《心率与心血管疾病一个重要而被忽视的问题》由会员分享，可在线阅读，更多相关《心率与心血管疾病一个重要而被忽视的问题（63页珍藏版）》请在金锄头文库上搜索。
1、心率与心血管疾病一个重要而被忽视的问题Stillwatersrundeep.流静水深流静水深,人静心深人静心深Wherethereislife,thereishope。有生命必有希望。有生命必有希望前言人们早已发现心率较快的小动物的寿命较短，而心率较慢的大动物，寿命较长。这一心率与寿命负相关现象除人类外，存在于所有哺乳动物。人类的平均心率为70次/分左右，其预期寿命为80岁，有人预测，将人类平均心率由70次/分减少到60次/分可使预期寿命增加到93.3岁。心率的重要性 心率（HR）是心肌耗氧量的最主要决定因素HR下降可增加缺血阈值，改善心肌做功HR是一个独立危险因素的证据，既来自Cohort研
2、究（有相同统计要素的一组人）也来自前瞻性双盲临床试验问题之一 普通人群中，HR对预后有何意义？五大流行病学研究评估了心率与CHD与CV病的关系lFramingham Heart StudylNational Health Examination SurverylMultifactor Primary PreventionlTrial in GoteberglChicago Heart Association结论共入选30000表面健康的人（大多为中年男性），随访5年36年结果：各种原因死亡与心血管病死亡的危险随HR升高而递增，特别是心率84次/分时，不论性别或种族如何，死亡率均一致性地与HR升
3、高相关与HR60次/分比较，HR9099次/分者,死亡率要高3倍!(主要死于冠心病) 问题之二 心率是否是高血压病人的重要预后因素?l 与血压正常对照组相比,高血压病人,静息时心率明显较快l4530例高血压随访观察显示,心率85次/分者死亡率比65次/分者高1倍,且此与有无传统的冠心病危险因素无关问题之三 心率对老年人是否是预后因素?l一项大型高危老年人群研究显示,在调整其他混杂因素后,心率每增加5次/分,其心梗与猝死危险性增加14% 问题之四（1） 急性心梗病人心率是否是一个重要预后因素?l根据病人住院时心率快慢,并随访一年分析显示,如入院2小时内心率由小于90次/分增加到大于100次/分,
4、则总死亡率增加1倍.l进一步分析死亡率与住院期间或出院前最高心率的关系显示,与7090次/分相比,100次/分者,死亡率增加达4-6倍.问题之四（2）入院时心率90次/分者比90次/分者严重心衰发生率要高10倍之多.(1990年)将病人进一步分为无心衰或轻、中、重度心衰组后,心率快慢仍是死亡率的重要预报因子。例如,轻至中度心衰病人中,入院90次/分者死亡率要比70次/分者高23倍.问题之五 我们从冠心病随机对照研究中对心率问题获得哪些信息?l多项-B试验均一致地显示可降低心梗后病人心源性猝死率,心血管死亡率与再梗死率l对16500例(11个前瞻性研究)心梗后病人研究显示,无内源性拟交感活性的-
5、B对心率与死亡率降低的效益最大;死亡率降低与心率减慢之间有明显线性关系,即每减少10次/分心率可使死亡率降低1520% ！问题之六心肌梗死存活者用-B后临床预后有何改观?l11个随机对照研究显示,心率与心梗面积(R=0.97.P0.001),死亡率(R=0.79,P0.005)与 非 致 命 性 再 梗 率(R=0.59,P0.05)显著相关l总体来看,用-B后心率至少应减少8-10次/分,才能使心梗面积与死亡率明显下降. 问题之七 用-B治疗急性心肌梗死临床效益究竟有多大? 答案是剂量足够,心率下降达到一定幅度,治疗效益是很大的.l无内源性-B治疗1000例病人可挽救2025个生命l溶栓药为
6、4045个生命 问题之八 （1）心率是如何影响心血管发病率与死亡率的？l HR下降降低MVO2l HR下降增加冠脉血流l HR下降缩小心梗面积l HR下降增加室颤阈值(用-B预处理后再结扎冠状动脉,可预防实验犬发生VF)问题之八（2）l HR降低有直接抗动脉粥样硬化作用。灵长目动物实验,在相同血压,血脂与体重条件下,心率慢者粥样化病变仅为心率快者的1/3左右.l用饱和脂肪酸喂饲的猴实验中显示,心率慢比心率快者,冠状动脉病变要轻l接受心得安治疗的猴子,尽管血脂水平仍高,但比未治疗者粥样硬化病变要轻得多.lPoor health and/or physical fitness 本类人群静息时心率常
7、偏快,本类人群比体力活动锻炼多的人易患冠心病l自主神经功能异常：心率快提示交感神经亢奋,迷走神经张力降低，易发生室颤. 7060504030201002530354540555060HT per 1.000 men/YrTransienttachycardiaTransientHypertension-+-+-+Figure 1. Predictive value of transient tachycardia or transient blood pressure increase for the development of hypertension during a 5-year fo
8、llow-up period. This study, performed in 22,741 American Army soldiers, was the first to document the predictive power of heart rate for the development of hypertension later in life, A transient heart rate increase showed the predictive power for the development of hypertension as did a transient b
9、lood pressure rise meant a significant increase inrisk. From Levy R.L. et al (1945). JAMA 129,585. Q5Q4Q3Q2Q10.51.52.5321Heart rate (bpm)Relative riskFigure 2. Risk of developing hypertension later in life on the basis of heart rate measured at the baseline visit in individuals enrolled in the Kaise
