arterial wall. As a result, the vessels become nonelastic无弹性的and narrowed, leading to decreased blood flow. One of the most important examples is coronary artery disease冠心病.,11,Autoimmune conditions Congenital abnormalities先
8、天性异常 Hypertension高血压 Diabetes糖尿病 Thyroid dysfunction (under and overactive)甲状腺功能异常 Diet, especially when high in saturated fat饱和脂肪and cholesterol,12,Injury or trauma Smoking Alcohol use Cocaine use可卡因 Anabolic steroid use促蛋白合成类固醇 Toxins, such as mercury水银, and sometimes chemotherapy drugs or HIV/AID
9、S drugs Bacterial infection Viral infection,13,心血管疾病 （一） 动脉粥样硬化及冠心病,动脉粥样硬化(atherosclerosis, AS)：多因素导致动脉壁增厚、变硬、弹性减弱和管腔缩小；病变动脉壁内层形成很多黄色粥样的斑块，局部出现脂质、复合糖类的积聚，易形成血栓，纤维组织增生和钙质沉着，动脉的退化和钙化。 根据侵犯部位不同分为脑动脉硬化、主动脉硬化、冠状动脉硬化、肾动脉硬化或周围动脉硬化等不同类型。,14,AS的病理机制,AS是多因素综合作用的复杂过程 。 内皮细胞损伤和单核-巨噬细胞浸润及平滑肌细胞转移 脂质的作用 血液凝集系统的激活及
10、血栓形成,15,16,正常和动脉粥样硬化动脉比较,17,毛细血管 奔涌的血管,18,动脉粥样血栓的形成,19,动脉粥样硬化视频动脉粥样硬化形成过程 .flv,20,二、冠心病及其他心血管事件,冠状动脉性心脏病(coronary artery heart disease, CHD)简称冠心病：各种原因致冠状动脉狭窄，供血不足而引起的心肌功能障碍和/或器质性病变 。 coronary heart disease (CHD) coronary artery disease (CAD) 95%以上CHD由冠状动脉粥样硬化引起，故常将CHD与冠状动脉粥样硬化性心脏病混用。 冠心病分为心绞痛和心肌梗死两种
11、临床类型。,21,22,（一）心绞痛 (angina)冠状动脉绝对或相对供血不足，心肌急剧而短暂的缺血（氧）所致的临床综合征。 稳定型心绞痛(stable angina pectoris, SAP) 劳累型，最常见 变异型心绞痛(variant angina pectoris,VAP) 休息或夜间熟睡后发生 不稳定型心绞痛(unstable angina pectoris,UAP )介于稳定型心绞痛与心肌梗死间,23,(二)急性心肌梗死 (acute myocardial infarction, AMI)某支冠状动脉闭塞，血液供应中断，其供血区域心肌因持久性缺血而发生的局部坏死。 透壁性心肌梗
12、死：梗死灶累及心室壁全层，又称Q波心肌梗死或ST段抬高心肌梗死。 灶性心肌梗死：梗死灶较小并灶性分布。 心内膜下心肌梗死：梗死灶局限于心壁内1/2，小灶性但分布较广。后两类AMI常无的典型心电图改变，统称非Q波心肌梗死（NQMI），生化检验有助诊断。,24,（三）急性冠脉综合征 急性冠脉综合征(acute coronary syndrome，ACS) ：UAP和AMI统称。 UAP：血栓部分阻塞 AMI：血栓完全阻塞 冠状动脉粥样硬化斑块由稳定转为不稳定，继而破裂导致血栓形成。,25,心肌病：心肌肥厚，扩张，纤维化，心肌小范围损伤。 心力衰竭（心功能不全）：泵血功能障碍。 高血压：原发性，继发
13、性,26,第二节 心血管疾病主要生化检测指标 一 动脉粥样硬化及冠心病的危险因素,(一) 危险因素 (risk factor) ：与某种疾病发生、发展有关的体内、行为和环境因素。 相对危险度(relative risk, RR)：暴露于该危险因素者与未暴露或低于危险水平者发病概率的比值。RR1才有意义，越大则预测价值越高。 (二) 动脉粥样硬化及冠心病的危险因素:,27,第二节 心血管疾病主要生化检测指标,一 心血管疾病危险因素相关生化指标 （一）血清脂质 致AS脂蛋白表型(致AS脂蛋白谱) 高TC、LDL-C, 低HDL-C作为AS独立危险因素早获公认。TC/HDL-C比值与冠心病危险度呈对
14、数线性关系， TC/HDL-C比值5冠心病风险显著增大。 新显现的AS脂质危险因素：高TG、高载脂蛋白ClII、Lp(a) 、 载脂蛋白B 。 常规测定： TG 、TC、LDL-C 、HDL-C,28,(二)超敏C反应蛋白(high sensitivity C-reaction protein, hs-CRP）CRP是多种致炎因素刺激肝细胞和血管内皮细胞产生的急性时相反应蛋白。Your liver produces C-reactive protein (CRP) in response to injury or infection. CRP is also produced by muscl
15、e cells within the coronary arteries. CRP is a general sign of inflammation, which plays a central role in atherosclerosis. 。,29,因AS为慢性炎症过程，只有检测到CRP轻度升高的状态才有价值。因此建立高灵敏度(灵敏度0.3 mg/L )的CRP检测方法，即hs-CRP的由来。高敏C反应蛋白的测定多采用其特异性抗体的定量免疫学方法，包括免疫浊度法、ELISA法、放射免疫法等。 参考值：用于AS危险性评估时，hs-CRP 10mg/L，则可能存在其他急性炎症，应在控制后重
