心率與心血管疾病一個重要而被視的問題

1、 心率與心血管疾病心率與心血管疾病 一個重要而被忽視的問題一個重要而被忽視的問題南京醫(yī)科大學第一附屬醫(yī)院黃元鑄 2008.4.1.前言人們早已發(fā)現(xiàn)心率較快的小動物的壽命較短，而心率較慢的大動物，壽命較長。這一心率與壽命負相關(guān)現(xiàn)象除人類外，存在于所有哺乳動物。人類的平均心率為70次/分左右，其預(yù)期壽命為80歲，有人預(yù)測，將人類平均心率由70次/分減少到60次/分可使預(yù)期壽命增加到93.3歲。心率的重要性 心率（hr）是心肌耗氧量的最主要決定因素hr下降可增加缺血閾值，改善心肌做功hr是一個獨立危險因素的證據(jù)，既來自cohort研究（有相同統(tǒng)計要素的一組人）也來自前瞻性雙盲臨床試驗問題之一 普通人

2、群中，hr對預(yù)后有何意義？五大流行病學研究評估了心率與chd與cv病的關(guān)系lframingham heart studylnational health examination surverylmultifactor primary preventionltrial in goteberglchicago heart association結(jié)論共入選30000表面健康的人（大多為中年男性），隨訪5年36年結(jié)果：各種原因死亡與心血管病死亡的危險隨hr升高而遞增，特別是心率84次/分時，不論性別或種族如何，死亡率均一致性地與hr升高相關(guān)與hr60次/分比較，hr9099次/分者,死亡率要高3倍!(

3、主要死于冠心病) 問題之二 心率是否是高血壓病人的重要預(yù)后因素?l 與血壓正常對照組相比,高血壓病人,靜息時心率明顯較快l4530例高血壓隨訪觀察顯示,心率85次/分者死亡率比65次/分者高1倍,且此與有無傳統(tǒng)的冠心病危險因素無關(guān)問題之三 心率對老年人是否是預(yù)后因素?l一項大型高危老年人群研究顯示,在調(diào)整其他混雜因素后,心率每增加5次/分,其心梗與猝死危險性增加14% 問題之四（1） 急性心梗病人心率是否是一個重要預(yù)后因素?l根據(jù)病人住院時心率快慢,并隨訪一年分析顯示,如入院2小時內(nèi)心率由小于90次/分增加到大于100次/分,則總死亡率增加1倍.l進一步分析死亡率與住院期間或出院前最高心率的關(guān)

4、系顯示,與7090次/分相比,100次/分者,死亡率增加達4-6倍.問題之四（2）入院時心率90次/分者比90次/分者嚴重心衰發(fā)生率要高10倍之多.(1990年)將病人進一步分為無心衰或輕、中、重度心衰組后,心率快慢仍是死亡率的重要預(yù)報因子。例如,輕至中度心衰病人中,入院90次/分者死亡率要比70次/分者高23倍.問題之五 我們從冠心病隨機對照研究中對心率問題獲得哪些信息?l多項-b試驗均一致地顯示可降低心梗后病人心源性猝死率,心血管死亡率與再梗死率l對16500例(11個前瞻性研究)心梗后病人研究顯示,無內(nèi)源性擬交感活性的-b對心率與死亡率降低的效益最大;死亡率降低與心率減慢之間有明顯線性關(guān)

5、系,即每減少10次/分心率可使死亡率降低1520% ！問題之六心肌梗死存活者用-b后臨床預(yù)后有何改觀?l11個隨機對照研究顯示,心率與心梗面積(r=0.97.p0.001),死亡率(r=0.79,p0.005)與非致命性再梗率(r=0.59,p0.05)顯著相關(guān)l總體來看,用-b后心率至少應(yīng)減少8-10次/分,才能使心梗面積與死亡率明顯下降. 問題之七 用-b治療急性心肌梗死臨床效益究竟有多大? 答案是劑量足夠,心率下降達到一定幅度,治療效益是很大的.l無內(nèi)源性-b治療1000例病人可挽救2025個生命l溶栓藥為4045個生命 問題之八 （1）心率是如何影響心血管發(fā)病率與死亡率的？l hr下降