10、r Permanente Study. Study participants, divided into heart rate quintiles (Q), showed a progressive increase in risk of hypertension with increasing baseline heart rate. Data had been adjusted for numerous confounding variables. Modified from Selby J.V. et al. (1990). Am J Epidemiol 131,1017.8070605
11、040306190100HR intervals in bpmAMI incideneceFigure 4. Incidence of acute myocardial infarction (AMI) adjusted for age during a 5-year follow-up period among 10,000 men divided into baseline heart rate (HR) classes. Note the significant increase in AMI incidence with increasing HR. Reproduced from M
12、edalie J.H., Kahn H.A. Neufeld H.N., Riss E,., Goldbourt U. (1973). Five-year myocardial infarction incidence-II. Association of single variables to age and birthplace. J. Chronic Dis 26,329, reprinted with permission from Elsevier Science.Nonfatal0.53421Relative riskFatalTotalNonfatalFatalTotalCV e
13、ventsAMIFigure 5. Relative risks of cardiovascular (CV) events and acute myocardial infarction (AMI) for a heart rate increase by 40 bpm in 5,209 individuals with hypertension enrolled in the Framingham Study and followed for 36 years. Note that the heart rate-linked risk increase was particularly g
14、reat for fatal events. Modified from Gillman M.W. et al. (1993). Am Heart J 125, 1148.Figure 6. Incidence of sudden death (SD) during a 26-year follow-up period in individuals enrolled in the Framingham Study, divided into baseline heart rate quintiles (Q1=heart rate 87 bpm). Among the men ,risk inc
15、reased progressively with increasing heart rate, while the trend among the women was much less clear and statistically insignificant. Modified from Kannel W.B. et al. (1985). Am Heart J 109,876.6420WomenMenp=NSP0.001Incidence of SD/1.000 cases1th quintile2th quintile3th quintile4th quintile5th quint
16、ileFigure 8. Predictors of life expectance in the Framingham Study. In this analysis, performed on men ages 50 through 75, low heart rate (HR) was an important predictor of increased survival with a predictive value equal to that of nonsmoking and low systolic blood pressure (SBP). Modified from Gol
17、dberg R.J. et al (1996). Arch Int Med 156,505.Nonsmoking0.521.51Relative riskLow SBPLow HRFigure 12. Heart rate (HR) values above which there was a marked increase in the risk of cardiovascular events and death: results from 8 epidemiological studies. Note that the threshold heart rate for risk incr
18、ease was between 80 and 90 bpm. Modified from Palatini P. (1999). Hypertension 33,622. 10090807060Medalie et al., 1973Dyeret al., 1980Dyeret al., 1980Dyeret al., 1980Kannelet al., 1987Gillumet al., 1991Gilmanet al., 1993Palatiniet al., 1999HR (bpm)MenwomenFigure 14. All-cause and cardiovascular mort