16、新测定。,30,hs-CRP是AS炎症状态危险因子中目前唯一实际应用者。研究证实其RR远远高于任何脂质因素，hs-CRP和TC/HDL-C联合应用，RR高达5.2。 hs-CRP亦是AS病变活跃，斑块破裂，血栓形成的标志。现推荐CHD患者常规监测hs-CRP，以预测AMI和冠脉性猝死等冠脉事件的发生，hs-CRP升高者需积极干预。 作业：简述超敏CRP与CRP的异同？,31,（三）新型炎症反应标志物IL-6、E-选择素(E-selectin)和P-选择素(P-selectin) 、可溶性细胞间粘附分子l(sICAM-1)已被列为新显现的AS危险因素，但仍主要在研究中应用。 脂蛋白相关磷脂酶A2
17、 ( Lp-PLA2 )巨噬细胞和淋巴细胞产生，独立危险因子,32,33,（四） 促血栓形成相关危险因子 (1)纤溶酶原激活剂抑制物1 (plasminogen activator inhibitor-1, PAI-1) 抑制激活纤溶酶原稳定血栓 (2)血浆纤维蛋白原(fibrinogen, Fg)即凝血因子I (3)凝血因子VII,34,（五）同型半胱氨酸 Homocysteine HCY 过多HCY形成硫内酯，与LDL表面载脂蛋白的游离氨基酸形成肽键，促进细胞摄取LDL，加速胆固醇沉积。 冠心病独立因素,35,正常空腹血浆总Hcy水平为515mol/L。研究表明：Hcy每升高5umol/L
18、脑卒中风险升高59%，缺血性心脏病风险升高32%； 代谢辅助因子如叶酸、维生素B6、B12缺乏，均可导致高同型半胱氨酸血症的发生。中国人的饮食习惯吃煮熟的食物(叶酸主要存在于蔬菜、肉类、动物肝脏等)，食物在煮熟的过程中90%以上的叶酸被破坏，导致中国人普遍的叶酸缺乏。,36,37,几种冠心病检测方法（指标）比较 血管造影：可显示血管狭窄，有创性检查，不适于普查、预防、检测。 血脂：最常用，受脂代谢影响，特异性较低 心肌梗死标志物：在心肌梗死时显著，预防意义较低。 Hs-CRP：较常用，受感染影响较大。 Hcy：较常用，易纠正 Lp-PLA2 ：不常用，贵，有前景,38,39,Risk Fact
19、ors and Coronary Heart Disease American Heart Association : http:/www.americanheart.org Extensive clinical and statistical studies have identified several factors that increase the risk of coronary heart disease and heart attack. Major risk factors are those that research has shown significantly inc
20、rease the risk of heart and blood vessel (cardiovascular心血管的) disease. Other factors are associated with increased risk of cardiovascular disease, but their significance and prevalence患病率,流行率 havent yet been precisely精确地 determined. Theyre called contributing risk factors.,40,The American Heart Asso
21、ciation has identified several risk factors. Some of them can be modified缓和,减轻 treated or controlled, and some cant. The more risk factors you have, the greater your chance of developing coronary heart disease. Also, the greater the level of each risk factor, the greater the risk. For example, a per
22、son with a total cholesterol of 300 mg/dL (milligram per deciliter ) has a greater risk than someone with a total cholesterol of 245 mg/dL, even though everyone with a total cholesterol greater than 240 is considered high-risk.,41,What are the major risk factors that cant be changed? Increasing age
23、Over 83 percent of people who die of coronary heart disease are 65 or older. Male sex (gender性别) Men have a greater risk of heart attack than women do, and they have attacks earlier in life. Even after menopause绝经(期), when womens death rate from heart disease increases, its not as great as mens.,42,
24、年龄与性别,43,44,Heredity 遗传 (including Race种族) Children of parents with heart disease are more likely to develop it themselves. African Americans have more severe high blood pressure than Caucasians高加索人,白种人 and a higher risk of heart disease. Heart disease risk is also higher among Mexican Americans, Am
