Text B Atherosclerosis

Pathogenesis

Atherosclerosis remains the major cause of death and premature disability in developed societies．Moreover，current predictions estimate that by the year 2020 cardiovascular diseases，notably atherosclerosis，will become the leading global cause of total disease burden．Although many generalized or systemic risk factors predispose to its development，atherosclerosis affects various regions of the circulation preferentially and yields distinct clinical manifestations depending on the particular circulatory bed affected．Atherosclerosis of the coronary arteries commonly causes myocardial infarction and angina pectoris． Atherosclerosis of the arteries supplying the central nervous system frequently provokes strokes and transient cerebral ischemia．In the peripheral circulation， atherosclerosis causes intermittent claudication and gangrene and can jeopardize limb viability．Involvement of the splanchnic circulation can cause mesenteric ischemia．Atherosclerosis can affect the kidneys either directly（e．g． renal artery stenosis）or as a frequent site of atheroembolic disease．

Even within a given arterial bed，stenoses due to atherosclerosis tend to occur focally，typically in certain predisposed regions．In the coronary circulation， for example，the proximal left anterior descending coronary artery exhibits a particular predilection for developing atherosclerotic disease．Likewise， atherosclerosis preferentially affects the proximal portions of the renal arteries and，in the extracranial circulation to the brain，the carotid bifurcation． Indeed，atherosclerotic lesions often form at branching points of arteries， regions of disturbed blood flow．Not all manifestations of atherosclerosis result from stenotic，occlusive disease．Ectasia and development of aneurysmal disease，for example，frequently occur in the aorta．In addition to focal，flow－limiting stenoses，nonocclusive intimal atherosclerosis also occurs diffusely in affected arteries，as shown by intravascular ultrasound and postmortem studies．

Atherogenesis in humans typically occurs over a period of many years， usually many decades．Growth of atherosclerotic plaques probably does not occur in a smooth，linear fashion，but rather discontinuously，with periods of relative quiescence punctuated by periods of rapid evolution．After a generally prolonged“silent”period，atherosclerosis may become clinically manifest．The clinical expressions of atherosclerosis may be chronic，as in the development of stable，effort－induced angina pectoris or of predictable and reproducible intermittent claudication．Alternatively，a dramatic acute clinical event，such as myocardial infarction，a stroke，or sudden cardiac death，may first herald the presence of atherosclerosis．Other individuals may never experience clinical manifestations of arterial disease despite the presence of widespread atherosclerosis demonstrated postmortem．

Initiation of Atherosclerosis

An integrated view of experimental results in animals and studies of human atherosclerosis suggests that the“fatty streak”represents the initial lesion of atherosclerosis．These early lesions most often seem to arise from focal increases in the content of lipoproteins within regions of the intima．This accumulation of lipoprotein particles may not result simply from an increased permeability，or“leakiness”of the overlying endothelium．Rather，these lipoproteins may collect in the intima of arteries because they bind to constituents of the extracellular matrix，increasing the residence time of the lipid－rich particles within the arterial wall．Lipoproteins that accumulate in the extracellular space of the intima of arteries often associate with glycosaminoglycans of the arterial extracellular matrix，an interaction that may slow the egress of these lipid－rich particles from the intima．1 Lipoprotein particles in the extracellular space of the intima，particularly those retained by binding to matrix macromolecules， may undergo oxidative modifications．Considerable evidence supports a pathogenic role for products of oxidized lipoproteins in atherogenesis．Lipoproteins sequestered from plasma antioxidants in the extracellular space of the intima become particularly susceptible to oxidative modification，giving rise to hydroperoxides，lysophospholipids，oxysterols，and aldehydic breakdown products of fatty acids and phospholipids．Modifications of the apoprotein moieties may include breaks in the peptide backbone as well as derivatization of certain amino acid residues．Local production of hypochlorous acid by myeloperoxidase associated with inflammatory cells within the plaque yields chlorinated species such as chlorotyrosyl moieties．Considerable evidence supports the presence of such oxidation products in atherosclerotic lesions．

Clinical Syndromes of Atherosclerosis

Atherosclerotic lesions occur ubiquitously in Western societies．Most atheromata produce no symptoms，and many never cause clinical manifestations．Numerous patients with diffuse atherosclerosis may succumb to unrelated illnesses without ever having experienced a clinically significant manifestation of atherosclerosis．What accounts for this variability in the clinical expression of atherosclerotic disease？