19、ality in a population of elderly men enrolled in the Castel Study. Participants were stratified into there groups by heart rate: elevated ( 80 bpm), intermediate (64-80 bpm), and low ( 64 bpm). Cardiovasculare and all-cause mortality was highest among individuals with tachycardia and lowest among th
20、ose with bradycardia. Modified from Palatini P. et al. (1999). Arch Int Med 159 (6), 585. 1999 American Medical Association. All rights re-served. Reprinted with permission from the American Medical Association.All-cause mortalityCardiovascular mortality1.00.80.60.4024681012Follow-up (Yrs)1.00.80.60
21、.4024681012Follow-up (Yrs)p=0.011p=0.000784Heart rate (bpm)Incidence/1,000 men/ 2 Yrs6050403020100CHDCVDAll-causeFigure 16. All- cause mortality, mortality from cadiovascular disease (CVD), and mortality from heart disease (CHD), in 5,209 men followed from 36 years in the Framingham Study. All types
22、 of increased progressively with increasing heart rate. Modified form Gillman M.W. et al. (1993). Heart J 125, 1148. Reprinted with permission from Mosby Year Book.1.000.950.900.8501234567891011 12MonthsSurvivalHeart rate (bpm)89Figure 17. Survival cures for 1,044 AMI patients stratified by admissio
23、n heart rate. Mortality during the 12-month follow-up period was substantially higher in patients with heart rates 89 bpm than in those with lower heart rates, and lowest in patients whose heart rate was 70 bpm. From Disegni E., Goldbourt U., Reicher-Reiss H. et al. (1955). The predictive value of a
24、dmission heart rate on mortality in patients with acute myocardial infarction. J. Clin. Epidemiol. 48, 1197. Reprinted with permission from Elsevier Science.060 120 180 240 300 360100%80%60%40%20%0%days060 120 180 240 300 360100%80%60%40%20%0%days060 120 180 240 300 360100%80%60%40%20%0%daysSurvival
25、Day 1Day 3Day 7* p0.05* p0.01*p0.001HR 80 bpmHR 80 bpmFigure 18. Predictive value of heart rate (HR) taken 1, 3, and 7 days after admission for acute myocardial infarction, for survival during a one-year follow-up period. Survival was greater among patients whose heart rate was less than 80 bpm than
26、 among those with higher heart rates. Heart rate showed the greatest predictive power at 7 days after admission. Data from Berton G. et al. (not published).1th quintile2th quintile3th quintile4th quintile3020100Death risk (%)Heart rateHRvariabilityLVEFFigure 19. Incidence of all-cause mortality amon
27、g 579 AMI survivors divided into mean heart rate (HR), HR variability, and left ventricular ejection fraction (LVEF) quartiles. For all three variables,there was an increase in mortality from the 1st to the 4th quartile. A clearer trend was observed for the HR quartiles. Modified from Copie X. et al
28、. (1996). J Am Coll Cardiol 27, 270.Table 2. Predictors of progression of coronary atherosclerosis among 56 male MI survivors who unwent coronary angiography immediately post-Ml and after 4-7 years. Note that minimum heart rate 24-hour Holter monitoring was a significant predictor of progression of