25、erican Indians, native Hawaiians and some Asian Americans. This is partly due to higher rates of obesity肥胖 and diabetes糖尿病. Just as you cant control your age, sex and race, you cant control your family history. Therefore, its even more important to treat and control any other risk factors you have.,
26、45,What are the major risk factors you can modify, treat or control by changing your lifestyle or taking medicine? High blood cholesterol As blood cholesterol rises, so does risk of coronary heart disease. When other risk factors (such as high blood pressure and tobacco smoke) are present, this risk
27、 increases even more. A persons cholesterol level is also affected by age, sex, heredity and diet.,46,Tobacco smoke Smokers risk of developing coronary heart disease is 24 times that of nonsmokers. Cigarette smoking is a powerful independent risk factor for sudden cardiac death in patients with coro
28、nary heart disease; smokers have about twice the risk of nonsmokers. Cigarette smoking also acts with other risk factors to greatly increase the risk for coronary heart disease. Exposure to other peoples smoke increases the risk of heart disease even for nonsmokers.,47,High blood pressure High blood
29、 pressure increases the hearts workload, causing the heart to thicken变厚 and become stiffer僵硬. It also increases your risk of stroke中风, heart attack, kidney failure and congestive heart failure充血性心力衰竭. When high blood pressure exists with obesity, smoking, high blood cholesterol levels or diabetes, t
30、he risk of heart attack or stroke increases several times.,48,Physical inactivity An inactive lifestyle is a risk factor for coronary heart disease. Regular, moderate-to-vigorous physical activity helps prevent heart and blood vessel disease. The more vigorous the activity, the greater your benefits
31、. However, even moderate-intensity中度强度 activities help if done regularly and long term. Physical activity can help control blood cholesterol, diabetes and obesity, as well as help lower blood pressure in some people.,49,Obesity and overweight People who have excess body fat especially if a lot of it
32、 is at the waist腰部 are more likely to develop heart disease and stroke even if they have no other risk factors. Excess weight increases the hearts work. It also raises blood pressure and blood cholesterol and triglyceride甘油三酯 levels, and lowers HDL (“good“) cholesterol levels. It can also make diabe