Arterial remodeling during atheroma formation represents a frequently overlooked but clinically important feature of lesion evolution．During the initial phases of atheroma development，the plaque usually grows outward，in an abluminal direction．Vessels affected by atherogenesis tend to increase in diameter，aphenomenon known as“compensatory enlargement”，in a type of vascular remodeling．2 The growing atheroma does not encroach upon the arterial lumen until the burden of atherosclerotic plaque exceeds 40％of the area encompassed by the internal elastic lamina．Thus，during much of its life history，an atheroma will not cause stenosis that can limit tissue perfusion．

Flow－limiting stenoses commonly form later in the history of the plaque． Many such plaques cause stable syndromes such as demand－induced angina pectoris or intermittent claudication in the extremities．In the coronary and other circulations，even total vascular occlusion by atheroma does not invariably lead to infarction．The hypoxic stimulus of repeated bouts of ischemia characteristically induce formation of collateral vessels in the myocardium，mitigating the consequences of an acute occlusion of an epicardial coronary artery．By contrast，we now appreciate that many lesions that cause acute or unstable atherosclerotic syndromes，particularly in the coronary circulation，may arise from atherosclerotic plaques that do not produce a flow－limiting stenosis．3 Such lesions may produce only minimal luminal irregularities on traditional angiograms and often do not meet the traditional criteria for“significance”by arteriography．Instability of such nonocclusive stenoses may explain the frequency of myocardial infarction as an initial manifestation of coronary artery disease（in at least one－third of cases）in patients who report no prior history of angina pectoris，a syndrome usually caused by flow－limiting stenoses．

Prevention and Treatment

The Concept of atherosclerotic risk factors．The systematic study of risk factors for atherosclerosis emerged from a coalescence of experimental results as well as cross－sectional and ultimately longitudinal studies in humans．The prospective，community－based Framingham Heart Study provided rigorous support for the concept that hypercholesterolemia，hypertension，and other factors correlated with cardiovascular risk．4 Similar observational studies performed worldwide bolstered the concept of“risk factors”for cardiovascular disease．

From a practical viewpoint，the cardiovascular risk factors that have emerged from such studies fall into two categories：those modifiable by lifestyle and／or pharmacotherapy and those such as age and gender that are immutable． The weight of evidence supporting various risk factors differs．For example， hypercholesterolemia and hypertension certainly predict coronary risk，but other so－called nontraditional risk factors，such as levels of homocysteine， lipoprotein（a）［Lp（a）］，or infection，remain controversial．Moreover，the causality of some biomarkers that predict cardiovascular risk，such as C－reactive protein（CRP），remains uncertain．The sections below will consider some of these risk factors and approaches to their modification．

Lifestyle modification．The prevention of atherosclerosis presents a long－term challenge to all health care professionals and for public health policy as well．Both individual practitioners and organizations providing health care should strive to help patients optimize their risk factor profile long before atherosclerotic disease becomes manifest．The current accumulation of cardiovascular risk in youth and in certain minority populations presents a particularly vexing concern from a public health perspective．

The care plan for all patients seen by internists should include measures to assess and minimize cardiovascular risk．Physicians must counsel patients regarding the health risks of tobacco use and provide guidance and resources regarding smoking cessation．Likewise，physicians should advise all patients about prudent dietary and physical activity habits for maintaining ideal body weight．Both National Institutes of Health and AHA （American Heart Association）statements recommend at least 30 min of moderate－intensity physical activity per day．Obesity，particularly the male pattern of centripetal or visceral fat accumulation，can contribute to the elements of the metabolic syndrome．Physicians should encourage their patients to take personal responsibility for behavior related to modifiable risk factors for development of premature atherosclerotic disease．5 Conscientious counseling and patient education may forestall the need for pharmacologic measures intended to reduce coronary risk．

