心率与心血管疾病一个重要而被忽视的问题

心率与心血管疾病 一个重要而被忽视的问题,南京医科大学第一附属医院 黄元铸 2008.4.1.,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 Framingham Heart Study National Health Examination Survery Multifactor Primary Prevention Trial in Goteberg Chicago 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? 与血压正常对照组相比,高血压病人,静息时心率明显较快 4530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? 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? 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,则总死亡率增加1倍. 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? 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 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-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? 11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 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. 无内源性-B治疗1000例病人可挽救2025个生命 溶栓药为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？ HR下降降低MVO2 HR下降增加冠脉血流 HR下降缩小心梗面积 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）,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. 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 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. Poor health and/or physical fitness 本类人群静息时心率常偏快,本类人群比体力活动锻炼多的人易患冠心病 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.,70,60,50,40,30,20,10,0,25,30,35,45,40,55,50,60,HT per 1.000 men/Yr,Transient tachycardia,Transient Hypertension,- + - +,- - + +,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 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 increase inrisk. From Levy R.L. et al (1945). JAMA 129,585.,Figure 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, 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.,Figure 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 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.,Figure 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 great 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 increased 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.,Figure 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 Goldberg R.J. et al (1996). Arch Int Med 156,505.,Figure 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 from Palatini P. (1999). Hypertension 33,622.,Figure 14. All-cause and cardiovascular mortality 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 those 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.,Figure 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 increasing heart rate. Modified form Gillman M.W. et al. (1993). Heart J 125, 1148. Reprinted with permission from Mosby Year Book.,Figure 17. Survival cures for 1,044 AMI patients stratified by admission 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 admission heart rate on mortality in patients with acute myocardial infarction. J. Clin. Epidemiol. 48, 1197. Reprinted with permission from Elsevier Science.,Figure 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. Heart rate showed the greatest predictive power at 7 days after admission. Data from Berton G. et al. (not published).,Figure 19. Incidence of all-cause mortality among 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. (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 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 Coronary Atherosclerosis,VARIABLE P Minimum heart rate on 24-hour HR recording 0.02 LDL/HDL ratio 0.03 Fibrinogen 0.12 Hypertension 0.23 Beta-blocker therapy 0.25 Lipoprotein A 0.58 Cigarette smoking 0.62 Time elapsed between angiographies 0.99,Figure 22. Markers of sympathetic activity in 4 different groups of subjects. Sympathetic 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 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.,Ischemic heart disease,Platelet