33、tes more likely to develop. Many obese肥胖的 and overweight people may have difficulty losing weight. But by losing even as few as 10 pounds, you can lower your heart disease risk.,50,肥胖,51,52,Diabetes Diabetes seriously increases your risk of developing cardiovascular disease. Even when glucose (blood
34、 sugar) levels are under control, diabetes increases the risk of heart disease and stroke, but the risks are even greater if blood sugar is not well controlled. About three-quarters of people with diabetes die of some form of heart or blood vessel disease.,53,What other factors contribute to heart d
35、isease risk? Individual response to stress may be a contributing factor. Some scientists have noted a relationship between coronary heart disease risk and stress in a persons life, their health behaviors and socioeconomic社会经济的 status. These factors may affect established确定的risk factors. For example,
36、 people under stress may overeat, start smoking or smoke more than they otherwise would.,54,Drinking too much alcohol can raise blood pressure, cause heart failure and lead to stroke. It can contribute to high triglycerides, cancer and other diseases, and produce irregular不齐的 heartbeats. It contribu
37、tes to obesity, alcoholism酒精中毒, suicide and accidents.,55,Cardiac Risk Assessment Formal name: Cardiac Risk Assessment Related tests: Lipid profile; hs-CRP; Lp(a) What is a cardiac risk assessment? This is a group of tests and health factors that have been proven to indicate your chance of having a
38、cardiovascular event such as heart attack or stroke. They have been refined精炼的to indicate the degree of risk: slight, moderate, or high.,56,What is included in a cardiac risk assessment? Perhaps the most important indicators for cardiac risk are those of your personal health history. Age, hereditary
39、 factors, weight, cigarette smoking, blood pressure, exercise history, and diabetes are all important in determining your risk. The lipid profile描绘,轮廓is the most important blood test for risk assessment. There are imaging tests, non-invasive and invasive侵入的, that may be used in cardiac risk assessme
40、nt.,57,第二节 心血管疾病主要生化检测指标,二、心肌损伤标志物 为什么不完全依靠心电图诊断？ 心电图阴性的？ 心电图阳性的？,58,理想的心肌损伤标志物应满足： 高度心肌特异性，心肌含量高，一旦心肌损伤便可迅速、大量释放，血中浓度升高即表明心肌损伤。 能检测早期心肌损伤，在血液中较稳定，有合适的“诊断窗口期” 。 能估计梗死范围大小，判断预后。 能评估溶栓效果。,59,Cardiac Biomarkers Cardiac biomarkers are substances that are released into the blood when the heart is damaged
41、. Measurement of these biomarkers is used to help diagnose, evaluate, and monitor patients with suspected acute coronary syndrome (ACS). Note: Cardiac biomarkers are not the same tests as those that are used to screen the general healthy population for their risk of developing heart disease. Those c
