1、 老年性瓣膜性心脏病 -主动脉瓣狭窄卫生部北京医院何青内 容n老龄和瓣膜病n老年AS 的临床特点n老年AS 的治疗策略内 容n老龄和瓣膜病老龄和瓣膜病n老年AS 的临床特点n老年AS 的治疗策略n1854 William Stokes 在他的教科书“The diseases of the heart and the aorta”中描述钙化性主动脉瓣病的特征为：(1)permanent patency of the valve in which the diameter may be increased or diminished;(2)an extreme ossific growth alo
2、ng the valve surrounding the ventricle,at which the valves are often destroyed;(3)an atheromatous deposit on the ventricular surface of the valve which is often seen in the context of fatty degeneration of the heart.n1904年Monchkebery 首先发现人在自然衰老过程中会出现退行性变，引起主动脉瓣的钙化、狭窄。n1910年Dewisky首先描述了二尖瓣环的钙化。Nalini
3、 M Rajamannan et al,Heart 2003;89:801805 1997年美国B.FENDLEY STEWART等人报道了52015201例例6565岁岁老年人的心血管健康研究，提示经心脏超声检查，主动脉瓣硬化发生率是26%26%，主动脉狭窄为2%2%。在7575岁岁的人群中，硬化发生率是37%37%，狭窄为2.6%2.6%。与退行性瓣膜病相关的独立危险因子包括年龄（年龄每增长十年危险增长2倍）、性别（男性为女性两倍）、吸烟（仍然吸烟者增加危险35%）和高血压（有高血压病史者危险增加20%）。其他明确的危险因子有LP（a）和LDL-C的水平。作者认为与主动脉瓣硬化和狭窄相关的
4、临床因素明确，且类似于动脉粥样硬化的危险因素。STEWART ET AL.AORTIC STENOSIS RISK FACTORS J Am Coll Cardiol 1997;29:6304n我国资料报道，301医院1986-1992年尸检心脏瓣膜病110例，中青年组未见钙化，50-60岁有轻度瓣膜钙化，而60岁以上者瓣膜钙化检出率随年龄增加而增高，且联合瓣膜病增多。老年瓣膜病与性别有关，主动脉钙化或硬化多见于男性，男女比例为2：1；二尖瓣环钙化多见于女性，1：2。王从容、王士雯等 老年退行性心脏瓣膜钙化的病理学研究 中华老年医学杂志1995年8月第14卷第4期nAS 在老年人是最为常见的心
5、脏瓣膜病变n年龄65岁人群，钙化性AS为2%-7%n80%的症状性AS为男性正常主动脉瓣膜正常主动脉瓣膜The normal aortic valve comprises 3 layers.The ventricularis,on the ventricular side of the leaflet,is composed of elastinrich fibers that are aligned in a radial direction,perpendicular to the leaflet margin.The fibrosa,on the aortic side of the l
6、eaflet,comprises primarily fibroblasts and collagen fibers arranged circumferentially,parallel to the leaflet margin.The spongiosa is a layer of loose connective tissue at the base of the leaflet,between the fibrosa and ventricularis,composed of fibroblasts,mesenchymal cells,and a mucopolysaccharide
7、-rich matrix.These layers work in concert to provide tensile strength and pliability for decades of repetitive motion.Freeman and Otto Calcific Aortic Valve Disease Circulation June 21,2005早期病变：瓣膜主动脉侧内皮下细胞、脂质和细胞外基质的积聚，伴内皮下弹力层的移位。晚期病变：更加明显的脂质、细胞、细胞外基质的聚集，弹力层移位、断裂。钙化性主动脉瓣疾病组织学改变钙化性主动脉瓣疾病组织学改变Potential
8、 pathways depicting calcific aortic valve disease.T lymphocytes and macrophages infiltrate endothelium and release cytokines that act on valvular fibroblasts to promote cellular proliferation and extracellular matrix remodeling.A subset of valvular fibroblasts within fibrosa layer differentiate into