（1，337 words）

New Words and Phrases

pathogenesis［,pæθə'dʒenɪsɪs］n． 发病机理

angina pectoris［æn'dʒaɪnə'pektərɪs］ 心绞痛

claudication［,klɔːdɪ'keɪʃən］n． 跛行

gangrene［'ɡæŋɡriːn］n． 坏疽

jeopardize［'dʒepədaɪz］v． 危及，损害

splanchnic［'splæŋknɪk］a． 内脏的

mesenteric［,mezən'terɪk］a． 肠系膜的

predilection［,priːdɪ'lekʃən］n． 偏爱，嗜好

extracranial［,ekstrə'kreɪnɪəl］a． （位于或发生于）颅外的

bifurcation［,baɪfə'keɪʃən］n． 分歧；分歧点；分叉

occlusive［ə'kluːsɪv］a． 闭塞的，咬合的

ectasia［ek'teɪʒə］n． （空腔或管状器官的）扩张；膨胀

aneurysmal［,ænjuː'rɪzməl］a． 动脉瘤的

postmortem［,pəʊst'mɔːtəm］a． 死后的；验尸的；事后的

atherogenesis［,æθərəʊ'dʒenɪsɪs］n． 动脉粥样化形成

plaque［plæk］n． 斑（块），空斑，蚀斑

quiescence［kwɪ'esns］n． 静止

fatty streak［'fætɪstriːk］ 脂肪纹；脂肪条痕

lipoprotein［,lɪpəʊ'prəʊtɪn］n． 脂蛋白

intima［'ɪntɪmə］n． 内膜

permeability［,pзːmɪə'bɪlɪtɪ］n． 渗透性

endothelium［,endəʊ'θiːlɪəm］n． 内皮

matrix［'meɪtrɪks］n． 基质；基层

glycosaminoglycan（GAG） 黏多糖；糖胺聚糖

［,ɡlaɪkəʊsə,miːnəʊ'ɡlaɪkæn］n．

egress［'iːɡres］n． 外出；出路，出口

macromolecule［,mækrəʊ'mɒlɪkjuːl］n． 大分子，高分子

pathogenic［,pæθə'dʒenɪk］a． 致病的，病原的

sequestered［sɪ'kwestəd］a． 隔绝的，分离的；隐蔽的

antioxidant［,æntɪ'ɒksɪdənt］n． 抗氧化剂

hydroperoxide［,haɪdrəʊpə'rɒksaɪd］n． 氢过氧化物

lysophospholipid［,laɪsəʊ,fɑːsəʊ'lɪpɪd］ 溶血磷脂；溶血磷脂类

oxysterol［'ɒksɪ'sterɒl］n． 氧甾酮，氧类固醇

aldehydic［,ældɪ'haɪdɪk］a． 乙醛的

phospholipid［,fɒsfə'lɪpɪd］n． 磷脂

apoprotein［,æpə'prəʊtiːn］n． 脱辅基蛋白；载脂蛋白

moiety［'mɒɪətɪ］n． 等分，一半；一部分

peptide［'peptaɪd］n． 肽

amino acid［ə,miːnəʊ'æsɪd］ 氨基酸

hypochlorous acid［,haɪpəʊ'klɔːrəsæsɪd］ 次氯酸

myeloperoxidase［,maɪələʊpə'rɒksɪdeɪs］n． 髓过氧物酶

chlorinated［'klɔːrɪ,neɪtɪd］a． 氯化了的，加氯的

chlorotyrosyl［'klɔːrə'taɪrə,sɪl］n． 氯代酪氨酰

atheroma［,æθə'rəʊmə］n． 粥样斑

abluminal［æb'luːmɪnəl］a． 来自管腔的；近腔的

lumen［'ljuːmən］（［复］lumina／lumens）n． （管状器官内的）内腔

internal elastic lamina 内弹性膜

hypoxic［haɪ'pɒksɪk］a． 含氧量低的，氧过少的

epicardial［,epɪ'kɑːdɪəl］a． 心外膜的

luminal［'ljuːmɪnəl］a． 腔的

angiogram［'ændʒɪəʊɡræm］n． 血管造影（照）片

arteriography［,ɑːtɪərɪ'ɒɡrɪəfɪ］n． 动脉造影术

coalescence［,kəʊə'lesəns］n． 合并，接合，联合

cross－sectional［'krɒs'sekʃənəl］a． 横断面的

hypercholesterolemia［,haɪpə（ː）kə,lestərəʊ'liːmɪə］n．高胆固醇血症

bolster［'bəʊlstə］v． 支撑；加固

pharmacotherapy［,fɑːməkəʊ'θerəpɪ］n． 药物疗法

immutable［ɪ'mjuːtəbl］a． 不可改变的

homocysteine［,hɒməʊ'sɪstɪiːn］n． 高半胱氨酸，同型半胱氨酸

manifest［'mænɪfest］a． 明白的，明显的

vexing［'veksɪŋ］a． 使人烦恼的；令人恼火的

internist［'ɪntənɪst］n． 内科医师

cessation［se'seɪʃən］n． （暂时）停止，休止；中断

centripetal［sen'trɪpɪtəl］a． 向心（力）的

forestall［fɔː'stɔːl］v． 先发制人，预先阻止

Notes

1．Lipoproteins that accumulate in the extracellular space of the intima of arteries often associate with glycosaminoglycans of the arterial extracellular matrix，an interaction that may slow the egress of these lipid－rich particles from the intima．

参考译文：蓄积于动脉内膜细胞外空隙处的脂蛋白经常与动脉细胞外基质的黏多糖结合，这是一个可以减缓富含脂蛋白微粒从内膜渗出过程的交互作用。