6、降低mvo2l hr下降增加冠脈血流l hr下降縮小心梗面積l hr下降增加室顫閾值(用-b預(yù)處理后再結(jié)扎冠狀動脈,可預(yù)防實驗犬發(fā)生vf)問題之八（2）l hr降低有直接抗動脈粥樣硬化作用。靈長目動物實驗,在相同血壓,血脂與體重條件下,心率慢者粥樣化病變僅為心率快者的1/3左右.l用飽和脂肪酸喂飼的猴實驗中顯示,心率慢比心率快者,冠狀動脈病變要輕l接受心得安治療的猴子,盡管血脂水平仍高,但比未治療者粥樣硬化病變要輕得多.lpoor health and/or physical fitness 本類人群靜息時心率常偏快,本類人群比體力活動鍛煉多的人易患冠心病l自主神經(jīng)功能異常：心率快提示交感神經(jīng)

7、亢奮,迷走神經(jīng)張力降低，易發(fā)生室顫. 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 follow-up period. this study, performed in

8、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 blood pressure rise meant a significant in

9、crease 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 kaiser permanente study. study participants, d

10、ivided 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 131,1017.8070605040306190100hr intervals in bpmami incide

11、necefigure 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 medalie j.h., kahn h.a. neufeld h.n., riss

12、 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 eventsamifigure 5. relative risks of cardi

13、ovascular (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 great for fatal events. modified from gill

14、man 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 increased progressively with increasing hear

15、t 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 quintilefigure 8. predictors of life expectanc

16、e 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 goldberg r.j. et al (1996). arch int med 156

17、,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 increase was between 80 and 90 bpm. modified

18、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 mortality in a population of elderly men enro

19、lled 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 those with bradycardia. modified from palat

20、ini 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)1.00.80.60.4024681012follow-up (yrs)p=0.011p=0.0007

21、84heart 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 of increased progressively with increasi

22、ng 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 admission heart rate. mortality during the 12-mon

23、th 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 admission heart rate on mortality in patie

24、nts 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%dayssurvivalday 1day 3day 7* p0.05* p0.01*p0.001hr 80

25、 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 among those with higher heart rates. hea

26、rt 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 among 579 ami survivors divided into mean hea

27、rt 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. (1996). j am coll cardiol 27, 270.table

28、 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 coronary artery disase and a predictor th

29、an 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-blocker therapy0.25lipoprotein a0.58ciga

30、rette 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. sympathetic tone show the greatest elevations in he

31、art 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 activity (msna measured croneurographical

32、ly 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 resistancesympathetic hyperactivity pvlvh hematocritvascu

33、lar 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 ventricular hypertrophyglucosebloodpressureinsu

34、lincholesterolbmihematocrittriglycerideshdlcholesterolheartratefigure 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. the mechanism underlying the associati

35、on 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.結(jié)論現(xiàn)有證據(jù)表明心率是高血壓與心血管與現(xiàn)有證據(jù)表明心率是高血壓與心血管與非心血管性死亡的非心血管性死亡的重要預(yù)報因素重要預(yù)報因素!心率與死亡率

36、的關(guān)聯(lián)存在于任何年齡的心率與死亡率的關(guān)聯(lián)存在于任何年齡的人群，且男性強于女性人群，且男性強于女性心動過速是交感神經(jīng)興奮性增高，副交心動過速是交感神經(jīng)興奮性增高，副交感神經(jīng)張力降低的一個強力指標感神經(jīng)張力降低的一個強力指標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 lesions and mean lesion area in a gro

37、up 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 which had their heart rate reduc

38、ed 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.10060301052010210410610810101012total number of heart beats/life

39、timelife 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 are remarkably stable among all ani

40、mal 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 in a group of mice with digoxin fr

41、om 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 90bpmheart failuresudden deathall-caus