9、 myofibroblasts that possess characteristics of smooth muscle cells.LDL that is taken into the subendothelial layer is oxidatively modified and taken up by macrophages to become foam cells.ACE is colocalized with apolipoprotein B(ApoB)and facilitates conversion of angiotensin II(AngII),which acts on
10、 angiotensin 1 receptors(AT-1R),expressed on valvular myofibroblasts.A subset of valvular myofibroblasts differentiate into osteoblast phenotype that is capable of promoting calcium nodule and bone formation.IL indicates interleukin;TGF,transforming growth factor;and MMP,matrix metalloproteinases.Fr
11、eeman and Otto Calcific Aortic Valve Disease Circulation June 21,2005病变早期病变早期：q内皮损伤 机械作用q细胞外脂质聚集q炎症反应q细胞外液和ACE作用病变晚期病变晚期：随着病变的进展，纤维膜层的纤维母细胞分化成具有平滑肌特点的成肌纤维细胞，瓣膜硬化。后者具有成骨作用，在炎症因子等的共同刺激下，钙盐沉积，瓣膜上进一步形成钙化结节。瓣膜的骨化，可能和钙盐的代谢有关，有研究认为钙盐沉积是一个主动的过程，也可能和遗传有一定的关系。病理机制病理机制脂蛋白聚集脂蛋白聚集细胞渗出细胞渗出细胞外基质形成细胞外基质形成瓣膜增厚、硬化、钙化
12、瓣膜增厚、硬化、钙化瓣叶活动受限瓣叶活动受限流出道受阻流出道受阻左室肥厚、左室舒张功能、收缩功能受损、左室肥厚、左室舒张功能、收缩功能受损、充血性心衰、心绞痛、心律失常、晕厥充血性心衰、心绞痛、心律失常、晕厥Freeman and Otto Calcific Aortic Valve Disease 3317导致导致AS的主要原因：的主要原因：q正常三叶瓣的钙化和退行性变，随年龄而增加q和冠心病相关的多种危险因子 常于AS相伴q先天性主动脉瓣畸形，二叶瓣、单叶瓣q风湿先天性主动脉二瓣畸形致狭窄先天性主动脉二瓣畸形致狭窄风湿性主动脉瓣狭窄风湿性主动脉瓣狭窄钙化的退行性主动脉瓣狭窄钙化的退行性主动
13、脉瓣狭窄内 容n老龄和瓣膜病n老年老年AS AS 的临床特点的临床特点n老年AS 的治疗策略Freeman and Otto Calcific Aortic Valve Disease Circulation June 21,2005瓣膜的钙化病变和形成动脉粥样硬化的临床因素类似瓣膜的钙化病变和形成动脉粥样硬化的临床因素类似n大部分主动脉瓣硬化的病人临床没有症状，或其心血管病危险因素已得到控制，但临床事件的发生率仍然是高的。n有16%诊断为主动脉瓣硬化的病人在8年内进展为严重的主动脉瓣狭窄。老年人主动脉瓣硬化和心血管发病率和死亡率的相关性老年人主动脉瓣硬化和心血管发病率和死亡率的相关性ASSO
14、CIATION OF AORTIC-VALVE SCLEROSIS WITH CARDIOVASCULAR MORTALITY AND MORBIDITY ASSOCIATION OF AORTIC-VALVE SCLEROSIS WITH CARDIOVASCULAR MORTALITY AND MORBIDITY IN THE ELDERLYIN THE ELDERLYCATHERINE M.O TTO et al.N Engl J Med 1999;341:142-7N=5621，年龄，年龄65岁，前瞻性研究，超声心动图检查，平均随访岁，前瞻性研究，超声心动图检查，平均随访5年年 Con
15、clusions:Conclusions:Aortic sclerosis is common in the elderly and is associated with an increase of approximately 50%in the risk of death from cardiovascular causes and the risk of myocardial infarction,even in the absence of hemodynamically significant obstruction of left ventricular outflow.CATHE
16、RINE M.O TTO et al.N Engl J Med 1999;341:142-7伴有伴有“良性良性”主动脉瓣增厚病人发生主动脉瓣狭窄的危险主动脉瓣增厚病人发生主动脉瓣狭窄的危险性性The Risk of the Development of Aortic Stenosis in Patients With“Benign”Aortic Valve ThickeningJohn E.Cosmi,et al,Arch Intern Med.2002;162:2345-2347N=2131，回顾性研究，心脏超声诊断，15.9%伴有伴有“良性良性”主动脉瓣增厚病人发生主动脉瓣狭窄的危险性主动
17、脉瓣增厚病人发生主动脉瓣狭窄的危险性The Risk of the Development of Aortic Stenosis in Patients With“Benign”Aortic Valve ThickeningJohn E.Cosmi,et al,Arch Intern Med.2002;162:2345-2347 Conclusions:Aortic valve thickening without stenosis is common,and it may progress to significant AS.It is possible that this developm