29、coronary artery disase and a predictor than dyslipidemia, hypertension, and smoking. Modified from Perski A. et al. (1992). Am H, J 123,609.Predicators of Progression of CoronaryAtherosclerosisVARIABLE PMinimum heart rate on 24-hour HR recording0.02LDL/HDL ratio0.03Fibrinogen0.12Hypertension0.23Beta
30、-blocker therapy0.25Lipoprotein A0.58Cigarette smoking0.62Time elapsed between angiographies0.991009080706050403020HR (bpm)Nor-EpiMSNAControlsHypertensivesObese patientsHeart failure patientsbpm, pg/dl, burst/minFigure 22. Markers of sympathetic activity in 4 different groups of subjects. Sympatheti
31、c tone show the greatest elevations in heart failure patients, followed in descending order by obese individuals, hyptensive patients, and controls. Heart rate was found to be a reliable marker of sympathetic activity, reflthing both circulating norepinephrine (Nor-Epi) and muscle sympathetic nerve
32、activity (MSNA measured croneurographically at the posterior peroneal nerve). Modified from Grassi G. et al. (1998). J Hypertens 1635. Reprinted with permission from Lippincott Williams & Wilkins-A Wolters Kluwer Company.Ischemicheart diseasePlateletactivationDyslipidemiaInsulin resistanceSympatheti
33、c hyperactivity PVLVH HematocritVascular hypertrophyArrhythmiaCoronary spasmSudden deathCoronary thrombosis Coronary reserveFigure 23. Pathogenetic mechanisms by increased sympathetic tone may lead to coronary artery disease, coronary events and sudden death.PV = plasma volume; LVH = left ventricula
34、r hypertrophyGlucoseBloodpressureInsulinCholesterolBMIHematocritTriglyceridesHDLcholesterolHeartRateFigure 24. Association between heart rate and other risk factors for atherosclerosis. In this diagram, heart rate, being a marker of sympathetic activity, is the link between the other risk factors. T
35、he mechanism underlying the association between sympathetic tone and cardiovascular risk factors is explained in the text. From Palatini P. Julius S. (1997), J Hypertens 15, 2. Modified with permission from Lippincott Williams & Wilkins A Wolters Kluwer Company.结论现有证据表明心率是高血压与心血管与现有证据表明心率是高血压与心血管与非心
36、血管性死亡的非心血管性死亡的重要预报因素重要预报因素!心率与死亡率的关联存在于任何年龄的心率与死亡率的关联存在于任何年龄的人群，且男性强于女性人群，且男性强于女性心动过速是交感神经兴奋性增高，副交心动过速是交感神经兴奋性增高，副交感神经张力降低的一个强力指标感神经张力降低的一个强力指标605040302010000.10.20.30.40.5High HRLow HRHigh HRLow HRp 0.02p 0.05% with stenosesmm2Figure 34. Percentage of coronary artery sections with 25% stenotic lesi
37、ons and mean lesion area in a group of monkeys in which heart rate (HR) was reduced by sinus node ablation and which were fed an atherogenic diet fo six months and in a control group of monkeys that did not undergo sinus node ablation but were also fed an atherogenic diet for six months. The monkeys