42、eheart 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 patients with a baseline heart rate (h

43、r) 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, 1199. 受體阻滯劑受體阻滯劑減慢心率的治減慢心率的治療效益療效益

44、人類藥物干預(yù)減低心率的研究均屬回顧性分析。研究使用的藥物大多為受體阻滯劑，且多數(shù)研究對象為急性心肌梗死后存活者。對29個臨床實驗meta分析顯示，早期使用受體阻滯劑作為二級預(yù)防性治療使心肌梗死后存活者全因死亡率減少13%（p0.02）。 由于使用不同受體阻滯劑治療，故心率減慢幅度亦不同（10.5%-22.8%），但值得指出的是，顯著降低死亡率的效果均出現(xiàn)在用藥后心率降低14次/min的人群中。 且降低再梗死率與死亡率的程度與心率減慢幅度相關(guān)，心率降低8次/min的患者死亡率并無任何減少。 對急性心梗發(fā)病后12小時進行藥物干預(yù)的研究進一步顯示心率減慢幅度與梗死面積縮小程度密切相關(guān)；心率至少應(yīng)減慢

45、15次/分，方能使梗死面積減少25%-30%；心率減少8次/分者不能縮小梗死面積；所有梗死后研究均顯示，靜息時心率減慢的幅度與死亡率降低程度相關(guān)（r=0.68，p90次/分平板運動試驗未能達到預(yù)期最大心率的85%（死亡率獨立預(yù)測因素）最大運動量后第一分鐘內(nèi)心率減慢12次/分（5年死亡率增加4倍）心率變異異常（緩慢深呼吸一分鐘內(nèi)，心率改變10次/分） horserathamstermonkeywoodchuckdogcattigergiraffewhalelionelephantfigure 39. an inverse relationship between heart rate and l

46、ife 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 decresase with increasing bod mass

47、, and life expectancy increases with decreasing heart rate.dokey途徑人一生中心率總數(shù)保持恒定，心率是反映代謝速率與能量需要的一個標志物，心率加快-代謝率增加-體溫升高土撥鼠（旱獺）marmot冬眠時心率可由150次/分下降到35次/分龜心率6次/分，壽命177年，耗子心率240次/分，平均壽命為5年 研究動態(tài)心率與心血管發(fā)病率與死亡率的密切關(guān)系引人注目,值得進一步研究 受體阻滯劑抗高血壓的優(yōu)勢與地位受體阻滯劑抗高血壓的優(yōu)勢與地位1、maphy研究顯示，美托洛爾優(yōu)于利尿劑，且前者對吸煙研究顯示，美托洛爾優(yōu)于利尿劑，且前者對吸煙人群仍

48、有顯著效果。人群仍有顯著效果。2、斯德哥爾摩研究：美托洛爾比利尿劑更能顯著降低心梗后、斯德哥爾摩研究：美托洛爾比利尿劑更能顯著降低心梗后、 高血壓患者的再梗死、卒中、冠脈搭橋與死亡的危險高血壓患者的再梗死、卒中、冠脈搭橋與死亡的危險（p0.01）3、2型糖尿病合并高血壓者獲益更大使急性心梗后高血壓者型糖尿病合并高血壓者獲益更大使急性心梗后高血壓者 長期死亡率下降長期死亡率下降35%35%，使合并心衰的高血壓患者死亡率下，使合并心衰的高血壓患者死亡率下 降降 39%39%（p=0.0022）。）。 故有各種并發(fā)癥的高血壓患者故有各種并發(fā)癥的高血壓患者-受體阻滯劑為首選藥受體阻滯劑為首選藥物或合并用藥的組成部分物或合并用藥的組成部分!4 4、-受體阻滯劑是聯(lián)合用藥的重要組成部分，越來越多專家受體阻滯劑是聯(lián)合用藥的重要組成部分，越來越多專家 認為降壓藥聯(lián)合治療中認為降壓藥聯(lián)合治療中應(yīng)包括減慢心率的藥物。應(yīng)