42、an be found under Cardiac Risk Assessment.,60,心肌损伤标志物主要包括： 1. 心肌损伤酶谱 2. 肌红蛋白 3. 肌钙蛋白T和I亚单位 4. 研究中的心肌损伤标志物（脂肪酸结合蛋白、糖原磷酸化酶同工酶PP，缺血修饰性清蛋白）,61,Only a few cardiac biomarker tests are routinely used by physicians. The current biomarker test of choice for detecting heart damage is troponin肌钙蛋白. Other cardi
43、ac biomarkers are less specific for the heart and may be elevated in skeletal muscle injury, liver disease, or kidney disease. Many other potential cardiac biomarkers are being researched, but their clinical utility has yet to be established.,62,Current cardiac biomarker tests used to help diagnose,
44、 evaluate, and monitor patients suspected of having Acute Coronary Syndrome (ACS):CK and CK-MB , Troponin , Myoglobin Additional biomarker tests that may be used to evaluate risk of future cardiac events (prognosis):BNP (or NT-proBNP) , hs-CRP Phased out biomarkers - the tests below are not specific
45、 for damage to the heart and are no longer recommended for evaluating patients with suspected ACS: AST , LDH,63,1. 心肌损伤酶谱 (enzyme profile of myocardial injury) 一般指天门冬氨酸氨基转移酶AST 、乳酸脱氢酶LD 、肌酸激酶CK 、以及后两者同工酶。,64,(1)天门冬氨酸氨基转移酶 (aspartate aminotransferase, AST) 人体内AST分子量约100 kD，在心肌中含量最高，因此而具有相对心肌分布特异性。AMI
46、发生后612 h血液中AST始出现升高，2448 h达峰值，若无再损伤发生，57 d 恢复正常水平。,65,因其体内分布广泛，多种器官病变均可致血中水平升高，特异性不高；此外，红细胞亦富含AST，轻度溶血即可致AST水平非病理性显著升高。 AST诊断AMI的特异性仅53%。AST分子较大， AMI发生612 h后血清AST 水平才出现升高，24 h左右才达峰值，远不能满足尽早干预，恢复有效血液灌注的要求。 现在建议不再用AST作为心肌损伤标志。,66,(2)乳酸脱氢酶(lactate dehydrogenase, LD)及其同工酶 LD是由肌(muscle, M)型和心(heart, H)型两
47、种亚单位组成的4聚体，分子量约134 kD。LD至少有5种同工酶，按电泳条带距阳极的近远，依次命名为LD1LD5 。LD广泛存在于各种器官组织胞浆，按含量多少依次为肝、心、肾、骨骼肌、红细胞、脑等。,67,LD1比总LD更具心肌特异性。LD作为心肌损伤标志物，包括血清LD总活性、LD1同工酶活性或相对比例测定。,68,临床意义及评价： 由于分子较大，AMI等心肌损伤发生后, 8 12h 血中LD及LD1始出现升高，3d 左右达峰值，812d缓慢恢复正常。 LD1主要分布于心肌，因此，心肌损伤时血中LD以LD1为主，并由此导致LD2的相对比例下降，出现LD1/ LD21的比值反转(flipped
48、 LD isoenzyme ratio)特点。,69,评价： 不能满足AMI早期诊断需要。血中升高出现时间较迟，同工酶谱检测周期较长。 特异性低。分布广泛，红细胞LD同工酶谱与心肌相似 ，溶血亦可表现为LD1/ LD21比值反转。LD活性诊断AMI的特异性仅53%，LD1/ LD2反转特异性亦仅85%90%。 不适宜用作再灌注标志。不提倡以LD及其同工酶作为心肌损伤标志。,70,(3) 肌酸激酶 (Creatine Kinase, CK) 催化：肌酸与ATP之间高能磷酸键转移生成磷酸肌酸和ADP的可逆反应，为肌肉收缩和运输系统提供能量来源。,71,CK及其同工酶的组织分布 组织 总酶活性(U/
49、g) CK-MM CK-MB CK-BB 骨骼肌 2500 98.9% 1.1% 0.06% 脑 555 0% 2.7% 97.3% 心脏 473 78.7% 20% 1.3% 骨骼肌里几乎都是CK-MM 脑中CK-BB含量明显高于其他组织 心肌是唯一含CK-MB较多的器官。,72,M亚单位存在易被血浆中羧肽酶水解的C-端赖氨酸残基，因此： 血清CK-MM同工酶存在3种亚型：CK-MM1(无C-端赖氨酸残基) CK-MM2 (1个C-端赖氨酸残基) CK-MM3(含2个C-端赖氨酸残基的原型)。 同理CK-MB同工酶存在2种亚型： CK-MB1(无C-端赖氨酸残基) CK-MB2(1个C-端赖氨酸残基的原型),73,测定方法 抗凝剂，可对CK活性产生影响，应以血清为活性检测标本。总CK活性测定推荐酶偶联法为参考方法。 pH为6.76.9时，CK催化磷酸肌酸和ADP生成肌酸和ATP(逆反应); 在己糖激酶催化下，ATP使葡萄糖磷酸化为6-磷酸葡萄糖; 再在6-磷酸葡萄糖脱氢酶催化下，氧化NADP+为NADPH。340nm监测NADPH的生成速率代表总CK活性。,