38、 which had their heart rate reduced showed marked slowing of the formation of coronary lesions versus the group of monkety whose heart rate remained elevated. Reproduced from Beere P.A. et al. (1999). Am J Hypertens 12, 1, part 3, with permission from Elsevier Science.1006030105201021041061081010101
39、2Total number of heart beats/lifetimeLife expectancy in yrsManElephantWhaleHorseLionCatCiraffcTigerWoodchuckRatMouseHamsterMonkeyDonkeyDogFigure 40. Relationship between life expect and total number of cardiac cycles during the time of mammals. Note that the total number of heart beats / lifetime ar
40、e remarkably stable among all animal species. Modified from levine (1997). Rest heart rate and life expectancy. Coll Cardiol 30, 4, 1104-1106. Reprinted with mission from Elsevier Science. 1100900700500Male miceFemale miceSurvival (days)571745750845p 0.0001p 0.02UntreatedTreatedFigure 41. Survival i
41、n a group of mice with digoxin from their few days of life untreated group. Life span was significantly among treated mice, in which heart rate proximately half that in untreated mice. Benefit from digoxin was particularly great mice. Modified from Coburn A.F. (1971). Med J 128, 168.HR 90bpmHR 90bpm
42、Heart failureSudden deathAll-causeHeart failureSudden deathAll-cause012Relative riskFigure 43. Relative risks of death from heart failure, sudden death and all-cause mortality among 519 patients with severe heart failure receiving amiodarone 300 mg/day or placebo and followed for two years. In patie
43、nts with a baseline heart rate (HR) greater than or equal to 90 bpm, amiodarone produced a marked reduction in risk of death from any cause. Patients whose baseline heart rate was less than 90 bpm derived no benefit from amiodarone therapy. Modified from Nul D.R. et al. (1997). J Am Coll Card 29, 11
44、99. 受体阻滞受体阻滞剂剂减慢心率的治减慢心率的治疗效益疗效益 人类药物干预减低心率的研究均属回顾性分析。研究使用的药物大多为受体阻滞剂，且多数研究对象为急性心肌梗死后存活者。对29个临床实验Meta分析显示，早期使用受体阻滞剂作为二级预防性治疗使心肌梗死后存活者全因死亡率减少13%（p0.02）。 由于使用不同受体阻滞剂治疗，故心率减慢幅度亦不同（10.5%-22.8%），但值得指出的是，显著降低死亡率的效果均出现在用药后心率降低14次/min的人群中。 且降低再梗死率与死亡率的程度与心率减慢幅度相关，心率降低8次/min的患者死亡率并无任何减少。 对急性心梗发病后12小时进行药物干预的研
45、究进一步显示心率减慢幅度与梗死面积缩小程度密切相关；心率至少应减慢15次/分，方能使梗死面积减少25%-30%；心率减少8次/分者不能缩小梗死面积；所有梗死后研究均显示，静息时心率减慢的幅度与死亡率降低程度相关（r=0.68，p90次/分平板运动试验未能达到预期最大心率的85%（死亡率独立预测因素）最大运动量后第一分钟内心率减慢12次/分（5年死亡率增加4倍）心率变异异常（缓慢深呼吸一分钟内，心率改变10次/分） HorseRatHamsterMonkeyWoodchuckDogCatTigerGiraffeWhaleLionElephantFigure 39. An inverse rela
46、tionship between heart rate and life expectance has been identified in the animal kingdom. The mouse has a heart rate greater than 500 bpm and lives little longer than two years, while the Galapagos tortoise has a heart rate of 6 bpm and an average life span of 177 years. Among mammals, heart rate d