activation,Dyslipidemia,Insulin resistance,Sympathetic hyperactivity, PV,LVH, Hematocrit,Vascular hypertrophy,Arrhythmia,Coronary spasm,Sudden death,Coronary thrombosis, Coronary reserve,Figure 23. Pathogenetic mechanisms by increased sympathetic tone may lead to coronary artery disease, coronary events and sudden death. PV = plasma volume; LVH = left ventricular hypertrophy,Glucose,Blood pressure,Insulin,Cholesterol,BMI,Hematocrit,Triglycerides,HDL cholesterol,Heart Rate,Figure 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 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非心血管性死亡的重要预报因素! 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 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,60,50,40,30,20,10,0,0,0.1,0.2,0.3,0.4,0.5,High HR,Low HR,High HR,Low HR,p 0.02,p 0.05,% with stenoses,mm2,Figure 34. Percentage of coronary artery sections with 25% stenotic lesions 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 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.,100,60,30,10,5,2,0,102,104,106,108,1010,1012,Total number of heart beats/lifetime,Life expectancy in yrs,Man,Elephant,Whale,Horse,Lion,Cat,Ciraffc,Tiger,Woodchuck,Rat,Mouse,Hamster,Monkey,Donkey,Dog,Figure 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 animal species. Modified from levine (1997). Rest heart rate and life expectancy. Coll Cardiol 30, 4, 1104-1106. Reprinted with mission from Elsevier Science.,1100,900,700,500,Male mice,Female mice,Survival (days),571,745,750,845,p 0.0001,p 0.02,Untreated,Treated,Figure 41. Survival in 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 90bpm,HR 90bpm,Heart failure,Sudden death,All-cause,Heart failure,Sudden death,All-cause,0,1,2,Relative risk,Figure 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 (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, 1199., 受体阻滞剂减慢心率的治疗效益,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，p0.05）。,上述Meta分析另一重要发现是治疗的获益取决于治疗前的基础心率，用药前心率偏慢者效果较差。此外，有内源性拟交感活性的受体阻滞剂，心率减慢幅度较小，其预防梗死与降低死亡率的效果也小于无内源性拟交感活性的受体阻滞剂。Kjekshus曾指出，心梗后病人使用内源性拟交感活性的受体阻滞剂犹如对疲马加鞭有害无益。,上述发现提示，尽管受体阻滞剂对心梗后患者有益作用的机制仍未完全阐明，但心率仍不失为观察治疗效果的一个有用指标。,自主神经功能障碍 与心血管危险性,自主神经功能平衡是机体维持生命与心血管正常功能的重要保证，一旦交感神经慢性激活，副交感神经功能减弱即可增加心血管事件的危险性 自主神经功能障碍的一个主要表现即心率增快，但长期被临床医师所忽视，仅少数聪明的医师认识到“正常”的窦性心律90次/分要比“异常”的窦性心律50次/分更具临床重要性。 真正有经验的医师一定深刻意识到急性心肌梗死病人最佳的预后指标是入院时的心率而不是Q波的范围或ST段偏移的程度,测定心脏自主神经功能的简易实用方法,静息时心率90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）,Horse,Rat,Hamster,Monkey,Woodchuck,Dog,Cat,Tiger,Giraffe,Whale,Lion,Elephant,Figure 39. An inverse relationship 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 decresase 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,1、MAPHY研究显示，美托洛尔优于利尿剂，且前者对吸烟人群仍有显著效果。 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、 高血压患者的再梗死、卒中、冠脉搭桥与死亡的危险（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 长期死亡率下降35%，使合并心衰的高血压患者死亡率下 降 39%（P=0.0022）。 故有各种并发症的高血压患者-受体阻滞剂为首选药物或合并用药的组成部分!,4、-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 指标，静息心率（早晨醒后10分钟测心率）达60次/分左右 时，提示交感 N.兴奋性控制最合适（治疗目标心率）。 5、青中年高血压伴高动力状态者也适宜用-受体阻滞剂 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 （倍他乐克）不需调节剂量。 7、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。,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。 人类研究： BCAPS发现小剂量美托洛尔（25mg/d）3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 与所有冠脉事件发生率也显著低于安慰剂组。,EIVA 研究 他汀+美托洛尔 他汀+安慰剂 结果：美托洛尔组IMT增长明显抑制（P0.001）,高胆固醇血症患者,3年,-阻滞剂在治疗心衰中地位不可取代,1.延长寿命、降低死亡率 2.减少住院时间 3.改善生活质量-三达标 显著降低猝死率的作用独一无二，但仅见于脂溶性-阻滞剂 。 充分体现-阻滞剂对心血管的全面保护作用,心率（HR）作为心血管危险因素的目前认识,1、大量流行病学研究与临床试验证实 HR与TOTAL AND/OR CV MORTALITY有关 2、上述关联与其他传统危险因素无关 3、心率每增加10bpm引起的心血管危险增加幅度相当于收缩压增加10mmHg 4、心率对人类的影响存在于所有年龄组人群与不同疾病患者中 5、上述关联在女性人群中的相关性较弱,受体阻滞剂在糖尿病患者中应用 的观念转变,实验发现： 1、交感神经激活常先于糖代谢紊乱 2、糖尿病患者静息心率要比无糖尿病者 快10次/分左右 3、静息心率增快是糖尿病患者发生心血管并 发症与死亡率增高的强