本句是复合句。lipoproteins是全句的主语，谓语是associate with，宾语是glycosaminoglycans of the arterial extracellular matri。an interaction．．．是同位语，解释主句。全句含有两个定语从句：that accumulate in the extracellular space of the intima of arteries和that may slow the egress of these lipid－rich particles from the intima。前者修饰主语lipoproteins，后者修饰同位语an interaction。

2．Vessels affected by atherogenesis tend to increase in diameter，a phenomenon known as compensatory enlargement，in a type of vascular remodeling．

参考译文：动脉粥样化形成所累及的血管往往管径增大，这一现象被称作补偿性增扩。

affected by atherogenesis是过去分词短语，作后置定语修饰主语vessels；aphenomenon是同位语，解释前句；过去分词短语known as compensatory enlargement作后置定语，修饰aphenomenon。

3．By contrast，we now appreciate that many lesions that cause acute or unstable atherosclerotic syndromes，particularly in the coronary circulation，may arise from atherosclerotic plaques that do not produce a flow－limiting stenosis．

参考译文：相比之下，我们现在充分意识到，许多粥样硬化性损伤会引起急性或不稳定的粥样硬化综合征，特别是在冠脉循环中。这些损伤可能是由不会引起限流性狭窄的动脉粥样硬化斑所致。

本句中有3个that引导的从句。第1个在及物动词appreciate之后，作宾语；第2个是定语从句，修饰many lesions；第3个亦为定语从句，修饰atherosclerotic plaques。

4．The prospective，community－based Framingham Heart Study provided rigorous support for the concept that hypercholesterolemia，hypertension， and other factors correlated with cardiovascular risk．

参考译文：具前瞻性、以社区为基础的弗雷明汉心脏研究为高胆固醇血症、高血压及其他因素与心血管疾病风险相关这一理念提供了严谨而有力的支持。

本句中that引导的从句是the concept的同位语。弗雷明汉是位于美国马塞诸塞州东部的城镇。

5．Physicians should encourage their patients to take personal responsibility for behavior related to modifiable risk factors for development of premature atherosclerotic disease．

参考译文：医生应该鼓励患者自觉保持良好生活方式以减少引起早期动脉粥样硬化发展的危险因素。

本句中related to modifiable risk factors for development of premature atherosclerotic disease是过去分词短语作后置定语，修饰前面的behavior；for development of premature atherosclerotic disease是介词短语作后置定语，修饰前面的factors。

Exercises

Ⅰ．Answer the following questions．

1．According to the passage，what disease will become the leading global cause of total disease burden by the year 2020？

2．Where does atherosclerosis preferentially affect？

3．What may first herald the presence of atherosclerosis in an acute clinical event？

4．When does the growing atheroma encroach upon the arterial lumen？

5．In preventing coronary risk，what advise should physicians give to all patients？

Ⅱ．Decide whether the following statements are True or False．

1．Atherosclerosis of the coronary arteries commonly causes strokes and transient cerebral ischemia．

2．Atherosclerotic lesions often form at branching points of arteries，regions of disturbed blood flow．

3．Growth of atherosclerotic plaques probably occurs in a smooth，linear fashion．

4．Considerable evidence supports a pathogenic role for products of oxidized lipoproteins in atherogenesis．

5．In the coronary and other circulations，total vascular occlusion by atheroma invariably leads to infarction．