47、ecresase with increasing bod mass, and life expectancy increases with decreasing heart rate.Dokey途径人一生中心率总数保持恒定，心率是反映代谢速率与能量需要的一个标志物，心率加快-代谢率增加-体温升高土拨鼠（旱獭）marmot冬眠时心率可由150次/分下降到35次/分龟心率6次/分，寿命177年，耗子心率240次/分，平均寿命为5年 研究动态心率与心血管发病率与死亡率的密切关系引人注目,值得进一步研究 受体阻滞剂抗高血压的优势与地位受体阻滞剂抗高血压的优势与地位1、MAPHY研研究究显显示示，美美托
48、托洛洛尔尔优优于于利利尿尿剂剂，且且前前者者对对吸吸烟烟人群仍有显著效果。人群仍有显著效果。2、斯德哥尔摩研究：美托洛尔比利尿剂更能显著降低心梗后、斯德哥尔摩研究：美托洛尔比利尿剂更能显著降低心梗后、 高高血血压压患患者者的的再再梗梗死死、卒卒中中、冠冠脉脉搭搭桥桥与与死死亡亡的的危危险险（p0.01）3、2型糖尿病合并高血压者获益更大使急性心梗后高血压者型糖尿病合并高血压者获益更大使急性心梗后高血压者 长期死亡率下降长期死亡率下降35%35%，使合并心衰的高血压患者死亡率下，使合并心衰的高血压患者死亡率下 降降 39%39%（P=0.0022）。）。 故故有有各各种种并并发发症症的的高高血血
49、压压患患者者-受受体体阻阻滞滞剂剂为为首首选选药药物或合并用药的组成部分物或合并用药的组成部分!4 4、-受体阻滞剂是联合用药的重要组成部分，越来越多专家受体阻滞剂是联合用药的重要组成部分，越来越多专家 认为降压药联合治疗中认为降压药联合治疗中应包括减慢心率的药物。应包括减慢心率的药物。 心率是反映交感神经系统兴奋性的最可靠、最简单的观察心率是反映交感神经系统兴奋性的最可靠、最简单的观察 指标，静息心率（早晨醒后指标，静息心率（早晨醒后1010分钟测心率）达分钟测心率）达6060次次/ /分左右分左右 时，提示交感时，提示交感 N.N.兴奋性控制最合适（治疗目标心率）。兴奋性控制最合适（治疗目
50、标心率）。5 5、青中年高血压伴高动力状态者也适宜用、青中年高血压伴高动力状态者也适宜用-受体阻滞剂受体阻滞剂6 6、各期肾功能不全包括接受透析治疗的患者使用美托洛尔、各期肾功能不全包括接受透析治疗的患者使用美托洛尔 （倍他乐克）不需调节剂量。（倍他乐克）不需调节剂量。7 7、强适应证对象：高血压合并冠心病或多种冠心病危险因强适应证对象：高血压合并冠心病或多种冠心病危险因 素、或合并心衰、快速性心律失常者。素、或合并心衰、快速性心律失常者。美托洛尔的抗动脉粥样梗化作用美托洛尔的抗动脉粥样梗化作用高血压与动脉粥样硬化密切相关动物实验： 美托洛尔可显著减轻兔的动脉粥样硬化程度。美托洛尔可显著减轻兔
51、的动脉粥样硬化程度。人类研究： BCAPSBCAPS发现小剂量美托洛尔（发现小剂量美托洛尔（2525mg/dmg/d）33年预防性年预防性 治疗，颈动脉内膜中层厚度显著小于安慰剂组，且总死亡率治疗，颈动脉内膜中层厚度显著小于安慰剂组，且总死亡率与所有冠脉事件发生率也显著低于安慰剂组。与所有冠脉事件发生率也显著低于安慰剂组。 EIVAEIVA 研究研究 他汀他汀+ +美托洛尔美托洛尔 他汀他汀+ +安慰剂安慰剂 结果：美托洛尔组结果：美托洛尔组IMTIMT增长明显抑制（增长明显抑制（P0.001P4500045000例陈旧性心梗患者，其中例陈旧性心梗患者，其中26%26%合合并糖尿病，并糖尿病，
52、 受体阻滞剂受体阻滞剂治疗后治疗后1 1年死年死亡率亡率低于无糖尿病者低于无糖尿病者，而与糖尿病有关，而与糖尿病有关的并发症并无增加。的并发症并无增加。Remember迄今为止对心率的研究充分揭示心率增快不仅是心血管病的一个独立危险因素，而且是预后不良的一个标志物!如何减慢心率已成为心血管病防治的另一个重要的目标!心率增快的临床重要性心率增快的临床重要性 大量资料证实，慢性心率增快不仅是一个重要的独立危险因素，而且还是一个预后不良的Marker. 专家们呼吁应该像关注血压一样关注心率快慢。 Cut off level 83次/min 8085bpm应考虑是病理性的。受体阻滞剂治疗的目标心率 慢
53、性冠心病：静息心率减慢至5060次和/或轻度活动时心率增快不超过20次/分（Braunwald心脏病学，2005年第七版） 慢性心力衰竭：静息心率降至5560次/分，似可反映病人的受体功能易获得充分阻滞。 高血压伴心率增快者，目标心率同上（尤其是糖尿病患者，心率快是病情严重，预后较差的重要标志物） 心率这一指标测定容易，信息无限，意义重大，但仍重视不够，值得今后特别关注！ 如同高血压需要降压达标一样，对使用受体阻滞剂治疗的患者心率达标也非常重要，以最大程度地降低患病率与死亡率！最新发现基于心率增快是心血管病的一个重要危险因素。国外近年已开发出窦房结其搏电流的特异性抑制剂，其中之一命名为If电流
54、或超极化激活电流，药名为Ivabradine，本药对心肌收缩力与冠状动脉张力无影响。亦不减慢房室传导与心室复极过程，但动物试验发现，本药除能减慢窦性心率外，对缺血心肌，顿抑心肌可改善其收缩力（通过减慢其心率起作用）。故本药是一种有希望的治疗稳定性心绞痛药物。 The effects of a reduction in Heart RateLower O2 consumption Improved diastolic Coronary flowAnti ischemic effectsIncreased VF thresholdAntithrombo-atherosclerotic effect
55、sPrevention of ischemic eventPrevention of Cardiomyopathy 最新研究Stable CHD, n=24913名，名， F/U 15 years。结果：结果：全因死亡，心血管死亡与再住院率均与心全因死亡，心血管死亡与再住院率均与心率快相关（率快相关（p0.0001）HR83次次/分者分者 HR为为1.32 （CI 1.19-1.4）大规模、多中心、前瞻性随访研究大规模、多中心、前瞻性随访研究Procoralar Procoralar (Ivabradine) (Ivabradine) 5mg5mgFirst Selective First Selective and specific Iand specific If f inhibitor inhibitor Servier-FranceServier-FranceHeart Rate作为一个确定无疑的心血管 危险因素，不应再被忽视！小动物大动物