18、ent of AS may be responsible for some of the increased morbidity and mortality in patients with AVT.1973年中华医学杂志“老年人冠状动脉粥样硬化性心脏病临床与病理的对照分析”一文报道一例明显钙化性主动脉瓣狭窄的老年病人尸检提示多处不同发展阶段内膜下心梗，但没有明显的冠脉狭窄病变，认为AS可以引起MI，而且这种梗塞是反复发生的和范围较小的。国内北京医院报道6例临床追随30年以上，又进行了尸解证实为严重钙化性主动脉瓣狭窄的老年病例，生前的临床特点均为逐渐出现并加重的心底部收缩期杂音，均有心电图的缺
19、血改变和心脏超声的左室肥厚、瓣膜钙化表现，6例中5例生前有心肌梗死病史。尸检的病理特点是反复发生，不同时间，分散和灶性的非透壁性心梗，冠脉病变可以较轻甚至无明显病变。6例中5例为猝死，其原因考虑与主动脉瓣狭窄患者的血液动力学障碍有关仍可有心梗的发生。齐欣、王瑞萍、钱贻简等 中华内科杂志2000年2月第39卷第2期内 容n老龄和瓣膜病n老年AS 的临床特点n老年老年AS AS 的治疗策略的治疗策略Joint Recommendations ofAmerican Heart Association and American College ofCardiology for aortic valve
20、 replacement in patients with aortic stenosisAortic valve replacement indicated In patients with severe aortic stenosis with its classic“SAD”symptoms(syncope,angina,and/or dyspnoea In patients with severe aortic stenosis who are having coronary artery bypass grafting In patients with severe aortic s
21、tenosis having surgery on the aorta or other heart valves In patients with severe aortic stenosis with left ventricular systolic dysfunction(ejection fraction 50%)Aortic valve replacement possibly indicated In patients with moderate aortic stenosis having coronary artery bypass grafting or surgery o
22、n the aorta or other heart valves In patients with asymptomatic severe aortic stenosis with abnormal response to exercise(such as development of symptoms or asymptomatic hypotension)In patients with asymptomatic severe aortic stenosis if there is likelihood of rapid progression(age,calcification,and
23、 coronary artery disease)or if surgery might be delayed at the time of symptom onset In patients with mild aortic stenosis having coronary artery bypass grafting when there is evidence ofmoderate to severe calcification,suggesting thatprogressionis likely and may be rapid In patients with asymptomat
24、ic extreme severe aortic stenosis(aortic valve area 60mmHg,or a jet velocity 5m/s)when the patients expected operative mortality is 1%外科治疗外科治疗内科治疗内科治疗内科药物治疗？不确切。相关的治疗：他汀类药物ACEI对症治疗目前研究尚未解决的问题目前研究尚未解决的问题nAS是否类似于动脉粥样硬化过程是不断进展的，可以通过药物来干预？n通过生活方式的改善或他汀类药物是否可以延缓AS的进程？n准备做心脏手术的无症状的轻度或中度AS患者是否需换瓣？n假设手术死亡率是
25、低的，是否建议无症状的重度AS患者选择瓣膜置换术以减少以后的发病率和死亡率？目前正在进行的关于主动脉瓣疾病的目前正在进行的关于主动脉瓣疾病的他汀类药物作用的研究他汀类药物作用的研究nSTOP-ASStop aortic stenosis(Cleveland Clinic,Cleveland,Ohio,USA)nSEASSimvastatin and the ezetimibe in aortic stenosis(Europe)nASTRONOMERAortic stenosis progression observation measuring effects of rosuvastatin(Canada)谢谢
